IM Board Review #7 - Multiple Sclerosis

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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Chapters

• 19:58 [Ad] Screen Deep
• 20:36 (Cont.) IM Board Review #7 - Multiple Sclerosis

Transcript

Michael Kentris: 0:00

Hello and welcome back, dear listener. You are listening to the Neurotransmitters podcast, your source for everything related to clinical neurology. I am your host, Dr Michael Kentris, and today we are continuing our internal medicine neurology subtopic board review series. Today's topic is multiple sclerosis. We are going to talk about the signs and symptoms that should make us think about multiple sclerosis, how we diagnose multiple sclerosis, what do the typical clinical courses look like for multiple sclerosis and what kind of treatment options do we have. So when should we think about multiple sclerosis, or MS as I'm going to call it from here forward? So MS is one of those diseases that can present in many different ways, but there are a few that are kind of classic and especially when we're talking about question stems on an exam, there are some that should really raise a red flag for you to pay attention to, and we can lump these together into a few different categories. I'm going to put these in the optic neuritis, brainstem syndromes, spinal cord syndromes and then kind of a miscellaneous grab bag. Let's start with optic neuritis. This will usually present with monocular, blurred vision, and one trick that I like to use to help us differentiate whether this is a refractive error, that is to say something in the globe itself, like the cornea or the lens or even in the other parts of the eye, versus in the optic nerve, is to use a pinhole occluder. That's one of those things that you cover the eye with that has just tiny little holes in it and you can kind of improvise one if you don't have one in your neurology bag. If you just take a note card and poke a hole with it with a pin, you can use that. And if someone's visual acuity improves with the pinhole occluder, that suggests that it's more of a refractive error in the eye rather than optic nerve related. Perhaps. You can also see things called red desaturation, where red colors are less vivid and you will sometimes have pain with eye movement. You may also see an afferent pupillary defect, that is to say when you do your swinging flashlight test, so you're shining in one eye and you immediately go to the other eye and back and forth. So when you're shining the light in the eye that is affected, the pupil will dilate to direct light, but if the other eye is normal it should constrict with consensual light and again this is called an afferent pupillary defect. Sometimes in the older literature you'll see it called a Marcus Gunn pupil.

Michael Kentris: 2:17

Now when someone is coming in with these symptoms and you're suspecting optic neuritis, it is important to do a fundoscopic exam. Acutely you may see evidence of papilledema or papillitis, and chronically they may have evidence of optic nerve atrophy. So you can sometimes see this if it is the anterior portion of the optic nerve affected, but if it's more in the posterior part of the optic nerve you may have a normal fundoscopic exam on these patients. So in the setting of MS, this is usually going to be unilateral Now. So in the setting of MS, this is usually going to be unilateral. Now there are some demyelinating syndromes that may present with bilateral optic neuritis, and so if you have bilateral optic neuritis, that should be a red flag for you to consider things that are demyelinating but not MS, things like neuromyelitis, optica or NMO, and myelin oligodendrocyte glycoprotein, abbreviated MOG or MOG. As a pretty big nerd myself, I can never hear MOG without thinking about the character from Final Fantasy. So if you're familiar, then you too also know that Final Fantasy VI is the best Final Fantasy game.

Michael Kentris: 3:15

Another category that we'll often see with MS are brainstem syndromes, and these can present with a variety of different symptoms as well, including nystagmus, dyplopia, other types of eye movement abnormalities, things of that nature. You can also get some cerebellar or vestibular type symptoms with ataxia or vertigo. One of the classic eye movement abnormalities that you may see or may be asked about is an INO or internuclear ophthalmoplegia, and this is an inability to adduct AD-duct one eye with nystagmus in the AB abducting eye, and this is usually due to a lesion in the MLF, the medial longitudinal fasciculus. There are, of course, many other eye abnormalities. I mention INO specifically because it is a favorite for test writers.

Michael Kentris: 3:59

Moving on to spinal cord syndrome, so this may present as a transverse myelitis type syndrome or other types of myelitis or spinal cord related type disabilities, weakness, numbness in the limbs, arms, legs, etc. Depending on what level it's at. You may get a sensory level in the thoracic spine, etc. There are a couple different symptoms that patients with MS may describe when they have lesions in the spinal cord. One of these is Lhermitte's sign, which is a shock-like sensation that runs down the spine or into the limbs with neck flexion, typically in the cervical spine. You can also get a quote MS hug, and this is a band-like sensation, often around the chest.

Michael Kentris: 4:38

Urinary symptoms can also be common when people have spinal cord lesions. These can include symptoms of urinary retention, urinary urgency or urinary incontinence and, as we mentioned earlier, there are a lot of miscellaneous or various hard-to-pin-down sort of symptoms that can occur with MS as well. People may fatigue more easily than normal. They may describe a quote, brain fog. There may be evidence of cognitive decline. On examination you can also get a phenomenon with people who have more long-standing MS, something called the Uthoff's phenomenon, which is a transient worsening of their baseline neurologic deficits. This is often in the setting of when they have an infection with fevers, in the setting of hot weather or if they physically overexert themselves, and this may lead into what sometimes is called a pseudo-relapse or a pseudo-flare, or essentially a recrudescence of prior neurologic deficits in the setting of some other stressor on the body.

Michael Kentris: 5:30

So now we know some symptoms to make us think about MS, but what about when we want to get to a diagnosis? There can be some challenges in coming to a diagnosis of MS because there are many things that can mimic it, and we'll talk about those in a minute. But the criteria that we're using presently are the revised McDonald criteria, and you may have heard this phrase. Dissemination in time and space Always makes me think of a Doctor who episode. But what we mean when we say dissemination in time and space is that we want multiple lesions on MRI or clinical events separated by at least two points in time or two points in space, that is to say in the neuroaxis. So there are a couple different permutations that can get us to that point. So let's say we have someone who has had two or more clinical attacks and we want to see at least two objective findings on MRI MRI being our main diagnostic imaging that we're using in MS. So if we see two lesions that correlate with those clinical symptoms, then that meets our criteria.

Michael Kentris: 6:27

If we have two or more clinical attacks with at least one lesion on imaging that correlates with our symptoms, that, plus the past history of an event that sounds suspicious for a demyelinating attack, can meet criteria. And this is why it's important when you're first seeing someone who you suspect may have MS is to really dig into that history and see how you had any of those past episodes going on for sometimes days to weeks of blurred vision, weakness, numbness, vertigo, etc. That could potentially represent a past attack. So that way you know if they've had a previous attack and now you have one new attack with an MRI abnormality at this time, then you can still lean a lot more favorably towards getting a definitive diagnosis.

Michael Kentris: 7:13

Where things can get a little tricky is if you have one clinical attack, or what we call clinically isolated syndrome, and we'll talk a little bit more about that as we go on. But if we have one clinical attack and you get your MRI and you see one old lesion and then one new and what we mean by a new lesion is one that is an enhancing with IV contrast so if you have an enhancing lesion and an old non-enhancing lesion, that is your dissemination in time. And if those are in different locations in the neural axis, there's your dissemination in space as well. But it gets even hairier sometimes. Let's say, we have one clinical attack clinically suspicious for multiple sclerosis and you have an MRI lesion that correlates with those symptoms that also look suspicious for demyelinating disease. So maybe you have a couple enhancing lesions. There's your dissemination in space, but you don't have any old lesions on MRI.

Michael Kentris: 8:02

This is where getting CSF studies tends to be the most beneficial as far as getting to a definitive diagnosis of MS. So we're checking our routine CSF labs and we're also checking oligoclonal bands, as they tend to be fairly specific to MS, although not 100%. So let's recap that once more. So we are looking for dissemination in space, that is, more than one T2 hyper-intense lesion. Now we talk about different types of white matter lesions. These are going to be usually more than three millimeters on their long axis. They tend to be a little fluffier than what we would see for patients with migraine or cerebrovascular disease and there are a few locations that tend to be more typical for MS. So we can see periventricular lesions and we're looking for more than one lesion, unless the patient is over the age of 50, right, because of those cerebrovascular risk factors, in which case you usually want to see a higher number. You can also see cortical or juxtacortical lesions, infratentorial lesions in the brainstem or cerebellum, and then spinal cord lesions. And to recap on the dissemination in time, if we have a first-time MRI that shows a new enhancing lesion as well as an old non-enhancing T2 hyper-intense lesion that is characteristic of demyelinating disease, that can meet our criteria for dissemination in time. Or if we have an old MRI that shows a T2 hyper intense lesion and then we get a new MRI and that new MRI shows a new lesion, 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.

Michael Kentris: 9:37

So let's dig a little bit more into the testing that we will often do. Working someone up for MS, as we've been talking about, mri is often the mainstay of the initial diagnostic battery. So we are looking often at the brain and, depending on symptoms, may also be looking at the cervical and or thoracic spine, and very often we are going to be getting these with and without IV gadolinium contrast, and that is because we're looking for enhancing lesions. Monitoring MRIs down the road may 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 much right now.

Michael Kentris: 10:10

If there is a clinical suspicion for past optic neuritis, there are a couple tests that can be done. So there are visual evoked potentials, or VEPs, and there is also optical coherence tomography or OCTs, and both of these can show evidence of prior optic neuritis and they tend to stay abnormal kind of indefinitely. So that can be a very helpful test in terms of if the MRI doesn't show any abnormalities, then you might get one of these tests to see if there is any evidence of prior injury to the optic nerve. We mentioned CSF studies earlier, alleloclonal bands being the main one that we're usually looking at, and these are usually present in MS and they have pretty good sensitivity depending on the study you look at anywhere from 80 to 90 plus percent and they also are fairly specific more than 60 percent in most studies, although again that varies depending on what data you look at. An important thing to note with the high sensitivity of alleloclonal bands, or O-bands, is that If they are negative in your CSF, you should really be wondering if you have the correct diagnosis, as there are again several other things that could potentially mimic multiple sclerosis.

Michael Kentris: 11:13

So let's dive into our differential diagnosis and I think we can put these into a few different categories. So we have, like other demyelodening diseases, systemic autoimmune or inflammatory disorders, metabolic or genetic disorders, infectious vascular neoplastic migraine and functional disorders. Let's start off with our other demyelinating diseases. One of these is ADEM acute disseminated encephalomyelitis. This is usually a post-infectious, post-viral type of process. We see it more often in the pediatric or young adult population, although you can sometimes see it in adults after certain kinds of infection. Legionella is the one that has a bit of an association and it often presents with a bit more confusion. Sometimes you may have seizures and they tend to have a lot of big fluffy lesions throughout the brain and or spinal cord. One of the main differences with ADEM as opposed to MS is that it is usually a monophasic type event and O-bands typically will be negative in these patients.

Michael Kentris: 12:14

Neuromyelitis optica is another type of demyelinating disorder that tends to affect, as the name suggests, the spinal cord and the optic nerves. As we mentioned earlier, bilateral simultaneous optic neuritis, very suggestive of NMO. And then there is also what we call longitudinally extensive transverse myelitis. That is, usually three or more segments of involvement and that tends to be more suggestive of one of these atypical demodding disorders NMO or MOG or even sarcoidosis potentially, but it is less commonly associated with MS. When we have this longitudinally extensive transverse myelitis, you'll still see a lot of people mentioning idiopathic, quote-unquote transverse myelitis. I would say that transverse myelitis is more of a syndrome rather than a diagnosis. Idiopathic transverse myelitis should only be left as quote idiopathic after a number of things have been excluded, including NMO, mog, sarcoidosis, other types of systemic autoimmune diseases. So this is very much an exclusionary diagnosis. So transverse myelitis should not be your final stopping point in your diagnostic workup by a long margin until you've exhausted a lot of other testing.

Michael Kentris: 13:19

Some of the more common systemic autoimmune syndromes that we also want to check for again, depending on the clinical context, are things like lupus, sjogren's syndrome, sarcoidosis, some unusual metabolic and genetic disorders. There are various adult-onset leukodystrophies. A couple of the ones to think about adrenal leukodystrophy or metachromatic leukodystrophy. Make sure to get that family history to make sure that there isn't anything like that to suggest that this may run in the family. Check also if there's a lot of spinal cord lesions, vitamin B12 deficiency, copper deficiencies, things of that nature, some infections that could present similarly HIV, lyme disease, syphilis and then one that we may not think about as much, but again, htlv-1. So this is also known as tropical spastic periparesis. So if we're seeing this progressive spasticity in the lower extremities in particular, this may suggest some sort of underlying infection. Or there are some genetic variants as well.

Michael Kentris: 14:14

In the vascular category we have different genetic stroke syndromes. One to think about is CATACYL, cerebral autosomal dominant arteriopathy with subacute infarcts and leukencephalopathy, and these will be younger people presenting with migraines and strokes, very often in the temporal lobes. Cns vasculitis can also cause some unusual presentations. Sussack syndrome is another one of these small vessel vasculitides and it tends to affect the retina cochlea as well as the corpus callosum, these small penetrating branches. So you'll also get visual changes, hearing loss, as well as these unusual strokes. They're sometimes described as like snowball-like around the corpus callosum.

Michael Kentris: 14:52

Sometimes different neoplasms may also suggest demyelinating disease. Things that may look similarly are different types of gliomas or CNS lymphoma. In these situations you may need a biopsy, as there is also something called tumfactive MS, where an MS lesion, an acute demyelinating lesion, may look more like a tumor. So in those situations sometimes a brain biopsy is necessary to come to a definitive diagnosis. You can also get different perineoplastic syndromes causing cerebellar or myeloneuropathy-type syndromes. You can also get encephalitis, behavioral changes with different perineoplastic syndromes. So it's important to also check for these in the appropriate clinical context.

Michael Kentris: 15:32

Lastly, migraines Very often people are getting MRIs of their brain to check on causes of headache and a lot of times you'll get a nonspecific report that says the differential includes quote demyelinating disease. And it's because people with migraine tend to have a higher burden of small white matter lesions compared to the general population. So it is important. If the person has never had any clinical events and the quote unquote lesions on MRI are not typical of demyelinating disease, you may not need to go any further down that diagnostic pathway. Just treat the person's migraines. Lastly, there are different functional disorders functional weakness, functional tremors, functional blindness that can sometimes mimic demyelinating disorders. Clinically and typically you would expect imaging studies and other diagnostic testing to be normal in these patients.

Michael Kentris: 16:20

Now let's talk a little bit about the clinical course that we can sometimes see with MS. So, as we mentioned a little bit earlier, we can sometimes start with what's called clinically isolated syndrome, and this is a first-time event when the imaging or clinical criteria don't meet a definition of definite MS. Now let's say we have a clinical event and we have a brain lesion on the initial MRI. So these people have a 10-year risk of about a 90% conversion to definite multiple sclerosis. However, if there is no brain lesion on the initial scan, their risk is lower, about 10 to 20%. Now flip that around a little bit. Let's say we have radiologically isolated syndrome. They've had no clinical episode, but for some reason they've gotten an MRI and the imaging findings are consistent with potential demyelinating disease. About 50% of these people will convert to MS over the next 10 years. So both these categories of people do require very close observation and in some cases it may be reasonable to talk about whether or not treatment should be started More for our clinically isolated syndromes who have the highest risk of converting to more definite relapsing-remitting multiple sclerosis.

Michael Kentris: 17:30

So relapsing-remitting multiple sclerosis it's the most common kind of presentation that we usually see in people who have a diagnosis of MS. So they tend to have an acute episode of some sort of neurologic deficit or worsening, and this is followed by a period of recovery, right. So they have a relapse and then those symptoms remit and over time they tend to have less improvement in between relapses, kind of this accumulation of neurologic disease burden over time. So without treatment approximately 50% of patients progress to secondary progressive MS and secondary progressive MS is where we see less remission and acute worsening, but you can still see continued gradual neurologic decline. Contrast this with primary progressive multiple sclerosis. So this is about 15% of people at presentation who have primary progressive MS and these people tend to not have the acute flares as much, but this again gradual worsening and accumulation of different neurologic disability.

Michael Kentris: 18:33

So let's talk a little bit about treatment and we can put these into a few different categories. That's what we might call lifestyle, general health recommendations, how we might treat acute exacerbations, long-term disease-modifying therapy and different symptomatic management strategies. So, starting off with our kind of lifestyle, non-pharmacologic interventions, it is important to maintain regular exercise, both aerobic and strengthening plans. This can help on a number of fronts, both with reducing increased weakness and deconditioning, as well as reducing osteoporosis risk, as people with MS do tend to have vitamin D deficiency as well. So it's often important to check those vitamin D levels and make sure to supplement appropriately.

Michael Kentris: 19:16

You also need to make sure that people are doing their best to avoid infection. Many of the people with MS who are on treatment are going to be on some form of immunosuppression, and so they are at risk for different types of infection depending on the agent that they're taking. So you want to make sure that they're vaccinated against the influenza virus as well as other specific viruses, depending on, again, what medication and what that patient's particular demographics are. If your patient is a smoker, smoking cessation is essential. These people have a significantly increased risk of conversion from relapsing remitting to secondary progressive MS, and they tend to accumulate disability faster than non-smokers. So smoking cessation is one of the most important things to counsel people with MS on.

Michael Kentris: 20:36

Lastly, pregnancy A lot of people with MS are younger women of childbearing years, and so many of these medications that we use for treatment of multiple sclerosis are not safe in pregnancy. So it is very important to plan ahead, have those conversations early, as we do know that about half of pregnancies in the United States are not planned. So there are a lot of considerations in terms of when to withdraw medication, when someone is trying to become pregnant and a lot of other things that are kind of beyond the scope of our kind of more broad overview today. So I'm not going to go too deep into those particular considerations right now.

Michael Kentris: 21:04

So for treatment of an acute exacerbation so someone has a diagnosis of MS or a suspected first-time episode of MS and we're looking usually for new or worsening neurologic symptoms lasting at least 24 hours. A lot of times people have pseudo-relapses. Maybe they have a UTI or a fever or pneumonia or something else triggered a relapse quote unquote of their previous symptoms. So if the symptoms are very, very similar to a past episode, it may be a pseudo relapse rather than a true new MS flare. And this is important to know, because the treatment is going to be different and we don't want to expose people to medications unnecessarily that could cause complications. So make sure to check for signs of infection or metabolic disturbances, as these can cause these recrudescence of prior neurologic deficits. So we've determined yes, this is an MS flare and we need to start treatment.

Michael Kentris: 21:56

The typical treatment is IV methylprednisolone one gram daily for three to five days, and this really does depend on the person's response to treatment about how long you go, as well as how bad are the deficits. If this is more of a numbness or paresthesia versus I can't see out of one eye or I can't lift one of my legs or arms right, if you are having functional disability from an acute flare, then you usually want to be a bit more aggressive in your treatment than if it's more of a non-disabling deficit, because what we do know is that acute treatments don't necessarily change long-term disability progression. They can hopefully shorten the duration of the acute relapse, however. So that is really what we're trying to do is shorten that acute worsening in these patients. So if we're giving high-dose steroids, we usually want to make sure the person's stomach is protective using some sort of antacid, ppi, h2 blocker, etc. And we also want to make sure, if this person is also diabetic, that we are treating that hyperglycemia that we may be worsening transiently, and that is also a consideration. I have certainly had patients in the past who came in with an MS flare, who had somewhat poorly controlled diabetes and we could not get that glucose to be where we wanted it to be. So we had to consider is the risk of this uncontrolled hyperglycemia due to the high-dose steroids that we're giving going to be worth the potential benefit from the treatment? So this is definitely a consideration.

Michael Kentris: 23:18

When there is more than one medical issue active at a time. In situations where steroids may not be an option or where people have not responded to steroids in the past, plasma exchange may also be an option and I should mention if you're trying to keep your patient out of the hospital, sometimes you can give oral prednisone. 1,250 milligrams per day is sometimes recommended. That is a lot of oral prednisone. So definitely make sure that you are communicating with both the pharmacy and the patient, as this may be a surprising amount.

Michael Kentris: 23:47

So let's jump into one of the meatier topics for MS and that is the disease-modifying therapy, and you can kind of categorize these in a couple different ways. There are injectables, oral medications and infusions, and these all have different timing frequencies and different side effects, and we'll talk about all of those. You can also think of it in terms of what we call standard therapy and then more aggressive or potent therapies as well. So our older generation tends to be what we think of as the more standard quote unquote therapy, and that includes some of the injectables and some of the oral medications. So, kind of going back to the OG, interferon beta 1A, and there are a couple of different formulations of this, but they all have very similar side effect profiles. So these are one of the injectables and, again, different formulations have different dosing frequencies, but some of the more common side effects that you have to watch out for are flu-like symptoms, injection site reaction and depression. Surprisingly, with the interferons, you're also going to want to make sure that you check the CBC and liver enzymes every three to six months.

Michael Kentris: 24:48

Next up on the injectables, we have glutaramer acetate. So this is another sub-Q injection here and we want to watch out for injection site reactions, and it can also cause some lipoatrophy of the skin at the injection site. So this is one of the few medications that can be used in pregnancy, and sometimes that'll be part of a strategy is to cross over from whatever the medication was that the woman was on previously and start glutiramer acetate. That's not always done, but it is something that is done sometimes depending on the clinical situation. A newer medication that is an injectable is ofatumumab, and this is an anti-CD20 medication that is given subcutaneously, and we'll talk a little bit about CD20 inhibitors when we get to some of the infusions.

Michael Kentris: 25:33

Moving to our oral medications, we have dimethylfumarate. This one is kind of notorious for causing diarrhea and some flushing. You also have to watch out for lymphopenia and there are some rare case reports of PML, although the data is a little mixed in terms of whether it was from the previous disease-modifying therapy or from the dimethylfumarate itself. But this one also requires monitoring of the CBC and you want to watch out for that. Lymphopenia that's going to be a recurrent theme for a lot of our medications is watching out for lymphopenia. There is also a newer medication in this family called deroxamilfumarate, and it's supposed 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 for some GI side effects, some alopecia, increased risk of respiratory infections and you are also going to be watching the CBC for lymphopenia as well as liver enzymes.

Michael Kentris: 26:25

Now we're going to move on to one of our quote higher potency oral medications and that is fingolimod. So this one does have a unique side effect in as much as it requires heart monitoring during the first dose, as there has been some bradycardia reported with the first dose because of its effect on the sphingosine receptors. Now, from a disease modifying standpoint, this is preventing the lymphocytes from exiting the lymph nodes. So an important thing to remember about fingolimod is that when you take someone off of fingolimod for whatever reason, that you can get rebound MS attacks because all those lymphocytes are still hanging out. They're just in the lymph nodes. So you take away those blockades, they start getting back into circulation and you can have kind of an aggressive MS attack. It can also cause some retinal edema. So you do need to get regular ophthalmologic examinations and you do need to monitor that CBC. There are also a couple newer medications in the same family as Fingolimod, ozanimod and Panesimod and they have slightly different side effect profiles but they're new enough that I don't expect you guys to get quizzed on them just yet, so we're going to skip over them a little bit for the sake of brevity.

Michael Kentris: 27:33

So let's move on to our infusions. First up we have natalizumab. So natalizumab, notoriously, is associated with PML. So you do have to screen for the JC virus and you do need to monitor titers of the JC virus over time, depending on how long your patient is on natalizumab time, depending on how long your patient is on natalizumab. That being said, despite these risks, in appropriately selected patients it can be a very effective treatment for slowing down MS progression.

Michael Kentris: 27:57

So over the last decade or so, there has been a bit of a paradigm shift towards B-cell depleting therapy. So our anti-CD20 type therapies. So before ocralizumab, a lot of people were using rituximab, but now that we have ocralizumab, this one is being used fairly often for people with more aggressive MS and it does require some pre-infusion testing. So we want to make sure that people don't have undiagnosed hepatitis. So you do need to check serologies for that. And then you want to make sure that they're up to date on their vaccinations and also getting a couple extra ones, including against zoster, strep, pneumonia and hepatitis B, and that helps reduce those risks of potential complications while on treatment down the road. Ocrelizumab was also the first medication that received an FDA approval for primary progressive MS, so it is also indicated for those patients.

Michael Kentris: 28:44

Next up is alimtuzumab, an anti-CD52 medication, and I kind of think this is the nuclear option, right? You're just obliterating people's white cell population and you kind of have to wait for it to come back, and these patients sometimes can develop new autoimmune processes down the road, in particular autoimmune thyroiditis and ITP. So lots of side effects and lots of monitoring that go into the administration of alimtuzumab. So very high risk, very potent medication. The last disease modifying therapy that I'm going to mention is mitoxantrone, and this is not used very often in my experience, but it does have a black box warning for cardiotoxicity. So you do have to watch out for cardiac function with echocardiograms, as well as the usual infection risks that come along with several of these higher potency medications.

Michael Kentris: 29:31

So people with MS can develop a lot of different neurologic issues and these kind of run the gamut from spasticity to neuropathic pain, to chronic fatigue, depression, cognitive issues, mobility issues, bladder dysfunction, pseudobulbar affect, tremors. So you do very much have to tailor your treatments to the individual and what their particular symptoms are. So, starting off with something that's fairly common spasticity. So, depending on where and how severe it is, you might try things like muscle relaxers, like baclofen or tizanidine, up to botulinum toxin. Again, this can be very effective for some people, depending on what their symptoms are and how it is affecting their daily function.

Michael Kentris: 30:10

Neuropathic pain can occur. We can also see central pain, depending on if there's more spinal cord lesions and things of that nature. So a lot of the pain management strategies that we use for neuropathic pain in MS are similar to what we would do for people with neuropathy or other causes of neuropathic pain. So we think of the gabapentin family, pregabalin, as well as the SNRIs. For people with MS who are dealing with chronic fatigue, sometimes we will also try different stimulants like modafinil or imodafinil, again depending on the situation, and you want to make sure that. Obviously the other side of that coin for chronic fatigue is making sure that people's sleep is restful and restorative. So a sleep study and appropriate interventions, depending on what you find from that, may be helpful in alleviating that chronic fatigue.

Michael Kentris: 30:53

For people with mobility issues, in particular slowing of walking, there are some medications that may be helpful. In particular, delphamphrodine has been shown to increase walking speed in some people with MS, so that is something to consider trying. You do have to watch out for side effects, so it can sometimes cause or worsen trigeminal neuralgia and or seizures. So if people have a history of trigeminal neuralgia or epilepsy, you definitely want to avoid this medication.

Michael Kentris: 31:18

Bladder dysfunction, again a very common issue for people who have spinal cord lesions. So if they're having urinary retention or urinary incontinence, it is important to work with a good urologist and depending on what kind of urinary issues they're having sometimes even bladder dysfunction different types of physical therapy or even botulinum toxin injections can be very helpful for some of these patients. So working with someone who is familiar with different causes of neurogenic bladder or neurogenic bladder dysfunction can be very helpful. Lastly, a somewhat uncommon phenomenon that we'll see in multiple sclerosis is pseudobulbar affect and this is kind of the emotional incontinence right Laughing or crying inappropriately, without the emotion associated with the physical manifestation and there is a medication that can sometimes be helpful for that. It is a combination of dextromethorphan and quinidine and that can sometimes be useful in these patients for helping to alleviate those symptoms. So there you have it.

Michael Kentris: 32:14

That's our quick rundown on multiple sclerosis, a quick overview. I know we did some superficial looks at a few things. Hopefully this gives you a good idea, a good framework to work from, and I hope you certainly found it useful in the care of your MS patients. Going forward, as always, you can find me online on X, formerly known as Twitter, at DrKentris D-R-K-E-N-T-R-I-S, or you can follow the podcast itself at neuro underscore podcast, and you can also check out our website, theneurotransmitterscom. Feel free to shoot me a message, let us know what you think and please do reach out with any questions or show suggestions. Going forward, it's always a pleasure to hear from people who found this work useful and really helps keep us going. So thank you so much for listening and I'll talk to you next time.