You can find out more about NPF's National Medical Director, Dr. Michael S. Okun, by also visiting the NPF Center of Excellence, University of Florida Center for Movement Disorders & Neurorestoration.

In this month’s What’s Hot in PD? column, I will review a few of the most important medication-related issues.

First, there can be negative effects from inactive drug ingredients, especially from the color dyes often used in pill manufacturing. There have been serious hypersensitivity reactions reported from common pill dyes. A patient recently reported on the NPF Ask the Doctor forum that he had swelling of the face, lips and mouth shortly after switching from a blue Sinemet CR 25/100 to a yellow generic formulation. We also know of patients who have reported rashes when making similar switches. It turns out that, though rare, the yellow dye commonly present in the generic form of Sinemet (carbidopa/levodopa) can  be responsible for these types of side effects.  Contact your doctor if you suspect you have a pill color allergy. Be aware that yellow dye allergies may occur more commonly in patients who are also allergic to aspirin.  The treatment for the allergy is simply to have your doctor change you to a blue pill formulation.  Some patients also benefit from avoiding yellow dyes in their diet.

Second, in 2010-2011 there was a national shortage of Sinemet.  This occurred as the brand was transitioned from Merck and Company, Inc. to Mylan Pharmaceuticals, Inc.  The transition resulted in a worrisome and short-term drug shortage.  When generic formulations became available, multiple complaints were reported to the NPF Helpline.  These complaints ranged from weaker efficacy of the generic, worsening of motor fluctuations, dyskinesia, allergy and skin rash. When switching to a generic form, patients should keep in mind that there may be as much as a 20% difference in treatment effect.  However, a generic may sometimes be desired, especially in PD patients who experience dyskinesia from tiny medication dosages (some people have referred to these cases as “brittle” PD). One should remember that FDA approval of a brand name drug requires demonstration of its pharmacokinetics, efficacy, safety and tolerability in both a healthy population and also in the PD population. In contrast, approval of a generic drug only requires demonstrating its bioequivalence in the blood, but not its clinical treatment effect in PD.

And a final and important issue that has surfaced recently has been the “eight Sinemet limit.”  Pharmacies and insurance companies have been citing the language in the original FDA approval of Sinemet, and denying prescription requests for PD patients requesting more than 8 tablets a day.  This issue was the subject of NPF’s November 2010 What’s Hot in PD? column, Calling for the FDA to Revise the Eight Sinemet a Day Rule. The advent of electronic medical records has been compounding this difficult issue for patients, as automatic limits are now being set by nationalized computer systems.  Once limits are in computer systems, they can be challenging for individual patients to change.  If your insurance carrier or pharmacy blocks filling of your Sinemet prescription purely based on number of daily pills, we suggest you contact your doctor, send an appeal letter and also contact the NPF Helpline at 1-800-4PD-INFO (1-800-473-4636), as we are here to assist you.  The Helpline will provide important information for your appeal, including the recent publication on this topic in the journal Movement Disorders.

Selected References
Go CL, Rosales RL, Schmidt P, Lyons KE, Pahwa R, Okun MS. Generic versus branded pharmacotherapy in Parkinson's disease: does it matter? A review. Parkinsonism Relat Disord. 2011 Jun;17(5):308-12. Epub 2011 Mar 1. Review.

Okun MS. Parkinson's disease patients cannot get their dopamine replacement: The 8-sinemet limit. Mov Disord. 2011 Dec 9. doi: 10.1002/mds.24038. [Epub ahead
of print].

You can find out more about NPF's National Medical Director, Dr. Michael S. Okun, by also visiting the NPF Center of Excellence, University of Florida Center for Movement Disorders & Neurorestoration.

Patients and family members have been waiting for news about the possibility of a blood test to detect Parkinson’s disease.   In November, a small article was published in the FASEB journal where Foulds and colleagues reported the results of a pilot study that examined phosphorylated alpha-synuclein as a potential candidate for use as a blood test in detection of Parkinson’s disease.  In this month’s What’s Hot column we will examine this recent paper, discuss the current state of the field, and discuss how the development of a blood test could affect those at risk, and those suffering from Parkinson’s disease.

The investigation focused on a protein called alpha-synuclein which is thought to be important to the cause of Parkinson’s disease, and is a critical component in the deposits that accumulate in the Parkinson brain.  The authors measured alpha-synulcein in both Parkinson’s disease and in control patients.  They reported that Parkinson’s disease patients had an abnormal phosphorylated form of alpha-synuclein.  The changes in the blood were sampled over a three-month period, and were found to be stable in 30 patients; and they were in general, not present in control subjects.

There were, however, several issues with this study.  First, the sample size was too small to conclude that this test will prove viable in a much larger population of Parkinson’s disease patients.  Second, the authors provided little information on the actual patients they studied. Parkinson’s disease is not one disease, and as groups develop blood tests, they will need to carefully characterize and report the clinical symptoms of the patients studied.  Additionally, groups will need to be cautious in understanding which types of patients will reveal blood changes, and more importantly, which groups will not.  Finally, changes in phosphorylated alpha-synuclein could possibly occur in other Parkinsonian syndromes, other neurological diseases, and other systemic diseases.  These other diseases must be carefully investigated.  Though there were important methodological issues with this study, it is still likely we will see Parkinson’s disease blood tests and biomarkers in the near future.

If successfully developed how would a blood test for Parkinson’s disease be used?  There are several potential options for this emerging technology.  First, if a disease modifying therapy can be developed, then identifying at risk patients for early intervention could be critical.  A blood test could potentially identify those at risk, and help to facilitate early intervention.  Another important use for a blood test could be in monitoring the symptomatic treatment of current Parkinson’s disease sufferers, especially in those enrolled in drug trials.  The test would however, need to reflect changes in biological activity over time, and would also need to closely correlate to changes in disease state (e.g. progression of symptoms). 

A blood test for Parkinson’s disease would also introduce important ethical considerations, especially for asymptomatic individuals.  Though the test may not reflect genetic status, it may unmask a Parkinson’s disease diagnosis.  Revealing a potential risk to develop Parkinson’s disease could profoundly change a person’s life.  Studies of genetic counseling have revealed that once patients understand the implications of a blood/genetic test, they will often decline it.  Additionally, for currently symptomatic individuals, close monitoring of disease status could result in stress, anxiety, and worry that may translate into a worsened overall quality of life.

It is important to understand that many groups around the world are attempting to develop blood tests and biomarkers for Parkinson’s disease.  It is likely that many of the methodological limitations limiting blood tests will soon wane, and that successful approaches will emerge.  As we move forward it will be important for the field to clearly define the potential uses of a blood test, and especially to protect patients and also to protect families.  It is also important that patients understand that there will likely be more than one blood test in the future, and that close communication with their doctors will be critical in deciding which test, or which battery of tests would be appropriate to check. In summary, the development of blood tests and biomarkers has the potential to improve the lives of many Parkinson’s disease patients, and also to push the research horizon in a positive direction.  These tests must be pursued cautiously and with an open mind as to how they will affect both the population at risk, and the people currently living with Parkinson’s disease.

Selected Reference
Foulds, P. G., Mitchell, J. D., Parker, A., Turner, R., Green, G., Diggle, P., Hasegawa, M., Taylor, M., Mann, D., Allsop, D. Phosphorylated alpha-synuclein can be detected in blood plasma and is potentially a useful biomarker for Parkinson’s disease. FASEB J. 25, 4127–4137 (2011). www.fasebj.org

You can find out more about NPF's National Medical Director, Dr. Michael S. Okun, by also visiting the NPF Center of Excellence, University of Florida Center for Movement Disorders & Neurorestoration.

Recently much attention has been focused on the use of stem cells as a potential treatment for Parkinson’s disease (PD). Now, researchers at Memorial Sloan-Kettering Cancer Center in New York City report that they have successfully placed embryonic stem cells into several PD animal models.  The findings are published in the November 6 issue of Nature. This month, I will review this exciting paper and outline the “next steps” for stem cell therapy.

In the study, Sonya Kriks, Ph.D., and the research team used embryonic stem cells to generate dopamine neuron cells. Then, they transplanted the new cells into 6-hydroxy-dopamine-lesioned mice and rats (laboratory models with induced Parkinsonism).  The new cells reportedly survived, and in two important tests of behavior, the animals’ Parkinsonian symptoms improved. After researchers implanted the new cells into monkeys (which are considered evolutionarily closer to humans) they also found that the cells survived, and test results showed positive behavioral benefits as well. Finally, no tumors were found in the laboratory models, which is important because tumor formation has been an ongoing concern for stem cell biologists interested in translating discoveries from the “bench-to-bedside.”

As patients and families continue to ask the key question, “Why don’t we start transplanting stem cells for this generation of Parkinson’s disease sufferers?” we must keep in mind findings from previous research.  In the past, simple cell transplantation experiments proved that, like Dr. Kriks and her team, “we can” place cells in the brain (this was done in human brain), and that with special techniques we can ensure cell survival. Unfortunately, we also have discovered that these transplanted cells can only reconstitute a small percentage of the critically affected brain regions in PD. 

Too, we know that with simple cell transplantation, the symptoms addressed are usually motor---tremor, stiffness and slowness.  Behavioral issues such as walking, talking and thinking have not been adequately addressed. The reason for this is thought to be related to the complexity of the brain and “neural” circuitry.  Also, recent cell transplants in humans have resulted in a difficult-to-treat side effect called “runaway dyskinesia.”  And, we know from brains that have been “turned in” (post-mortem brain bank specimens), that transplanted cells have become “sick” with PD proteins that promote disease progression.

That said, this research by Dr. Kriks’ team and other scientists is proving critical in helping to move stem cell research forward and to bring new therapies to people with PD. However, many challenges still need to be overcome before these therapies are ready for prime-time.  The new generation of stem cell scientists will have to better address the following: 1. all symptoms of PD (motor and non-motor/behavioral); 2. levodopa resistant symptoms (such as walking, talking and thinking); and 3. how to protect newly transplanted cells against “sickness.”  Additionally, any new therapy will need to be proven safe, ensuring runaway behavioral manifestations and other adverse events do not occur.  Future models also will need to prevent tumor formation.

We remain encouraged that stem cell therapy can play a role in the treatment of PD in the future, and we look forward to a new generation of scientists who will pursue these current challenges.  We congratulate Dr. Kriks and the other study authors for having taken another important step forward.  We would encourage stem cell researchers to continue to “think outside the box” and to combine their cell based techniques with novel delivery systems, which we hope will lead to developments of new therapies that will improve and rescue much larger areas of brain in people with PD.

Selected Reference
Kriks S, Shim JW, Piao J, Ganat YM, Wakeman DR, Xie Z, Carrillo-Reid L, Auyeung G, Antonacci C, Buch A, Yang L, Beal MF, Surmeier DJ, Kordower JH, Tabar V, Studer L. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature. 2011 Nov 6. doi:
10.1038/nature10648. [Epub ahead of print] PubMed PMID: 22056989.

You can find out more about NPF's National Medical Director, Dr. Michael S. Okun, by also visiting the NPF Center of Excellence, University of Florida Center for Movement Disorders & Neurorestoration.

Many Parkinson’s disease patients and families members have been unnecessarily alarmed by the continuing reports that Sinemet and/or Madopar (European Sinemet) may accelerate disease progression, and that doses and drug intervals should be limited.  These reports have unfortunately been fueled by sparse human evidence. Patients need to be aware that dopamine replacement therapies such as Sinemet and Madopar remain the single most effective, and single most important treatment for Parkinson’s disease worldwide.  This month’s “What’s Hot” column will focus on the evidence including the most recent paper on this important topic.

In this month’s issue of Neurology, important evidence is presented that dopamine replacement therapy is not toxic, and does not accelerate disease progression.  Parkkinen and colleagues at Queen Square in London examined pathology in 96 post-mortem Parkinson’s disease brains, and paired the tissue with clinical information including levodopa use.  The study concluded that in the human condition “chronic use of L-dopa does not enhance progression of Parkinson’s pathology.” 

In an accompanying editorial, two prominent neurologists in the field pointed out that there “remains lingering concerns as to whether levodopa is toxic to dopamine neurons and accelerates the degenerative process.”  The science quoted to support these claims has included levodopa undergoing auto-oxidation, and forming reactive oxygen species and toxic protofibrils.  Additionally, the science includes a classical experiment that showed when levodopa was mixed with brain cells placed in a dish, there was toxicity.  The research, however, has fallen short in demonstrating toxicity of the drug in the human form of Parkinson’s disease.  In fact, there now exists broad levels evidence from many studies across many countries (including most recently the ELLDOPA study) that levodopa is extremely beneficial to the human patient, and that levodopa has had a positive effect on disease course. Sinemet was recently reported as the most commonly administered drug among 4000+ patients being followed longitudinally in the National Parkinson Foundation Quality Improvement Initiative study.  Expert practitioners who reported in this database, utilized levodopa more than any other drug-- including dopamine agonists, and they used levodopa more (not less) as disease durations increased.

What all this adds up to for patients and for Parkinson’s sufferers is that Sinemet and Madopar should be considered safe and effective as treatments for Parkinson’s disease.  The doses and intervals should be frequently adjusted by an experienced neurologist/practitioner in order to maximize benefits, and to tailor to individual symptoms. Patients and families should keep in perspective that the “talk” about levodopa being toxic and accelerating disease progression can prove a major distractor to good care practices.  Precious minutes in the doctor-patient relationship should not be wasted on these claims, and prescribers should not avoid or under-dose this critical therapy, especially in patients with treatable symptoms.  Critics of Sinemet and Madopar will need to bring forward much stronger human data if they wish to change clinical practice.  In the mean time, we need to serve our patients by sharing with them the weight of the evidence which strongly supports that levodopa replacement therapy is not toxic, and does not accelerate Parkinson’s disease.

Selected References:
Parkkinen L, O'Sullivan SS, Kuoppamäki M, Collins C, Kallis C, Holton JL, Williams DR, Revesz T, Lees AJ. Does levodopa accelerate the pathologic process in Parkinson disease brain? Neurology. 2011 Oct 11;77(15):1420-6. Epub 2011 Sep 14.

Warren Olanow C, Obeso JA. Levodopa toxicity and Parkinson disease: Still a need for equipoise. Neurology. 2011 Oct 11;77(15):1416-7. Epub 2011 Sep 14.

Fahn S. Parkinson disease, the effect of levodopa, and the ELLDOPA trial. Earlier vs Later L-DOPA. Arch Neurol. 1999 May;56(5):529-35.

You can find out more about NPF's National Medical Director, Dr. Michael S. Okun, by also visiting the NPF Center of Excellence, University of Florida Center for Movement Disorders & Neurorestoration.

One of the most common questions we hear from patients is, “what can I do to be sure I am getting the best possible treatment for my Parkinson’s disease?” Most doctors focus on treatment-based recommendations (e.g. drugs, exercise, diet, etc.). The initial answer to this patient question should probably simply be “make sure you are co-managed by both a neurologist and a primary care physician.”

In the August 30, 2011 issue of Neurology, Willis and colleagues asked a provocative question: Will involving a neurologist in the care of a Parkinson’s disease patient makes a difference in outcome? From 2002-2005, they carefully reviewed 138,000 PD Medicare beneficiaries and discovered that only 68% of patients received neurologist care, with the remainder receiving primary care. The authors observed that neurologist-treated patients were “less likely to be placed in a skilled nursing facility, had a lower risk of hip fracture, and had a lower adjusted likelihood of death.” Another interesting finding was that women and minorities received less specialty care compared to white males. The diagnosis of PD was not confirmed by a PD specialist in this study, and data was not available as to whether patients actually saw a movement disorders or Parkinson’s disease specialist.

In an age where patients and clinicians seek more and more expensive diagnostic tests, it is intriguing to consider that a simple referral to a neurologist for co-management with a primary care physician may have the biggest and most important impact on a Parkinson’s disease patient’s outcome. In a way, this finding should not be surprising. After all, the best diagnostic test for Parkinson’s disease remains an expert neurological examination, and it would follow that the best clinical optimization of the patient should therefore be placed in the hands of a neurologist. A Parkinson’s disease patient is complex and motor, non-motor, behavioral, and, in some cases, surgical options must be considered for best management. The pharmacological strategies for Parkinson’s disease are also complicated, and often require multiple medications, multiple doses and medication intervals as close as every 2-3 hours. Despite the limitations in the methodology of this type of study (drawing data from Medicare beneficiaries), if the findings are true and confirmed, there could be a tremendous economic savings to the healthcare system by simply executing a referral, and co-managing Parkinson’s disease patients with primary care physicians. An even better recommendation would be for co-management by a movement disorders neurologist (expert in Parkinson’s disease treatment and care) and a primary care physician (if both are available in your area).

Reference:
Willis AW, Schootman M, Evanoff BA, Perlmutter JS, Racette BA. Neurologist care in Parkinson disease: A utilization, outcomes, and survival study. Neurology. 2011 Aug 30;77(9):851-7. Epub 2011 Aug 10.