A “peek” at Parkinson’s: The new diagnostic test
BACKGROUND: Parkinson's disease (PD) is a nervous system disorder that results in the degradation of motor skills in both men and women. PD, like other motor system diseases, is caused by the loss of dopamine-producing brain cells. Dopamine allows nerve cells to successfully transmit messages that control muscle movement. Devoid of the chemical, the brain scrambles commands, subsequently impairing muscular functions.
Parkinson's is a chronic, progressive disease and varies in severity. Though PD typically affects adults over the age of 50, it has been documented to afflict young adults and in rare cases, children. Researchers have not identified a cause for the loss of dopamine-producing cells and there are no standard blood or laboratory tests to conclusively identify the disease. (Source: U.S. National Library of Medicine).
SYMPTOMS: Shaking and tremors are the most common symptoms associated with Parkinson's disease, though it may take decades for them to develop. Other PD symptoms include difficulty speaking, swallowing, chewing and sleeping. Some patients have experienced emotional changes, skin irritation, urinary issues and constipation.
TREATMENT: There is no known cure for Parkinson's disease. Patients diagnosed with PD are often prescribed medications to offset the effects of dopamine loss and improve muscle control. The most common drugs prescribed are L-Dopa, Sinemet, Atamet, Mirapex, Requip, Parlodel, Eldepryl, Deprenyl, Azilect, Amantadine and Entacapone. In addition to movement-related medications, doctors may prescribe pharmaceuticals to treat autonomic dysfunction, impaired cognitive processes, sleeping disorders and to alleviate pain. (Source: U.S. National Library of Medicine, National Institute of Neurological Disorders and Stroke)
NEW DIAGNOSTIC TOOL: VA Medical Center and Virginia Commonwealth University researchers have identified a new method to screen patients for Parkinson's disease. The study suggests that patients with PD cannot sustain focus when asked to gaze upon a target on a computer monitor. Researchers observed an ocular tremor among PD patients regardless of whether they have received treatment or not. Only two control participants exhibited the tremor. One of the two patients who experienced the tremor experienced and reported Parkinson's symptoms within two years. (Source: U.S. Dept. of Veteran Affairs)
Mark Baron, M.D., Director of the Southeast Veterans Affairs Parkinson's Disease Research, Education and Clinical Center (PADRECC) Professor of Neurology Virginia Commonwealth University Medical Center, talks about a new eye test that could help detect Parkinson’s disease earlier
When did you get interested in researching Parkinson’s?
Dr. Baron: I’ve been interested in Parkinson’s research forever; since I started a fellowship, which was actually more laboratory based research. The clinical research came gradually later. For example, the project we’re on right now we’ve been working on for about ten years.
How many projects do you have right now?
Dr. Baron: We have a number of other projects that that have gone on at the same time. Beginning as a fellow at Emory University, I was involved in the original study in this country to evaluate doing pallidotomy, burning a whole in the globus pallidus to treat Parkinson’s disease. At Emory, we were the first group to modernize surgical approaches to Parkinson’s disease by doing intraoperative monitoring of the electrical brain activity. We were actually burning small holes and that was beginning in 1992. We published that and that was one of the first studies to use modern surgical approaches to treating Parkinson’s disease. Pallidotomy has since been largely replaced by DBS or deep brain stimulation surgery and as one of six veteran affairs PADRECC centers we are involved in a large study comparing two different sites in the brain for implanting deep brain stimulators for Parkinson’s disease.
There’s tons of research out there so why the eye movement?
Dr. Baron: The eye studies actually came about as a separate interest. Dr. Paul Wetzel, a biomedical engineer at the Virginia Commonwealth University where I’m also affiliated, was assessing eye movements in air force pilots. This led to an interest in using the same equipment to assess the eye movements of people with Parkinson’s disease. While testing a large number of people with Parkinson’s disease with our initial cruder equipment, we recognized the huge usefulness of this and over time it has evolved and become a bigger and bigger story. So we really didn’t realize where it was going when it was started; it was quite fortuitous.
Where is it going now?
Dr. Baron: We have now tested hundreds of people with Parkinson’s disease using a much improved, highly sensitive eye tracking system and just recently published our first paper. The paper described our findings in more than 120 patients with Parkinson’s disease and every one of them and everyone we have tested since with Parkinson’s disease has a very characteristic and specific type of tremor behind their eyes. It doesn’t matter how far along someone is in their disease. More recently we asked the question, well if it’s there in everyone when does it even start? One thing we know about Parkinson’s disease is that it probably starts a decade, or two or three, before you even start having motor symptoms. So before you start shaking, before you start slowing down, you’re beginning to lose dopamine cells and other brain cells that are involved in Parkinson’s disease. If we could identify it even before that with the eye testing that would be extremely valuable. So we began testing people that are at a high risk to get Parkinson’s disease. About half of them will eventually get Parkinson’s disease. We reasoned that if our eye testing could pick it up very early, then we should see the same eye findings in up to half of them and that is what we are finding. Remarkably, this is in a condition that occurs on average at least 10 years before the onset of Parkinson’s disease. It’s not actually always a separate disease but in these cases represents early symptoms of Parkinson’s disease. We wondered well if these people are going to get Parkinson’s disease can we actually predict whether they’re going to get it from the eye testing and the answer is yes we can.
You could say with 100% certainty who will get Parkinson’s?
Dr. Baron: So we believe, but this is all very preliminary. We just presented this in Ireland at the International Congress of Movement Disorders, and what we presented was, at the time, the first 10 people we tested. These are 10 people that are predicted to get Parkinson’s disease in the next 10 years or even longer and out of all those people, roughly 50% of them should go on to get it and that’s exactly what we found; 5 out of 10 of them had the eye findings. Basically it suggests that we can identify them but we’re trying to prove that now.
What do you actually see behind the eye?
Dr. Baron: What we see behind the eye is a tremor. If you think of a 360° circle, the tremor is only an average 0.2°, 2 tenths of a degree. So it’s something micro small that cannot be detected just by looking at someone’s eyes. It is not something that can even be detected by an ophthalmologist or optometrist for example, but if they had this very sensitive eye equipment and know what to look for, it can be readily identified. It is pretty phenomenal that researchers are trying to see if they can diagnose Parkinson’s disease doing spinal taps or drawing blood, and this is so simple and non-invasive. There’s so much effort right now being invested in trying to find a blood test for Parkinson’s disease, well here we have a test that we feel is just about 100% accurate and not only is it accurate, but seemingly, it can pick it up way before people even start slowing down or showing hand tremor. If you’re going to start a treatment that can slow down the disease, you don’t want to have to wait to start it when people have already lost 50 to 60% of their brain cells that are responsible for the Parkinson’s disease. Ideally, you’re going to want to start it at least 10 years before. We envision that this could be a screen for everyone. Just like you screen for colon cancer, you could begin to screen for Parkinson’s disease.
Is this for people that have a history of Parkinson’s in the family?
Dr. Baron: We’re looking at the people with the condition called REM behavior disorder which is a sleep disorder were people toss and turn in their sleep. Normally, when you go into REM or dream sleep your body actually shuts down; it doesn’t move. We started testing people who don’t shut down and those people have perhaps a 50% chance of getting Parkinson’s disease. The principal reason we picked these people is that it is a way to answer the question of can our eye test pick up Parkinson’s disease early before you get symptoms. What we envision is that everyone will get screened perhaps annually. Although screening everyone now is not that valuable, it will be, we hope, very shortly when we actually have treatments to slow down the disease. There are a number of treatments that have been tried but have failed. For example, co-enzyme Q and carnitine and a number of other agents have been tried that theoretically could slow down Parkinson’s disease. These agents have not worked, but maybe by the time these agents were tried the disease was already too well established. One of the things that was discussed at the recent Movement Disorders conference was that what we’re seeing in our clinics is really late Parkinson’s disease. When people have the characteristic signs of Parkinson’s disease, they are not at the beginning of the disease; that’s instead a later phase. Earlier phases could be instead defined by such symptoms as REM behavior disorder or autonomic nervous system problems such as constipation. By the time of clinical diagnosis, they are well into the disease. So if we can pick it up earlier with the eye testing, we could start testing therapies at earlier phases before the disease is well established and hopefully slow it down and even prevent people from getting to the later motor phase.
Do you think this changes how we look at phases of Parkinson’s disease?
Dr. Baron: I don’t know if the eye testing would change it. It would just allow us to identify it at an earlier phase. At least the eye testing could help to establish that yes, all these changes are already occurring in the brain. This could help us to figure out maybe when it is even starting. We don’t know how far into the disease though that you would have to be to get the eye changes, that is whether you would have to lose for example 10% or 20% of your dopamine or other brain cells. Studies suggest that people have lost perhaps 50% of their dopamine brain cells before they get such clinical symptoms as tremor.
What are some of the signs that people don’t think about?
Dr. Baron: Typical symptoms include tremor and slowing down with shuffling gait, and we talk about rigidity but that’s something the clinician feels on the examination.. Depression is also very common and often it’s not a reaction to having the disease but rather occurs due to a chemical imbalance in the brain. As already mentioned, you can get sleep disorders and autonomic disturbances, causing problems with bowel, bladder, and blood pressure regulation. A lot of people as a result will stand up and their blood pressure will drop, causing them to be dizzy and on occasion to even pass out. Also, dementia and mood disorders beside depression can occur and I discussed REM behavior disorder.
Could you go into detail about that?
Dr. Baron: REM behavior disorder is a condition that about 50% of the people with Parkinson’s disease get. Also, among those that develop REM behavior disorder and are not showing signs of Parkinson’s disease, about 50% will later develop Parkinson’s. It doesn’t mean you will get it, it means you have perhaps about a 50% chance. Normally during REM sleep, which is your dream sleep, your body shuts down so you just lie there, but what happens in REM behavior disorder is you act out your dreams. People may actually punch their spouse or through themselves out of the bed. Our body is fortunately designed that when we go into dream sleep we just shut down, our spinal cord is giving signals to not move, but those signals are lost in many people with in Parkinson’s disease.
When should people worry about that?
Dr. Baron: Well if you have this condition there are a couple reasons you might see a physician. Often you are referred to a sleep doctor, and the reason you would go see that physician would be to figure out why you’re moving so much in your sleep. But low and behold, what’s becoming more known now is that if you have this condition there is a high likelihood, maybe 50%, that you’re going to go on to either get Parkinson’s disease or a number of other conditions that we know about that are actually rarer than Parkinson’s disease. There’s something in the brain called alpha-synuclein which we now understand is part of the pathology of Parkinson’s disease. So, there’s a chance you have what is called alpha-synucleinopathy, which one of them happens to be Parkinson’s disease.
Is it a game changer?
Dr. Baron: What the eye testing allows us to do is to pick it up earlier and to confirm the diagnosis so from these standpoints, arguably it is a game changer. When we have therapies in place that slow down Parkinson’s disease, the eye testing will allow us to identify who should be started on them hopefully well before the motor symptoms are apparent. Even if these therapies do not completely prevent the disease, at least if we can identify those at risk and can start slowing it down 10 or 20 years before they start showing symptoms that’s going to have a huge impact compared to waiting until the disease has progressed to the point that they are starting to shake. Also, even if they are showing clinical features such as shaking, they might be misdiagnosed, so it would be important to routinely do the eye testing and establish that it’s really Parkinson’s disease. Many patients are misdiagnosed. We have people that occasionally come in that have been misdiagnosed for up to even 10 years. They’re coming in being pushed in a wheelchair because they were misdiagnosed. If the eye testing had been used routinely to screen these people, it would have proven they had Parkinson’s disease and they wouldn’t have been in that wheelchair. The therapies we have now do not yet slow the disease down but critically will for the most part keep people mostly out of a wheelchair. We also regularly see people who are misdiagnosed as having Parkinson’s disease when the do not and the eye testing could have guided the physician towards another diagnosis.
How long do you think it will take for something like this to be in a doctor’s office?
Dr. Baron: First you have to get past skepticism. I presented a poster of our findings at a conference, the one in Ireland. Although there were many scientific sessions emphasizing the critical need for the means to diagnose Parkinson’s disease presymptomatically, our work was not mentioned. This was perhaps because they didn’t know about it. There were more than a thousand abstracts at the conference and ours simply may not have caught the attention of enough people.
Do you think it’s hard to believe because it is such a debilitating disease and such a simple concept?
Dr. Baron: Yes, I think that’s one of the problems. First of all people have to see it and so unless you see it, you don’t know about it, which I think is one of the problems. Secondly, yes, another one is that it’s so simplistic. When I started this it did not occur to me that we had a test that was going to be accurate for Parkinson’s disease. Everyone who we see doesn’t have tremor, so why would everyone have a tremor behind their eyes? Well they all do and it’s almost too good to believe. If I wasn’t involved in this, I don’t know, maybe I would be skeptical too. Again it is not something that we logically said, okay there must be a tremor behind the eyes that would be more sensitive than the hand tremor so let’s see if it can accurately predict parkinson’s. As I mentioned, it evolved largely in response to an interest of Dr. Wetzel’s, the biomedical engineer, because he happened to be studying air force pilots. I had at one point, too many projects going on to keep up with them all, and I was able to say, well most of those were not as important as this one is. Why is this more important? Because we were lucky enough to have been studying it.
You do have another project right?
Dr. Baron: In my laboratory at the VA hospital, I am working on understanding the underlying abnormalities in electrical discharge activity that are responsible for the motor problems in Parkinson’s disease and related disorders. I am in particular studying dystonia, which can be a debilitating symptom of Parkinson’s disease, as well as being its own isolated disorder. In the clinic, we are also interested in defining the source for rigidity in Parkinson’s disease. Dr. Paul Wetzel has been working on developing a piece of equipment to study it, which should be very soon available to begin testing subjects. We’re not the first people to study this. I just have a different idea about what is causing rigidity which differs from what is generally believed. Dr. Qutubuddin, my colleague in our VA Parkinson’s Center is looking at the role of various exercise approaches to treating Parkinson’s disease. “Dr. Q” is a a rehab doctor who is pretty unique because he was trained as a fellow in our program, while most other people who get trained in Movement Disorders as fellows are neurologists. He has stayed on with us and is most interested in rehab aspects of Parkinson’s disease. Also, my colleague, Dr. Kap Holloway who heads the DBS surgical program at the VA and at VCU, has been heading up studies to improve surgical approaches for treating Parkinson’s disease and related disorders.
Do you think that this test can revolutionize how we screen for parkinson’s?
Dr. Baron: Definitely. Right now there is no accepted test to diagnose Parkinson’s disease, so the only test you have is you see your doctor, preferably a neurologist or even better a movement disorder specialist who does an examination on you and then decides whether you do or you don’t have Parkinson’s. Even with a specialist maybe ten percent of the time they cannot tell the first time whether you do or do not have Parkinson’s disease. There are many people I’ve seen who have seen other movement disorder specialists who have been misdiagnosed with Parkinson’s disease, or oppositely were told they didn’t have it, but really do. That’s not that uncommon so in that respect, yeah it’s huge that you can use a simple eye test to diagnose Parkinson’s disease. In my clinic, we do this now routinely. I send my patients down the hall for George Gitchel, our graduate student and VA employee, to test them. There’s even a running joke that George makes all the diagnoses and I just prescribe. We also recognize that the eye testing can diagnose not just Parkinson’s disease but many other movement disorders. We submitted a paper that’s being reviewed right now for publication which describes very different and characteristic eye movement findings in people that have another common condition, Essential Tremor. There are many other movement disorders we see in our clinic and each one has its own signature eye movement findings and so we’ve been using this not just for Parkinson’s disease but to help characterize and diagnose many other conditions.
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