April 29, 2024 • 49 mins
On popular demand, we invited Dr. Andreas Charidimou once again, to discuss amyloid spells or Cerebral Amyloid Angiopathy-related Transient Focal Neurological Episodes (CAA-TFNEs)
- What are CAA-TFNEs and its suggested pathophysiology?
- What are some of its differentials?
- Clinical features of TIA vs TFNE
- How many TIAs are really CAA-TFNEs?
- Who to start on anti-seizure meds and how long do you continue?
- Neuroimaging findings and when to repeat imaging?
- Possible relationship with Amyloid-related imaging abnormalities (ARIA)
All this and more! Tune in now!
You can find Dr. Charidimou on Twitter/X at @a_charidimou or email him at antreas.charidimou@bmc.org
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The views expressed do not necessarily represent those of any associated organizations. The information in this podcast is for educational and informational purposes only and does not represent specific medical/health advice. Please consult with an appropriate health care professional for any medical/health advice.
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Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Dr. Michael Kentris (00:01):
Hello and welcome back to the
Neurotransmitters.
I'm your host, Dr.
Michael Kentris, and I'm reallythrilled to be recording
today's episode, as we arerejoined by a friend of the show
, Dr.
Andreas Charidimou, and todaywe are talking about a topic
that I find very fascinating,very challenging, and that is
amyloid spells.
Thank you again for joining ustoday, Andreas.
Dr. Andreas Charidimou (00:24):
Thank you so much for inviting me
again and I'm thrilled to talkagain about one of my favorite
subtopics in CEA.
Dr. Michael Kentris (00:32):
Yes, Just before we were hitting record,
you were saying that, obviously,for those who know you, you are
very well-published in thearena of amyloid angiopathy
cerebral amyloid angiopathy andyou were telling me that during
some of the talks that you get,whether or not you mention it
directly, one of the topics thatcomes up time after time is
(00:54):
these amyloid spells.
So could you just tell us alittle bit about what is an
amyloid spell and when should webe considering that on our
differential diagnosis?
Dr. Andreas Charidimou (01:03):
Yeah, sure.
So historically andtraditionally, the presentation
that most people have linkedwith cerebral amyloid angiopathy
, or CAA, is that of lobarintracerebral hemorrhage, and
this has been known for at least30 to 40 years with the advent
of neuroimaging 40 years withthe advent of neuroimaging.
(01:27):
One least known presentation,at least as of 10 years ago, is
these presentations with whatused to be called amyloid spells
or transient focal neurologicalepisodes related to CAA.
And, as the name implies, theseare episodes that are transient
, neurologic in nature and focal, and the prototypical
(01:51):
descriptions of these episodesare basically positive symptoms,
so paresthesias, pins andneedles, feeling, which are
migrating, and the syndrome thatwas first described and is more
characteristically associatedwith symptoms is spreading
positive sensory symptoms in thearm up to the mouth and then
(02:13):
slowly going back to normal inthe same fashion.
However, there is a spectrum,essentially from a symptomatic
point of view, it includes anytransient symptoms that they
might look similar to TIA.
So there might be negativesymptoms speech impairments,
focal weakness, arm or leg orthey can resemble auras visual
(02:40):
auras typically that they mightremind you the auras that you
typically see with migraine.
And, as you can tell, it is atough symptom to link directly,
tough phenomenology and notspecific to link directly to CAA
, because the differential isbroad.
(03:01):
When you see transient symptomsof any nature in neurology, but
when you should be suspectingthis, I think it's in any
patient that is on the olderspectrum of age, so any patient
older than 55 or 60 years oldcoming with transient symptoms,
(03:24):
you should be thinking.
When you think about TIAs,essentially you should be
thinking whether this isCA-related phenomenon and one of
the characteristics whichdifferentiates this from TIAs
actually is that these episodesare multiple and stereotypical,
whereas a TIA typically is goingto, you know, you're going to
(03:45):
have the episode once and thenprobably a different kind of
focal phenomenology if thepatient has a second TIA.
So in that sense it resembles abit focal seizure activity,
because focal seizure is anotherdifferential when you see a
patient with recurrent episodesand you think about TIAs, but
(04:05):
it's too stereotypical, happenedtoo many times, so you might
consider that this is a focalseizure.
So in that context I think youwould consider seizure-related
amyloid spells.
Dr. Michael Kentris (04:18):
Yeah, I'm going to have to update my
lecture that I give to traineesabout the differential diagnosis
for first-time seizure eventsto include amyloid spells.
But that is one of the trickythings, right, we always talk
about with migraine, withseizures, this kind of spreading
cortical depression, all thiskind of stuff, and it almost
sounds kind of like that samekind of phenomenon in this
(04:41):
situation.
And I know it gets even hairierwhen we start talking about
things in the epilepsy worldlike negative motor seizures and
things of that, which are alsostereotyped.
So one other thing you hadmentioned is that, whether these
are focal dysfunction versus,is it actually edging into the
(05:03):
territory of causing seizuresand when do you start to
consider one versus the other?
Or how does that kind of affecthow you approach these patients
?
Dr. Andreas Charidimou (05:13):
Yeah, it's a tough question, I think,
taking one step back.
Essentially, the question iswhat is the pathophysiology of
these symptoms?
Yes, excellent, and the answeris that we don't really know,
because we haven't studied thisphenomenon from a
(05:34):
pathophysiological point of view.
What happens is that behindthese symptoms there is
typically superficial bleedingin the form of a convex
subarachnoid hemorrhage in theacute phase, when this
phenomenon first occurs, orcortical superficial sclerosis,
(05:55):
which essentially reflectsvessel wall cracking in the
leptomeningeal space due to CAA,leading to even one drop of
blood on the surface of thecortex, which it creates a lot
of irritation.
So what has been suggested as amechanism based on how
(06:15):
stereotypical these episodes are, the positive phenomenology and
the spreading pattern, alongwith the timing of this spread,
is this might resemble amechanism similar to cortical
spreading depression, because incortical spreading depression
you have a slow wave ofexcitation which then is
followed by total inhibition ofcortical neurons, and this might
(06:40):
correlate in some of thesymptoms with the spreading
excitation creating the positivesymptoms and then slowly for
example, if you have pins andneedles going from the arm up in
the mouth and then slowly thosesymptoms going away.
But this is like a theoreticalassumption about the
(07:02):
pathophysiology, now that weknow that there is a huge
spectrum of these symptoms, frompositive to negative, I'm
thinking that maybe the negativesymptoms might be focal
seizures, again, maybe initiatedby the irritating aspect of
having blood on the surface ofthe brain, or sometimes having
(07:24):
acute microbleeds in corticalareas that are symptomatogenic,
and there is some indirectevidence that we should be
thinking about a seizuremechanism.
There was a recent study fromMayo Clinic and another one from
Italy where they look at theprevalence of epilepsy in
patients with CA specificallyand they did EEGs and they found
(07:48):
that the factors associatedwith epilepsy and focal seizures
, specifically based on EEGcaptures in CA is the presence
of cortical superficialsclerosis, which is very common
and underpins these amyloidspells, and the patient having
inflammatory CA.
There is a different kind ofmechanism because inflammatory
(08:10):
CA is a very it's a differentkind of disease with brain edema
and inflammation.
So I think the bottom line is,and the message that I want to
send is that probably patientspresenting with transient focal
immunological episodes, theydon't get enough EEGs and this
(08:33):
is underutilized in many centers.
Even when you do the brain MRIand you see an area of acute
subarachnoid hemorrhage orsiderosis, even when you ascribe
this to being CA-related.
I think an EEG would still beuseful because it's going to
change the symptomaticmanagement of these patients.
Dr. Michael Kentris (08:55):
That makes sense.
Dr. Andreas Charidimou (08:56):
Yeah.
Dr. Michael Kentris (08:57):
Now, again, I don't know the data well
enough when we look at and maybethe data isn't there when we
look at EEGs in patients withCAA or suspected CAA, plus or
minus the transient focalneurologic events, is the
sensitivity for, say, a routineEEG still that proposed around
(09:17):
50%, in which case a positiveresult is much more useful than
a negative result and perhapsyou might treat regardless if
there is a clinical history ofrecurrent stereotyped events,
particularly with positivesymptoms.
Dr. Andreas Charidimou (09:33):
Yeah, I don't think the data are there.
I would assume that thesensitivity should be similar to
the sensitivity in other focalseizures.
So if you capture something, Ithink it's very useful and a
positive indication.
If you don't capture anything,you might consider repeating it
if the symptoms recur, or useyour clinical judgment on how to
(09:56):
manage this.
In most of these patients, thesymptoms tend to resolve on
their own, presumably as theblood gets resorbed.
However, I think it makes sensein patients with negative
symptoms to look a bit deeperfor a focal seizure focus, and
also in patients even withpositive symptoms, when they get
(10:19):
too many of these I mean, Ihave had patients having 20
episodes per day.
Too many of these, I mean, Ihave had patients having 20
episodes per day.
So these are interfering withtheir life.
So in those patients you mightconsider a low dose
anti-epileptic which you wouldkeep the patient on for three to
six months, with the aim thento remove it as the symptoms
(10:40):
subside.
But this is, you know, know,this is just for the symptomatic
aspect of things.
The importance of theseepisodes are not the symptoms
per se, but it's what theyindicate, and they indicate
bleeding on the surface of thebrain which is is dangerous in
the setting of CAA.
(11:01):
So that's, you know, that's thesecond layer.
Dr. Michael Kentris (11:13):
So hypothetically.
So let's say we have a patientwho you know.
They come in with a kind of TIAlike event, you know an episode
of you know face weakness ornumbness or what have you.
That resolves spontaneously.
We get the MRI done and itshows maybe a small microbleed
that would localizeappropriately.
But they've only had one eventand let's say they're following
(11:34):
up in the neurology clinic three, six months later and when they
come back now they're havingthese events recurrently, so
kind of a change in frequency,if you will.
Would it be appropriate inthose patients to repeat imaging
to see like, is there arecurrence of a microbleed at
that point in time?
Dr. Andreas Charidimou (11:53):
Totally yes.
So if you have the diagnosis ofCA-related TFNEs, if there is a
silent period over two, threemonths and then the patient
presents again with even thesame symptoms, I think it's a
good indication to repeatimaging to see if there has been
a new bleeding event Inpatients that you have diagnosed
(12:16):
.
You know they have been havingrecurrent similar symptoms.
You don't necessarily need torepeat imaging.
But if one of those patientspresents with a totally
different symptomatology, thenagain the question is have they
had a small bleeding in anotherarea?
Because these symptoms arebasically it's like a clinical
(12:37):
marker of fragility of theleptomeningeal vessels in CAA
and this is a patchy diseasewhich means that there might be
other small bleeding events inother areas.
So yes, this is exactly thepatient population that you're
going to have.
Low threshold to re-image,because it's the only way to see
(13:00):
what has been the progression.
Dr. Michael Kentris (13:04):
Gotcha.
Now that makes complete senseand I think that's a great point
to emphasize right that CAA isa progressive neurodegenerative
condition.
Dr. Andreas Charidimou (13:15):
So we should expect this to be kind of
a moving target for a lot ofpatients.
Also, the other relevance ofthis is that, let's say you have
the patient you mentionedcoming to the emergency
department with some sort ofstereotypical transient
neurological symptoms.
Most clinicians at the top ofthe differential we're going to
have the TIA right and not allpatients will get immediately a
(13:39):
brain MRI, because to diagnosethis as amyloid spells you need
brain MRI with blood sensitivesequences.
Now, the big clinicalimplications in this scenario is
that if you think the patienthas a TIA and you don't have a
brain MRI, what's the treatmentfor?
Typically a TIA?
(13:59):
You start.
You start antithrombotics,right, yeah, and then you do the
workup.
However, if this was indeed anepisode of ca related tfnes due
to a small acute subarachnoidhemorrhage, by prescribing
antithrombotics you're pushingthe patient to bleed.
Dr. Michael Kentris (14:20):
More essentially, right, and would
this be a common scenario?
Because I've encountered thisonce or twice myself.
Obviously, at a you knowsmaller institution, our volumes
aren't going to be quite ashigh, but where we have someone
who comes in, it sounds like atia.
And then you get the mri andyou see like maybe, maybe they
don't meet full criteria for caa, but they're kind of in that
(14:43):
possible camp where you've gotlike a you know micro hemorrhage
in.
You know, maybe they came inwith aphasia and it's kind of in
that left temporal or frontalarea and you're like was this,
was this?
an amyloid event.
I don't have enough,necessarily.
I've got them on dualanti-platelet therapy right now.
Maybe I should deescalate thatto maybe just like a low-dose
aspirin.
Dr. Andreas Charidimou (15:03):
Yeah, we can discuss all sorts of
different scenarios.
But let me put it this way Evenone such patient if you get a
brain MRI, even if the patientfulfills criteria for probable
CAA, it doesn't mean that theepisode is due to CAA.
I think the highest level ofcertainty is when you see
(15:27):
siderosis or subarachnoidhemorrhage in an area
corresponding to the symptoms.
In that scenario you canbasically say that probably it
has something to do with thatacute bleeding and we can
discuss later.
But there is a wholedifferential of convexal
subarachnoid hemorrhage.
It's not the message, shouldnot be.
(15:48):
You see the CAA, it has a hugelist of potential diagnosis.
Now, if you only see amicrobleed but it's in the right
spot, I think you should pauseand think whether it's related
to that and maybe look for otherless sensitive markers of CA.
(16:14):
If this is a microblit in theright spot and the patient has
severe perivascular spaces inthe centrum semiovale or they
have these small subcorticalwhite matter spots that are
included in the BOSTON criteria,it kind of raises the pre-test
probability of these beingrelated to the symptoms.
In any case, you would stillneed to do a full workup for a
TIA because if on that site youhave a carotid stenosis, then
(16:39):
obviously, you know, the plotthickens but you need to address
that as well.
So in some patients it's verydifficult to have the exact set
diagnosis and there are casesthat at 1.5 Tesla using GRE, you
might see only a micro-bleeds.
And then you repeat imaging ona 3 Tesla MRI with an SWI
(17:02):
susceptibility-weighted imagingand then you see that oh,
actually there is a tiny spot ofsclerosis.
So imaging is not you know.
Dr. Michael Kentris (17:12):
Now I'll create a beautiful yeah.
No, that's a great point.
And I know our institution juststarted using SWI sequences in
some of their protocols,thankfully, so that has been
helpful.
So we're kind of finally cominginto the 20th century a little
bit.
But yeah, no, I think that's agreat point, and I've certainly
(17:33):
had those patients, as youintimated, where you know, maybe
you've got a little bit ofhemorrhage, you've got a bad
carotid, maybe they also have ahistory of epilepsy too and
you're like well, which one ofthese is the culprit this time
around?
And it does become very, verychallenging.
Dr. Andreas Charidimou (17:49):
Yeah, yeah, it is very challenging and
we don't know what's the sizeof the problem.
In other words, how many ofthese patients are missed.
How many are they diagnosed asTIAs or as focal seizures?
The only study that I'm awareof is a study from Calgary where
they actually wentretrospectively and they looked
(18:11):
at their TIA registry.
I think they had around 400patients and they reviewed the
MRIs to see how many patientsfulfilled BOSTON criteria for
CAA and in how many of thosethere was an area of bleeding
anatomically correspondingpotentially to the symptoms.
(18:32):
And I think they reported thatin about 1% of their total
population.
Actually retrospectively, theythought that those were actually
not TIAs but they weretransient focal neurological
episodes due to CAA, which itdoesn't sound like a huge number
.
But if you put into perspectiveon how common TIAs are, the
(18:56):
absolute number of patientsgetting misdiagnosed, especially
in centers or countries thatMRI is not part of the initial
workup, then this number ispretty high.
Dr. Michael Kentris (19:11):
No, that's a great point, especially, like
you said, in rural areas.
I know that there's differentprotocols, like where you get
the CTAs to make sure there'snot a hot carotid or anything
like that, and you kind of workthem up over the next two weeks
as an outpatient, yeah.
But yeah, that's a great point,there are certainly things that
will not be captured, kind ofdoing that low resource triage.
Dr. Andreas Charidimou (19:35):
And actually my involvement in CAA
started by seeing one of thesepatients.
There was a patient that cameto the emergency department of
University College London at thetime when I was starting my PhD
, with a lobar hemorrhage andwhen we looked back a few days
before, the patient presented tohis PCP a primary care
(20:00):
physician with some sort oftransient episodes positive in
nature I think the left arm wasaffected and up the mouth, and
at the time I don't know if it'sstill the case in the UK the
protocol was that the patientgets a CT, you initiate
antiplatelet therapy and thenthey go to a TIA clinic at some
(20:23):
point and this is what they havedone.
When we saw the brain MRI,close to the area of the
hemorrhage there was an area ofacute subarachnoid hemorrhage
and some chronic sclerosis, alsoin remote areas.
And when we went back to the CTwe actually saw that there was
(20:44):
a tiny, tiny bit of blood in theright sulcus and at the time I
had no idea what that was.
And my PhD supervisor, davidWaring, he says, oh yeah, this
is probably amyloid spells.
And looking in the literaturewe realized that there were just
(21:07):
some case reports of thisphenomenon and this is how we
started assembling a multicentercohort to see, indeed, if this
is a common phenomenon, what arethe symptoms and what is the
risk of bleeding.
And this is how siderosisactually gained validity in the
(21:32):
CA field as a good imagingpredictor of the disease and the
risk of bleeding through theseTFNEs or amyloid spells.
Dr. Michael Kentris (21:41):
Fascinating , yeah, and I was telling you
before we started recording.
You know, I've only really hadthese in my consciousness for
about three to four years myself, which, you know, going through
epilepsy and things like that Iwould expect to have.
You know, transient neurologicevents are kind of our thing, so
I would have really expected tohave heard more about them.
(22:01):
But it is one of those thingswhere it's, you know, kind of
the most common disorder you'venever heard of is how it feels.
Dr. Andreas Charidimou (22:08):
Yeah, yeah, yeah.
I wonder if some patients theymight have a very brief episodes
they don't even seek uh uh, youknow medical care and some of
them they then, you know,develop a hemorrhage or they
might not have any othersymptoms for good periods of
time.
So those are totally missed.
Dr. Michael Kentris (22:29):
No, it makes complete sense.
Those are totally missed.
No, it makes complete sense.
And so one thing that I've beenkind of curious about, if
you're willing to speculatewildly with me we know that
there's a lot of anti-amyloidtherapies kind of coming into
the public consciousness thesedays, like aducanumab, lacanumab
, all those kinds of things thatare these anti-amyloid types of
(22:52):
treatments, and we know thatthere is this inflammatory
subtype of CAA.
How, or if, do you think thereis any pathophysiologic
relatedness between the aria,these inflammatory adverse
effects that we're seeing withsome of these anti-amyloid
therapies, as opposed to theselike transient focal neurologic
(23:15):
events that we see in thecontext of CIA, versus like
Alzheimer's disease in general?
I know it's a very broadquestion for which there's not a
huge amount of literature, butI'm just curious what your
perspective may be.
Dr. Andreas Charidimou (23:28):
Why are you asking this question?
Have you seen a patient thatmakes you wonder about
inflammation in the setting oftransient spells?
Because your question is veryat the point, I have to say.
Dr. Michael Kentris (23:41):
So I have had a couple inflammatory
CAA-type patients come in.
They kind of almost have thattumor-factive or neoplastic look
on the initial MRI and yourepeat it again three to six
months later and it's quieteddown a bit some residual
hemorrhage there.
But they will come in sometimes.
Sometimes they will come inlike maybe in focal status or
(24:01):
maybe have had a seizure atonset, things like that.
And then we've got these ARIAepisodes with the anti-amyloid
therapies and there's, you know,again, right, these kind of
various neurologic phenomenathat tend to occur, whether
those are visual sensory kind ofdisturbances and it's, you know
, it just seems too close to becoincidence.
Uh, just from an observationyeah, you're totally right.
Dr. Andreas Charidimou (24:24):
I think if we put it simply a bit
simplistic, but I think it worksfor our discussion is that, uh,
aria is basically iatrogenic.
Ca related inflammation, thethe two are, you know, mirror
images.
One is caused by a treatmentthat we do, the other one occurs
(24:46):
spontaneously.
So we can learn a lot fromCA-related inflammation, because
many of those things probablyapply to ARIA, including the
spectrum of the disease.
So CA-related inflammationtypically it was considered a
condition during which thepatient will be very severely
(25:11):
affected, an encephalitis kindof picture, with changes in the
level of consciousness, seizures, commonly with status
epilepticus, and basically thesepatients will end up in the
neuro ICU and on the MRI CSF.
All the workup and on the MRICSF, you know, all the workup
(25:35):
you will and often a brainbiopsy you will land on the
correct diagnosis.
Now I think, with greaterawareness and more widespread
use of brain MRI and bloodsensitive sequences, we're
realizing that this is only thetip of the iceberg.
There are patients with CRNinflammation that they present
(25:55):
with minimal symptoms, at themilder end of the spectrum, I
think, our patients with CRNinflammation that they present
with amyloid spells.
I have no idea how common thispresentation is, but for the
past year I have encounteredthree patients.
These patients they presentedwith positive or negative
symptoms, transient,stereotypical.
(26:18):
On the brain MRI there wasevidence of bleeding in the
right area.
And these patients, they keptcoming to the hospital with more
episodes and more acutebleeding in that same area,
which makes you wonder.
This is not the typical, youknow wild variety of amyloid
(26:40):
spells that they will have oneepisode and then things are
going to go silent.
There was evidence of somethinggoing on locally.
Vessels keep bleeding.
I think in these patients,completely anecdotally, a
contrast study will be usefulbecause in these patients that I
mentioned, a contrast studyshowed leptomeningeal
(27:01):
enhancement in the very areathat was bleeding, which makes
you think if there was aninflammatory element.
And in fact two of thosepatients we treated empirically
with corticosteroids and thereis no control group.
(27:27):
But the patients are doing welland they haven't had any
bleeding since.
So, translating this to ARIAARIA is also a spectrum from
asymptomatic, so just imagingmanifestation, which, by the way
, I think is the only case thatshould be called ARIA.
Asymptomatic is the onlyscenario that you should be
calling this amyloid-relatedimaging abnormalities.
When the patients are havingsymptoms, there are no imaging
(27:50):
abnormalities alone any longer.
It's like they come with asymptom.
We should have a better name tomaybe sulcal hemorrhage or
(28:11):
maybe fluid extravasation oredema focally.
Now we might not encounterthose patients very often,
because when a patient is onleucanumab, let's say, these
patients are monitored prettyclosely with serial brain MRIs,
(28:34):
typically after the fourthinfusion, after the seventh
infusion, and this is when ARIAhas higher likelihood of
happening.
In other words, you mightcapture ARIA on imaging before
it started manifesting withsymptoms, aria on imaging before
it started manifesting withsymptoms.
But I think it is possible thatsome of these amyloid spells,
(28:57):
especially recurrent anddifferent types, or even the
same types, sometimes they mighthave an inflammatory basis,
with or without anti-amyloidtreatments.
This is something that is acompletely new realization.
There are only a couple of casereports, I believe, interesting
(29:17):
.
Dr. Michael Kentris (29:18):
Because I have wondered in the past
because, if I remember correctly, a history of intracranial
hemorrhage of various types iskind of a contraindication to
starting these anti-amyloidtherapies.
So are we causing this or arewe unmasking it with some of
these anti-amyloid therapies?
I don't know if there's a goodanswer to that.
Dr. Andreas Charidimou (29:40):
It's a very good question.
First of all, I think in somepatients the anti-amyloid drug
is like a crash test to revealif there is underlying CAA,
because it's going to push thepatient to express the
cerebrovascular amyloidpathology.
(30:01):
And for ARIA, I mean, we don'treally know what's the cause.
Right, there are twopredominant hypotheses.
The first one is that eitherthe anti-amyloid antibody binds
directly to the vascular amyloid, with different affinity but
still binds there, inducinginflammation and vessel wall
(30:22):
breakdown, or alternatively, asthe amyloid plaques and the
antibody and the inflammationkind of gets broken down, some
of that needs to be removed fromthe brain via the perivascular
space and the perivascular spaceis the scene where amyloid
angiopathy also manifests.
(30:44):
So there is a problem with theperivascular drainage in
patients with CAA.
So those again simplistichypothesis is that these
breakdown products, they getclogged in there again, inducing
(31:04):
inflammation.
So essentially one of theprimary risk factors for
developing ARIA is havingunderlying amyloid angiopathy
(31:32):
recommendations.
When they say you shouldn't begiving these treatments to
patients who have four or moremicroblades or to patients who
have sclerosis, essentiallyindirectly you're saying you
shouldn't be giving thesepatients when it's very obvious
they might have evidence ofadvanced CAA.
But many patients have eitherfewer microblades or more silent
CAA and then you do the crashtest.
(31:53):
So essentially, these patientsneed to be very carefully
selected and obviously veryclosely monitored.
Dr. Michael Kentris (32:05):
That makes good sense.
Something you mentioned earlieris you know, it seems like a
lot of the emphasis on kind ofthese transient, focal
neurologic events is related tomore of the superficial
siderosis, so the kind of thatcortical surface.
But we need to not anchor onthat too much.
So you mentioned that you havea differential diagnosis that
(32:26):
you kind of work through whenyou see these cortical bleeds.
What kind of things also gothrough your mind as far as
potential underlying etiology.
Dr. Andreas Charidimou (32:34):
Yes.
So I think we can approach this.
First, obviously you have adifferential diagnosis of the
episodes, of the episodesthemselves, and we mentioned
TIAs especially for a firstcomer with these episodes.
First comer with these episodes, so TIAs, focal seizures,
(32:57):
migraine with aura, sometimesmetabolic abnormalities.
I mean I'm sure you have seenpatients with hypoglycemia who
have focal symptoms, functionalurological disorders.
So there is a wholedifferential just based on the
clinical symptoms and thecontext and then based on
imaging.
If you see acute subarachnoidhemorrhage, there is a whole
(33:21):
different differential diagnosiswhich includes things like
small AVM, any sort of vascularmalformation causing the bleed
in that area, sometimes smallaneurysm.
You can have endocarditiscausing an aneurysm there,
(33:42):
inflammatory again in nature, orseptic embolism causing the
bleeding.
You might have RCVS which cancause convex subarachnoid
hemorrhage.
There the age is a goodindicator.
For example, the most commoncause of convex subarachnoid
hemorrhage in someone youngerthan 50 years old is typically
(34:05):
RCVS, whereas the most commoncause in someone older than 60
years it's amyloid angiopathy.
Then you can have IV drug usecocaine, heroin can cause, via a
similar mechanism to RCVS,convexal subarachnoid hemorrhage
.
(34:25):
So for that again, the clinicalhistory and what are the other
imaging findings are going toguide you on what might be the
underlying diagnosis.
Do you see other areas ofchronic superficial bleeding,
any other areas of sclerosis?
Do you see lower micron bleeds?
In other words, is thereevidence that there have been
(34:47):
similar bleeding events in anelderly individual, evidence
that there have been similarbleeding events in an elderly
individual, solidifying yourdifferential that this might be
CAA?
But again, you keep an openmind because you still need to
do a workup for the rest of thepatients, including vessel
imaging.
Dr. Michael Kentris (35:06):
No, that makes complete sense.
Now, something you mentionedabout some of these people with
recurrent, sometimes disablingor very frequent episodes that
are disturbing to them.
Potentially, you mentionedyou'll put them on an
anti-seizure medication forsometimes a dedicated period of
time, like three to six months.
Is it likely that after theacute hemorrhage, that when you
(35:31):
wean them off the anti-seizuremedication, that these spells
will not recur, or do you findthat this is more of a lifelong
anti-seizure medication for somepatients?
Dr. Andreas Charidimou (35:40):
Yeah, so this is kind of different with
patients with focal seizures inthat the idea.
So the idea is that theseepisodes, unless there is more
bleeding, they will tend tosubside because the blood will
get absorbed into hemocytogenand it's going to be less
irritating.
(36:00):
So the majority of thesepatients will have resolution of
the symptoms over a period ofthe next three to six months.
The idea of putting someone onan anti-epileptic patient I mean
with a CRLTFN is twofold.
First, if you have identified afocal seizure on EEG as the
(36:21):
mechanism and you believe thisis just CAA, then you would put
the patient on anti-epileptics.
If you haven't identified thatmechanism which I guess is your
question if there are multipleepisodes, you're going to put
this patient on ananti-epileptic with the hope
that it might help with quickerresolution and with the idea
(36:43):
that as soon as the episodes getresolved which might relate to
the natural history of thecondition, which might relate to
the natural history of thecondition, then you try to get
off the patient from theanti-epileptic.
It's not going to be for life,so typically the longest I have
used anti-epileptic in one ofthese patients is up to a year.
(37:05):
Okay, no, that's good to know.
So then you take them off.
I'm not even sure if theanti-epileptics were doing
something or the symptoms weredeemed to get resolved.
Dr. Michael Kentris (37:15):
Their natural history, taking care of
itself.
Yeah, that's a good point.
Dr. Andreas Charidimou (37:19):
There are some people that try to use
anti-epileptic medications thatthere are ex vivo data that they
actually might affect corticalspreading depression.
Dr. Michael Kentris (37:33):
I think lamotrigine is one of them more
in the sodium channel?
Yeah, I would imagine.
Dr. Andreas Charidimou (37:38):
Yeah so that's another rationale.
That may be with the with someantiepileptics, where you're
targeting cortical spreadingdepression in addition to
epileptogenicity.
So but Keppra, I think, as inmany other areas of urology, is
often to go to medication 500milligrams.
(37:59):
Right, just plug and play Twiceper day, which is a low dose
but still a good dose in anelderly individual.
Lacosamide is the one I used aswell.
Dr. Michael Kentris (38:15):
Again, completely non-evidence based,
right.
Well, I gotta start somewhere.
Dr. Andreas Charidimou (38:18):
Yeah, and this is not this is a rare
scenario to start on to have somany episodes that you're gonna
start an anti-epileptic.
It's like maybe 10% of all theCA-related TFNs You're going to
need to do that.
Dr. Michael Kentris (38:34):
Gotcha, yeah.
So my takeaway as far asanti-seizure meds would be
recurrent stereotyped episodes,maybe more of a preponderance of
positive symptoms, and ifthey're disabling, obviously,
and you find no evidence of Like, in the absence of recurrent
bleeding, would you say or plusor minus.
Dr. Andreas Charidimou (38:56):
So I would go purely by the
recurrence of clinical symptoms.
Okay now, if there was arecurrent bleed without any
evidence of either a new seizureor a new episode, there is no
indication to continueanti-epileptics.
Dr. Michael Kentris (39:11):
You wouldn't do it prophylactically
okay because I know we stillthere's a little bit of debate
out there for like some of theyou know intraparenchymal
hemorrhages, about uh,prophylactic anti-seizure
medications, but I see a lot of,because sometimes these these
consults will come more to theneurosurgeon than to the
neurology team as far as like a,a small subarachnoid hemorrhage
(39:33):
, so everyone gets put on youknow capra or something like
that for seven days.
Dr. Andreas Charidimou (39:38):
You know kind of like the traumatic
brain injury type uh, yeah, Iguess it varies between
institutions.
Dr. Michael Kentris (39:45):
So right, right yeah but no, those, those
are all very helpful points.
I really love the the tip aboutusing the contrast at mri.
It's not something I thinkabout with um, with these types
of patients, with when I'm kindof doing the tia or caa kind of
evaluation, but I'm going todefinitely keep that one in my
back pocket going forward yeah,especially when you see a
patient that is a bit differentor atypical to the patients you
(40:10):
have seen before, with theseepisodes.
Any other questions that youfind come up a lot from people
asking you about amyloid spellsor the TFNEs that you think
would be useful for people toknow about or would help them
identify these patients.
Dr. Andreas Charidimou (40:27):
I think there are two questions that
they have been coming up a lot.
The first one is okay, thepatient comes to the ED with
these symptoms.
You do a brain MRI or even a CTinitially and you see there is
an acute subarachnoid hemorrhage.
Is an acute subarachnoidhemorrhage, how do you treat
(40:48):
this patient?
And my answer is that it'sreasonable to send this patient
to the new ICU with the aim of,essentially, you should treat it
as a hemorrhage, as a brainhemorrhage, intraparenchymal
hemorrhage in terms of loweringthe blood pressure, having a
very strict target closelymonitoring these patients for
(41:08):
any recurrence of the bleeding.
And it might be a short stay itmight be just one day just to
control the blood pressure if itwas high and have a more
definite diagnosis.
So this again depends onavailability in each individual
center, but I think the bloodpressure in the acute setting,
in the first 24 hours, is areasonable target to have in the
(41:32):
management of these patients.
So this is in the acute setting.
The second question that comesup very often is what is the
risk of these patients having alower hemorrhage and what do you
do when you find out that theyhave AFib or they have another
indication for anticoagulation,which is something that we
(41:54):
discussed in the previouspodcast.
But I think the overallapproach is that these patients
again they should be treatedsimilarly to a patient who had a
lower hemorrhage due to CAA interms of the future risk of
hemorrhage, because it's notthat the amyloid spells increase
(42:18):
the risk of future hemorrhage.
The reason that these patientshave high risk of hemorrhage is
that they have a lot of corticalsuperficial sclerosis.
So the imaging manifestation isa biomarker of severe or
advanced CAA.
So it's likely that you know,very stochastically, one of
(42:41):
these small vessels will pop andthe hemostatic mechanism might
not be enough to seal the crackand these patients might end up
with a lower hemorrhage.
So we know from observationalstudies that these patients they
might have risk of futurehemorrhage from 15 to 20 percent
(43:03):
per year, risk of futurehemorrhage from 15% to 20% per
year.
And the risk you can kind ofquantify it based on what are
the imaging manifestations of CAon the rest of the brain?
Do they have multiple areas ofsiderosis?
Did they come with a secondepisode of acute subarachnoid
hemorrhage?
Both of those scenariosincrease the risk of hemorrhage.
(43:25):
We also know that they haveconsiderably high risk of an
ischemic stroke, just based onhow common vascular risk factors
are in these elderly patients.
So it is a good target group totry something other than
anticoagulants.
(43:46):
Probably they are at the highend of the spectrum in terms of
future hemorrhage where probablymany neurologists will feel
uncomfortable putting thepatient on an anticoagulant.
So these are the patients thatprobably they might warrant a
discussion with cardiology.
If they have AFib, that is, toget a left atrial appendage
(44:09):
occlusion device, and the ideabehind it is that both CAA and
atrial fibrillation areconditions that inevitably
they're going to progress areconditions that inevitably
they're going to progress.
So by considering an occlusiondevice early, it's probably a
(44:35):
good idea to reduce thelong-term risk of both
hemorrhagic and ischemic stroke.
So, yeah, it comes back to oneof the thorny dilemmas in CA,
which is what do you do when youhave tons of glycolate Right?
Yeah, it comes back to one ofthe third-needle dilemmas in CA,
which is what do you do whenyou have tons of glycolate Right
?
Dr. Michael Kentris (44:47):
Yeah, stroking versus bleeding, and I
know the data is fairly equalpoise.
As far as, like you know, alow-dose aspirin or like mono
antiplatelet agent, I don'tthink the risk, if I remember
correctly, isn't particularlyelevated in terms of the balance
between ischemic versushemorrhagic stroke.
Is that correct?
Dr. Andreas Charidimou (45:08):
I think this is fair to say that there
are no randomized data just onthis population.
But based on this rationale youmentioned, in some centers
instead of givinganticoagulation they might give
low-dose aspirin to at leastmitigate some of the bleeding
risk while gaining something interms of preventing ischemic
(45:30):
strokes.
So the ongoing trials in thefield that they're randomizing
patients with hemorrhage,intracerebral hemorrhage they
don't explicitly include thesepatients that they present with
just sulcal subarachnoidhemorrhage and they have CAA.
Only one of the studies inCanada initially included these
(45:55):
patients, but there was.
They published a letter in lastneurology saying that the
interim review of theirmonitoring committee saw that
these patients are at high riskof events when they're
randomized to anticoagulationtreatment.
So they have stopped recruitingthis patient in the trial.
(46:18):
This was a trial looking on oralanticoagulation versus I don't
remember what was the other armaspirin or standard of care in
patients with intracerebralhemorrhage or CAA, and they had
these amyloid spells patientspotentially.
My rating of this is thatprobably, even when multiple
(46:42):
trials that are now ongoing arecompleted, we might not have a
good answer for this subgroup ofCA patients, either because
they're not included or becausethe risk was too high to even
randomize.
So we might need to just go inthe absence of evidence and
discuss what would be the mostrational and beneficial approach
(47:05):
.
Dr. Michael Kentris (47:06):
No, that makes sense.
Definitely a very challengingclinical scenario that it comes
up Not super duper rare, butyeah, no, I always appreciate
every time we talk I feel like Ilearn so much every time, so I
really do appreciate it.
Any final thoughts?
Anything you'd want to sharewith our listeners today?
(47:28):
Projects you're working onPlaces.
They can find you online.
Dr. Andreas Charidimou (47:31):
Yeah, sure, so I'm pretty active on
Twitter or X and I tend to postabout these dilemmas or ideas
about mechanisms, these dilemmasor ideas about mechanisms, and
you can share my email as wellin your webpage, and whoever I
(47:52):
mean.
If there are any questions, I'mhappy to answer.
I'm currently working on how tofurther improve diagnosis of CA
in different patientpopulations, using cohorts of
patients who had in vivo MRIplus neuropathology at some
(48:12):
point when they died or whenthere was a biopsy.
So I'm very open and seekingcollaborations because we need
numbers Awesome.
Dr. Michael Kentris (48:22):
Now we'll make sure to include your X
handle and your email in theshow notes for today, but thank
you so much.
I always really appreciate itand I really did learn a lot
today.
It's definitely going to changesome of the things I'm thinking
about as I encounter thesepatients in the future.
So thank you very much, thankyou.
Dr. Andreas Charidimou (48:40):
Thank you so much because your
questions made me think a lotand you're asking, like the
pertinent questions, about howto approach these patients and
what might be the underlyingmechanism.
So, yeah, I really enjoyedmeeting with you again.
Dr. Michael Kentris (48:57):
Oh, you're too kind.
And for anyone who wants tofind more, you can obviously
check out our past interviewwith Dr Charidimou about
cerebral amyloid angiopathy andour other episodes.
You can find us on all of yourmajor platforms and you can also
find more of our work at theneurotransmitterscom and you can
find our podcast handle on X atneuro underscore podcast and
(49:20):
myself at Dr KentrisD-R-K-E-N-T-R-I-S.
Thank you again, andreas andmyself at drkentris
D-R-K-E-N-T-R-I-S.
Thank you again, Andreas, it'salways a pleasure.
Dr. Andreas Charidimou (49:27):
Thank you Likewise.
Hello and welcome back to the
Neurotransmitters.
I'm your host, Dr.
Michael Kentris, and I'm reallythrilled to be recording
today's episode, as we arerejoined by a friend of the show
, Dr.
Andreas Charidimou, and todaywe are talking about a topic
that I find very fascinating,very challenging, and that is
amyloid spells.
Thank you again for joining ustoday, Andreas.
Dr. Andreas Charidimou (00:24):
Thank you so much for inviting me
again and I'm thrilled to talkagain about one of my favorite
subtopics in CEA.
Dr. Michael Kentris (00:32):
Yes, Just before we were hitting record,
you were saying that, obviously,for those who know you, you are
very well-published in thearena of amyloid angiopathy
cerebral amyloid angiopathy andyou were telling me that during
some of the talks that you get,whether or not you mention it
directly, one of the topics thatcomes up time after time is
(00:54):
these amyloid spells.
So could you just tell us alittle bit about what is an
amyloid spell and when should webe considering that on our
differential diagnosis?
Dr. Andreas Charidimou (01:03):
Yeah, sure.
So historically andtraditionally, the presentation
that most people have linkedwith cerebral amyloid angiopathy
, or CAA, is that of lobarintracerebral hemorrhage, and
this has been known for at least30 to 40 years with the advent
of neuroimaging 40 years withthe advent of neuroimaging.
(01:27):
One least known presentation,at least as of 10 years ago, is
these presentations with whatused to be called amyloid spells
or transient focal neurologicalepisodes related to CAA.
And, as the name implies, theseare episodes that are transient
, neurologic in nature and focal, and the prototypical
(01:51):
descriptions of these episodesare basically positive symptoms,
so paresthesias, pins andneedles, feeling, which are
migrating, and the syndrome thatwas first described and is more
characteristically associatedwith symptoms is spreading
positive sensory symptoms in thearm up to the mouth and then
(02:13):
slowly going back to normal inthe same fashion.
However, there is a spectrum,essentially from a symptomatic
point of view, it includes anytransient symptoms that they
might look similar to TIA.
So there might be negativesymptoms speech impairments,
focal weakness, arm or leg orthey can resemble auras visual
(02:40):
auras typically that they mightremind you the auras that you
typically see with migraine.
And, as you can tell, it is atough symptom to link directly,
tough phenomenology and notspecific to link directly to CAA
, because the differential isbroad.
(03:01):
When you see transient symptomsof any nature in neurology, but
when you should be suspectingthis, I think it's in any
patient that is on the olderspectrum of age, so any patient
older than 55 or 60 years oldcoming with transient symptoms,
(03:24):
you should be thinking.
When you think about TIAs,essentially you should be
thinking whether this isCA-related phenomenon and one of
the characteristics whichdifferentiates this from TIAs
actually is that these episodesare multiple and stereotypical,
whereas a TIA typically is goingto, you know, you're going to
(03:45):
have the episode once and thenprobably a different kind of
focal phenomenology if thepatient has a second TIA.
So in that sense it resembles abit focal seizure activity,
because focal seizure is anotherdifferential when you see a
patient with recurrent episodesand you think about TIAs, but
(04:05):
it's too stereotypical, happenedtoo many times, so you might
consider that this is a focalseizure.
So in that context I think youwould consider seizure-related
amyloid spells.
Dr. Michael Kentris (04:18):
Yeah, I'm going to have to update my
lecture that I give to traineesabout the differential diagnosis
for first-time seizure eventsto include amyloid spells.
But that is one of the trickythings, right, we always talk
about with migraine, withseizures, this kind of spreading
cortical depression, all thiskind of stuff, and it almost
sounds kind of like that samekind of phenomenon in this
(04:41):
situation.
And I know it gets even hairierwhen we start talking about
things in the epilepsy worldlike negative motor seizures and
things of that, which are alsostereotyped.
So one other thing you hadmentioned is that, whether these
are focal dysfunction versus,is it actually edging into the
(05:03):
territory of causing seizuresand when do you start to
consider one versus the other?
Or how does that kind of affecthow you approach these patients
?
Dr. Andreas Charidimou (05:13):
Yeah, it's a tough question, I think,
taking one step back.
Essentially, the question iswhat is the pathophysiology of
these symptoms?
Yes, excellent, and the answeris that we don't really know,
because we haven't studied thisphenomenon from a
(05:34):
pathophysiological point of view.
What happens is that behindthese symptoms there is
typically superficial bleedingin the form of a convex
subarachnoid hemorrhage in theacute phase, when this
phenomenon first occurs, orcortical superficial sclerosis,
(05:55):
which essentially reflectsvessel wall cracking in the
leptomeningeal space due to CAA,leading to even one drop of
blood on the surface of thecortex, which it creates a lot
of irritation.
So what has been suggested as amechanism based on how
(06:15):
stereotypical these episodes are, the positive phenomenology and
the spreading pattern, alongwith the timing of this spread,
is this might resemble amechanism similar to cortical
spreading depression, because incortical spreading depression
you have a slow wave ofexcitation which then is
followed by total inhibition ofcortical neurons, and this might
(06:40):
correlate in some of thesymptoms with the spreading
excitation creating the positivesymptoms and then slowly for
example, if you have pins andneedles going from the arm up in
the mouth and then slowly thosesymptoms going away.
But this is like a theoreticalassumption about the
(07:02):
pathophysiology, now that weknow that there is a huge
spectrum of these symptoms, frompositive to negative, I'm
thinking that maybe the negativesymptoms might be focal
seizures, again, maybe initiatedby the irritating aspect of
having blood on the surface ofthe brain, or sometimes having
(07:24):
acute microbleeds in corticalareas that are symptomatogenic,
and there is some indirectevidence that we should be
thinking about a seizuremechanism.
There was a recent study fromMayo Clinic and another one from
Italy where they look at theprevalence of epilepsy in
patients with CA specificallyand they did EEGs and they found
(07:48):
that the factors associatedwith epilepsy and focal seizures
, specifically based on EEGcaptures in CA is the presence
of cortical superficialsclerosis, which is very common
and underpins these amyloidspells, and the patient having
inflammatory CA.
There is a different kind ofmechanism because inflammatory
(08:10):
CA is a very it's a differentkind of disease with brain edema
and inflammation.
So I think the bottom line is,and the message that I want to
send is that probably patientspresenting with transient focal
immunological episodes, theydon't get enough EEGs and this
(08:33):
is underutilized in many centers.
Even when you do the brain MRIand you see an area of acute
subarachnoid hemorrhage orsiderosis, even when you ascribe
this to being CA-related.
I think an EEG would still beuseful because it's going to
change the symptomaticmanagement of these patients.
Dr. Michael Kentris (08:55):
That makes sense.
Dr. Andreas Charidimou (08:56):
Yeah.
Dr. Michael Kentris (08:57):
Now, again, I don't know the data well
enough when we look at and maybethe data isn't there when we
look at EEGs in patients withCAA or suspected CAA, plus or
minus the transient focalneurologic events, is the
sensitivity for, say, a routineEEG still that proposed around
(09:17):
50%, in which case a positiveresult is much more useful than
a negative result and perhapsyou might treat regardless if
there is a clinical history ofrecurrent stereotyped events,
particularly with positivesymptoms.
Dr. Andreas Charidimou (09:33):
Yeah, I don't think the data are there.
I would assume that thesensitivity should be similar to
the sensitivity in other focalseizures.
So if you capture something, Ithink it's very useful and a
positive indication.
If you don't capture anything,you might consider repeating it
if the symptoms recur, or useyour clinical judgment on how to
(09:56):
manage this.
In most of these patients, thesymptoms tend to resolve on
their own, presumably as theblood gets resorbed.
However, I think it makes sensein patients with negative
symptoms to look a bit deeperfor a focal seizure focus, and
also in patients even withpositive symptoms, when they get
(10:19):
too many of these I mean, Ihave had patients having 20
episodes per day.
Too many of these, I mean, Ihave had patients having 20
episodes per day.
So these are interfering withtheir life.
So in those patients you mightconsider a low dose
anti-epileptic which you wouldkeep the patient on for three to
six months, with the aim thento remove it as the symptoms
(10:40):
subside.
But this is, you know, know,this is just for the symptomatic
aspect of things.
The importance of theseepisodes are not the symptoms
per se, but it's what theyindicate, and they indicate
bleeding on the surface of thebrain which is is dangerous in
the setting of CAA.
(11:01):
So that's, you know, that's thesecond layer.
Dr. Michael Kentris (11:13):
So hypothetically.
So let's say we have a patientwho you know.
They come in with a kind of TIAlike event, you know an episode
of you know face weakness ornumbness or what have you.
That resolves spontaneously.
We get the MRI done and itshows maybe a small microbleed
that would localizeappropriately.
But they've only had one eventand let's say they're following
(11:34):
up in the neurology clinic three, six months later and when they
come back now they're havingthese events recurrently, so
kind of a change in frequency,if you will.
Would it be appropriate inthose patients to repeat imaging
to see like, is there arecurrence of a microbleed at
that point in time?
Dr. Andreas Charidimou (11:53):
Totally yes.
So if you have the diagnosis ofCA-related TFNEs, if there is a
silent period over two, threemonths and then the patient
presents again with even thesame symptoms, I think it's a
good indication to repeatimaging to see if there has been
a new bleeding event Inpatients that you have diagnosed
(12:16):
.
You know they have been havingrecurrent similar symptoms.
You don't necessarily need torepeat imaging.
But if one of those patientspresents with a totally
different symptomatology, thenagain the question is have they
had a small bleeding in anotherarea?
Because these symptoms arebasically it's like a clinical
(12:37):
marker of fragility of theleptomeningeal vessels in CAA
and this is a patchy diseasewhich means that there might be
other small bleeding events inother areas.
So yes, this is exactly thepatient population that you're
going to have.
Low threshold to re-image,because it's the only way to see
(13:00):
what has been the progression.
Dr. Michael Kentris (13:04):
Gotcha.
Now that makes complete senseand I think that's a great point
to emphasize right that CAA isa progressive neurodegenerative
condition.
Dr. Andreas Charidimou (13:15):
So we should expect this to be kind of
a moving target for a lot ofpatients.
Also, the other relevance ofthis is that, let's say you have
the patient you mentionedcoming to the emergency
department with some sort ofstereotypical transient
neurological symptoms.
Most clinicians at the top ofthe differential we're going to
have the TIA right and not allpatients will get immediately a
(13:39):
brain MRI, because to diagnosethis as amyloid spells you need
brain MRI with blood sensitivesequences.
Now, the big clinicalimplications in this scenario is
that if you think the patienthas a TIA and you don't have a
brain MRI, what's the treatmentfor?
Typically a TIA?
(13:59):
You start.
You start antithrombotics,right, yeah, and then you do the
workup.
However, if this was indeed anepisode of ca related tfnes due
to a small acute subarachnoidhemorrhage, by prescribing
antithrombotics you're pushingthe patient to bleed.
Dr. Michael Kentris (14:20):
More essentially, right, and would
this be a common scenario?
Because I've encountered thisonce or twice myself.
Obviously, at a you knowsmaller institution, our volumes
aren't going to be quite ashigh, but where we have someone
who comes in, it sounds like atia.
And then you get the mri andyou see like maybe, maybe they
don't meet full criteria for caa, but they're kind of in that
(14:43):
possible camp where you've gotlike a you know micro hemorrhage
in.
You know, maybe they came inwith aphasia and it's kind of in
that left temporal or frontalarea and you're like was this,
was this?
an amyloid event.
I don't have enough,necessarily.
I've got them on dualanti-platelet therapy right now.
Maybe I should deescalate thatto maybe just like a low-dose
aspirin.
Dr. Andreas Charidimou (15:03):
Yeah, we can discuss all sorts of
different scenarios.
But let me put it this way Evenone such patient if you get a
brain MRI, even if the patientfulfills criteria for probable
CAA, it doesn't mean that theepisode is due to CAA.
I think the highest level ofcertainty is when you see
(15:27):
siderosis or subarachnoidhemorrhage in an area
corresponding to the symptoms.
In that scenario you canbasically say that probably it
has something to do with thatacute bleeding and we can
discuss later.
But there is a wholedifferential of convexal
subarachnoid hemorrhage.
It's not the message, shouldnot be.
(15:48):
You see the CAA, it has a hugelist of potential diagnosis.
Now, if you only see amicrobleed but it's in the right
spot, I think you should pauseand think whether it's related
to that and maybe look for otherless sensitive markers of CA.
(16:14):
If this is a microblit in theright spot and the patient has
severe perivascular spaces inthe centrum semiovale or they
have these small subcorticalwhite matter spots that are
included in the BOSTON criteria,it kind of raises the pre-test
probability of these beingrelated to the symptoms.
In any case, you would stillneed to do a full workup for a
TIA because if on that site youhave a carotid stenosis, then
(16:39):
obviously, you know, the plotthickens but you need to address
that as well.
So in some patients it's verydifficult to have the exact set
diagnosis and there are casesthat at 1.5 Tesla using GRE, you
might see only a micro-bleeds.
And then you repeat imaging ona 3 Tesla MRI with an SWI
(17:02):
susceptibility-weighted imagingand then you see that oh,
actually there is a tiny spot ofsclerosis.
So imaging is not you know.
Dr. Michael Kentris (17:12):
Now I'll create a beautiful yeah.
No, that's a great point.
And I know our institution juststarted using SWI sequences in
some of their protocols,thankfully, so that has been
helpful.
So we're kind of finally cominginto the 20th century a little
bit.
But yeah, no, I think that's agreat point, and I've certainly
(17:33):
had those patients, as youintimated, where you know, maybe
you've got a little bit ofhemorrhage, you've got a bad
carotid, maybe they also have ahistory of epilepsy too and
you're like well, which one ofthese is the culprit this time
around?
And it does become very, verychallenging.
Dr. Andreas Charidimou (17:49):
Yeah, yeah, it is very challenging and
we don't know what's the sizeof the problem.
In other words, how many ofthese patients are missed.
How many are they diagnosed asTIAs or as focal seizures?
The only study that I'm awareof is a study from Calgary where
they actually wentretrospectively and they looked
(18:11):
at their TIA registry.
I think they had around 400patients and they reviewed the
MRIs to see how many patientsfulfilled BOSTON criteria for
CAA and in how many of thosethere was an area of bleeding
anatomically correspondingpotentially to the symptoms.
(18:32):
And I think they reported thatin about 1% of their total
population.
Actually retrospectively, theythought that those were actually
not TIAs but they weretransient focal neurological
episodes due to CAA, which itdoesn't sound like a huge number
.
But if you put into perspectiveon how common TIAs are, the
(18:56):
absolute number of patientsgetting misdiagnosed, especially
in centers or countries thatMRI is not part of the initial
workup, then this number ispretty high.
Dr. Michael Kentris (19:11):
No, that's a great point, especially, like
you said, in rural areas.
I know that there's differentprotocols, like where you get
the CTAs to make sure there'snot a hot carotid or anything
like that, and you kind of workthem up over the next two weeks
as an outpatient, yeah.
But yeah, that's a great point,there are certainly things that
will not be captured, kind ofdoing that low resource triage.
Dr. Andreas Charidimou (19:35):
And actually my involvement in CAA
started by seeing one of thesepatients.
There was a patient that cameto the emergency department of
University College London at thetime when I was starting my PhD
, with a lobar hemorrhage andwhen we looked back a few days
before, the patient presented tohis PCP a primary care
(20:00):
physician with some sort oftransient episodes positive in
nature I think the left arm wasaffected and up the mouth, and
at the time I don't know if it'sstill the case in the UK the
protocol was that the patientgets a CT, you initiate
antiplatelet therapy and thenthey go to a TIA clinic at some
(20:23):
point and this is what they havedone.
When we saw the brain MRI,close to the area of the
hemorrhage there was an area ofacute subarachnoid hemorrhage
and some chronic sclerosis, alsoin remote areas.
And when we went back to the CTwe actually saw that there was
(20:44):
a tiny, tiny bit of blood in theright sulcus and at the time I
had no idea what that was.
And my PhD supervisor, davidWaring, he says, oh yeah, this
is probably amyloid spells.
And looking in the literaturewe realized that there were just
(21:07):
some case reports of thisphenomenon and this is how we
started assembling a multicentercohort to see, indeed, if this
is a common phenomenon, what arethe symptoms and what is the
risk of bleeding.
And this is how siderosisactually gained validity in the
(21:32):
CA field as a good imagingpredictor of the disease and the
risk of bleeding through theseTFNEs or amyloid spells.
Dr. Michael Kentris (21:41):
Fascinating , yeah, and I was telling you
before we started recording.
You know, I've only really hadthese in my consciousness for
about three to four years myself, which, you know, going through
epilepsy and things like that Iwould expect to have.
You know, transient neurologicevents are kind of our thing, so
I would have really expected tohave heard more about them.
(22:01):
But it is one of those thingswhere it's, you know, kind of
the most common disorder you'venever heard of is how it feels.
Dr. Andreas Charidimou (22:08):
Yeah, yeah, yeah.
I wonder if some patients theymight have a very brief episodes
they don't even seek uh uh, youknow medical care and some of
them they then, you know,develop a hemorrhage or they
might not have any othersymptoms for good periods of
time.
So those are totally missed.
Dr. Michael Kentris (22:29):
No, it makes complete sense.
Those are totally missed.
No, it makes complete sense.
And so one thing that I've beenkind of curious about, if
you're willing to speculatewildly with me we know that
there's a lot of anti-amyloidtherapies kind of coming into
the public consciousness thesedays, like aducanumab, lacanumab
, all those kinds of things thatare these anti-amyloid types of
(22:52):
treatments, and we know thatthere is this inflammatory
subtype of CAA.
How, or if, do you think thereis any pathophysiologic
relatedness between the aria,these inflammatory adverse
effects that we're seeing withsome of these anti-amyloid
therapies, as opposed to theselike transient focal neurologic
(23:15):
events that we see in thecontext of CIA, versus like
Alzheimer's disease in general?
I know it's a very broadquestion for which there's not a
huge amount of literature, butI'm just curious what your
perspective may be.
Dr. Andreas Charidimou (23:28):
Why are you asking this question?
Have you seen a patient thatmakes you wonder about
inflammation in the setting oftransient spells?
Because your question is veryat the point, I have to say.
Dr. Michael Kentris (23:41):
So I have had a couple inflammatory
CAA-type patients come in.
They kind of almost have thattumor-factive or neoplastic look
on the initial MRI and yourepeat it again three to six
months later and it's quieteddown a bit some residual
hemorrhage there.
But they will come in sometimes.
Sometimes they will come inlike maybe in focal status or
(24:01):
maybe have had a seizure atonset, things like that.
And then we've got these ARIAepisodes with the anti-amyloid
therapies and there's, you know,again, right, these kind of
various neurologic phenomenathat tend to occur, whether
those are visual sensory kind ofdisturbances and it's, you know
, it just seems too close to becoincidence.
Uh, just from an observationyeah, you're totally right.
Dr. Andreas Charidimou (24:24):
I think if we put it simply a bit
simplistic, but I think it worksfor our discussion is that, uh,
aria is basically iatrogenic.
Ca related inflammation, thethe two are, you know, mirror
images.
One is caused by a treatmentthat we do, the other one occurs
(24:46):
spontaneously.
So we can learn a lot fromCA-related inflammation, because
many of those things probablyapply to ARIA, including the
spectrum of the disease.
So CA-related inflammationtypically it was considered a
condition during which thepatient will be very severely
(25:11):
affected, an encephalitis kindof picture, with changes in the
level of consciousness, seizures, commonly with status
epilepticus, and basically thesepatients will end up in the
neuro ICU and on the MRI CSF.
All the workup and on the MRICSF, you know, all the workup
(25:35):
you will and often a brainbiopsy you will land on the
correct diagnosis.
Now I think, with greaterawareness and more widespread
use of brain MRI and bloodsensitive sequences, we're
realizing that this is only thetip of the iceberg.
There are patients with CRNinflammation that they present
(25:55):
with minimal symptoms, at themilder end of the spectrum, I
think, our patients with CRNinflammation that they present
with amyloid spells.
I have no idea how common thispresentation is, but for the
past year I have encounteredthree patients.
These patients they presentedwith positive or negative
symptoms, transient,stereotypical.
(26:18):
On the brain MRI there wasevidence of bleeding in the
right area.
And these patients, they keptcoming to the hospital with more
episodes and more acutebleeding in that same area,
which makes you wonder.
This is not the typical, youknow wild variety of amyloid
(26:40):
spells that they will have oneepisode and then things are
going to go silent.
There was evidence of somethinggoing on locally.
Vessels keep bleeding.
I think in these patients,completely anecdotally, a
contrast study will be usefulbecause in these patients that I
mentioned, a contrast studyshowed leptomeningeal
(27:01):
enhancement in the very areathat was bleeding, which makes
you think if there was aninflammatory element.
And in fact two of thosepatients we treated empirically
with corticosteroids and thereis no control group.
(27:27):
But the patients are doing welland they haven't had any
bleeding since.
So, translating this to ARIAARIA is also a spectrum from
asymptomatic, so just imagingmanifestation, which, by the way
, I think is the only case thatshould be called ARIA.
Asymptomatic is the onlyscenario that you should be
calling this amyloid-relatedimaging abnormalities.
When the patients are havingsymptoms, there are no imaging
(27:50):
abnormalities alone any longer.
It's like they come with asymptom.
We should have a better name tomaybe sulcal hemorrhage or
(28:11):
maybe fluid extravasation oredema focally.
Now we might not encounterthose patients very often,
because when a patient is onleucanumab, let's say, these
patients are monitored prettyclosely with serial brain MRIs,
(28:34):
typically after the fourthinfusion, after the seventh
infusion, and this is when ARIAhas higher likelihood of
happening.
In other words, you mightcapture ARIA on imaging before
it started manifesting withsymptoms, aria on imaging before
it started manifesting withsymptoms.
But I think it is possible thatsome of these amyloid spells,
(28:57):
especially recurrent anddifferent types, or even the
same types, sometimes they mighthave an inflammatory basis,
with or without anti-amyloidtreatments.
This is something that is acompletely new realization.
There are only a couple of casereports, I believe, interesting
(29:17):
.
Dr. Michael Kentris (29:18):
Because I have wondered in the past
because, if I remember correctly, a history of intracranial
hemorrhage of various types iskind of a contraindication to
starting these anti-amyloidtherapies.
So are we causing this or arewe unmasking it with some of
these anti-amyloid therapies?
I don't know if there's a goodanswer to that.
Dr. Andreas Charidimou (29:40):
It's a very good question.
First of all, I think in somepatients the anti-amyloid drug
is like a crash test to revealif there is underlying CAA,
because it's going to push thepatient to express the
cerebrovascular amyloidpathology.
(30:01):
And for ARIA, I mean, we don'treally know what's the cause.
Right, there are twopredominant hypotheses.
The first one is that eitherthe anti-amyloid antibody binds
directly to the vascular amyloid, with different affinity but
still binds there, inducinginflammation and vessel wall
(30:22):
breakdown, or alternatively, asthe amyloid plaques and the
antibody and the inflammationkind of gets broken down, some
of that needs to be removed fromthe brain via the perivascular
space and the perivascular spaceis the scene where amyloid
angiopathy also manifests.
(30:44):
So there is a problem with theperivascular drainage in
patients with CAA.
So those again simplistichypothesis is that these
breakdown products, they getclogged in there again, inducing
(31:04):
inflammation.
So essentially one of theprimary risk factors for
developing ARIA is havingunderlying amyloid angiopathy
(31:32):
recommendations.
When they say you shouldn't begiving these treatments to
patients who have four or moremicroblades or to patients who
have sclerosis, essentiallyindirectly you're saying you
shouldn't be giving thesepatients when it's very obvious
they might have evidence ofadvanced CAA.
But many patients have eitherfewer microblades or more silent
CAA and then you do the crashtest.
(31:53):
So essentially, these patientsneed to be very carefully
selected and obviously veryclosely monitored.
Dr. Michael Kentris (32:05):
That makes good sense.
Something you mentioned earlieris you know, it seems like a
lot of the emphasis on kind ofthese transient, focal
neurologic events is related tomore of the superficial
siderosis, so the kind of thatcortical surface.
But we need to not anchor onthat too much.
So you mentioned that you havea differential diagnosis that
(32:26):
you kind of work through whenyou see these cortical bleeds.
What kind of things also gothrough your mind as far as
potential underlying etiology.
Dr. Andreas Charidimou (32:34):
Yes.
So I think we can approach this.
First, obviously you have adifferential diagnosis of the
episodes, of the episodesthemselves, and we mentioned
TIAs especially for a firstcomer with these episodes.
First comer with these episodes, so TIAs, focal seizures,
(32:57):
migraine with aura, sometimesmetabolic abnormalities.
I mean I'm sure you have seenpatients with hypoglycemia who
have focal symptoms, functionalurological disorders.
So there is a wholedifferential just based on the
clinical symptoms and thecontext and then based on
imaging.
If you see acute subarachnoidhemorrhage, there is a whole
(33:21):
different differential diagnosiswhich includes things like
small AVM, any sort of vascularmalformation causing the bleed
in that area, sometimes smallaneurysm.
You can have endocarditiscausing an aneurysm there,
(33:42):
inflammatory again in nature, orseptic embolism causing the
bleeding.
You might have RCVS which cancause convex subarachnoid
hemorrhage.
There the age is a goodindicator.
For example, the most commoncause of convex subarachnoid
hemorrhage in someone youngerthan 50 years old is typically
(34:05):
RCVS, whereas the most commoncause in someone older than 60
years it's amyloid angiopathy.
Then you can have IV drug usecocaine, heroin can cause, via a
similar mechanism to RCVS,convexal subarachnoid hemorrhage
.
(34:25):
So for that again, the clinicalhistory and what are the other
imaging findings are going toguide you on what might be the
underlying diagnosis.
Do you see other areas ofchronic superficial bleeding,
any other areas of sclerosis?
Do you see lower micron bleeds?
In other words, is thereevidence that there have been
(34:47):
similar bleeding events in anelderly individual, evidence
that there have been similarbleeding events in an elderly
individual, solidifying yourdifferential that this might be
CAA?
But again, you keep an openmind because you still need to
do a workup for the rest of thepatients, including vessel
imaging.
Dr. Michael Kentris (35:06):
No, that makes complete sense.
Now, something you mentionedabout some of these people with
recurrent, sometimes disablingor very frequent episodes that
are disturbing to them.
Potentially, you mentionedyou'll put them on an
anti-seizure medication forsometimes a dedicated period of
time, like three to six months.
Is it likely that after theacute hemorrhage, that when you
(35:31):
wean them off the anti-seizuremedication, that these spells
will not recur, or do you findthat this is more of a lifelong
anti-seizure medication for somepatients?
Dr. Andreas Charidimou (35:40):
Yeah, so this is kind of different with
patients with focal seizures inthat the idea.
So the idea is that theseepisodes, unless there is more
bleeding, they will tend tosubside because the blood will
get absorbed into hemocytogenand it's going to be less
irritating.
(36:00):
So the majority of thesepatients will have resolution of
the symptoms over a period ofthe next three to six months.
The idea of putting someone onan anti-epileptic patient I mean
with a CRLTFN is twofold.
First, if you have identified afocal seizure on EEG as the
(36:21):
mechanism and you believe thisis just CAA, then you would put
the patient on anti-epileptics.
If you haven't identified thatmechanism which I guess is your
question if there are multipleepisodes, you're going to put
this patient on ananti-epileptic with the hope
that it might help with quickerresolution and with the idea
(36:43):
that as soon as the episodes getresolved which might relate to
the natural history of thecondition, which might relate to
the natural history of thecondition, then you try to get
off the patient from theanti-epileptic.
It's not going to be for life,so typically the longest I have
used anti-epileptic in one ofthese patients is up to a year.
(37:05):
Okay, no, that's good to know.
So then you take them off.
I'm not even sure if theanti-epileptics were doing
something or the symptoms weredeemed to get resolved.
Dr. Michael Kentris (37:15):
Their natural history, taking care of
itself.
Yeah, that's a good point.
Dr. Andreas Charidimou (37:19):
There are some people that try to use
anti-epileptic medications thatthere are ex vivo data that they
actually might affect corticalspreading depression.
Dr. Michael Kentris (37:33):
I think lamotrigine is one of them more
in the sodium channel?
Yeah, I would imagine.
Dr. Andreas Charidimou (37:38):
Yeah so that's another rationale.
That may be with the with someantiepileptics, where you're
targeting cortical spreadingdepression in addition to
epileptogenicity.
So but Keppra, I think, as inmany other areas of urology, is
often to go to medication 500milligrams.
(37:59):
Right, just plug and play Twiceper day, which is a low dose
but still a good dose in anelderly individual.
Lacosamide is the one I used aswell.
Dr. Michael Kentris (38:15):
Again, completely non-evidence based,
right.
Well, I gotta start somewhere.
Dr. Andreas Charidimou (38:18):
Yeah, and this is not this is a rare
scenario to start on to have somany episodes that you're gonna
start an anti-epileptic.
It's like maybe 10% of all theCA-related TFNs You're going to
need to do that.
Dr. Michael Kentris (38:34):
Gotcha, yeah.
So my takeaway as far asanti-seizure meds would be
recurrent stereotyped episodes,maybe more of a preponderance of
positive symptoms, and ifthey're disabling, obviously,
and you find no evidence of Like, in the absence of recurrent
bleeding, would you say or plusor minus.
Dr. Andreas Charidimou (38:56):
So I would go purely by the
recurrence of clinical symptoms.
Okay now, if there was arecurrent bleed without any
evidence of either a new seizureor a new episode, there is no
indication to continueanti-epileptics.
Dr. Michael Kentris (39:11):
You wouldn't do it prophylactically
okay because I know we stillthere's a little bit of debate
out there for like some of theyou know intraparenchymal
hemorrhages, about uh,prophylactic anti-seizure
medications, but I see a lot of,because sometimes these these
consults will come more to theneurosurgeon than to the
neurology team as far as like a,a small subarachnoid hemorrhage
(39:33):
, so everyone gets put on youknow capra or something like
that for seven days.
Dr. Andreas Charidimou (39:38):
You know kind of like the traumatic
brain injury type uh, yeah, Iguess it varies between
institutions.
Dr. Michael Kentris (39:45):
So right, right yeah but no, those, those
are all very helpful points.
I really love the the tip aboutusing the contrast at mri.
It's not something I thinkabout with um, with these types
of patients, with when I'm kindof doing the tia or caa kind of
evaluation, but I'm going todefinitely keep that one in my
back pocket going forward yeah,especially when you see a
patient that is a bit differentor atypical to the patients you
(40:10):
have seen before, with theseepisodes.
Any other questions that youfind come up a lot from people
asking you about amyloid spellsor the TFNEs that you think
would be useful for people toknow about or would help them
identify these patients.
Dr. Andreas Charidimou (40:27):
I think there are two questions that
they have been coming up a lot.
The first one is okay, thepatient comes to the ED with
these symptoms.
You do a brain MRI or even a CTinitially and you see there is
an acute subarachnoid hemorrhage.
Is an acute subarachnoidhemorrhage, how do you treat
(40:48):
this patient?
And my answer is that it'sreasonable to send this patient
to the new ICU with the aim of,essentially, you should treat it
as a hemorrhage, as a brainhemorrhage, intraparenchymal
hemorrhage in terms of loweringthe blood pressure, having a
very strict target closelymonitoring these patients for
(41:08):
any recurrence of the bleeding.
And it might be a short stay itmight be just one day just to
control the blood pressure if itwas high and have a more
definite diagnosis.
So this again depends onavailability in each individual
center, but I think the bloodpressure in the acute setting,
in the first 24 hours, is areasonable target to have in the
(41:32):
management of these patients.
So this is in the acute setting.
The second question that comesup very often is what is the
risk of these patients having alower hemorrhage and what do you
do when you find out that theyhave AFib or they have another
indication for anticoagulation,which is something that we
(41:54):
discussed in the previouspodcast.
But I think the overallapproach is that these patients
again they should be treatedsimilarly to a patient who had a
lower hemorrhage due to CAA interms of the future risk of
hemorrhage, because it's notthat the amyloid spells increase
(42:18):
the risk of future hemorrhage.
The reason that these patientshave high risk of hemorrhage is
that they have a lot of corticalsuperficial sclerosis.
So the imaging manifestation isa biomarker of severe or
advanced CAA.
So it's likely that you know,very stochastically, one of
(42:41):
these small vessels will pop andthe hemostatic mechanism might
not be enough to seal the crackand these patients might end up
with a lower hemorrhage.
So we know from observationalstudies that these patients they
might have risk of futurehemorrhage from 15 to 20 percent
(43:03):
per year, risk of futurehemorrhage from 15% to 20% per
year.
And the risk you can kind ofquantify it based on what are
the imaging manifestations of CAon the rest of the brain?
Do they have multiple areas ofsiderosis?
Did they come with a secondepisode of acute subarachnoid
hemorrhage?
Both of those scenariosincrease the risk of hemorrhage.
(43:25):
We also know that they haveconsiderably high risk of an
ischemic stroke, just based onhow common vascular risk factors
are in these elderly patients.
So it is a good target group totry something other than
anticoagulants.
(43:46):
Probably they are at the highend of the spectrum in terms of
future hemorrhage where probablymany neurologists will feel
uncomfortable putting thepatient on an anticoagulant.
So these are the patients thatprobably they might warrant a
discussion with cardiology.
If they have AFib, that is, toget a left atrial appendage
(44:09):
occlusion device, and the ideabehind it is that both CAA and
atrial fibrillation areconditions that inevitably
they're going to progress areconditions that inevitably
they're going to progress.
So by considering an occlusiondevice early, it's probably a
(44:35):
good idea to reduce thelong-term risk of both
hemorrhagic and ischemic stroke.
So, yeah, it comes back to oneof the thorny dilemmas in CA,
which is what do you do when youhave tons of glycolate Right?
Yeah, it comes back to one ofthe third-needle dilemmas in CA,
which is what do you do whenyou have tons of glycolate Right
?
Dr. Michael Kentris (44:47):
Yeah, stroking versus bleeding, and I
know the data is fairly equalpoise.
As far as, like you know, alow-dose aspirin or like mono
antiplatelet agent, I don'tthink the risk, if I remember
correctly, isn't particularlyelevated in terms of the balance
between ischemic versushemorrhagic stroke.
Is that correct?
Dr. Andreas Charidimou (45:08):
I think this is fair to say that there
are no randomized data just onthis population.
But based on this rationale youmentioned, in some centers
instead of givinganticoagulation they might give
low-dose aspirin to at leastmitigate some of the bleeding
risk while gaining something interms of preventing ischemic
(45:30):
strokes.
So the ongoing trials in thefield that they're randomizing
patients with hemorrhage,intracerebral hemorrhage they
don't explicitly include thesepatients that they present with
just sulcal subarachnoidhemorrhage and they have CAA.
Only one of the studies inCanada initially included these
(45:55):
patients, but there was.
They published a letter in lastneurology saying that the
interim review of theirmonitoring committee saw that
these patients are at high riskof events when they're
randomized to anticoagulationtreatment.
So they have stopped recruitingthis patient in the trial.
(46:18):
This was a trial looking on oralanticoagulation versus I don't
remember what was the other armaspirin or standard of care in
patients with intracerebralhemorrhage or CAA, and they had
these amyloid spells patientspotentially.
My rating of this is thatprobably, even when multiple
(46:42):
trials that are now ongoing arecompleted, we might not have a
good answer for this subgroup ofCA patients, either because
they're not included or becausethe risk was too high to even
randomize.
So we might need to just go inthe absence of evidence and
discuss what would be the mostrational and beneficial approach
(47:05):
.
Dr. Michael Kentris (47:06):
No, that makes sense.
Definitely a very challengingclinical scenario that it comes
up Not super duper rare, butyeah, no, I always appreciate
every time we talk I feel like Ilearn so much every time, so I
really do appreciate it.
Any final thoughts?
Anything you'd want to sharewith our listeners today?
(47:28):
Projects you're working onPlaces.
They can find you online.
Dr. Andreas Charidimou (47:31):
Yeah, sure, so I'm pretty active on
Twitter or X and I tend to postabout these dilemmas or ideas
about mechanisms, these dilemmasor ideas about mechanisms, and
you can share my email as wellin your webpage, and whoever I
(47:52):
mean.
If there are any questions, I'mhappy to answer.
I'm currently working on how tofurther improve diagnosis of CA
in different patientpopulations, using cohorts of
patients who had in vivo MRIplus neuropathology at some
(48:12):
point when they died or whenthere was a biopsy.
So I'm very open and seekingcollaborations because we need
numbers Awesome.
Dr. Michael Kentris (48:22):
Now we'll make sure to include your X
handle and your email in theshow notes for today, but thank
you so much.
I always really appreciate itand I really did learn a lot
today.
It's definitely going to changesome of the things I'm thinking
about as I encounter thesepatients in the future.
So thank you very much, thankyou.
Dr. Andreas Charidimou (48:40):
Thank you so much because your
questions made me think a lotand you're asking, like the
pertinent questions, about howto approach these patients and
what might be the underlyingmechanism.
So, yeah, I really enjoyedmeeting with you again.
Dr. Michael Kentris (48:57):
Oh, you're too kind.
And for anyone who wants tofind more, you can obviously
check out our past interviewwith Dr Charidimou about
cerebral amyloid angiopathy andour other episodes.
You can find us on all of yourmajor platforms and you can also
find more of our work at theneurotransmitterscom and you can
find our podcast handle on X atneuro underscore podcast and
(49:20):
myself at Dr KentrisD-R-K-E-N-T-R-I-S.
Thank you again, andreas andmyself at drkentris
D-R-K-E-N-T-R-I-S.
Thank you again, Andreas, it'salways a pleasure.
Dr. Andreas Charidimou (49:27):
Thank you Likewise.
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