Brain Support Network and Stanford University co-hosted a webinar on Wednesday, August 30th about diagnosing Progressive Supranuclear Palsy.
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RECORDING
We’ve posted the webinar recording here —
www.youtube.com/watch?v=X1hBA9epCX8&list=PLrukR7WKf08QnjkBL9_-nTv0Kb2a9Y0o4&t=3s&index=2
It’s the speaker’s presentation (about 30 minutes).
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RESOURCES
For additional information on the topics addressed during the webinar, see:
PSP Education, by Brain Support Network
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NOTES
Our terrific volunteer, Denise Dagan, took notes from the webinar.
Webinar
Diagnosing Progressive Supranuclear Palsy
Speaker: Kathleen Poston, MD, movement disorders specialist, Stanford University
Host: Robin Riddle, CEO, Brain Support Network
August 30, 2017
PRESENTATION
We are focusing on the diagnosis of progressive supranuclear palsy today, and particularly paying attention to why the new diagnostic criteria was developed, how it can be applied in a clinical setting both from the perspective of clinicians and the patient and patient’s family.
Why have there been revisions in the clinical diagnostic criteria?
PSP can be a very difficult disorder to properly diagnose. The more classic of the PSP syndromes, called Richardson Syndrome, is one of the easier versions of PSP to diagnose.
In several studies, only about 63% of people diagnosed with PSP, who donated their brains for scientific research, actually had PSP confirmed by autopsy.
That’s a pretty low number especially for clinical trials because when you are studying a treatment for PSP you only want to recruit people who have PSP. If it turns out only 63% of the people enrolled in your study actually have PSP, your results are askew. The results are showing you your treatment only works on about half the people in your study which doesn’t look very effective. When, in fact, it may be working very well on every person who has PSP but you can’t see it because there are so many people enrolled who don’t have PSP.
What is misdiagnosed at PSP?
Dr. Poston showed a slide showing a Venn diagram of the types of disorders commonly misdiagnosed as PSP from a study of 181 patients who’s brain underwent autopsy, including one circle labeled as the 63% who actually had PSP.
The biggest group of misdiagnosed disorders is “Parkinsonism,” which is a collection of disorders which includes Parkinson’s disease (PD), Dementia with Lewy Bodies (DLB) and a broader parkinsonism, which in these autopsy cases means the clinician thought it was some form of parkinsonism but couldn’t definitively say it was either Parkinson’s disease or Dementia with Lewy Bodies versus some other parkinsonism disorder.
This group is 13% of cases misdiagnosed as PSP during life, but found to have Parkinsonism on autopsy.
The other commonly misdiagnosed disorders were less frequent:
corticobasal degenerative disease, which is also frequently confused with PSP = 2%
frontotemporal degeneration = 3%
Alzheimer’s disease = 4%
What are the clinical features of PSP:
Motor:
* Parkinsonism, a syndrome defined by axial rigidity (rigidity in the neck and trunk), postural instability (poor balance), bradykinesia (slowness of movement and facial expression muscles), reduced blink
* Supranuclear gaze palsy (SGP) – This is the feature that most accurately helps diagnose PSP. When we quickly look up, down, right, or left it is called a saccadic eye movement. When we move our eyes slowly, it is called called a smooth pursuit. These movements are controlled by the cortex of the brain, above the nucleus that controls the eye muscles (supranuclear). That is the part of the eye movement that is most impacted by PSP. Patients, at first, have trouble with the saccadic movements, and eventually have trouble looking up or down at all, even with smooth pursuit. This is in contrast to a gaze movement below the level of the nucleus (infra nuclear) in which you move the head in one plane can the eyes move around and the eyes are not affected.
* Dysphagia/dysarthria – speech and swallowing difficulties
Cognitive Profile:
* Executive dysfunction – cognitive profile / thinking challenges
Behavior:
* Apathy, obsessive/compulsive behaviors, lack of inhibition
When these cognitive and behavior dysfunctions are present, it can make it difficult to distinguish PSP from other types of memory problems, like Alzheimer’s disease (AD) and Frontemporal Dementia (FTD). When there’s more of a motor component to presenting symptoms, it becomes difficult to distinguish PSP from Parkinson’s disease and parkinsonisms.
The original diagnostic criteria was developed in 1996. They were based on a series of autopsy cases for people who had been followed throughout their life and were found at autopsy to have PSP in their brains. When they looked back at the clinical symptoms to see what clinical symptoms distinguished PSP from other disorders they came up with:
– Gradually progressive (to distinguish from stroke, which causes sudden changes)
– Presenting symptoms over the age of 40
– Vertical supranuclear gaze palsy
– Postural instability with a propensity to fall within the first year of symptoms
There are a lot of other supporting features but those tended to differentiate PSP from other disorders, but were unspecific, like rigidity in the neck and trunk, tendency to fall backward, poor response to levodopa, and some cognitive symptoms. These supporting features didn’t do a good job of distinguishing people who had PSP from other disorders, and what was used in the study of 181 people thought to have PSP in which only 63% actually had PSP on autopsy.
What has been identified since is that most patients would have the classic parts of PSP (supranuclear gaze palsy, and tendency to fall) early on and can be properly diagnosed within 1-3 years. But a lot of patients didn’t have those particular features early on in the disorder. Over time those symptoms tend to emerge into the classic Richardson syndrome, but it can be so many years (6 or 7 years) before those symptoms present and getting the right diagnosis. In fact, people have actually died before presenting the classic Richardson syndrome symptoms of PSP.
This is frustrating for patients, their families, and clinicians trying to only enroll people who actually have PSP in their clinical trial studies.
Dr. Poston showed a slide at time stamp 14:52 showing the accuracy of a PSP diagnosis, depending on early symptom presentation.
1. PSP Richardson syndrome – supranuclear gaze palsy & early falls = very likely properly diagnosed with PSP
2. PSP-P Parkinsonism symptoms – slowness, stiffness, subtle eye movement abnormalities, no early falls = less than 1/2 the time accurately diagnosed with PSP
3. PSP Primary Freezing of Gait – difficulty initiating walking early on. Not part of the classic Richardson Syndrome. Very difficult to diagnose, but more accurately diagnosed with PSP than those below.
These four disorders are a very small percentage of people with PSP, but they do exist and it is important to understand that. That is part of the logic behind the somewhat complex nature of the new diagnostic criteria. Because they are a small percentage, we will focus on the first three.
4. Cortobasal syndrome
5. Nonfluid Primary Progressive Aphasia
6. Behavior variant FTD
7. Cerebellar ataxia
PSP- RS / PSP Richardson Syndrome is the most common clinical variant. People presenting these symptoms are most likely to actually have PSP pathology on autopsy.
* Unexplained falls, Unsteady gait, Bradykinesia (slowness of movement)
* Personality changes (apathy, disinhibition)
* Cognitive slowing, Executive dysfunction (difficulty problem solving and organizing your day)
* Slow, spastic, and hypophonic speech, Dysphagia (difficulty swallowing)
* Impaired eye movement (slow vertical saccades, apraxia eyelid opening)
* Vertical supranuclear gaze palsy, but onset is variable, for example:
— Might not present for 3-4 years after disease onset
— May present early on as decreased velocity, amplitude of vertical > horizontal saccadic (can’t look all the way up or all the way down)
— May present as decreased or absent optokinetic nystagmus. There are some easy to use apps to test OKN in your doctor’s office.
PSP-P / PSP-Parkinsonism is the one that has the most difficulty distinguishing between PSP and Parkinson’s disease or PSP and Dementia with Lewy Bodies. This subtype of PSP was identified in the last 10 years by an autopsy study done in the UK where they looked at a bunch of patients who had donated their brain and had PSP on autopsy but did not have a diagnosis of PSP during their life. A lot of those patients had features very similar to classic Parkinson’s disease, particularly early on.
We always thought PSP should be very symmetric without a lot of tremor, but these folks had a lot of asymmetry and a lot of tremor and a good many of them had an early, good response to Levodopa. As years progressed this response went away and the asymmetry became symmetric, but early on it really resembled classic Parkinson’s disease and this made us realize that early on some patients are early to distinguish.
It was uncommon for these people with PSP Parkinsonism to develop the classic Levodopa-induced dyskinesias, they didn’t have the autonomic dysfunction (blood pressure drops common in Parkinson’s), or hallucinations common in Dementia with Lewy Bodies (DLB) and that’s really important in distinguishing PSP from DLB. DLB is a variant of Parkinson’s disease where the visual hallucinations are a distinguishing feature. Asking whether visual hallucinations are present is key in distinguishing PSP from DLB.
(Slide summary)
PSP-P Parkinsonism. People presenting these symptoms are less than 1/2 the time accurately diagnosed with PSP.
* Early features of PD
* Asymmetric onset tremor, Bradykinesia, Rigidity, Moderate initial response to Levodopa
* Resembles idiopathic Parkinson’s disease
* Levodopa-induced dyskinesias, autonomic dysfunction, and visual hallucination are less common in patients with PSP-P (compared to the patients with PD)
PSP-PGF / PSP Primary Gait Freezing – very tough to diagnose but important to recognize it is a variant of PSP as almost all patients have PSP pathology at autopsy.
* Pure Akinesia with Gait Freezing – primarily have difficult initiating walking, feet really stick to the floor
* Isolated gait disorder (5-6) years before development of other PSP-RS
* Progressive gait disturbance with start hesitation
* Subsequent freezing of gait
* Sometimes difficulties with initiating or completing speech or writing
* Without tremor, rigidity, dementia, or eye problems during first 5 years
The new 2017 diagnostic criteria:
* Sporadic occurrence (to distinguish from stroke)
* Age 40 or older at onset
* Gradual progression of PSP-related symptom
* Core Features:
— Oculomotor dysfunction
— Postural instability
— Akinesia
— Cognitive dysfunction
What does Probably PSP mean?
We cannot say someone definitely has PSP without autopsy finding. It is not possible at this point, based on clinical exam, brain imaging, or blood test to say someone definitely has PSP. Research is underway.
Highly specific: If someone meets probable PSP criteria, there is a very high chance that the underlying pathological diagnosis will be PSP. These are the people we are most certain about.
Good for use in clinical trials where you only want to enroll people who have the real underlying pathology.
But not very sensitive for PSP. Most people who have PSP pathology will not fully meet the Probable Criteria. Means that if you don’t have Probable PSP based on criteria, there’s still a really good chance you have PSP.
Slide at time stamp 26:10 showing the diagnostic levels of certainty when certain symptoms are present early on. In all cases, the oculomotor dysfunction must be present or it would be too hard to distinguish from PD or DLB.
To be diagnosed with Probable PSP-RS (Richardson Syndrome) you must have:
1. Either a vertical supranuclear gaze palsy or slow velocity of vertical saccades AND
2. Either repeated unprovoked falls within 3 years or a tendency to fall on the pull-test within 3 years.
To be diagnosed with Probable PSP-P (Parkinsonism) you must have:
1. Either a vertical supranuclear gaze palsy or slow velocity of vertical saccades AND
2. Parkinsonism, akinetic-rigid, predominantly axial, and levodopa resistant or Parkinsonism, with tremor and/or asymmetric and/or levodopa responsive.
To be diagnosed with Probable PSP-PGF (Gait Freezing) you must have:
1. Either a vertical supranuclear gaze palsy or slow velocity of vertical saccades AND
2. Progressive gait freezing within 3 years
Dr. Poston showed a slide at time stamp 29:30 showing imaging scans that are helpful in diagnosis when they appear. Similar to the eye movement abnormalities, when doctors see these they are very helpful in making a diagnosis. Unfortunately, most patients do not present so clearly on imaging. The lack of these distinguishing scan features does not mean you do not have PSP, it just means this tool didn’t present any compelling evidence for a PSP diagnosis. Clinical observation will have to suffice.
* The hummingbird sign shows thinning of the midbrain, which is classic to PSP
* The morning glory sign or mickey mouse ears, also shows thinning of the midbrain.
Dr. Poston showed slides of PSP pathology under the microscope at autopsy at time stamp 30:33, and discussed:
* Neurofibrillary tangles or neuropil threads or both, in the basal ganglia and the brainstem.
* Microscopic features:
— Neuronal loss
— Gliosis
— Neurofibrillary tangles
— Neuropil threads
— Tufted astrocytes
— Oligodendroglial coiled bodies