The “Parkinson’s glove”

In the last couple weeks lots of people have asked me about the “Parkinson’s glove.” Many had seen a report on the Today Show that made some extraordinary claims about reversal of Parkinson disease (PD) symptoms, and some read a much more muted report about the glove via the Michael J Fox Foundation. Many asked whether I had read the studies, and asked where they could get the glove. Although this was news to me also, because so many have asked, because it generated so much excitement, I have been looking into this and am responding with this short article, despite the fact that I am not a researcher. I just try to keep my eye on PD and will act as a science reporter here.

First, what are we talking about? A Stanford Medicine team led by Peter Tass, MD, PhD, is trialing a “vibrotactile” glove intended to lessen or alleviate motor symptoms caused by Parkinson’s disease (PD). Per the 12/14/2022 Research News article by the Fox Foundation “results from initial pilot studies in roughly a half-dozen participants suggest that it may ease tremors, slowness and stiffness… Participants wore a glove on each hand for several hours per day. The gloves deliver light vibration through the fingertips. Study researchers suggest that this stimulation can ‘reset’ abnormal electrical activity in the brain, which happens in Parkinson’s disease.” I will discuss the pilot studies below.

Before that however, and as interesting a concept as this is, let’s linger for a moment on the point that pilot studies are not adequate to make an assessment of how people will generally respond to some intervention. Pilot studies are typically small and preliminary, meant to see if a device or medication is feasible, and for example, to see if the design should be improved before launching into larger studies. Pilot studies occur before or at the beginning of the typical phase I-IV trials needed for FDA approval. Even if results are remarkable, we need to see how considerably more than a handful of patients will respond before we can make generalizations.

It is also a good idea to take into consideration that the lay press often unintentionally distorts what is being presented, in part because the reporters might not understand the science (or the scientific method in many cases). Much of what has been presented in lay press so far around this topic has been testimonial, not science. A lot of hyperbolic discussion has taken place in these reports: words such as “miraculous” or “transformative” that raise red flags. And, it is often problematic to present incomplete information via the media and generally not a good idea to have media coverage prior to completion of studies.

One more aside. Please don’t mistake my statements about the media reports for a lack of interest in, or a dismissal of this topic. That is not the case. We just don’t have have all of the information yet, even if the videos seem amazing. Looking at this from a different angle, it is also often true that revolutionary innovation is mocked or heckled prior to being understood. That is not my position either. I would guess a lot of big breakthroughs first suffered this way. And, I can only assume it is almost a rite of passage for any genius to first be called crazy. Considering those points, and given that we don’t want to be among those Einstein called “mediocre minds,” it is also a good idea to recall the words of Carl Sagan: “extraordinary claims require extraordinary evidence.” Let’s keep all of that in our thoughts as we evaluate this with our mental toolbox.

The Today Show December 13, 2022 presented clips of Kanwar Bhutani, a 58-year-old man who was diagnosed with PD at age 39. Mr. Bhutani was shown prior to treatment with the glove on a day in 2018. In that scene he was stuck in a doorway with freezing of gait. Per correspondent Jacob Soboroff, Mr. Bhutani had been “bound to a wheelchair and taking twenty-five medications to treat his symptoms. But, after his very first session wearing the gloves for just four hours, Kanwar saw remarkable results.” The monologue is superimposed over a video of the Mr. Bhutani walking upright with a seemingly normal pace and near-normal stride. The subject verified that this was “day one…I was in disbelief…the good news today is I only take two medicines.” Mr. Soboroff then said “You’ve gone from twenty-five to two.”

Point of clarification: It is likely that Mr. Bhutani was taking twenty-five tablets daily, not twenty-five different medicines for PD. And, it is more likely that he is taking “two” different medications with different dosing times, than two tablets daily, but that is only conjecture. The information is not given in the story. Perhaps he was able to reduce medications, but the representation is likely media distortion number one.

Next, there was a clip of Bhutani reportedly finishing the New York City Marathon “just three months after his first treatment.” To this day he was stated to have completed multiple 5K races. Mr. Bhutani said, “It has changed my life, totally transformed me.” It seems remarkable.

On the same Today Show segment a man was shown with “stiff steps”, and in the next clip it appeared the same man was working with gymnasts’ bars. Likewise, another man with a shuffling gait was shown performing “happy dances.” The Today Show stated that 20 patients were involved in the “first round of clinical trials…So far, they say everyone that’s used the gloves has seen some improvement…for Dr. Tass, and the team at Stanford Medicine, they say they’ve had thousands of people already apply for their next trial. They hope to have the gloves approved by the FDA and available for purchase in about two years.”

There is a lot to unpack there. We don’t know for example, whether these patients were examined (and filmed) on or off medications, which would of course make a huge difference for many people with PD. In the “on” state medications are working and movement is better. In the “off” state, medications are not working and movement is worse: stiffness of muscles, slowness of gait, for example. In the case of advanced PD fluctuation of symptoms throughout the day is common, whether or not medications have been taken. If you catch someone in an off fluctuation, they will look much worse than in an “on” state. I’m sure you know that walking is very different from gymnastics or dancing, and it would have been better to show efforts at any activities before and after use of the glove for a one-to-one comparison: here he is walking before the glove, here he is walking in the same location after the glove. There are also are numerous reports of preserved motor function in one task or another despite severe PD gait impairment. In other words, some abilities may be normal, even in a person with advanced disease. In 2010 for example, there was a widely distributed report of a man with severe gait impairment who appeared normal while riding a bicycle. As for the before and after of Mr. Bhutani walking through a doorway versus walking on a straightaway, that is also an uneven comparison. Doorways can be notoriously difficult for PD patients and a prime location for freezing of gait, even when gait may look relatively normal otherwise. Finally, PD is a clinical diagnosis and there can be mimicking conditions. We don’t have any information about these patients on the basis of this news report to know how the diagnosis was made. Certainly, other points could be made, but I will stop here. Suffice it to say, the program was not science, and if anything, leaned a little toward sensationalized reporting. Let’s not get swept up in that. This is not to say there is no science reporting on this topic, or that the efforts of the Dr. Tass team are not legitimate. There will be a little more on that below. I would also say that Stanford is known for cutting edge investigation. Still, a person’s or an institution’s standing alone is not enough. We should still apply all of our tools of critical analysis.

Where did this idea come from? It turns out vibration therapy is not new. French neurologist Jean-Martin Charcot (1825-1893) first reported that vibrations from a train or carriage ride might transiently make patients with PD more comfortable and sleep better. Charcot lectured multiple times about vibration therapy, and even developed an automated vibratory chair (fauteuil trépidant) to simulate the rhythm of train travel. I can say anecdotally that I have many times heard from caregivers or patients that gait has been better in the exam room than they expected after a long drive to my office. Maybe this is the same effect. However, I would also note that data has not been consistent in that area of investigation, and attempts to evaluate vibratory chairs have not always been positive. For example Christopher Goetz’s team at Rush University found no benefit in 2012. There have been many other investigations into vibration therapy, whether focal to a specific part, or whole body therapy.

Some patients have pointed me towards a 2022 Stanford Alumni presentation by Dr. Tass in which he explained the gloves. This was not a scientific, but more of an informational presentation. Nonetheless, he stated that he was relying on medicine, math, physics and “self-organization systems theories” that allow one to understand how complex systems generate order. Per Dr. Tass “the standard self-organization issue problem is synchronization.” Here he refers to synchronization of brain neurons.

I want to interject here to try to simplify this and say that the basic cell of the brain is the neuron. When one neuron “fires”, it sends a message to another neuron. That is the basis of thinking, moving, and feeling in the brain. When two or more neurons fire together, that is synchrony. Sometimes synchrony is good, and sometimes synchrony is bad, depending on several factors. Many diseases are known to have some degree of abnormal synchrony. For example, a seizure is a “hypersynchronous discharge” of multiple neurons. Instead of the back-and-forth communication of millions or billions of neurons, some begin to fire together, disrupting the normal background, and a seizure occurs. You can imagine, other dysfunction might also be possible.

I realize thinking about how brains work is not something most people do. Here is an analogy that might help to understand the synchrony issue. There is a crowded auditorium where you’ve gone to hear someone speak. Pretend the auditorium is the brain, and people inside (including you) are the neurons. Before the start of the evening there is a din of talk, laughter, and other sounds (the normal background activity). There is no obvious synchrony on the level of the floor, or if it is present, it is not overriding. Things change when the speaker walks on stage. First a few, then many, then the whole place begin to clap. That is synchrony. It is fine in short bursts but imagine if it did not stop. That would be a noisy evening and you probably would not be able to hear the speaker (abnormal synchrony). You would want to break up, or de-synchronize (ultimately stopping) the clapping so you could hear the speaker. That is idea.

Dr. Tass notes that where synchronization in the brain is concerned, “too much of it massively impairs brain functioning” because different neurons have to process different types of information. “If everybody does the same thing that’s not good and can cause massive impairment.” Thus, he states “we were able to design stimulation techniques that allow us to move systems from this pathological synchronized state to a better state, to physiological, desynchronized states…desynchronizing stimulation enables us to make networks unlearn the abnormal connectivity and hence make them unlearn to produce abnormal synchrony. ..that’s the core of what we are doing.”

So, why a glove? The fingertips have a huge cortical representation. This means the fingertips are very sensitive, with many, many nerve endings and a large area of the brain is devoted to deciphering information from them. The glove system reportedly uses what is called “coordinated reset,” which “means that if you have a large neuron population you do not stimulate everybody at the same time. What you do is you stimulate at different sites, different times, weakly. These are weak vibratory bursts. …in this way we disrupt synchrony and cause therapeutic effects.”

How does that work? The Stanford group uses vibrotactile coordinated reset (vCR) fingertip stimulation in hopes that it will affect neurons in the sensory cortex and thalamus of the brain, both of which are connected to the basal ganglia. Vibratory stimulation may affect brainwave rhythms which can be detected by EEG as well.

There are multiple scientific papers published in peer-reviewed journals by Dr. Tass and his team going back over several years. This brings us to the above-mentioned pilot studies. In 2021 the team reported on two clinical feasibility studies involving a total of eight patients in the journal Frontiers in Physiology. The article is free and can be read by anyone. If you want to delve into the science of this, to read a great deal more about the proposed mechanism, and observe the study design and results, take a look. The results of these trials were also published in the journal Neural Regeneration Research in July 2022. Briefly, in group one during the acute phase of treatment “five out of six patients showed a clinically significant acute reduction of MDS-UPDRS III scores.” The MDS-UPDRS III is a measure of motor function in PD. After three months of treatment “all patients showed a clinically significant cumulative reduction of MDS-UPDRS III scores.” I would point out that five of the six had only a 4 – 6 point change in the MDS-UPDRS III scores. This is not a big difference on a scale ranging from 0 – 137. In group two “all three patients showed sustained cumulative therapeutic effect as demonstrated by a significant linear decrease of the off medication MDS-UPDRS III scores as well as off medication tremor subscores.” The changes were overall more impressive than group one. Additionally, two of the three patients were able to lower dopaminergic medication use. The data is hopeful, but again, larger studies are needed. Even among this small group of patients the results varied a fair amount.

To summarize, the premise is that groups of neurons in the brain may begin to fire together in a way that is harmful and may cause symptoms of disease, and that is not a new concept. That is part of what deep brain stimulation intervenes upon. However, DBS does not typically improve gait or sense of smell; whereas these reports indicate the glove does. The hope is that by vCR with a glove that causes tiny vibrations in the fingertips, information will be carried to the brain, abnormally synchronized neurons will become desynchronized, and symptoms will improve. These are extraordinary claims, and the videos are compelling, but raise so many questions. It is potentially groundbreaking, but we need more evidence. I will be watching and waiting for publication of the clinical trials. I encourage you to do so also if this is something that interests you. As time goes on perhaps a trail will be available near you. That is what moves science forward.

URLs checked on date of publication, 12/31/2022

Orthostatic hypotension

Orthostatic hypotension (OH) is commonly encountered in Parkinson disease (PD) and in the related condition known as multiple systems atrophy (MSA). OH is the result of blood pressure falling as one stands. That sudden drop in blood pressure is associated with a lightheaded feeling. OH can be mild, occurring rarely with slight swooning, or severe, with frequent symptoms and sometimes passing out completely. Falls, especially when one has passed out and does not reflexively try to break the fall, can of course result in serious injury. When present in PD, OH tends to start with mild symptoms and progress over time. Fortunately for most people with PD, severe OH is not common. Still, minor symptoms are frequent when one has had disease for several years, and it might help to understand what is going on and how to deal with it.

What causes orthostatic hypotension?

Under normal circumstances, there should be little variation in blood pressure between lying down, sitting, and standing. This is because of a complicated system of checks and balances in the body. Blood pressure is regulated by the autonomic nervous system (ANS). Behind the scenes, the ANS is constantly dealing with the effects of gravity, such as when we go from sitting to a standing position, and making subtle changes of which we humans are typically unaware. There are pressure monitors built into the carotid and renal arteries known as baroreceptors which tell the brain our blood pressure at any given time, for example. Through the ANS, the brain can respond by constricting or dilating blood vessels, strengthening contractions of the heart, or changing the pace of the heartbeat, among other measures.

The ANS is divided into two components: The sympathetic nervous system (SNS), and the parasympathetic nervous system (PSNS). The SNS is the “fight or flight” part of the nervous system which causes adrenaline to release, the pulse to quicken, sometimes to the blood pressure to rise if we are suddenly startled. The PSNS is the “rest and digest” part of the nervous system that might slow pulse and shunt blood to the digestive tract after a large meal for example. In the case of PD-associated OH, there is a problem in the ANS. The medulla, at the bottom of the brain stem, is home to many cells of the ANS. The medulla is also one of the earliest parts of the brain in which Lewy bodies, the pathologic hallmark of PD, are found. This gives the disease a long time to affect the medulla, and therefore the ANS.

What can one expect with orthostatic hypotension?

The most common time people notice lightheadedness due to OH is when standing after prolonged sitting, such as a long car ride (or a long wait at the doctor’s office). Factors that might make OH symptoms more likely include dehydration, anemia, diuretics (fluid pills), blood pressure medications, neuropathy (nerve damage), or the consumption of large meals. If one eats a large meal the PSNS will initiate “rest and digest,” with a drop in blood pressure as a large volume of blood tends to go to the GI tract to aid in the digestion of food. Thus, the larger the meal you eat, the more likely you are to have OH symptoms.

Another common time for OH symptoms is when first getting out of bed in the morning. At this time people tend to be slightly dehydrated, and going from lying down to standing is an even greater challenge than from sitting to standing. Sometimes, just bending over or squatting to pick something up can be enough to trigger OH on the way back to upright posture. Finally, some people report OH symptoms during exercise. This is in part due to dehydration, but can also be due to a general difficulty with the ANS in controlling heart rate and appropriate blood pressure needed to carry out exercise. A high volume of blood is needed in the muscles to exercise. And, capillaries in the skin dilate when we exercise. This carries blood to the surface to aid in cooling the body down. Both of these actions lower the volume of blood available to the brain in order to maintain a normal level of consciousness. Even well-conditioned athletes sometimes feel dizzy during strenuous exercise. None of this is to say that one should not exercise; rather, the opposite is true (see below).

How does a doctor test for orthostatic hypotension?

If you have described the symptoms of orthostatic hypotension to your doctor they may want to measure your blood pressure while lying down, and then while standing at timed intervals. This will give information about whether or not your blood pressure drops inappropriately, or your pulse quickens beyond a normal rate. Your doctor may also screen for signs or symptoms of neuropathy. A blood test to evaluate you for anemia or some other issues might be necessary as well.

Are there general recommendations for people who have orthostatic hypotension?

If you have OH, you should go over your medication list with your doctor try to determine whether you absolutely need medications that might exacerbate symptoms, or whether you might take a smaller dose. Blood pressure medications are frequently lowered or stopped in this setting. Some mood medications might exacerbate OH as well. Unfortunately, some PD medications might also be contributory. Smaller, more frequent doses of medication are generally used in that case.

It is probably a good idea to raise the head of your bed by about 5-6 inches (or use extra pillows) to keep your head up when sleeping at night. This might actually decrease nighttime bathroom trips, and therefore the dehydration which some patients experience first thing in the morning.

When waking in the morning, one should practice caution when first standing. I typically advise people to sit on the edge of the bed in the morning and make sure they are symptom-free before standing. A glass of water at the bedside placed there the night before could be consumed at that point. One might pump the legs on the floor, pushing down with the ball of the foot a few times to get blood flowing in the legs before standing. When standing, rise slowly, and make sure you feel no symptoms before starting to walk. A similar strategy should be used after prolonged sitting. If you stand and feel lightheaded, sit back down and repeat. Sometimes tightening the fists and flexing the ankles might also help to raise the blood pressure just a bit. Some authors have suggested using other counter maneuvers, such as tiptoeing, leg crossing, bending forward, or squatting to improve blood pressure, though the efficacy of these interventions is somewhat controversial.

A person with OH should take particular care not to rise from a seated position and speed across the room. I have many times heard from patients who have fainted several steps away from a chair or couch.

Compression stockings are sometimes worn. These might be helpful, but are expensive and difficult to put on and take off.

When standing for prolonged period of time, try to shift positions.

Regular aerobic exercise is helpful, just make sure to “exercise smart.” Make sure you stay hydrated when exercising.

With meals, a good strategy is smaller amounts eaten more frequently than the traditional three meals daily. And, eat a healthy diet. Do not eat excessive carbohydrates, and do not eat meals that are very difficult to digest, such as very high fat foods or large portions of red meat. If you are able to tolerate table salt, then it is often recommended. Those with heart or kidney disease should check with their doctors. If it is tolerated, another way to get salt would be through certain beverages such as sports drinks with electrolytes.

Water is a very good thing, and you should stay hydrated (footnote). Some patients have limitations because they have heart or kidney disease as well, and should check with their doctors.

Some doctors recommend the avoidance of coffee because of the diuretic effect. I think as long as there is an adequate volume of liquid consumed, and not an over-consumption of caffeine, coffee tends not to have a significant effect on the symptoms of OH. The same may be said of the small volumes of alcohol.

Are there medications to treat orthostatic hypotension?

Your doctor might prescribe medication such as midodrine, fludrocortisone, or droxidopa, depending upon the severity of your symptoms, and other considerations such as your underlying health and prescription drug list. If taking one of these medications, there is a risk of supine hypertension, an elevation of blood pressure when lying flat. This tends to occur for the first five or so hours after a dose of medication, and if a nap must be taken during that time, the head should be kept elevated at least 15 degrees. Fludrocortisone is sometimes associated with lower levels of calcium in the blood, swelling of the feet, and exacerbation of congestive heart failure. Midodrine is sometimes associated with tingling of the limbs, itching, and piloerection (the bristling of hairs). Droxidopa (Northera) is sometimes associated with elevated temperature, confusion, exacerbation of ischemic heart disease, abnormal heart rhythms, or congestive heart failure. A variety of other medications have been used in attempts to treat OH. One of the more common ones is pyridostigmine (Mestinon). The drug is sometimes associated with abdominal discomfort, nausea, and drooling.

In summary

If you feel lightheaded when you stand up, you might have orthostatic hypotension. Check with your doctor if you think that you do, and take care not fall.

Footnote: Hydration is very important, and I take that to heart myself. In fact, over 70% of my body is water.

Gastroparesis in PD

Periodically I will hear from a patient about excess bloating. They are not alone. The gastrointestinal (GI) system is involved to some degree in over 90% of patients with Parkinson disease (PD), which has been discussed here in MPDN. (1-3) GI issues may affect drug absorption, PD motor symptoms, and quality of life. Before we get started with the problems, let’s take a moment for the sake of terminology, to know that doctors tend to divide the GI system as follows: upper GI: mouth to stomach, and lower GI: small intestine to rectum. The GI tract is controlled to some degree by nerve centers in the brainstem dorsal motor nucleus (DMN) via the vagus nerve “the wanderer.” There is also an enteric nervous system (ENS), which some refer to as “the second brain,” consisting of about 100 million neurons. If that sounds like a lot, consider a healthy adult brain, which is estimated to be made up of 80-100 billion neurons (and many, many more glial cells).

Why are there GI issues in PD?

That is a big topic, too big to cover in depth here. The issues are likely multifactorial. Alpha-synuclein aggregation in neurons of the gut and the DMN, and issues with the gut-brain axis are big factors. For more on those issues, read articles 1 and 4 in the references below.

Let’s talk about the stomach

The stomach is a single chamber, which is functionally considered in three regions: the proximal stomach, the distal stomach, and the pylorus. These regions operate in unison to maintain normal gastric emptying. The stomach must also maintain intragastric pressure in order to allow continued meal ingestion until satiation. In other words, the stomach contains the food you have eaten so that you can eat until you feel appropriately satisfied. There are many variations on that theme however, which may in part explain some under-, and overweight individuals. Whatever the case, in normal circumstances after a meal, strong contractile pulses in the distal stomach break up food particles. This allows the stomach to empty into the first part of the small intestine. But emptying of the stomach may not occur on time.

Delayed gastric emptying affects 70% of PD patients at some point. If the problem becomes chronic and symptomatic doctors refer to it as “gastroparesis.” The symptoms of gastroparesis include nausea, vomiting, retching, early satiety, bloating, loss of appetite, and abdominal discomfort. Longer PD duration is not associated with worse gastroparesis as you might expect. However, advancing motor severity (the stiffness, slowness, and tremors of PD) does correlate with worse gastric emptying delay. This is largely to do with where L-dopa (levodopa) is absorbed: the small intestine. Obviously, if the drug cannot get there, it cannot be absorbed. Gastric emptying speed is therefore the rate-limiting step in the absorption of L-dopa. Because of these drug absorption problems, gastroparesis contributes to drug response fluctuations. This means some doses of L-dopa might be delayed in working, work only partially, abruptly stop working at an unpredictable time, or not work at all. (5,6)

Is there a treatment for gastroparesis in PD?

Some doctors attempt to use the dopamine receptor antagonist metoclopramide (Reglan). This drug does help empty the stomach, but has the unfortunate function of blocking dopamine receptors in the brain. This not only prevents dopamine from doing its job, but can cause severe PD symptoms. While metoclopramide is the mainstay of treatment for gastroparesis in the general population, there is the potential for so-called extrapyramidal side effects such as “parkinsonism.” In people with PD or parkinsonism, metoclopramide is not suitable for long-term use. I tend to use this drug very rarely in my practice.

Domperidone is not FDA-approved for any indication in the United States, but is in trials (7), and is used by U.S. movement disorder and gastroenterology doctors nonetheless (usually via compounding pharmacies). In the U.S., compounding domperidone is an expensive proposition. Because the drug is available in Canada (and many other countries), it can be purchased much less expensively over the internet (usually from Canada). However you get it, Medicare and most insurance companies will not pay for it due to the above lack of an indication per the FDA. In terms of how it works, and whether it might affect parkinsonism, domperidone does not cross the blood brain barrier, has been shown to enhance gastric emptying, and to enhance L-dopa bioavailability (allowing L-dopa to function). It is the drug of choice for delayed gastric emptying in PD in essentially the rest of the world.

Macrolide antibiotics (such as erythromycin) are sometimes used for short periods of time (antimicrobial properties, i.e., action against bacteria, limit its long-term use). These drugs enhance gastric emptying and are effective in gastroparesis.

It should be noted that a small number of patients with gastric complaints will be colonized with the bacteria Helicobactor pylori. This microbe is also known to be a culprit in gastric ulcer formation. Among PD patients evidence of H. pylori colonization is associated with motor fluctuations. And, after H. pylori eradication, L-dopa absorption and motor fluctuations can be improved. (8,9)

If you think you might have delayed gastric emptying or gastroparesis, talk with your doctor. Severe symptoms might require a gastroenterology consultation. Very mild symptoms might be due to some other factor, or respond to minor medication changes.

References

What is the Gut-Brain Axis? Maine PD News, April 2017. https://mainepdnews.org/2017/04/17/what-is-the-gut-brain-axis/
Constipation in PD. Maine PD News, June 2016. https://mainepdnews.org/2016/06/12/constipation-in-pd/
PD and diet. Maine PD News, January 2017. https://mainepdnews.org/2017/01/11/pd-and-diet/
What’s so bad about alpha-synuclein? Maine PD News. April 2016. https://mainepdnews.org/2016/04/25/whats-so-bad-about-alpha-synuclein/
Doi H, Sakakibara R, Sato M, et al. Plasma levodopa peak delay and impaired gastric emptying in Parkinson’s disease. J Neurol Sci 2012;319:86-88.
Muller T, Erdmann C, Bremen D, et al. Impact of gastric emptying on levodopa pharmacokinetics in Parkinson disease patients. Clin Neuropharmacol 2006;29:61-67.
Pipeline drugs, part 2: gastric emptying agents. Maine PD News. June 2018. https://mainepdnews.org/2018/06/21/pipeline-drugs-part-2-gastric-emptying-agents/
Lee WY, Yoon WT, Shin HY, Jeon SH, Rhee P-L. Helicobacter pylori infection and motor fluctuations in patients with Parkinson’s disease. Mov Disord 2008;23:1696-1700.
Pierantozzi M, Pietroiusti A, Brusa L, et al. Helicobacter pylori eradication and l-dopa absorption in patients with PD and motor fluctuations. Neurology 2006;66:1824-1829.

Getting the most out of seeing your neurologist

Whether you are a first time neurology patient or recurrent visitor to a movement disorders specialist, it would help to take a few minutes to think about your history so that you and your doctor can make the most of your visit. It is important to us that you feel understood, and likely important to you too, that that we learn as much as possible about your symptoms. Because we do this all the time, and are very familiar with these neurologic problems, neurologists have some insight into how to have this conversation. This article is a sort of a guide to what to do, and what not to do.

First, let’s clear up the idea that doctors are talking to each other on computers, or that doctors can see everything on other computers at other offices.

We are not, though when we ask about history, we are often told, “it should be in the computer,” or “in Dr. So-and-so’s chart.” If this is your first time seeing a neurologist, you shouldn’t assume your new doctor can see your referring doctor’s chart in a computer. We usually cannot for reasons given below. Most of the time the records must be sent from one office to another, and it is a task choosing what to send, and literally a task for someone in the referring office to send those files. You may think this is all squared away because your doctor made the referral. But, don’t assume that records from referring doctors have actually arrived and that the new doctor knows the medical facts of your case. That might also be a problem. Let’s walk through how this works in 2019.

A neurologist is consulted by another doctor. This means that other doctor has asked for help. But, the communication is not always clear. In spite of the fact that we have moved into the age of electronic medical records (EMR) on the dreaded computer (frankly how a lot of us feel about it), we are not all connected.

Due to legal and technical issues often the consultant has not been sent anything through a computer.

Instead, they have been faxed a few pieces of demographic information about who you are, where you live, what your insurance is, and hopefully the question being asked. Sometimes there are a few office notes. Amazingly, the reason for consult is not always included (though Medicare and insurance carriers usually require this information). This issue slows down time for getting an appointment. There are also a huge variety of formats for the forms sent. Sometimes the consultant cannot find needed information because it is buried on page five (or page 50 for that matter). Sometimes the name of the person has been altered to protect identity. Great, but who is this? Sometimes the computer coding is so heavy that a practically unreadable document is sent. Sometimes a copy of a copy is faxed and all abnormal (and therefore highlighted) lab values have become illegible.

A lot of this has to do with huge changes in medicine over the last couple decades, resulting in a clunky system that is far from perfect. We are required to use computers, and under Medicare guidelines can actually be fined for not using them. Still, we are unable to communicate as easily as you might think. Many different software vendors employ armies of information technology people who write complex software that results in systems that don’t talk and are not easy to learn. Most doctors recoil at the phrase “mandatory computer training.” Aside from the steep learning curve, software changes all the time, meaning two things: you’ve gotta keep up (who has the time?), and there will be unintended consequences of software upgrades, which some of us call “downgrades.” And, seemingly well-intentioned laws are not so easy to navigate.

Under Federal HIPAA law, your medical history is protected, and unless you have signed a release of information, it will not be available. HIPAA is a big reason why computers at different offices or organizations are almost never connected.

Even if you have signed a release, your records may be incomplete.

Your referring doctor might think you have Parkinson disease (PD), yet the records that arrive at the neurology office may be incomplete to the point of little or no supporting documentation about the signs or symptoms (this is often unintentional). The consulting neurologist wants to know what the other doctor has seen to lead to this consultation. Another scenario is that your referring doctor might have requested a second opinion. In that case, sometimes the notes that arrive do not include the first neurologist’s evaluation. These examples are problems on many levels. Consider these actual examples I have seen in referrals for which I was sent no records (and was therefore unaware) of a dangerous reaction to a medication, a critical lab value, or a brain aneurysm. I would recommend that you make sure the notes from your prior neurologist are sent to the consultant’s office to avoid a counterproductive and potentially dangerous situation.

There is also a simple fact of modern healthcare that time is limited.

Doctors see a lot more patients in a day than they used to, and are often unable to complete all of the notes, paperwork, etc., that piles up each day. An appointment without records will probably waste at least some of the appointment, and might result in a second “get to know you” visit in the future. No one thinks that is ideal. Consider it this way: you’ve waited weeks or months for an appointment only to find the doctor has no idea about your complex history, and can’t do much to help until they do. When is that next appointment going to be open?

Brain imaging (MRI, CT)

Brain images are not always necessary in PD, but sometimes are ordered when there is a question about some other cause of your symptoms. MRI of the brain is a very complex test which takes hundreds of images. To a neurologist this a way to see the anatomy and take into account many different factors. But, the way we see these films has changed. In the “old days” before computers were everywhere in medicine, images were on film, often transported by the patient if going from one institution to another. These days brain images are stored as huge digital files with hundreds of images too big to “send” over the internet. If your images are from another hospital or network, they are probably not “on the computer” at the new doctor’s office. The images are almost never sent by referring doctors for a variety of reason, firstly, they don’t have them. Referring doctors are not usually neurologists or radiologists, and often haven’t seen the images. Many referring doctors rely on radiology to read the films and give a report. They will then tell the patient something about the study, and the patient will tell the neurologist about that conversation. However, “I was told it was fine” just will not do.

Sometimes the radiology report is faxed with the referral. That is helpful, but neurologists usually want to see the images. Your brain anatomy is highly unique and may tell a neurologist a great deal about you. A good plan is for you to call the film library at your hospital or radiology department and get the images on a computer disc to bring to your appointment. Otherwise, waiting to see the images at the next visit slows your care down and leaves your doctor with an incomplete understanding of you and your workup.

Here I should mention that I have met a few patients who have intentionally tried to get a “fresh start” with no prior records. It is not a good idea. If anything, intentionally withholding prior records is a red flag to doctors. Both sides need to be completely open and honest. Give your new doctor a chance to read why the prior one came to the conclusion they did, even if you disagree.

Even when records have been forwarded, they may not tell the complete story. This is why it is very helpful to think about your PD history and come prepared to answer questions about it. Interview styles vary, but in my own practice when first meeting a patient, I will typically ask dozens of “closed-ended” questions which can be answered with a single, or just a few words. I can learn a lot quickly this way. So, be succinct. For example, if I ask what year the tremor started, the answer should be something like “1995.” The answer should not be expansive or tangential, such as this response in which names and details have been changed to illustrate a point:

“Let’s see, I was visiting my cousin Ed. I do every spring. He has an apple orchard up in Camden. We were going to walk around the property, and take in the sunset. It’s beautiful up there. Anyway, later that day after we had been all around the place and eaten dinner, I was drinking coffee. Ed makes good coffee. I don’t usually like it, but his is so good. Ed asked me if I wanted another and I said “no,” because I don’t usually drink it, and especially not that late. Then Ed said he had been reading on the internet about tremors. Then he said he had been noticing some shaking with me. We both first thought it was something else. Of course, it could have been the coffee, but then I haven’t had coffee today, and I’m shaking. And, it’s getting worse, so, probably not the coffee. After Ed I went to my doctor and first he thought it was essential tremor. But then I started reading on the internet myself…” and so on.

After that paragraph we still do not know the answer to the question of what year the tremor started (though Ed’s place sounds nice). Mainers tell me this is the “all the way around barn” approach to answering a question. I am probably not going to make it through my dozens of other questions if the responses keep up like this. I would advise patients to listen to the question being asked and answer it, only it, one question at a time.

When taking a history, a neurologist is looking for a timeline of specific details from your past in order to piece together your case in a way that leads them back to the proper diagnosis and an understanding of the progression of your illness. In the case of PD there are several illnesses or drug exposures that might be mimics, and one of the things neurologists who interview patients is trying to do is eliminate those other items by asking focused questions.

Like a detective, a meeting with a neurologist sometimes feels like less of a conversation than an interrogation. But there are good reasons for this.

I would recommend you not try to direct the conversation, but simply let the neurologist ask the questions they need to cover. If something is left out, then let them know at the end. In your own best interest, you should prepare and come armed with lots of information about your own history. I have included a form with this article which covers most of the things we will ask about. Please fill out the form, it will help a lot.

For your consult, you should specifically think about what year your first symptoms started, and what those symptoms were, for example: loss of sense of smell, constipation, REM behavior disorder (acting out vivid dreams in the night, thrashing in your sleep, screaming), tremor, stiffness of muscles, slowness of movement, changes in the way you walk, balance problems, falls, soft speech, memory issues, mood issues, what studies were done. If you have had gene testing or other unusual labs, bring the results. Three labs neurologists usually want to know about in PD are vitamins B6, B12, and D. Other labs we commonly might want to see include CMP, CBC, ESR, A1C, TSH.

Make a list of medications and doses of those medications you have tried for PD.

Write down any side effects you may have had with medications. Think about how the symptoms of your disease changed over time. If we established for example, that your hand tremor started in 1995, arrange your disease as it progressed over time, such as this: “It slowly worsened and my handwriting changed in 1996 or so. In 1998 my left hand started to shake and the same year I noticed shuffling when I walked.”

Also think about your family history.

If others in your family have had PD or something like it, ask them about it, and make a list of those family members along with any known diagnosis.

Who should be present at my consult or office visits?

I try whenever possible to collect history directly from the patient. Sometimes, especially if one has memory problems, it is helpful to have someone else present who can give a focused history. Someone else does not mean everyone else however. It is generally a very good idea to limit the number of other people present in the room at the time of a neurology visit, as it is difficult to get a clear history from multiple sources. Also, if you bring someone else, be consistent. Bringing a different friend or family member to every appointment creates a lack of continuity, and typically consumes a lot of the appointment time in order to bring the new person up to speed, or go over history that has already been covered. That is usually not helpful for the patient and is often counterproductive.

So that your neurologist can spend the entire visit with you, arrive on time.

It seems obvious, but every day in my clinic one or more patients will arrive late. Sometimes late patients cannot be seen. In my office, new patient consults are asked to arrive 15 minutes early for the first visit. This time is important for the staff to make sure certain records are correct, go over medications, check vital signs, and so on. However, a significant number of patients ignore this request, and that is not helpful.

If you have a follow-up visit, and there is some new issue, a change of some kind, or specific questions, let your doctor know at the beginning of the appointment. Urgent issues should be discussed first. Don’t wait until the end of the appointment to mention you were recently in the emergency room, for example.

Do not change, stop, or start PD medications without your neurologist.

Call if there is a problem.

Phone calls

Most offices have a medication refill line and a nurse triage line. Triage is for urgent issues. Routine questions should be addressed at follow up, not the phone. But, if you are not sure how serious something is, it is better to run it by a nurse. Neurology nurses tend to have a very good idea of what is important and what is not. That is what is triage is all about. There is also a neurologist on-call all the time. If your doctor is on-call they are probably busy tending to hospital or emergency room patients. After-hours issues in PD rarely warrant paging a doctor. Medical emergencies should of course be directed to 911.

I hope this helps.

New Parkinson disease patient checklist Download

Thanks to Grace Plummer, LCSW, Sarah Savard, RN, and Liz Stamey, RN, LMT for review and commentary.

The secret life of dopamine

This fall I gave a pair of talks, one in Brewer, and another in Brunswick. What follows is a summary of that information, or at least the heart of those discussions, which essentially amounted to a review of frequently asked questions on the topic of dopamine (DA). I think understanding DA, and its pharmaceutical friend levodopa a little better might help people with Parkinson disease (PD) understand how the disease becomes a problem, and how and why certain medication regimens are needed. I also hope this information sheds a little more light on the issue of why you should not adjust meds on your own, a topic I covered in the spring 2016 issue of MPDN (1). Please read that article if you are a medication “self-adjustor.”

The issue of medication self-adjustment comes up almost daily in my office, and should not be ignored because these medications can have good and bad results, depending on how they are used.

I should also note that this article might not be for everyone. It requires some small consideration of brain biochemistry, of study data, and numbers. I will walk you through it, but some people will not want to do that sort of mental heavy lifting, and don’t use math as a language to describe nature. If you are among them, and don’t want to read this article, I will give you this pearl:

Levodopa is a tool, and should be used properly. If it is not abused, it is less likely to be a problem. However, it does affect the brain, and should only be adjusted by a doctor, and even then might not be well tolerated. Also, like any drug, if taken improperly, it is likely to lead to problems.

To understand these issues, you should know that one of the key factors in PD is a deficiency of DA in the brain. DA is used for many purposes, and when it runs low people may experience increased muscle tone (rigidity) and/or unwanted movements such as tremors. This might seem obvious today, but it was not until the 1960s that scientists confirmed DA was depleted in PD. After learning this fact, the first logical step in attempting to help was to give people with PD DA. Giving DA by mouth was often unsuccessful because it caused nausea. Because of this side effect, doctors attempted to give anti-nausea drugs, and this caused another problem. Anti-nausea drugs usually block DA receptors in the brain, including the ones that DA is meant to target (footnote #1). Giving drugs that act against each other was, and is, generally not a good idea. And, because of this blocking effect, to get enough DA to the brain researchers would sometimes give what seem today like very high doses of DA. Within a couple of years, patients exposed to these high doses began to show significant advances in their parkinsonism, which led many to ask whether DA was toxic. It also meant finding another way to replace DA in the brain.

Scientists had learned some key points that were helpful in taking next steps. Under normal circumstances DA is produced in the brain. The building blocks of DA come from certain foods rich in proteins. Eating those foods allows us to break the proteins down into smaller components called amino acids. Our bodies recycle amino acids to make other proteins and neurotransmitters like DA. One specific amino acid we get from eating proteins is tyrosine. In the brain, tyrosine is converted into L-dopa, and L-dopa into DA. Giving tyrosine alone did not help, and this further supported the idea that it was a breakdown in the production of DA that caused the deficiency.

Under normal circumstances DA formation takes place in the midbrain (a part of the brainstem). Specifically, DA is made in the midbrain’s substantia nigra, or “dark substance.” It had been known since the 1950s that this dark substance was missing or depleted in people with PD; thus, researchers would learn this meant DA could not be formed.

In 1967 it was found that L-dopa could also improve parkinsonian symptoms because it could be easily converted by the brain into DA. Some people use the terms L-dopa and levodopa interchangeably. Levodopa is the international non-proprietary drug (generic) name of L-dopa.

The finding that levodopa helped PD symptoms was an important breakthrough. However, the drug still might cause nausea in some patients because when it is taken by mouth it has to leave the GI tract and enter the bloodstream, where it will pass through the liver. The liver contains an enzyme which can break levodopa down into DA, bringing us back to the nausea issue. To fix that problem, the specific enzyme was identified, and a drug designed to block it: carbidopa. It followed that carbidopa/levodopa was trialed in people.

Carbidopa/levodopa was a revolutionary drug, which enabled people to live without some of the severe parkinsonian motor symptoms. And, patients began to describe a phenomenon known as “ON” versus “OFF.”

When a person feels ON there is a decrease or absence of some or all motor and nonmotor signs and symptoms of PD, such as tremor, stiffness, slowness, low energy, fatigue, and soft speech. When a person is OFF, the signs or symptoms return.

Before levodopa, PD patients would slowly and progressively develop the signs and symptoms of disease. Many would become bed-, or wheelchair-bound, and succumb to the effects of wasting, deconditioning, clots in immobile limbs, infections, pneumonia, and so on. There were wards in some hospitals dedicated to the long term care of these unfortunate patients.

At first, doctors did not know how to titrate the drug. And, in those early days of the levodopa era, very large doses were routinely given. It seemed appropriate to treat until symptoms were completely controlled. There were also many advanced patients, treated with dopamine for the first time, who seemed to require high doses. Just as had happened with DA treatment, it did not take long for disease to seemingly progress, for levodopa to lose efficacy, and for scientists, patients, and doctors to question whether or not the drug might be at fault. This question has never been fully eradicated from the literature, though many attempts have been made to settle the issue.

Several retrospective analyses have compared death and disability before and after the levodopa era (2-5). In short, when numerous sources of data were pulled together it was found that before the levodopa era, in the first five years of disease over 25% of PD patients developed severe disability or died; whereas these devastating results occurred in less than 10% after the introduction of levodopa. The numbers over time are even more telling. With PD present up to 10 years death or severe disability was seen in over 60% of patients in the pre-levodopa era, and about 20% after. By 15 years, over 80% of the pre-levodopa era patients were either severely disabled or dead; and under 40% after. The bottom line is that life spans generally normalized, or at least become significantly prolonged after levodopa was introduced as a treatment because people had fewer and less severe complications of PD.

Still, it was reported in the levodopa era that after about 5 years of treatment with levodopa up to 50% of patients developed what are known as motor fluctuations, meaning that function might not be so predictable or that medications might wear off too soon (6). This end of dose wearing off phenomenon began to occur in 70% or more patients after 15 years of treatment, as did unpredictable fluctuations and dyskinesias (involuntary twisting-turning movements which are not tremors). It was not clear at this time however, whether this was all due to progression of disease or levodopa. Confusing matters, doctors began to use the term “levodopa-induced dyskinesias.” It is true that virtually any person with PD will have dyskinesia temporarily if given too high a dose of levodopa.

It is not clear whether levodopa over the long term causes dyskinesia. It seems more likely the answer is that levodopa doesn’t, though there might be some exceptions, and more than a few caveats. The issue is complicated.

Over the course of disease with PD as less DA is produced in the brain, more levodopa is needed. Levodopa is converted to DA and stored in a part of the brain called the basal ganglia. Early in disease the basal ganglia is able to store the large amount of DA the brainstem is able to produce. In this case, a person will usually take relatively low and infrequent doses to make up for a small deficit. A little goes a long way. However, over time less DA is produced in the brain and the basal ganglia is less able to store as much because of the progression of the disease itself. People with PD lose those cells that store DA in the basal ganglia. It could be thought of like a car that starts out with a large gas tank. In this car analogy, the gas tank is slowly shrinking. A car with a smaller gas tank has to make more frequent stops at gas stations to avoid running out of gas and shutting off. By the same analogy, a PD patient with a smaller basal ganglia storage has to take more frequent doses of levodopa. This means ON time is shorter.

Unfortunately, as disease progression goes forward, the threshold at which dyskinesia occurs becomes lower also. This means that a person can no longer tolerate large doses of DA without experiencing involuntary movements. When disease advances, taking smaller and more frequent doses of levodopa is one strategy for avoiding or minimizing dyskinesias and OFF time. Even with the best of treatment though, by the time of advanced disease many patients will have dyskinesia whenever they are ON. The key is in minimizing the severity of dyskinesia and other issues.

Because of the advent of dyskinesias in treated patients, since at least the 1980s major thought leaders in PD have debated about whether levodopa could safely be started early or late in the course of the disease (7,8). After all, most of the time dyskinesias only occur in treated patients in the ON state. This might lead one to conclude that it is the medication causing the problem. Several studies suggested that dyskinesias could be predicted by high daily levodopa dose and longer duration of levodopa treatment. Delaying the initiation of levodopa was thought by many to be the best therapeutic strategy to prevent motor fluctuations and dyskinesias. Thus, the term “levodopa phobia” was coined, to refer to neurologists and patients who withheld the introduction of adequate levodopa therapy as long as possible (9). And, in the 1980s other medications such as DA agonists were developed, which were able to stave off some of the motor symptoms of disease. However, this class of drugs is not always tolerated in doses that would be needed to reach the same efficacy as levodopa.

In the 1990s researchers set out to settle the issue as to whether levodopa alters the natural history of PD, or whether levodopa hastens the loss of brain cells (neurodegeneration) in the ELLDOPA (Earlier vs. Later LevoDOPA in PD) trial (10,11). This was a randomized, double-blind, placebo-controlled, parallel group, multi-center trial at 33 sites in U.S. and 5 sites in Canada. The study was designed to include 360 early, mild PD patients who had not previously required levodopa treatment, but were symptomatically ready to try medication. Patients were placed in different groups of three times daily dosing of: placebo, levodopa 50mg, levodopa 100mg, levodopa 150mg, and levodopa 200mg. The primary outcome variable measured was a change in total Unified Parkinson disease Rating Scale (UPDRS) scores from baseline to 40 weeks after randomization, and after 14 days washout from meds (to see if there was a persistent effect) (footnote #2). Patients who took higher doses of levodopa showed the most improvement in motor scores. Some of that data Is summarized here.

3 x daily dose dyskinesia (%) wearing off (%)

Placebo (3.3) (13.3)

50 (3.3) (16.3)

100 (2.3) (18.2)

200 (16.5) (29.7)

The table shows that the 200mg three times daily group had the highest rate of dyskinesia (at least five times as much as the other groups), and considerably more wearing off at the end of the study. It would seem that early in disease 200mg three times daily might be too high and associated with earlier motor complications. However, it is also interesting to note that even the placebo group had some degree of dyskinesia, evidence that dyskinesia is part of the disease-though it can be exacerbated by medications (footnote #3). A key insight from the ELLDOPA trial is that it is difficult to determine when an early dose of a drug such as levodopa is too high. It takes a great deal of investigation to detect these nuanced issues.

Later, the CALM-PD trial followed long term use of DA agonists (12). Post-hoc analysis of this trial showed that the onset of dyskinesias was an expected complication of disease that was independent of when levodopa was started.

Other authors have suggested that cumulative levodopa dose (how much a person has taken in their life) may be an independent predictor of dyskinesias in patients with PD (13). This line of reasoning has led many to believe they should delay starting levodopa, or that there is a “shelf-life” for taking levodopa. They seem to believe there is a set number of years they can take levodopa before it “stops working.” However, evidence favors starting levodopa when it is needed, though avoiding a too much, too soon approach. Observations and trials such as the above-mentioned ELLDOPA study have shown that high doses of levodopa early in disease can result in early appearance of dyskinesia and possible irreversible advance of disease. One of the problems with proving it is not the drug itself, but high doses of the drug, is that it would be unethical to design a study to test this idea in people. However, in PD model rats treated with higher levodopa doses for short periods dyskinesias developed earlier than in rats treated chronically with lower doses, although the lower daily dose rats ultimately were given higher cumulative doses (14). At least in rats, the cumulative dose hypothesis does not seem to fit and when levodopa therapy was started did not change the risk of motor complications.

Finally, in 2014 Italian researchers set out again to determine if starting levodopa early in disease had an effect on progression of PD (15). Investigators went to Ghana, Africa, where they found 59 PD patients who for a variety of reasons had never tried levodopa, and an additional 32 patients who took low doses of the drug. These patients were matched by age, sex, and disease duration with groups of Italians (2282, only 50 of whom had never tried levodopa). Patients were followed over several years. In both groups the average time it took for patients to develop medication failure was 5-6 years. The average time to develop dyskinesia was 6-7 years. The only group with early medication failure or dyskinesia were those who took high daily doses of levodopa. Duration of time one had taken levodopa was not a risk factor. However, duration of disease itself was a risk factor, as one would expect if these complications are also simply features of the disease.

As if to illustrate these points, one patient with advanced PD of several years had dyskinesias with the first ever dose of levodopa.

In summary, levodopa is the strongest, most effective drug available for the motor symptoms of PD. It is a tool, and must be used properly. If you have made it to the end of this article and are still a medication self-adjuster, you should know that the understanding of that proper use is complex, and not something that should be taken for granted. And, you should know that there is much more to the story, not discussed here. The science of brain DA and levodopa in PD are not easy data sets to follow. I cannot stress enough that medication adjustment is something best left in the hands of the specialist. Thus, as complicated as this article might seem, it only touches the surface of the secret life of dopamine.

Footnotes:

This is a bit of biochemistry and cell biology, but DA is sort of like a key, and the DA receptor is sort of like an ignition: one fits specifically into the other and has an activating effect. It is one way brain cells communicate with each other, or get each other to do something, such as move a muscle in the body. There are many different receptors in the brain that respond to specific neurotransmitters such as DA. Another tricky detail is that there are subtypes of the DA receptor in different parts of the brain. Each has a different set of functions.
It was discovered in post-hoc analysis of this trial that a full washout would take 28 days.
In fact, dyskinesia can be seen with DA agonists of enzyme blockers used to treat PD. Levodopa does not have to be involved. And, when patients have deep brain stimulation the device itself may trigger dyskinesia.

REFERENCES

Should you adjust your own Parkinson’s meds? Spring 2016, MPDN
Poewe WH et al. Neurology. 1996;47(suppl 3):S146-S152.
Hoehn MM, Yahr MD. Neurology. 1967;17:427-442.
Hoehn MMM. J Neural Transm Suppl. 1983;19:253-264.
Diamond SG et al. Ann Neurol. 1987;22:8-12.
Lang & Lozano. N Engl J Med. 1998;339:1130-1143.
Fahn S. Parkinson disease, the effect of levodopa, and the ELLDOPA trial. Arch Neurol 1999; 56: 529–35.
Fahn S. A new look at levodopa based on the ELLDOPA study. J Neural Transm 2006; 70 (Suppl): 419–26.
Kurlan R. “Levodopa phobia”: a new iatrogenic cause of disability in Parkinson disease. Neurology 2005; 64: 923–4.
Fahn S. Parkinson disease, the effect of levodopa, and the ELLDOPA trial. Earlier vs Later L-DOPA Arch Neurol. 1999;56:529-535.
Parkinson Study Group. Levodopa and the progression of Parkinson’s disease. N Engl J Med. 2004;351:2498-2508.
Constantinescu, et al. CALM-PD Investigatorsof the Parkinson Study Group, Impact of pramipexole on the onset of levodopa-related dyskinesias. Mov Disord 2007; 22: 1317–9.
Hauser, et al. Factors associated with the development of motor fluctuations and dyskinesias in Parkinson disease. Arch Neurol 2006; 63: 1756–60
Tsironis, et al. The course of dyskinesia induction by different treatment schedules of levodopa in Parkinsonian rats: is continuous DArgic stimulation necessary? Mov Disord 2008; 23: 950–7.
Cilia, et al. The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain. 2014;137(Pt 10):2731-42

Inhaled levodopa (Inbrija) approved by the FDA.

The FDA has approved inhaled levodopa (Inbrija), indicated for the intermittent treatment of OFF episodes in patients with Parkinson’s disease who are treated with carbidopa/levodopa. Inbrija is therefore a “rescue drug,” not meant to replace oral levodopa, but to be given when it is failing. Acorda Therapeutics, who owns the patent to this drug, projects Inbrija will be on pharmacy shelves in the first quarter of 2019. As yet, the cost of Inbrija is not being disclosed. For a summary of the study data leading to approval, see the Spring MPDN article “Pipeline drugs, part I: levodopa.”

Per the prescribing information of Inbrija, dosing will allow a patient to inhale the contents of two 42 mg capsules as needed for OFF symptoms, up to 5 times daily. Inbrija capsules are not meant to be swallowed. The maximum dose per OFF period is 84 mg, and the maximum recommended daily dosage of is 420 mg.

In summary of potential side effects seen in studies: in the phase II safety trial, among the 43 people who used the drug, the most frequently reported adverse events were dizziness, cough, and nausea, (each seen in 3 patients). In the phase III clinical/efficacy trial 339 participants were randomized to 84 mg, 60 mg, or placebo, and were allowed to self-administer treatment up to five times daily for 12 weeks. In the 84 mg dose group nausea was reported in 5.3% (2.7% with placebo), cough in 15% (1.8% with placebo), upper respiratory tract infection in 6% (2.7% with placebo). When cough was reported, it was “typically mild and reported once per participant during the course of treatment.” Three people discontinued the study due to cough.

The manufacturer recommends doctors monitor patients on MAO-B inhibitors for orthostatic hypotension, and dopamine D2 antagonists, isoniazid, and iron salts, which may reduce the effectiveness of Inbrija.

Inbrija is contraindicated in patients currently taking a nonselective monoamine oxidase (MAO) inhibitor (e.g., phenelzine and tranylcypromine) or who have recently (within 2 weeks) taken a nonselective MAO inhibitor. Hypertension can occur if these drugs are used concurrently.

Some serious warnings are listed with the drug prescribing information, and these represent potential problems with using the drug:

sleep attack: falling asleep during activities of daily living, a rare side effect which can be seen in patients taking dopaminergic drugs

withdrawal-emergent hyperpyrexia and confusion: a very rare condition which may occcur with sudden discontinuation or rapid dose reduction of dopaminergic medications

hallucinations/ exacerbation of psychosis: patients with a
major psychotic disorder should not be treated with this drug

impulse control disorders: see the article in MPDN last winter on ICD in PD

dyskinesia: may be triggered or exacerbated

asthma, COPD, or other chronic underlying lung disease: not recommended in patients with these conditions

Pipeline drugs, part 4: apomorphine

Apomorphine (Apokyn) is a dopamine delivered by multi-dose glass cartridges, 30 mg/3 mL with a multiple dose pen injector (APOKYN Pen). Apokyn is FDA approved in the U.S. for the acute, intermittent treatment of hypomobility, OFF episodes, and unpredictable ON/OFF episodes associated with advanced Parkinson disease (PD). It is used by a relatively small number of patients in the U.S. However, different formulations of apomorphine are available outside the U.S., and different formulations are under investigation within our borders.

One study evaluated APL-130277, a sublingual (beneath the tongue) apomorphine oral strip, as an acute, effective, noninvasive treatment for OFF episodes (1). This was a phase II, open-label, proof-of-concept study.

In open-label studies, patients know they are taking the study drug and there is no placebo, thus no blind. Proof-of-concept studies are designed to verify that some concept has practical potential, such as using a sublingual version of the drug for a certain indication.

In this study patients presented to clinic in the morning hours “in the practically defined OFF state” (before taking their morning medications) and were given APL-130277 10 mg. PD motor scores using MDS-UPDRS III were recorded before dosing and at 15, 30, 45, 60, and 90 minutes. If a full ON state was not achieved within 3 hours, the dose was increased in 5 mg increments until the patient was either ON, or had taken 30 mg. Of the 19 people with PD treated, 15 (78.9%) reached a full ON response within 30 minutes, and 6 of the 15 patients reached ON within 15 minutes. Average duration of ON was 50 minutes, and nine patients remained fully ON for 90 or more minutes. No patients discontinued the drug due to adverse event, though dizziness occurred in 36.8%, sleepiness in 31.6%, and nausea in 21.1%.

NCT0254269 is an open-label phase III study to examine long-term safety, tolerability, and efficacy of APL-1320277 in doses ranging from 10-35 mg for the treatment of OFF episodes in patients with PD (2). Estimated enrollment will be 226 patients and recruitment is ongoing at many centers in the U.S. and Canada.

Apomorphine has also been developed as a drug which may be administered by pump. Already available in some countries, it is currently in trials in the U.S. The apomorphine pump is being tested as a method to avoid fluctuations in the motor symptoms of PD. In a study published in 2017, authors noted that people with advanced PD and contraindications for deep brain stimulation (DBS) might benefit from apomorphine as an add-on to existing medications, and evaluated the motor and nonmotor symptoms in advanced PD (3).

A small cohort of 12 patients with advanced PD were assessed before and after 6 months of apomorphine with a type of brain imaging called 18F-fluorodeoxyglucose positron emission tomography (PET scan) and “exhaustive clinical assessments.” Authors noted that after 6 months of therapy they were able to significantly reduce oral PD meds (and thus reduce risk of side effects from those meds), and that motor and nonmotor scores improved “with a beneficial effect on executive functions, quality of life and apathy.” Brain PET scan of these patients reportedly revealed significant metabolic changes consistent with the improvements in clinical scores. The authors noted, “these preliminary results have to be confirmed by further studies.”

NCT02339064 is a phase III, 52-week safety study being called INFUS-ON, which is an actively recruiting, multicenter, open-label trial to assess the long-term safety and tolerability of continuous subcutaneous infusion of apomorphine in advanced PD patients with unsatisfactory motor fluctuations while using levodopa and at least one other class of drugs or mode of therapy for PD (4). The study will also evaluate reductions in OFF time and improvements in ON time without troublesome dyskinesias.

REFERENCES

Hauser, et al. Sublingual apomorphine (APL-130277) for the acute conversion of OFF to ON in Parkinson’s disease. Mov Disord. 2016;31(9):1366-72.
https://clinicaltrials.gov/ct2/show/NCT02542696?term=sublingual+apomorphine&cond=Parkinson+Disease&rank=36
Auffret, et al, Apomorphine pump in advanced Parkinson’s disease: Effects on motor and nonmotor symptoms with brain metabolism correlations. J Neurol Sci. 2017;372:279-287.
https://clinicaltrials.gov/ct2/show/NCT02339064?term=apomorphine+pump&cond=Parkinson+Disease&rank=6

FDA approval of inhaled levodopa delayed

In the spring, 2018 issue of MPDN, the drug INBRIJA was discussed (1). INBRIJA is a self-administered, orally inhaled form of levodopa (similar to an asthma inhaler) which if approved by the Food and Drug Administration (FDA), will be indicated for symptoms of OFF periods in people who take carbidopa/levodopa for Parkinson’s disease. In other words, it will serve as a rescue drug for OFF periods. As noted in that article, in February Acorda Therapeutics, Inc. announced the FDA had accepted the New Drug Application (NDA) for INBRIJA. Under the Prescription Drug User Fee Act (PDUFA), the FDA set a target date of October 5, 2018. However, the FDA announced on September 13 that PDUFA date for the drug been extended to January 5, 2019. This delay comes after Acorda provided more data in response to FDA requests for additional information on chemistry, manufacturing, and controls (CMC). Per the Acorda website press release, “FDA determined that these submissions constitute a major amendment and will take additional time to review” (2).

Cognitive Behavior Therapy: Changing The Way We Think About Things

by Grace Plummer, LCSW

All of us experience times when we may feel down about something; the loss of a pet, a conflict with our spouse or, for those of us here in Maine during the long winters, the news of yet another snow storm. We may notice that our thoughts about the event are quite negative. We might be able to observe an “attitude” that we know isn’t helpful to our mood and so, in these moments, are capable of making a shift into thinking more positively.

Some of us, however, may not be able to catch these negative thinking traps; our mind just dances along to an unending script of destruction. And some of us may experience constant, pessimistic or maladaptive thinking even without the presence of a stressor.

Dr. Aaron T Beck, a brilliant psychiatrist who studied depression in the 1960s, recognized that these spontaneous streams of negative thoughts, which he named “automatic thoughts,” had the potential to be changed through intentional awareness and evaluation, leading people to experience more positive emotions and better functioning. He found himself helping patients shift their underlying beliefs about themselves, the world and the future, which were at the root of the depression, resulting in long term change. His model was eventually named Cognitive Behavioral Therapy (CBT).

CBT has been studied extensively and shown to be effective at managing many psychological disorders, including those found secondary to medical problems (History of Cognitive Behavior Therapy, 2016). Since we know that depression symptoms impact about half of people with PD (Aarsland D, et al, 1999) and that many people with PD will also experience anxiety, another psychiatric disorder highly responsive to CBT, seeking out this type of support may be beneficial for you.

Therapists who use CBT are likely to follow up the initial clinical interview, completed in the first session, with homework assignments focused on recording thoughts, moods and behaviors. You can expect to review these handouts in follow up visits where attention is given particularly to distorted thoughts, which are also defined and explored in session. Expect to experience a focused and directed exchange. Your therapist will also prioritize management of the therapeutic alliance, where long term change is rooted, which is created by offering compassion and empathy, and encouraging challenge and a push towards forward movement.

CBT is a model that many local therapists here in Maine are trained in and comfortable helping patients learn. Finding the right therapist for you begins with talking with your PCP or neurologist about your mood and symptoms, remembering also that behaviors such as withdrawing from friends or disconnecting from normally enjoyed activities can be signs of depression. Additionally, visiting psychologytoday.com can provide a place to read about local therapists. Many practicing clinicians in our community are happy to receive phone calls with questions about their practice style and what you can expect from working with them.

In closing, we encourage you to consider caring for your thoughts and emotions the same way you would for a tremor or balance issue, by asking for help. We are here for you.

References

Aarsland D, Larsen JP, Lim NG, et al. Range of neuropsychiatric disturbances in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 1999; 67: 492.

History of Cognitive Behavior Therapy. (2016). Retrieved from https://beckinstitute.org/about-beck/our-history/history-of-cognitive-therapy/

Thoughts on the dopamine pump, an interview with Conner Moore, M.D. (retired)

DUOPA, the dopamine pump, was FDA approved in January 2015 as an orphan drug (drugs or products intended for treatment of rare conditions affecting fewer than 200,000 people in the United States). Though there are probably closer to a million people with Parkinson disease (PD) in the U.S., only a minority would be considered for DUOPA use. DUOPA approval was based on a Phase III, 12-week, double-blind, double-placebo, active control, parallel group, multi-center trial with 71 patients (1). In the trial, DUOPA was compared to oral, immediate-release (IR) carbidopa/levodopa tablets in advanced PD patients. At 12 weeks DUOPA patients had reduced daily OFF time (when medications are not working and symptoms are not controlled) an average of about two hours. At the same time, this group had also improved average ON time (when the medication is working and symptoms are controlled) without troublesome dyskinesia (uncontrolled movement that does not interfere with normal daily activities) by two hours (footnote). Use has been limited in the United States for a variety of reasons. We are happy in this interview to hear about the DUOPA pump from someone who is well-versed in medicine and in PD.

Conner Moore, M. D. is a retired pediatrician who practiced for 40 years in the Saco/Biddeford area until 2008, and worked part-time in 2010. That same year he began to notice the signs of PD. Like his mother, who also had the condition, tremors were never a big part of the disease. Over time, his PD progressed and fortunately he responded to carbidopa/levodopa (Sinemet). As far as I know among Maine movement disorder neurologists, he is the first patient in our state to have the DUOPA pump. Dr. Moore took some time to speak with me by phone and describe his experience with DUOPA at the end of February 2018. This was a casual conversation and he was speaking strictly from his own experience, not offering medical advice on a professional basis, and not representing AbbVie Pharmaceuticals. I appreciate his thoughts and insight.

MPDN: What was your PD like in the years prior to getting the pump?

CM: It started out gradually and on one side like most people. But I was always very active, and I knew that there were studies supporting the role of exercise in Parkinson’s. I took a fairly high dose of carbidopa/levodopa to participate in sports and other activities. It was a trade-off and I knew that might also mean dyskinesias might come earlier. It seemed worth it to me. And, I’ve been involved in the New England Parkinson’s Ride (see article in the summer, 2016 issue) and 4 years ago I was able to complete 30 miles. In 2016 I was only able to do 10 miles and took more rest stops, mostly due to fatigue. Last September, 2017 I wasn’t able to participate because of balance and other factors. Also, I wasn’t using the pump yet.

MPDN: I understand that for the two years leading up to the pump dyskinesias had become an increasing problem, sometimes severe enough to be exhausting, and medication failure was an issue. This led to you taking more frequent doses of carbidopa/levodopa. But, this meant trying to work with diet was also a problem because certain foods might interfere with levodopa absorption. How did you manage that before the pump?

CM: I was taking Sinemet every two hours and was very sensitive to protein with the oral drug. I could eat maybe four grams of protein at a time and I’d have to try to get more in later in the day. All the while, weight loss was a problem.

MPDN: Did carbidopa/levodopa work as long as you took it every two hours?

CM: As is often the case after several years, unpredictable OFF times began to occur more frequently, and sometimes I couldn’t leave the house. Even when I was ON, a troublesome issue was that OFF times would come on suddenly, like somebody slammed a window down.

MPDN: Did you consider other options such as deep brain stimulation (DBS) before the pump?

CM: I saw Dr. Kleinman and discussed options. They don’t like to put the wires of DBS in your brain when you’re older, and I asked about other choices. It didn’t take two minutes to decide about the DUOPA pump.

MPDN: When did you go through this process?

CM: I started using the pump in late September 2017 and participated in the PROVIDE study, which monitored bodily movement for two months prior, and three months after starting the pump.

MPDN: How are the results?

CM: Dyskinesia is now less overall. There is less OFF time. I was getting a lot of blank shots with Sinemet, but the pump works every time. My mood is better, and I can do more around the house. There have been adjustments, but it’s been very good so far. The people at AbbVie have been fantastic and there is a number you can call 24/7. The nurse coordinator is very helpful. After the pump I started to put a little weight back on. It is complicated because some people have actually gone off the pump due to weight loss. Since it was already an issue for me I have watched calories to make sure I’m getting enough. I’m up about 10 pounds. I am exercising and using a Theracycle about 30 minutes daily, also using a stationary bike at the gym.

MPDN: Are there other dietary considerations?

CM: Apropos to your article (B6, friend or foe?, fall 2016), there have been reports of neuropathy with dopamine pumps and I have checked my B vitamins. It is a really fascinating disease. The more I learn about this illness, the less I find that I know about it, and there are new questions. But that is often the case in science and medicine.

MPDN: Too true. The pump requires a PEG J tube, a tube that is placed through the upper abdomen (below the ribs) and enters the small intestine downstream from the stomach. Is it difficult to manage?

CM: Care of the pump, tubing, and the PEG tube is not as complicated as I thought it might be. There is also the opening in your skin for the tube, known as a stoma. The only complication I’ve run into has to do with soup. If I eat a little too much there might be a little leakage, not a big problem.

MPDN: How do you get the medication for the pump?

CM: It comes in 16 hour cassettes air shipped frozen from the Midwest and

“The pouch on the vest, etc. that holds the pump has a clear plastic window that you push buttons through for bolus function or to change rate or shut down pump to remove when showering. It has a number of alarms – for kinked tubing, or high pressure when I fail to loosen a clamp.”

FedEx has been right on time, even in a snow storm this winter. It runs on AA batteries but they send those too, they send everything you need. The 16 hour daily cassettes contain the carbo/levodopa in gel form and clip onto the pump. The total unit size is 7.5 x 3.5 inches and weighs a pound. There are vests, hip packs and shoulder slings available to hold the pump. I quickly adapted to my new addition and am generally not aware of its presence.

MPDN: Is it difficult to operate?

CM: There are considerations about operating the pump, a learning curve and some getting used to. It takes some dedication to this project. Most people use the pump during the day and turn it off at night.

MPDN: What is a typical day with the pump?

CM: I wake around 5am and feel I am not yet in an OFF state. I’m able to get up and do a few things around the house for about an hour. Then I start to feel the typical tightening of the face and decrease in left arm swing that let me know I’m wearing off. When I attach and turn on the pump after about 20 minutes there may be a brief period of dyskinesia. After that it levels out. During the day the pump provides a base rate of medication such as 40 mg levodopa every hour. It has given me a sense of freedom. I can go into a theatre now, have dinner, and don’t have to worry about wearing off. If that happens it is much more gradual, a slow process that I can feel coming on, unlike before. If that feeling comes on I can give myself a 50 mg bolus by pushing a little button on the pump and it kicks in within minutes. It has improved my quality of life tremendously.

MPDN: Do you still sometimes have wearing OFF?

CM: There might be wearing OFF with a high protein meal, but I can eat about twice as much protein in one sitting than I could before. The other thing is exercise. Sometimes I need to give myself a bolus if I’m working out too hard. Usually I don’t think about it.

MPDN: Are there any personal limitations with the pump?

CM: I don’t think there is anything I would put in that category. I have only tried one overnight away from home, but have talked with PD pump patients who have traveled with the pump. It requires planning because of refrigeration requirements.

MPDN: How about shutting it down for the day?

CM: At first I was concerned I might have to write down a lot of complicated procedure. There are about 15 steps to turning it off and putting everything away at night, but it all becomes so routine that it’s like brushing your teeth. When you shut it off you flush the tubing with tap water and the nice thing about that is that you are flushing medicine into yourself and get about 30 minutes more levodopa from the tube. Then, it is time to sleep. Not everyone shuts it down at bedtime. Some people run it all night. I don’t think I need that at this time.

MPDN: There is a peer mentor program for people considering the pump. What was your experience?

CM: I used the peer mentor program before getting the pump and met people who had been in the study, and had the pump for about six years. They told me the maintenance was low with the equipment and it had generally lasted that long. I wound up signing on myself for that program. People interested in the pump can call and get one of us on the phone to talk about our experience. It’s a good resource because you are talking to a person with experience.

MPDN: Any last thoughts Dr. Moore?

CM: Just that it has been positive for me, and I hope it helps others to know about this.

Dr. Moore also sent me a comment by email after we talked:

We did not talk about the cost. My Medicare and supplemental insurance pays everything. But I think the President is going to look at entitlement programs to balance the budget. The DUOPA is part of the pump package so it falls under Part B durable equipment and does not go through Part D and the drug insurance process. The government gets a discount, but not much.

Comments by Michael Kleinman, D.O.

The most common indication for the pump is for patients with severe motor fluctuations. If someone is taking medication every 3 hours or less and is still with a significant amount of off time then I would consider them for the DUOPA pump. Traditionally these patients would be first considered for deep brain stimulation surgery but for those patients who may not be good candidates for deep brain stimulation surgery or who are not willing to go through the surgery, then this is a good option. The percent increase in ON time is actually similar to that achieved with surgery.

The company which supplies the medication has a support system in place to help patients get used to administering the medication themselves at home. This has run very smoothly in the experience that we have had here. The medication is started for the first time in the office. At that visit the patient will come in without having taken their medication from the prior night. That visit will be 3-6 hours long. The initial bolus dose and continual infusion dose of the DUOPA infusion will be set based on how much oral medication the patient was taking prior to starting DUOPA. We will then monitor how long it takes for the medication to start working, whether there is evidence of too much medication such as dyskinesia, and whether there is any wearing off. The patient and their caregiver are also educated during that visit on how to operate the pump.

Follow up visits will be more frequent than usual in the beginning to fine tune the dose of medication. If the initial programmed dosing is working well then visits can quickly go back to being every few months. Patients can be given a range of settings to work with at home as well. They can call with a report on how they are doing and be instructed on what change to make to their infusion settings without the need to come in for a visit to have the pump settings changed.

Footnote: In the above mentioned phase III trial of DUOPA, the most common adverse events were listed if occurring in more than 7% of patients, and occurring more frequently with DUOPA than carbidopa/levodopa IR and included complication of device insertion, nausea, constipation, incision site erythema (redness), dyskinesia, depression, post procedural discharge, peripheral edema, hypertension, upper respiratory tract infection, oropharyngeal pain, atelectasis, confusional state, anxiety, dizziness and hiatal hernia.

REFERENCES

Olanow, et al; for LCIG Horizon Study Group. Lancet Neurol. 2014;13(2):141-149.

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