Category Archives: MSA

Explanation of statistics in “Clinical outcomes” paper

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Recently I had posted about this O’Sullivan “Clinical outcomes” paper.  And I had asked if anyone knew statistics and could understand what “older age of onset” means (the abstract indicates in MSA “older age of onset” is a factor “predicting shorter disease duration until death”) and what “early autonomic dysfunction” means (in MSA “early autonomic dysfunction” is a factor predicting shorter survival).

Well….local support group member Ted is a biostatistician!  He has answered these two questions in addition to providing a useful (and short) summary and some interesting comments about what is statistically significant.  Here’s Ted’s email below.  It’s just in time for the support group meeting tomorrow:  I know some of you MSA caregivers are really interested in this article!  Thanks Ted!

Robin

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From Ted, local Brain Support Network group member

This is a complicated paper, so I’ll try just to summarize the parts I think are interesting, without adding very many thoughts of my own.

First, the very short version: MSA tends to start at a younger age than PSP.  Survival after getting the disease averages about 8 years for both diseases.

If you have PSP, you will tend to live longer if your early symptoms are more like typical Parkinson’s, if you are younger when you get the disease (though the difference isn’t large), if you are female, or if it is a comparatively long time before you hit your first “clinical milestone”, a list of bad things that happen as the disease progresses (I have a list below).

If you have MSA, you will tend to live longer if you are admitted to residential care at some point, if you do not have early autonomic dysfunction (various symptoms related to urination, digestion, sweating, blood pressure, and sexual function, within the first two years after onset; list below), if you are younger when you get the disease (again, not a big difference), if you are male (but this is a little complicated, as I explain below), and if it is a comparatively long time before you reach your first clinical milestone.

For both diseases, the degree of response to L-dopa does not appear to be associated with survival, at least in this study.

In this paper, the diagnosis of PSP or MSA is based on autopsy results.  The authors note that the accuracy of diagnosis during the patients’ lifetimes was less than 100%, and that PSP and MSA are often hard to distinguish during the patient’s lifetime.   All the conclusions presented were based on a set of 110 PSP patients and 83 MSA patients who had sought treatment and permitted autopsies at the Queen’s Square Brain Bank for Neurological Disorders.  This group of patients may not be exactly comparable to our own group of family members with PSP and MSA.

Now the less short version, in answer to your two questions:

Older age of onset:  First, “age of onset” means the age at which the first symptom attributable to PSP or MSA appeared in the patient’s medical record.  This is usually earlier than age at diagnosis (by 3-4 years on average; table 1).  “Older age of onset” does not refer to any specific cutoff age, but instead to the authors’ finding that patients who are older at onset tend not to live as long as patients who are younger at onset.  The “hazard ratio” for age of onset increases at 5% per year for both MSA and PSP (table 2).  The “hazard” is the rate at which patients die, so it would be measured in units like 10 deaths per year per 100 patients.   So, for example, patients with age of onset 64 would have a hazard approximately 20% higher (hazard ratio 1.2) than that of otherwise comparable patients with an age of onset of 60 (4 years younger at onset times 5% per year).

This is a small effect compared to some of the others shown in the table.  As an example, for PSP patients, male gender has a hazard ratio of 1.7 (meaning men have a 70% higher hazard than comparable women), which is equivalent to about an 11-year age difference at onset (the actual calculation is somewhat more complicated than just multiplying number of years times 5%).  So for PSP patients, a male with onset at 60 would have about the same hazard as an otherwise similar female with onset at 71.  Age isn’t in the same league as the big hazard ratios in the table, such as early autonomic dysfunction for MSA patients (hazard ratio 6.0).   I don’t think it’s clear from the paper how much of the age effect is due to differences in the progression of the disease versus just the increased hazard you would see in any comparison of older people versus younger.

Early autonomic dysfunction:  The autonomic nervous system regulates bodily functions like heart rate, respiration, digestion, salivation, urination, and sexual arousal.   For the purposes of the paper, autonomic dysfunction was defined to mean either an abnormal autonomic function test result, or (and I think this was what was used for the vast majority of cases) having two or more of the following set of symptoms, as reported by the patient:

  1. Frequent or urgent need to urinate, or “nocturia without hesitancy”, which sounds like it might mean either bedwetting or urgently needing to get up during the night to urinate; I’m not sure of the exact medical usage;
  2. Chronic constipation;
  3. Postural hypotension, presenting either as a complaint from the patient or just from observing a sufficient difference between sitting and standing blood pressure in the doctor’s office;
  4. Sweating abnormalities; and
  5. Erectile dysfunction.

Autonomic dysfunction was classified as early if it appeared within 2 years of onset (as defined above, first attributable symptom in the medical record).  The presence of erectile dysfunction on the list is a complicating factor, because it is a symptom that only men can experience, which means it is easier for a male patient to be classified as having early autonomic dysfunction than a female patient.  The authors mention this, and note that, as one would expect, a higher proportion of male patients had early autonomic dysfunction.  I’ll say a bit more about this later.

Finally, some unsolicited bonus commentary:

If you read the paper yourself, the word “significant”, or “statistically significant”  is used in a technical sense different from the everyday meaning.  A statistically significant effect is one for which the evidence is strong.  The effect itself may be rather weak (or it may not be).  So, for example, in table 2 the effect of age of onset is statistically significant, but it doesn’t have a very large effect on the hazard ratio compared with, say, the RS phenotype for PSP.

OK, then going over table 2, the biggest effect for PSP seems to be the RS phenotype.  This means that time to survival is shorter for patients whose main symptoms during the first two years are falls, cognitive dysfunction, supranuclear gaze palsy, abnormal saccadic (quick) eye movements, and postural instability.  PSP-P patients, whose first two years are more along the lines of typical Parkinson’s, with slow movement, tremor, some response to L-dopa, asymmetric onset and limb stiffness, tend to survive longer.  The hazard ratio is 2.37.   There were some patients for whom it was not clear which group they fell into, and they were excluded from the analysis.  Male gender is associated with shorter survival (hazard ratio 1.7), as is older age of onset, but for age it’s not a big difference.  Finally, patients who reach their first clinical milestone later tend to survive longer.  This is another per-year effect, with each year of delay for the first milestone reducing hazard by 20%.  On average, PSP patients’ time to first milestone varies by two or three years (bottom rows of table 3, showing a standard deviation of 2.7 years for PSP), so at 20% per year this is a pretty big effect.

For MSA, the big effects, which are really big, are early autonomic dysfunction (hazard ratio 6.0), and female gender (hazard ratio 3.0).  Both of these shorten survival, and I think they have to be viewed as a unit because of the erectile dysfunction symptom, which makes it easier for men to be classified as having early autonomic dysfunction.  It seems to me the high estimated hazard ratio for the female group may partly be explained as a “penalty” the female group pays for the greater proportion of undiagnosed early autonomic dysfunction in that group (this is my opinion, not the authors’, and I could be wrong).  Again for MSA patients, age of onset and interval to first milestone show up, with similar results.  Finally, not being admitted to residential care has an estimated hazard ratio of 2.8, so (perhaps surprisingly) residential care seems to increase survival for MSA.

The clinical milestones are a list of seven bad things that may happen to patients between disease onset and death: (1) frequent falls (2/year or more); (2) dependency on a wheelchair; (3) unintelligible speech; (4) severe dysphagia (difficulty swallowing); (5) use of a urinary catheter; (6) cognitive impairment; and (7) entering residential care.  Most patients experience at least a few of these (figure 2), but very few experience all seven.  Table 3 is a big summary of roughly when each milestone tends to occur (among patients that experience it), and a comparison of frequency of milestones between the disease groups.  Figure 4 plots the average times at which milestones occur, relative to the disease course, for Parkinson’s, PSP, and MSA.  The figure also shows time of diagnosis.  I’m a little dismayed to see how MSA patients seem to have a pileup of milestones at the end of life (although again, most patients don’t experience all milestones, and the times shown are the average for patients that do experience it).   I like the way the figure displays the average age of onset and duration for the three diseases.

Here’s the figure four of the O’Sullivan paper:

O’Sullivan et al, Fig. 4

Well, I think that’s all I have to say.  I hope it’s not too incomprehensible.  Please feel free to distribute this, or parts of it, to the group.

 

Ted

“Clinical outcomes” paper – PSP and MSA

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This is a very interesting article written by some of Europe’s top PSP researchers (and presumably top MSA researchers too).  The first author is O’Sullivan.  This is also a very important paper because it includes analysis of brains donated to the University College of London brain bank.

110 pathologically-confirmed PSP cases and 83 pathologically-confirmed MSA cases were examined for early clinical features and survival.  PSP cases were divided according to the D. Williams criteria of Richardson’s syndrome (RS) and PSP-parkinsonism.  MSA cases were divided according to the presence of early autonomic failure.

The PSP findings confirms what D. Williams has told us before:

“In PSP an RS phenotype, male gender, older age of onset and a short interval from disease onset to reaching the first clinical milestone were all independent predictors of shorter disease duration to death. Patients with RS also reached clinical milestones after a shorter interval from disease onset, compared to patients with PSP-P.”

The MSA findings are new to me (though maybe not to many of you):

“In MSA early autonomic failure, female gender, older age of onset, a short interval from disease onset to reaching the first clinical milestone and not being admitted to residential care were independent factors predicting shorter disease duration until death. The time to the first clinical milestone is a useful prognostic predictor for survival.”

Interesting (and scary?) that “not being admitted to residential care” predicts *shorter* disease duration in MSA.

I’ve copied below the abstract.

Update:  the full paper is now available at no charge.  See our post here with links.

Robin

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Brain. 2008 Apr 2 [Epub ahead of print]

Clinical outcomes of progressive supranuclear palsy and multiple system atrophy.

O’Sullivan SS, Massey LA, Williams DR, Silveira-Moriyama L, Kempster PA, Holton JL, Revesz T, Lees AJ.

Reta Lila Weston Institute of Neurological Studies, Institute of Neurology, Queen Square Brain Bank for Neurological Disorders and Institute of Neurology, Sara Koe PSP Research Centre, Institute of Neurology, University College London, London, UK, Faculty of Medicine (Neuroscience), Monash University (Alfred Hospital Campus) and Department of Neurosciences, Monash Medical Centre, Melbourne, Australia.

Prognostic predictors have not been defined for progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). Subtypes of both disorders have been proposed on the basis of early clinical features. We performed a retrospective chart review to investigate the natural history of pathologically confirmed cases of PSP and MSA.

Survival data and several clinically relevant milestones, namely: frequent falling, cognitive disability, unintelligible speech, severe dysphagia, dependence on wheelchair for mobility, the use of urinary catheters and placement in residential care were determined.

On the basis of early symptoms, we subdivided cases with PSP into ‘Richardson’s syndrome’ (RS) and ‘PSP-parkinsonism’ (PSP-P).

Cases of MSA were subdivided according to the presence or absence of early autonomic failure.

Sixty-nine (62.7%) of the 110 PSP cases were classified as RS and 29 (26.4%) as PSP-P.

Of the 83 cases of MSA, 42 (53.2%) had autonomic failure within 2 years of disease onset.

Patients with PSP had an older age of onset (P < 0.001), but similar disease duration to those with MSA. Patients with PSP reached their first clinical milestone earlier than patients with MSA (P < 0.001). Regular falls (P < 0.001), unintelligible speech (P = 0.04) and cognitive impairment (P = 0.03) also occurred earlier in PSP than in MSA.

In PSP an RS phenotype, male gender, older age of onset and a short interval from disease onset to reaching the first clinical milestone were all independent predictors of shorter disease duration to death. Patients with RS also reached clinical milestones after a shorter interval from disease onset, compared to patients with PSP-P.

In MSA early autonomic failure, female gender, older age of onset, a short interval from disease onset to reaching the first clinical milestone and not being admitted to residential care were independent factors predicting shorter disease duration until death. The time to the first clinical milestone is a useful prognostic predictor for survival.

We confirm that RS had a less favourable course than PSP-P, and that early autonomic failure in MSA is associated with shorter survival.

PMID: 18385183

“Frontal-subcortical dementias” (PSP, CBD, LBD, and MSA)

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This newly-published abstract reviews the clinical presentation of frontal-subcortical dementias, lists them, and suggests how they relate to cortical dementias. The classic “cortical dementia” is Alzheimer’s Disease. Three dementias in our atypical parkinsonism group are mentioned as frontal-subcortical dementias — Parkinson disease dementia (also called Lewy body dementia), progressive supranuclear palsy, and corticobasal degeneration.

Interestingly, multiple system atrophy is listed as a frontal-subcortical dementia though dementia is exclusionary for MSA.

Robin

The Neurologist. 2008 Mar;14(2):100-107.

Frontal-Subcortical Dementias.

Bonelli RM, Cummings JL.
>From the *Department of Psychiatry, Graz Medical University, Graz, Austria; and the †Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Frontal-subcortical dementias are a heterogeneous group of disorders that share primary pathology in subcortical structure and a characteristic pattern of neuropsychologic impairment. Their clinical presentation is characterized by memory disorders, an impaired ability to manipulate acquired knowledge, important changes of personality (apathy, inertia, or depression), and slowed thought processes (or bradyphrenia). It also has marked frontal dysfunction.

Classic frontal-subcortical dementias include Huntington chorea, Parkinson disease dementia, progressive supranuclear palsy, thalamic degeneration, subcortical vascular dementia, multiple sclerosis, the acquired immunodeficiency syndrome dementia complex, depressive pseudodementia, and some other rare dementias like spinocerebellar degenerative syndromes, Hallervorden-Spatz disease, choreoacanthocytosis, idiopathic basal ganglia calcification, Guamanian parkinsonism-dementia complex, corticobasal degeneration, multiple system atrophy, Wilson disease, metachromatic leukodystrophy, adrenoleukodystrophy, hypoparathyroidism, sarcoidosis, and other CNS inflammatory disorders.

Anatomic data suggest that the frontal signs result from a disconnection of the frontal cortex from the basal ganglia. However, most frontal-subcortical dementias show cortical atrophy in later stages, and cortical dementias have subcortical pathology at some point. In fact, the concept might be seen as a continuum, and only the 2 extremes would be represented by pure cortical or subcortical pathology. Anyway, subcortical disorders may still be more similar to one another than they are to AD. Possibly, frontal-subcortical and cortical dementias are the description of the prior main target of the disease process, ending up in both cases in a global dementia. Although the dichotomy cortical versus frontal-subcortical dementia is not strict, the 2 concepts still seem to have advantages.

PubMed ID#: 18332839 (see pubmed.gov for abstract only)

Overview of Atypical Parkinsonism

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This is an overview of Atypical Parkinsonism written by our friend Dr. Golbe. Of course covering five disorders in a two-page document means that lots of information is left out, including subtleties and exceptions. But overall, I think this is a reasonably good overview of these disorders. (The first four disorders are in our local support group. Vascular Parkinsonism is not; I know nothing about it.) I read about this article on an MSA-related Yahoo!Group today. Unfortunately the newsletter isn’t available online yet so there’s nothing to link to; for future reference the APDA’s website is apdaparkinson.org.

“Atypical Parkinsonism”
by Lawrence I. Golbe, MD, Professor of Neurology, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ
The American Parkinson Disease Association Winter 2008 Newsletter

You may have been told by your doctor that you have not Parkinson’s disease but “atypical parkinsonism,” “Parkinson’s-plus” or “Parkinson’s syndrome.” Confused?

What is “Parkinson’s syndrome”?
A “syndrome” is a group of signs and symptoms that often occur together and may be caused by any of a variety of diseases. A “disease” is an abnormal process, usually with a specific cause. For example, the syndrome called the “flu,” which includes fever, muscle aches, cough and headache, can be the result of any of several diseases, only one of which is an infection by the influenza virus.

Similarly, a combination of slowness, muscle rigidity, tremor and impaired balance is a syndrome called “Parkinson’s syndrome” or just “parkinsonism.” The disease that most commonly causes it is “Parkinson’s disease” (PD). PD is strictly defined as parkinsonism associated with gradual loss of certain groups of brain cells that, as they sicken, form within them microscopic balls called Lewy bodies.

Parkinsonism may also be caused by a dozen diseases other than PD. Most of these cause other signs and symptoms in addition to the parkinsonism, which is why they are also called the “Parkinson-plus disorders or the “atypical parkinsonisms.”

Progressive Supranuclear Palsy
The most common atypical parkinsonism is “progressive supranuclear palsy” or PSP. There are only about 20,000 people with PSP in the US, while there may be one million with PD. What’s “atypical” about PSP is its failure to respond to levodopa/carbidopa or other PD medications, difficulties looking up and down, an erect or even backwardly arched neck posture, and the relatively early appearance of falls, slurred speech and swallowing difficulty. Most of these features can occur in PD, but not with the intensity or frequency with which they appear in PSP. Instead of Lewy bodies, the brain cells in PSP have “neurofibrillary tangles.” While Lewy bodies are mostly made up of a protein called alpha-synuclein, neurofibrillary tangles are made of a different protein called “tau.”

Multiple System Atrophy
The next most common atypical parkinsonism is “multiple system atrophy” or MSA. In addition to parkinonism, MSA usually features the type of poor coordination and balance that arises from disorders of the cerebellum, giving some sufferers a “drunken” appearance. Other “atypical” features in most people with MSA are low blood pressure, sensations of being too hot or cold, constipation, urinary difficulties and brief episodes of shortness of breath or sleep apnea. These arise from “dysautonomia” which is a loss of brain cells that control the autonomic nervous system. The dysautonomia of MSA was called “Shy-Drager syndrome” before it was recognized in the early 1990’s as part of a specific disease that can have several forms. Like PSP, MSA causes earlier balance problems than PD and medication for PD usually has little benefit. However, there is medication for most of the dysautonomic features. In MSA, the protein that aggregates is alpha-synuclein, as in PD, but it does so in a different set of brain cells and looks different from Lewy bodies. The protein aggregates in MSA are called “glial cytoplasmic inclusions.”

Corticobasal Degeneration
The third leading atypical parkinsonism is “corticobasal degeneration” (CBD). CBD affects one side of the body first and worst. This is also true, but to a far lesser extent, for PD. For PSP and MSA, the problem is usually symmetric, with left and right sides affected nearly equally. CBD, in addition to parkinsonism, features abnormally heightened reflexes as elicited by tapping with a hammer, and small, sudden, rapid involuntary movements called myoclonus. Its most distinctive feature is apraxia, which is a loss of the ability to perform complex movements with the hands or feet. There is also difficulty with the ability to perceive the spatial features of objects. At present, no medication is effective, unfortunately, and the disorder is treated with physical therapy. In CBD, the protein that aggregates is tau, as in PSP, but it does so mostly on one side of the brain, and disproportionately in the area of the brain responsible for planning complex movement tasks, the frontal lobes.

Dementia with Lewy Bodies
“Dementia with Lewy bodies” is a parkinsonian disorder that often starts with confusion, depression or psychosis (that is, hallucinations or delusions). However, the mental symptoms appear before or together with the movement symptoms and not afterwards, as in PD. The movement difficulty may even be very mild and, as for most of the atypical parkinsonisms, tremor at rest is far less common than in PD. In DLB, the behavioral symptoms can vary greatly over periods of minutes to days and can include periods of unresponsiveness, elaborate delusions and visual hallucinations in addition to the difficulty with memory and thinking. The hallucinations of DLB can occur without levodopa or other dopamine-enhancing medications, while in PD, any hallucinations are a side effect of those medications. The parkinsonism of DLB responds to levodopa/carbidopa. The movement and behavioral symptoms can be severely and dangerously exacerbated by drugs that block dopamine such as Haldol (haloperidol), Compazine (prochlorperazine), and Reglan (metoclopramide).

Vascular Parkinsonism
Another common condition causing atypical parkinsonism is “vascular parkinsonism” or “arteriosclerotic parkinsonism.” This is the eventual result of many tiny strokes, no one of which may be large enough to cause symptoms at the time it occurs. The strokes can be seen on an MRI scaan. Over the years, the cumulative effect causes movement difficulty, especially with walking and other movement of the legs. The condition does not respond to PD medication, but its progression can often be slowed or even stopped by controlling risk factors such as high blood pressure, smoking, or high lipids. Physical therapy is helpful in dealing with the gait problem.

How Do I Tell If I Have Atypical Parkinsonism?
Atypical parkinsonism rather than PD should be suspected when someone with the parkinsonian syndrome has little or no response to a moderate dosage of levodopa/carbidopa or when there is the early appearance of falls, behavioral changes, swallowing problems, abnormal eye movements, bladder problems or lightheadedness on standing. The physician should order an MRI scan, which can show the small strokes of vascular parkinsonism, the asymmetric shrinking of corticobasal degeneration, the unusual pattern of brain shrinkage of progressive supranuclear palsy, or the abnormal pattern of iron and scarring of PSP or multiple system atrophy. Some other radiologic tests such as PET and SPECT can also be helpful in special circumstances.

While the atypical parkinsonism are more difficult to treat than PD, the good news is that they do not run in families nearly as often as PD does. While 20-25% of people with PD have some close relative with PD, fewer than 1% of those with PDP, MSA or CBD have a relative with atypical parkinsonism. For DLB and vascular parkinsonism, the fraction is slightly higher. The causes of the atypical parkinsonism are started to be worked out. As we learn more about the abnormal processes in the brain cells in these conditions, treatments that may slow, stop or even reverse their course will become possible.

Applause sign (clap test) – updated research

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Here’s some new research that probably speaks to the results that Dubois got in ’05 when he and other French researchers said that the “applause sign helps to discriminate PSP from FTD and PD.”

This newly-published research looks at those with PD and “various forms of atypical parkinsonism.” (I’ll have to get the full article to know which forms were included.) These Dutch researchers found: “Although the proportion with an abnormal clapping test was significantly higher in atypical parkinsonism, the clapping test did not discriminate well between Parkinson’s disease and atypical parkinsonism.”

Journal of Neurology. 2007 Oct 15; [Epub ahead of print] Diagnostic accuracy of the clapping test in Parkinsonian disorders.

Abdo WF, van Norden AG, de Laat KF, de Leeuw FE, Borm GF, Verbeek MM, Kremer PH, Bloem BR.
Parkinson Centre Nijmegen (ParC), Institute of Neurology, Radboud University Nijmegen Medical Centre, The Netherlands.

BACKGROUND : To determine the diagnostic value of the clapping test, which has been proposed as a reliable measure to differentiate between progressive supranuclear palsy (where performance is impaired) and Parkinson’s disease (where performance should be normal).

METHODS : Our study group included a large cohort of consecutive outpatients including 44 patients with Parkinson’s disease, 48 patients with various forms of atypical parkinsonism and 149 control subjects. All subjects performed the clapping test according to a standardized protocol.

RESULTS : Clapping test performance was normal in all control subjects, and impaired in 63% of the patients with atypical parkinsonism. Unexpectedly, we also found an impaired clapping test in 29% of the patients with Parkinson’s disease.

CONCLUSION : Although the proportion with an abnormal clapping test was significantly higher in atypical parkinsonism, the clapping test did not discriminate well between Parkinson’s disease and atypical parkinsonism.

PubMed ID#: 17934886

The “applause sign” is where you ask someone who might have PSP to clap. While clapping, you tell them to stop. The person with PSP continues to clap; it takes them awhile to stop.

In a study done by Dubois, 30 out of 42 patients diagnosed with PSP could not stop applauding immediately after being told to stop. Interestingly, none of those with FTD or PD had trouble stopping.

Here’s the abstract of the Dubois article (published 6/05 in Neurology):

*Neurology. 2005 Jun 28;64(12):2132-3.

“Applause sign” helps to discriminate PSP from FTD and PD.

Dubois B, Slachevsky A, Pillon B, Beato R, Villalponda JM, Litvan I.
INSERM, Fédération de Neurologie, Hôpital de la Salpêtrière, Paris, France.

“Applause sign” helps to discriminate PSP from FTD and PD
The “applause sign” is a simple test of motor control that helps to differentiate PSP from frontal or striatofrontal degenerative diseases. It was found in 0/39 controls, 0 of 24 patients with frontotemporal dementia (FTD), 0 of 17 patients with Parkinson disease (PD), and 30/42 patients with progressive supranuclear palsy (PSP). It discriminated PSP from FTD (p < 0.001) and PD (p < 0.00). The “three clap test” correctly identified 81.8% of the patients in the comparison PSP and FTD and 75% of the patients in the comparison of PSP and PD.

PubMed ID#: 15985587 (see pubmed.gov)