A
couple of
href="http://www.merck.com/mmpe/sec16/ch221/ch221g.html"
rel="tag">Parkinson's Disease related items came
across the news wires,
briefly. There are lessons in both of them, but both leave me
with unresolved questions.
The first one I noticed was a report based upon a journal article,
rev="review"
href="http://www.neurology.org/cgi/content/abstract/69/2/187">Risk
factors for somnolence, edema, and hallucinations in early Parkinson
disease. The second was based on a
different article (in the same journal),
href="http://www.neurology.org/cgi/content/abstract/01.wnl.0000268695.63392.10v1">The
impact of depressive symptoms in early Parkinson disease.
Both are in the journal, Neurology®.
Regarding the first article, there were several news reports, all
similar to this one (Forbes):
href="http://www.forbes.com/forbeslife/health/feeds/hscout/2007/07/11/hscout606197.html">Patients
With Early Parkinson's Exhibit Sleepiness, Hallucinations
07.11.07, 12:00 AM ET
WEDNESDAY,
July 11 (HealthDay News) -- Factors such
as gender, age and overall health may help predict which people with
early Parkinson's disease will experience hallucinations, sleepiness or
swelling, a new study says.
These symptoms are reported more frequently by people with early
Parkinson's disease than the general population, the study authors
said...
This was based upon the following journal article:
href="http://www.neurology.org/cgi/content/abstract/69/2/187">Risk
factors for somnolence, edema, and hallucinations in early Parkinson
disease
Kevin M. Biglan, MD, MPH, Robert G. Holloway, Jr, MD, MPH, Michael P.
McDermott, PhD, Irene H. Richard, MD and The Parkinson Study Group
CALM-PD Investigators
NEUROLOGY 2007;69:187-195
Background: The CALM-PD trial evaluated the
development of motor complications in subjects with early Parkinson
disease (PD) randomized to initial treatment with either pramipexole or
levodopa. A secondary finding of the trial was a higher than
anticipated development or worsening of somnolence and edema and
development of hallucinations.
Objectives: To investigate risk factors for
somnolence, edema, and hallucinations in patients with early PD
initiating dopaminergic therapy.
Methods: This was a secondary analysis of data
from the CALM-PD trial. Baseline patient characteristics were evaluated
for their associations with the development or worsening of somnolence
and edema and the development of hallucinations using Cox proportional
hazards regression models.
Results: Kaplan-Meier estimates of the 4-year
incidence of the development or worsening of somnolence and edema and
the development of hallucinations were 35%, 45%, and 17%. Initial
pramipexole treatment (hazard ratio [HR] 2.22, 95% CI 1.41, 3.50, p
< 0.001), male gender (HR 1.79, 95% CI 1.09, 2.93, p = 0.02),
and >5 systems with a comorbid illness (HR 1.62, 95% CI 1.04,
2.51, p = 0.03) were associated with somnolence. Initial pramipexole
treatment (HR 3.18, 95% CI 1.95, 5.18, p < 0.0001), female
gender (HR 1.46, 95% CI 0.94, 2.27, p = 0.09), and comorbid cardiac
disease (HR 1.59, 95% CI 1.02, 2.47, p = 0.04) were associated with
edema. Age ≥65 (HR 2.06, 95% CI 0.98, 4.32, p = 0.06),
Mini-Mental State Examination score >28 (HR 0.42, 95% CI 0.19,
0.91, p = 0.03), and >5 systems with a comorbid illness (HR
3.42, 95% CI 1.59, 7.38, p = 0.002) were associated with hallucinations.
Conclusions: Comorbid illnesses are important and
overlooked risk factors for the development of somnolence, edema, and
hallucinations. When initiating therapy with pramipexole, patients
should be counseled about and monitored for somnolence and edema.
Slight decrements in cognitive function and older age are associated
with an increased risk of hallucinations.
The point of the study was quite different that the point of the news
article. The news article focused on the fact that some
people with early Parkinson's Disease develop certain symptoms, and
that there are some identified risk factors. The point of the
journal article was that it is possible to identify certain risk
factors for the development of particular symptoms, in the
context of treatment with dopaminergic drugs.
The article did not answer the question I had, that led me to look into
it in the first place. They did mention that there was an
unexpectedly high incidence of somnolence in the patients treated with
href="http://en.wikipedia.org/wiki/Pramipexole">pramipexole
(Mirapex).
What I want to know is, how many patients had problems with
falling asleep suddenly, without warning? And secondarily,
how many developed impulse control problems?
There is a small literature on using pramipexole as an adjunctive
treatment for treatment-resistant depression, but I have been reluctant
to use it very much because of these cautions:
IMPORTANT
SAFETY INFORMATION ABOUT MIRAPEX: MIRAPEX may cause you to fall asleep
without any warning, even while doing normal daily activities such as
driving. When taking MIRAPEX hallucinations may occur and sometimes you
may feel dizzy, sweaty or nauseated upon standing up. The most common
side effects in clinical trials for RLS were nausea, headache, and
tiredness. You should talk with your doctor if you experience these
problems.
Patients and caregivers should be informed that impulse control
disorders/compulsive behaviors may occur while taking medicines,
including pramipexole, to treat Parkinson's disease and RLS.
It would be nice to get a realistic idea of how big those risks really
are.
The other thing I want to know is, of the patients who developed
hallucinations, how many had hallucinations that were resistant to
treatment. I am accustomed to using
href="http://en.wikipedia.org/wiki/Quetiapine" rel="tag">quetiapine
(Seroquel)
or even clozapine
(Clozaril)
for treating hallucinations. In my limited experience, it is
common to get the hallucinations calmed down enough that the patient no
longer changes his or her behavior in response to the hallucinations.
It is uncommon to get them to go away completely.
But I see such a limited subset of the patients that I wonder
how typical those outcomes are.
The second article presents different lessons and questions.
This instance is from UPI:
href="http://www.upi.com/Consumer_Health_Daily/Briefing/2007/07/11/depression_untreated_in_parkinsons/3312/">Depression
untreated in Parkinson's
Published: July 11, 2007
ROCHESTER, N.Y., July 11 (UPI) -- Depression appears to be common in
early Parkinson's disease, but it is often not treated or diagnosed,
according to a U.S. and Canadian study.
Dr. Bernard Ravina of the University of Rochester and Dr. Richard
Camicioli of the University of Alberta found that about 27 percent of
Parkinson's disease subjects screened positive for depression, while 40
percent of subjects' depression went untreated, according to the study
published in the journal Neurology...
The journal article is not in print yet, but the abstract and PDF are
available now.
href="http://www.neurology.org/cgi/content/abstract/01.wnl.0000268695.63392.10v1">
href="http://www.neurology.org/cgi/content/abstract/01.wnl.0000268695.63392.10v1">The
impact of depressive symptoms in early Parkinson disease
B. Ravina MD, MSCE*, R. Camicioli MD, P. G. Como PhD, L. Marsh MD, J.
Jankovic MD, D. Weintraub MD, and J. Elm MA
Published online before print June 20, 2007 (Neurology 2007,
doi:10.1212/01.wnl.0000268695.63392.10)
Background: Depressive disorders may affect up to
50% of patients with Parkinson disease (PD) and are associated with
increased disability and reduced quality of life. No previous study has
systematically examined the impact of depressive symptoms in early,
untreated PD. Methods: We administered the 15-item
Geriatric Depression Scale (GDS-15) as part of two NIH-sponsored phase
II clinical trials in PD, enrolling 413 early, untreated PD subjects.
We used linear mixed models to examine the relationship of depressive
symptoms, measured by the GDS-15, with motor function and activities of
daily living (ADLs), as measured by the Unified PD Rating Scale
(UPDRS). A time-dependent Cox model was used to examine the effect of
demographic and clinical outcome measures as predictors of
investigator-determined time to need for symptomatic therapy for PD. Results:
A total of 114 (27.6%) subjects screened positive for depression during
the average 14.6 months of follow-up. Forty percent of these subjects
were neither treated with antidepressants nor referred for further
psychiatric evaluation. Depression, as assessed by the GDS-15, was a
significant predictor of more impairment in ADLs (p < 0.0001)
and increased need for symptomatic therapy of PD (hazard ratio = 1.86;
95% CI 1.29, 2.68). Conclusions: Clinically
important depressive symptoms are common in early Parkinson disease
(PD), but are often not treated. Depressive symptoms are an important
contributor to disability and the decision to start symptomatic therapy
for motor-related impairment in early PD, highlighting the broad
importance of identifying and treating depression in this population.
Again, the popular news article misses the important points.
Yes, a high percentage of patients with Parkinson's Disease
also have depression. And yes, a lot of them don't get
treatment. But there are two critical points left out.
One, the depression is associated with earlier use of
antiparkinsonian drugs. Now, perhaps the thinking on this has
changed since I was in training. Back then, the idea was that
the antiparkinsonian drugs could only buy you a certain amount of time.
The earlier the drugs were started, the earlier the patient
would get to the point that the drugs lost their effectiveness.
So, one of the reasons the journal article is important, is that if
there is anything that can be done to delay the initiation of
antiparkinsonian drugs, then we want to know about it and make use of
it.
The second point I'd like to make about this article, is based on a
passage in the text, but not in the abstract:
Of
the 114 patients who screened positive for depression, 28 (25%) were
already receiving treatment for their depression, but had persistent
depressive symptoms.
That 25% is not a terribly high figure, but we want it to be zero.
One of the most fundamental principles in the treatment of
depression is that you want to treat until remission is achieved.
25% of the patients were being treated, but were not in
remission.
There is not any way to tell from the article if that was because the
patients were not being treated aggressively enough, or if they were
refractory to treatment. If the former, it should serve as a
reminder of the importance of treating to remission.
The question that is left unanswered is this: if patients with both
Parkinson's Disease and depression are treated adequately for their
depression, is it possible to delay the initiation of antiparkinsonian
medication. If so, does it improve clinical outcomes to do
so? The data suggest that it is likely to be the case, and it
certainly would be what I would expect, but we need at least one more
study to find out for sure.
When I first started to write this, I was planning on complaining about
how the news reports missed the main points of the journal articles.
After thinking about it some more, I've decided that would
not be appropriate. It probably is not realistic to think
that a nonspecialist, working with a tight deadline, could extract the
main points every time. Rather, it is more
appropriate to stress the need for the scientists to express clearly
why their studies are important.
I never know why news organization choose to pick up on some journal
articles and not others. Probably it has to do with the
investigator's institutions submitting press releases.
Perhaps if they do that, they should take one extra step to
make sure that the press release makes it clear why the study is really
important.
Perhaps the people who write the press releases are focused on trying
to take some highly technical information, and translating it into
something understandable to the general public. That is a
pretty big challenge. In general, I think they do a good job
of that. But paying more attention to that one additional
step would make the whole process much more useful.
- Log in to post comments
I think the data suggest that early treatment onset reduces mortality and does not hasten progression.
http://scholar.google.com/scholar?q=parkinson%27s+early+treatment&hl=en…
http://www.neurology.org/cgi/content/abstract/66/7/976
Psychiatrically, there is a definite concern, and there are some practice parameters out there. This looks useful:
D. Aarsland, M. Emre, A. Lees, W. Poewe, C. Ballard, E. B. Montgomery, J. M. Miyasaki, and G. Gronseth
Practice Parameter: Evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology
Neurology, January 2, 2007; 68(1): 80 - 81.
It's a big need, and underidentified. There's also the concern with medications interacting with each other - antipsychotics and l-dopa potentiate and diminish motor and psychotic symptoms, so it's a messy balancing act.
I look at many of these kinds of articles as coming from the desire for recognition by getting something published in the literature. Things that people throw at you when you first meet, challenging your competence before they've even had any demonstration of it. Someone reads these, patient or family member, then comes in armed as if they are an expert on this, and they just want to make sure you're considering these things. As if all the years you spend in training, out in practice, reading these articles and others on your own, have insufficiently prepared you to make good decisions without their help and supervision.
So you figuratively bite your tongue, take a deep breath, and go on. I will usually make some effort to address some issues, but I make it clear I'm not there to stand up to the media-based Inquisition or pass some layman's test of my neurologic prowess. If that's what the visit is all about, let's part ways while you search for some other "whippin' boy."
I don't doubt the absolute validity of these articles about compulsive gambling, but surely they're overblown, since I have yet to see an example in my practice. And while there is something to be said about depression as an associated feature, it's important to be careful and not perceive the motor signs of parkinsonism as definite signs of depression, since they're quite similar. Furthermore, there is a definite sensitivity to medications of all sorts that patients with parkinsonism have, so trying to limit unnecessary polypharmacy for every little stinking symptom they have is also in our minds.
Yes, and sometimes people see an article about, say, Mirapex and gambling, they they try to blame the problem on the drug. Never mind that the problem began before the drug was even invented.
Hi all,
I thought, based on the subject matter at hand, you might be interested in some of my research on the gambling/dopamine agonist question. This issue has not just been overhyped by the press, the first three studies themselves are, at very best, incredibly flimsy, and, at worst, simply do not present sufficient evidence to support their conclusions - and in one case, highly relevant information was omitted.
Here is the link to my blog overall:
http://anukets-crusade.blogspot.com/
And here are the links to specific gambling-related entries:
http://anukets-crusade.blogspot.com/2006/09/gambling-and-dopamine-agoni…
http://anukets-crusade.blogspot.com/2007/02/pathological-gambling-assoc…
http://anukets-crusade.blogspot.com/2007/02/letter-to-fda-alleging-rese…
Finally, to Greg P, while i can imagine that it could become tedious to continually have to correct the erroneous information patients "arm" themselves with, i hope that most neurologists will keep in mind that where they have seen both what the patient is going through and the info they bring with them thousands of times, this is all new for each individual patient.
I would bet that, while there are doubtless some people out there who do actually want to see their neurologist jump through hoops, the vast majority are just terrified at what is happening to them and are simply trying to educate themselves in an effort to feel at least a little bit less out of control. They no doubt truly believe that they have found some piece of info that is relevant to their medical care and that is why they present it to you - not, in the vast majority of cases i would wager, in order to challenge your prowess as a neurologist.
Unfortunately, all too often the outlets people rely on for their education are inaccurate.
I would welcome any thoughts anyone might have, including criticism (constructively offered, preferably) of anything in my blog. I am not interested in thinking I am right if I am not.
A note to those who think Mirapex and gambling are NOT related. I am proof they are. I am 54 years old and Never gambled in my life or had any other compulsive behaviour before taking Mirapex. I almost destroyed my life before finding out it could be the drug. I stopped the drug and the urge to gamble went away. It is sad that people can accept a side effect that involves your digestive system, blood pressure, heart, ect...but can't accept that it could affect your brain, reasoning and logic. This is a very real problem that Mirapex users should be made aware of. Of course all gamblers do not take Mirapex. But it is a real side affect and should be treated as such.
i started requip back in 9/06 for RLS and it was a miracle. Stopped working six months later and made symptoms worse. Started mirapex last week. only other drug taken was protonix. took mirapex as usual 6 p.m. on friday night. Sat am went to Lowe's with my husband and i was fine. Took him home around 9 am and then proceeded to fast food for breakfast. Stopped at red light at an extremely busy intersection near my home. Reachedh over to get money out of middle compartment in car. Took out $7.00 and the next thing I knew, I was going straight through the intersection right into oncoming traffic. it was as if i was in the middle of a bad dream. i looked to the left, saw cars coming and could not react. felt the impact and was then tossed across 4 lanes of traffic. I "woke up" when someone was yelling at me to pull my car out of traffic. At that point I realized just what had happened but had no clue as to why. I was trying to figure out what to say to the police as to what had just happened. thank God no one was seriously hurt but every time i close my eyes I see that car coming at me and it was as if it had been a horrific night mare. did not equate it to mirapex until being up all night thinking of nothing else. i knew not to drive when taking prescription drugs and I didn't. no one told me that i could be affecte 14 hours later. I don't know what happened to me, but i don't know what else it could have been. someone please help that could explain
I am 40 yr.old woman diagnosed 2yrs. I switched to Mirapex after suffering through psychosis with Requip which was probably the worst time period of my life. Mirapex was a welcome relief though it does cause me to fall asleep at random times but my family and I have learned to adjust to it and actually find some humor in it. On another note, I suffer from edema only on my right side, the same side as my Parkinson's...nothing helps, including Lasix, any ideas on this as to why?