Anne Louise Oaklander | Small Fibers, Big Pain || Radcliffe Institute

Anne Louise Oaklander | Small Fibers, Big Pain || Radcliffe Institute


[MUSIC PLAYING] – Good afternoon, and
welcome to Radcliffe. My name is Janet Rich-Edwards. I am the Faculty Director for
the Life Sciences programming here at Radcliffe,
and an epidemiologist at the school across the
road there, across the river. I particularly
want to welcome you to this, our second lecture, in
the Epidemics Science Lecture Series. If you haven’t picked up
one of these hot pink cards, they’re in the way back
when you’re on your way out. In addition to this terrific
lecture that we have today, we’re also going to be talking
about the epidemic of poverty a week from today,
later on, obesity, more complex than you
think, and Alzheimer’s. So these promise to be, I
think, really exciting lectures, and we’re certainly glad
to have really, very qualified, and
thrilling faculty, including Dr. Anne
Louise Oaklander, who will be talking today about
small fibers, and big pain. She’s Associate Professor of
Neurology at Harvard Medical School. She was trained at Rutgers,
and at Johns Hopkins, has both an M.D. And
a PhD in neuroscience. She directs MGHs nerve unit,
and a federally funded research team at Mass General that
studies peripheral nerve disorders. Her team has discovered a new
neuropathy common in children and young adults, and its
first treatment, which is an immunotherapy, and
she’ll talk about that today. They’ve also linked fibromyalgia
to small fiber neuropathy. She served on advisory
panels for the NIH, the FDA, and the Institute of Medicine. I will take a moment to tell
you how we’re going to run. Dr. Oaklander will
talk, give her talk, and then we’re going to open
up to you guys for about a half hour of questions. We have a roving mic
that can come to you, and I would just
say at this point, while Dr. Oaklander, I’m sure,
is a very good clinician, this is not going to be
a clinical consultation. So you might think now,
if you have questions about personal things
you’ve experienced, how to phrase it in a
way that is more general, and applicable to everybody. So I encourage you to do that. And I think with no further
ado, let’s welcome Dr. Oakland. [APPLAUSE] – Thank you, Janet. Now, what was that
word you used? Was it thrilling? Thrilling, did
she say thrilling? Wow, that’s a tall
order, and I guess it’s appropriate
because I understand that there are people here
from even other states. Did anybody come here
from another state, drive a long distance? Where are you from? – New Hampshire. – New Hampshire, OK. Not that far. How about far off states? Wisconsin. OK, does she get the
prize for farthest driving in cold weather
to come hear this talk? Anyway, I’ll certainly
try to be thrilling, and it’s always hard
to talk about science with a mixed audience. Some of the people here
are faculty members, or graduate students, some
are members of the public, there’s people who know a lot,
people who don’t necessarily know a lot, have a lot of
interest I’m going to try and see if I can
straddle things a bit, but don’t worry if you don’t
understand every single word on every slide. It’s intended sometimes,
for trying to satisfy those who might have great curiosity. I’ll start at the
simple beginning, which is what are nerves,
and what is neuropathy? That’s what we’re
talking about today. The peripheral
nerves is the part of the nervous
system that’s outside of the brain and
the spinal cord. That’s what a lot of
people think about when they think of neurology. What we’re talking
about today is the wiring that connects our
CPU to the outside world. When we take a cross-section
through a peripheral nerve of a human, we can see
these small fibers, which are the kind
of nerve axons that I’ll be
talking about today. These are these tiny
little thin guys. That’s why they’re
called small fibers. There’s a bunch of different
ones including C-fibers, A-deltas, and autonomics. Because of these many different
functions, as you’ll see, polyneuropathy can have
different medical causes, and cause different symptoms. The functions of
these small fibers are so diverse that when
people develop neuropathies that affect them,
they can just develop a lot of different symptoms. And we’re going to go over
some of those symptoms, but I think there’s an
underlying problem, which is that a lot of patients who
have this kind of neuropathy, it’s not even picked up. They’re searching for answers. They know they’ve got problems
in more than one organ system. People haven’t put
the pieces together. It’s like the blind
men and the elephant. So let’s go over
some of the symptoms, and again, not every
patient has every symptoms, and I’m not able to talk
about all of the symptoms. So I’m just focusing on
the most common ones, and clearly, one of them
is chronic widespread pain. That means it’s not like
you fell down, and banged your knee, and you
have pain in your leg, but it’s really pain
affecting both sides of your body for
no clear reason, or no better explanation. Pain from small fiber neuropathy
comes in two varieties. So the most common is
so-called distal pain, which means it starts in
the feet and the hands. And I’ve shown you a picture
of a woman, a patient of mine, who has the erythromelalgia
phenotype, which means that in addition to having
painful legs, they’re also red, and they’re swollen. So when we see those
three things together, the Greek for that
is erythromelalgia. It’s just a particular flavor
of small fiber neuropathy. Not everybody with
erythromelalgia has this neuropathy,
but at least 50% do. And for those of you with a
particular interest in this, there is May 9th,
Erythromelalgia Awareness Day with events at the Statehouse
on the other side of the river, including yours truly. But not everybody has pain
that starts in the feet. About one quarter of
patients, it starts elsewhere, and you can see this woman has
the erythromelalgia as well. Equally, perhaps
even more common, are cardiovascular symptoms,
except people don’t say gee, you know what? I woke up this morning, and I
got cardiovascular symptoms. What is it that
they actually say? They say you know, I
woke up this morning, and I can’t get out of bed. I feel lousy. I feel terrible. Maybe I’m coming
down with something. But the problem is when
it goes on day after day, week after week, month after
month, year after year, it’s not just that
you have the flu. Something different
is going on, and it can be very
difficult to pinpoint what exactly the cause is. The kind of cardiovascular
problems that are most common is you can see here,
this poor guard standing on duty for hour after
hour has fainted. Something called
orthostatic hypotension, which means people can feel
dizzy, or actually faint, typically, when
they’re standing up. Sometimes after meals. Another one is just
chronic fatigue– inability to do
your normal routine. We’re going to talk more
about that in the next slide, but I wanted to particularly
draw your attention to my colleague David
Systrom at Brigham who specializes in
this, and he knows more about this kind of causes
of fatigue than anyone I know. So he’s the one to talk to. Patient education, which
I suspect there are a few of you in the audience who
maybe some of your patients. Maybe some of you
might find out you are patients from this talk. Is education is just
critically important because very often, there’s
so much stuff you can do. If you just understand
what’s going on, you can control things yourself. And in that sense, patient
advocates and patient support groups are very important. I see Leslie Levine here. Can you raise your hand, Leslie? Who runs one of the
local support groups. So she’s a resource, and
I wanted to point out Dysautonomia International. Can you folks raise
your hand as well? Are you national
or international? – International – International support
group for patients. Do you have some
literature in the back? – [INAUDIBLE] – That sounds great,
and they’re not even paying me anything
to say this, truly. In fact– yeah, definitely not. And so these are
some of the things that patients can learn to
do to control their symptoms, improve them themselves. I think first and foremost, is
the use of support stockings, and I like that
photo because it goes to show that support stockings
don’t all have to be ugly. So here’s some science behind
this, for those of you that are so inclined, and
this explains, I think, the best explanation for
why people with neuropathy can have this kind of fatigue,
and inability to get out of bed, and do their routine. These are microscope
slides, unfortunately, not out of my lab, but out of a
very skilled colleague of mine. And what these show is muscle
cells under the microscope. I think they’re best seen here. But the focus is not on the
muscle cells themselves, it’s on the blood
vessels that bring the blood, the oxygen, the
glucose, the cookies you just ate stayed downstairs on
the way in to the muscles so that the muscles
can do their job. And the problem that
these patients have– the muscles are still there, but
what you can see in the slides from the top with
a healthy person is there are all these
axons, these nerve cells that come
running down, and they control the blood vessels. See this round
blood vessel here? The little yellow
squiggles are the nerves that tell the blood vessel
when to open and close. And what you can see is in
the slides from the bottom, there’s far fewer nerves,
and the blood vessel is gaping open. So the point is that when
your nerves are messed up, they control the blood
vessels, your muscles may not get the
oxygen and nutrients they need to function. And in many people,
not all, that’s why they can’t get out
of bed in the morning when they have neuropathy. This is an emerging area that
I think is of great importance, hasn’t been
addressed, and that’s the fact that small fiber
neuropathy can actually affect the brain as well. And so it happens in
a variety of ways. They haven’t been
adequately studied. I hope there might be
some brain scientist or experimental psychologists
here in the audience who might become interested in
taking this up themselves, and looking into this. This picture that
you can’t see is just to show you formal
cognitive testing that’s done on patients who have this
kind of problem when they’re lying down, flat,
and their blood can make it to their brain, and
then they’re on a tilt table. The tilt table stands them up
vertically, just as I am now, and their blood can’t make it
all the way up to their brain, and so their brain
function detriments, and that’s been captured
in testing, and published. Gastrointestinal symptoms
are very common as well. This is a microscope
slide from my lab. Heather Downs, where
are you Heather? Raise your hand, Heather. So Heather Downs
is the person who made this slide for you–
this beautiful image that shows you these are the
intestinal crypts, and all the little squiggly green
lines are the small fibers. So you can see that your
gut is under the control of these nerve
cells, and I think that explains why many patients
develop all sorts of symptoms– upper GI, lower GI, and they
go to see a gastroenterologist, but in fact, it
could be neurologic. In the worst case
scenario, some patients lose so much weight from
intractable vomiting that they have to be nourished
with a nasogastric tube, or some of them even by vein. Treating these symptoms. They can be treated, and again,
if you know what you have, if you get the tests
that are recommended, there’s stuff you can do to
make your gut feel better, and calm down from neuropathy. This also is to show that
it’s not worth doing MRIs. A lot of patients with
neuropathies have MRIs. The only MRI finding here is
that this little boy’s colon is full of feces. Again, because he
can’t move his bowels because the nerves
that control the bowels aren’t working right. The bones and joints, even,
are innervated by these nerves. Orthopedists, immunologists
don’t think of it that much, but the bone marrow
even is densely innervated by this particular
type of small fiber nerve endings. You can see here in
one of my patients with the hereditary
neuropathy, that he’s even had loss of the bones in
the ends of his fingers. In order to track
all these symptoms, there are so many
that we realized we had to develop
our questionnaire, and there was no questionnaire
anywhere in the world. And so with the help of my
former post-doctoral fellow, Roy Treister, we developed
this questionnaire. We’re continuing to
improve it, right Gary? With Gary Zirpoli. But we’ve published
at least one paper that shows reasonable
validation, and performance of this. And these are questions–
you can’t read it, but this is something that
is increasingly available. This captures the symptoms
we’ve heard from our patients, not just what’s in the textbook. OK, so what are the tests
that can confirm small fiber? As you can see, the neuro
exam is not that sensitive, and may not pick it up. The usual tests– EMG nerve conduction
study don’t detect it. Even nerve biopsies
may not pick it up. So skin biopsy is
really the test that we recommend, and again,
Heather Downs is the person who manages our skin biopsy lab. These biopsies sound
worse than they are. They’re done under
local anesthesia, but they need to
be done by somebody who knows what they’re doing. They can be requested to be
performed at Mass General, or a doc locally can
do them, and ship them into Mass General for analysis. Either way, the instructions
for this are on our website. Max Klein, and others from our
group, have done a lot of work on the normative data,
and these are studies that depend on normal volunteers. More than 400 of them
have come to our lab, and allowed us to remove
a tiny bit of skin, and measure the nerve endings. And I show this to you, showing
you these more than 500. What you can see is
these normal people vary a lot in the amount of
nerve endings they start with. Normal kids, the red marks here,
have far more nerve endings to begin with than
normal adults do, and the problem is is that
a lot of the commercial labs just use one threshold,
and if the count that’s measured in you is above the
threshold, they say fine, you’re normal. It’s below the threshold, they
say oh, you’ve got neuropathy. But it’s really much
more mathematically complex than that. We’ve done modeling, and so
when you have a skin biopsy please ask which lab
your biopsy is being sent to for interpretation. And for young people,
our lab is the only one that I know of anywhere
in the world with accurate norms for kids and teens. We’re big fans of
physiology, which means how the nervous
system is functioning, not necessarily what it looks
like under the microscope. The test there–
autonomic function test, as far as I know, Mass
General and the Brigham are the places that offer
them here in Boston. They measure a bunch
of different aspects of nervous system
functions Sweating is particularly important. Something called the QSART,
and this person here, has loss of normal sweating
from the ends of their legs. So let’s turn a little bit now–
now that you know the symptoms, and you know the
tests for neuropathy, let’s turn a little bit to
some of our discoveries. Neuropathy– anybody here who’s
a physician in the audience will agree that
what we were trained is that neuropathy
affects over people. Diabetes, cancer chemotherapy,
these are the common causes. So one of the things
that’s come out of our lab that I think has
been very useful is the information that
neuropathy affects kids much more often than
anybody realized. And we knew that there were
some rare genetic causes. Our lab is very interested in
genetic causes of neuropathy, and in so far as I
know, Mass General is really the place
to come for families with these kind of neuropathies. We have a Nerve Gene
Family Clinic where we can see entire families. You can see these
three very nice boys that are photographed here. We’re interested in other
genetic neuropathies as well, and this shows another family
we follow that has HSAn1. Remember, I showed you the dad,
and his terrible hand up there? We’re seeing his
daughters in our clinic as well with the idea of trying
to treat their neuropathy before it gets so bad. Karen, are you here? Karen Weintraub. Karen’s done it. Oh, there she is. She’s lurking in the back. She’s got a terrific job
of helping us to bring this to awareness, and there’s more
information on the Stat website if you’re interested. But how about
non-genetic causes? Everything I’ve shown
you before is very rare. Again, kids were not thought
to have neuropathy because they don’t have the medical
causes of neuropathy, and I believed the party
line until I met this college student from New
Hampshire who got admitted to Brigham with
severe pain out of nowhere. Very healthy guy, but
look at those legs. That’s that
erythromelalgia again. And we figured out that in him,
it was small fiber neuropathy, but we really had no idea
why he should have it. All of his tests
came back normal. On a hunch that it
might be autoimmune, we started treating
him for that, and literally within
an hour or two, his pain started to improve. So this was truly what’s
called the index case, and it changed my
career, and now look at how many other people
are hearing this story. So the importance of
one patient’s story. Well, one patient is
not proof of anything, and so with Max Klein– Max, there you are,
my right hand person. We went back and looked at the
records of all the young people we’d seen with the onset of
chronic pain before age 21, and Max and I
published this paper in the Journal of Pediatrics
in 2013 that really laid out this new disease that had
never before been described. And again, you can see some
of the characteristics. 3/4 of the patients
were girls or women. Some of them were grown now, but
they’ve had the onset of pain before age 21. And again, look at all
the different kinds of symptoms they have. You guys know all this stuff. Oh, I can skip this slide now. It just shows you that a
lot of these young people had abnormalities on
their skin biopsies, or on their autonomic
function tests. It really showed
objective evidence that they had neuropathy. So we looked at
these young people to figure out– what
was it, 41, I think? To figure out what
the cause were, and then well, none of them
had the genetic diseases that you just heard
about, and they didn’t have family histories. What came out is that
although some of them were said to have psychiatric
problems, in fact, and had hospitalizations,
none of them really had serious
psych diseases. But what they did
have is a history of autoimmune illnesses, or
when your immune system begins to attack your own body. That paper was published in
the pediatric literature, but it’s important
to realize that there are a lot of these
people who began to be sick during their
teen or early adult years, and they may now be in
their 40s, 50s, or 60s, and they could still
have this, and still improve with treatment. So we next started with
prospective studies, where we specifically recruited
people, and matched controls to further test this
hypothesis, and we chose to study fibromyalgia. Anybody have fibromyalgia here? Anybody been told. Wow, OK, so this is of interest. Fibromyalgia affects 1%
to 5% of the population in the literature, and there’s
a consensus case definition, which makes it
good for research. We looked at all the different
measures of small fiber neuropathy we had
at our disposal, but we particularly prioritized
the objective test results because they can’t be
faked or exaggerated, and that study showed that 40%
of the fibromyalgia patients versus only one in the
group had objective evidence of neuropathy. Kind of hard to get
that one published. What I was saying
sounded so strange because no one’s really found
any biological underpinnings until then. But of course, what’s
happened since is I know of more than
a dozen studies that have looked at
this, and they all are reporting the same thing. It doesn’t cause
all of fibromyalgia, but what we would say
a substantial minority. And again, there
is a review article that came out in
Scientific American Mind that talks to some of
the different investigators. This study is for the
technicians in the audience, and it explains how small fiber
neuropathy can cause pain, and that it’s similar. When they look and study
patients with fibromyalgia, and small fiber, they find
the same electrophysiologic abnormalities, where
these pain neurons, they’re normally only
supposed to fire if somebody’s sticking a knife
or a pin in you, but they’re firing
spontaneously. Those nerves are active. They’re sending pain
messages up to your brain, even when nothing painful is
actually happening to you, and those pain neurons
also fire excessively, and in a prolonged way. This other very technical slide
from my colleague Frank Rice from Albany shows evidence
under the microscope that the arteriovenous shunts,
again, the blood vessels, are abnormal in these
patients with fibromyalgia. And again, it’s the blood
vessel abnormalities that we think underlies
some of the symptoms we see like erythromelalgia. With Max, we turned
our attention to another unexplained
similar vague illness known as Gulf War Illness. That’s still a
problem now for people who were in the Gulf War in
the first and second Gulf Wars in the early 90s. We have several
grants from the DOD, and Max’s study shows
strong evidence that some of the veterans–
not all of them– with Gulf War
Illness, probably have the same underlying
early onset small fiber that came on at the time
they were military recruits, and it’s persisted. The next step if you’re
diagnosed with neuropathy is to figure out
what the cause is, and again, indeed, there are
a lot of different underlying causes. We recommend that patients
speak with their doctor about getting these
blood tests performed. These are the ones that are
supported by published papers in the medical literature. We’ve looked into this
ourselves, as I’ll show you. And it’s really
important to figure out what the cause is in each
person so you can treat it. This blood test checklist
is available on our website. When these tests
were administered to the young people,
we didn’t find evidence that they had diabetes
or heavy metal toxicity. The only thing
really that came up were blood tests
that are associated with autoimmune conditions,
and the majority of the patients, the
young onset patients, did have immune markers. When we step back to look at
the value of these blood tests in patients of all ages who have
idiopathic neuropathy– what does idiopathic mean? It sounds like that’s
the cause of it. That’s the kind of
neuropathy you have. If a doctor tells you that
you have idiopathic anything, just saying no. That’s not a diagnosis. Idiopathic is Latin
for we are idiots. All it means is the
doctor doesn’t actually know what the cause is in you. And so they turn it into
Latin, and then the patient thinks oh, I’ve got
a diagnosis now. I’ve got idiopathic neuropathy. Not so much. Press your doctor for
the real diagnosis. We looked at these
blood tests in patients with idiopathic small fiber
neuropathy, and what we found is that we could pick up an
underlying medical abnormality that could be causal in
more than half of them. Very surprisingly, it turned
out that diabetes and high blood sugar, which is said to be the
most common cause of neuropathy in the US, was not common
in this population. The reason for
that is that people who have diabetes, and who
develop burning and tingling in their feet, or
nausea, they kind of know that they have
diabetic neuropathy, and they’re not
labeled as idiopathic. In fact, again,
we found evidence of unsuspected immune
blood test abnormalities. Well, all this medical
stuff and research, it’s all fine and dandy, but
at the end of the day, what the patients want,
what the doctors want, what even the insurance
companies want is treatment. That’s really what
it’s all about. And so the
information that we’ve gathered from our
patients has enabled us to start treating them. In the study of
the young people, it wasn’t everybody who
got immunotherapy, only 15 among that very small group. The immunotherapy helped
about 80% of them. So very high level. Let’s talk for a little bit more
about autoimmune neuropathy, and what this is, what this
concept is that we are really bringing to public attention. So the job of the
immune system is to protect our body from
outside invaders like the flu. I think every one of us knows
that the flu is going around. But what happens sometimes
is those immune cells can be fooled, and
mistakenly attack some of our body’s
own cells, mistakenly thinking that they’re invaders. And there are
autoimmune diseases that affect pretty much
every cell in our body. Everything from
rheumatoid arthritis, to multiple sclerosis,
to vitiligo, you name it, there’s autoimmune diseases. Because the nerves, and the
brain, and the spinal cord are so important,
they’re actually hidden behind an immunologic
barrier which protects them. But these small fibers are in
a very interesting situation. Since their job, overall, is to
help defend us against threats, they actually go
outside the walls, and they stick
their cell bodies, and they stick their distal
axons outside of the barrier, and they are so in-tune
with immune cells, they actually secrete
immune mediators, and they have physical contact
with some of the immune cells, in particular, mast cells. This shows you the
dorsal root ganglion, which is where the cell
bodies, the CPU if you will, of these small
fibers is located. And as you can see, it’s
outside of the spinal cord. So not protected from
autoimmune attack. What I’m telling you– I stand up here, I’m a
Harvard faculty member, it makes perfect sense, but
the stuff I’m telling you is not in the medical textbooks. It’s controversial. But what is it I’m
supposed to be again? Exciting? – Thrilling – Thrilling. OK, so I got to tell
you guys stuff that’s not in the medical textbooks,
and you judge for yourself whether what I’m saying
make sense to you. What is in the
medical textbook now is really only two immune causes
of small fiber neuropathy, of which a rhemotologic disease
called Sjogren’s is by far, the most common. The major symptoms of Sjogren’s
are dry eyes or dry mouth. So if you have dry
eyes or dry mouth along with neuropathy
symptoms, it’s something for you to consider. But even a lot of doctors
don’t realize how common– polyneuropathy can be the
presenting symptom of Sjogren’s in up to a quarter of patients. And a lot of the patients
with Sjogren’s are what’s called seronegative,
meaning their blood test may not even show it. They’re also very rare
immune neuropathies that are associated with cancer. But hey, in our
most recent paper, which studied 55 patients,
a quarter of them had known autoimmune diseases,
but 3/4 of them didn’t. So what the heck
is going on here? Well, I think it’s thrilling. I think it’s thrilling
because I think we might be discovering a new disease. Maybe you guys can help. We really haven’t found
a good name for this. So when we write our NIH
grants and our papers, we have to be very
conservative, and rightly so. And so what we’re
calling this now is apparently autoimmune
small-fiber neuropathy. And see, I can’t even say
immune because we’re just starting to do the basic
science studies that are needed to prove this. So I’m calling it
apparently autoimmune, but this takes up a lot of
space when we write grants. So if anybody has a
better name, if you could come up to me afterwards,
and tell me your suggestions. And we’re involved now in
a whole series of papers that we’re publishing
with collaborators inside and outside of the lab. How about that
celiac paper, Maddy? You’re going to do it, right? OK, I’ve got a commitment. Showing the overlap and
links between various types of autoimmune disease
and neuropathy. There are different kinds
of autoimmune diseases, and the evidence so far suggests
that auto antibodies may be– and B-cells, which
are made by B-cells, is probably more important
here for a bunch of reasons. You don’t see a lot of cells
when you do spinal taps, or when you do biopsies
from these patients. And there also are detailed
blood test abnormalities, for instance, in the
complement pathway that are most consistent
with B-cell immune mediated dysfunction. Although, clearly when you
have longstanding cases, helper T-cells,
without any question, are involved in sustaining that. So putting this all together,
again, treatment is our focus. Our most recent paper reported
on the first ever study of immunotherapy for apparently
autoimmune small-fiber neuropathy. This is a retrospective study. Meaning it’s a look
back at patients who were already treated. It’s not the so-called
gold standard, the placebo controlled
randomized trial. The reason for that
is because those costs millions and
millions of dollars, and you’ve got to get
the money from NIH or other similar funding
agency, and the problem is they are not going to give
you the taxpayers’ money to do this kind of study unless
there is some published evidence in the literature
that you’re barking up the right tree, and
not the wrong tree. So we’ve now published
the paper that I think shows some
evidence that it might be reasonable to
consider these kinds of trials. This is what’s called a proof
of concept research publication. This was done with my former
post-doctoral fellow, Doctor Liu, and we looked
back, again, at patients who had received a particular
treatment called IVIg, which is the best treatment
for other types of autoimmune neuropathies. So we had given it to
some of our patients here. We selected them
very rigorously. We do not want to give these
treatments to people who have other causes of neuropathy. That wouldn’t work, and it would
be a lot of time, and effort, and wasted money. These are very expensive
treatments, I should mention. We tracked how patients did. The symptom important to a
lot of patients was pain. We tracked objective
measurements from AFT, autonomic
function testing. The difference in AFT
results is shown here. The blue are the
abnormal ATFT results before going on this treatment. The red is after. So 93% had abnormal results
before starting the treatment. 54% had abnormal
results after treatment, and the adverse events
were pretty similar in other illnesses. So we’re building on something
that we call a small fiber registry, and what a
registry is, is it’s when you go to a
doc, and they really try to track the information
they get from you, and they try to collect the
information in a standard way. And it’s a heck of a lot
of effort to develop this. Again, it’s not something
that is grant funded, but you kind of need it
in order to do research. And yeah, I’m looking at the
epidemiologists in the audience who would agree. Any other epidemiologists
here, by the way? Yeah, OK, so I’ve got
to just look at you two. And this just shows you some
of the types of information that we have. We’re very interested and very
bullish on the blood samples, and if any of my patients are
here who’ve donated our blood, we’re incredibly grateful
to you because this is a tremendous resource
for future research. This goes to show you some
of the kinds of experiments that we do with this blood. I think the most important
experiments, overall, are the ones that
involve something called passive transfer. And this is what’s
used to really prove whether a disease is
autoimmune or not, and it involves taking a frozen
sample of that patient’s blood. We’re able to take extracts
of that patient’s blood, and inject it into
little lab animals, and then see whether
those mice or rats develop symptoms of neuropathy. And if we do, that’s something
that we can capture in our lab as well, and that provides
proof that in that patient, they have an autoimmune cause,
or something in their blood that’s causing their neuropathy. This kind of research is
being done more and more in the cancer field, where
patient’s own samples are used to create individual mice or
rats that then can be used to test the effects of
specific treatments, like specific chemotherapy– what’s going to work
in that patient. So this is a very
powerful technique. And what you can
see here is the rat that was injected with
blood from the patient shown on the bottom. It’s the serum from the
blood, not all the blood. Developed some
behavioral abnormalities, some signs of pain in the
paw of that particular rat. Whereas another
rat, shown in blue, maintained normal
sensory functions. So again, we’re going
to see differences in the different animals,
depending on which patient serum was used. We’re also developing
standardized exam forms, and that’s a project in
particular of Shawn Downs– there you go– with the
guidance of Gary Zirpoli, and this allows us
to figure out which aspects that become abnormal
are most useful for diagnosing neuropathy. And all these tests
I’m telling you about, all these fancy tests, is
wonderful for the people who can come and get
them, but we’re well aware that 99.9% of
the people in the world can’t come here to
Cambridge, and Boston, or similar universities to
have these kinds of tests. So what we’re trying
to do is we ask the people who are coming
for these fancy shmancy tests to also see if they’re
willing to let us take a few noninvasive simple tests,
and see how the results of that correlate. The idea is that if we can
develop simple, easy, cheap tests, and show that
they work almost as well as the
expensive tests, then they might be able to be
used all around the world. And with Max, who’s
an engineer, and some of our other collaborators,
and Dr. Serrador from Rutgers, we’re looking at the pupil
responses in the eye. The eye is a window
to the nervous system. Some people say the eyes
the window to the soul, but I prefer to think of
it as to the nervous system because those same
nerves control the functions of your eye. And so you can see this eye
from one of my young patients is very dilated. Her pupil is very dilated. With these pupil
metric goggles, what we’re able to do in
our lab is to measure these pupillary
reflexes, record them, to test whether these
are useful things. If it turns out
to be useful, it’s something that could
be very widely used. For instance,
perhaps, maybe it’s something that could
be put on a cell phone. There aren’t any biotech
entrepreneurs here, are there? Just checking. That’s proprietary. So I’m going to wrap up by
stepping back, and bringing this up to think
well, I’ve told you about rare genetic diseases. I’ve told you about
common diseases, diabetes, a lot of different
causes of neuropathy. How big is this problem, anyway? Well, here’s a clue. This is the epidemics
lecture series. So I’ve run some sort
of hand-waving thought experiments. No one knows the numbers. No one knows the
right answer here, but if you look back at
what’s been published, there’s really only
one epidemiologic study so far out of the Netherlands. And if you apply the numbers
they got to the world population, it suggests there
might be four million cases of small fiber in the world. The only problem with
that is for that study, you had to have a physician
verified objective diagnosis, and what I’ve been telling
you is that more than 90% of the people don’t even
know they have this disease, and they’ve never even
seen a neurologist. So it may be that there’s
closer to 40 million cases in the world than four million. But here’s another way
you could look at it. Fibromyalgia effects
several percent of the world’s population. Given that a dozen labs
are pretty much showing that maybe 40% of these may
have small fiber neuropathy, well, then that yields
the idea that there may be 75 million fibromyalgia
patients around the world who could have small fiber, but
not all small fiber patients have been diagnosed
with fibromyalgia. So when you go back, and
you factor the rest of them then, well, now you’re
starting to look at numbers in the hundreds of millions. And again, I’m not
saying that that’s how many people have this. We really don’t know. The information
just isn’t there. But whether it’s 40 million,
four million, 400 million, either way, this told
us we need to start looking at this at the
population level, not only just with the individual patients
that make it into my office. And so for that reason,
we’re collaborating with epidemiologists
at the Harvard School of Public Health. And Gary and I, with
our collaborators, are getting ready to publish the
first ever epidemiologic study. Now, this is all peripheral
neuropathy, not just small fiber neuropathy. In the US, and this is
through the Nurses’ Health Study 2, which has
been tracking over 100,000 nurses all across
the US for decades, and we have impeccable
information about their health care records, which
one has diabetes, which one was treated for
cancer, what drugs were used in many of them. And we’ve been able to pick
out more than 3,000 people who say, yeah, my doc
has told me that I’ve got peripheral neuropathy. So by going, and sending out
special additional surveys to them, we
anticipate that we’re going to be able to learn more
about peripheral neuropathy than has ever been known
anywhere in the world. That’s the power
of epidemiology. OK, so to allow
time for questions, I’m going to give you
a small summary first, and then we’re going to move
into the question period. So I’m going to give you a
small summary of a big topic. That the symptoms of
small fiber neuropathy include pain and itch,
fatigue, [INAUDIBLE],, things that people don’t
associate with neuropathy. I’ve told you what some of the
recommended diagnostic tests are. That blood tests are very
useful in identifying– not in everybody, but in
the majority of people, in providing hints as to
what the cause might be. Sometimes the tests need to
be repeated more than once, or some people may need
specialized genetic tests, or other special tests to
figure out what’s going on. That there’s strong evidence
from labs all around the world that patients who have,
whether it’s CME, CFS, Gulf War Illness, chronic Lyme, that
a substantial proportion– somewhere between a third to
a half of people who receive these labels may in fact,
have an actual underlying, potentially treatable
medical disease. So that’s maybe the single
most important message, is to take this information out. Every one of us, I think,
has family members or friends who are suffering
from these illnesses. It’s really important
that they know that they can ask their doctor
have we thought about this? Would it be reasonable to think
about testing me for this? Some of the patients with
this type of neuropathy probably have immune
causes, and in them, the treatments for other
immune neuropathies are quite reasonably safe,
and appear to be effective. We don’t know the
numbers of people who have this around the
world, but either way, it’s a heck of a lot. Either way it’s too many. And my point is is let’s
step away from this whole opioid crisis business, and
giving people painkillers. I’ve got nothing
against painkillers, but we’re so much
smarter than that now, and we can find
better treatments. Treatments that actually fight
back at the disease, not just masking the pain
that you have to take for decade after decade. So let’s move onto the era
of smart medicine treatment. And I’d like to extend
my thanks to Radcliffe for this wonderful opportunity,
this auditorium, the publicity. By the way, the cookies
downstairs are fabulous. So thank you for the cookies. I especially like to thank my
patients because again, what I’m telling you is not
stuff that’s in textbooks. We’re writing the
textbooks, and we’re writing the textbooks
because of what we’ve learned from our patients. So all of those people who’ve
let me ask them questions, who’ve spent more than an hour
in my office talking to me, thank you so much. Thank you to the members
of our research team, past and present. I’m presenting the work
of dozens and dozens of collaborators. And thank you also to our
funders, both the National Institutes of Health, the
Department of Defense. We have several people
in private foundations who have made substantial
donations to our group, which is very important, something we
can put directly to good use. And I’ll end by mentioning that
a lot of the information I have told you is available on our
website, our Neuropathy Commons website. My phone is telling
me something, probably that it’s time to end. Thank you, again,
for your attention. [APPLAUSE] – All right, so we
have some roving mics. So go ahead, and– oh,
lots of questions already. Great. I’ll leave it up to you. – So why don’t we start in the
back of the room for a change. Who’s farthest back? Is that you? – Thank you. So in the beginning
of the talk, you mentioned that GI
symptoms were frequently a symptom of
peripheral neuropathy, and then at the end
of the talk, when you were talking
about autoimmune, you mentioned something like
celiac related neuropathy. So I’m wondering, how do we
know that the GI symptoms are a result of the neuropathy,
as opposed to the neuropathy being a result of a GI problem. – Great question. I mentioned celiac because
it’s autoimmune, but only a minority. Only a few patients
actually have celiac. We test for it routinely
because so many of these people have GI symptoms, and because
people can have celiac, and have no GI symptoms. But it’s only a very rare cause. Maddie, here, is going to
write the paper with me that will define how common it is. It’s pretty rare as a cause. From the back with
the pink shirt. – Is there any relationship
between the mechanism of the post-herpetic herpes
pain, and the small fiber? – That’s not a
plant, by the way. Absolutely. And so I actually started
my research career at Johns Hopkins where I
trained, and my first research grant was on
post-herpetic neuralgia. And our lab showed that
post-herpetic neuralgia is associated with severe
damage to these same small fiber neurons because again,
they’re the neurons that transmit pain signals. And shingles or
zoster, specifically damages sensory neurons. And so yes, we view
post-herpetic neuralgia, and also post-herpetic itch,
which my group put on the map, as kind of a restricted
form of these same– I’m pointing here because this
is the most common location where people get shingles– as a restricted form of
a small fiber neuropathy. And by the way, in
case you haven’t heard, there’s a very effective
new shingles vaccine that’s going to be
coming to the market within the next few months, and
it’s dramatically effective, even in older people. Not that that’s any
of us here, but if you know anybody who hasn’t been
vaccinated against shingles, now’s the time. I’ll let you– I’m not very good at picking,
so I’ll let you do the picking, and I think there’s time
for everybody to get their questions answered. – Hi, thanks for your talk. I was wondering if
you had any thoughts on chronic regional
pain syndrome being a diagnosis related to
small fiber neuropathy, and one more, any thoughts
on amino acid peptides? And my friend next to
me has questions too. – What was your second question? – My second question was about
a treatment being peptides– amino acid peptides. No? – That’s simple. No, I don’t know about amino
acids peptides as a treatment. – And the first one
was CRPS for RSD. – After we wrote
papers on shingles, and we turned our attention to
complex regional pain syndrome, which has a lot of
similar symptoms– the unexplained pain, swelling,
color changes, changes in hair, and we published the first
objective evidence that that is what we call a regional
small fiber neuropathy, where only a part of the
body’s nerves are affected. I’ve been telling you
about polyneuropathy, which means it’s a
generalized nerve problem. So yes, we think CRPS
is very closely linked, and that it’s a regional
small fiber neuropathy. And furthermore,
CRPS, which is when people have a kind of an
injury, a skiing accident, or cut their leg, or a sprain. It’s something that
would just get better, and for whatever reason,
it just doesn’t get better, and the pain, and problems
can go on for years sometimes. We think that in some
of those patients, they may actually have
an underlying small fiber polyneuropathy, and
it’s for that reason that their nerves
aren’t able to recover after they’ve been injured. – Thank you. – Yes, I had a question. It was a really great lecture,
and it’s very informative. So in terms of the skin biopsy
that you do in patients, have you had any sort
of insight in terms of if it’s done once on a
patient in the beginning of their symptoms, and their
symptoms are progressing, and the initial biopsy is
not showing anything, what is your protocol, and what
happens to patients who are progressively getting worse? Would you repeat it soon? How do you observe
those patients. And the second question was
about when we mentioned– – Wait, the first question. – Oh, sorry. – Let me just answer the
first question first. So the question is
about skin biopsies, and that’s currently
the best test available, but it’s far from perfect. There’s no medical test
that’s 100% perfect. And so what I would
say if the skin biopsy shows that you have
severe nerve damage, then it’s highly
likely that you do have this kind of neuropathy. That’s called positive
predictive value. But on the other hand, it
doesn’t always pick it up. As you say, what if the biopsy
is done early in the course? Or what if it’s taken from
the wrong part of the body? So the fact that you
have a normal skin biopsy doesn’t mean you don’t have
this kind of neuropathy. It makes it less likely. And some patients I’ve
been following for years, their skin biopsies were
normal at the beginning, we would suggest they
might want to repeat it a few years later if we still
didn’t know what was going on. And in some of them, it’s
dropped over the years. It might still be
in the normal range, but it might have started out
at the 70 or 80th percentile, and it’s dropped 60, 40, 20. So that tells us their nerves
are going, or not healthy, or it drops into
the abnormal range. So they’re not perfect, but
it’s still very important. It’s a very important,
very useful test. And what was your
second question? The second question
is about Sjogren’s. You mentioned that a lot of
patients are seronegative. How do you correlate
patients who might have the autonomic testing
showing positive, and the sweat testing, but then
they’re seronegative? What is the next steps? And they do have–
they’re very symptomatic. – That’s kind of a complicated
question because the sweat testing isn’t the recommended
test for diagnosing Sjogren’s. So Sjogren’s requires a
rheumatology evaluation by somebody who’s
really familiar with it. They factor in a lot of
things– the symptoms you have, looking in the eyes, their
formal diagnostic criteria. Sometimes they take
a biopsy from the lip to look at the
salivary glands, and it can take a few years to work
out a Sjogren’s diagnosis. Shall we work our way towards
some of the patient people? We can come back
to the back, but I want to also get some equal
representation from the front. – Hi, I’m a patient, and I
just want to understand better the impact on the brain. – Could you raise
your hand again? Oh, great. Thank you, OK. – I’d like to understand
better the impacts on the brain both ways. One of your slides
mentioned polypharmacy as a potential cause. So I don’t know if that’s
too many medications impacting the brain. And then also, could occipital
neuralgia be a headache caused by small fiber neuropathy? – That’s a whole complex topic. I don’t know if any one– I’m a neuroscientist, and I’m
in the neurology department. I’m surrounded by experts
on cognitive function, by experts on
headache, and I don’t know of any of them that’s
looking at small fiber neuropathy yet. So another one of my goals– I hope I have some colleagues,
and fellow researchers in the audience. Another reason to
give this talk is to excite people who are
working in different areas to start taking up
their own projects. We’d be thrilled to have
experts start to look at this. What I tried to summarize
in that complicated slide is that peripheral neuropathy,
specifically small fiber, can affect the brain in
a lot of different ways. For one thing, those cells, we
think of them as peripheral, but they actually send
part of their cell up into the spinal cord. So it’s part of the central
nervous system, as well as the peripheral nervous system. Even the ones that don’t send
an axon up the spinal cord, but that end where they
come into the spinal cord, they synapse. They connect with
other nerve cells. So there are
tran-synaptic effects. And then there are
network effects in the brain when the brain
cells change their function, for instance, because of
reduced sensory input coming in. And then what you
mentioned is what I call the downward spiral,
which was when people are sick, and they don’t know
what’s going on, and they’re doing
all this stuff, and they get on medication
for this for their stomach, for their pain, they
become depressed, they become inactive. All of these things have
effects on the brain as well, and so those really are
tertiary and quaternary effects of being so sick. So it affects the brain at
a lot of different levels. – Thank you. – Hi, I was asking about
ESR because you used that as one of your
tests, and I’ve heard that it’s kind of unreliable,
and I was wondering what sort of ranges
you’re looking at, and why you chose that test. – We actually don’t rely on
any one test of autoimmunity. It’s not a black or a
white situation for exactly the reason that you
point out, which is that these tests that are
used to track immune function, I wouldn’t call them unreliable,
but I’d call them nonspecific. And so that means they
don’t correlate that well. Somebody could have
an autoimmune disease, and have a normal blood test. A certain number of people have
abnormal blood test results, and they don’t have
autoimmune diseases. So they’re statistically
associated, but it’s not a black
or white relationship, and that’s why I mentioned
these things like– I don’t remember
the exact percent have abnormal ESR, which stands
for erythrocyte sedimentation rate. Others may have
a low complement. Others may have a test called
ANA, anti-nuclear antibodies. And again, none of these are
specific for small fiber, or any particular
disease at all, but together, they kind
of give a hint, a clue, when they’re elevated in such
a high percentage of patients that there may be a
link to an autoimmunity. Not in each person. – Hi, thank you for the talk. I wanted to ask– you mentioned
CFS or chronic fatigue, and it’s one of these
idiopathic things that might have small fiber
neuropathy as the underlying cause. What sort of work has your
group or others done on that? – My collaboration with
David Systrom and his team at the Brigham,
I think, is going to publish some really exciting
data coming out of that, and I think it’s OK
for me to mention it since we’ve already published
it in preliminary abstract form. And what that’s going to show
is that a substantial percent of people who present– he’s not a neurologist. He’s not a nerve doc. He’s a lung and circulation doc. People who go to him because of
this lack of energy, and just difficulty getting out
of bed, and inability to do their routine, a
substantial percent of them do, in fact, have this kind
of peripheral neuropathy. So not everybody, but enough
that a doctor should always think about it as part of
their differential diagnosis. And it’s treatable. Once you know– there
are many reasons not to be able to get out of bed. Depression, for instance,
is a very common one. So it’s important to go beyond
the I have chronic fatigue, to let me go see a
doctor like Systrom who can do the tests to
actually measure my blood flow, and my heart
rate, and my blood pressure under
different circumstances, and hone in on what’s
the exact cause in me because he’s got
effective treatments. – So I wanted to ask more
broadly, we have about half of patients with POTS, and
chronic fatigue syndrome, and fibromyalgia. The syndromic disorders
have a tangible small fiber neuropathy, and you’re
looking at the immunotherapy in these patients. Has anybody– – In some of them. – In some of these
patients, right. Has anybody looked for
functional receptor antibodies that maybe don’t
cause a neuropathy, or haven’t yet, at whatever
stage in the illness, doing like the passive transfer
work to rabbits or something, with serum from patients who
don’t have the neuropathy to see if the immunological
profile you’re finding might be in those patients too? – Yeah, we would always
use controlled sera, and so it’s very important to
thank not only the patients who come for research, but
also the normal controls, and people with other diseases
because all of the work we do, we have to compare what we
find from patients to what we find in the general population. And so yes, we would always
use serum from non-patients to do these kinds of
experiments as well. – I had two observations
I’d like to share. It seems that the cause of
this problem is in the plasma, and that it’s an
immunecomplex problem. There are immune antibodies
that are in the plasma. Has plasmapheresis been
considered as a treatment to remove the offending plasma,
and replace it with colloid, or clean plasma. Instead of infusing
immunoglobulin G to down regulate the
production of auto antibodies, perhaps plasmapheresis could
remove the offending agent. That’s one observation. The other observation
I had was that– or question– there’s talk
about genetic involvement. Has consideration been given
to the abnormal gene sequences being viral inserts,
and not inherited from a prior infection? DNA from a particular
virus, enterovirus perhaps. So if it lies in the
genes, in that sense, that would account for the
chronicity of the illness, and that would account
for the remissions, and then the relapses
because the genes are still there expressing themselves. So I’m wondering– I guess the
point is has consideration been given to the fact that
these might be gene inserts, not mutations, and
not inherited– – Great question. Great question. So actually, a couple of
questions and comments, and one is about other types
of immunotherapy. And again, immunotherapy
is only one treatment, and it’s a treatment for
those people who it turns out we think have an autoimmune
cause, which is really not everybody. But for immunotherapy, you
have to think and individualize the treatment for the
different patients, and there are different
immunotherapies. There’s no one size fits all. And so yes, absolutely. I do have some patients
who use plasma exchange. Taking out their own
blood– it’s like dialysis. It dialyzes away
their autoantibodies. But again, another
expensive therapy that’s very hard to get approval for. It’s got its own
problems, and so it’s not something that is routine. We try to start with the
simpler, more mainstream immunotherapies. There’s a whole host
of new immunotherapies that are coming to market. Eculizumab, for instance,
is newly approved for a neurologic
autoimmune indication. So it’s really exciting
days, and that’s why it’s so important that basic
scientists get involved in this so that we can
actually figure out what the molecular
epitopes are, what the targets are of antibodies
because when we really know what’s going on at
the molecular level, then we can use much more
targeted therapies. As you say, IVIg is kind of
a dirty drug that is a very crude way of approaching it. It’s the best
treatment we have now, but I think as this
comes into sharper focus, and as other research teams
get involved beyond my own, it’s going to open the door
to much better therapies. With regard to the genes,
the genes are involved. Without any question,
genes are involved in autoimmune diseases. We’re interested in
looking at the HLA antigen. Some people have just
unknown genetic mutations. I was at NIH last week working
on a family with a novel very clear familial genetic
cause that’s never been described in the literature. So by doing detailed
mapping of the genes from that family, the
affected individuals, the unaffected
individuals, we’re likely going to discover a new
gene that causes neuropathy. But even in people who don’t
have familial neuropathies, we know that tendencies
are genetically inherited. And so when we can
get our database up to the level of
tens of thousands of samples, right Gary? At that point,
then you can really start doing population genetics,
epigenetics, and much more sophisticated genetics. – Hi. Thank you so much for your talk. I have two questions for you. – Was it thrilling? – I said thank you so
much for your talk. Yes, it was thrilling. – Thank you. – And my sister
just texted me very excitedly about your slides
being posted on the website. I’m sure she will find it as
thrilling, if not more so. So she is actually the
one who has sent me along with two questions. The first one is you mentioned
IVIg as the primary therapy, but are you familiar with
subcutaneous immunoglobulin, and if any of your
patients have used it as an effective treatment? – So the question is
what’s the relative roles of the same treatment,
which is pooled human Ig immunoglobulins taken
from blood donors, such as us, healthy
blood donors– comparing it when it’s
given intravenously, which is what IVIg stands for,
as opposed to subcutaneously, which is SCIg. There are pros and cons
of giving it either way. They both get it into your body. They’re both effective. It’s really a logistic
issue, and there are different logistics,
different insurance companies approve it in different ways. By the way, I’m telling you
this that we published a paper, that it’s reasonably effective
as if that means you can then go out, and get it. Maybe you know already,
but for the rest of the audience is that the
insurance companies pretty much don’t approve
these treatments, and it’s very rare that
they will approve it. The reason is they don’t
come to lectures like this. There aren’t any
medical insurance? See? I told you so. I told you so. And because of
that, they may not know the things that are
emerging from the leading research universities. And so therefore,
even though things were published, when your
doc tries to get approval for treatment, whether it’s
subcutaneous or IV, pretty much, typically, the
response is no way. That’s why we put our
paper on the website. And if your sister
is interested, she needs to get a
copy of that paper because you have to physically
take the published evidence, give it to your own
treating doctor, and have your treating
doctor send it to the insurance company. And say, well, hey, now there
is evidence that it works. So please consider it. – Thank you. And the second
question was could you tell us a little bit
about your thoughts on the relation of mast
cells or mast cell activation disorder to neuropathy? – I’m very interested
in that, but it’s such complicated
questions that let’s defer that to the
discussion time afterwards. Yes, very important. Very interesting. – Hi. Thank you. I have one question
that may just be restating what
you’ve said, so I apologize if that is all it is. But just to clarify, if
you had a patient whose say, had a diagnosis of
POTS, and fibromyalgia, just as an example, maybe
they were poorly controlled, is that enough to say
let’s test for this? Or are there specific
physical symptoms that they should have as well? – That’s a great question. That is a great question. And I think, again,
it’s an emerging area. It’s very unclear. We don’t know for sure who
will, who will not have this. We don’t even have– as with
the skin biopsy question, there’s no perfect test. The good news is that there’s
an upcoming meeting that will bring together
experts around the world to develop what’s called a
consensus case definition. And when there’s
a case definition, it’s very, very helpful, even
though they’re not perfect either. But at least what
it means is there’s a mutually agreed upon
diagnostic standard as to who has it, and
who doesn’t have it. So that’s going to
be very helpful. Well, fibromyalgia– if I
were a fibromyalgia patient, I think patients
want to get better. And when you have an illness
that is really a label– that’s the key point, is
that fibromyalgia is not a diagnosis. It’s a label. It’s a word that we put on
a collection of symptoms. It doesn’t have one cause. Those same symptoms
have different causes in different people,
and it’s so important to move beyond the label, and
press your doctor to tell you what’s the underlying
medical cause in you. And even if they might
not know it in 2017, maybe they could figure
it out in 2018, or 2019. So I think it’s up to each
person with fibromyalgia. People have, unfortunately,
different levels of medical coverage. Some docs are more interested
in pursuing things than others. I know what I would do
if I were the patient. – Thank you. I just– oh, sorry. I just had one other quick
observation if that’s OK. – Sure, let me just look at time
for one or two more questions. And in the interest of side
of the room parity, and gender parity, I also want to
invite this gentleman here, who’s had his hand up
since the beginning. Kristen, maybe you could
put your hand up again. Why don’t you ask
your last question– And I’m happy to stick around. So if you didn’t get your
question answered in public. – This, I hope, is a
fairly short question. I’m interested in the
dynamics of the pathology. In other words, if you have a
patient with a positive skin test who responds– – Could you speak
a little louder? – If you have a patient
with a positive skin test who responds to
immunotherapy of some sort, how rapidly does the
skin biopsy return? – Great question. We don’t recommend repeating
skin biopsies more often than once a year because the
pathology, as important, as vital as it is, changes slowly. Then it takes a while for
the nerve cells to regrow, and they may not even
regrow in everybody, and they may regrow at different
rates than somebody who’s 15, than somebody who’s 65. So as of now, the
skin biopsies are most helpful for initial
diagnosis, and their role in tracking patients. In fact, we’re just
applying for an NIH grant to try and better clarify
which are the outcomes that are most useful for
longitudinal tracking, as opposed to initial
cross-sectional diagnosis. Good question. Worth waiting for. – As was this lecture. So I think I have to cut off
the questions, officially, for the group, and let people
get out who need to get out. But I know that Dr. Oaklander
is going to stay up here, and can answer a few more
questions from you, personally. And I just want to
thank you again. This is just terrific stuff. [APPLAUSE]

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