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. 

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. 


  1. 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.  
  2. It was discovered in post-hoc analysis of this trial that a full washout would take 28 days.
  3. 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. 


  1. Should you adjust your own Parkinson’s meds?  Spring 2016, MPDN
  2. Poewe WH et al. Neurology. 1996;47(suppl 3):S146-S152.
  3. Hoehn MM, Yahr MD. Neurology. 1967;17:427-442.
  4. Hoehn MMM. J Neural Transm Suppl. 1983;19:253-264.
  5. Diamond SG et al. Ann Neurol. 1987;22:8-12.
  6. Lang & Lozano. N Engl J Med. 1998;339:1130-1143.
  7. Fahn S. Parkinson disease, the effect of levodopa, and the ELLDOPA trial. Arch Neurol 1999; 56: 529–35.
  8. Fahn S. A new look at levodopa based on the ELLDOPA study. J Neural Transm 2006; 70 (Suppl): 419–26.
  9. Kurlan R. “Levodopa phobia”: a new iatrogenic cause of disability in Parkinson disease. Neurology 2005; 64: 923–4.
  10. Fahn S.  Parkinson disease, the effect of levodopa, and the ELLDOPA trial. Earlier vs Later L-DOPA  Arch Neurol. 1999;56:529-535.
  11. Parkinson Study Group. Levodopa and the progression of Parkinson’s disease. N Engl J Med. 2004;351:2498-2508.  
  12. 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.
  13. Hauser, et al. Factors associated with the development of motor fluctuations and dyskinesias in Parkinson disease. Arch Neurol 2006; 63: 1756–60
  14. 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.
  15. 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.



  1. 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.
  3. 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.

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).

  1. Pipeline drugs, part 1: levodopa

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 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.



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



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.


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

Impulse control disorder in Parkinson disease

People with Parkinson disease (PD) have low dopamine stores, and many of the drugs used to treat PD are aimed at either replacing or simulating dopamine.  Carbidopa/levodopa (Sinemet) provides levodopa to the brain, which is then converted to dopamine.  There is also a class of dopamine simulating drugs, the dopamine agonists (DA).  DA are synthetic drugs that are meant to stimulate the basal ganglia (BG) in a way similar to dopamine.

The BG is the part of the brain that uses dopamine to normalize movement and eliminate tremor.  The BG is, in a way, the quality control center for movement, is linked to several other parts of the brain, and is involved in various functions.  For our purposes here, it regulates learned movements such as typing, playing the piano, handwriting, walking, dancing, or riding a bike.  When walking, the BG helps determine how much muscle tone you should use, how far your foot should go when you step, and where it should land.  Those functions may fail to some degree when a person has PD (think of shuffling gait, for example).  If dopamine is replaced or simulated, the functions may improve.  That is the goal in giving these medications.

The reason dopamine replacement helps is because the cells of the BG have structures called dopamine receptors.  Dopamine binds to the receptors and the cell is then activated to do something, such as change muscle tone.  There are many different cell types and many different effects.  DA bind to the same receptors, but there are some differences between dopamine and DA.

One big issue is that after one takes a carbidopa/levodopa pill to replace dopamine, levodopa only spends about 90 minutes in the blood at a reasonable concentration.  During that time, it washes through the brain’s blood supply and is absorbed by and stored in the BG. When that happens, the BG can convert levodopa to dopamine, and more or less distribute dopamine appropriately to the cells that need it, as they need it.  It is sort of like filling a gas tank.  The problem is that the brain’s ability to store dopamine decreases over time in PD, as if the gas tank keeps shrinking.  People with PD generally have to take doses of levodopa more frequently over the course of disease because of this decrease.

DA are not stored in the brain, and instead circulate in the blood for several hours after taking a dose.

This means that the entire brain is washed with DA for those several hours, during which time the receptors can be stimulated and symptoms reduced.   The effect is weaker than pure dopamine, but often the duration of the drug is longer.   This might become a problem, however, because there are other dopamine receptors in the brain that are not involved in movement and yet may be stimulated by the constantly available drug.

A part of the brain that is sometimes affected is the limbic system.  The limbic system is involved in craving, lust, emotion, risk-taking, and addiction.   Let’s think about risk-taking for a moment. You are with a friend, we’ll say his initials are E.K., and he is a motorcycle stunt artist.   He has a really fast Harley Davidson and he likes to pop wheelies and jump over things.  It is fun to watch him perform, and he seems fearless.  One day E.K. asks if you would like to jump over the fountains at a hotel in Las Vegas with him.  For a split second it sounds exciting, and you think, “cool.”  Your brain swings into action to deal with this situation.

Let’s talk brain anatomy.  There is a part of your brain that analyzes risk.  It is called the dorsolateral prefrontal cortex (DLPFC).   This is the part of the brain that tries to peer into the future and consider possible outcomes:  if X happens, then Y will be the result.  It is purely logical (to the extent that you are logical).  Its risk assessment says “if you jump the fountains on that motorcycle, you will probably crash:  bad idea.”  Among other neurotransmitters, the DLPFC is connected to the limbic system with a steady flow of dopamine, and for our purposes, we will focus only on dopamine.

Dopamine generally makes the limbic system feel good, and that seems to be the default.

So, there should be some trickle of dopamine flowing at all times. When you like an idea or the risk is low, dopamine is steady or even increased.   When your DLPFC says you should not do something, dopamine flow to the limbic system is decreased.  That gives us a negative emotional feeling about the risk and then the logical and emotional parts of the brain can be in agreement.  “No thanks E.K., I don’t want to break any bones or die today.”  But what if the limbic system is stimulated by DA washing the brain?  Does it become harder to follow the instructions of the DLPFC?

For a minority of people, the answer is yes.   These people may develop what is called impulse control disorder (ICD).

ICD was defined by the American Psychiatric Association as a group of psychiatric disorders characterized by a failure to resist an impulse, drive or temptation to perform an act that is harmful to the individual or to others (1). 

The key word here is “harmful.”  Not all behaviors are harmful, and it is important to keep in mind that not everyone agrees on what is considered bad behavior.  ICD in PD has been called “hedonistic homeostatic dysregulation” (2) and “dopamine dysregulation syndrome” (3).  It should also be noted that ICDs have been reported with all anti-parkinsonian drugs, though it is most often seen with DA.

ICD behaviors can include compulsions for shopping, spending, traveling, eating, sex/libido, reckless driving, and pathological gambling.  Patients with ICD may also exhibit obsessive-compulsive disorder (OCD) features such as repetitive behaviors, checking (light switches or locks, for example), religious obsession, sexual obsession, symmetry and ordering, washing, cleaning, and punding.  Punding is intense fascination with some action such as writing, repetitive handling, examining, sorting, arranging, craft-making, collecting, hoarding, repairing, or gardening.  There is a range of severity from excess interest in hobbies to prolonged stereotyped activity that interferes with normal activities of daily living.  If your other interests fail so that you can keep repetitively perform some function, you may be punding.

Patients with ICD often abuse dopaminergic drugs in a way that resembles addiction.

These people tend to take very high doses of drugs and sometimes surpass the upper limits of doses approved by the FDA.  Needless to say, they are often not following the advice of a doctor (4), though ICD does sometimes occur at prescribed doses.

ICD is often present when a person with PD has a history of other psychiatric or neurologic disorders such as substance use disorder, antisocial personality disorder, major mood disorder, or anxiety (5-9), though it may occur without these features as well.  ICD may be more common in people with young-onset PD.  Combining high doses of DA with high dose levodopa is also a risk factor (10).

What can we do about ICDs?

Always follow your doctor’s instructions.  Do not change doses on your own.  Reducing or stopping the offending medication with your doctor is usually effective.  Sometimes a switch to a different DA is helpful.  Failing these interventions, caretakers may need to limit access to money or credit cards.  Sometimes appointing a financial guardian is needed.  One may need to cut off internet access or firewall away gambling sites.  PD support groups may be helpful.  It is not clear whether other groups such as Gamblers Anonymous are helpful for PD patients.  Other medications have been tried, such as opioid antagonists, antipsychotics, selective serotonin reuptake inhibitors, and amantadine.

The person with the ICD is typically quite aware the behavior is unusual and is too embarrassed to admit to it.  However, knowing this may be related to medications should give you some idea that it is not unheard of, and can be helped.  Telling your physician is a good first step.


  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorder, 4th ed, Text Revision. Washington DC: American Psychiatric Association; 2000.
  2. Giovannoni et al. Hedonistic homeostatic dysregulation in patients with Parkinson’s disease on dopamine replacement therapies. J Neurol Neurosurg Psychiatry. 2000;68:423–428.
  3. Evans et al.  Impulsive and Compulsive Behaviors in Parkinson’s Disease.  Movement Disorders 2009;24(11): 1561–1570.
  4. Stamey W, Jankovic J. Impulse control disorders and pathological gambling in patients with Parkinson’s disease.  The Neurologist 2008:14(2);89-99.
  5. Black DW, Moyer T. Clinical features and psychiatric comorbidity of subjects with pathological gambling behavior. Psychiatr Serv. 1998; 49:1434 –9.
  6. Crockford DN, Goodyear B, Edwards J, et al. Cue-induced brain activity in pathological gamblers. Biol Psychiatry. 2005;58:787–795.
  7. Potenza MN, Fiellin DA, Heninger GR, et al. Gambling: an addictive behavior with health and primary care implications. J Gen Intern Med. 2002;17:721–32.
  8. Petry NM, Stinson FS, Grant BF. Comorbidity of DSM-IV pathological gambling and other psychiatric disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry. 2005;66:564 –74.
  9. Petry NM. Comorbidity of disordered gambling and other psychiatric disorders. In: Petry NM, ed. Pathological Gambling. Etiology, Comorbidity,and Treatment. Washington, DC: American Psychological Association;2005:85–115.
  10. Evans et al., Impulsive and Compulsive Behaviors in Parkinson’s Disease. Movement Disorders Vol. 24, No. 11, 2009, pp. 1561–1570.



How close are we to focused ultrasound for PD in Maine?

Focused ultrasound (FUS) is a specialized technique that was FDA approved to treat essential tremor (ET) in 2016.  Patients undergoing treatment receive a noninvasive MRI-guided procedure in which there is no incision, no breach of the skull as in deep brain stimulation (DBS).  Instead, beams of acoustic energy are directed from 1,024 tiny transducers toward the same target in the brain, the VIM nucleus of the thalamus.  Ultrasound energy combines at the VIM to lesion the nucleus by generating heat powerful enough to coagulate (and thus destroy) tissue.  The result is similar to any intervention that burns, freezes, or otherwise jams the signal in a brain region (much of the programming of DBS for example, is meant to jam a signal).  As of yet, with ET only one side is treated by FUS.


In a major U.S. study involving 76 patients with medication-refractory ET, a 32-point clinical tremor rating scale was used to measure outcomes (1).  Hand tremor scores improved after FUS, from 18.1 at baseline to 9.6 three months after the procedure.  In other words, on average, tremor intensity lessened by about 50%.  Patients receiving a sham procedure averaged a drop from 16.0 to 15.8 points.  However, about 14% of the patients had a less than 20% improvement.  At three months, adverse events in the treatment group included gait disturbance (36%) and tingling/numbness (38%).  Slurred speech occurred in 1% of treated patients, but this apparently resolved.  At 12 months, gait disturbance was still present in 9% and tingling in 14%.  Overall, in the treatment group, disability was reduced by about 60% and about half of patients reported improvements in quality of life, which were maintained for the entire year of the study.


In another trial (2), 30 patients with severe medication-resistant tremor underwent FUS:  18 with ET, 9 with PD, and 3 with both ET and PD.  The average age of the study population was 68.9 ± 8.3 years, with an average disease duration of 12.1 ± 8.9 years.  Patients with PD showed an average reduction in motor score (part III of the Unified Parkinson’s Disease Rating Scale) from 24.9 ± 8.0 to 16.4 ± 11 at one month, and 13.4 ± 9.2 at six months after treatment.  Over the two- year follow up, tremor reappeared in two of the PD patients and in two who had combined ET-PD.  In this study, reportedly no adverse event lasted beyond three months.

There are other considerations, and as of yet there is no FDA approval for PD.  At the annual meeting of the American Academy of Neurology (AAN) held this past spring in Boston, the topic of FUS in PD was discussed (3).  Dr. Paul Fishman noted that while some results were very positive in studies, going through the procedure itself might be uncomfortable.  Some patients felt like the metal frame required for the procedure was uncomfortable, and many complained of a feeling of heat or sense of “whirling.”  Since the original study, another 186 patients have been followed in open label studies of FUS.  According to Dr. Fishman, 83% of adverse events were rated as mild and 2% as severe.  Some of the adverse events had been persistent, and he noted, “This is not a risk-free technique,” though the overall incidence of serious adverse events was less than that of DBS.  Dr. Michael Okun also spoke at the AAN meeting on this topic.  By comparison, during DBS implantation a specialist is able to verify that the lead is in the exact right target of the brain; whereas “with ultrasound you cannot test to make sure you have hit the right target.  If you have adverse events that include paresthesias in the face, tongue and leg, you missed.”   There is also data showing that tremor may, more or less, “creep” back in the months after a FUS.  More concerning, he noted,

“You can’t troubleshoot an ultrasound lesion. When you have a problem, you’ve got a problem.  The lesion is irreversible.  It can’t be programmed or modulated.

The opposite is true of DBS, wherein programming changes can often alleviate a particular symptom.

In September 2015, Kimberly Spletter of Maryland was one of the first PD patients to receive FUS, and was featured on Michael J. Fox Mobile News (5).  There is a 5-minute video on the site with some impressive before/after footage and interesting graphics.  In Spletter’s case, the indication was not tremor, but her advanced dyskinesias (6).  For this, a different target was chosen for FUS, the globus pallidus.  She was one of forty patients were enrolled in a study of FUS in PD.  It is my understanding that the study is completed, but the data is not yet published.  To see an follow up video of her in January, 2017 click this link:


As for FUS in Maine, we are yet to have a case done here.  I spoke with functional neurosurgeon Dr. Anand Rughani on the topic, who gave the following statement:

“It is an interesting option to consider for lesioning.  The concept of lesioning is not new in treating movement disorders such as essential tremor and Parkinson’s disease.  A lesion in the thalamus, for example, is called a thalamotomy, and has been widely used to treat tremor.  Other methods of creating a lesion include radiosurgery using Gamma Knife, which is not an actual surgery, and radiofrequency lesioning, which is an actual surgery.  In general, a few comments can be made when comparing lesioning to stimulation, as in deep brain stimulation.  Lesions can only be done on one side of the brain.  Lesions are not usually as durable as stimulation, meaning that the benefit may not last as long.  The side effects of lesions are not reversible in the same way that they can be with stimulation.  While there is now FDA approval for the treatment of essential tremor using focused ultrasound in the US, patients with Parkinson’s disease will need to consider this option through participation in an experimental trial.”

FUS is done in a few academic centers, such as Brigham and Women’s in Boston (4).  On the BW Neurosurgery website, the following key considerations are listed:  currently, insurance plans do not cover this procedure, and not everyone is eligible for focused ultrasound; eligibility requires evaluation by a neurologist and a neurosurgeon.  One consideration is skull thickness; too much is not good for FUS.  Senator Anthony Pollina of Vermont, for example, was disqualified from FUS for his PD for this reason, and opted instead for DBS (7).

Thus, there is a lot to be hopeful about with this new procedure, but it will be some time before it is available in Maine.  More data needs to be collected, and FDA approval given.  Still, over time it is likely that the procedure will continue to be refined and advanced.


  1. Elias, et al.,  A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor. N Engl J Med. 2016;375(8):730-9.
  2. ZAaroor, et al.  Magnetic resonance-guided focused ultrasound thalamotomy for tremor: a report of 30 Parkinson’s disease and essential tremor cases. J Neurosurg. 2017 Feb 24:1-9.
  3. Susman, E.  Pro and Con: Is Focused ultrasound More Effective than DBS for Parkinson’s Disease? Neurology Today. 2017;17(1):34-5.


Levodopa at 50

Levodopa, active ingredient of Sinemet, is the most effective drug we have for PD.  The discovery of levodopa as a drug for use against parkinsonism in the late 1960s transformed life for people suffering with the disease.  Prior to that time, the eventuality for many was to experience progressive stiffness and slowness until they became wheelchair- or bed-bound.  I have heard of Parkinson wards in hospitals, where sufferers lingered until they died a premature death related to the complications of immobility.  Levodopa liberated people with PD and brought lifespans to that of the general population.   As happy as the patients were with this potent new drug, the exciting discoveries with levodopa also attracted bright minds to neurology and neuroscience, which led to a better understanding of the brain’s basal ganglia, which is affected in PD, and to related problems, such as dystonia, chorea, and tics.

The historical perspective

No history of levodopa can be complete.  There were many contributors in science and medicine likely not given credit.  I do not review the very interesting story in Oliver Sacks’ book Awakenings, though I recommend that related story regarding his work with parkinsonsim and levodopa.  And, here I do not delve into Eastern medicine or the use of medicinal plants such as Mucuna pruriens, which was discussed in the article “PD and diet” (MPDN winter 2016/2017). Instead I will give a brief history of scientific discovery.  What follows is a timeline as I understand it.  It is also a window into how some of the most complex discoveries in science are made.  It is a story of collaboration of sorts, the sharing of information and sometimes the reconsideration of some fact through the lens of another mind.  It is amazing to me that so many labs from around the world were involved over such a long time.  There is probably an earlier point of origin, but for the sake of starting, I will begin here with a timeline.

In 1895, visible lesions of the upper brainstem (a stalk-like structure connecting the brain and spinal cord) were described at autopsy of PD sufferers by Brissaud, who was a professor of pathology in Paris.  Brissaud proposed these lesions were significant, but could not define precisely how.  At the time, function of this structure was not known.  Over the years, dopamine would be detected in the brain but it took time to determine the origin or function.  Thus, it was an unconnected discovery when dopamine was synthesized in London by George Barger and James Ewens in 1910.  At the same lab, Henry Dale discovered dopamine was chemically similar to epinephrine.  There were limitations in biochemistry, and not until three decades later did Peter Holtz of Germany discover the enzyme which converts levodopa to dopamine (aromatic-L-amino-acid decarboxylase, a.k.a. dopa decarboxylase).  This discovery would become very important because it gave researchers a mechanism to form dopamine in the brain, though at the time the meaning of this discovery, that it would help people with PD, was not yet understood.  You and I can stand in the future and easily see why this discovery was important.

Dopamine, if given by mouth, cannot get from the bloodstream to the brain because it cannot cross the protective blood brain barrier, which shields the brain from many, but not all compounds in the blood. 

On the contrary, levodopa is not blocked, and can cross the blood-brain barrier, after which it will be converted by this enzyme to dopamine.  That is the basis of treatment with levodopa.  However, that would take years to grasp.  In fact, around that time Herman Blaschko in Cambridge hypothesized that levodopa and dopamine could be converted to epinephrine and norepinephrine (adrenaline), which was later proven, but again, missed the significance of dopamine in PD.  In the next several years dopamine was found in other bodily organs such as the adrenal glands, the heart, and the kidneys, all interesting discoveries apart from the immediate significance in PD.

Redirection back to PD came in 1953 when Drs. Greenfield and Bosanquet of Queen’s Square, University of Oxford, reported the loss of pigment cells of the brainstem substantia nigra (which produce dopamine).  In 1956, Oleh Hornykiewicz began working in Blaschko’s lab to clarify whether blood pressure was directly affected by dopamine, versus some breakdown product.  He proved dopamine lowered blood pressure and that levodopa had a similar effect.  In the 1950s and 60s American cardiac researcher Bernard Brodie showed that the drug reserpine lowered serotonin levels, which he proposed was responsible for controlling blood pressure and the heart rate.  His postdoctoral fellow, Arvid Carlsson, was given the task of investigating how the drug reserpine does this.  Carlsson argued that it was not serotonin, but a different related molecule responsible for lowering blood pressure.  After returning to Sweden and starting his own research own laboratory he showed that an important side effect of reserpine could be reversed by levodopa and not serotonin.  Reserpine depleted dopamine in the lab rabbits’ brains, resulting in a drug-induced parkinsonian syndrome, and in high enough doses, total unresponsiveness.  Even in that state, when given levodopa, the rabbits’ ears would pop up and they would become alert.  Kathleen Montagu, in London at around the same time, was the first to prove that dopamine was present in the brain.  Carlsson developed a new technique to measure dopamine in tissue, and showed soon after that dopamine was present in the brain, but depleted with reserpine and restored with L-dopa.  Two medical students in Carlsson’s lab, Ike Bertler and Evald Rosengren, mapped the distribution of dopamine in the dog’s brain, and showed concentrations in the basal ganglia.  This work was repeated in humans by one of Carlsson’s collaborators, Isamu Sano in Japan.

These findings led Carlsson to speculate, at the 1959 International Pharmacology meeting, that Parkinson disease was related to dopamine.

Following this, in Vienna, Oleh Hornykiewicz began to measure dopamine both in people with Parkinson’s and with post-encephalitic parkinsonism, and in 1960 published a paper showing a marked depletion of dopamine in the basal ganglia (specifically the caudate and putamen) of patients with both of these conditions, but not in people with other brain disorders such as Huntington chorea.

How dopamine was formed in the brain was not known until the early 1960s, when Toshiharu Nagatsu, a postdoctoral fellow at the National Institutes of Health, discovered the enzyme tyrosine hydroxylase, which converts the amino acid tyrosine to levodopa.  Thus, it was known that proteins break down to release amino acids such as tyrosine, which is converted to levodopa by tyrosine hydroxylase.  Levodopa is then converted to dopamine.

In 1966, Oleh Hornykiewicz proposed that dopamine deficiency in the striatum of the basal ganglia is correlated with most of the motor symptoms of PD. 

Over the next several years, using the new technique of histofluorescence, Swedish researchers Annica Dahlström, Kjell Fuxe, and Nils-Eric Andén mapped dopamine pathways in the brain and discovered the nigrostriatal pathway. Meanwhile, Ted Sourkes and Louis Poirier in Montreal demonstrated that, in animals, striatal dopamine levels fall when the nigra is injured.  This connected the work of the two groups.

Dopamine as a treatment

In 1960, Oleh Hornykiewicz had begun to consider levodopa as a possible treatment for PD.  He and Walther Birkmayer, a Viennese neurologist, found that intravenous injections of levodopa produced dramatic, though short-lived benefits in PD patients.  Investigators around the globe demonstrated sometimes positive and sometimes negative results with higher doses of levodopa.  For example, Pat McGeer in Vancouver failed to benefit patients with 5 gram doses of the drug D, L-dopa.  A major limiting factor was nausea (and perhaps medications used to prevent nausea, which we now know can block dopamine in the brain and cause parkinsonism).

In 1967, Greek researcher George Cotzias showed in a U.S. trial that if one starts with a low dose of levodopa and gradually increases, up to 16 grams daily, benefit can be found without nausea and vomiting. This was verified in several double-blind studies and was the birth of modern treatment.

Nausea was a factor because of the dopamine decarboxylase enzyme, which converts levodopa to dopamine in the body.  As above, dopamine cannot cross the blood-brain barrier, and causes nausea.  However, the addition of carbidopa to levodopa would increase the strength of levodopa about four-fold and allow most of the drug to reach the brain.  This is because carbidopa blocks dopa decarboxylase.  Thus, the drug Sinemet, a Latin derivation meaning “without vomit,” was made.  Over time, researchers would show that lower doses were effective and perhaps less associated with complications, another complex history, for another time.

Different forms of levodopa

There have been multiple variations on carbidopa/levodopa, such as immediate release, controlled release, and the orally dissolving Parcopa formulation.  We have also seen the addition of entacapone (a COMT enzyme inhibitor) in the drug Stalevo.  In 2015, the FDA approved Rytary (a combination of long and short-acting carbidopa/levodopa) in a capsule of pellets, which are absorbed at different rates in the GI tract and allow a wider interval between doses in advanced disease than one would expect with the immediate or controlled release forms alone.  The Duodopa dopamine pump was approved in Europe over a decade ago, and the Duopa dopamine pump was FDA approved in 2016.  Duopa is a gel with a concentration of 20 mg levodopa per 5 mL infused continuously to the GI tract over the course of 16 hours per day.   It requires a PEG-J tube (a tube from the small bowel sticking out of the body just below the rib cage) which is attached to the pump.  It is typically used in patients who would not qualify for deep brain stimulation but suffer from uncontrolled motor fluctuations.

The levodopa drug development pipeline

The accordion pill, a novel gastro-retentive delivery system, is being developed by Intec Pharma. The pill expands like an accordion in the gut to keep it there while it slowly releases medication.  The accordion pill has recently completed a phase II trial of 60 PD patients with doses of 250-500 mg levodopa over a 7-21 day period, given once or twice daily, and per the company’s website (unpublished data) there was a reduction in OFF time and dyskinesias.  The baseline characteristics of the patients, including disease severity, were not apparent on the website.  The drug will need to complete a phase III trial before FDA approval is sought.

Subcutaneous levodopa (a patch/pump system, clinical trials identifier ND0612), by Neuroderm, is a subcutaneous delivery system of up to 360 mg levodopa over a 24 hour continuous infusion of a patch/pump (a patch with a small needle placed under the skin).  It is designed for moderate to severe PD as an alternative to the Duopa pump or deep brain stimulation.  Two phase II studies have shown the drug is safe and tolerable.  I understand the phase III studies will begin soon.  At this point, Boston will probably be the closest option.

Inhaled levodopa, CVT-301, is a self-administered, inhaled form of levodopa by Acorda Pharmaceuticals which has recently completed a phase III trial with a new drug application submission.  The idea with inhaled levodopa is to have rapidly effective levels of the drug in the blood, and subsequently, the brain.   Thus, the drug would be ideal for rescue from unpredictable off times, such as at a restaurant or a movie.

More delivery systems are being investigated.  Levodopa it seems, is going strong at 50.