May 7, 2024 • 33 mins
Hello and welcome back to our ongoing internal medicine - neurology board review series!
Today we are covering multiple sclerosis (MS).
Tune in to learn more about
- What signs & symptoms should prompt concern for MS?
- What goes into the diagnosis of MS?
- What does the clinical course of MS look like?
- What kind of treatments are out there for MS?
And this just scratches the surface!
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- Find me on 𝕏 @DrKentris
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.
Michael Kentris (00:00):
Hello and welcome back, dear listener.
You are listening to theNeurotransmitters podcast, your
source for everything related toclinical neurology.
I am your host, Dr MichaelKentris, and today we are
continuing our internal medicineneurology subtopic board review
series.
Today's topic is multiplesclerosis.
We are going to talk about thesigns and symptoms that should
(00:21):
make us think about multiplesclerosis, how we diagnose
multiple sclerosis, what do thetypical clinical courses look
like for multiple sclerosis andwhat kind of treatment options
do we have.
So when should we think aboutmultiple sclerosis, or MS as I'm
going to call it from hereforward?
So MS is one of those diseasesthat can present in many
different ways, but there are afew that are kind of classic and
(00:42):
especially when we're talkingabout question stems on an exam,
there are some that shouldreally raise a red flag for you
to pay attention to, and we canlump these together into a few
different categories.
I'm going to put these in theoptic neuritis, brainstem
syndromes, spinal cord syndromesand then kind of a
miscellaneous grab bag.
Let's start with optic neuritis.
This will usually present withmonocular, blurred vision, and
(01:05):
one trick that I like to use tohelp us differentiate whether
this is a refractive error, thatis to say something in the
globe itself, like the cornea orthe lens or even in the other
parts of the eye, versus in theoptic nerve, is to use a pinhole
occluder.
That's one of those things thatyou cover the eye with that has
just tiny little holes in itand you can kind of improvise
one if you don't have one inyour neurology bag.
(01:26):
If you just take a note cardand poke a hole with it with a
pin, you can use that.
And if someone's visual acuityimproves with the pinhole
occluder, that suggests thatit's more of a refractive error
in the eye rather than opticnerve related.
Perhaps.
You can also see things calledred desaturation, where red
colors are less vivid and youwill sometimes have pain with
(01:48):
eye movement.
You may also see an afferentpupillary defect, that is to say
when you do your swingingflashlight test, so you're
shining in one eye and youimmediately go to the other eye
and back and forth.
So when you're shining thelight in the eye that is
affected, the pupil will dilateto direct light, but if the
other eye is normal it shouldconstrict with consensual light
(02:11):
and again this is called anafferent pupillary defect.
Sometimes in the olderliterature you'll see it called
a Marcus Gunn pupil.
Now when someone is coming inwith these symptoms and you're
suspecting optic neuritis, it isimportant to do a fundoscopic
exam.
Acutely you may see evidence ofpapilledema or papillitis, and
chronically they may haveevidence of optic nerve atrophy.
So you can sometimes see thisif it is the anterior portion of
(02:33):
the optic nerve affected, butif it's more in the posterior
part of the optic nerve you mayhave a normal fundoscopic exam
on these patients.
So in the setting of MS, thisis usually going to be
unilateral Now.
So in the setting of MS, thisis usually going to be
unilateral.
Now there are somedemyelinating syndromes that may
present with bilateral opticneuritis, and so if you have
bilateral optic neuritis, thatshould be a red flag for you to
consider things that aredemyelinating but not MS, things
(02:57):
like neuromyelitis, optica orNMO, and myelin oligodendrocyte
glycoprotein, abbreviated MOG orMOG.
As a pretty big nerd myself, Ican never hear MOG without
thinking about the characterfrom Final Fantasy.
So if you're familiar, then youtoo also know that Final
Fantasy VI is the best FinalFantasy game.
Another category that we'lloften see with MS are brainstem
(03:18):
syndromes, and these can presentwith a variety of different
symptoms as well, includingnystagmus, dyplopia, other types
of eye movement abnormalities,things of that nature.
You can also get somecerebellar or vestibular type
symptoms with ataxia or vertigo.
One of the classic eye movementabnormalities that you may see
or may be asked about is an INOor internuclear ophthalmoplegia,
(03:40):
and this is an inability toadduct AD-duct one eye with
nystagmus in the AB abductingeye, and this is usually due to
a lesion in the MLF, the mediallongitudinal fasciculus.
There are, of course, manyother eye abnormalities.
I mention INO specificallybecause it is a favorite for
test writers.
Moving on to spinal cordsyndrome, so this may present as
(04:02):
a transverse myelitis typesyndrome or other types of
myelitis or spinal cord relatedtype disabilities, weakness,
numbness in the limbs, arms,legs, etc.
Depending on what level it's at.
You may get a sensory level inthe thoracic spine, etc.
There are a couple differentsymptoms that patients with MS
may describe when they havelesions in the spinal cord.
(04:23):
One of these is Lhermitte'ssign, which is a shock-like
sensation that runs down thespine or into the limbs with
neck flexion, typically in thecervical spine.
You can also get a quote MS hug, and this is a band-like
sensation, often around thechest.
Urinary symptoms can also becommon when people have spinal
cord lesions.
These can include symptoms ofurinary retention, urinary
(04:44):
urgency or urinary incontinenceand, as we mentioned earlier,
there are a lot of miscellaneousor various hard-to-pin-down
sort of symptoms that can occurwith MS as well.
People may fatigue more easilythan normal.
They may describe a quote,brain fog.
There may be evidence ofcognitive decline.
On examination you can also geta phenomenon with people who
(05:05):
have more long-standing MS,something called the Uthoff's
phenomenon, which is a transientworsening of their baseline
neurologic deficits.
This is often in the setting ofwhen they have an infection
with fevers, in the setting ofhot weather or if they
physically overexert themselves,and this may lead into what
sometimes is called apseudo-relapse or a pseudo-flare
, or essentially a recrudescenceof prior neurologic deficits in
(05:27):
the setting of some otherstressor on the body.
So now we know some symptoms tomake us think about MS, but what
about when we want to get to adiagnosis?
There can be some challenges incoming to a diagnosis of MS
because there are many thingsthat can mimic it, and we'll
talk about those in a minute.
But the criteria that we'reusing presently are the revised
McDonald criteria, and you mayhave heard this phrase.
Dissemination in time and spaceAlways makes me think of a
(05:50):
Doctor who episode.
But what we mean when we saydissemination in time and space
is that we want multiple lesionson MRI or clinical events
separated by at least two pointsin time or two points in space,
that is to say in the neuroaxis.
So there are a couple differentpermutations that can get us to
that point.
So let's say we have someonewho has had two or more clinical
(06:12):
attacks and we want to see atleast two objective findings on
MRI MRI being our maindiagnostic imaging that we're
using in MS.
So if we see two lesions thatcorrelate with those clinical
symptoms, then that meets ourcriteria.
If we have two or more clinicalattacks with at least one lesion
on imaging that correlates withour symptoms, that, plus the
(06:35):
past history of an event thatsounds suspicious for a
demyelinating attack, can meetcriteria.
And this is why it's importantwhen you're first seeing someone
who you suspect may have MS isto really dig into that history
and see how you had any of thosepast episodes going on for
sometimes days to weeks ofblurred vision, weakness,
numbness, vertigo, etc.
(06:55):
That could potentiallyrepresent a past attack.
So that way you know if they'vehad a previous attack and now
you have one new attack with anMRI abnormality at this time,
then you can still lean a lotmore favorably towards getting a
definitive diagnosis.
Where things can get a littletricky is if you have one
clinical attack, or what we callclinically isolated syndrome,
(07:18):
and we'll talk a little bit moreabout that as we go on.
But if we have one clinicalattack and you get your MRI and
you see one old lesion and thenone new and what we mean by a
new lesion is one that is anenhancing with IV contrast so if
you have an enhancing lesionand an old non-enhancing lesion,
that is your dissemination intime.
(07:38):
And if those are in differentlocations in the neural axis,
there's your dissemination inspace as well.
But it gets even hairiersometimes.
Let's say, we have one clinicalattack clinically suspicious
for multiple sclerosis and youhave an MRI lesion that
correlates with those symptomsthat also look suspicious for
demyelinating disease.
So maybe you have a coupleenhancing lesions.
There's your dissemination inspace, but you don't have any
(08:01):
old lesions on MRI.
This is where getting CSFstudies tends to be the most
beneficial as far as getting toa definitive diagnosis of MS.
So we're checking our routineCSF labs and we're also checking
oligoclonal bands, as they tendto be fairly specific to MS,
although not 100%.
So let's recap that once more.
So we are looking fordissemination in space, that is,
(08:23):
more than one T2 hyper-intenselesion.
Now we talk about differenttypes of white matter lesions.
These are going to be usuallymore than three millimeters on
their long axis.
They tend to be a littlefluffier than what we would see
for patients with migraine orcerebrovascular disease and
there are a few locations thattend to be more typical for MS.
So we can see periventricularlesions and we're looking for
(08:46):
more than one lesion, unless thepatient is over the age of 50,
right, because of thosecerebrovascular risk factors, in
which case you usually want tosee a higher number.
You can also see cortical orjuxtacortical lesions,
infratentorial lesions in thebrainstem or cerebellum, and
then spinal cord lesions.
And to recap on thedissemination in time, if we
(09:06):
have a first-time MRI that showsa new enhancing lesion as well
as an old non-enhancing T2hyper-intense lesion that is
characteristic of demyelinatingdisease, that can meet our
criteria for dissemination intime.
Or if we have an old MRI thatshows a T2 hyper intense lesion
and then we get a new MRI andthat new MRI shows a new lesion,
(09:29):
whether it is enhancing or not,and so that can also establish
our dissemination in time,because we have new lesions from
point A to point B.
So let's dig a little bit moreinto the testing that we will
often do.
Working someone up for MS, aswe've been talking about, mri is
often the mainstay of theinitial diagnostic battery.
So we are looking often at thebrain and, depending on symptoms
(09:51):
, may also be looking at thecervical and or thoracic spine,
and very often we are going tobe getting these with and
without IV gadolinium contrast,and that is because we're
looking for enhancing lesions.
Monitoring MRIs down the roadmay or may not need gadolinium.
That is more of a situation,case-by-case basis, so we're not
going to go into that too muchright now.
If there is a clinical suspicionfor past optic neuritis, there
(10:13):
are a couple tests that can bedone.
So there are visual evokedpotentials, or VEPs, and there
is also optical coherencetomography or OCTs, and both of
these can show evidence of prioroptic neuritis and they tend to
stay abnormal kind ofindefinitely.
So that can be a very helpfultest in terms of if the MRI
doesn't show any abnormalities,then you might get one of these
(10:34):
tests to see if there is anyevidence of prior injury to the
optic nerve.
We mentioned CSF studiesearlier, alleloclonal bands
being the main one that we'reusually looking at, and these
are usually present in MS andthey have pretty good
sensitivity depending on thestudy you look at anywhere from
80 to 90 plus percent and theyalso are fairly specific more
than 60 percent in most studies,although again that varies
(10:55):
depending on what data you lookat.
An important thing to note withthe high sensitivity of
alleloclonal bands, or O-bands,is that If they are negative in
your CSF, you should really bewondering if you have the
correct diagnosis, as there areagain several other things that
could potentially mimic multiplesclerosis.
So let's dive into ourdifferential diagnosis and I
(11:15):
think we can put these into afew different categories.
So we have, like otherdemyelodening diseases, systemic
autoimmune or inflammatorydisorders, metabolic or genetic
disorders, infectious vascularneoplastic migraine and
functional disorders.
Let's start off with our otherdemyelinating diseases.
One of these is ADEM acutedisseminated encephalomyelitis.
(11:38):
This is usually apost-infectious, post-viral type
of process.
We see it more often in thepediatric or young adult
population, although you cansometimes see it in adults after
certain kinds of infection.
Legionella is the one that hasa bit of an association and it
often presents with a bit moreconfusion.
Sometimes you may have seizuresand they tend to have a lot of
(11:58):
big fluffy lesions throughoutthe brain and or spinal cord.
One of the main differenceswith ADEM as opposed to MS is
that it is usually a monophasictype event and O-bands typically
will be negative in thesepatients.
Neuromyelitis optica is anothertype of demyelinating disorder
that tends to affect, as thename suggests, the spinal cord
and the optic nerves.
As we mentioned earlier,bilateral simultaneous optic
(12:21):
neuritis, very suggestive of NMO.
And then there is also what wecall longitudinally extensive
transverse myelitis.
That is, usually three or moresegments of involvement and that
tends to be more suggestive ofone of these atypical demodding
disorders NMO or MOG or evensarcoidosis potentially, but it
is less commonly associated withMS.
(12:42):
When we have thislongitudinally extensive
transverse myelitis, you'llstill see a lot of people
mentioning idiopathic,quote-unquote transverse
myelitis.
I would say that transversemyelitis is more of a syndrome
rather than a diagnosis.
Idiopathic transverse myelitisshould only be left as quote
idiopathic after a number ofthings have been excluded,
(13:02):
including NMO, mog, sarcoidosis,other types of systemic
autoimmune diseases.
So this is very much anexclusionary diagnosis.
So transverse myelitis shouldnot be your final stopping point
in your diagnostic workup by along margin until you've
exhausted a lot of other testing.
Some of the more common systemicautoimmune syndromes that we
also want to check for again,depending on the clinical
(13:25):
context, are things like lupus,sjogren's syndrome, sarcoidosis,
some unusual metabolic andgenetic disorders.
There are various adult-onsetleukodystrophies.
A couple of the ones to thinkabout adrenal leukodystrophy or
metachromatic leukodystrophy.
Make sure to get that familyhistory to make sure that there
isn't anything like that tosuggest that this may run in the
family.
Check also if there's a lot ofspinal cord lesions, vitamin B12
(13:49):
deficiency, copper deficiencies, things of that nature, some
infections that could presentsimilarly HIV, lyme disease,
syphilis and then one that wemay not think about as much, but
again, htlv-1.
So this is also known astropical spastic periparesis.
So if we're seeing thisprogressive spasticity in the
lower extremities in particular,this may suggest some sort of
(14:10):
underlying infection.
Or there are some geneticvariants as well.
In the vascular category we havedifferent genetic stroke
syndromes.
One to think about is CATACYL,cerebral autosomal dominant
arteriopathy with subacuteinfarcts and leukencephalopathy,
and these will be youngerpeople presenting with migraines
(14:34):
and strokes, very often in thetemporal lobes.
Cns vasculitis can also causesome unusual presentations.
Sussack syndrome is another oneof these small vessel
vasculitides and it tends toaffect the retina cochlea as
well as the corpus callosum,these small penetrating branches
.
So you'll also get visualchanges, hearing loss, as well
as these unusual strokes.
They're sometimes described aslike snowball-like around the
corpus callosum.
Sometimes different neoplasmsmay also suggest demyelinating
(14:56):
disease.
Things that may look similarlyare different types of gliomas
or CNS lymphoma.
In these situations you mayneed a biopsy, as there is also
something called tumfactive MS,where an MS lesion, an acute
demyelinating lesion, may lookmore like a tumor.
So in those situationssometimes a brain biopsy is
necessary to come to adefinitive diagnosis.
You can also get differentperineoplastic syndromes causing
(15:19):
cerebellar ormyeloneuropathy-type syndromes.
You can also get encephalitis,behavioral changes with
different perineoplasticsyndromes.
So it's important to also checkfor these in the appropriate
clinical context.
Lastly, migraines Very oftenpeople are getting MRIs of their
brain to check on causes ofheadache and a lot of times
(15:39):
you'll get a nonspecific reportthat says the differential
includes quote demyelinatingdisease.
And it's because people withmigraine tend to have a higher
burden of small white matterlesions compared to the general
population.
So it is important.
If the person has never had anyclinical events and the quote
unquote lesions on MRI are nottypical of demyelinating disease
(16:01):
, you may not need to go anyfurther down that diagnostic
pathway.
Just treat the person'smigraines.
Lastly, there are differentfunctional disorders functional
weakness, functional tremors,functional blindness that can
sometimes mimic demyelinatingdisorders.
Clinically and typically youwould expect imaging studies and
other diagnostic testing to benormal in these patients.
Now let's talk a little bitabout the clinical course that
(16:22):
we can sometimes see with MS.
So, as we mentioned a littlebit earlier, we can sometimes
start with what's calledclinically isolated syndrome,
and this is a first-time eventwhen the imaging or clinical
criteria don't meet a definitionof definite MS.
Now let's say we have aclinical event and we have a
brain lesion on the initial MRI.
So these people have a 10-yearrisk of about a 90% conversion
(16:46):
to definite multiple sclerosis.
However, if there is no brainlesion on the initial scan,
their risk is lower, about 10 to20%.
Now flip that around a littlebit.
Let's say we haveradiologically isolated syndrome
.
They've had no clinical episode, but for some reason they've
gotten an MRI and the imagingfindings are consistent with
(17:07):
potential demyelinating disease.
About 50% of these people willconvert to MS over the next 10
years.
So both these categories ofpeople do require very close
observation and in some cases itmay be reasonable to talk about
whether or not treatment shouldbe started More for our
clinically isolated syndromeswho have the highest risk of
converting to more definiterelapsing-remitting multiple
(17:29):
sclerosis.
So relapsing-remitting multiplesclerosis it's the most common
kind of presentation that weusually see in people who have a
diagnosis of MS.
So they tend to have an acuteepisode of some sort of
neurologic deficit or worsening,and this is followed by a
period of recovery, right.
So they have a relapse and thenthose symptoms remit and over
time they tend to have lessimprovement in between relapses,
(17:53):
kind of this accumulation ofneurologic disease burden over
time.
So without treatmentapproximately 50% of patients
progress to secondaryprogressive MS and secondary
progressive MS is where we seeless remission and acute
worsening, but you can still seecontinued gradual neurologic
decline.
(18:13):
Contrast this with primaryprogressive multiple sclerosis.
So this is about 15% of peopleat presentation who have primary
progressive MS and these peopletend to not have the acute
flares as much, but this againgradual worsening and
accumulation of differentneurologic disability.
So let's talk a little bit abouttreatment and we can put these
(18:36):
into a few different categories.
That's what we might calllifestyle, general health
recommendations, how we mighttreat acute exacerbations,
long-term disease-modifyingtherapy and different
symptomatic managementstrategies.
So, starting off with our kindof lifestyle, non-pharmacologic
interventions, it is importantto maintain regular exercise,
(18:56):
both aerobic and strengtheningplans.
This can help on a number offronts, both with reducing
increased weakness anddeconditioning, as well as
reducing osteoporosis risk, aspeople with MS do tend to have
vitamin D deficiency as well.
So it's often important tocheck those vitamin D levels and
make sure to supplementappropriately.
(19:16):
You also need to make sure thatpeople are doing their best to
avoid infection.
Many of the people with MS whoare on treatment are going to be
on some form ofimmunosuppression, and so they
are at risk for different typesof infection depending on the
agent that they're taking.
So you want to make sure thatthey're vaccinated against the
influenza virus as well as otherspecific viruses, depending on,
again, what medication and whatthat patient's particular
(19:39):
demographics are.
If your patient is a smoker,smoking cessation is essential.
These people have asignificantly increased risk of
conversion from relapsingremitting to secondary
progressive MS, and they tend toaccumulate disability faster
than non-smokers.
So smoking cessation is one ofthe most important things to
counsel people with MS on.
(20:06):
Lastly, pregnancy A lot ofpeople with MS are younger women
of childbearing years, and somany of these medications that
we use for treatment of multiplesclerosis are not safe in
pregnancy.
So it is very important to planahead, have those conversations
early, as we do know that abouthalf of pregnancies in the
United States are not planned.
So there are a lot ofconsiderations in terms of when
to withdraw medication, whensomeone is trying to become
pregnant and a lot of otherthings that are kind of beyond
(20:26):
the scope of our kind of morebroad overview today.
So I'm not going to go too deepinto those particular
considerations right now.
So for treatment of an acuteexacerbation so someone has a
diagnosis of MS or a suspectedfirst-time episode of MS and
we're looking usually for new orworsening neurologic symptoms
lasting at least 24 hours.
(20:48):
A lot of times people havepseudo-relapses.
Maybe they have a UTI or afever or pneumonia or something
else triggered a relapse quoteunquote of their previous
symptoms.
So if the symptoms are very,very similar to a past episode,
it may be a pseudo relapserather than a true new MS flare.
And this is important to know,because the treatment is going
(21:10):
to be different and we don'twant to expose people to
medications unnecessarily thatcould cause complications.
So make sure to check for signsof infection or metabolic
disturbances, as these can causethese recrudescence of prior
neurologic deficits.
So we've determined yes, thisis an MS flare and we need to
start treatment.
The typical treatment is IVmethylprednisolone one gram
daily for three to five days,and this really does depend on
(21:32):
the person's response totreatment about how long you go,
as well as how bad are thedeficits.
If this is more of a numbnessor paresthesia versus I can't
see out of one eye or I can'tlift one of my legs or arms
right, if you are havingfunctional disability from an
acute flare, then you usuallywant to be a bit more aggressive
in your treatment than if it'smore of a non-disabling deficit,
(21:53):
because what we do know is thatacute treatments don't
necessarily change long-termdisability progression.
They can hopefully shorten theduration of the acute relapse,
however.
So that is really what we'retrying to do is shorten that
acute worsening in thesepatients.
So if we're giving high-dosesteroids, we usually want to
make sure the person's stomachis protective using some sort of
(22:14):
antacid, ppi, h2 blocker, etc.
And we also want to make sure,if this person is also diabetic,
that we are treating thathyperglycemia that we may be
worsening transiently, and thatis also a consideration.
I have certainly had patientsin the past who came in with an
MS flare, who had somewhatpoorly controlled diabetes and
we could not get that glucose tobe where we wanted it to be.
(22:35):
So we had to consider is therisk of this uncontrolled
hyperglycemia due to thehigh-dose steroids that we're
giving going to be worth thepotential benefit from the
treatment?
So this is definitely aconsideration.
When there is more than onemedical issue active at a time.
In situations where steroidsmay not be an option or where
people have not responded tosteroids in the past, plasma
(22:56):
exchange may also be an optionand I should mention if you're
trying to keep your patient outof the hospital, sometimes you
can give oral prednisone.
1,250 milligrams per day issometimes recommended.
That is a lot of oralprednisone.
So definitely make sure thatyou are communicating with both
the pharmacy and the patient, asthis may be a surprising amount
.
(23:17):
So let's jump into one of themeatier topics for MS and that
is the disease-modifying therapy, and you can kind of categorize
these in a couple differentways.
There are injectables, oralmedications and infusions, and
these all have different timingfrequencies and different side
effects, and we'll talk aboutall of those.
You can also think of it interms of what we call standard
(23:38):
therapy and then more aggressiveor potent therapies as well.
So our older generation tendsto be what we think of as the
more standard quote unquotetherapy, and that includes some
of the injectables and some ofthe oral medications.
So, kind of going back to theOG, interferon beta 1A, and
there are a couple of differentformulations of this, but they
(23:59):
all have very similar sideeffect profiles.
So these are one of theinjectables and, again,
different formulations havedifferent dosing frequencies,
but some of the more common sideeffects that you have to watch
out for are flu-like symptoms,injection site reaction and
depression.
Surprisingly, with theinterferons, you're also going
to want to make sure that youcheck the CBC and liver enzymes
every three to six months.
Next up on the injectables, wehave glutaramer acetate.
(24:21):
So this is another sub-Qinjection here and we want to
watch out for injection sitereactions, and it can also cause
some lipoatrophy of the skin atthe injection site.
So this is one of the fewmedications that can be used in
pregnancy, and sometimes that'llbe part of a strategy is to
cross over from whatever themedication was that the woman
was on previously and startglutiramer acetate.
(24:43):
That's not always done, but itis something that is done
sometimes depending on theclinical situation.
A newer medication that is aninjectable is ofatumumab, and
this is an anti-CD20 medicationthat is given subcutaneously,
and we'll talk a little bitabout CD20 inhibitors when we
get to some of the infusions.
Moving to our oral medications,we have dimethylfumarate.
(25:06):
This one is kind of notoriousfor causing diarrhea and some
flushing.
You also have to watch out forlymphopenia and there are some
rare case reports of PML,although the data is a little
mixed in terms of whether it wasfrom the previous
disease-modifying therapy orfrom the dimethylfumarate itself
.
But this one also requiresmonitoring of the CBC and you
want to watch out for that.
(25:26):
Lymphopenia that's going to bea recurrent theme for a lot of
our medications is watching outfor lymphopenia.
There is also a newermedication in this family called
deroxamilfumarate, and it'ssupposed to have better GI
tolerability but,similarity-wise, a lot of the
same things to watch out for.
Next up is teraflunamide,another one of our oral
medications.
Again, have to watch out forsome GI side effects, some
(25:46):
alopecia, increased risk ofrespiratory infections and you
are also going to be watchingthe CBC for lymphopenia as well
as liver enzymes.
Now we're going to move on toone of our quote higher potency
oral medications and that isfingolimod.
So this one does have a uniqueside effect in as much as it
requires heart monitoring duringthe first dose, as there has
(26:07):
been some bradycardia reportedwith the first dose because of
its effect on the sphingosinereceptors.
Now, from a disease modifyingstandpoint, this is preventing
the lymphocytes from exiting thelymph nodes.
So an important thing toremember about fingolimod is
that when you take someone offof fingolimod for whatever
reason, that you can get reboundMS attacks because all those
(26:30):
lymphocytes are still hangingout.
They're just in the lymph nodes.
So you take away thoseblockades, they start getting
back into circulation and youcan have kind of an aggressive
MS attack.
It can also cause some retinaledema.
So you do need to get regularophthalmologic examinations and
you do need to monitor that CBC.
There are also a couple newermedications in the same family
as Fingolimod, ozanimod andPanesimod and they have slightly
(26:53):
different side effect profilesbut they're new enough that I
don't expect you guys to getquizzed on them just yet, so
we're going to skip over them alittle bit for the sake of
brevity.
So let's move on to ourinfusions.
First up we have natalizumab.
So natalizumab, notoriously, isassociated with PML.
So you do have to screen forthe JC virus and you do need to
monitor titers of the JC virusover time, depending on how long
(27:15):
your patient is on natalizumabtime, depending on how long your
patient is on natalizumab.
That being said, despite theserisks, in appropriately selected
patients it can be a veryeffective treatment for slowing
down MS progression.
So over the last decade or so,there has been a bit of a
paradigm shift towards B-celldepleting therapy.
So our anti-CD20 type therapies.
So before ocralizumab, a lot ofpeople were using rituximab,
(27:38):
but now that we have ocralizumab, this one is being used fairly
often for people with moreaggressive MS and it does
require some pre-infusiontesting.
So we want to make sure thatpeople don't have undiagnosed
hepatitis.
So you do need to checkserologies for that.
And then you want to make surethat they're up to date on their
vaccinations and also getting acouple extra ones, including
against zoster, strep, pneumoniaand hepatitis B, and that helps
(28:02):
reduce those risks of potentialcomplications while on
treatment down the road.
Ocrelizumab was also the firstmedication that received an FDA
approval for primary progressiveMS, so it is also indicated for
those patients.
Next up is alimtuzumab, ananti-CD52 medication, and I kind
of think this is the nuclearoption, right?
You're just obliteratingpeople's white cell population
(28:24):
and you kind of have to wait forit to come back, and these
patients sometimes can developnew autoimmune processes down
the road, in particularautoimmune thyroiditis and ITP.
So lots of side effects andlots of monitoring that go into
the administration ofalimtuzumab.
So very high risk, very potentmedication.
The last disease modifyingtherapy that I'm going to
mention is mitoxantrone, andthis is not used very often in
(28:48):
my experience, but it does havea black box warning for
cardiotoxicity.
So you do have to watch out forcardiac function with
echocardiograms, as well as theusual infection risks that come
along with several of thesehigher potency medications.
So people with MS can develop alot of different neurologic
issues and these kind of run thegamut from spasticity to
(29:08):
neuropathic pain, to chronicfatigue, depression, cognitive
issues, mobility issues, bladderdysfunction, pseudobulbar
affect, tremors.
So you do very much have totailor your treatments to the
individual and what theirparticular symptoms are.
So, starting off with somethingthat's fairly common spasticity
.
So, depending on where and howsevere it is, you might try
(29:29):
things like muscle relaxers,like baclofen or tizanidine, up
to botulinum toxin.
Again, this can be veryeffective for some people,
depending on what their symptomsare and how it is affecting
their daily function.
Neuropathic pain can occur.
We can also see central pain,depending on if there's more
spinal cord lesions and thingsof that nature.
So a lot of the pain managementstrategies that we use for
(29:49):
neuropathic pain in MS aresimilar to what we would do for
people with neuropathy or othercauses of neuropathic pain.
So we think of the gabapentinfamily, pregabalin, as well as
the SNRIs.
For people with MS who aredealing with chronic fatigue,
sometimes we will also trydifferent stimulants like
modafinil or imodafinil, againdepending on the situation, and
(30:10):
you want to make sure that.
Obviously the other side ofthat coin for chronic fatigue is
making sure that people's sleepis restful and restorative.
So a sleep study andappropriate interventions,
depending on what you find fromthat, may be helpful in
alleviating that chronic fatigue.
For people with mobility issues,in particular slowing of
walking, there are somemedications that may be helpful.
In particular, delphamphrodinehas been shown to increase
(30:32):
walking speed in some peoplewith MS, so that is something to
consider trying.
You do have to watch out forside effects, so it can
sometimes cause or worsentrigeminal neuralgia and or
seizures.
So if people have a history oftrigeminal neuralgia or epilepsy
, you definitely want to avoidthis medication.
Bladder dysfunction, again avery common issue for people who
have spinal cord lesions.
So if they're having urinaryretention or urinary
(30:56):
incontinence, it is important towork with a good urologist and
depending on what kind ofurinary issues they're having
sometimes even bladderdysfunction different types of
physical therapy or evenbotulinum toxin injections can
be very helpful for some ofthese patients.
So working with someone who isfamiliar with different causes
of neurogenic bladder orneurogenic bladder dysfunction
(31:16):
can be very helpful.
Lastly, a somewhat uncommonphenomenon that we'll see in
multiple sclerosis ispseudobulbar affect and this is
kind of the emotionalincontinence right Laughing or
crying inappropriately, withoutthe emotion associated with the
physical manifestation and thereis a medication that can
sometimes be helpful for that.
It is a combination ofdextromethorphan and quinidine
(31:39):
and that can sometimes be usefulin these patients for helping
to alleviate those symptoms.
So there you have it.
That's our quick rundown onmultiple sclerosis, a quick
overview.
I know we did some superficiallooks at a few things.
Hopefully this gives you a goodidea, a good framework to work
from, and I hope you certainlyfound it useful in the care of
your MS patients.
Going forward, as always, youcan find me online on X,
(32:01):
formerly known as Twitter, atDrKentris D-R-K-E-N-T-R-I-S, or
you can follow the podcastitself at neuro underscore
podcast, and you can also checkout our website,
theneurotransmitterscom.
Feel free to shoot me a message, let us know what you think and
please do reach out with anyquestions or show suggestions.
Going forward, it's always apleasure to hear from people who
(32:21):
found this work useful andreally helps keep us going.
So thank you so much forlistening and I'll talk to you
next time.
Hello and welcome back, dear listener.
You are listening to theNeurotransmitters podcast, your
source for everything related toclinical neurology.
I am your host, Dr MichaelKentris, and today we are
continuing our internal medicineneurology subtopic board review
series.
Today's topic is multiplesclerosis.
We are going to talk about thesigns and symptoms that should
(00:21):
make us think about multiplesclerosis, how we diagnose
multiple sclerosis, what do thetypical clinical courses look
like for multiple sclerosis andwhat kind of treatment options
do we have.
So when should we think aboutmultiple sclerosis, or MS as I'm
going to call it from hereforward?
So MS is one of those diseasesthat can present in many
different ways, but there are afew that are kind of classic and
(00:42):
especially when we're talkingabout question stems on an exam,
there are some that shouldreally raise a red flag for you
to pay attention to, and we canlump these together into a few
different categories.
I'm going to put these in theoptic neuritis, brainstem
syndromes, spinal cord syndromesand then kind of a
miscellaneous grab bag.
Let's start with optic neuritis.
This will usually present withmonocular, blurred vision, and
(01:05):
one trick that I like to use tohelp us differentiate whether
this is a refractive error, thatis to say something in the
globe itself, like the cornea orthe lens or even in the other
parts of the eye, versus in theoptic nerve, is to use a pinhole
occluder.
That's one of those things thatyou cover the eye with that has
just tiny little holes in itand you can kind of improvise
one if you don't have one inyour neurology bag.
(01:26):
If you just take a note cardand poke a hole with it with a
pin, you can use that.
And if someone's visual acuityimproves with the pinhole
occluder, that suggests thatit's more of a refractive error
in the eye rather than opticnerve related.
Perhaps.
You can also see things calledred desaturation, where red
colors are less vivid and youwill sometimes have pain with
(01:48):
eye movement.
You may also see an afferentpupillary defect, that is to say
when you do your swingingflashlight test, so you're
shining in one eye and youimmediately go to the other eye
and back and forth.
So when you're shining thelight in the eye that is
affected, the pupil will dilateto direct light, but if the
other eye is normal it shouldconstrict with consensual light
(02:11):
and again this is called anafferent pupillary defect.
Sometimes in the olderliterature you'll see it called
a Marcus Gunn pupil.
Now when someone is coming inwith these symptoms and you're
suspecting optic neuritis, it isimportant to do a fundoscopic
exam.
Acutely you may see evidence ofpapilledema or papillitis, and
chronically they may haveevidence of optic nerve atrophy.
So you can sometimes see thisif it is the anterior portion of
(02:33):
the optic nerve affected, butif it's more in the posterior
part of the optic nerve you mayhave a normal fundoscopic exam
on these patients.
So in the setting of MS, thisis usually going to be
unilateral Now.
So in the setting of MS, thisis usually going to be
unilateral.
Now there are somedemyelinating syndromes that may
present with bilateral opticneuritis, and so if you have
bilateral optic neuritis, thatshould be a red flag for you to
consider things that aredemyelinating but not MS, things
(02:57):
like neuromyelitis, optica orNMO, and myelin oligodendrocyte
glycoprotein, abbreviated MOG orMOG.
As a pretty big nerd myself, Ican never hear MOG without
thinking about the characterfrom Final Fantasy.
So if you're familiar, then youtoo also know that Final
Fantasy VI is the best FinalFantasy game.
Another category that we'lloften see with MS are brainstem
(03:18):
syndromes, and these can presentwith a variety of different
symptoms as well, includingnystagmus, dyplopia, other types
of eye movement abnormalities,things of that nature.
You can also get somecerebellar or vestibular type
symptoms with ataxia or vertigo.
One of the classic eye movementabnormalities that you may see
or may be asked about is an INOor internuclear ophthalmoplegia,
(03:40):
and this is an inability toadduct AD-duct one eye with
nystagmus in the AB abductingeye, and this is usually due to
a lesion in the MLF, the mediallongitudinal fasciculus.
There are, of course, manyother eye abnormalities.
I mention INO specificallybecause it is a favorite for
test writers.
Moving on to spinal cordsyndrome, so this may present as
(04:02):
a transverse myelitis typesyndrome or other types of
myelitis or spinal cord relatedtype disabilities, weakness,
numbness in the limbs, arms,legs, etc.
Depending on what level it's at.
You may get a sensory level inthe thoracic spine, etc.
There are a couple differentsymptoms that patients with MS
may describe when they havelesions in the spinal cord.
(04:23):
One of these is Lhermitte'ssign, which is a shock-like
sensation that runs down thespine or into the limbs with
neck flexion, typically in thecervical spine.
You can also get a quote MS hug, and this is a band-like
sensation, often around thechest.
Urinary symptoms can also becommon when people have spinal
cord lesions.
These can include symptoms ofurinary retention, urinary
(04:44):
urgency or urinary incontinenceand, as we mentioned earlier,
there are a lot of miscellaneousor various hard-to-pin-down
sort of symptoms that can occurwith MS as well.
People may fatigue more easilythan normal.
They may describe a quote,brain fog.
There may be evidence ofcognitive decline.
On examination you can also geta phenomenon with people who
(05:05):
have more long-standing MS,something called the Uthoff's
phenomenon, which is a transientworsening of their baseline
neurologic deficits.
This is often in the setting ofwhen they have an infection
with fevers, in the setting ofhot weather or if they
physically overexert themselves,and this may lead into what
sometimes is called apseudo-relapse or a pseudo-flare
, or essentially a recrudescenceof prior neurologic deficits in
(05:27):
the setting of some otherstressor on the body.
So now we know some symptoms tomake us think about MS, but what
about when we want to get to adiagnosis?
There can be some challenges incoming to a diagnosis of MS
because there are many thingsthat can mimic it, and we'll
talk about those in a minute.
But the criteria that we'reusing presently are the revised
McDonald criteria, and you mayhave heard this phrase.
Dissemination in time and spaceAlways makes me think of a
(05:50):
Doctor who episode.
But what we mean when we saydissemination in time and space
is that we want multiple lesionson MRI or clinical events
separated by at least two pointsin time or two points in space,
that is to say in the neuroaxis.
So there are a couple differentpermutations that can get us to
that point.
So let's say we have someonewho has had two or more clinical
(06:12):
attacks and we want to see atleast two objective findings on
MRI MRI being our maindiagnostic imaging that we're
using in MS.
So if we see two lesions thatcorrelate with those clinical
symptoms, then that meets ourcriteria.
If we have two or more clinicalattacks with at least one lesion
on imaging that correlates withour symptoms, that, plus the
(06:35):
past history of an event thatsounds suspicious for a
demyelinating attack, can meetcriteria.
And this is why it's importantwhen you're first seeing someone
who you suspect may have MS isto really dig into that history
and see how you had any of thosepast episodes going on for
sometimes days to weeks ofblurred vision, weakness,
numbness, vertigo, etc.
(06:55):
That could potentiallyrepresent a past attack.
So that way you know if they'vehad a previous attack and now
you have one new attack with anMRI abnormality at this time,
then you can still lean a lotmore favorably towards getting a
definitive diagnosis.
Where things can get a littletricky is if you have one
clinical attack, or what we callclinically isolated syndrome,
(07:18):
and we'll talk a little bit moreabout that as we go on.
But if we have one clinicalattack and you get your MRI and
you see one old lesion and thenone new and what we mean by a
new lesion is one that is anenhancing with IV contrast so if
you have an enhancing lesionand an old non-enhancing lesion,
that is your dissemination intime.
(07:38):
And if those are in differentlocations in the neural axis,
there's your dissemination inspace as well.
But it gets even hairiersometimes.
Let's say, we have one clinicalattack clinically suspicious
for multiple sclerosis and youhave an MRI lesion that
correlates with those symptomsthat also look suspicious for
demyelinating disease.
So maybe you have a coupleenhancing lesions.
There's your dissemination inspace, but you don't have any
(08:01):
old lesions on MRI.
This is where getting CSFstudies tends to be the most
beneficial as far as getting toa definitive diagnosis of MS.
So we're checking our routineCSF labs and we're also checking
oligoclonal bands, as they tendto be fairly specific to MS,
although not 100%.
So let's recap that once more.
So we are looking fordissemination in space, that is,
(08:23):
more than one T2 hyper-intenselesion.
Now we talk about differenttypes of white matter lesions.
These are going to be usuallymore than three millimeters on
their long axis.
They tend to be a littlefluffier than what we would see
for patients with migraine orcerebrovascular disease and
there are a few locations thattend to be more typical for MS.
So we can see periventricularlesions and we're looking for
(08:46):
more than one lesion, unless thepatient is over the age of 50,
right, because of thosecerebrovascular risk factors, in
which case you usually want tosee a higher number.
You can also see cortical orjuxtacortical lesions,
infratentorial lesions in thebrainstem or cerebellum, and
then spinal cord lesions.
And to recap on thedissemination in time, if we
(09:06):
have a first-time MRI that showsa new enhancing lesion as well
as an old non-enhancing T2hyper-intense lesion that is
characteristic of demyelinatingdisease, that can meet our
criteria for dissemination intime.
Or if we have an old MRI thatshows a T2 hyper intense lesion
and then we get a new MRI andthat new MRI shows a new lesion,
(09:29):
whether it is enhancing or not,and so that can also establish
our dissemination in time,because we have new lesions from
point A to point B.
So let's dig a little bit moreinto the testing that we will
often do.
Working someone up for MS, aswe've been talking about, mri is
often the mainstay of theinitial diagnostic battery.
So we are looking often at thebrain and, depending on symptoms
(09:51):
, may also be looking at thecervical and or thoracic spine,
and very often we are going tobe getting these with and
without IV gadolinium contrast,and that is because we're
looking for enhancing lesions.
Monitoring MRIs down the roadmay or may not need gadolinium.
That is more of a situation,case-by-case basis, so we're not
going to go into that too muchright now.
If there is a clinical suspicionfor past optic neuritis, there
(10:13):
are a couple tests that can bedone.
So there are visual evokedpotentials, or VEPs, and there
is also optical coherencetomography or OCTs, and both of
these can show evidence of prioroptic neuritis and they tend to
stay abnormal kind ofindefinitely.
So that can be a very helpfultest in terms of if the MRI
doesn't show any abnormalities,then you might get one of these
(10:34):
tests to see if there is anyevidence of prior injury to the
optic nerve.
We mentioned CSF studiesearlier, alleloclonal bands
being the main one that we'reusually looking at, and these
are usually present in MS andthey have pretty good
sensitivity depending on thestudy you look at anywhere from
80 to 90 plus percent and theyalso are fairly specific more
than 60 percent in most studies,although again that varies
(10:55):
depending on what data you lookat.
An important thing to note withthe high sensitivity of
alleloclonal bands, or O-bands,is that If they are negative in
your CSF, you should really bewondering if you have the
correct diagnosis, as there areagain several other things that
could potentially mimic multiplesclerosis.
So let's dive into ourdifferential diagnosis and I
(11:15):
think we can put these into afew different categories.
So we have, like otherdemyelodening diseases, systemic
autoimmune or inflammatorydisorders, metabolic or genetic
disorders, infectious vascularneoplastic migraine and
functional disorders.
Let's start off with our otherdemyelinating diseases.
One of these is ADEM acutedisseminated encephalomyelitis.
(11:38):
This is usually apost-infectious, post-viral type
of process.
We see it more often in thepediatric or young adult
population, although you cansometimes see it in adults after
certain kinds of infection.
Legionella is the one that hasa bit of an association and it
often presents with a bit moreconfusion.
Sometimes you may have seizuresand they tend to have a lot of
(11:58):
big fluffy lesions throughoutthe brain and or spinal cord.
One of the main differenceswith ADEM as opposed to MS is
that it is usually a monophasictype event and O-bands typically
will be negative in thesepatients.
Neuromyelitis optica is anothertype of demyelinating disorder
that tends to affect, as thename suggests, the spinal cord
and the optic nerves.
As we mentioned earlier,bilateral simultaneous optic
(12:21):
neuritis, very suggestive of NMO.
And then there is also what wecall longitudinally extensive
transverse myelitis.
That is, usually three or moresegments of involvement and that
tends to be more suggestive ofone of these atypical demodding
disorders NMO or MOG or evensarcoidosis potentially, but it
is less commonly associated withMS.
(12:42):
When we have thislongitudinally extensive
transverse myelitis, you'llstill see a lot of people
mentioning idiopathic,quote-unquote transverse
myelitis.
I would say that transversemyelitis is more of a syndrome
rather than a diagnosis.
Idiopathic transverse myelitisshould only be left as quote
idiopathic after a number ofthings have been excluded,
(13:02):
including NMO, mog, sarcoidosis,other types of systemic
autoimmune diseases.
So this is very much anexclusionary diagnosis.
So transverse myelitis shouldnot be your final stopping point
in your diagnostic workup by along margin until you've
exhausted a lot of other testing.
Some of the more common systemicautoimmune syndromes that we
also want to check for again,depending on the clinical
(13:25):
context, are things like lupus,sjogren's syndrome, sarcoidosis,
some unusual metabolic andgenetic disorders.
There are various adult-onsetleukodystrophies.
A couple of the ones to thinkabout adrenal leukodystrophy or
metachromatic leukodystrophy.
Make sure to get that familyhistory to make sure that there
isn't anything like that tosuggest that this may run in the
family.
Check also if there's a lot ofspinal cord lesions, vitamin B12
(13:49):
deficiency, copper deficiencies, things of that nature, some
infections that could presentsimilarly HIV, lyme disease,
syphilis and then one that wemay not think about as much, but
again, htlv-1.
So this is also known astropical spastic periparesis.
So if we're seeing thisprogressive spasticity in the
lower extremities in particular,this may suggest some sort of
(14:10):
underlying infection.
Or there are some geneticvariants as well.
In the vascular category we havedifferent genetic stroke
syndromes.
One to think about is CATACYL,cerebral autosomal dominant
arteriopathy with subacuteinfarcts and leukencephalopathy,
and these will be youngerpeople presenting with migraines
(14:34):
and strokes, very often in thetemporal lobes.
Cns vasculitis can also causesome unusual presentations.
Sussack syndrome is another oneof these small vessel
vasculitides and it tends toaffect the retina cochlea as
well as the corpus callosum,these small penetrating branches
.
So you'll also get visualchanges, hearing loss, as well
as these unusual strokes.
They're sometimes described aslike snowball-like around the
corpus callosum.
Sometimes different neoplasmsmay also suggest demyelinating
(14:56):
disease.
Things that may look similarlyare different types of gliomas
or CNS lymphoma.
In these situations you mayneed a biopsy, as there is also
something called tumfactive MS,where an MS lesion, an acute
demyelinating lesion, may lookmore like a tumor.
So in those situationssometimes a brain biopsy is
necessary to come to adefinitive diagnosis.
You can also get differentperineoplastic syndromes causing
(15:19):
cerebellar ormyeloneuropathy-type syndromes.
You can also get encephalitis,behavioral changes with
different perineoplasticsyndromes.
So it's important to also checkfor these in the appropriate
clinical context.
Lastly, migraines Very oftenpeople are getting MRIs of their
brain to check on causes ofheadache and a lot of times
(15:39):
you'll get a nonspecific reportthat says the differential
includes quote demyelinatingdisease.
And it's because people withmigraine tend to have a higher
burden of small white matterlesions compared to the general
population.
So it is important.
If the person has never had anyclinical events and the quote
unquote lesions on MRI are nottypical of demyelinating disease
(16:01):
, you may not need to go anyfurther down that diagnostic
pathway.
Just treat the person'smigraines.
Lastly, there are differentfunctional disorders functional
weakness, functional tremors,functional blindness that can
sometimes mimic demyelinatingdisorders.
Clinically and typically youwould expect imaging studies and
other diagnostic testing to benormal in these patients.
Now let's talk a little bitabout the clinical course that
(16:22):
we can sometimes see with MS.
So, as we mentioned a littlebit earlier, we can sometimes
start with what's calledclinically isolated syndrome,
and this is a first-time eventwhen the imaging or clinical
criteria don't meet a definitionof definite MS.
Now let's say we have aclinical event and we have a
brain lesion on the initial MRI.
So these people have a 10-yearrisk of about a 90% conversion
(16:46):
to definite multiple sclerosis.
However, if there is no brainlesion on the initial scan,
their risk is lower, about 10 to20%.
Now flip that around a littlebit.
Let's say we haveradiologically isolated syndrome
.
They've had no clinical episode, but for some reason they've
gotten an MRI and the imagingfindings are consistent with
(17:07):
potential demyelinating disease.
About 50% of these people willconvert to MS over the next 10
years.
So both these categories ofpeople do require very close
observation and in some cases itmay be reasonable to talk about
whether or not treatment shouldbe started More for our
clinically isolated syndromeswho have the highest risk of
converting to more definiterelapsing-remitting multiple
(17:29):
sclerosis.
So relapsing-remitting multiplesclerosis it's the most common
kind of presentation that weusually see in people who have a
diagnosis of MS.
So they tend to have an acuteepisode of some sort of
neurologic deficit or worsening,and this is followed by a
period of recovery, right.
So they have a relapse and thenthose symptoms remit and over
time they tend to have lessimprovement in between relapses,
(17:53):
kind of this accumulation ofneurologic disease burden over
time.
So without treatmentapproximately 50% of patients
progress to secondaryprogressive MS and secondary
progressive MS is where we seeless remission and acute
worsening, but you can still seecontinued gradual neurologic
decline.
(18:13):
Contrast this with primaryprogressive multiple sclerosis.
So this is about 15% of peopleat presentation who have primary
progressive MS and these peopletend to not have the acute
flares as much, but this againgradual worsening and
accumulation of differentneurologic disability.
So let's talk a little bit abouttreatment and we can put these
(18:36):
into a few different categories.
That's what we might calllifestyle, general health
recommendations, how we mighttreat acute exacerbations,
long-term disease-modifyingtherapy and different
symptomatic managementstrategies.
So, starting off with our kindof lifestyle, non-pharmacologic
interventions, it is importantto maintain regular exercise,
(18:56):
both aerobic and strengtheningplans.
This can help on a number offronts, both with reducing
increased weakness anddeconditioning, as well as
reducing osteoporosis risk, aspeople with MS do tend to have
vitamin D deficiency as well.
So it's often important tocheck those vitamin D levels and
make sure to supplementappropriately.
(19:16):
You also need to make sure thatpeople are doing their best to
avoid infection.
Many of the people with MS whoare on treatment are going to be
on some form ofimmunosuppression, and so they
are at risk for different typesof infection depending on the
agent that they're taking.
So you want to make sure thatthey're vaccinated against the
influenza virus as well as otherspecific viruses, depending on,
again, what medication and whatthat patient's particular
(19:39):
demographics are.
If your patient is a smoker,smoking cessation is essential.
These people have asignificantly increased risk of
conversion from relapsingremitting to secondary
progressive MS, and they tend toaccumulate disability faster
than non-smokers.
So smoking cessation is one ofthe most important things to
counsel people with MS on.
(20:06):
Lastly, pregnancy A lot ofpeople with MS are younger women
of childbearing years, and somany of these medications that
we use for treatment of multiplesclerosis are not safe in
pregnancy.
So it is very important to planahead, have those conversations
early, as we do know that abouthalf of pregnancies in the
United States are not planned.
So there are a lot ofconsiderations in terms of when
to withdraw medication, whensomeone is trying to become
pregnant and a lot of otherthings that are kind of beyond
(20:26):
the scope of our kind of morebroad overview today.
So I'm not going to go too deepinto those particular
considerations right now.
So for treatment of an acuteexacerbation so someone has a
diagnosis of MS or a suspectedfirst-time episode of MS and
we're looking usually for new orworsening neurologic symptoms
lasting at least 24 hours.
(20:48):
A lot of times people havepseudo-relapses.
Maybe they have a UTI or afever or pneumonia or something
else triggered a relapse quoteunquote of their previous
symptoms.
So if the symptoms are very,very similar to a past episode,
it may be a pseudo relapserather than a true new MS flare.
And this is important to know,because the treatment is going
(21:10):
to be different and we don'twant to expose people to
medications unnecessarily thatcould cause complications.
So make sure to check for signsof infection or metabolic
disturbances, as these can causethese recrudescence of prior
neurologic deficits.
So we've determined yes, thisis an MS flare and we need to
start treatment.
The typical treatment is IVmethylprednisolone one gram
daily for three to five days,and this really does depend on
(21:32):
the person's response totreatment about how long you go,
as well as how bad are thedeficits.
If this is more of a numbnessor paresthesia versus I can't
see out of one eye or I can'tlift one of my legs or arms
right, if you are havingfunctional disability from an
acute flare, then you usuallywant to be a bit more aggressive
in your treatment than if it'smore of a non-disabling deficit,
(21:53):
because what we do know is thatacute treatments don't
necessarily change long-termdisability progression.
They can hopefully shorten theduration of the acute relapse,
however.
So that is really what we'retrying to do is shorten that
acute worsening in thesepatients.
So if we're giving high-dosesteroids, we usually want to
make sure the person's stomachis protective using some sort of
(22:14):
antacid, ppi, h2 blocker, etc.
And we also want to make sure,if this person is also diabetic,
that we are treating thathyperglycemia that we may be
worsening transiently, and thatis also a consideration.
I have certainly had patientsin the past who came in with an
MS flare, who had somewhatpoorly controlled diabetes and
we could not get that glucose tobe where we wanted it to be.
(22:35):
So we had to consider is therisk of this uncontrolled
hyperglycemia due to thehigh-dose steroids that we're
giving going to be worth thepotential benefit from the
treatment?
So this is definitely aconsideration.
When there is more than onemedical issue active at a time.
In situations where steroidsmay not be an option or where
people have not responded tosteroids in the past, plasma
(22:56):
exchange may also be an optionand I should mention if you're
trying to keep your patient outof the hospital, sometimes you
can give oral prednisone.
1,250 milligrams per day issometimes recommended.
That is a lot of oralprednisone.
So definitely make sure thatyou are communicating with both
the pharmacy and the patient, asthis may be a surprising amount
.
(23:17):
So let's jump into one of themeatier topics for MS and that
is the disease-modifying therapy, and you can kind of categorize
these in a couple differentways.
There are injectables, oralmedications and infusions, and
these all have different timingfrequencies and different side
effects, and we'll talk aboutall of those.
You can also think of it interms of what we call standard
(23:38):
therapy and then more aggressiveor potent therapies as well.
So our older generation tendsto be what we think of as the
more standard quote unquotetherapy, and that includes some
of the injectables and some ofthe oral medications.
So, kind of going back to theOG, interferon beta 1A, and
there are a couple of differentformulations of this, but they
(23:59):
all have very similar sideeffect profiles.
So these are one of theinjectables and, again,
different formulations havedifferent dosing frequencies,
but some of the more common sideeffects that you have to watch
out for are flu-like symptoms,injection site reaction and
depression.
Surprisingly, with theinterferons, you're also going
to want to make sure that youcheck the CBC and liver enzymes
every three to six months.
Next up on the injectables, wehave glutaramer acetate.
(24:21):
So this is another sub-Qinjection here and we want to
watch out for injection sitereactions, and it can also cause
some lipoatrophy of the skin atthe injection site.
So this is one of the fewmedications that can be used in
pregnancy, and sometimes that'llbe part of a strategy is to
cross over from whatever themedication was that the woman
was on previously and startglutiramer acetate.
(24:43):
That's not always done, but itis something that is done
sometimes depending on theclinical situation.
A newer medication that is aninjectable is ofatumumab, and
this is an anti-CD20 medicationthat is given subcutaneously,
and we'll talk a little bitabout CD20 inhibitors when we
get to some of the infusions.
Moving to our oral medications,we have dimethylfumarate.
(25:06):
This one is kind of notoriousfor causing diarrhea and some
flushing.
You also have to watch out forlymphopenia and there are some
rare case reports of PML,although the data is a little
mixed in terms of whether it wasfrom the previous
disease-modifying therapy orfrom the dimethylfumarate itself
.
But this one also requiresmonitoring of the CBC and you
want to watch out for that.
(25:26):
Lymphopenia that's going to bea recurrent theme for a lot of
our medications is watching outfor lymphopenia.
There is also a newermedication in this family called
deroxamilfumarate, and it'ssupposed to have better GI
tolerability but,similarity-wise, a lot of the
same things to watch out for.
Next up is teraflunamide,another one of our oral
medications.
Again, have to watch out forsome GI side effects, some
(25:46):
alopecia, increased risk ofrespiratory infections and you
are also going to be watchingthe CBC for lymphopenia as well
as liver enzymes.
Now we're going to move on toone of our quote higher potency
oral medications and that isfingolimod.
So this one does have a uniqueside effect in as much as it
requires heart monitoring duringthe first dose, as there has
(26:07):
been some bradycardia reportedwith the first dose because of
its effect on the sphingosinereceptors.
Now, from a disease modifyingstandpoint, this is preventing
the lymphocytes from exiting thelymph nodes.
So an important thing toremember about fingolimod is
that when you take someone offof fingolimod for whatever
reason, that you can get reboundMS attacks because all those
(26:30):
lymphocytes are still hangingout.
They're just in the lymph nodes.
So you take away thoseblockades, they start getting
back into circulation and youcan have kind of an aggressive
MS attack.
It can also cause some retinaledema.
So you do need to get regularophthalmologic examinations and
you do need to monitor that CBC.
There are also a couple newermedications in the same family
as Fingolimod, ozanimod andPanesimod and they have slightly
(26:53):
different side effect profilesbut they're new enough that I
don't expect you guys to getquizzed on them just yet, so
we're going to skip over them alittle bit for the sake of
brevity.
So let's move on to ourinfusions.
First up we have natalizumab.
So natalizumab, notoriously, isassociated with PML.
So you do have to screen forthe JC virus and you do need to
monitor titers of the JC virusover time, depending on how long
(27:15):
your patient is on natalizumabtime, depending on how long your
patient is on natalizumab.
That being said, despite theserisks, in appropriately selected
patients it can be a veryeffective treatment for slowing
down MS progression.
So over the last decade or so,there has been a bit of a
paradigm shift towards B-celldepleting therapy.
So our anti-CD20 type therapies.
So before ocralizumab, a lot ofpeople were using rituximab,
(27:38):
but now that we have ocralizumab, this one is being used fairly
often for people with moreaggressive MS and it does
require some pre-infusiontesting.
So we want to make sure thatpeople don't have undiagnosed
hepatitis.
So you do need to checkserologies for that.
And then you want to make surethat they're up to date on their
vaccinations and also getting acouple extra ones, including
against zoster, strep, pneumoniaand hepatitis B, and that helps
(28:02):
reduce those risks of potentialcomplications while on
treatment down the road.
Ocrelizumab was also the firstmedication that received an FDA
approval for primary progressiveMS, so it is also indicated for
those patients.
Next up is alimtuzumab, ananti-CD52 medication, and I kind
of think this is the nuclearoption, right?
You're just obliteratingpeople's white cell population
(28:24):
and you kind of have to wait forit to come back, and these
patients sometimes can developnew autoimmune processes down
the road, in particularautoimmune thyroiditis and ITP.
So lots of side effects andlots of monitoring that go into
the administration ofalimtuzumab.
So very high risk, very potentmedication.
The last disease modifyingtherapy that I'm going to
mention is mitoxantrone, andthis is not used very often in
(28:48):
my experience, but it does havea black box warning for
cardiotoxicity.
So you do have to watch out forcardiac function with
echocardiograms, as well as theusual infection risks that come
along with several of thesehigher potency medications.
So people with MS can develop alot of different neurologic
issues and these kind of run thegamut from spasticity to
(29:08):
neuropathic pain, to chronicfatigue, depression, cognitive
issues, mobility issues, bladderdysfunction, pseudobulbar
affect, tremors.
So you do very much have totailor your treatments to the
individual and what theirparticular symptoms are.
So, starting off with somethingthat's fairly common spasticity
.
So, depending on where and howsevere it is, you might try
(29:29):
things like muscle relaxers,like baclofen or tizanidine, up
to botulinum toxin.
Again, this can be veryeffective for some people,
depending on what their symptomsare and how it is affecting
their daily function.
Neuropathic pain can occur.
We can also see central pain,depending on if there's more
spinal cord lesions and thingsof that nature.
So a lot of the pain managementstrategies that we use for
(29:49):
neuropathic pain in MS aresimilar to what we would do for
people with neuropathy or othercauses of neuropathic pain.
So we think of the gabapentinfamily, pregabalin, as well as
the SNRIs.
For people with MS who aredealing with chronic fatigue,
sometimes we will also trydifferent stimulants like
modafinil or imodafinil, againdepending on the situation, and
(30:10):
you want to make sure that.
Obviously the other side ofthat coin for chronic fatigue is
making sure that people's sleepis restful and restorative.
So a sleep study andappropriate interventions,
depending on what you find fromthat, may be helpful in
alleviating that chronic fatigue.
For people with mobility issues,in particular slowing of
walking, there are somemedications that may be helpful.
In particular, delphamphrodinehas been shown to increase
(30:32):
walking speed in some peoplewith MS, so that is something to
consider trying.
You do have to watch out forside effects, so it can
sometimes cause or worsentrigeminal neuralgia and or
seizures.
So if people have a history oftrigeminal neuralgia or epilepsy
, you definitely want to avoidthis medication.
Bladder dysfunction, again avery common issue for people who
have spinal cord lesions.
So if they're having urinaryretention or urinary
(30:56):
incontinence, it is important towork with a good urologist and
depending on what kind ofurinary issues they're having
sometimes even bladderdysfunction different types of
physical therapy or evenbotulinum toxin injections can
be very helpful for some ofthese patients.
So working with someone who isfamiliar with different causes
of neurogenic bladder orneurogenic bladder dysfunction
(31:16):
can be very helpful.
Lastly, a somewhat uncommonphenomenon that we'll see in
multiple sclerosis ispseudobulbar affect and this is
kind of the emotionalincontinence right Laughing or
crying inappropriately, withoutthe emotion associated with the
physical manifestation and thereis a medication that can
sometimes be helpful for that.
It is a combination ofdextromethorphan and quinidine
(31:39):
and that can sometimes be usefulin these patients for helping
to alleviate those symptoms.
So there you have it.
That's our quick rundown onmultiple sclerosis, a quick
overview.
I know we did some superficiallooks at a few things.
Hopefully this gives you a goodidea, a good framework to work
from, and I hope you certainlyfound it useful in the care of
your MS patients.
Going forward, as always, youcan find me online on X,
(32:01):
formerly known as Twitter, atDrKentris D-R-K-E-N-T-R-I-S, or
you can follow the podcastitself at neuro underscore
podcast, and you can also checkout our website,
theneurotransmitterscom.
Feel free to shoot me a message, let us know what you think and
please do reach out with anyquestions or show suggestions.
Going forward, it's always apleasure to hear from people who
(32:21):
found this work useful andreally helps keep us going.
So thank you so much forlistening and I'll talk to you
next time.
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