Category: Treatment

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.

REFERENCES

  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.

HOW EFFECTIVE IS FUS FOR ET?

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.

WHAT ABOUT FUS FOR PD?

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: http://www.localdvm.com/news/maryland/more-than-a-year-after-breakthrough-parkinsons-disease-treatment-woman-does-better-than-expected/642454168

WHAT ABOUT MAINE?

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.

REFERENCES

  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.
  4. http://www.brighamandwomens.org/Departments_and_Services/neurosurgery/NeurosurgicalTechnology/default.aspx?sub=1
  5. https://www.michaeljfox.org/mobile/news-detail.php?how-focused-ultrasound-helped-my-dyskinesia-from-parkinson
  6. https://www.michaeljfox.org/foundation/news-detail.php?first-patient-treated-in-dyskinesia-study-using-ultrasound-technology
  7. https://vtdigger.org/2017/01/16/digger-dialogue-surgery-gives-sen-anthony-pollina-new-lease-life/#.Wclu3VtSyM9

 

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.

 

What about medical marijuana and PD?

I am asked almost daily about medical marijuana for PD.  For the purposes of this essay, I will call marijuana “MJ.”  I am not alone in being asked this question; my movement disorder colleagues around the state have had similar experiences.  The National Parkinson Foundation (NPF) states that, among physicians surveyed at their 40 NPF Centers of Excellence, 95% of neurologists reported PD patients had asked for a medical MJ prescription, and 80% of patients with PD had used MJ, whereas only 10% of physicians had recommended it, and 75% of physicians felt that MJ would have a negative effect on short term memory (1).

MJ in PD is a complex subject, and to be clear, under Federal law, is not legal, though a couple of drugs derived from MJ are:  dronabinol (Marinol) and nabilone (Cesamet).  Since President Nixon signed the Controlled Substances Act in 1970, MJ has been classified by the FDA as a Schedule I drug, defined as a drug with a “high potential for abuse … no currently accepted medical use.”   Schedule I designation is an impedance to scientific study for potential medical use.   In other words, it is hard to conduct trials with this designation.  However, trials or not, in Maine medical MJ has been approved since 1999.  Under the Rules Governing the Maine Medical Use of Marijuana Program (MMMP), there are certain indications for the use of medical MJ, but PD is not one of them (2).  Regardless of medical law, the recent citizen initiative to legalize recreational MJ passed.  Access is legal (within certain limits) for adults under State law.  Many people with PD tell me they will be, or have already been, trying MJ.  I have heard from people who report improved tremors and dyskinesia, some who have better sleep, some who say it does nothing, and some who do not tolerate it due to side effects.  This is all anecdotal.  What does science show?

The pharmacology of MJ is complicated.  Most MJ strains come from two species of plant: Cannabis sativa, and Cannabis indica.  Over 60 neuroactive compounds have been identified in MJ.  Many of these work on the brain’s endocannabinoid system, which is known to affect neurotransmission in the motor system of the brain, and there are many receptors in the basal ganglia – the main region dopamine is used.  Endocannabinoids also are implicated in the control of mood, cognition, and pain.   THC is found in a higher concentration in sativa plants, and is thought to be the primary psychotropic compound in MJ, the cause of paranoia, and other psychotic features.  Cannabidiol (CBD) is a non-psychoactive substance, and is in higher concentration in indica strains.  CBD has sedating, anti-emetic (helps with nausea and vomiting), and analgesic (pain) properties.

There is a lot of data about MJ in the basic science, and some in the medical literature about people taking MJ as an intervention.  The type of study is important. Case reports may describe the experience of only one, or of very few patients with an intervention.   An open label study is one in which there is no placebo, and the concern is that there may be bias, whether conscious or unconscious, on the part of the participant or the evaluator.  In other words, if you know you are taking an intervention, you may believe you are changed by that intervention.  Belief is important in the mind-body connection, and is the basis of the “placebo effect.”  This is not to say that open label trials are useless, just that they must be interpreted with caution.

In one open label observational study at an academic movement disorder center, 22 PD patients were tested at baseline and at 30 min after smoking MJ (3).  The group showed improvements of tremor, rigidity, and bradykinesia in the UPDRSIII motor score used to evaluate PD patients, improving on average from 33.1 to 23.2 after consumption.  If the score means nothing to you, know that the UPDRSIII score ranges from 0, with no PD, to 108, the worst PD imaginable.  Therefore, the lower the UPDRSIII score, the better, sort of like golf.

The scientific approach to prove the effectiveness of any drug or intervention would be to progress through trials which demonstrate safety with a few patients (phase I), a larger group (phase II), and efficacy (phase III).  In all phases, side effects are noted.   In the phase III trial, the gold standard is the well-designed, randomized, double-blinded, controlled trial (RDBCT).  In this trial participants must meet certain criteria for entry, and take either the trial intervention (for example, MJ), or a placebo.  When people participate in studies, they are evaluated periodically to measure effect.  A study is double-blinded when neither the study participant nor the evaluator know who is taking the intervention, and who is taking placebo.  All data is eventually collected, interpreted, described and discussed in peer-reviewed medical journals.   Doctors then read these articles and use their own skills of critical analysis to interpret the study.   There are many variables at play, and a study may raise many questions.  A single study may need additional support.  A study that shows unique results should ideally be repeated by a separate group of researchers and study participants.

Larger study groups tend to provide more valid information about how people may respond generally because researchers are able to average a lot of data.  Unfortunately, there is very little study data with MJ in large groups of PD patients or the RDBCT.   Some authors have tried to go through the available data and produce a conclusion from several case reports and studies.  For example, researchers looked at a collection of papers and showed that oral cannabis extract (OCE) is probably ineffective for treating levodopa-induced dyskinesias (4).

Papers such as this led a subcommittee of the American Academy of Neurology to review multiple studies involving the use of MJ in the treatment of neurologic diseases (5).  These studies showed that, in PD, treatment with the compound  9-tetrahydocannabiol (THC) or with OCE are probably ineffective in treating tremor.  OCE is probably ineffective for treating levodopa-induced dyskinesias in PD.  They noted that among 34 studies the risk of serious adverse psychopathologic effects was about 1%. The authors reported that comparative effectiveness of medical MJ vs. other therapies is unknown for these indications.

In 2015, researchers published in the journal of the Movement Disorders Society another summary of study data, which concluded that MJ is probably not helpful for the treatment of tremors or dyskinesias (6).

There are concerns about MJ in PD beyond paranoia and psychotic features.  While MJ might help with pain, insomnia, nausea, and weight loss, it might cause side effects.   MJ use decreases reaction time, has negative effects on cognitive and executive function, may lead to risky behaviors, create apathy or a lack of motivation, cause dizziness and blurred vision, cause mood or behavioral changes, affect balance, or just make a person sleepy.  All of these are already potential problems in PD, which may be exacerbated.  Chronic use of MJ has been shown to unmask underlying psychiatric disorders.  Finally, smoking MJ is associated with increased risk of lung cancer and stroke.  Vaporizing MJ is also probably not a healthy option.

In conclusion, there is not much data to support the use of MJ in PD, but there is a huge political will to legalize it, and a growing feeling among patients that it is safe to try.  This may not be true.  As with any neuroactive substance, large RDBCTs are needed to demonstrate benefit and safety.  In addition, if effective, MJ, which is a very potent compound, would ideally go through approval process with the FDA.  MJ has not, and physicians do not have label or dose recommendations, timing instructions, or adequate description of all potential side effects.

References

  1. http://www.parkinson.org/understanding-parkinsons/treatment/complementary-treatment/medical-marijuana-and-parkinsons-disease
  2. http://www.maine.gov/dhhs/mecdc/public-health-systems/mmm/documents/MMMP-Rules-144c122.pdf
  3. Lotan et al. Cannabis (medical marijuana) treatment for motor and non-motor symptoms of Parkinson disease: an open-label observational study. Clin Neuropharmacol. 2014;37(2):41-4
  4. Koppel et al.  Systematic review of medical marijuana 1948-2013.  Neurology.  2014;82(17):1556-63
  5. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014 Apr 29;82(17):1556-63.
  6. Kluger et al, The therapeutic potential of cannabinoids for movement disorders.  Mov Disord. 2015;30(3):313-327

 

The Neuropsychological Evaluation for Deep Brain Stimulation

by Tom Miller, Ph.D.

 

A neuropsychological evaluation is a method for examining the quality of brain function and for determining a patient’s cognitive strengths and any limitations. It involves several steps:

 

  • a clinical interview to obtain information from the patient and his or her spouse or other family members about daily functioning, details of ongoing problems, and any concerns about cognitive functioning (e.g. problems with attention, memory, mental processing, etc.);
  • obtaining additional background information from medical records and reports, review of any previous testing, and other relevant information;
  • the administration of various tests to examine cognitive functioning in a number of areas, including intellectual abilities, attention, language, learning and memory, visuospatial abilities, sensory-motor functioning, executive function, emotional status, and personality.

These areas of cognition involve different regions of the brain, and a person’s performance on testing can reveal the relative efficiency or impairment in these brain regions.

A neuropsychological evaluation is scheduled before a deep brain stimulation procedure (DBS) for several reasons:

  • to establish of pre-surgical baseline of functioning in these areas of cognition;
    to determine whether there are any difficulties that may be exacerbated by surgery;
  • to determine whether there are any difficulties that may interfere with adjustment after surgery.

DBS involves implanting electrodes into brain regions that regulate attention, aspects of language, and memory retrieval. Parkinson’s disease can contribute to difficulties in these areas of functioning. It is important to determine the extent of any difficulties before making a decision whether to proceed with DBS.

Memory impairment can make it difficult for a patient to follow recommendations and adhere to a medication schedule, and significant memory impairment may indicate early signs of dementia.

It is important to determine whether problems with memory are beyond the ordinary occasional memory lapses that many of us encounter from time to time. Testing is necessary to determine the nature and extent of memory problems: distinguishing between:

  • “ordinary” and occasional lapses of memory (no interference with functioning);
    inefficiencies in memory (may be annoying at times but without much interference);
  • mild memory impairment (difficulties with remembering details of events occurring in recent weeks or months);
  • moderate memory impairment (inability to recall many details of events, conversations, appointments occurring more recently; needing frequent reminders, increasing interference with daily functioning);
  • severe memory impairment (inability to recall information within minutes, requiring multiple repetition of instructions or requests, inability to follow conversation, etc);
  • lapses of attention and memory (difficulties with memory may actually be related to lapses of attention, distractibility, or inability to concentrate effectively).

Memory testing helps to determine whether difficulties are related to initial encoding of new information; the process of storing new information; or the retrieval of information from memory. These stages of memory involve different areas of the brain – and information about performance provides your doctor with information about functioning in specific brain regions.

It is also important to examine emotional status and personality functioning. Acute anxiety or deep depression interferes with thinking, planning, and problem solving. An inability to function effectively in these areas might impair judgment to an extent that the process of managing DBS becomes overly complicated and the advantages of DBS become difficult to see. Personality functioning itself may suffer, and a person may find themselves overly anxious and worried, or without interest or motivation in their lives.

It is possible to master bouts of anxiety or hopelessness by learning and practicing various mental or behavioral strategies – sometimes referred to as cognitive-behavior therapy, or CBT. The use of these tools can help restore emotional balance along with a sense of confidence and ease. If significant emotional distress is a factor, a referral can be made for therapy to help improve overall functioning.

 

Dr. Tom Miller practices at Maine Medical Center Department of Psychiatry, Geriatric Outpatient Psychiatry, 66 Bramhall Street, Portland, ME 04102

Constipation in PD

Unexplained and persistent constipation in adults is associated with an increased risk of PD.  Nearly one third of patients will have been diagnosed with a GI disturbance within the year prior to PD diagnosis (1), and many more will have noticed a change in bowel habits without having received a formal diagnosis. There is a preponderance of data to support this.

In 2001, the Honolulu Heart Program (2), a large population-based prospective study, showed a 2.7-fold risk of developing PD for men with less than one bowel movement daily, when compared with men having one or more daily.   In 2011, a large prospective study of over 100,000 people also showed that over the next six years, relative risk of developing PD was was nearly five times greater for men who had one bowel movement every three days or less (3), compared with men having a daily BM.   A 16-year prospective study of 8,166 people with PD and 46,755 without PD in the United Kingdom reported that, in the two years prior to diagnosis of PD, 32% had constipation (4).

Unfortunately, the prevalence of GI disturbances in PD increases with age and longer duration of disease.  Ultimately, constipation is reported by almost 60% of PD patients (5).

The reasons for constipation in PD are complex.  As discussed in the Spring 2016 issue of this newsletter, in the article “What’s so bad about alpha-synuclein?,” disease-specific pathology may be seen in the gut years prior to the development of motor symptoms of PD, and that pathology may be part of the culprit leading to disease (see also the slides from the April talk on alpha-synuclein).

The problem seems to arise from a slowing down of the gut in PD.  There may be a delayed gastric emptying, followed by slow transit of stool. This allows the over-production of bacteria which results in gas, and sometimes, colic.  Another problem is that stool is supposed to dry out as it moves through the colon.  The slower it goes, the drier it gets, and in a self-perpetuating cycle, the drier it gets, the slower it goes.  Some patients with PD have such slow transit they develop a hard stool called a fecalith, or “feces rock.”  In rare cases, all movement of stool may stop, a medical urgency/emergency known as impaction.

So, what can a person with PD do about constipation?

First, educate yourself.  Drugs used to treat many conditions, including those meant to help PD, can cause constipation.  Some of these drugs include anticholinergics such as trihexyphenidyl (Artane), benztropine (Cogentin), and even carbidopa/levodopa (Sinemet).  Other medication-induced causes of constipation include narcotics, antihistamines, tricyclic antidepressants such as amitriptyline, certain antipsychotics, some antihypertensives, lipid-lowering drugs, calcium supplements, iron tablets, and even antacids (APDA).  Before stopping any of these medications, check with your prescribing doctor.

Daily exercise is helpful, and you should check with your doctor about any recommendations or limitations you may have.

There are certain foods and beverages that may lead to, or enhance, constipation, for example, cheeses, red meats, dairy products, processed foods, fast food, fried food, and “junk” food, are all culprits (your mother was right).  Caffeine, while stimulating bowel movements in some, is actually a diuretic, which may dry the stool out even more.  The same is true of alcohol.  If you drink either caffeine or alcohol, compensate with water.  People with constipation should stay hydrated, and eat foods which aid in digestion, such as raw vegetables and fruits, dried prunes, bran, and high-fiber foods.  To learn more about diet and find a recipe for a high fiber mix that may help, see the APDA handout on constipation (6).

Generally, one should eat at regular times, and try to have a bowel movement about 30 minutes following the morning meal.  This naturally occurs due to a phenomenon called the gastrocolic reflex, in which the brain sends messages to the GI tract to defecate when the stomach is distended.

The Guidelines

In 2006, the American Academy of Neurology (AAN) wrote in their guidelines for the treatment of non-motor symptoms of PD that increased water and dietary fiber intake have shown clinical benefit in relieving constipation (7).  The AAN found only limited, or “weak” evidence regarding medications at the time, but supported  isosmotic macrogol (polyethylene glycol), available as Miralax over the counter, which “may be considered to treat constipation in PD.”  The benefit of Miralax is that it is not systemically absorbed, and instead, pulls water like a sponge into the gut, where it can help hydrate stools.   Soluble fiber has the same effect and is not absorbed into the bloodstream.   However, using Miralax or fiber alone is often inadequate.

Calin Stoicov, M.D., a gastroenterologist at Mid Coast Medical Group in Brunswick, points out that we should be careful in how we define constipation. The definition is not solely based on the frequency of bowel movements, though less than three weekly is a place to start the description. Also, there is straining at lumpy, hard stools, a sensation of incomplete evacuation, and a sensation of rectal obstruction or blockage with 25% of bowel movements.

Stoicov noted that, broadly, the constipation in PD is treated similarly to other forms.  “The agents are divided into four groups: bulking agents such as dietary fiber or artificial fiber (Benefiber, Citrucel), osmotic agents (Miralax), stimulants (senna), and pharmacological agents (Amitiza or Linzess).”   He noted that constipation is usually not painful.  If there is pain associated with constipation, one should think of another culprit, such as irritable bowel syndrome (IBS).   That patient should be evaluated by a physician.  For patients with PD who have simple constipation, he recommends starting with Miralax, and to use it liberally, as it is not absorbed.   Some patients will try lactulose, but should be careful, as it may be more likely to cause bloating.  When patients are prescribed Amitiza or Linzess, they may find more success, but should be careful as these medications may be a little too successful, and result in diarrhea.

People should not expect immediate results, either.   I often hear that this or that approach did not help after a few days, so it was abandoned. Or, some people will note that they may have a loose stool on some days, and a hard stool once a week.  In this case, there is too much dried out stool in the colon, and loose stool is moving around it.  It is better in that case to have a regular, daily bowel regimen, to keep everything moving.  Per Dr. Stoicov, medications are usually effective within about a week.  He notes that stimulants, such as the herbal laxative senna, have a tendency to stain the colon black, which may be seen during colonoscopy. Some data suggest that this condition, known as melanosis coli, might predispose to polyps.

Finally, it is not good to wait until constipation becomes a problem.  Be proactive, educate yourself, and promote good bowel health.  This really is a situation wherein you get out what you put in.

1.  Makaroff et al. Gastrointestinal Disorders in Parkinson’s Disease: Prevalence and Health Outcomes in a US Claims Database. J Parkinsons Dis. 2011;1(1):65–74.
2. Abbott  et al. Frequency of bowel movements and the future risk of Parkinson’s disease. Neurology. 2001;57:456–62.
3. Gao et al. A prospective study of bowel movement frequency and risk of Parkinson’s disease. Am J Epidemiol. 2011;174:546–51.
4. Schrag et al. Prediagnostic presentations of Parkinson’s disease in primary care: a case-control study. The Lancet Neurology, 2014;14(1):57-64.
5. Magerkurth et al. Symptoms of autonomic failure in Parkinson’s disease: prevalence and impact on daily life. Clin Auton Res. 2005;15(2):76–82.
6. http://www.apdaparkinson.org/uploads/files/Constipation-8-25-15-er0.pdf
7. https://www.aan.com/Guidelines/Home/GetGuidelineContent/409

What is deep brain stimulation?

Your brain is the most complicated machine known, a mass of billions of interconnected  neurons, each of which may form an average of about 7,000 synapses (connections with other neurons), forming your personal and highly unique connectome – the map of all of those connections.  At each of these synapses, electrochemical signaling fires in patterns that may be individual or in networks, which generate a signal strong enough to detect with electrodes on the scalp.  This is what allows us to study brain waves on an electroencephalogram (EEG).  Brain electrical activity can also be changed in a way that helps patients with neurologic diseases, and is the basis of deep brain stimulation (DBS).

However, the story of how we got here goes back farther than most would guess. For example, in the first century A.D. the Roman physician Scribonius Largo described using the electric ray fish, torpedo, to shock the heads of headache sufferers (1).    Since the common ray can deliver a charge of up to 200 volts to immobilize prey, one can imagine the effect on a person might be less than pleasant.  Electric fishes were actually used in European medicine at least into the eighteenth century.  There were many other experimental uses of electricity, on living and expired subjects, in centuries past.  Thus it was not so unusual that in the early twentieth century electroconvulsive therapy was established in psychiatric medicine.

Work with electricity also led to a greater understanding of how our brains operate. In the 1930s, Canadian neurosurgeon Wilder Penfield famously mapped functional regions of the brains of awake patients with electrical stimulation during surgery (2).   He was not alone in using electricity to study or modulate the brain.  These early pioneers led the way to the formation of DBS.

DBS as we know it today begins in the early 1950s, when Spanish neuroscientist Jose Delgado reported implantation of electrodes in humans (3).   A decade later he described  radio-equipped electrodes which he had placed in various animals, and in 25 people.  In 1963, he demonstrated he could stop a bull from charging (or at least veer off-course) with the device. Over the following decades, investigators around the world experimented with brain electrodes.  Two groups in 1991 ushered in modern technology when they successfully demonstrated that DBS could treat tremor (4,5).

DBS was FDA-approved in 1997 for tremor associated with essential tremor and Parkinson disease (6). In 2002, the indications were expanded to include other symptoms of Parkinson disease.   Previously, patients may have undergone surgical procedures such as thalamotomy or pallidotomy, which affected or diminished motor symptoms by surgically destroying a specific brain region. After DBS was approved, it became the preferred, or much more commonly administered, treatment.  There are several reasons for this, such as the facts that DBS is not intended to destroy brain tissue, is adjustable and programmable, and is at least as equally effective as the older surgical procedures. DBS is also reversible.  It may be turned off and sometimes will be removed, though this is uncommon.  It has been implanted a great deal since 1997.  According to the International Neuromodulation website, between 1997 and 2012 there were over 80,000 DBS implants around the world for a variety of indications (7).

Who should have DBS?

In Parkinson disease, the procedure is usually intended to treat disabling motor complications, tremor, and dystonia refractory to medical treatment.  For example, patients may want DBS when dyskinesias become intolerable, or when medications fail to work in a predictable way.  Some patients complain of sudden, unpredictable off time when medications should be working.  DBS may help, as it is a continuous delivery system instead of the pulsatile approach of medication dosing.  There are also PD patients whose tremors respond inadequately, or not at all, to medications.   Typically, if other symptoms of PD such as stiffness and slowness respond to medication, then DBS may be a good option for tremor control in these patients.  DBS does not cure PD, but helps to diminish some of the motor symptoms.  Because of this, patients are usually able to cut back on medications, and thus, medication side effects.

And, who should not have DBS?

Medtronic, the manufacturer of the first, and still most widely used DBS platform, offers the following exclusion criteria:   no longer responsive to medications; severely disabled, even in the best “on” state; medical conditions that prevent surgery; and onset of dementia. It may be hard to define exactly when a person has reached each of these states, and this is where having a team-based approach to assessing the patient can be helpful.  In Maine, a team composed of a neurosurgeon, movement disorder neurologists, neuropsychologists, and specialized nurses meet to discuss potential cases and outcomes.

What are the risks? 

Risks of surgery can be serious and fortunately occur in only a small minority of patients. These can include stroke, paralysis, coma, death, bleeding in the brain, cerebrospinal fluid leak, seizure, infection, allergic reaction to implanted material, confusion, pain at surgery sites, and headache.   These risks should not be taken lightly and should be discussed at length with your doctor prior to making a decision to proceed.  Since no two patients are the same, there may be other risks unique to that person, and sometimes the risks are too great.

Programming of DBS is meant to stop motor symptoms of PD, but may also cause unwanted side effects, such as tingling, temporary worsening of symptoms, speech problems (for example, slurred speech or trouble producing words), double vision, dizziness, weakness of the face or limbs, temporary worsening of dyskinesia, coordination problems, feelings of shocks or jolts, numbness, and very rarely, behavioral disturbance.  Usually, programming changes can eliminate these issues.  In the rare circumstance where relief from side effects cannot be found, DBS can be turned off.

Who has had the procedure in Maine?

Lots of people.  Before 2013, patients were implanted in other states.  Since 2013, dozens of implants have been done in Maine with Dr. Rughani.  I asked a couple of my patients about their experience as I was writing this article.

Barbara Keezer of Augusta, Maine, told me that she had suffered with PD for over 14 years when, in 2005, the development of uncontrolled dyskinesias led to deep brain stimulation with Dr. Van Horne in Boston.  She states she “could tell a difference right away, dyskinesias stopped.  I couldn’t walk before the surgery because I never stopped moving. I was in a wheelchair, but after DBS I could walk by myskeezerself.” Her husband Gordon notes that she had several good years.  Still, with a 25 year course, the disease has progressed. In the last 2 -3 years she has needed a wheelchair again, and a lot of help from him.  “She has gone downhill gradually with the Parkinson’s, you can’t change that.  But, she still wants to do things, to be independent.”   Barbara states her husband is always reminding her “don’t do that by yourself.”  He says, “I have to watch her, and make sure she doesn’t fall.”  Yet, Barbara reports that DBS is still helpful and keeps her doing what she can.  “If you turn the DBS off, I can’t move at all.  So, it’s doing something good.” For her it was, and still is, a definite benefit.

Forty-three year-old Melinda Jewell has young-onset PD, and in 2013 had right brain DBS in Boston. In 2015 the left brain was implanted by Dr. Rughani in Portland.  She is happy with the results and tells me the local Jewellexperience was ”really good, with a great team.”  She was a little nervous about going through it a second time in a different place. At the procedure,”Dr. Rughani talked to me and I think he was distracting me a little,” she smiles.  “And, the anesthesiologist was funny.  He made jokes and I listened to country music.  I forgot to be nervous and I am glad I did it.”  As to whether or not it has been helpful, she says, “Yes! I still have some issues, but I probably wouldn’t be working now if I hadn’t had DBS.”

PPatricia Joyceatricia Joyce has had PD since 2005, and underwent DBS surgery in 2014 with Dr. Rughani. She notes, “I didn’t think the surgery was bad at all.  It was pretty cool actually. They warned me that the worst part was staying still for so long. I did get a little itchy, but other than that, it was fine. I’m happy I did it, and I’d do it again.”

Still, as Dr. Rughani notes in our interview, the risk and benefit should be taken very seriously, and carefully considered before proceeding with surgery.

1. Debru, A. The power of torpedo fish as a pathological model to the understanding of nervous transmission in antiquity. C. R. Seances Soc. Biol. Fil. 2006;329: 298–302.

2. Penfield, W., Boldrey, E.  Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation. Brain  1937; 60, 389–443.

3. Delgado et al.  Technique of intracranial electrode implacement for recording and stimulation and its possible therapeutic value in psychotic patients.  Confin. Neurol.  1952;12:315-19.

4. Benabid et al.  Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet 1991; 337:403–406.

5. Blond, S., and Siegfrid, J. Thalamic stimulation for the treatment of tremor and other movement disorders. Acta Neurochir. 1991; S52: 109–111.

6.http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm451152.htm

7. http://www.neuromodulation.com/deep-brain-stimulation

Psychosis in Parkinson disease

by Markos Poulopoulos, M.D.

Introduction

James Parkinson, in his pivotal work “An Essay on the Shaking Palsy” (published in 1817), was the first to recognize the condition that later was named after him.

Dr. Poulopoulos practices in Bangor, Maine
Dr. Poulopoulos practices in Bangor, Maine

He defined it as “involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forwards: the senses and intellects being uninjured.” He then noticed that “the sleep becomes much disturbed,” “the bowels, in most cases, demand stimulating medicines of very considerable power,” and “the urine is passed involuntarily; and at the last, constant sleepiness, with slight delirium, and other marks of extreme exhaustion” (1).

Despite his above observations, little attention was given to the non-motor manifestations of Parkinson disease up until the last 10-15 years. For quite a long time, the scientific focus was heavily on the motor symptoms, which are still used for making the diagnosis (tremor, stiffness/rigidity, slowness/bradykinesia and gait instability). One could say that we were only looking at the tip of the iceberg.iceberg3

But there is so much more than the physical symptoms, other difficulties that are far more difficult to deal with and cry for more vigorous research and effective treatment development. Psychosis is perhaps the most problematic and intrusive constellation of symptoms, and the subject of this discussion.

What do we mean by psychosis?

Psychosis in Parkinson disease is defined (2) as the presence of at least one of the following symptoms:

⦁ Illusions – This is when you mistake a real object for something else.

⦁ False sense of presence passage (hallucinations) – This when you think there is somebody behind you, or a vague figure is quickly passing by your side. However, when you turn your head to look at it, there is nothing there.

⦁ Hallucinations – This is when you see (less often hear, smell or feel) people or animals typically in front of you that clearly do not exist, and there is no other real object to be mistaken for what you experience.

⦁ Delusions – This pertains to unusual, disruptive beliefs or ideas, usually of a paranoid nature, e.g. persecution, theft, infidelity.

We need to highlight the importance of early recognition and treatment of even benign aspects such as illusions. There is about an 80% chance for these to progress to more complex and persistent symptoms such as hallucinations and delusions, which in turn can be very difficult to treat and have a significant impact on your life and that of your family. If psychosis gets out of hand, it is usually a reason for nursing home placement, and results in an increased rate of other complications, including decreased survival. For example, one may lose insight and firmly believe that the hallucinations (people or animals) are real, react by attacking them or running away from them, and subsequently fall and break a hip.  These events can lead to a domino effect with potentially serious complications.

Hence, knowing the nature of psychosis will help the doctors, patients, and care givers to ask pertinent questions in search of subtle signs that would otherwise go unnoticed. It is always better to treat early, rather than late.

How frequent is psychosis?

Overall, psychosis can be present in up to 60% of Parkinson disease patients at some point in time. The more fearsome aspect is visual hallucination, which can be present in 7-25% of patients with Parkinson disease. However, if we consider only patients with dementia (so-called Parkinson disease dementia), hallucinations have a frequency from 40 to 80% (3).

Psychosis is more likely to happen when a patient with Parkinson disease also has dementia. However, it is also well documented in patients with Parkinson disease without dementia. In this situation, psychosis can happen in 20% of patients. In more detailed breakdown, frequency of visual hallucinations is about 13%, auditory hallucinations 7%, illusions 7%, and paranoia 5% (4).

Other non-motor manifestations of Parkinson disease that sometimes predict the development of psychosis are REM sleep behavior disorder (acting out the dream content) and depression/ anxiety.

Do medications play a role? Yes and no. 

The answer is yes for most medications, and debatable for carbidopa/levodopa. Although the common practice is to try to reduce the dose or stop medications in hopes of decreasing or stopping the psychosis (see management section), there is evidence that psychosis can happen before the start of any treatment with such medications. It is intriguing that psychosis may happen in up to 40% of drug-naïve patients, as opposed to 5% of individuals without Parkinson disease. In this scenario the good news is that insight is almost always retained, and the type of psychosis is by and large a simple sense of presence or feeling that somebody is passing by (rarely visual hallucination) (5).

What can we do? How can we treat it?

⦁ Knowledge – First of all, knowledge of the nature of psychosis, being able to recognize and communicate its existence without guilt or fear, is paramount and the starting point.

⦁ Search for triggers – The doctor should work with the caregiver and the patient in an attempt to identify potential triggers such as infections, dehydration, insomnia, malnutrition, new medications/dose escalation, home/environmental changes, bereavement, and exacerbation of depression.

⦁ Ideally, a team approach – Behavioral care, case management, and physical, speech, language, and occupational therapy aiming at an individualized treatment plan to relieve distress, provide direction, promote adaptation, and optimize quality of life.

⦁ Decrease or stop medications for Parkinson disease (3) – Typically, we wean off, or at least decrease the usual culprits with first and foremost the dopamine agonists (e.g. pramipexole/Mirapex, ropinirole/Requip), anticholinergics (e.g. trihexyphenidyl/Artane, amantadine), and other medications we may use to treat Parkinson disease. Carbidopa/levodopa (Sinemet) is the last medication that should be decreased, and certainly never stopped. There is no clear evidence that this medication can definitely aggravate psychosis.  Easily said, but it is usually difficult to implement the above, since decreasing anti-Parkinson medications will lead to worsening of the physical performance (tremor, gait, balance, and overall movement).

⦁ Add medications that mitigate or stop psychosis (brand name in parentheses) (3)

⦁ rivastigmine (Exelon):  In a 24-week, prospective, placebo-controlled trial, this medication, designed as a memory enhancer, both improved memory and decreased hallucinations (6).

⦁ quetiapine (Seroquel):  The evidence is rather equivocal in favor of this medication directly improving visual hallucinations based on studies (7).   However, it is widely used in clinical practice with good results based on anecdotal and personal experience. The main reasons are the ease of use and titration, and the favorable side effect profile (compared to all the other antipsychotics, it has the least potential for increased mortality).

⦁ clozapine (Clozaril): This medication has, so far, the best evidence with respect to efficacy reducing visual hallucinations (8).  However, frequent blood draws, the rare but very significant danger of reducing white blood cells that fight infections, frequent drowsiness, weight gain, and dizziness make it not the first choice for most doctors.

New treatment

Pimavanserin (Nuplazid) is the latest medication tested for treatment of visual hallucinations in Parkinson disease.

Based on a 6-week trial (randomized, double-blind, placebo-controlled) on a total of 200 patients (the largest number tested compared with the other medications listed above, apart from the rivastigmine trial), it did produce a statistically significant reduction in hallucinations, improved night time sleep, and decreased daytime sleepiness (9).

Furthermore, pimavanserin did not aggravate the motor symptoms of Parkinson disease and was overall well tolerated, probably better than quetiapine and clozapine, by extrapolation. This is likely due to a pharmacological action that differs from the other antipsychotic medications. All of the others block the various dopamine receptors in the brain and typically worsen Parkinson disease symptoms, since the levodopa (which converts into dopamine in the brain) cannot act on the dopamine receptors because they are occupied (blocked) by the antipsychotics. Pimavanserin does not act on dopamine receptors. Rather, it acts on serotonin receptors (specifically 5-HT2a). Pimavanserin may cause leg swelling (7%), nausea (7%), confusion (6%), and constipation (4%).

The pressing need for better treatments for psychosis in Parkinson disease led to FDA discussion for early approval on May 1, 2016

In conclusion, it is very important for patients and caregivers to report to the doctor symptoms in keeping with psychosis, so that we can search for triggers (as mentioned above), monitor symptom evolution and prevent/treat, if possible.

References 
1. James Parkinson.  An Essay on the Shaking Palsy. Neuropsychiatric classics. 1817.

2. Bernard Ravina et al. Diagnostic Criteria for Psychosis in Parkinson’s Disease: Report of an NINDS, NIMH Work Group. Movement Disorders, Vol. 22, No. 8, 2007, pp. 1061–1068.

3. Dag Aarsland et al. Psychiatric issues in cognitive impairment. Movement Disorders, Vol. 29, No. 5, 2014. Pages: 651-662.

4. Angela H Lee et al. Psychosis in Parkinson’s Disease Without Dementia: Common and Comorbid With Other Non-Motor Symptoms.  Movement Disorders, Vol. 27, No. 7, 2012. Pages: 858-863.

5. Javier Pagonabarraga et al. Minor Hallucinations Occur in Drug-Naïve Parkinson’s Disease Patients, Even From the Premotor Phase. Movement Disorders, Vol. 31, No. 1, 2016. Pages 45-52.

6. Burn D et al. Effects of rivastigmine in patients with and without visual hallucinations in dementia associated with Parkinson’s disease.  Movement Disorders 2006; 21:1899-1907.

7. Ondo WG et al. Double-blind, placebo-controlled, unforced titration parallel trial of quetiapine for dopaminergic-induced hallucinations in Parkinson’s disease. Movement Disorders 2005; 20:958-63.

8. The Parkinson study group. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson’s disease.  NEJM 1999;340:757-63.

9. Cummings J. Pimavanserin for patients with Parkinson’s disease psychosis: a randomized, placebo-controlled phase 3 trial. Lancet 2014,(8);383:533-540.

Immediate release carbidopa/levodopa 25/100 can cause allergic skin reactions 

Sinemet (carbidopa-levodopa) 25/100 immediate release (IR) tablets contain a yellow dye, D&C Yellow #10 Lake.  Per the prescribing information, rash is a possible side effect (1).

carbidopa/levodopa (Sinemet) 25/100
carbidopa/levodopa (Sinemet) 25/100

There are a few case reports to support rash as a possible side effect in two publications.   The first paper to cite this effect noted five patients who experienced rash associated with carbidopa/levodopa 25/100, and authors concluded the yellow dye in this formulation was responsible (2). Substitution with carbidopa/levodopa 25/250 or 10/100, formulations that do not contain the yellow dye, did not cause a rash.

The second paper reported two patients with rashes resulting from IR carbidopa/levodopa 25/100 (3).  In both cases, stopping the drug resolved the rash.  In one case, compounded pure levodopa and Stalevo 100 (carbidopa 25 mg/levodopa 100 mg/entacapone 200 mg), both of which are made without the yellow dye, were given in successive trials with no rash.

These are old reports, and searches for any more current information come up dry.  The incidence is apparently very low, and the phenomenon not well known.  I have seen this in patients and tend to try the CR, ER, or SA formulations, which do not contain the yellow dye, as alternatives.

Anecdotally, I have heard of allergic gastritis with IR carbidopa/levodopa, but have not seen this reported in literature.  Some patients may also experience nausea with the IR, but not other formulations of carbidopa/levodopa.

1. https://www.merck.com/product/usa/pi_circulars/s/sinemet/sinemet_pi.pdf
2. Goetz CG.  Skin rash associated with Sinemet 25/100.  N Engl J Med 1983;309:1387-88.
3. Chou and Stacey. Skin rash associated with Sinemet does not equal levodopa allergy. Neurology. 2007 Mar 27;68(13):1078-9.

The role of the speech pathologist in the treatment of speech, voice, and swallowing disorders associated with PD

by Yonca Berk-Giray, SLP

Eighty-nine percent of individuals with PD have speech and voice difficulties at the onset of the disease. As the disease progresses, this number rises to 100%. Most individuals with PD also experience varying degrees of swallowing difficulties.

Speech and voice difficulties are often overlooked by the patients and their physicians until the problem becomes severe enough that communication is affected. Many patients with PD experience difficulty socializing and being understood by others, and feel left out of conversations. Individuals experience decreases in vocal loudness levels, speech intelligibility, expression in their

speech and voice, and facial expression, as well as hoarse voice quality. Since these changes happen slowly over many years, most patients are not aware of them. Often it is their loved ones who first become aware of the communication issues.

Lee Silverman Voice Therapy (LSVT) is a voice and speech therapy program that is specifically designed for treating individuals with PD. It has been scientifically researched for the past 25 years and proven to be effective in treating voice, speech and communication difficulties associated with PD. LSVT follows a standardized treatment protocol that is customized to the needs of the individual. Mid Coast Rehabilitation Services currently has two clinicians who are certified in delivering this program. For those patients who are homebound, the therapy is also available through certified clinicians at CHANS home health services. For more information on LSVT Loud, and a list of certified clinicians, please see www.LSVTGlobal.com.

Swallowing difficulties associated with PD are much more subtle at the onset of disease, and can become serious and life threating as the disease progresses. Patients usually complain of drooling, foods getting stuck in the cheeks or throat, coughing with liquids or solids during meals, and difficulty taking their pills. Two main concerns with swallowing difficulties are the risk of aspiration related pneumonia and weight loss. Recognizing early signs of swallowing difficulties, and receiving treatment for them, is very important in staying ahead of the muscle atrophy that can happen. There are various methods and treatments available that are proven to be effective in treating swallowing difficulties in PD. See a physician or speech pathologist for more information.

It is important and strongly recommended that patients are proactive in receiving treatment early for speech, voice and swallowing difficulties to maximize their functioning for years to come.