March 26, 2025 • 58 mins
Dr. Denis Balaban joins us today to talk about a very challenging topic within neurology, neuroimmunology.
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Dr. Michael Kentris (00:00):
Hello and welcome back to the
Neurotransmitters.
I am your host, dr MichaelKentris, and today we are going
to be talking aboutneuroimmunology a scary topic
for many of us in neurology, butI am very happy to have an
expert with me today, dr DennisBalaban from the Division of
Neuroimmunology andNeuroinfectious Diseases from
(00:21):
Massachusetts General Hospitaland Harvard Medical School.
Is it all right if I call youDennis today?
Yes, absolutely.
Thank you so much for coming onthe show and talking with us
about such a fascinating andconfusing topic.
Dr. Denis Balaban (00:35):
Thank you for having me.
I always love talking aboutneuroimmunology, so I relish any
opportunity to do so.
Dr. Michael Kentris (00:43):
Now, as we were talking before we hit
record, let's start with the50,000 foot view.
What do we mean when we sayneuroimmunology?
Dr. Denis Balaban (00:52):
Yeah, absolutely so.
What we mean is any sort ofneurological disorder in which
it is caused by a dysfunction ofthe immune system leading to
the neurological disorder, adysfunction of the immune system
leading to the neurologicaldisorder.
So you have, you know, anantibody-mediated disease
(01:14):
attacking your peripheral nervesor brain.
You have, you know, t or Bcells causing that.
If you have a cytokine storm,as you can see in neurotoxicity
in the setting of CAR T cells,all of those are under the broad
umbrella of neuroimmunology.
Dr. Michael Kentris (01:28):
Yes, I know one of our favorite things to
do in neurology is just tackneuro onto the front of a
pre-existing discipline.
Dr. Denis Balaban (01:35):
Indeed exactly.
Dr. Michael Kentris (01:39):
So what does the pathway to becoming a
neuroimmunologist or aneuroimmunology specialist look
like for people who might bekind of looking to explore that,
whether they're in neurologyresidency or medical students or
in some other primary residencydiscipline?
Dr. Denis Balaban (02:09):
people can take.
The way I got intoneuroimmunology was I had no
idea I would be doing this inmedical school.
My big question was I want todo neurology right, and internal
medicine, you know, gave mesome questioning thoughts
because I love that detectivework, but nothing was ever going
to be as fascinating as thebrain.
So when I went into residency Ithought I was going to do like
cognitive behavioral and then Irealized that that was not my
(02:32):
cup of tea personally and Ireally found that I love being
on the inpatient generalneurology service where a lot of
our like folks with newdiagnoses of MS, autoimmune
encephalitis or we don't knowwhat this is yet, but we shall
try some steroids and look, theygot better.
So I really loved treatingthose patients because I felt
(02:59):
like I had to be at my best inorder to be able to diagnose
them.
So that means like I had toreally.
It encouraged me to read upeven more than I was.
It encouraged me to ask thatvery specific question that
maybe no one else asked toreally try to get to the
diagnosis, try differentexamination maneuvers that maybe
(03:22):
others have not done.
I really thought it was, youknow, neurology on steroids,
figuratively and literally.
And so once I knew that I wantedto be in neuroimmunology,
there's a plethora of differentfellowships that are available
for those interested, and sortof the usual question that
(03:45):
residents face is do I want tobe mostly MS, do I want to be
like MS plus a few otherneuroimmunological diseases that
I know about, or just likeneuroimmunology?
The broad gamut includeinfectious disease in there.
What sort of neuroimmunology doI want to practice?
Because historically it's beenMS and the other demyelinating
(04:09):
disorders, but now people have abit more options.
So that is how, and I decidedto go as broad as possible and I
went to the Advanced GeneralAutoimmune Neurology Fellowship
at MGH.
But there are people who getinto neuroimmunology first from
a research standpoint.
They'll have done a phd,they'll have, uh, you know, you
(04:29):
know, done their research andpublished quite a bit, and then
they realize, no, I actuallywant to be treating these
patients too.
And so then they can find theirway, uh, into a clinical
practice, uh, through thatavenue so many roads, I would
say no, that's, that's.
Dr. Michael Kentris (04:44):
That's great to know, because it is one
of those things where we see,you know, as the testing and the
identification of thesedifferent syndromes has evolved,
so too has the trainingpathways.
Indeed, indeed.
So what does the practice?
You know, I know there's amixture of inpatient and
outpatient.
(05:04):
So what is the general vibe inthe practice?
You know, I know there's amixture of inpatient and
outpatient.
Dr. Denis Balaban (05:09):
So what is the general vibe in the clinic?
Yeah, absolutely so.
In clinic I have a practicethat is, again broad.
I will see patients with allsorts of different things People
in my general neurologypractice whom I've diagnosed
with MS and then I bring to myneuroimmunopractice people with
autoimmune encephalitis,neurosarcoidosis, vasculitis,
(05:32):
stiff person syndrome, you nameit.
So it runs the gamut.
And I also have patients whoI'm following where I'm not
exactly sure what might be goingon quite yet.
But they are complicated.
And could there be somethingneuromunological going on?
Sure, have I been able to provethat yet?
(05:53):
Not really, but I'm keeping aneye on them and I'm going to be
keeping them in my practice inneuroimmuno as a just to get
more time, uh, with them in myfollow-ups.
Uh, because I have a longerfollow-up for, uh, minor
immunology patients depending ontheir diagnosis or complexity.
Um, on the inpatient side, Imean, you know so many different
(06:17):
things that can happenMeningitis, encephalitis, uh,
you know new strokes from avasculitis, you name it.
Myelitis, my gosh, I could any.
Any itis I could name.
So I think the trickiest partwhen it comes to figuring out is
really making the diagnosis andreally raising the suspicion of
(06:39):
should I be thinking about aneuroimmunological diagnosis in
my patients?
Because you know, most peopleare going to first see either
their primary care doctor ortheir general neurologist as
sort of that first step.
And I'll say that with betterknowledge of things like
autoimmune encephalitis beingmore in the zeitgeist, it's less
(07:03):
of a problem these days of thediagnostic delay and in fact
sometimes there is anover-diagnosis of such things as
a paper not too long ago waspublished describing
misdiagnoses.
But really the goal, I think,is for the general neurologist,
(07:25):
when hearing certain things onthe history or seeing certain
things on the examination, toraise a flag to say, hey, maybe
I should be thinking about aneuroimmunological diagnosis.
And the thing withneuroimmunology is it can touch
any part of the nervous systemand it can present either
acutely, subacutely, chronically, it all depends.
(07:55):
So then people wonder well, howdo I put my arms around this?
How do I know that this couldbe neuroimmunological?
Talk today, I think, of whatare ways in which that in my
general neurology practice I canstart to have that intuition
and suspicion for somethingneuroimmunological afoot.
So much like in making anydiagnosis in neurology.
(08:20):
Onset and pace are of incredibleimportance.
Onset and pace are ofincredible importance and really
diving down to understand howthe symptoms unfolded.
And this might seem obvious toany neurologist listening, but
it can be more fine-tuned thanone might think.
(08:45):
So, for example, I had seen apatient who presented with a
two-year history of cognitivedecline and they were, you know,
in, they were older than theage of 50.
And the family seemed fairlyused to things by then.
(09:06):
And you know, it was, I think,anybody in a very busy setting
with distractions coming in,phone calls, et cetera.
Oh, two year history, cognitivedecline, probably
neurodegenerative, we're done.
Probably neurodegenerative,we're done.
(09:29):
What was helpful is that someonehad gotten a brain MRI that had
shown that there were these T2hyperintensities in their
temporal lobes.
And, oh my gosh, this isactually a limbic encephalitis.
And if you just went by thisone-liner of two-year history
history, you might miss the factthat actually what happened was
two years ago.
Within about three months,there was this rapid decline and
(09:52):
then they plateaued for therest of the time.
And then you, we find out, okay, they have hyponatremia.
Okay, they have these briefdizziness spells and lo and and
behold, it's LGI1.
So I think, really trying towhen you ask well, how long has
this been going on X years.
Okay, and how did that reallyevolve?
(10:15):
I think that is a key point insome of these and if there were
changes, that happened, when didthose changes occur?
Really trying to hone in onexactly when those changes
occurred, because that gives youa much more accurate picture.
Because there are someneuroimmunological diseases that
are characterized not by agradual decline but by
(10:39):
punctuated declines, sosomething like a mononuritis
multiplex or multiplemononuropathies, for example,
where it's like, yeah, I hadthis carpal tunnel and you know
it was painful but I'm a littleweak, but you know it's okay and
oh well, and now I have a footdrop and oh, now I have this.
And so really understanding,like, is this happening in quick
(11:02):
succession?
Or if the are these like yearsapart, then okay, maybe not and
you should look for somethingelse.
But these are that's why Imentioned, like pace onset as
like one of the number onethings to focus on first,
because that will get you thediagnosis.
Dr. Michael Kentris (11:19):
That's the first step in making a
neurological diagnosis, alongwith localization, of course,
course that's a great point isthat a lot of times we in the
specialty clinics or, you know,even just general neurology,
being in some places right three, six months to get in, um, you
wind up where you are seeingthem at the tail after the
(11:40):
action has happened, so to speak, and it is like you're you're
asking these people to to goback to these probably much.
It is like you're you're askingthese people to go back to
these probably much morestressful times in their memory
and you know, as you said, likesomeone's made peace with it, as
it were, they don't want to goback and think about when things
weren't as bad necessarily.
It's hard to handle thosememories sometimes.
Dr. Denis Balaban (12:01):
Yeah.
So, um, yeah, being able torecognize these things and, uh,
you know, offer a diagnosis andtreatment like that can be
powerful, because those, uh,those patients with encephalitis
, depending on the type, um,they, they can be reversible and
treatable and they can get backa lot of their quality of life,
um, depending, of course.
Dr. Michael Kentris (12:25):
And I think you also bring up a really good
point.
One thing I think there's beena big trend towards over
probably a few decades now isthis in medical training,
especially at the medicalstudent level, we see a lot of
emphasis on open ended questions, and I find that the more and
more that I learn uh, you reallyneed to know how to ask a
(12:47):
closed-ended question, and whatthose closed-ended questions
need to be is just as importantabsolutely, I, I love that you
brought that up and uh, becauseI think on a first meeting,
open-ended questions are great,because that's sort of like, if
you're if information were fish,you know that's the widest net
you can catch and like that'swhat you're going to bring in,
(13:09):
but then, um, you know, ifyou're really looking for that
specific thing, uh, the netapproach might miss it.
Dr. Denis Balaban (13:17):
You might need to spear fish for those
questions, and I fully agree.
Um, so, for some of those andthose knowing when and what
those key questions ask reallydepends on how the patient is
presenting.
So, for example, if someone istelling me like, oh my gosh,
(13:38):
like I have all this terriblestiffness and I have these
episodes of spasms that are justkilling me stiffness, and I
have these episodes of spasmsthat are just killing me, you
know, one question that I ask inthose contexts is well, tell me
, are you more easily surprisedthan you used to be when this
started?
And people will often like whydo you ask that?
(13:58):
Like they'll have thisquizzical look on their face.
Really, you know, yeah, I do, Iam a bit more easily startled.
Their face, really.
You know, yeah, I do, I, I am abit more easily startled.
Why did you and and then okay,and um and that can be a very
helpful uh question to ask.
In something like a stiff personspectrum disorder, uh, where
their startle is increased, thespasms can be triggered by
startle as well.
I had a patient where, um, theyactually had a stiff limb
(14:23):
syndrome and if I brought myhand to the affected limb, not
even touching them, it wouldtrigger the startle.
So not even a tactile stimulus,just like the possibility of a
tactile stimulus, and they werefully aware they were watching
me do it as I was moving towardsit.
(14:43):
Not even that much of a startle.
So asking a pointed questionlike that can be helpful In
somebody who has a subacutecognitive decline, for example.
In those cases I think it's avery easy question to ask about
fascia brachial tonic seizures.
Easy question to ask aboutfacial brachial tonic seizures.
(15:03):
And so the way I ask that islike have you ever had episodes
where your arm or the and thecorner of your mouth sort of
come together almost and I actedout for them, because you know,
if the picture is worth athousand words, then actually
acting it out is worth even more.
And I often ask patiently ifthere's a funny movement that
(15:24):
occurs, like can you act thatout?
Tell me like what that?
Show me what that looks like,and then they can perfectly act
out what I might've beenpicturing in my head and like,
okay, yeah, that's it.
Okay, asking, and that's agreat question for LGI1
specifically.
Another thing for LGI1 areasking about brief dizziness
(15:46):
spells which can occur, whichare thought to be seizures, but
we're still not exactly sure.
But essentially it's these likefive to 10 second episodes of
people have described them aslike a chill or a vertigo or a
dizziness.
And you know they can happenwith low frequency to begin with
, but then as time moves forward, they can start to happen
(16:07):
weekly, then daily, thenmultiple times a day, and that
is also a nice clue for thepossibility of an LGI-1.
You know, if you're wonderingabout MS, you know something you
could ask about is are yoursymptoms worse in a hot shower
or if you've been exercising alot?
And that's asking about, youknow, the UTOF phenomenon.
(16:29):
So these are like, so, knowingthe specific questions, that if
you have certain, if you have alist of diagnoses already in
mind that might fit the clinicalsyndrome, ask about those
specific things.
That can be quite helpful.
Dr. Michael Kentris (16:46):
Right, and that's as you said.
The challenging part withneuroimmunology is that it
radically could affect any partof the neural system, from the
brain to the muscles, and so youkind of have to have your
algorithm for each potentialcomplaint locked and loaded
before you can go and get it.
Dr. Denis Balaban (17:04):
Yeah, exactly Like you having an idea of the
syndrome that you're dealingwith and then trying to ask
those questions.
That's and like having that,having that knowledge already in
store, because there there aresome things that are very easily
up-to-date-able or Google-able,but knowing a disease and
(17:30):
exactly how it presents in thestory of that disease, that's
not something that a quicksearch generally accomplishes
and I'll speak.
Dr. Michael Kentris (17:42):
you know not to throw any shade at the
writers for up-to-date, but I dofind the neurology up-to-date
articles for a lot of topics arenot up-to-date.
To speak to that right, likeneuroimmunology is one of the
biggest culprits.
Oh yeah, the rate of newknowledge is just such a
breakneck pace.
(18:02):
Oh my gosh yeah, it's almostimpossible to keep a compendium
like that current.
Dr. Denis Balaban (18:10):
Exactly, yeah , it's one of the fastest moving
fields and makes it reallyexciting, but also takes work to
stay up to date.
Dr. Michael Kentris (18:22):
Now in the outpatient setting, is there
anything that you know, anychief complaint that perhaps
represents the lion's share ofreferrals, or is it a pretty
varied spectrum?
Dr. Denis Balaban (18:34):
as far as what you've anecdotally observed
, oh my gosh, it's such a variedspectrum Because people get
referred to neuroimmunology fora wide variety of reasons.
Some are due to like an initialworkup that revealed something
(18:55):
inflammatory appearing.
So one example is a meningitisseen on MRI, where you have
either a leptomeningeal orpacumenengeal enhancement and so
then say, oh my God, they havea pacumenengeitis, send them to
neuroimmuno and many times thoseare actually just chronic CSF
leaks.
But you know, depending on thestory or lack thereof, for a
(19:20):
chronic CSF leak we'll do theinvestigations and find that
everything is bland.
There's no history that'ssuggestive uh, by like prior
autoimmune history or familyhistory or anything of that
nature.
And then, oh, they have ahistory of men, years, okay, and
uh, csf leaks in men years cango hand in hand.
(19:41):
Um, so then it says, okay, soCSF leak and we can try and
treat that.
Um, then there's other peoplewho come in because of funny
spots in their brain, uh, on mri, which may or may not be, uh,
related to their symptoms, uh,whole, whole variety of things.
Or, and the numbness andtingling in the setting of a
(20:04):
recent cancer diagnosis, forexample, could this be
pyreneoplastic or could this besome sort of inflammatory,
something related to a myelomaand the high M spike, for
example.
Dr. Michael Kentris (20:20):
So all sorts of reasons people can be
referred no-transcript, you know, frustrating, let's say to the
general neurologist to approachand that is the, the so-called
unidentified or, you know,poorly defined, the UBO, the
(20:41):
object on MRI, someone's rightT2 flare lesion that maybe it's
demyelinating there's one spotit's not enhancing, there's no
clinical.
They got that for like aheadache workup or something
like that.
And they're like how far downthe rabbit trail do I need to
run for investigating forsomething like multiple
sclerosis or things like that?
(21:02):
Yep, so in your practice, let'sstart with someone with that
vagueness of a complaint.
Sure, how did you deal withthat kind of setting?
Dr. Denis Balaban (21:12):
Great question, so okay, so just to
make sure I got it so somebodywith these T2 hyperintensities
on brain MRI discovered due tosome maybe potentially or
initially sounding vaguesymptoms.
So then what I do in evaluatingthis patient is I, first off,
(21:34):
who is the patient?
Are they an 80-year-old malewith history of high blood
pressure, diabetes andhyperlipidemia?
Are they a young woman with nosignificant past medical history
?
And maybe they don't even getheadaches at all, even get
(21:59):
headaches at all?
So I sort of just go down like,okay, well, what could these be
in neuroimmunology?
Could these be indicative of MS?
So then I ask like, okay, haveyou had episodes that could be
significant for MS, like a patchof numbness or tingling that
lasted several days to a week?
Have you had optic neuritis?
Or you know?
I ask about the optic neuritissymptoms of, like painful eye
movements with vision loss.
(22:19):
I ask about new onsetconstipation or urinary
frequency and urgency.
And one thing I want to say isthat I feel like in seeing
people ask about urinarysymptoms are you peeing a lot?
No, I'm not peeing a lot andthen you get to it it's like, oh
, you're peeing every two hours.
(22:40):
Yeah, it's better than peeingevery hour.
Um, so, like the, the way I askabout it is okay.
Um, when you feel like you needto pee, are you able to hold
your urine, uh, urine, for like30 minutes to an hour, or are
you racing to the bathroom or doyou?
Are you very like, cognizant of, like, your urinary habits?
(23:03):
And that has gotten me a lotfarther than a more broad
question, because then I'll havepeople say, oh my gosh, yeah,
if I don't, if I don't get to abathroom within five minutes, I
worry I could pee my pants.
Or, yeah, I really have to peeevery three hours, otherwise bad
(23:24):
things will happen.
So that has gotten me a lot.
And then, for bowel movements,for example, I had a patient who
had new onset constipation forno apparent reason.
Um, they were a uh, healthyperson and they were even
hospitalized, uh, for this newconstipation that came out of
(23:45):
nowhere, and I know.
And it turned out that, um,after everything was said and
done, that it was due to ademanding lesion in the spinal
cord that had yet to bediscovered.
Um, so, no, not at all.
But, um, so, but that's justpart of the assessment.
So then, uh, after like, newnumbness, tingling, weakness, uh
(24:07):
, like, uh, stiffness in thelegs.
Um, the exercise have, as yourworkout routines, gotten harder
for any reason, are Are youlifting less weights?
Are you not able to squat asmuch?
If they're active, that's sohelpful, because that sort of
high level of activity will be amuch more sensitive marker than
(24:29):
for someone who is sedentaryand like, yeah, I walk up a
flight of stairs every now andthen.
You might not notice thedecrements happening until they
are quite severe.
Um, so then I also take intoaccount, like key past medical
history questions.
Um, that again, epic is uh, orthe medical record can be a
minefield of chartomas or, uh, adearth of information.
(24:50):
That's a new one for me.
I'm going to keep that one.
Oh yeah, I can't claimownership of that.
Dr. Michael Kentris (24:54):
That's a new one for me.
I'm going to keep that one ohyeah, I can't claim ownership of
that.
Dr. Denis Balaban (24:58):
I had heard that somewhere years ago.
But you can ask about historyof MS, for example infectious
mono, big one.
I have significantly raised myown suspicion for MS in someone
who is otherwise asymptomatic atthe moment due to their history
(25:21):
of infectious mono and anasymmetric reflex or two.
And lo and behold, it was MS,because it's one of its.
The highest risk factor,acquired risk factor, I'll say
for MS.
The highest risk factor,acquired risk factor, I'll say
for MS.
But if you're not thinkingabout MS in particular and
you're wondering about, you know, neuroimmunology, rheumatology
(25:44):
not otherwise specified, thenyou can ask a whole host of
questions that wouldn't come upin a usual general neurology
visit for migraine, let's say.
So you could ask about, youknow, things such as do you have
any new rashes, do you have anynew joint pains, and they might
say no.
They might say like, yeah, Ihave this like weird lacy rash
(26:08):
that's been on my thighs thatjust won't go away and it's new.
And you know they're wearingpants and jeans and so you're
not going to be able to see thatright away.
But you know, a levado orlevidoid rash can sometimes be a
symptom of something like avasculitis can be seen in,
excuse me, intravascularlymphoma, all sorts, not exactly
(26:31):
neuroimmunology but you, but onthe rare zebra spectrum of
things.
So asking about those things,asking about history of uveitis,
because many rheumatologicdisorders can present with
either an anterior or aposterior or pan uveitis, even
MS, for intermediate uveitisthat can be seen in MS.
(26:55):
Sometimes Oral or genitalulcers can be seen in things
like Batchett's or lupus, atleast for the oral versions.
Constitutional symptoms, fevers, chills, night sweats that
drench the clothing or the bed,unexplained weight loss drenched
(27:17):
the clothing or the bed,unexplained weight loss.
I've had a patient with apresumed inflammatory myopathy
who had lost almost 100 poundsover the past several years and
cancer workup was completelynegative and it was presumed due
to an underlyingundifferentiated connective
(27:39):
tissue disorder and seems to bedoing better with some
immunotherapy and then otherthings that can cause the immune
system to act a little haywireHistory of HIV to act.
A little haywire History of HIV.
I've seen there's some thoughtthat the HIV can lead to
disimmune problems.
(28:00):
For example, we've seen apatient who had in their past
the age of 65, new onset oftumifactive demyelination,
relapsing, remitting.
A biopsy was even done to makesure it wasn't something strange
like PML or something otherwiseand just demyelinating, looked
(28:22):
just like what you'd see in MS.
But they had well-controlledHIV for decades and we presume
that this was a you know, adisimmune problem related to the
HIV, leading to demyelinatinglesions.
And then for autoimmuneencephalitis of many stripes, a
history of herpetic infections,neurologic or systemic.
(28:45):
So HSE encephalitis if you seea recurrent encephalitis, be
thinking NMDA, not a recurrenceof their HSV encephalitis,
assuming it was properly treated.
But even systemic infections oflike HHV-6, for example, have
been associated with rarely withautoimmune encephalitis For
(29:09):
things like GBS or otherneuropathies, dbs or other
neuropathies, history ofinfection in the last two to six
weeks.
That can be indicative or raisea suspicion.
And then, of course, likecurrent cancer or a tumor that
looks a lot like cancer, orhistory of smoking paired with
(29:32):
constitutional symptoms, theseall can be concerning, for maybe
there's a perineoplasticproblem going on.
Oh, and one other thingfrequent infections.
Yeah.
So common variableimmunodeficiency or other
immunodeficiencies can createthis seeming paradox of someone
who has an immune system thatdoesn't seem to work and they
(29:55):
get lots of infections but thenat the same time can bounce
right back to them and causeautoimmune problems.
Dr. Michael Kentris (30:02):
Fascinating .
Yeah, it is like again.
Like you were mentioning thatdisimmune sort of thing where
it's not necessarily just a.
We call things deficiencies butit's not quite accurate 100% of
the way.
Dr. Denis Balaban (30:25):
Yeah, like a Goode syndrome, for example, is
another good example of this,where there is both an
immunodeficiency as well as aproblem of autoimmunity in some
cases.
Dr. Michael Kentris (30:32):
Now something that kind of came to
mind while you were talkingabout like these historical
questions.
You know, like the classicsystemic rheumatologic disease
symptoms dry eyes, dry mouth, ohyeah.
All that, all the rashes, allthat kind of stuff, and that
always to me brings up a bit ofa conundrum.
Right, because we're talkingabout neuroimmunologic syndromes
(30:53):
, but it may not be in isolation.
So when you see perhaps a moresystemic autoimmune condition,
like, let's say, lupus orrheumatoid arthritis or any of
the other hundred other thingsthat are out there, raise your
(31:16):
antenna for a concurrentneurologic manifestation of that
same syndrome or a separateautoimmune condition that is
just comorbid with the otherprevious diagnosis.
Dr. Denis Balaban (31:24):
So just to make sure I understand, if you
have a patient who has a knownsystemic autoimmune disease and
then you have a new neurologicsymptom, is that related to the
systemic autoimmune disease oris it just a another one that
they have also affecting theirbrain?
Dr. Michael Kentris (31:43):
like uh, an example I think I saw a case
reporter series recently.
It was like uh, people who havelike a diagnosis of systemic
lupus and then they getdiagnosed with neuromyelitis,
optica spectrum disorder, withlike the positive aquaporin four
.
Yeah, that lupus still, or isit lupus and nmo?
Dr. Denis Balaban (32:02):
um, if they have a positive nmo antibody,
then that's nmo.
Um, it's just a uh.
And I and people, some peoplethink that all the the many
cases of like lupus myelitisdiagnosed in the past, maybe
those were just NMO before wehad the antibody.
So I think that's more of anexample of autoimmune diseases
(32:23):
grouping together rather than itall being under one autoimmune
disease.
And the other thing is that, uh,sometimes, uh, you know,
patient will come in for asymptom and it might be as
simple as like really, reallybad migraines and in the course
(32:43):
of just my like review ofsystems, all like, yep, I got
dry eyes and yep, I got ulcersin my mouth and and like, oh,
and then I ask more because myinterest is peaked now and
they'll have have like somethinglike Sjogren's or Bechets or
something like that, and they'relike oh my God, are my
headaches because of this?
I'm like, well, or like ameningitis, for example, you
(33:05):
have a systemic autoimmunedisease and that might be
playing a role in your terriblemigraines.
But at the end of the day,they're just terrible migraines
and we will treat them as such.
(33:26):
And maybe, if yourrheumatologist is treating your
systemic autoimmune disease,maybe that could help
potentially.
But yeah, so we see neurologicproblems in the patient with a
systemic autoimmune issue andthey have nothing.
They have uh, it's not aneuroimmunological issue per se.
I'll say that.
Dr. Michael Kentris (33:48):
I'm going to ask you a loaded question,
okay.
Uh now this is anecdotal, youknow, just to the places I've
practiced myself.
But it seems that a lot oftimes I'll have a
neuroimmunologist or not, a dime, a dozen across the country.
So a lot of times I'll betrying to work in conjunction
with a rheumatologist and itseems like, if it's not a
(34:13):
systemic rheumatologic disorder,that they don't necessarily
have a huge amount of interestin becoming involved in the
management of these patients.
And I was just curious is thatbecause it is neurology and no
one except neurologists likeneurology?
Dr. Denis Balaban (34:31):
Or is it something else that I'm missing?
I think that I can't speak towhat the rheumatologists that
you've encountered are thinking,but I have noticed this as well
, where if it's not a systemicrheumatologic disorder, then
it's like, well, I'm not surewhat to do with this.
Like, for example, trying totreat somebody with autoimmune
(34:54):
encephalitis and partnering witha rheumatologist.
I don't think that therheumatologist would feel
comfortable doing that, eventhough we use the steroids and
you know things that they wouldprobably be very the treatments
they would be very comfortablewith, but in terms of what it is
, I don't think that they have.
(35:15):
I don't think they received thetraining in that specific thing
and thus they would logicallynot feel comfortable with that.
I think that if it is aneuro-rheumatologic issue, where
they have a systemic rheumissue and they have a
neurological issue, so Sjogren'sganglionopathy, for example, or
lupus cerebritis or somethingof that nature, then I think
(35:38):
they would feel much morecomfortable treating that.
But if it doesn't fit sort ofthe main things that they are
used to seeing or have thetraining for, I think there
would be logically less of anappetite.
That would be my guess.
Dr. Michael Kentris (35:55):
That's fair .
I remember I had a case with agood friend of mine who's a
rheumatologist.
She had an extensive transversemyelitis.
It was probably like seven oreight segments long and
everything came back negative.
Even the LP just had elevatedprotein kind of mild lymphocytic
(36:17):
thiositosis, Nothing knockingyour socks off and the only
thing that came back positivewas a double-stranded DNA.
But she didn't have anysystemic symptoms.
Yep, Is this something?
And he was like I don't thinkit's something.
And I was like I'm going togive her steroids anyway,
steroids anyway.
Dr. Denis Balaban (36:35):
And he's like okay, and what did you say?
Dr. Michael Kentris (36:38):
the symptom was that she came in.
She had a really bad lowerextremity weakness and numbness.
Dr. Denis Balaban (36:43):
So it was oh, yeah, the myelin.
Yeah, in that case, yeah, Imean, yeah, that would be
concerning I, you know.
Similarly, I had a patient who,uh, when I was a resident they
had come with subacute cognitivedecline and at first we were
like, oh, it's a UTI, oh wait,we treated the UTI.
But now they have C diff.
Oh, shoot, okay, well, they'restill confused, but this makes
sense, it's all toxic, metabolic, right.
(37:04):
And then our attending rightlywas like, wait, they've been on
antibiotics for a week now andthey're still not better.
Okay, no.
And so then we did a lot morework up and all that came back
was a sky-high ana and asky-high dsdna and mri brain,
normal csf, normal eeg, you know, non-specific um and really lup
(37:31):
, no constitutional anything atall, nothing else that would
have met criteria for lupus.
And we consulted Rheum and theywere interested, but they were
like it's hard to call thislupus, but we're going to treat
them like lupus and got betterwith steroids and rituximab.
So, yeah, we see stuff likethat.
Dr. Michael Kentris (37:54):
Yeah, that's, that's see, that's why
no one likes neuroimmunology oh,that's why I love neuroimmuno.
Dr. Denis Balaban (37:59):
It's so cool, it's like what is this, what's
going on?
And they got better uh with,with treating, uh with their
immunosuppressive medications.
There's just, it's such, it's afield so ripe for discovery.
It's a field ripe withexcitement and wonder.
Yeah, everyone should be aneurobiologist.
Dr. Michael Kentris (38:22):
It's very funny you say that Because I
mean it is exciting, it's likehey, maybe we can do something
to fix this and that'd be greatfor everybody.
And I think a lot of it is alittle bit of a holdover from,
kind of the old guard ofneurology.
I remember one of my MSattendings in residency saying
that neurologists are weenies.
End quote what Talkingspecifically about giving these
(38:49):
more robust chemotherapeuticagents.
Well, robust remilitive rightLike rituximab or
cyclophosphamide or things likethat right.
It's like, you know, becauseshe she was retired military so
she would say sometimes you justhave to put on your big boy
pants and make a decision.
You know, I've tried to embodythat spirit, even sometimes when
(39:12):
I was like, oh, I think this isthe right thing to do and you
know there's not a lot of goodevidence sometimes in some of
these situations.
But it's like, mechanisticallyI gotta take a page critical
care colleagues.
It's like, well, physiologically, this should make sense.
Yes, uh, you know.
Dr. Denis Balaban (39:28):
Just cross your fingers and pray for the
best I mean there there's somuch yet to be discovered in
neuroimmunology.
I think we've come a long way.
But there's so many cases whereit's like we don't have an
antibody for this, we don't havea test for this.
The way this is acting, the waythis looks at MRI, the way that
(39:49):
your symptoms are worsening,like yeah, we should do steroids
because we've looked at youknow, it's not a metabolic thing
, we've checked the labsreasonable to check, we've.
You know, we don't think thisfits the profile of like
something else neurodegenerativeor vascular or something like
that.
And so then we just have toempirically treat.
(40:13):
You know, anyone who's treatedsomeone for seronegative
autoimmune encephalitis can knowthat internal tension of how
sure am I, this is an autoimmuneencephalitis?
How sure am I about my historyin getting this like three month
subacute decline?
What about that?
Like three month subacutedecline?
(40:37):
What about that?
You know, well, maybe thisstarted actually a few years ago
with this symptom, but or maybethat was just their depression,
or like, like, I've played thisgame with myself, like trying
to make sure that I feel ascomfortable as possible with the
history that I've gotten.
And sometimes you know, you dothe MRI, you do the lumbar
puncture.
You check your amyloid to makesure it wasn't like some sort of
(40:59):
neurodegenerative thing, atleast commonly and if you're not
coming up with things thatwould reasonably fit otherwise.
And if you look at the Grouse2016 criteria for a possible
seronegative, a possibleautoimmune encephalitis, and
it's lining up not so bad Atrial of six weeks of steroids.
(41:24):
You know if it gets better,well worth it.
And if it doesn't, well, yougot IVIG.
You can try too, and if itdoesn't work, then maybe it's
not immunoresponsive.
But sometimes the diagnosis isin the treatment, which we don't
like.
But sometimes that's what wehave and sometimes it works.
Dr. Michael Kentris (41:48):
Very true, I find you know.
In the epilepsy world as well,I find myself doing that.
It's like doing that.
It's like those recurrentspells.
Your eegs have been normal, butwe haven't caught a spell.
So here's some kepra.
Dr. Denis Balaban (42:01):
Let's see how things go over the next four
weeks yep, uh, yeah, definitelyyou've done that too and uh,
that has worked sometimes andit's great.
Dr. Michael Kentris (42:10):
You know, it's I I remember one of my my
fellowship instructors.
You know it's.
I remember one of my myfellowship instructors and he
would say, like it is just sohumbling because you are just
wrong, so like your initial gutcheck is wrong, so often you
just have to.
You know it doesn't fit that,but yeah, anchor on this too
hard just yet.
Dr. Denis Balaban (42:30):
Yeah, and so just to like for another story
of empiric treatment, wepublished a case of somebody who
had presented withhallucinations, altered mental
status and personality andhemichorea, and it was onset was
(42:53):
like a week or so and MRI wasnormal, labs were normal, csf
normal, everything normal.
So it wasn't like a stroke orhyperglycemia or any phospholip
syndrome or anything like that.
It was seronegative somethingand treated with IVIG Korea
(43:22):
melted away and it was one ofthose rare cases of a
seronegative autoimmune movementdisorder and it was relapsing.
So I think it was when we saidthree to five months of no
immunotherapy, then it wouldcome right back and so
(43:43):
mycophenolate then evened thingsout.
But yeah, that was a case whereno test was ever going to give
you the answer and sometimes youhave to treat.
Now, when it comes to treatingthings with like
cyclophosphamide, for example,or rituximab you want to, you
try to be much more certainbecause those carry higher risk
(44:04):
than once weekly pulse dosesteroids, because those carry
higher risk than once-weeklypulse dose steroids.
But I've run into some cases ofrecurrent stroke where we try to
treat with all the things usualto treat stroke at maximal
(44:25):
medical therapy and they keephaving TIAs, they keep having
infarcts and we've done all thework up there we can think of to
try and make ourselves moresure about a vasculitis first,
and sometimes there are no goodbiopsy sites.
Sometimes there are no greatplaces to even think about a
biopsy, or like there's nonothing on the MRI that is
(44:47):
biopsiable.
And we had a case where wetreated with cyclophosphamide
once monthly for six months andno more strokes, no more TIAs.
So yeah, and I was nervousabout treating with that, but
after, I mean, it was what weneeded to do and I, you know,
(45:09):
made sure everyone was on thesame page and it worked.
So again, few and far between,but there are.
There are those cases where youneed to do that, so having the
courage to treat, but then thereare also the cases where you
must have the courage not totreat as well then there are
(45:29):
also the cases where you musthave the courage not to treat as
well.
Dr. Michael Kentris (45:31):
So from a kind of practical, I know people
are going to wonder, I, becauseI'm wondering myself.
So if you are seeing someonewho you're thinking has like
maybe a subacute, you know,autoimmune encephalitis or
something like that, thatsubacute cognitive decline,
what's your, what's your steroiddosing regimen look like for
that period of time?
Dr. Denis Balaban (45:46):
Oh yeah, so let so if they meet criteria for
autoimmune encephalitis andyou've done your work up with,
like, making sure it's nothingmetabolic, making sure that
you've got an MRI, csf, um, andfor CSF I don't just treat, I
don't just um, you know, use thebasics plus the Mayo autoimmune
(46:06):
panel, but I also check foroligoclonal bands, igg index,
beta-2 microglobulin, which is alymphocyte turnover marker,
because those can be sort ofsecondary measures of
inflammation.
And I've definitely seen thosecases where CSF is completely
bland but, like the IgG indexcould be elevated and that's
(46:29):
helpful.
But for steroid treatment, thisis based off of Mayo's
structured steroids protocolwhere they use one gram of
solumedrol for three days in arow and then they do once weekly
for six to twelve weeks, twelvefor, like, the cases that have
(46:53):
seizures, six for those thatdon't and you reassess for
treatment response and ifthere's not been a response then
you can go to using IVIG.
And if there's no response withthat and these are in the
seronegative cases, specifically, if you have an antibody that
helps guide your treatment.
So yeah, especially if it's a,so like that's like for the all
(47:17):
comer, like you know, in generallike first line treatments for
autoimmune encephalitis In thecases of a like high risk
antibody for something like highrisk for cancer, antibodies.
So these would be like your um,anna, one anti-yo, um you know
(47:39):
where.
If you see the antibody, evenwithout any neurological symptom
, you're still looking for thecancer.
Or amphiphysin, yeah, um, ifthat's causing encephalitis,
then like steroids,cyclophosphamide.
Still looking for the cancer.
Or amphiphysin, yeah, um, ifthat's causing encephalitis,
then like steroids,cyclophosphamide.
Get rid of the cancer.
Because and the reason forjumping the cyclophosphamide in
those cases is because these aregenerally t-cell mediated
(47:59):
diseases and your steroids can,are going to help with that.
Your, your IVIG probably not asmuch, and then your rituximab
doesn't really touch your Tcells, so cyclophosphamide does
so, yeah, and in the ataxiacases too, like if you have an
(48:20):
autoimmune cerebellitis, thoseare often T cell mediated
disorders and that's whereyou're reaching earlier for the
cyclophosphamide as well, gotcha.
Dr. Michael Kentris (48:29):
That makes sense, yeah.
So one last clinical conundrumI would like.
When you get a referral from ageneral neurologist, let's say
who was like patient with, let'sjust say, x vague symptom, they
get a, you know, mayoperineoplastic panel and you get
this weak.
Dr. Denis Balaban (48:51):
I love it.
I love it.
Dr. Michael Kentris (48:52):
I'm gonna send you to neuro.
I'm gonna send you to an expertyeah let's send you to the
neuroimmunology guys down thehallway here and uh, what do you
guys do with that?
Uh, other than I assume lots ofcounseling uh, well, yes, a lot
of Um.
Dr. Denis Balaban (49:07):
So we do see cases of like I think the the
GAD 65 is the neurologist's ANA.
Um, yeah, so for low levels ofGAD 65 antibody, um, first I
like, do you have symptoms likethat would be relevant to a
(49:28):
GAD-65 antibody?
So those things would be likestiff person syndrome and
autoimmune encephalitis,seizures, things of that nature.
And if they do not, then Icounsel that this is not an
antibody that is relevantneurologically likely.
(49:49):
Some people think that it canbe a marker of like tendency to
inflammation.
So, because GAD-65autoantibodies are seen in type
1 diabetes and sometimes thatcan exist before the type 1
diabetes starts, and so if youhave the diabetic phenotype and
(50:12):
you got the GAD-65 antibodies,that's type 1 diabetes, whatever
the level.
But if it's for stiff persons,at least a neurological level,
like a neurological level um.
So depending on if you're using, uh, you know, a radioimmune
assay versus a enzymeimmunoassay, like your level,
cutoffs vary, um, but these,there are published cutoffs
(50:36):
there that should raise or loweryour suspicion.
Then you start to get moreconcerned about something like a
stick persons and then go fromthere um, but know, I've also
seen like very weak positivityto something like you know, a
voltage-gated calcium channelautoantibody for example, and
(50:56):
you know, completely normalautonomic function.
Their muscle strength is fine,there's no fatigability.
And then I say somethingsimilar, like you might have a
tendency to autoimmunity and ifthey have another autoimmune
disorder but they have zerosymptoms of you know, whatever
the antibody is generallyassociated with and it might be
just like your immune syndrome,like kicking off something else.
(51:19):
I mean, they're definitely like, for example, in lupus, like
you can have some positiverheumatoid factor, positive
Sjogren's.
It's not that they haveSjogren's necessarily, but they
might just be tagalongs.
We see tagalong antibodies notinfrequently like GFAP
antibodies, for example thesetting of NMO or NMDA.
(51:51):
They probably have NMDA and NMO, not a GFAP astrocytopathy.
Dr. Michael Kentris (52:00):
So I think just putting the antibody into
the clinical context is theimportant thing.
I think that is somewhere we'reprobably lagging behind the
rheumatology folks is, uh, likeputting our pre-test
probabilities into a betterperspective as far as like, what
does it mean if it comes back?
You know, weakly positive,strongly positive?
Does it match the clinicalphenotype right, because we've
definitely seen you?
Dr. Denis Balaban (52:19):
know I've had patients.
Dr. Michael Kentris (52:20):
You know they have like an rf factor.
You know like two, three, fourhundred, whatever yeah, they
have no joint pain, they have no, no stiffness, blah, blah, blah
.
So there's nothing clinicallythere, and so they're like well,
you don't have RA, yeah.
And I'm like oh okay, I thinkwe're probably heading in that
direction, as we start seeingthese panels getting ordered
(52:42):
more and more often for more andmore vague complaints.
Dr. Denis Balaban (52:47):
Yep, Absolutely absolutely.
Dr. Michael Kentris (52:52):
Any final thoughts or clinical pearls that
you think the trainee out thereshould be aware of, whether
neurology, internal medicine,what have you that should raise
the?
I know we've talked about a lotof things already, but the
biggest takeaway for you fromthis discussion should raise the
(53:12):
raise.
I know we've talked about a lotof things already.
Dr. Denis Balaban (53:15):
The biggest takeaway for you from this
discussion would be what learnone thing from our conversation?
Oh my gosh, you're limiting meto just one thing.
Okay, one to three.
Okay, I think, let me thinkabout that, I think, let me
think about that.
So I think one point is makingsure that if the syndrome and
(53:37):
the symptoms could fit with arheumatologic disease or a
neurone immunologic disorder,make sure that you're asking
specific questions for thosedisorders.
So, if you're worried aboutsomething like a vasculitis,
(53:57):
don't just ask about strokesymptoms.
Ask about systemic symptomslike coughing, coughing up blood
, sinus issues, peeing blood,rashes, things like that.
So that's, they're asking thosein your HPI and review of
systems.
(54:17):
Similarly, getting a really goodfamily history.
And not just do you have anyfamily history of autoimmune
disease?
No one knows what that means,or very few people do, like, do
you have a family history ofautoimmune disease?
No one knows what that means,or very few people do, um, like,
do you have a family history ofpsoriasis, celiac, lupus,
rheumatoid arthritis,inflammatory bowel disease?
Just list them, um, and youwill sometimes be surprised by
(54:39):
the answers.
You so I think that's.
I'm going to lump that as one,two, really dive in to the onset
(55:03):
and the pacing of the symptomsand make sure that you have that
as down pat as possible.
So that's number two, and do Ihave the third one as a catch
all for our discussions?
I will just say be curious.
And that applies to bothinteracting with your patients,
(55:26):
as well as reading more andfamiliarizing yourself with the
wondrous world ofneuroimmunology.
Dr. Michael Kentris (55:36):
That's a great point.
I can't.
I probably said it today, Ijust finished rounding a few
hours ago, and probably at leasta handful of times I had to say
what do you mean by that, inresponse to something the
patient had just told me.
Yes, you know it's like.
Could you tell me, tell me moreabout exactly it is?
That's that funny thing oflanguage where they know exactly
(56:00):
what they mean, but I I don't.
So I need you to break it downfor me tell me more about.
Dr. Denis Balaban (56:06):
That is my favorite open-ended question.
That that is.
That is one of the most usefulopen-ended questions in my
experience it's just like, yeah,I don't know there's, there's
already something satisfying.
Dr. Michael Kentris (56:18):
It's like you finally have heard something
in the history is liketriggered yes, for you to go
down.
It's like maybe I can figureout what's going on here it's
like a lifeline for me to tryand solve this puzzle.
Dr. Denis Balaban (56:29):
Yes, it's the clearing in the forest,
absolutely.
Dr. Michael Kentris (56:34):
Well, thank you so much for taking the time
and talking with us.
We'll definitely have to haveyou back on and talk about more
specific neuroimmunologicdisorders in the future.
Dr. Denis Balaban (56:43):
Oh, thank you .
Yes, I would love to do that.
Thank you so much for having me.
Dr. Michael Kentris (56:48):
And if people want to find you, find
your work, uh, where should they?
Or should they track you downonline?
Dr. Denis Balaban (56:56):
So I do have a uh Twitter slash X accounts,
um, just at Dennis Balaban MD.
I'll say that I do not post asfrequently as I once did, um,
but I have that account.
Um, let's see, I mean I have, Ihave my MGH websites that uh
(57:17):
people can look me up uh as well, but yeah, and then PubMed, I
suppose.
Dr. Michael Kentris (57:26):
A real researcher, not like me.
Dr. Denis Balaban (57:31):
I'm slowly getting more publications to my
name, but there are certainlyfar more published than I.
Dr. Michael Kentris (57:41):
So, thank you so much.
And, as always, you can alwaysfind me also on Twix.
I've heard people call it Twix.
I kind of like that.
It's a little bit better than X, I think.
Oh, twix you so much.
And, as always, you can alwaysfind me also on twix.
I've heard people call it twix.
I kind of like that.
Uh, it's a little bit betterthan x, I think oh, twix, I I do
like that, though.
Dr. Denis Balaban (57:53):
I think the candy bar company may have words
about that.
Dr. Michael Kentris (57:56):
That's true but I'm at dr kentris
d-r-k-e-n-t-r-i-s and you can,of course, find all of our past
stuff on the website at theneurotransransmitterscom.
Dennis, thank you again so much.
Really appreciate you takingthe time.
Dr. Denis Balaban (58:10):
Thank you so much for having me.
This was a treat.
Dr. Michael Kentris (58:14):
Likewise.
Hello and welcome back to the
Neurotransmitters.
I am your host, dr MichaelKentris, and today we are going
to be talking aboutneuroimmunology a scary topic
for many of us in neurology, butI am very happy to have an
expert with me today, dr DennisBalaban from the Division of
Neuroimmunology andNeuroinfectious Diseases from
(00:21):
Massachusetts General Hospitaland Harvard Medical School.
Is it all right if I call youDennis today?
Yes, absolutely.
Thank you so much for coming onthe show and talking with us
about such a fascinating andconfusing topic.
Dr. Denis Balaban (00:35):
Thank you for having me.
I always love talking aboutneuroimmunology, so I relish any
opportunity to do so.
Dr. Michael Kentris (00:43):
Now, as we were talking before we hit
record, let's start with the50,000 foot view.
What do we mean when we sayneuroimmunology?
Dr. Denis Balaban (00:52):
Yeah, absolutely so.
What we mean is any sort ofneurological disorder in which
it is caused by a dysfunction ofthe immune system leading to
the neurological disorder, adysfunction of the immune system
leading to the neurologicaldisorder.
So you have, you know, anantibody-mediated disease
(01:14):
attacking your peripheral nervesor brain.
You have, you know, t or Bcells causing that.
If you have a cytokine storm,as you can see in neurotoxicity
in the setting of CAR T cells,all of those are under the broad
umbrella of neuroimmunology.
Dr. Michael Kentris (01:28):
Yes, I know one of our favorite things to
do in neurology is just tackneuro onto the front of a
pre-existing discipline.
Dr. Denis Balaban (01:35):
Indeed exactly.
Dr. Michael Kentris (01:39):
So what does the pathway to becoming a
neuroimmunologist or aneuroimmunology specialist look
like for people who might bekind of looking to explore that,
whether they're in neurologyresidency or medical students or
in some other primary residencydiscipline?
Dr. Denis Balaban (02:09):
people can take.
The way I got intoneuroimmunology was I had no
idea I would be doing this inmedical school.
My big question was I want todo neurology right, and internal
medicine, you know, gave mesome questioning thoughts
because I love that detectivework, but nothing was ever going
to be as fascinating as thebrain.
So when I went into residency Ithought I was going to do like
cognitive behavioral and then Irealized that that was not my
(02:32):
cup of tea personally and Ireally found that I love being
on the inpatient generalneurology service where a lot of
our like folks with newdiagnoses of MS, autoimmune
encephalitis or we don't knowwhat this is yet, but we shall
try some steroids and look, theygot better.
So I really loved treatingthose patients because I felt
(02:59):
like I had to be at my best inorder to be able to diagnose
them.
So that means like I had toreally.
It encouraged me to read upeven more than I was.
It encouraged me to ask thatvery specific question that
maybe no one else asked toreally try to get to the
diagnosis, try differentexamination maneuvers that maybe
(03:22):
others have not done.
I really thought it was, youknow, neurology on steroids,
figuratively and literally.
And so once I knew that I wantedto be in neuroimmunology,
there's a plethora of differentfellowships that are available
for those interested, and sortof the usual question that
(03:45):
residents face is do I want tobe mostly MS, do I want to be
like MS plus a few otherneuroimmunological diseases that
I know about, or just likeneuroimmunology?
The broad gamut includeinfectious disease in there.
What sort of neuroimmunology doI want to practice?
Because historically it's beenMS and the other demyelinating
(04:09):
disorders, but now people have abit more options.
So that is how, and I decidedto go as broad as possible and I
went to the Advanced GeneralAutoimmune Neurology Fellowship
at MGH.
But there are people who getinto neuroimmunology first from
a research standpoint.
They'll have done a phd,they'll have, uh, you know, you
(04:29):
know, done their research andpublished quite a bit, and then
they realize, no, I actuallywant to be treating these
patients too.
And so then they can find theirway, uh, into a clinical
practice, uh, through thatavenue so many roads, I would
say no, that's, that's.
Dr. Michael Kentris (04:44):
That's great to know, because it is one
of those things where we see,you know, as the testing and the
identification of thesedifferent syndromes has evolved,
so too has the trainingpathways.
Indeed, indeed.
So what does the practice?
You know, I know there's amixture of inpatient and
outpatient.
(05:04):
So what is the general vibe inthe practice?
You know, I know there's amixture of inpatient and
outpatient.
Dr. Denis Balaban (05:09):
So what is the general vibe in the clinic?
Yeah, absolutely so.
In clinic I have a practicethat is, again broad.
I will see patients with allsorts of different things People
in my general neurologypractice whom I've diagnosed
with MS and then I bring to myneuroimmunopractice people with
autoimmune encephalitis,neurosarcoidosis, vasculitis,
(05:32):
stiff person syndrome, you nameit.
So it runs the gamut.
And I also have patients whoI'm following where I'm not
exactly sure what might be goingon quite yet.
But they are complicated.
And could there be somethingneuromunological going on?
Sure, have I been able to provethat yet?
(05:53):
Not really, but I'm keeping aneye on them and I'm going to be
keeping them in my practice inneuroimmuno as a just to get
more time, uh, with them in myfollow-ups.
Uh, because I have a longerfollow-up for, uh, minor
immunology patients depending ontheir diagnosis or complexity.
Um, on the inpatient side, Imean, you know so many different
(06:17):
things that can happenMeningitis, encephalitis, uh,
you know new strokes from avasculitis, you name it.
Myelitis, my gosh, I could any.
Any itis I could name.
So I think the trickiest partwhen it comes to figuring out is
really making the diagnosis andreally raising the suspicion of
(06:39):
should I be thinking about aneuroimmunological diagnosis in
my patients?
Because you know, most peopleare going to first see either
their primary care doctor ortheir general neurologist as
sort of that first step.
And I'll say that with betterknowledge of things like
autoimmune encephalitis beingmore in the zeitgeist, it's less
(07:03):
of a problem these days of thediagnostic delay and in fact
sometimes there is anover-diagnosis of such things as
a paper not too long ago waspublished describing
misdiagnoses.
But really the goal, I think,is for the general neurologist,
(07:25):
when hearing certain things onthe history or seeing certain
things on the examination, toraise a flag to say, hey, maybe
I should be thinking about aneuroimmunological diagnosis.
And the thing withneuroimmunology is it can touch
any part of the nervous systemand it can present either
acutely, subacutely, chronically, it all depends.
(07:55):
So then people wonder well, howdo I put my arms around this?
How do I know that this couldbe neuroimmunological?
Talk today, I think, of whatare ways in which that in my
general neurology practice I canstart to have that intuition
and suspicion for somethingneuroimmunological afoot.
So much like in making anydiagnosis in neurology.
(08:20):
Onset and pace are of incredibleimportance.
Onset and pace are ofincredible importance and really
diving down to understand howthe symptoms unfolded.
And this might seem obvious toany neurologist listening, but
it can be more fine-tuned thanone might think.
(08:45):
So, for example, I had seen apatient who presented with a
two-year history of cognitivedecline and they were, you know,
in, they were older than theage of 50.
And the family seemed fairlyused to things by then.
(09:06):
And you know, it was, I think,anybody in a very busy setting
with distractions coming in,phone calls, et cetera.
Oh, two year history, cognitivedecline, probably
neurodegenerative, we're done.
Probably neurodegenerative,we're done.
(09:29):
What was helpful is that someonehad gotten a brain MRI that had
shown that there were these T2hyperintensities in their
temporal lobes.
And, oh my gosh, this isactually a limbic encephalitis.
And if you just went by thisone-liner of two-year history
history, you might miss the factthat actually what happened was
two years ago.
Within about three months,there was this rapid decline and
(09:52):
then they plateaued for therest of the time.
And then you, we find out, okay, they have hyponatremia.
Okay, they have these briefdizziness spells and lo and and
behold, it's LGI1.
So I think, really trying towhen you ask well, how long has
this been going on X years.
Okay, and how did that reallyevolve?
(10:15):
I think that is a key point insome of these and if there were
changes, that happened, when didthose changes occur?
Really trying to hone in onexactly when those changes
occurred, because that gives youa much more accurate picture.
Because there are someneuroimmunological diseases that
are characterized not by agradual decline but by
(10:39):
punctuated declines, sosomething like a mononuritis
multiplex or multiplemononuropathies, for example,
where it's like, yeah, I hadthis carpal tunnel and you know
it was painful but I'm a littleweak, but you know it's okay and
oh well, and now I have a footdrop and oh, now I have this.
And so really understanding,like, is this happening in quick
(11:02):
succession?
Or if the are these like yearsapart, then okay, maybe not and
you should look for somethingelse.
But these are that's why Imentioned, like pace onset as
like one of the number onethings to focus on first,
because that will get you thediagnosis.
Dr. Michael Kentris (11:19):
That's the first step in making a
neurological diagnosis, alongwith localization, of course,
course that's a great point isthat a lot of times we in the
specialty clinics or, you know,even just general neurology,
being in some places right three, six months to get in, um, you
wind up where you are seeingthem at the tail after the
(11:40):
action has happened, so to speak, and it is like you're you're
asking these people to to goback to these probably much.
It is like you're you're askingthese people to go back to
these probably much morestressful times in their memory
and you know, as you said, likesomeone's made peace with it, as
it were, they don't want to goback and think about when things
weren't as bad necessarily.
It's hard to handle thosememories sometimes.
Dr. Denis Balaban (12:01):
Yeah.
So, um, yeah, being able torecognize these things and, uh,
you know, offer a diagnosis andtreatment like that can be
powerful, because those, uh,those patients with encephalitis
, depending on the type, um,they, they can be reversible and
treatable and they can get backa lot of their quality of life,
um, depending, of course.
Dr. Michael Kentris (12:25):
And I think you also bring up a really good
point.
One thing I think there's beena big trend towards over
probably a few decades now isthis in medical training,
especially at the medicalstudent level, we see a lot of
emphasis on open ended questions, and I find that the more and
more that I learn uh, you reallyneed to know how to ask a
(12:47):
closed-ended question, and whatthose closed-ended questions
need to be is just as importantabsolutely, I, I love that you
brought that up and uh, becauseI think on a first meeting,
open-ended questions are great,because that's sort of like, if
you're if information were fish,you know that's the widest net
you can catch and like that'swhat you're going to bring in,
(13:09):
but then, um, you know, ifyou're really looking for that
specific thing, uh, the netapproach might miss it.
Dr. Denis Balaban (13:17):
You might need to spear fish for those
questions, and I fully agree.
Um, so, for some of those andthose knowing when and what
those key questions ask reallydepends on how the patient is
presenting.
So, for example, if someone istelling me like, oh my gosh,
(13:38):
like I have all this terriblestiffness and I have these
episodes of spasms that are justkilling me stiffness, and I
have these episodes of spasmsthat are just killing me, you
know, one question that I ask inthose contexts is well, tell me
, are you more easily surprisedthan you used to be when this
started?
And people will often like whydo you ask that?
(13:58):
Like they'll have thisquizzical look on their face.
Really, you know, yeah, I do, Iam a bit more easily startled.
Their face, really.
You know, yeah, I do, I, I am abit more easily startled.
Why did you and and then okay,and um and that can be a very
helpful uh question to ask.
In something like a stiff personspectrum disorder, uh, where
their startle is increased, thespasms can be triggered by
startle as well.
I had a patient where, um, theyactually had a stiff limb
(14:23):
syndrome and if I brought myhand to the affected limb, not
even touching them, it wouldtrigger the startle.
So not even a tactile stimulus,just like the possibility of a
tactile stimulus, and they werefully aware they were watching
me do it as I was moving towardsit.
(14:43):
Not even that much of a startle.
So asking a pointed questionlike that can be helpful In
somebody who has a subacutecognitive decline, for example.
In those cases I think it's avery easy question to ask about
fascia brachial tonic seizures.
Easy question to ask aboutfacial brachial tonic seizures.
(15:03):
And so the way I ask that islike have you ever had episodes
where your arm or the and thecorner of your mouth sort of
come together almost and I actedout for them, because you know,
if the picture is worth athousand words, then actually
acting it out is worth even more.
And I often ask patiently ifthere's a funny movement that
(15:24):
occurs, like can you act thatout?
Tell me like what that?
Show me what that looks like,and then they can perfectly act
out what I might've beenpicturing in my head and like,
okay, yeah, that's it.
Okay, asking, and that's agreat question for LGI1
specifically.
Another thing for LGI1 areasking about brief dizziness
(15:46):
spells which can occur, whichare thought to be seizures, but
we're still not exactly sure.
But essentially it's these likefive to 10 second episodes of
people have described them aslike a chill or a vertigo or a
dizziness.
And you know they can happenwith low frequency to begin with
, but then as time moves forward, they can start to happen
(16:07):
weekly, then daily, thenmultiple times a day, and that
is also a nice clue for thepossibility of an LGI-1.
You know, if you're wonderingabout MS, you know something you
could ask about is are yoursymptoms worse in a hot shower
or if you've been exercising alot?
And that's asking about, youknow, the UTOF phenomenon.
(16:29):
So these are like, so, knowingthe specific questions, that if
you have certain, if you have alist of diagnoses already in
mind that might fit the clinicalsyndrome, ask about those
specific things.
That can be quite helpful.
Dr. Michael Kentris (16:46):
Right, and that's as you said.
The challenging part withneuroimmunology is that it
radically could affect any partof the neural system, from the
brain to the muscles, and so youkind of have to have your
algorithm for each potentialcomplaint locked and loaded
before you can go and get it.
Dr. Denis Balaban (17:04):
Yeah, exactly Like you having an idea of the
syndrome that you're dealingwith and then trying to ask
those questions.
That's and like having that,having that knowledge already in
store, because there there aresome things that are very easily
up-to-date-able or Google-able,but knowing a disease and
(17:30):
exactly how it presents in thestory of that disease, that's
not something that a quicksearch generally accomplishes
and I'll speak.
Dr. Michael Kentris (17:42):
you know not to throw any shade at the
writers for up-to-date, but I dofind the neurology up-to-date
articles for a lot of topics arenot up-to-date.
To speak to that right, likeneuroimmunology is one of the
biggest culprits.
Oh yeah, the rate of newknowledge is just such a
breakneck pace.
(18:02):
Oh my gosh yeah, it's almostimpossible to keep a compendium
like that current.
Dr. Denis Balaban (18:10):
Exactly, yeah , it's one of the fastest moving
fields and makes it reallyexciting, but also takes work to
stay up to date.
Dr. Michael Kentris (18:22):
Now in the outpatient setting, is there
anything that you know, anychief complaint that perhaps
represents the lion's share ofreferrals, or is it a pretty
varied spectrum?
Dr. Denis Balaban (18:34):
as far as what you've anecdotally observed
, oh my gosh, it's such a variedspectrum Because people get
referred to neuroimmunology fora wide variety of reasons.
Some are due to like an initialworkup that revealed something
(18:55):
inflammatory appearing.
So one example is a meningitisseen on MRI, where you have
either a leptomeningeal orpacumenengeal enhancement and so
then say, oh my God, they havea pacumenengeitis, send them to
neuroimmuno and many times thoseare actually just chronic CSF
leaks.
But you know, depending on thestory or lack thereof, for a
(19:20):
chronic CSF leak we'll do theinvestigations and find that
everything is bland.
There's no history that'ssuggestive uh, by like prior
autoimmune history or familyhistory or anything of that
nature.
And then, oh, they have ahistory of men, years, okay, and
uh, csf leaks in men years cango hand in hand.
(19:41):
Um, so then it says, okay, soCSF leak and we can try and
treat that.
Um, then there's other peoplewho come in because of funny
spots in their brain, uh, on mri, which may or may not be, uh,
related to their symptoms, uh,whole, whole variety of things.
Or, and the numbness andtingling in the setting of a
(20:04):
recent cancer diagnosis, forexample, could this be
pyreneoplastic or could this besome sort of inflammatory,
something related to a myelomaand the high M spike, for
example.
Dr. Michael Kentris (20:20):
So all sorts of reasons people can be
referred no-transcript, you know, frustrating, let's say to the
general neurologist to approachand that is the, the so-called
unidentified or, you know,poorly defined, the UBO, the
(20:41):
object on MRI, someone's rightT2 flare lesion that maybe it's
demyelinating there's one spotit's not enhancing, there's no
clinical.
They got that for like aheadache workup or something
like that.
And they're like how far downthe rabbit trail do I need to
run for investigating forsomething like multiple
sclerosis or things like that?
(21:02):
Yep, so in your practice, let'sstart with someone with that
vagueness of a complaint.
Sure, how did you deal withthat kind of setting?
Dr. Denis Balaban (21:12):
Great question, so okay, so just to
make sure I got it so somebodywith these T2 hyperintensities
on brain MRI discovered due tosome maybe potentially or
initially sounding vaguesymptoms.
So then what I do in evaluatingthis patient is I, first off,
(21:34):
who is the patient?
Are they an 80-year-old malewith history of high blood
pressure, diabetes andhyperlipidemia?
Are they a young woman with nosignificant past medical history
?
And maybe they don't even getheadaches at all, even get
(21:59):
headaches at all?
So I sort of just go down like,okay, well, what could these be
in neuroimmunology?
Could these be indicative of MS?
So then I ask like, okay, haveyou had episodes that could be
significant for MS, like a patchof numbness or tingling that
lasted several days to a week?
Have you had optic neuritis?
Or you know?
I ask about the optic neuritissymptoms of, like painful eye
movements with vision loss.
(22:19):
I ask about new onsetconstipation or urinary
frequency and urgency.
And one thing I want to say isthat I feel like in seeing
people ask about urinarysymptoms are you peeing a lot?
No, I'm not peeing a lot andthen you get to it it's like, oh
, you're peeing every two hours.
(22:40):
Yeah, it's better than peeingevery hour.
Um, so, like the, the way I askabout it is okay.
Um, when you feel like you needto pee, are you able to hold
your urine, uh, urine, for like30 minutes to an hour, or are
you racing to the bathroom or doyou?
Are you very like, cognizant of, like, your urinary habits?
(23:03):
And that has gotten me a lotfarther than a more broad
question, because then I'll havepeople say, oh my gosh, yeah,
if I don't, if I don't get to abathroom within five minutes, I
worry I could pee my pants.
Or, yeah, I really have to peeevery three hours, otherwise bad
(23:24):
things will happen.
So that has gotten me a lot.
And then, for bowel movements,for example, I had a patient who
had new onset constipation forno apparent reason.
Um, they were a uh, healthyperson and they were even
hospitalized, uh, for this newconstipation that came out of
(23:45):
nowhere, and I know.
And it turned out that, um,after everything was said and
done, that it was due to ademanding lesion in the spinal
cord that had yet to bediscovered.
Um, so, no, not at all.
But, um, so, but that's justpart of the assessment.
So then, uh, after like, newnumbness, tingling, weakness, uh
(24:07):
, like, uh, stiffness in thelegs.
Um, the exercise have, as yourworkout routines, gotten harder
for any reason, are Are youlifting less weights?
Are you not able to squat asmuch?
If they're active, that's sohelpful, because that sort of
high level of activity will be amuch more sensitive marker than
(24:29):
for someone who is sedentaryand like, yeah, I walk up a
flight of stairs every now andthen.
You might not notice thedecrements happening until they
are quite severe.
Um, so then I also take intoaccount, like key past medical
history questions.
Um, that again, epic is uh, orthe medical record can be a
minefield of chartomas or, uh, adearth of information.
(24:50):
That's a new one for me.
I'm going to keep that one.
Oh yeah, I can't claimownership of that.
Dr. Michael Kentris (24:54):
That's a new one for me.
I'm going to keep that one ohyeah, I can't claim ownership of
that.
Dr. Denis Balaban (24:58):
I had heard that somewhere years ago.
But you can ask about historyof MS, for example infectious
mono, big one.
I have significantly raised myown suspicion for MS in someone
who is otherwise asymptomatic atthe moment due to their history
(25:21):
of infectious mono and anasymmetric reflex or two.
And lo and behold, it was MS,because it's one of its.
The highest risk factor,acquired risk factor, I'll say
for MS.
The highest risk factor,acquired risk factor, I'll say
for MS.
But if you're not thinkingabout MS in particular and
you're wondering about, you know, neuroimmunology, rheumatology
(25:44):
not otherwise specified, thenyou can ask a whole host of
questions that wouldn't come upin a usual general neurology
visit for migraine, let's say.
So you could ask about, youknow, things such as do you have
any new rashes, do you have anynew joint pains, and they might
say no.
They might say like, yeah, Ihave this like weird lacy rash
(26:08):
that's been on my thighs thatjust won't go away and it's new.
And you know they're wearingpants and jeans and so you're
not going to be able to see thatright away.
But you know, a levado orlevidoid rash can sometimes be a
symptom of something like avasculitis can be seen in,
excuse me, intravascularlymphoma, all sorts, not exactly
(26:31):
neuroimmunology but you, but onthe rare zebra spectrum of
things.
So asking about those things,asking about history of uveitis,
because many rheumatologicdisorders can present with
either an anterior or aposterior or pan uveitis, even
MS, for intermediate uveitisthat can be seen in MS.
(26:55):
Sometimes Oral or genitalulcers can be seen in things
like Batchett's or lupus, atleast for the oral versions.
Constitutional symptoms, fevers, chills, night sweats that
drench the clothing or the bed,unexplained weight loss drenched
(27:17):
the clothing or the bed,unexplained weight loss.
I've had a patient with apresumed inflammatory myopathy
who had lost almost 100 poundsover the past several years and
cancer workup was completelynegative and it was presumed due
to an underlyingundifferentiated connective
(27:39):
tissue disorder and seems to bedoing better with some
immunotherapy and then otherthings that can cause the immune
system to act a little haywireHistory of HIV to act.
A little haywire History of HIV.
I've seen there's some thoughtthat the HIV can lead to
disimmune problems.
(28:00):
For example, we've seen apatient who had in their past
the age of 65, new onset oftumifactive demyelination,
relapsing, remitting.
A biopsy was even done to makesure it wasn't something strange
like PML or something otherwiseand just demyelinating, looked
(28:22):
just like what you'd see in MS.
But they had well-controlledHIV for decades and we presume
that this was a you know, adisimmune problem related to the
HIV, leading to demyelinatinglesions.
And then for autoimmuneencephalitis of many stripes, a
history of herpetic infections,neurologic or systemic.
(28:45):
So HSE encephalitis if you seea recurrent encephalitis, be
thinking NMDA, not a recurrenceof their HSV encephalitis,
assuming it was properly treated.
But even systemic infections oflike HHV-6, for example, have
been associated with rarely withautoimmune encephalitis For
(29:09):
things like GBS or otherneuropathies, dbs or other
neuropathies, history ofinfection in the last two to six
weeks.
That can be indicative or raisea suspicion.
And then, of course, likecurrent cancer or a tumor that
looks a lot like cancer, orhistory of smoking paired with
(29:32):
constitutional symptoms, theseall can be concerning, for maybe
there's a perineoplasticproblem going on.
Oh, and one other thingfrequent infections.
Yeah.
So common variableimmunodeficiency or other
immunodeficiencies can createthis seeming paradox of someone
who has an immune system thatdoesn't seem to work and they
(29:55):
get lots of infections but thenat the same time can bounce
right back to them and causeautoimmune problems.
Dr. Michael Kentris (30:02):
Fascinating .
Yeah, it is like again.
Like you were mentioning thatdisimmune sort of thing where
it's not necessarily just a.
We call things deficiencies butit's not quite accurate 100% of
the way.
Dr. Denis Balaban (30:25):
Yeah, like a Goode syndrome, for example, is
another good example of this,where there is both an
immunodeficiency as well as aproblem of autoimmunity in some
cases.
Dr. Michael Kentris (30:32):
Now something that kind of came to
mind while you were talkingabout like these historical
questions.
You know, like the classicsystemic rheumatologic disease
symptoms dry eyes, dry mouth, ohyeah.
All that, all the rashes, allthat kind of stuff, and that
always to me brings up a bit ofa conundrum.
Right, because we're talkingabout neuroimmunologic syndromes
(30:53):
, but it may not be in isolation.
So when you see perhaps a moresystemic autoimmune condition,
like, let's say, lupus orrheumatoid arthritis or any of
the other hundred other thingsthat are out there, raise your
(31:16):
antenna for a concurrentneurologic manifestation of that
same syndrome or a separateautoimmune condition that is
just comorbid with the otherprevious diagnosis.
Dr. Denis Balaban (31:24):
So just to make sure I understand, if you
have a patient who has a knownsystemic autoimmune disease and
then you have a new neurologicsymptom, is that related to the
systemic autoimmune disease oris it just a another one that
they have also affecting theirbrain?
Dr. Michael Kentris (31:43):
like uh, an example I think I saw a case
reporter series recently.
It was like uh, people who havelike a diagnosis of systemic
lupus and then they getdiagnosed with neuromyelitis,
optica spectrum disorder, withlike the positive aquaporin four
.
Yeah, that lupus still, or isit lupus and nmo?
Dr. Denis Balaban (32:02):
um, if they have a positive nmo antibody,
then that's nmo.
Um, it's just a uh.
And I and people, some peoplethink that all the the many
cases of like lupus myelitisdiagnosed in the past, maybe
those were just NMO before wehad the antibody.
So I think that's more of anexample of autoimmune diseases
(32:23):
grouping together rather than itall being under one autoimmune
disease.
And the other thing is that, uh,sometimes, uh, you know,
patient will come in for asymptom and it might be as
simple as like really, reallybad migraines and in the course
(32:43):
of just my like review ofsystems, all like, yep, I got
dry eyes and yep, I got ulcersin my mouth and and like, oh,
and then I ask more because myinterest is peaked now and
they'll have have like somethinglike Sjogren's or Bechets or
something like that, and they'relike oh my God, are my
headaches because of this?
I'm like, well, or like ameningitis, for example, you
(33:05):
have a systemic autoimmunedisease and that might be
playing a role in your terriblemigraines.
But at the end of the day,they're just terrible migraines
and we will treat them as such.
(33:26):
And maybe, if yourrheumatologist is treating your
systemic autoimmune disease,maybe that could help
potentially.
But yeah, so we see neurologicproblems in the patient with a
systemic autoimmune issue andthey have nothing.
They have uh, it's not aneuroimmunological issue per se.
I'll say that.
Dr. Michael Kentris (33:48):
I'm going to ask you a loaded question,
okay.
Uh now this is anecdotal, youknow, just to the places I've
practiced myself.
But it seems that a lot oftimes I'll have a
neuroimmunologist or not, a dime, a dozen across the country.
So a lot of times I'll betrying to work in conjunction
with a rheumatologist and itseems like, if it's not a
(34:13):
systemic rheumatologic disorder,that they don't necessarily
have a huge amount of interestin becoming involved in the
management of these patients.
And I was just curious is thatbecause it is neurology and no
one except neurologists likeneurology?
Dr. Denis Balaban (34:31):
Or is it something else that I'm missing?
I think that I can't speak towhat the rheumatologists that
you've encountered are thinking,but I have noticed this as well
, where if it's not a systemicrheumatologic disorder, then
it's like, well, I'm not surewhat to do with this.
Like, for example, trying totreat somebody with autoimmune
(34:54):
encephalitis and partnering witha rheumatologist.
I don't think that therheumatologist would feel
comfortable doing that, eventhough we use the steroids and
you know things that they wouldprobably be very the treatments
they would be very comfortablewith, but in terms of what it is
, I don't think that they have.
(35:15):
I don't think they received thetraining in that specific thing
and thus they would logicallynot feel comfortable with that.
I think that if it is aneuro-rheumatologic issue, where
they have a systemic rheumissue and they have a
neurological issue, so Sjogren'sganglionopathy, for example, or
lupus cerebritis or somethingof that nature, then I think
(35:38):
they would feel much morecomfortable treating that.
But if it doesn't fit sort ofthe main things that they are
used to seeing or have thetraining for, I think there
would be logically less of anappetite.
That would be my guess.
Dr. Michael Kentris (35:55):
That's fair .
I remember I had a case with agood friend of mine who's a
rheumatologist.
She had an extensive transversemyelitis.
It was probably like seven oreight segments long and
everything came back negative.
Even the LP just had elevatedprotein kind of mild lymphocytic
(36:17):
thiositosis, Nothing knockingyour socks off and the only
thing that came back positivewas a double-stranded DNA.
But she didn't have anysystemic symptoms.
Yep, Is this something?
And he was like I don't thinkit's something.
And I was like I'm going togive her steroids anyway,
steroids anyway.
Dr. Denis Balaban (36:35):
And he's like okay, and what did you say?
Dr. Michael Kentris (36:38):
the symptom was that she came in.
She had a really bad lowerextremity weakness and numbness.
Dr. Denis Balaban (36:43):
So it was oh, yeah, the myelin.
Yeah, in that case, yeah, Imean, yeah, that would be
concerning I, you know.
Similarly, I had a patient who,uh, when I was a resident they
had come with subacute cognitivedecline and at first we were
like, oh, it's a UTI, oh wait,we treated the UTI.
But now they have C diff.
Oh, shoot, okay, well, they'restill confused, but this makes
sense, it's all toxic, metabolic, right.
(37:04):
And then our attending rightlywas like, wait, they've been on
antibiotics for a week now andthey're still not better.
Okay, no.
And so then we did a lot morework up and all that came back
was a sky-high ana and asky-high dsdna and mri brain,
normal csf, normal eeg, you know, non-specific um and really lup
(37:31):
, no constitutional anything atall, nothing else that would
have met criteria for lupus.
And we consulted Rheum and theywere interested, but they were
like it's hard to call thislupus, but we're going to treat
them like lupus and got betterwith steroids and rituximab.
So, yeah, we see stuff likethat.
Dr. Michael Kentris (37:54):
Yeah, that's, that's see, that's why
no one likes neuroimmunology oh,that's why I love neuroimmuno.
Dr. Denis Balaban (37:59):
It's so cool, it's like what is this, what's
going on?
And they got better uh with,with treating, uh with their
immunosuppressive medications.
There's just, it's such, it's afield so ripe for discovery.
It's a field ripe withexcitement and wonder.
Yeah, everyone should be aneurobiologist.
Dr. Michael Kentris (38:22):
It's very funny you say that Because I
mean it is exciting, it's likehey, maybe we can do something
to fix this and that'd be greatfor everybody.
And I think a lot of it is alittle bit of a holdover from,
kind of the old guard ofneurology.
I remember one of my MSattendings in residency saying
that neurologists are weenies.
End quote what Talkingspecifically about giving these
(38:49):
more robust chemotherapeuticagents.
Well, robust remilitive rightLike rituximab or
cyclophosphamide or things likethat right.
It's like, you know, becauseshe she was retired military so
she would say sometimes you justhave to put on your big boy
pants and make a decision.
You know, I've tried to embodythat spirit, even sometimes when
(39:12):
I was like, oh, I think this isthe right thing to do and you
know there's not a lot of goodevidence sometimes in some of
these situations.
But it's like, mechanisticallyI gotta take a page critical
care colleagues.
It's like, well, physiologically, this should make sense.
Yes, uh, you know.
Dr. Denis Balaban (39:28):
Just cross your fingers and pray for the
best I mean there there's somuch yet to be discovered in
neuroimmunology.
I think we've come a long way.
But there's so many cases whereit's like we don't have an
antibody for this, we don't havea test for this.
The way this is acting, the waythis looks at MRI, the way that
(39:49):
your symptoms are worsening,like yeah, we should do steroids
because we've looked at youknow, it's not a metabolic thing
, we've checked the labsreasonable to check, we've.
You know, we don't think thisfits the profile of like
something else neurodegenerativeor vascular or something like
that.
And so then we just have toempirically treat.
(40:13):
You know, anyone who's treatedsomeone for seronegative
autoimmune encephalitis can knowthat internal tension of how
sure am I, this is an autoimmuneencephalitis?
How sure am I about my historyin getting this like three month
subacute decline?
What about that?
Like three month subacutedecline?
(40:37):
What about that?
You know, well, maybe thisstarted actually a few years ago
with this symptom, but or maybethat was just their depression,
or like, like, I've played thisgame with myself, like trying
to make sure that I feel ascomfortable as possible with the
history that I've gotten.
And sometimes you know, you dothe MRI, you do the lumbar
puncture.
You check your amyloid to makesure it wasn't like some sort of
(40:59):
neurodegenerative thing, atleast commonly and if you're not
coming up with things thatwould reasonably fit otherwise.
And if you look at the Grouse2016 criteria for a possible
seronegative, a possibleautoimmune encephalitis, and
it's lining up not so bad Atrial of six weeks of steroids.
(41:24):
You know if it gets better,well worth it.
And if it doesn't, well, yougot IVIG.
You can try too, and if itdoesn't work, then maybe it's
not immunoresponsive.
But sometimes the diagnosis isin the treatment, which we don't
like.
But sometimes that's what wehave and sometimes it works.
Dr. Michael Kentris (41:48):
Very true, I find you know.
In the epilepsy world as well,I find myself doing that.
It's like doing that.
It's like those recurrentspells.
Your eegs have been normal, butwe haven't caught a spell.
So here's some kepra.
Dr. Denis Balaban (42:01):
Let's see how things go over the next four
weeks yep, uh, yeah, definitelyyou've done that too and uh,
that has worked sometimes andit's great.
Dr. Michael Kentris (42:10):
You know, it's I I remember one of my my
fellowship instructors.
You know it's.
I remember one of my myfellowship instructors and he
would say, like it is just sohumbling because you are just
wrong, so like your initial gutcheck is wrong, so often you
just have to.
You know it doesn't fit that,but yeah, anchor on this too
hard just yet.
Dr. Denis Balaban (42:30):
Yeah, and so just to like for another story
of empiric treatment, wepublished a case of somebody who
had presented withhallucinations, altered mental
status and personality andhemichorea, and it was onset was
(42:53):
like a week or so and MRI wasnormal, labs were normal, csf
normal, everything normal.
So it wasn't like a stroke orhyperglycemia or any phospholip
syndrome or anything like that.
It was seronegative somethingand treated with IVIG Korea
(43:22):
melted away and it was one ofthose rare cases of a
seronegative autoimmune movementdisorder and it was relapsing.
So I think it was when we saidthree to five months of no
immunotherapy, then it wouldcome right back and so
(43:43):
mycophenolate then evened thingsout.
But yeah, that was a case whereno test was ever going to give
you the answer and sometimes youhave to treat.
Now, when it comes to treatingthings with like
cyclophosphamide, for example,or rituximab you want to, you
try to be much more certainbecause those carry higher risk
(44:04):
than once weekly pulse dosesteroids, because those carry
higher risk than once-weeklypulse dose steroids.
But I've run into some cases ofrecurrent stroke where we try to
treat with all the things usualto treat stroke at maximal
(44:25):
medical therapy and they keephaving TIAs, they keep having
infarcts and we've done all thework up there we can think of to
try and make ourselves moresure about a vasculitis first,
and sometimes there are no goodbiopsy sites.
Sometimes there are no greatplaces to even think about a
biopsy, or like there's nonothing on the MRI that is
(44:47):
biopsiable.
And we had a case where wetreated with cyclophosphamide
once monthly for six months andno more strokes, no more TIAs.
So yeah, and I was nervousabout treating with that, but
after, I mean, it was what weneeded to do and I, you know,
(45:09):
made sure everyone was on thesame page and it worked.
So again, few and far between,but there are.
There are those cases where youneed to do that, so having the
courage to treat, but then thereare also the cases where you
must have the courage not totreat as well then there are
(45:29):
also the cases where you musthave the courage not to treat as
well.
Dr. Michael Kentris (45:31):
So from a kind of practical, I know people
are going to wonder, I, becauseI'm wondering myself.
So if you are seeing someonewho you're thinking has like
maybe a subacute, you know,autoimmune encephalitis or
something like that, thatsubacute cognitive decline,
what's your, what's your steroiddosing regimen look like for
that period of time?
Dr. Denis Balaban (45:46):
Oh yeah, so let so if they meet criteria for
autoimmune encephalitis andyou've done your work up with,
like, making sure it's nothingmetabolic, making sure that
you've got an MRI, csf, um, andfor CSF I don't just treat, I
don't just um, you know, use thebasics plus the Mayo autoimmune
(46:06):
panel, but I also check foroligoclonal bands, igg index,
beta-2 microglobulin, which is alymphocyte turnover marker,
because those can be sort ofsecondary measures of
inflammation.
And I've definitely seen thosecases where CSF is completely
bland but, like the IgG indexcould be elevated and that's
(46:29):
helpful.
But for steroid treatment, thisis based off of Mayo's
structured steroids protocolwhere they use one gram of
solumedrol for three days in arow and then they do once weekly
for six to twelve weeks, twelvefor, like, the cases that have
(46:53):
seizures, six for those thatdon't and you reassess for
treatment response and ifthere's not been a response then
you can go to using IVIG.
And if there's no response withthat and these are in the
seronegative cases, specifically, if you have an antibody that
helps guide your treatment.
So yeah, especially if it's a,so like that's like for the all
(47:17):
comer, like you know, in generallike first line treatments for
autoimmune encephalitis In thecases of a like high risk
antibody for something like highrisk for cancer, antibodies.
So these would be like your um,anna, one anti-yo, um you know
(47:39):
where.
If you see the antibody, evenwithout any neurological symptom
, you're still looking for thecancer.
Or amphiphysin, yeah, um, ifthat's causing encephalitis,
then like steroids,cyclophosphamide.
Still looking for the cancer.
Or amphiphysin, yeah, um, ifthat's causing encephalitis,
then like steroids,cyclophosphamide.
Get rid of the cancer.
Because and the reason forjumping the cyclophosphamide in
those cases is because these aregenerally t-cell mediated
(47:59):
diseases and your steroids can,are going to help with that.
Your, your IVIG probably not asmuch, and then your rituximab
doesn't really touch your Tcells, so cyclophosphamide does
so, yeah, and in the ataxiacases too, like if you have an
(48:20):
autoimmune cerebellitis, thoseare often T cell mediated
disorders and that's whereyou're reaching earlier for the
cyclophosphamide as well, gotcha.
Dr. Michael Kentris (48:29):
That makes sense, yeah.
So one last clinical conundrumI would like.
When you get a referral from ageneral neurologist, let's say
who was like patient with, let'sjust say, x vague symptom, they
get a, you know, mayoperineoplastic panel and you get
this weak.
Dr. Denis Balaban (48:51):
I love it.
I love it.
Dr. Michael Kentris (48:52):
I'm gonna send you to neuro.
I'm gonna send you to an expertyeah let's send you to the
neuroimmunology guys down thehallway here and uh, what do you
guys do with that?
Uh, other than I assume lots ofcounseling uh, well, yes, a lot
of Um.
Dr. Denis Balaban (49:07):
So we do see cases of like I think the the
GAD 65 is the neurologist's ANA.
Um, yeah, so for low levels ofGAD 65 antibody, um, first I
like, do you have symptoms likethat would be relevant to a
(49:28):
GAD-65 antibody?
So those things would be likestiff person syndrome and
autoimmune encephalitis,seizures, things of that nature.
And if they do not, then Icounsel that this is not an
antibody that is relevantneurologically likely.
(49:49):
Some people think that it canbe a marker of like tendency to
inflammation.
So, because GAD-65autoantibodies are seen in type
1 diabetes and sometimes thatcan exist before the type 1
diabetes starts, and so if youhave the diabetic phenotype and
(50:12):
you got the GAD-65 antibodies,that's type 1 diabetes, whatever
the level.
But if it's for stiff persons,at least a neurological level,
like a neurological level um.
So depending on if you're using, uh, you know, a radioimmune
assay versus a enzymeimmunoassay, like your level,
cutoffs vary, um, but these,there are published cutoffs
(50:36):
there that should raise or loweryour suspicion.
Then you start to get moreconcerned about something like a
stick persons and then go fromthere um, but know, I've also
seen like very weak positivityto something like you know, a
voltage-gated calcium channelautoantibody for example, and
(50:56):
you know, completely normalautonomic function.
Their muscle strength is fine,there's no fatigability.
And then I say somethingsimilar, like you might have a
tendency to autoimmunity and ifthey have another autoimmune
disorder but they have zerosymptoms of you know, whatever
the antibody is generallyassociated with and it might be
just like your immune syndrome,like kicking off something else.
(51:19):
I mean, they're definitely like, for example, in lupus, like
you can have some positiverheumatoid factor, positive
Sjogren's.
It's not that they haveSjogren's necessarily, but they
might just be tagalongs.
We see tagalong antibodies notinfrequently like GFAP
antibodies, for example thesetting of NMO or NMDA.
(51:51):
They probably have NMDA and NMO, not a GFAP astrocytopathy.
Dr. Michael Kentris (52:00):
So I think just putting the antibody into
the clinical context is theimportant thing.
I think that is somewhere we'reprobably lagging behind the
rheumatology folks is, uh, likeputting our pre-test
probabilities into a betterperspective as far as like, what
does it mean if it comes back?
You know, weakly positive,strongly positive?
Does it match the clinicalphenotype right, because we've
definitely seen you?
Dr. Denis Balaban (52:19):
know I've had patients.
Dr. Michael Kentris (52:20):
You know they have like an rf factor.
You know like two, three, fourhundred, whatever yeah, they
have no joint pain, they have no, no stiffness, blah, blah, blah
.
So there's nothing clinicallythere, and so they're like well,
you don't have RA, yeah.
And I'm like oh okay, I thinkwe're probably heading in that
direction, as we start seeingthese panels getting ordered
(52:42):
more and more often for more andmore vague complaints.
Dr. Denis Balaban (52:47):
Yep, Absolutely absolutely.
Dr. Michael Kentris (52:52):
Any final thoughts or clinical pearls that
you think the trainee out thereshould be aware of, whether
neurology, internal medicine,what have you that should raise
the?
I know we've talked about a lotof things already, but the
biggest takeaway for you fromthis discussion should raise the
(53:12):
raise.
I know we've talked about a lotof things already.
Dr. Denis Balaban (53:15):
The biggest takeaway for you from this
discussion would be what learnone thing from our conversation?
Oh my gosh, you're limiting meto just one thing.
Okay, one to three.
Okay, I think, let me thinkabout that, I think, let me
think about that.
So I think one point is makingsure that if the syndrome and
(53:37):
the symptoms could fit with arheumatologic disease or a
neurone immunologic disorder,make sure that you're asking
specific questions for thosedisorders.
So, if you're worried aboutsomething like a vasculitis,
(53:57):
don't just ask about strokesymptoms.
Ask about systemic symptomslike coughing, coughing up blood
, sinus issues, peeing blood,rashes, things like that.
So that's, they're asking thosein your HPI and review of
systems.
(54:17):
Similarly, getting a really goodfamily history.
And not just do you have anyfamily history of autoimmune
disease?
No one knows what that means,or very few people do, like, do
you have a family history ofautoimmune disease?
No one knows what that means,or very few people do, um, like,
do you have a family history ofpsoriasis, celiac, lupus,
rheumatoid arthritis,inflammatory bowel disease?
Just list them, um, and youwill sometimes be surprised by
(54:39):
the answers.
You so I think that's.
I'm going to lump that as one,two, really dive in to the onset
(55:03):
and the pacing of the symptomsand make sure that you have that
as down pat as possible.
So that's number two, and do Ihave the third one as a catch
all for our discussions?
I will just say be curious.
And that applies to bothinteracting with your patients,
(55:26):
as well as reading more andfamiliarizing yourself with the
wondrous world ofneuroimmunology.
Dr. Michael Kentris (55:36):
That's a great point.
I can't.
I probably said it today, Ijust finished rounding a few
hours ago, and probably at leasta handful of times I had to say
what do you mean by that, inresponse to something the
patient had just told me.
Yes, you know it's like.
Could you tell me, tell me moreabout exactly it is?
That's that funny thing oflanguage where they know exactly
(56:00):
what they mean, but I I don't.
So I need you to break it downfor me tell me more about.
Dr. Denis Balaban (56:06):
That is my favorite open-ended question.
That that is.
That is one of the most usefulopen-ended questions in my
experience it's just like, yeah,I don't know there's, there's
already something satisfying.
Dr. Michael Kentris (56:18):
It's like you finally have heard something
in the history is liketriggered yes, for you to go
down.
It's like maybe I can figureout what's going on here it's
like a lifeline for me to tryand solve this puzzle.
Dr. Denis Balaban (56:29):
Yes, it's the clearing in the forest,
absolutely.
Dr. Michael Kentris (56:34):
Well, thank you so much for taking the time
and talking with us.
We'll definitely have to haveyou back on and talk about more
specific neuroimmunologicdisorders in the future.
Dr. Denis Balaban (56:43):
Oh, thank you .
Yes, I would love to do that.
Thank you so much for having me.
Dr. Michael Kentris (56:48):
And if people want to find you, find
your work, uh, where should they?
Or should they track you downonline?
Dr. Denis Balaban (56:56):
So I do have a uh Twitter slash X accounts,
um, just at Dennis Balaban MD.
I'll say that I do not post asfrequently as I once did, um,
but I have that account.
Um, let's see, I mean I have, Ihave my MGH websites that uh
(57:17):
people can look me up uh as well, but yeah, and then PubMed, I
suppose.
Dr. Michael Kentris (57:26):
A real researcher, not like me.
Dr. Denis Balaban (57:31):
I'm slowly getting more publications to my
name, but there are certainlyfar more published than I.
Dr. Michael Kentris (57:41):
So, thank you so much.
And, as always, you can alwaysfind me also on Twix.
I've heard people call it Twix.
I kind of like that.
It's a little bit better than X, I think.
Oh, twix you so much.
And, as always, you can alwaysfind me also on twix.
I've heard people call it twix.
I kind of like that.
Uh, it's a little bit betterthan x, I think oh, twix, I I do
like that, though.
Dr. Denis Balaban (57:53):
I think the candy bar company may have words
about that.
Dr. Michael Kentris (57:56):
That's true but I'm at dr kentris
d-r-k-e-n-t-r-i-s and you can,of course, find all of our past
stuff on the website at theneurotransransmitterscom.
Dennis, thank you again so much.
Really appreciate you takingthe time.
Dr. Denis Balaban (58:10):
Thank you so much for having me.
This was a treat.
Dr. Michael Kentris (58:14):
Likewise.
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