Atypical Parkinsonian Disorders

Podcast Transcript

Neuro Pathways Podcast Series

Release Date: October 15, 2024

Expiration Date: October 15, 2025

Estimated Time of Completion: 25 minutes

Atypical Parkinsonian Disorders

Junaid Siddiqui, MD

Description

Each podcast in the Neurological Institute series provides a brief, review of management strategies related to the topic.

Learning Objectives

• Review up to date and clinically pertinent topics related to neurological disease
• Discuss advances in the field of neurological diseases
• Describe options for the treatment and care of various neurological disease

Target Audience

Physicians and Advanced Practice providers in Family Practice, Internal Medicine & Subspecialties, Neurology, Nursing, Pediatrics, Psychology/Psychiatry, Radiology as well as Professors, Researchers, and Students.

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CREDIT DESIGNATION

• American Medical Association (AMA)
  Cleveland Clinic Center for Continuing Education designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
  
  Participants claiming CME credit from this activity may submit the credit hours to the American Osteopathic Association for Category 2 credit.

• American Nurses Credentialing Center (ANCC)
  Cleveland Clinic Center for Continuing Education designates this enduring material for a maximum of 0.50 ANCC contact hours.

• Certificate of Participation
  A certificate of participation will be provided to other health care professionals for requesting credits in accordance with their professional boards and/or associations.

• American Board of Surgery (ABS)
  Successful completion of this CME activity enables the learner to earn credit toward the CME requirements of the American Board of Surgery’s Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit.

Credit will be reported within 30 days of claiming credit.

Podcast Series Director

Imad Najm, MD
Epilepsy Center

Additional Planner/Reviewer

Cindy Willis, DNP

Faculty

Junaid Siddiqui, MD
Center for Neurological Restoration

Host

Glen Stevens, DO, PhD
Cleveland Clinic Brain Tumor and Neuro-Oncology Center

Agenda

Atypical Parkinsonian Disorders

Junaid Sidduiqui, MD

Disclosures

In accordance with the Standards for Integrity and Independence issued by the Accreditation Council for Continuing Medical Education (ACCME), The Cleveland Clinic Center for Continuing Education mitigates all relevant conflicts of interest to ensure CME activities are free of commercial bias.

The following faculty have indicated that they may have a relationship, which in the context of their presentation(s), could be perceived as a potential conflict of interest:

The following faculty have indicated they have no relationship which, in the context of their presentation(s), could be perceived as a potential conflict of interest: Cindy Willis, DNP; Junaid Sidduiqui, MD.

CME Disclaimer

The information in this educational activity is provided for general medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options of a specific patient's medical condition. The viewpoints expressed in this CME activity are those of the authors/faculty. They do not represent an endorsement by The Cleveland Clinic Foundation. In no event will The Cleveland Clinic Foundation be liable for any decision made or action taken in reliance upon the information provided through this CME activity.

HOW TO OBTAIN AMA PRA Category 1 Credits™, ANCC Contact Hours, OR CERTIFICATE OF PARTICIPATION:

Go to: Neuro Pathways Podcast October 15, 2024 to log into myCME and begin the activity evaluation and print your certificate If you need assistance, contact the CME office at myCME@ccf.org

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Introduction: Neuro Pathways, a Cleveland Clinic podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab, and psychiatry.

Glen Stevens, DO, PhD: Atypical parkinsonian disorders, or APDs, are a group of neurodegenerative conditions that present some of the most challenging diagnostic puzzles in the field of neurology, and their progressive nature can make them difficult to treat. In today's episode of Neuro Pathways, we're discussing diagnosis and management of atypical parkinsonian disorders.

I'm your host, Glenn Stevens neurologist, neuro oncologist in Cleveland Clinic's Neurological Institute. Today I'm joined by Dr. Junaid Siddiqui. Junaid Siddiqui, MD is a movement disorders neurologist in Cleveland Clinic's Center for Neurological Restoration. Junaid, welcome to Neuro Pathways.

Junaid Siddiqui, MD: Thank you.

Glen Stevens, DO, PhD: So Junaid, to start off, why don't you tell the folks out there a little bit about yourself, where you grew up, how you made your way to Cleveland clinic and what you do.

Junaid Siddiqui, MD: Yeah, so I grew up in Saudi Arabia. I'm originally from Pakistan. I did my medical school in Pakistan. I finished my internal medicine certification, MRCP, from the Royal College of Physicians in London in 2004. And then I started working in neurology. So I saw general neurology patients for about six years before I came here, to the Cleveland Clinic for fellowship in movement disorders. And then I did a second fellowship in movement disorders at University Hospitals, and then I did my residency for four years at the University of Missouri in movement disorders. And then Dr. Fernandez asked me to come here, and that's why I'm here.

Glen Stevens, DO, PhD: Well, we're happy to have you here. Welcome.

Junaid Siddiqui, MD: Thank you.

Glen Stevens, DO, PhD: So before we talk about atypical parkinsonian disorders, let's just very briefly just discuss Parkinson's disease. Tell us what Parkinson's disease is and what the classic features are.

Junaid Siddiqui, MD: So Parkinson's disease is the commonest cause of parkinsonism. So if you can start with actually parkinsonism, that may be a better prelude. So whenever somebody has a rigidity bradykinesia and they may or may not have tremor, that's called parkinsonism, that can be from medication exposure, from Parkinson's disease, from some of the other conditions. The commonest cause of this syndrome is Parkinson's disease, which is a neurodegenerative condition. It starts off with milder symptoms, usually involving one side of the body, but over years, it starts involving the other side. And gradually progressive symptoms involve more balance trouble, thinking problems, and then becoming wheelchair bound in about 100% of patients over decades.

Glen Stevens, DO, PhD: So let's move now to atypical parkinsonian disorders. What's the difference between Parkinson's disease and an atypical parkinsonian disorder?

Junaid Siddiqui, MD: As I mentioned, Parkinson's disease is the commonest cause of parkinsonism. So when people have parkinsonism from Parkinson's disease because it's so common, we know that how the story goes, we know it's gradually progressive and it follows this typical trajectory in almost all the patients with Parkinson's disease. So that's why it's called typical parkinsonism. So that's typical Parkinson's disease. Whenever somebody follows a trajectory that looks different from Parkinson's disease, we call it atypical parkinsonism. And that would include earlier memory problems, earlier balance difficulties or falls, or significantly deranged dysautonomia. So those would be some of the reasons to consider somebody has an atypical parkinsonian disorder if somebody starts falling earlier, earlier memory decline, and dementia. So those would be atypical characteristics.

Glen Stevens, DO, PhD: So if we look at some of the atypical parkinsonian disorders, we see things like progressive supranuclear palsy, multisystem atrophy, cortical basal syndrome, and dementia with Lewy bodies. Let's just go through these a little bit. What is progressive supranuclear palsy?

Junaid Siddiqui, MD: So these are the four major primary parkinsonian disorders that are atypical. So progressive supranuclear palsy is when people have severe balance difficulties, they end up falling backwards, they have vertical supranuclear gaze palsy, that's why it got its name. It's supranuclear because when patients are asked to follow the finger up or down vertically with their eyes, they're unable to make the eye movements. But you can overcome those movements by moving the head while they're looking at a stationary object. So that means the problems in eye movements they're supranuclear, they're not infranuclear as somebody may have from a brainstem lesion or a cranial nerve palsy. So that's supranuclear palsy, it's progressive, it causes a lot of disability. Patients are wheelchair-bound by the time they actually start seeing the first or second neurologist, it can cause dementia, as well.

Glen Stevens, DO, PhD: And responsiveness to dopamine agonists?

Junaid Siddiqui, MD: So that's one thing that is common to almost all the atypical parkinsonian disorders that they either do not respond to levodopa, or if they do respond, the response is short-lived and mild.

Glen Stevens, DO, PhD: Multisystem atrophy. Why don't we talk about that for a little bit?

Junaid Siddiqui, MD: Yeah. So multisystem atrophy, or multiple system atrophy, is another atypical parkinsonian disorder. This is marked by significant balance difficulty that can be from cerebellar dysfunction, in which case it's called MSA-C from cerebellar dysfunction, or it could be MSA-P where people have more parkinsonism, they may have a tremor address or something like that. But the common thing between both of these subcategories of the MSA is that they have a lot of dysautonomia. So they have severe neurogenic orthostatic hypotension, which is severely limiting. And they also are wheelchair-bound by the time they actually seek medical attention for the first or second neurologist. They have a lot of other autonomic problems like drooling. They have urinary incontinence. Erectile dysfunction may predate by several years. They may have REM sleep behavior disorder.

Glen Stevens, DO, PhD: And as a fun fact, I guess people that have multiple system atrophy can have an unusual appearance on an MRI scan. Do you want to just tell us what that is?

Junaid Siddiqui, MD: Yeah, so there are a couple of distinguishing features in MRIs for MSA. There is something called putaminal rim sign where there's hyper intensity around the putamen, and then there's something called a hot cross bun sign, which is in the brainstem from atrophy and fibrosis of the fibers. So it causes this hot cross bun sign.

Glen Stevens, DO, PhD: And I guess just going back a second, with progressive supranuclear palsy, you can also get an interesting MRI visual feature. You want to mention that?

Junaid Siddiqui, MD: It's called a hummingbird sign and it's from midbrain atrophy, the midbrain atrophies, the pons appears larger, it's coming from the midbrain. So it gives this hummingbird appearance or a penguin sign, it's sometimes called. But to be noted is that not everybody with PSP will have those radiological files. They're now explaining that there are seven or eight subtypes of PSP, and the hummingbird sign is specific for the Steele-Richardson subtype of PSP. You may have PSP but not have those imaging findings. Same thing with MSA. You may have MSA but not have those MRI findings.

Glen Stevens, DO, PhD: Good. So moving on to dementia with Lewy bodies. What characterizes that disorder?

Junaid Siddiqui, MD: So dementia with Lewy bodies may, actually, deceivingly appear similar to Parkinson’s disease. Some people consider that this as a continuum of Parkinson’s disease because they're both synucleinopathies and they can have the same anosmia REM sleep behavior disorder. But in DLB, patients have a more severe and earlier cognitive decline. It has been arbitrarily said about one year from onset of symptoms, people actually start having significant memory decline, visual hallucinations. The visual hallucinations in DLB are usually very detailed. They can talk about if they're seeing animals or human beings, they would actually detail the wrinkles on the person's face on those images, so they're very detailed.

Glen Stevens, DO, PhD: And you've mentioned it a couple of times, but maybe just a little bit more about REM sleep disorders.

Junaid Siddiqui, MD: So REM sleep behavior disorder or RBD, it's called, so normally when we sleep in the REM stage of the sleep, it's called rapid eye movement. So our eyes are moving, but our bodies are supposed to be paralyzed. So even if we're watching a dream that we are fighting an intruder or whatever, our bodies are paralyzed. We don't move normally. But when people have REM sleep behavior disorder, their bodies are not paralyzed. So when they see active dreams like they're fighting off an intruder, they will actually swing their arms. Sometimes they hit their bed partners or sometimes they injure themselves by hitting on the wall or fall off the bed, and that can result in severe injury, of course. So that is a characteristic of some of the synucleinopathies including Parkinson's disease, DLB and MSA. So that's one thing that can be common in those conditions. The RBD is usually more common or more frequent with DLB and MSA than Parkinson's disease.

Glen Stevens, DO, PhD: And then corticobasal syndrome.

Junaid Siddiqui, MD: So corticobasal syndrome is another. So syndrome is the term given for the general characteristics. Corticobasal degeneration is more specific for the primary parkinsonian disorder, which is an atypical parkinsonian disorder. It is also a gradually progressive condition. It leads to early memory decline, dementia, it can have a lot of spasticity, dystonia, apraxia, alien limb phenomenon, and that can be quickly progressive as well. The corticobasal syndrome, so having similar features with dementia and apraxia and one-sided dystonia can actually happen with other conditions, like even PSP can cause those symptoms. Alzheimer's disease can present as corticobasal syndrome, but corticobasal degeneration is the specific condition that causes those symptoms.

Glen Stevens, DO, PhD: So I'm getting a little bit older, I get a little mild tremor, I've kind of slowed down in my movements. I think I might have Parkinson's. I come and see you. How good are you at diagnosing Parkinson's disease?

Junaid Siddiqui, MD: We have gotten good in picking up parkinsonism, especially in the movement disorder world. So that's how we start. Whenever somebody comes in with a tremor, the first thing we notice is the tremor, symmetric or asymmetric, is it addressed or does it come out with use of hands? The handwriting size, has it become larger or smaller? Then we ask questions about a sense of smell, REM sleep behavior disorder or constipation. So we get both non-motor symptoms, motor symptoms. We try to make a trajectory of when the symptoms started, how long it has been since the symptoms have begun and how severe they are. That gives us an idea of how aggressive underlying condition is.

Then we talk about the possibilities. If somebody has an asymmetric tremor at rest with micrographia hyposomia, they have REM sleep behavior disorder or constipation and they've had these symptoms for the last four or five years, it is more likely to be Parkinson disease rather than an atypical parkinsonian disorder because atypical parkinsonian disorders, like I mentioned earlier, they would present with either falls, initially, or very quick onset of memory decline and dysautonomia.

Glen Stevens, DO, PhD: So you define some fairly distinct findings with all of these atypical disorders. But again, I come in to see you and I'm concerned I have an atypical disorder. How good are we at picking up the atypical disorders? Is it more difficult? Are there any ancillary tests that we can use? Does imaging help?

Junaid Siddiqui, MD: So history is the most important thing that we can do. If you can get a history of the patient is trying to tell you what they have. So history gives us 80% or more of a diagnosis. So if somebody comes in with parkinsonism and they have falls before three years of disease onset, they have memory problems within a year of disease onset, they have severe dysautonomia. So we already know that they have an atypical parkinsonian disorder. All you need to figure out if this is a synucleinopathy or is a tauopathy. So synucleoinpathy would be MSA or DLB and tauopathy would be PSP and CBD. So when people have, if they have REM sleep behavior disorder, if they have anosmia, we think of synucleinopathies like MSA or DLB. If they have severe dysautonomia, that goes more with MSA if we have visual hallucination. So history and examination are the most important part.

But now, more recently, we have a DAT scan available that has been available for the last decade or so. They say it's like 70-100% sensitive and picking up neurodegenerative parkinsonian disorder. So it just checks the density of dopaminergic receptors in the striatum and compare that with the normal population. So that's hugely very sensitive, but not everybody with these conditions have a positive DAT scan, unfortunately. So it's not 100% sensitive. Now more recently, there's been a skin biopsy. It's called SYN-I test that looks for alpha-synuclein deposition under the skin. And that, now we are employing more regularly in patients we're thinking of having synucleinopathies like MSA or DLB or Parkinson disease even, or if there's a confusion between PSP and MSA. So we order that, and that can sometimes help us differentiate between them.

Glen Stevens, DO, PhD: And where do you biopsy?, Does it matter?

Junaid Siddiqui, MD: Yes, so it's standardized. The biopsy is taken from the outer lower leg by ankle, and the lower thigh front just above the knee, and the third is the mid between the neck and the upper back.

Glen Stevens, DO, PhD: And does insurance cover that?

Junaid Siddiqui, MD: Most insurances cover it. We have an order set and somebody takes care of that and order goes through insurance. If it's approved, they call the patient to schedule an appointment, they come back and then we do the biopsy. I started doing the biopsy here and I trained other providers to do it, as well. So we're doing the regularly here.

Glen Stevens, DO, PhD: And how long does it take to get the results?

Junaid Siddiqui, MD: I think in a week or so.

Glen Stevens, DO, PhD: Okay. And what percent of patients are you doing that on?

Junaid Siddiqui, MD: Until now, I think we're doing it for about 5 or 10% of patients. I'm trying to do it more often now instead of asking for a DAT scan and so you depend on other people to interpret the scan and they tell you it's positive or negative or grade one or grade two, versus a skin biopsy, it's either there or it's not there. So I am liking the skin biopsy more at this time.

Glen Stevens, DO, PhD: Good. So you mentioned, we talked about the four big atypical disorders. How many total are there, APDs?

Junaid Siddiqui, MD: The primary parkinsonian disorders, that means neurodegenerative, primary parkinsonian disorders are the ones that we spoke of. Parkinson's is the common, the typical one. The atypical ones are PSP, MSA, CBD and DLB. So those are the primary ones. Then there are some of the differential diagnosis of atypical parkinsonian disorders, like people coming with memory decline and they have a shuffling gait and they have urinary incontinence and they have parkinsonism on examination. So you image their brain, you get an MRI, and if you find that they have large ventricles, it could be NPH. And NPH is a treatable condition. So that's important to, whenever you have a patient with parkinsonism, always get an MRI or some sort of a brain scan, like an CT scan or an MRI. That's usually helpful, especially if you're suspecting an atypical parkinsonian disorder. There are other conditions like drug-induced parkinsonism, vascular parkinsonism, but the history is usually a little bit different. Imaging is clearly different.

Glen Stevens, DO, PhD: And I believe you were recently involved with developing a diagnostic algorithm for these atypical parkinsonian disorders. Would you like to talk about that a little bit?

Junaid Siddiqui, MD: Yeah, so it actually was very, very interesting activity and I contributed in that a little bit. But what we tried to do was develop this algorithm for the general neurologist who encounters a parkinsonian patient and they think it might be an atypical parkinsonian disorder because you don't have an atypical parkinsonian disorder clinic everywhere. So just to get started, how to think about, okay, parkinsonism, and then you suspect an atypical parkinsonian disorder so that you take it through this algorithm. So get an MRI or a CT scan if it's abnormal, if it's suggestive of large ventricles, think of NPH, if there's a vascular parkinson possibility. If that's negative, then think of these other possibilities. And then so skin biopsy and other, and of course if there's confusion, if there's a possibility that you can get an opinion, refer to a movement disorder clinic.

Glen Stevens, DO, PhD: How long have you been employing the algorithm?

Junaid Siddiqui, MD: Well, this just came out a few months ago, but I guess subconsciously, we've been doing this forever. We just came up with on paper more recently for everybody.

Glen Stevens, DO, PhD: And the results of using the algorithm, do we have any numbers with sensitivity, specificity, those types of things?

Junaid Siddiqui, MD: Not yet, but we're looking forward to collecting that data.

Glen Stevens, DO, PhD: If somebody wanted to try and utilize the algorithm, is it available, is it on the computer, is it a paper test or what is it?

Junaid Siddiqui, MD: Yeah, it's actually published in the neurology journal, Neurology and Clinical Practice. They can go online, AAN.com and search this article and that gives you the tables, it has the algorithm itself. It's very useful.

Glen Stevens, DO, PhD: Okay. You go through the algorithm, you feel pretty comfortable, in terms of what your diagnose is. You may or may not have done a skin biopsy, may or may not have done a DAT scan, but your patient now has one of these big four of the atypical parkinsonian disorders. Treatment options? I guess a lot of the treatment is really symptom based as opposed to doing something to affect the neurodegenerative process, right?

Junaid Siddiqui, MD: That's right. So historically, because Parkinson's disease has been the most common condition and it's the slowest to progress, so that gives the opportunity to develop more research and spend more on medications. So these conditions, which are more aggressive, they've never gotten a lot of attention. But nowadays, that has changed. And then we're developing these, there are research trials for both MSA and PSP. Cleveland Clinic is part of it, and I'm part of those clinical trials, as well. So they're experimenting with medications that may help slow down the disease. We don't know if it works or not, but this is a significant development. This has never happened in the past. No medication for any atypical parkinsonian disorders has ever been proposed or experimented on.

Glen Stevens, DO, PhD: And are these North American wide trials or they're single institution trials?

Junaid Siddiqui, MD: They're actually worldwide trials. There is the MSA study is the ONO study, and for the PSP.

Glen Stevens, DO, PhD: And if somebody was interested, they had a family member or a patient that had one of these disorders and they're looking for a trial, where would they go to access this information?

Junaid Siddiqui, MD: So the best thing is a couple of things they can do. You can go to the CurePSP website, curepsp.org, so you can get a lot of information about atypical parkinsonian disorders. I think you can have access to the algorithm there, as well. But information on clinical trials and which are the nearest facilities that are doing those, so you can get that information from there, or clinicaltrials.gov would be the website to check where is the nearest clinical trial.

Glen Stevens, DO, PhD: Okay. And any insights to the PSP medication, mechanism of action, or is it single medicine, or are they looking at various medications?

Junaid Siddiqui, MD: For now, it's a single medication. It's supposed to improve how the endoplasmic reticulum works, ribosomes work, so they reduce the cellular stress, but we don't know if it's going to work or not.

Glen Stevens, DO, PhD: And any additional therapeutic options on the horizon that you're aware of for these disorders?

Junaid Siddiqui, MD: Not at this time, but PSP, we have tried levodopa. Sometimes it helps for a while. Sometimes amantadine helps with the gait and walking. Of course, physical therapy is the cornerstone.

Glen Stevens, DO, PhD: Anything that we haven't discussed that you think's important for our listeners to hear?

Junaid Siddiqui, MD: I think in general, if providers are looking for guidance on treating and detecting parkinsonism and atypical parkinsonism, just to start off with parkinsonism, identify that. Whenever you have a patient with parkinsonism look for any red flags that would indicate an atypical parkinsonian disorder. And if you have a patient that you suspect that they may have an atypical parkinsonian disorder, the patient with atypical parkinsonian disorder don't have a lot of time because it's a very aggressive condition, it would be best to expedite workup or referral if you can. And certainly don't deprive them of physical therapy, occupational therapy, and speech therapy, that can make a lot of difference. Trying levodopa. And then, of course, when you refer to a center that is doing research trial, that will be helpful.

Glen Stevens, DO, PhD: Well, it's exciting to hear that there's a trial ongoing for the PSP patients because my understanding was there really wasn't an active medication that would change the trajectory of these patients. So it's good to hear that there are medications they're looking at.

Junaid Siddiqui, MD: Both for PSP and MSA.

Glen Stevens, DO, PhD: Good. Well listen, I'd like to thank you for updating us and taking the time today to educate us a little more on these atypical parkinsonian disorders or parkinsonisms that are out there. It's always good to keep it on everybody's radar. And I think the simple answer is if levodopa's not working, you need to start thinking about some of these other disorders for patients. All right, well listen, thank you very much, Junaid. You take care.

Junaid Siddiqui, MD: Thank you.

Closing: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's @CleClinicMD, all one word. And thank you for listening.