CurePSP: Atypical Parkinsonian Disorders -

TRanscript 07 hello I'm dr. Stephen professor of neurology at the University of Maryland here in Baltimore and I'm 0:14 pleased the opportunity to talk with you about atypical parkinsonian disorders this 0:20 talk is sponsored by cure PSP and the slide set was put together by myself dr. 0:27 shawn smith as well as dr. alexander pant a lot the objectives in this 0:32 presentation are threefold first to improve your ability to recognize parkinsonian syndromes and distinguish 0:40 them from the more common Parkinson's disease second is to be familiar with 0:45 the prognosis and the management options for people who have parkinsonian syndromes and lastly to learn about the 0:52 resources available for your patients and their families who have these disorders the outline of the talk first 1:01 will speak briefly about the importance of recognizing these disorders and distinguishing them from Parkinson's 1:07 disease we'll talk about the diagnostic features of some of the individual parkinsonian syndromes both their 1:14 clinical features as well as the role of ancillary testing we'll talk about management of some of the atypical 1:21 parkinsonian syndromes their prognosis and lastly we'll talk about some 1:26 available resources why is it important to distinguish parkinsonian syndromes 1:32 from Parkinson's disease they're similar but distinctive disorders the first is 1:38 that if you recognize that someone has one of these parkinsonian syndromes then that often obviates the need for 1:45 additional and unnecessary testing it's important because it provides the 1:50 patient with prognostic information since they do have a different natural history than Parkinson's disease 1:57 likewise once you recognize that they don't have Parkinson's disease they have one of these specific parkinsonian 2:03 syndromes you can direct them towards specific resources directed at that syndrome for networking and care 2:10 sometimes this may even involve a clinical trial and then you can use more specific features treatment wise 2:18 directed at the parkinsonian syndromes which you might not employ for Parkinson's disease so there are many 2:24 reasons patient-care why it's important to recognize who with parkinsonism doesn't 2:31 have Parkinson's disease but instead has one of the parkinsonian syndromes let's 2:38 start off with the definition of parkinsonism this is a rather generic term which refers to a specific set of 2:45 symptoms and signs this includes brady kinesia or slowness of movement 2:50 other features include rigidity a tremor particularly a resting tremor as well as 2:57 impairment of postural writing reflexes and difficulty walking now it's 3:02 important to recognize that not everyone who has parkinsonism has Parkinson's 3:08 disease even though the majority of people with parkinsonism do have Parkinson's disease what's the 3:15 differential diagnosis and how do we tease out what's Parkinson's disease from what's a parkinsonian syndrome or a 3:22 secondary cause of parkinsonism in this flow diagram here it gives you a general 3:27 scheme of how we approach these disorders the majority of people who have parkinsonism again that 3:34 constellation of slowness stiffness tremor gait disorder and imbalance will 3:40 have a degenerative disease and most of them will have Parkinson's disease yet a significant number will have one of 3:47 these atypical parkinsonian disorders such as progressive supranuclear palsy or corticobasal syndrome which we'll 3:54 come back to and there are a variety of other hereditary degenerative disorders that look like Parkinson's disease on 4:02 the other end of the spectrum are what we call secondary causes of parkinsonism 4:07 and these are typically disorders that are not associated with neuro degeneration 4:12 these include systemic ideologies for instance an underactive thyroid may 4:18 mimic parkinsonism because of the slowness medications toxins etc and then 4:23 there are other brain conditions again which are not neurodegenerative but may mimic Parkinson's disease and this 4:30 includes a multi-infarct state with vascular parkinsonism or normal pressure 4:35 hydrocephalus in terms of the differential diagnosis of degenerative causes of parkinsonism 4:42 far and away is mentioned the most common is Parkinson's disease but up to 4:47 25 percent of people who are initially called Parkinson's disease at autopsy 4:53 will ultimately be found to have an alternative diagnosis and the most common alternative diagnosis is in fact 5:00 a parkinsonian syndrome the most common of these include progressive supranuclear palsy which from now on all 5:07 referred to as PSP multiple system atrophy or MSA corticobasal syndrome CBS 5:15 or dementia with Lewy bodies there are some rarer degenerative diseases that 5:21 also have parkinsonism as part of its phenotype and this isn't a complete list but at least on this side of the strain 5:28 our most common causes of degenerative parkinsonism we tend to in a very broad 5:34 way think about parkinsonism particularly the degenerative disorders in two broad categories and this is 5:41 based on the abnormal protein of the mutated protein that accumulates in certain cells usually but not always 5:47 neurons on one end of the spectrum are these synuclein AAPA thiis in which 5:52 mutated alpha-synuclein accumulates either within the neurons or the glial 5:58 cells this includes Parkinson's disease and diffuse Lewy body disease as well as 6:04 multiple system atrophy so collectively known as synuclein AAPA thiis on the 6:10 other end of the spectrum is hyper phosphorylated tau which accumulates in neurons and other conditions typically 6:17 PSP corticobasal syndrome frontotemporal dementia linked to chromosome 17 in the 6:24 Parkinson's dementia complex of Guam and ultimately this is a histological 6:29 diagnosis but clinically we tend to group these together in terms of secondary causes of parkinsonism and as 6:37 I mentioned before most of these are not associated with neuro degeneration this includes vascular parkinsonism or 6:44 multi-infarct state usually characterized by what is known as lower half parkinsonism 6:50 that is people are more parkinsonian from the waist down than the waist up there's often a history of significant 6:57 vascular risk factors often at EIA or stroke or stepwise progression and the 7:03 MRI scan is usually indicative there as well normal pressure hydrocephalus may 7:09 present as parkinsonism rarely space-occupying lesion x' toxins but the 7:15 most important category in this group of secondary causes of parkinsonism far and 7:20 away is drug-induced parkinsonism and it's been demonstrated that physicians are not very good at recognizing 7:27 drug-induced parkinsonism it's important to take a very careful drug history not 7:32 only what medications patients are on at the time that you see them but going back over the past year because 7:39 drug-induced parkinsonism can often last for a number of months even up to a year after the offending medication has been 7:46 stopped so the patient may not be on the offending drug at the time that they present to you 7:52 rarer causes post encephalitic as well as a sequelae of significant and often 7:58 repeated head trauma in terms of making the diagnosis of a specific cause of 8:03 parkinsonism these are some of the clues from the examination to pay particular attention to first is the history and 8:11 the examination consistent with parkinsonism do they truly have the brady kinesia that we talked about the 8:18 cogwheel rigidity impaired postural writing reflexes is it highly 8:23 asymmetrical and that's important because only two causes of parkinsonism 8:28 typically at least degenerative parkinsonism present in a highly 8:33 asymmetrical fashion the first is Parkinson's disease which typically 8:38 begins as Hemme Parkinson's disease in the second is corticobasal syndrome and 8:44 we'll come back to corticobasal syndrome a little bit later it's important when you see the patient to ask yourself and 8:50 again we'll come back to this are there any atypical features that is are there signs that don't fit with Parkinson's 8:57 disease and again as I mentioned before the importance of a careful drug history 9:03 one of the key features to distinguish Parkinson's disease from these a typical 9:08 parkinsonian syndromes is the response to levodopa one of the key features of 9:13 the parkinsonian syndromes is that either they don't respond at all to levodopa or they have a limited response 9:21 and it's often short-lived compared to Parkinson's disease in which we're reassured when there's a significant 9:28 beneficial and especially a sustained response to levodopa over at least five 9:34 years and we're further reassured when patients develop dyskinesias as well 9:39 we'll come back and talk about some of the non motor features that we see with both Parkinson's disease as well as the 9:46 parkinsonian syndromes but just one particular example of that would be dementia in terms of distinguishing 9:53 parkinsonian syndromes from Parkinson's disease dementia which is common in 9:58 Parkinson's disease is typically a late complication of Parkinson's disease therefore a patient who presents with 10:05 parkinsonism who has dementia at the beginning or early in the clinical 10:10 course that's a that's an important non motor feature it's a clue that suggests 10:16 it's probably not Parkinson's disease and lastly do any of the ancillary tests 10:22 help steer you in one particular category or another for instance the scan and Parkinson's disease is normal 10:29 and we'll come back and talk about some of these particulars in terms of the criteria for Parkinson's disease for the 10:37 most part we rely on the UK Parkinson's disease Society Brain Bank criteria 10:43 these require that the cine quinone which is present is brady kinesia or 10:50 slowness of movement so if you don't have brady kinesia you don't have parkinsonism or in this 10:56 case Parkinson's disease and that's important because patients who present with an isolated parkinsonian tremor and 11:03 no brady kinesia whatsoever that's an important red flag that it may not be 11:08 Parkinson's disease so again the first part of the criteria for Parkinson's disease is brady kinesia 11:15 and according to the criteria you must have one or more of the following 11:20 rigidity a resting tremor the typical pill rolling tremor or postural 11:26 instability the key thing about the postural instability though is the timing even though postural instability 11:33 is common in Parkinson's disease it typically happens after five seven eight 11:39 nine years into the course of the disease so again as another red flag the patient with parkinsonism who has 11:46 impaired postural writing reflexes at presentation or early into the course of 11:52 the disease particularly if their Falls that's a red flag to suggest that it's 11:57 not Parkinson's disease and often that's the presenting scenario of progressive 12:02 supranuclear palsy some of the supportive features for Parkinson's 12:07 disease typically Parkinson's disease early on is Hemi parkinsonism so a 12:13 strictly unilateral or at least highly asymmetrical presentation particularly 12:19 if accompanied by a resting tremor is usually a very important scenario or very important picture to suggest 12:26 Parkinson's disease not known at the beginning when you first see the patient but as you follow the patient along does 12:32 the natural history run true to form a Parkinson's disease is a very very gradually progressive disorder so the 12:39 patient who progresses very quickly that is the patient is already starting to fall within the first few years or 12:46 starting to use a walker or wheelchair that's an important red flag because again with Parkinson's disease a it's a 12:53 very very insidious and slow natural history patients virtually always survive at least ten years and often 13:01 many many more years than that in contrast to parkinsonian syndromes where 13:06 patients often succumb within a decade sometimes sooner than that so a the natural history of the disease 13:12 progression and also what you want to see as I mentioned before that there's not only a beneficial initial response 13:18 to levodopa but that that response is sustained over many years and that 13:23 patients develop dyskinesias which you typically do not see with parkinsonian 13:28 syndromes let's talk a little bit now about the atypical parkinsonian disorder 13:34 sometimes called parkinsonian syndromes these are all degenerative diseases 13:39 beginning after age 50 the ones we'll be concentrating on today again include PSP 13:45 CBS or corticobasal syndrome corticobasal disease implies it is in 13:51 pathological conformation multiple system atrophy and dementia with Lewy 13:56 bodies as I said before these conditions can easily be confused at least early on 14:02 with Parkinson's disease and sometimes Alzheimer's disease as well even though 14:09 there are validated criteria for these parkinsonian syndromes we recognize that 14:14 they do not have 100% sensitivity and specificity and it's not uncommon that 14:20 the clinical diagnosis will not be confirmed at autopsy the diagnosis of 14:25 these disorders in most cases is a clinical diagnosis since we really do not have any clear biomarkers for these 14:33 disorders and it's important as I mentioned before to be familiar with the red flags and to look for these 14:40 throughout the course it's not uncommon at all that someone initially is thought to have Parkinson's disease and that's 14:47 even the case by a Parkinson's specialist but as you see the patient for the next two or three or four years 14:53 only then does it become clear that it's not running true to form the patient 14:58 start to develop a typical features or have an unusually rapidly progressive natural history so whenever you make the 15:06 diagnosis of Parkinson's disease it's important that each subsequent visit to ask yourself does that diagnosis still 15:13 fit some of the clues to distinguish Parkinson's disease from these parkinsonian syndromes are here as I 15:21 mentioned before there are really only two causes of parkinsonism which start 15:26 off being markedly asymmetrical sometimes even unilateral that's very typical for Parkinson's disease and it's 15:33 also a feature of corticobasal syndrome most of the other parkinsonian syndromes tend to 15:39 the bilateral and symmetrical not uncommon Li there can be a little asymmetry they don't start off being 15:45 actually unilateral as I mentioned before this beneficial and particularly a sustained response to levodopa is a 15:53 very important key to distinguish parkinson's disease from parkinsonian syndromes but it's important to remember 16:00 that even the parkinsonian syndromes may respond initially to levodopa and rarely 16:06 you actually may see a fairly robust response which makes you think that it's Parkinson's disease so it's easy to be 16:13 fooled by these disorders and you have to stay on top of them as you follow the patient along but the key feature with 16:20 the parkinsonian syndromes even if they initially do have a good response to levodopa that beneficial response 16:28 unlike Parkinson's disease tends not to be sustained another important sign is a classic 16:34 resting tremor the pill rolling tremor is usually indicative of Parkinson's disease we usually do not see classic 16:42 resting tremor in some of these parkinsonian syndromes you may occasionally but that's not the usual 16:50 state of affairs it's not unusual though to see other types of tremor is we'll 16:55 talk about for instance in patients who have multiple system atrophy they not not uncommon ly have a low amplitude 17:02 somewhat jerky postural tremor of the fingers and sometimes the hands 17:07 but a classic unilateral resting tremor by itself usually is a very important 17:13 sign that you're dealing with Parkinson's disease and not one of the parkinsonian syndromes a helpful acronym 17:21 for approaching these parkinsonian syndromes is alert and again this 17:26 reinforces what we've been talking about before about some of the clinical signs to distinguish Parkinson's disease from 17:33 parkinsonian syndromes so the a stands for atypical for Parkinson's disease so 17:39 these are signs on the examination which would cast doubt on the diagnosis of Parkinson's disease and steer you toward 17:46 one of these parkinsonian syndromes for instance apraxia or wyah clonise 17:52 saccade changes the secod remember our the rapid refix ation eye movements that 17:58 we use to look from one target to another in Parkinson's disease the cicadas can be a bit hypo metric that as 18:05 they may fall a little short of the target but the speed of the secod in Parkinson's disease is normal compared 18:13 to parkinsonian syndromes characteristically progressive supranuclear palsy where the cicadas are 18:19 actually slow and it's the vertical cicadas which are initially affected so 18:24 again looking at the rapid eye movements can be very helpful to distinguish Parkinson's disease and get a clue about 18:30 a parkinsonian syndrome other features which are atypical for Parkinson's disease include parietal or cortical 18:37 sensory loss such as extinction - double simultaneous stimulation a graph is 18:43 theshia or what it known what is known as an alien limb this is a limb that has a quote mind of its own and typically 18:51 that scene in corticobasal syndrome the presence of cerebellar signs or upper 18:56 motor neuron signs that is spasticity upgoing toe clonise hyperreflexia these are not 19:03 features of Parkinson's disease certain types of dystonia or dyskinesia retro 19:09 callus that is the extension of the head or anthro callus that is when the neck is forward these are features of 19:15 progressive supranuclear palsy and multiple system atrophy respectively 19:21 another form of what's called atypical blepharospasm as eyelid opening apraxia which is another clues suggesting that 19:28 the patient with parkinsonism probably does not have Parkinson's disease 19:33 I mentioned before the rate of progression what's known as the wheelchair sign someone who's called 19:39 quote Parkinson's disease who comes to your office within three four maybe even five years already in a wheelchair 19:47 probably does not have Parkinson's disease and instead of parkinsonian syndrome the L as we've discussed before 19:55 stands for lack of response to medication and specifically here levodopa the key thing to make this 20:02 distinction is that the patient should have at least 1,000 milligrams per day of levodopa 20:08 before calling the patient unresponsive one small exception to that is when 20:14 Parkinson's disease is dominated by tremor but again they still have brady kinesia rigidity etc sometimes those 20:22 patients don't respond very well to levodopa again if the problem is predominantly a large amplitude tremor 20:29 but in general patients with Parkinson's disease should have a good sustained 20:35 response to levodopa often with the eventual appearance of dyskinesias lack 20:41 of response to levodopa lack of a sustained response to levodopa are important clues to suggest a 20:47 parkinsonian syndrome Easton's for early and these are features which do happen 20:53 in Parkinson's disease but typically happen in the middle to latter stages of the disease and if these signs happen 21:01 early or are a presentation again it casts doubt in the diagnosis of Parkinson's disease as I mentioned 21:08 before even though people with Parkinson's disease have impaired postural writing reflexes and fall 21:14 that's not an early sign so the patient who has parkinsonism with early Falls 21:20 that's an important clue to suggest progressive supranuclear palsy likewise early bulbar dysfunction with 21:27 dysphagia and dysarthria is another red flag early dementia early executive 21:33 dysfunction early personality changes such as apathy or impulsivity these are 21:40 all features which do happen in Parkinson's but not early on early hallucinations and delusions are not 21:47 part of Parkinson's disease and when they happen at the beginning that suggests dementia with Lewy bodies you 21:53 certainly can get autonomic dysfunction with Parkinson's disease constipation sexual dysfunction 22:00 orthostatic hypotension but these tend to be mild if it all present early in 22:05 the course of the disease and again are usually a complication that we see as the disease progresses so the patient 22:11 with parkinsonism who has significant prominent desire dis aughtta knowmia early in the course of the 22:18 that's a red flag the are of the alert acronym suggests that you need to refer 22:25 patients not just with Parkinson's disease but with these parkinsonian syndromes to helpful resources can be 22:32 very useful to refer them for a second opinion to a movement disorder specialist to help confirm the diagnosis 22:38 speech and swallowing therapist since it's often the ancillary services and 22:43 supportive care which become the mainstay of treatment for the parkinsonian syndromes rather than 22:49 medication and lastly even though these syndromes have not to be very responsive 22:54 to medication there are a number of symptoms that we can still help pharmacologically I mentioned before 23:01 autonomic dysfunction again very common in Parkinson's disease but when it's prominent and early it suggests multiple 23:08 system atrophy some of the features to be aware of include orthostatic hypotension everyone's aware of the 23:16 typical scenario of causing postural lightheadedness or near syncope or Frank syncope but it's important to recognize 23:23 that many patients who have ortho static hypotension may not necessarily have those classic symptoms but instead there 23:30 may be fatigue some confusion visual blurring or another unusual but somewhat 23:36 common and distinctive sign notice the coathanger sign that is when patients are upright they may get pain 23:44 over the occiput the neck or the shoulders and this is thought to be due 23:49 to muscle hypoperfusion other autonomic dysfunction seen with Parkinson's and 23:54 parkinsonian syndromes include a rectal dysfunction this is very common and it's 24:00 the type of problem that patients rarely will voice to the physician so you have to specifically ask about it urinary 24:07 bladder problems are common in virtually all forms of Parkinson's including urgency frequency urge incontinence and 24:15 nocturia diminished sweating but some people for instance with Parkinson's disease will actually have excessive 24:22 sweating sometimes patients can actually develop usually with multiple system 24:27 atrophy paralysis of a vocal cord and the students to present within Spiteri strider who is what you may hear when 24:35 you see the patient or what the patient's caregiver may report likewise patients with multi system 24:41 atrophy may have cold dusky violaceous hands so again paying particular 24:47 attention to dysautonomia not only for diagnostic help but these are often 24:53 problems it can be treated and are very disabling for patients so now let's talk 24:58 a little bit about some of the specific parkinsonian syndromes the first one to talk about is progressive supranuclear 25:05 palsy some of the features of that they do have parkinsonism 25:10 but unlike Parkinson's disease the brady kinesia tends to be more axial than 25:15 appendicular they often have relatively little slowness for instance when doing finger or toe tapping but they'll have a 25:23 great deal of difficulty getting up from a chair or walking or sitting back down 25:28 in a chair tremor is uncommon in PSP and they virtually never get a classic 25:34 resting tremor like Parkinson's disease they do tend to get rigidity but like 25:40 the brady kinesia the rigidity tends to be more axial than appendicular often at 25:45 the neck and that's an important place to test as we talked about before patients with PSP with rare exceptions 25:52 tend to have a poor response to levodopa the key diagnostic feature though for 25:57 progressive supranuclear palsy is supranuclear vertical ophthalmoplegia 26:03 that as patients have trouble moving their eyes not only up but down as well 26:08 before there's actual ophthalmoplegia though the key finding is that patients 26:13 will have slow vertical cycads and that allows you to make an earlier diagnosis 26:19 of PSP the best way to test that is to have the patient look from side to side 26:24 between horizontal targets it'll notice that they can generally make accurate and quick cicadas there when they're 26:31 asked to look between vertical targets they'll notice that their eyes are slow as though they're moving through 26:36 molasses a nice way to bring that out which will show a little bit later I 26:42 believe in one of the videos is using the optokinetic tape that is 26:47 when you move the tape horizontally patients will pursue it in the direction the tape is moving and be able to make a 26:54 fast phase back to the next target yet when you do the same test vertically 27:00 patients will pursue it up or down but cannot generate that fast phase to the 27:06 next target they often have frequent saccadic intrusions these are tiny 27:12 little movements of the eyes that take it off of target other features of 27:17 progressive supranuclear palsy as I mentioned before the extension of the neck which is called retro callus and 27:23 they often have prominent bulbar dysfunction early on trouble speaking and particularly trouble swallowing 27:30 there's a cognitive profile of PSP as well typically frontal dysfunction with 27:36 prominent atrophy executive dysfunction impulsivity and something that you'll 27:41 see a little bit later which known as the applause sign and this is a sign of 27:46 perseveration and the patient is asked to quickly clap three times but because 27:53 of the perseveration due to frontal lobe dysfunction and PSP patients will keep 27:59 clapping so when asked to clap three times they'll just continue on as such 28:05 you can see that applause sign in other parkinsonian syndromes so it's not 28:11 specific to PSP but you rarely ever see it in Parkinson's disease it's important 28:18 to recognize that there are different presentations of progressive supranuclear palsy the classic 28:24 presentation is known as Richardson syndrome this was originally described 28:30 in 1964 by John Steele who's still living an important part of the cure PSP 28:36 society Richardson and the neuropathologist Olszewski the classic 28:41 PSP is again the early Falls the super nuclear vertical ophthalmoplegia and the frontal syndrome 28:48 but we now recognize from clinical pathological studies most of which have 28:53 come through the London Brain Bank that there are other less common present actions of what ultimately proves to be 29:00 pathologically confirmed PSP there's a PSP parkinsonism which early on can look 29:06 like Parkinson's disease rarely even having a resting tremor slower rate of 29:12 progression sometimes may respond to levodopa it can sometimes look like 29:17 corticobasal syndrome at presentation sometimes it can present with nonfluent 29:22 aphasia frontotemporal dementia what's known as pure akinesia with gait 29:29 freezing so people who just cannot propel themselves forward and often in 29:35 some of these atypical presentations of PSP the super nuclear vertical 29:41 ophthalmoplegia happens late in the course and that's why it can be difficult to make the diagnosis some of 29:48 the imaging features of progressive supranuclear palsy on the sagittal view here when you're looking at the midbrain 29:54 because of the atrophy it can look as though it looked like a hummingbird and you can see here the beak of the 30:01 hummingbird in the midbrain likewise midbrain atrophy can have the 30:06 appearance of the Morning Glory flower so you can see here that this is an abnormal midbrain it's kind of splayed 30:13 apart here and there's widening of the interpeduncular fossa again the Morning 30:19 Glory signs in terms of the pathological change with PSP remember that this is a 30:25 tau APPA the-- there's neuronal loss diffusely subcortical e the the Globus 30:32 pallidus particularly the subthalamic nucleus some of the other areas which you can see here on the slide there are 30:39 no February tangles neuro pill threads and tuft astrocytes as you can see here 30:45 there there are tau positive wheel inclusions and coiled bodies and 30:51 remember the PSP like corticobasal syndrome is known as a tau appa the-- 30:56 let's go now from PSP to talking about a related to APPA the corticobasal 31:02 syndrome this was previously called corticobasal disease but we now use that 31:09 term only when there's path logical confirmation and during life we call it corticobasal syndrome and as 31:17 you'll see here on the slide we recognize that only about 50% of patients who during life or thought to 31:23 have corticobasal syndrome will have pathological confirmation there is a 31:28 fair amount of overlap with progressive supranuclear palsy as well as Alzheimer's disease in addition to 31:35 Parkinson's disease corticobasal syndrome is one of the other few parkinsonian disorders that tends to 31:41 present unilaterally or markedly asymmetrically but there's some exceptions to that they have rigidity 31:48 and slowness although that tends to not be as prominent as you see with Parkinson's disease 31:54 I mentioned the unilateral onset they often present with dystonia or stimulus 32:00 sensitive Maya clonise they can have a very jerky often a quote useless limb 32:06 pyramidal signs bulbar dysfunction and while they don't actually tend to get 32:11 slowing of the secod there can be very slow they can be very slow to initiate 32:17 the secod and that can fool you into thinking that the secod is actually absent that they have super nuclear 32:24 ophthalmoplegia so it's important to actually see a saccade to confirm that it's really slow as opposed to just 32:31 inability to initiate a saccade some of the other features of corticobasal syndrome and again this reflects the 32:37 name the cortical component and the basal or basal ganglia component the 32:42 cortical features include or may include apraxia particularly unilateral an alien 32:48 limb or a cow Coulee up they may get parietal lobe sensory deficits such as a 32:54 graph a seizure a steric Knossos extinction - double simultaneous stimulation and they may also present 33:01 with what looks like a primary dementing syndrome with early frontal dementia global dementia I mentioned before 33:08 nonfluent aphasia or apraxia of speech so again the presentation of both PSP 33:15 and corticobasal syndrome can be very protein it can mimic many other disorders just like with progressive 33:22 supranuclear palsy we recognize now that there can be a variety of different presentations of 33:28 corticobasal syndrome as distinct from the originally described disorder with 33:34 prominent cortical as well as basal ganglia features particularly presenting unilaterally it can overlap with 33:41 features of PSP as well as features of frontal temporal dementia primary 33:46 progressive aphasia and some patients will have mixed pathology with corticobasal degeneration and they may 33:53 have admixed Alzheimer's changes or even vascular changes as well some of the 33:59 imaging features which you might see with corticobasal syndrome include selective atrophy and the parietal lobes 34:06 and it's often asymmetrical as you can see here it's worse on the right side than it is on the left 34:12 the pathology remember again like PSP this is a tau APPA the-- you can see the 34:18 selective cortical atrophy you can see the neuronal loss and gliosis here in 34:23 the cortex and this is a tau stain here of the angular gyrus showing the balloon 34:28 cells of corticobasal syndrome this is another tau stain here in the white matter showing an astrocyte o'clock 34:36 let's go on now we've talked about the tau APPA these progressive supranuclear 34:42 palsy and corticobasal syndrome let's go on to the other synuclein APPA the-- another parkinsonian syndrome multiple 34:49 system atrophy it's worth pointing out that multiple system atrophy is now the 34:54 umbrella term for what used to be their stride all nitrile degeneration or the 35:00 shy-drager syndrome or Olive open toe cerebellar atrophy we now recognize that 35:05 those are really different expressions of the same disease MSA largely falls 35:11 into two broad but somewhat overlapping categories on one hand or patients who 35:17 have dysautonomia and parkinsonism known as MSA p or MSA parkinsonism on the 35:23 other side are patients who have MS AC or dissident Omiya with cerebellar 35:29 findings it's really kind of a hodgepodge of making the diagnosis all 35:35 patients with multiple system atrophy have to have dysautonomia and this can either be 35:40 orthostatic hypotension or a combination of urinary incontinence and in men this is combined with 35:48 erectile dysfunction so you have to have disowned amia and if you have dis 35:53 aughtta no Meah with cerebellar findings and again not an alternative diagnosis 35:59 then that's suggestive of MS a type C or the cerebellar type if you have dis 36:04 autonomia with parkinsonism that's MSA P you can get pyramidal tract findings as well in 36:11 multiple system atrophy some of the red flags which suggest MSA and allow you to 36:18 tease that out from Parkinson's disease include oral facial dystonia which is 36:23 not necessarily drug-induced I mentioned before that in progressive supranuclear palsy they tend to have extension of the 36:29 neck called retro collars a particularly form of cervical dystonia as compared to 36:35 multiple system atrophy in which there is an taro callus and the neck tends to be flexed likewise there can be severe 36:43 tilting of the spine to one side known as the PISA syndrome or flexion known as 36:49 camp to cor meum some of the other features which can suggest multiple system atrophy include inspiratory 36:56 stridor I mentioned before vocal cord paralysis an occasional expert ory size 37:05 is something that you might hear when you're interviewing the patient because of the bulbar dysfunction and the risk 37:11 of vocal cord paralysis you have to pay careful attention to sleep apnea asking 37:16 the spouse or the bed partner about features of that dysphonia and is r3 37:21 early on they may get contractures of the hands and feet which typically does 37:27 not happen in Parkinson's disease I mentioned before they may get cold dusky hands they typically do not get a 37:34 classic resting tremor but it's not uncommon to have a somewhat jerky irregular postural tremor often 37:41 involving the fingers and like some of the other parkinsonian syndromes they may get pathological laughter crying a 37:48 so-called pseudobulbar a affect some of the imaging features of 37:53 multiple system atrophy very distinctive was known as a hot cross bun sign here 37:59 you can see this is in the pons and it looks like a hot cross bun you can also 38:05 see increased signal in the middle cerebellar peduncle and you can see some 38:10 changes in the basal ganglia as well the pathology of multiple system atrophy 38:16 remember this is a synuclein APPA the-- but the alpha synuclein accumulation 38:23 here is not in neurons so there are no actual Lewy bodies again it accumulates 38:28 in the oligodendrocyte o plasma 38:35 conclusions along with significant neuronal loss and gliosis in the striata pathway Olive o Ponte cerebellar 38:42 pathway medulla a particularly a variety of the autonomic structures as well 38:48 the last syndrome that I want to talk about is dementia with Lewy bodies or 38:54 diffuse Lewy body disease this is reported to be the second most cause of 38:59 dementia next to Alzheimer's disease the key feature of dementia with Lewy bodies 39:05 is that these patients have parkinsonism it typically tends to be symmetrical 39:11 they usually don't have classic resting tremor although they may but the key 39:16 feature there is that admixed early on is dementia as compared to Parkinson's 39:22 disease in which dementia is common but it happens in the middle and typically 39:27 the latter stages so again the distinguishing feature between Parkinson's disease and dementia with 39:33 Lewy bodies is largely the timing of the dementia and this may be somewhat artificial because there is a fair 39:40 amount of clinical and pathological overlap the criteria calls for dementia 39:46 with Lewy bodies to have the dementia occurring with one year of the onset of parkinsonism there may be fluctuating 39:53 levels of alertness and consciousness sometimes what's called pseudo delirium I mentioned before early onset 40:00 hallucinations which typically occur late in the course of Parkinson's and patients with dementia 40:06 with Lewy bodies are often very sensitive to anti-psychotic medication the key feature with dementia with Lewy 40:14 bodies as compared to Parkinson's is the greater extent of distribution of the Lewy bodies not only in the 40:20 nigrostriatal pathway but predominantly in the cortex as well it's important to 40:27 recognize that even though we've talked about distinctive features of all of these disorders there is a great deal of 40:33 overlap and that can make it very difficult to make the diagnosis here we have kind of in the center progressive 40:40 supranuclear palsy corticobasal syndrome multiple system atrophy but we could likewise have Parkinson's disease there 40:47 and again all of these have a prominent motor component but in addition to that 40:52 cognitive features affective disorders impairments of sleep to sorta Gnostic 41:04 Lee but therapeutically when you're caring for patients with Parkinson's disease or any of these syndromes you 41:10 not only have to pay attention to the movement component or the motor component but very careful attention to 41:16 the non motor features sometimes they can be more disabling and often there is 41:22 more that we can do for some of the non motor features than the motor features in some of these non motor features we 41:29 begin some clues cognitive dysfunction Frank dementia executive dysfunction 41:35 affective disorders very common apathy fatigue very common in Parkinson's 41:41 disease in particular Parkinson's disease is very commonly associated with 41:48 sleep disorders which you may see in some of the other conditions as well characteristic of the synuclein AAPA 41:55 thiis is a REM sleep behavioral disorder in which patients enact their dreams and 42:01 often that can long proceed by years or even decades the clinical features of the motor disorder dissin amia we've 42:08 talked about both in the context of Parkinson's as well as multiple system atrophy constipation urinary bladder 42:16 dysfunction wrecked-tile dysfunction orthostatic hypotension heat intolerance etc you can 42:23 get a variety of sensory abnormalities impaired smell characteristically in Parkinson's disease restless leg 42:30 syndrome akathisia double vision as well so again it's important to pay 42:35 particular attention to the non motor features not just for their diagnostic relevance but also because of their role 42:43 in treating the patient we're going to change paces now and dr. Shawn Smith is 42:48 going to show you some pictures as well as videos illustrating many of the clinical features of the parkinsonian 42:55 syndromes that we've been talking about thank you doctor rich this first 43:00 photograph that we're going to review is of a woman with PSP and what you see is 43:06 a somewhat anguished look on her face the slight opening of the eyes though on 43:12 many patients with PSP there is more of an eye opening us or surprised look to 43:18 their face we're evaluating the secod of an individual with PSP there is mild 43:25 slowing of horizontal saccades however in the vertical direction there's 43:30 significant slowing and there's also vertical ophthalmoplegia in the up gaze 43:35 direction my thumb again I nose thumb nose 43:45 and my thumb and my nose look up at the ceiling and then look down at your lap 43:56 and the ceiling in the same woman with 44:02 PSP we're testing optokinetic nystagmus in the horizontal directions she follows 44:08 the direction of the tape and make small but impaired fast corrective saccade 44:14 however in the vertical direction there is a gradual up days and down days with 44:20 no fast corrective saccade here while testing postural stability she falls 44:27 backwards with retro poll ssin even without a tug on her shoulders which 44:32 would be the normal test for retro poll shown as is typical in PSP there's more 44:37 axial than appendicular rigidity which is shown here with resistance especially 44:43 to neck flexion and extension out of proportion to what is seen when moving her arms as has been mentioned the brady 44:50 kinesia of PSP is typically axial however in this clip you see severe 44:57 Brady Keynesian hypokinesia of finger tapping movements bilaterally a little 45:02 worse on the left side this is also present for hand grasping motions on the 45:08 left and right side 45:15 as well as with foot-stomping for both of his feet the left foot is almost 45:24 impossible to lift as is often seen in PSP there's an uncontrolled descent or 45:32 plopping or crashing down into a chair though for safety reasons he has helped back into his seat as previously 45:39 mentioned the applause sign or the patient's response when they're trying to imitate three claps the examiner 45:46 makes is quite prolonged in some individuals with PSP as a sign of 45:51 perseveration and possibly inhibitory control this gentleman continues to clap 45:58 until he is stopped eventually as is often seen in corticobasal syndrome there is clenched 46:05 fist dystonia with an Associated irregular postural tremor while more 46:11 common in MSA here we see in a regular kinetic tremor of both upper extremities 46:17 again associated with dystonia of the left hand here we see asymmetric brady 46:24 kinesia as well as left hand dystonia as is often seen in corticobasal syndrome 46:30 here on an interlocking finger test looking at praxis and spatial motor 46:37 functions this gentleman has difficulties orienting his hands and fingers in 46:43 appropriate planes with each other as well as imitating the posture of the examiner 47:08 as is typical for MSA here on repeating Buttercup and Methodist Episcopal you 47:14 hear a squeaky hypotonia and dysarthria but a good but a good but mezu Pazuzu 47:21 mezzo buzu method visible as one of the 47:27 cerebellar signs and MSA here you see dysrhythmia of rapid alternating 47:32 movements or supination pronation movements as opposed to simple brady kinesia that you may see in other 47:38 disorders another cerebellar sign is 47:44 overshoot or hyper metria on finger chase maneuver typically for cerebellar 47:51 disorders you see an overshoot with the correction however the correction is not seen here this demonstrates impaired 47:59 check reflex a cerebellar sign here you see impaired tandem stance from 48:05 cerebellar dysfunction lastly we see irregular cadence a wide 48:11 base and veering on his casual gait now we'll go back to dr. rich for the 48:17 remainder of this presentation Thank You Shawn for reviewing those clinical videos now let's go on and talk about 48:24 ancillary testing and management of parkinsonian syndromes as I said before 48:30 the key to make the diagnosis that parkinsonian syndromes is largely 48:36 clinical or bedside ancillary testing can be helpful in terms of structural 48:42 brain imaging I reviewed with you before some of the features of that specific 48:47 parkinsonian syndromes just as the hummingbird sign and PSP and the Hot 48:53 Cross Buns signed in multiple system atrophy again it can help make sure that the patient doesn't have a multi infarct 48:59 state but again the findings on the scan have to correlate with the clinical picture it can rule out a structural 49:06 lesion which is very uncommon or normal pressure hydrocephalus so it's worthwhile if there's any hint at all 49:13 that the patient doesn't have Parkinson's disease to get an image it can be argued that for patients who have 49:19 typical features of markinson's no red flags that may not be necessary at all to do any imaging the 49:27 DAT scan or dopamine transporter imaging is a nuclear medicine test in which the 49:33 presynaptic dopamine transporter is labeled by a particular ligand there is 49:40 diminished binding if you have Nigro striatal degeneration in general a DAT 49:46 scan is probably not necessary for patients who have typical Parkinson's disease but if there's something unusual 49:54 than a DAT scan can be helpful particularly if you're trying to distinguish Parkinson's disease from 50:00 drug-induced parkinsonism or normal pressure hydrocephalus but it's important to recognize that a DAT scan 50:07 cannot distinguish Parkinson's disease from a parkinsonian syndrome because 50:13 they're all associated with Nigro striatal degeneration and it's also worth remembering that the actually only 50:20 official approval or indication for a DAT scan is to distinguish parkinsonism 50:26 from essential tremor although I will add personally that clinically that's 50:31 rarely a diagnostic challenge so again that scan can sometimes be helpful but 50:37 recognize that it's not going to make a distinction between Parkinson's disease and other degenerative parkinsonian 50:43 syndromes and again just some routine lab testing just to make sure that the patient doesn't have any thing else that 50:50 might be contributing low vitamin b12 thyroid etc but again this has to be 50:56 dictated by the clinical perspective in general for patients who have parkinsonism the lab is not very useful 51:03 or needed now let's talk a little bit about management of these parkinsonian 51:08 syndromes I mentioned before that they typically don't respond to levodopa but 51:15 if the patient does have brady kinesia then it's worth a trial of levodopa sand 51:20 sometimes there can be a reasonable response at least early on and patients 51:26 should have at least a thousand milligrams of levodopa before calling them unresponsive it's important when 51:32 you use levodopa that you use regular levodopa since if you use the controlled-release levodopa you have 51:39 to use a lot more to get the required 1,000 milligrams and patients should 51:44 receive their levodopa optimally that is during the waking part of the day and ideally on an empty stomach 51:51 the cholinesterase inhibitors can be tried particularly if there's dementia associated with the parkinsonian 51:57 syndrome if the patient has problematic Colusa nations or delusions particularly 52:03 with dementia with Lewy bodies or advanced Parkinson's disease the antipsychotics particularly the second 52:10 generation the atypicals these include quetiapine or close a rail can be used 52:18 if the patient has depression or anxiety then the usual medications SSRIs or 52:23 tricyclics can be used again you have to be careful about side-effects for instance if the patient already has 52:30 orthostatic hypotension or significant constipation you should shy away from a 52:36 tricyclic for the Maya clonus which can sometimes be seen with corticobasal syndrome if it's problematic 52:43 levetiracetam or clonazepam can be tried for orthostatic hypotension 52:49 nonpharmacologic measures first reviewing all their medications to make sure they don't have any other drugs 52:55 which are contributing to low blood pressure such as antihypertensives adequate water salt intake avoiding 53:03 getting up quickly after a meal hot baths or showers lots of water is very 53:08 very important when the nonpharmacologic measures aren't enough options include 53:14 fludrocortisone mitt adrene or the norepinephrine precursor known as Drakh 53:19 seed opa botulinum toxin can be used for cial areia certain aspects of dystonia 53:26 as well so again just to emphasize that the parkinsonian syndromes should not be 53:32 viewed as untreatable there are still many things that we can do to help the patient improve their quality of life 53:39 supportive measures are particularly helpful here physical and occupational therapy speech and swallowing therapy 53:47 help for the caregiver social work support groups notably cure PSP and 53:52 palliative care can be very helpful as well and ultimately for the parkinsonian 53:58 syndromes in which medications play a relatively small role it's really 54:03 concentrating on these ancillary services in supportive care which is helpful and this includes careful 54:09 attention to the status of the caregiver a little bit of that management of PSP I 54:14 mentioned a trial of levodopa if certain types of dystonia are problematic like 54:20 blepharospasm or eyelid opening apraxia botulinum toxin can be used a me trip to 54:27 lean is something that was used in the past in general it's not very helpful likewise amantadine these are all things 54:33 that can be tried but in general medical therapy tends to not be very useful for 54:39 progressive supranuclear palsy and it's important to be judicious if there's not clear improvement don't continue the 54:45 medication if someone else has already started a medication it might be an opportunity to address whether it's 54:52 really helping by tapering it off walkers with wheels can be very very 54:57 helpful my preference is the you step walker home safety can be very important 55:03 rails in the bathroom etc I've listed here a variety of research clinical 55:09 trials that are either taking place or will be taking place then again another advantage of making the diagnosis it 55:17 allows patients to consider participating corticobasal syndrome some 55:22 of the similar things levodopa tends not to be very effective can be tried if 55:27 they're significant brady kinesia again if there's dystonia botulinum toxin treatment for the Maya clonus for 55:35 the cognitive impairment you can consider cholinesterase inhibitors looking carefully for affective 55:42 disorders again none of the parkinsonian syndromes are amenable to deep brain 55:47 stimulation and participation in clinical trials a little bit about the management of multiple system atrophy 55:54 again if there's MS aap a very judicious trial of leave it oppan sometimes it can be helpful you 56:01 have to watch that it doesn't worse than the orthostatic hypotension we talked before about some other treatments for 56:07 orthostatic hypotension the nonpharmacologic and the pharmacologic options there are things that can be 56:13 done for a neurogenic bladder often with the help of a urologist some patients 56:18 ultimately have to resort to intermittent catheterization there generally are not very good therapies at 56:25 least pharmacologic therapies for ms AC that is the cerebellar component again 56:30 botulinum toxin beacon can be considered if dystonia or drooling is a problem as 56:36 well as consideration of clinical trials for dementia with Lewy bodies again 56:41 tends to not be all that responsive to levodopa but it's worth a trial watching 56:47 carefully that it doesn't exacerbate the mental status cause hallucinations or worsen orthostatic hypotension the 56:54 cholinesterase inhibitors can be effective and it's worth trying them we've listed memantine as well and again 57:02 if there's depression or anxiety that can be treated antipsychotics unless 57:07 absolutely necessary for problematic hallucinations delusions should be 57:12 avoided because patients tend to be very sensitive this is generally not a problem though with quetiapine or 57:19 clozaril which have very little anti dopaminergic activity and for all 57:24 patients with dementia a structured and supportive environment can be helpful the prognosis for the parkinsonian 57:31 syndromes is very different than that of Parkinson's disease many people with 57:37 Parkinson's disease will lead a normal lifespan and often patients with parkinson's will pass away from 57:43 something other than complications of the disease this is not true for patients with Parkinson ian's syndromes 57:49 they tend to survive in general between six and ten years after the onset 57:55 although there is some variability and they do succumb generally to 58:00 consequences of the disease from complications of immobility with a DVT infection hopefully not pressure ulcers 58:08 aspiration pneumonia etc so to conclude now we've talked about parkinsonian 58:14 syndromes they have protein manifestations they can sometimes be 58:19 difficult to diagnose at the front end be aware of the atypical features that distinguish these from Parkinson's 58:26 disease they're a typical natural history compared to Parkinson's disease again paying close attention to the non 58:33 motor features concentrating on supportive palliative care other 58:39 resources and particular attention throughout the course of the disease to the caregiver and I've listed here are 58:47 some useful contacts for additional information 58:58 you