Music Improves Parkinson’s Gait

Post prepared by Quoc-Sy Kinh Nguyen Drexel University College of Medicine Class of 2014

Walking through the park

Parkinson’s disease is a progressive, neurodegenerative disorder that affects 1% of people over the age of 60.
It is a clinical diagnosis that requires 2 out of 3 of the following signs: resting tremors, rigidity, and bradykinesia.
Although there is no cure, there are certain medications that can slow down the process: Levodopa is currently the most effective medical treatment for Parkinson’s, but long-term use can lead to levodopa-induced dyskinesias (LID), which include chorea, athetosis, and dystonia. This condition is difficult to treat and significantly affects a patient’s quality of life.

Fortunately, once LID has developed, lowering the dosage of levodopa may help. Medications such as amantadine and atypical neuroleptics can also be used to alleviate the symptoms of LID. Though a bit more invasive, deep brain stimulation is another alternative.

Ultimately, LID is caused by chronic levodopa therapy. Therefore, if one can avoid its use or lower the dosage of levodopa while still treating symptoms of Parkinson’s, then this whole ordeal can be circumvented. To avoid developing LID, one can initially take dopamine agonists such as pramipexole to delay the need for levodopa. As the disease progresses, dopamine agonists become less effective, and levodopa must then be introduced. Once it is introduced, taking levodopa at a lower dosage may decrease the risk of developing LID. In practical terms, one must lower the threshold to symptomatic relief of Parkinson’s by levodopa.

In the pilot study “Ambulosono: A Sensorimotor Contingency-Based Musical Walking Program For People Living With Parkinson’s Disease,” researchers aimed to do just that.

They used the accelerometer of the fourth-generation iPod to monitor differences in stride length among Parkinson’s patients tied to a music program.

The patients were told to do long-distance, large-stride walking every day, with the iPod strapped in a pouch above the patients’ knees, connected by wireless headphones. It was set up to have continuous music playback when a certain stride length was reached. The music playlist consisted of musical cues that have reported effectiveness in activating the limbic and other associated motor networks.

The researchers followed 42 patients with Parkinson’s over a period of 320 days with a cumulative walking distance of 3500 km and 700 hours of music playback. They found significant improvements in stride length (10–30%) and walking speed (10–20%), as well as improvements in other functional areas, like arm swinging, facial expression, long-term fear and anxiety of using escalators, and activity avoidance resulting from depression and anxiety.

This novel approach of employing current accessible technology in the functional improvement of Parkinson’s disease reduces the burden linked to taking levodopa. While this is a small study and further investigations are still needed, it provides a different perspective of Parkinson’s treatment that has the potential to greatly improve patients’ quality of life by decreasing exposure to medications and their many side effects.

“Frozen Addicts” – An Unusal Twist on Drug-Induced Parkinsonism

The term “frozen addicts” was coined by Californian neurologist Dr William Langston after he had encountered an outbreak of akinetic rigid Parkinsonism in 6 drug users in Santa Clara County California:
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The story actually starts in 1947 with Hoffman-La-Roche chemist Dr Albert Ziering, who first synthesized synthetic opioid  Desmethylprodine 1,3-Dimethyl-4-phenyl-4-propionoxypiperidine (MPPP).  The drug was never developed or marketed.

The story continues with chemist Barry Kidston, who in the 1970s synthesized MPPP using Dr Ziering’s recipe and a home chemistry set.  However, a few days after injecting himself with a sample from a newly synthesized batch of drug, Kidston became frozen, unable to speak or walk.  He was taken to the hospital by his parents, misdiagnosed with catatonic schizophrenia, and treated with electroconvulsive therapy for months.  He was ultimately diagnosed him with Parkinson’s disease, and improved with L-dopa treatment.  Soon after, researchers analyzed the tainted drugs, and concluded that it was comprised of both MPPP and a similar compound, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).  Kidston died of cocaine overdose shortly afterwards.  His autopsy showed loss of dopaminergic cells in the substantia nigra, the hallmark of Parkinson’s disease.  The case was written up in the Journal Psychiatry Research in 1979.

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In July 1982, a 42 year old named George Carillo was hospitalized in San Jose frozen like a statue in a bent twisted position.

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Then a neurologist in Watsonville, only 30 miles away, reported 2 drug-addict brothers in their 20s  both with advanced symptoms of Parkinson’s.

Ultimately seven addicts came down with these same symptoms.

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A sample of tainted heroin was ultimately analyzed, and one of the toxicologists involved remembered reading about the Kidston case in Psychiatry Research.

William Langston, the neurologist who first treated Carillo, looked the case report up and found that Kidston had prepared drugs based on a 1947 paper by Albert Ziering.  But when Langston he went to the Stanford University library to read that original paper, he found that it had been cut out of the journal.  Some enterprising college chemist was cooking up MPPP and selling it as heroin, but like Kidston had made a mistake in his recipe and produced MPTP instead.

Once inside the brain, MPTP is metabolized into 1-methyl-4-phenylpyridinium which is toxic to dopamine producing neurons in the substantia nigra.

Since then MPTP has been used to develop an animal model of Parkinson’s disease, and this has allowed researchers to investigate surgeries to repair the injured region of the brain, new techniques using electrical stimulation, and more recently stem cell replacement of damaged cells.

These Frozen Addicts have also posed a question that we have yet to answer. If a street-drug impurity can trigger on form of Parkinson’s, could other “idiopathic” cases also have a chemical source? Recent studies have found that ingestion of the pesticide Rotenone can bring on Parkinson-like symptoms in mice. Loss of motor control, stiffening of muscles, and even loss of facial expression have been noted among the rare side effects of the high blood pressure medication, Reserpine, and the heartburn drug, Metoclopramide.

Lytico-Bodig Syndrome, You Might Get it From Eating Bats

Posted by Daniel Rubio, Drexel University College of Medicine Class of 2014

“A man” obsessing over “bats”…

“A man” eating “bats”…


The patients above are displaying symptoms resulting from a disease known as Lytico-Bodig Syndrome (LBS), a neurologic disease resembling amyotrophic lateral sclerosis (ALS/Lou Gehrig’s Disease), Parkinson’s disease, and Alzheimer’s disease.  The country with the greatest number affected is the US territory of Guam.  In fact, between the 1940-1960 it was the leading cause of death among the Chamorro people, a tribe found on the island of Guam.  The afflicted were usually between the ages of 25-40 years of age.

What’s up with the bats?

Although yet to be proven, it is believed that the high incidence of LBS is due to the consumption of fruit bat, a cultural delicacy on the island.  These fruit bats feed on specific fruits containing high concentrations of an altered amino acid called beta-N-methylamino-L-alanine (BMAA). BMAA is a known neurotoxin and is believed to be the cause of LBS.  BMAA is a protein building block that is incorporated into neuronal proteins to produce an abnormal form that creates clumps with neurons resulting in their dysfunction and death.

I don’t eat bat though?

I addition to the high concentrations found in the fruit bats on the island of Guam, multiple sources have been proposed leading to BMAA exposure within the United States.  Certain bacteria in fresh and salt waters produce BMAA; and, fish and crustaceans will concentrate BMAA within their tissues when they consume the bacteria as part of their normal diet.  It is believed that human consumption of fish and crustaceans in at-risk areas might increase the incidence of neurodegenerative diseases, like Alzheimer’s, Parkinson’s, and Lou Gehrig’s.  This association has been seen in many areas within the United States, especially around the gulf regions and around large bodies of water.  Click here for more details about this.

Am I more lytico or bodig?

Presenting symptoms exist along the continuum of lytico-bodig.  Patients on the lytico spectrum present more like ALS/Lou Gehrig’s disease.  These patients have muscle wasting/atrophy and accompanying weakness, paralysis of mouth and tongue, and an inability to swallow resulting in choking to death.  Over time, paralysis involves the breathing muscles requiring mechanical ventilation to help the patient breath and to prevent choking on secretions.  Lytico patients remain aware of their deterioration.  The form of LBS is fatal in all cases.

On the other end of the spectrum, patients with bodig presentations look more like Parkinson’s disease and Alzheimer’s disease patients.  Bodig patients present with “freezing” with progressive immobility with loss of starting purposeful movement and loss of spontaneous movement.  Progressive dementia with loss of speech and irrational behavior, including violence and rapid fluctuations in mood, are common.  Over time, patients are left in stiff and immobile postures with inability to speak and swallow.

How would I know if I had LBS?

Currently Lytico-Bodig syndrome is diagnosed based upon appropriate history and physical exam by a neurologist.  Definite LBS is declared in post-mortem autopsy.  However, there is research being done to develop rapid tests using cerebral spinal fluid analysis.

What can I do if I have LBS?

Treatment is mainly supportive as is based upon symptoms present, whether it’s Parkinson’s, Alzheimer’s, ALS, or a combination of the three spectrums of diseases.   The more the symptoms resemble Lytico, the greater the mortality: in patients with predominantly lytico-type symptoms the disease is practically 100% fatal.

GDNF and Parkinson’s Disease

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We have already blogged about the difficulties in treating advanced Parkinson’s Disease, and the need for new strategies including stem cell therapy.

Another therapeutic approach is use of a trophic factor to replenish or prevent the loss of those dopamine producing cells in the first place.

Glial cell-derived neurotrophic factor (GDNF) has been considered a potential therapy for Parkinson’s Disease for many years.

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GDNF has been known to protect and restore these cells in animal models of Parkinson’s Disease since the 1990s.

However, human studies have shown mixed results so far:

Early small open label studies of GDNF infusions into the putamen showed promising results:

These results were not confirmed in a larger double blind study, although this study has been criticized for early termination and other issues:

Furthermore, subsequent studies have confirmed the clinical benefits of GDNF infusions in Parkinson’s patients, and have even shown a sustained benefit after the infusions were discontinued in one patient.

There are ongoing trials of direct infusions of GDNF into the putamen in the UK using a novel infusion pump:

Another potential approach is to use gene therapydelivering a virus that carries the DNA to make GDNF directly into the putamen by a single injection. The “infected” neurons will make GDNF on their own to treat the disease.

So, at this point the jury is still out on GDNF and Parkinson’s, watch this space for more information!

A new kind of stem cell treatment for Parkinson’s Disease?

ParkinsonsResearch

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First, what is Parkinson’s Disease?

Parkinson’s disease (PD) is a degenerative disorder of the central nervous system, characterized by the death of dopamine-generating cells in the substantia nigra, leading to neurologic symptoms including tremor, rigidity, slowness of movement and difficulty with walking.  Traditionally a clinical diagnosis, uncertain cases can now be more readily confirmed using a DaTscan.

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Early PD, showing L>R rest tremor, awkward movement of the L hand, rest tremor walking, and increased tone in the L arm:

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More advanced PD, showing stooped posture, rest tremor, slow hesitant gait and difficulty turning, and poor postural reflexes (risk of falls).

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How is it usually treated?

Modern treatments are effective at managing the early motor symptoms of the disease, by:

1. Taking extra dopamine, in the form of the precursor drug L-Dopa,

2. Taking MAO-B or COMT inhibitors, which inhibit the breakdown of dopamine, or

3.  Taking synthetic dopamine agonist drugs, which bypass dopamine, and bind directly to the dopamine receptors.

Patient with moderately severe PD, fist untreated (left panel), then after taking L-Dopa medication (right panel).

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Then what happens?

Unfortunately, as the disease progresses, patients develop motor complications characterized by involuntary movements called dyskinesias and fluctuations in the response to medication.  As this occurs, PD patients a can change from phases with good response to medication and few symptoms (“on” state, center panel in video below), to phases with no response to medication and significant motor symptoms (“off” state, left panel in video below), then to dyskinesias (right panel in video below).  It becomes harder and harder to keep the patient “on” (middle panel) with medical treatment.

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What about surgery for PD?

Deep brain stimulation (DBS) surgery to implant a medical device called a brain pacemaker in to the subthalamanic nucleus or globus pallidus can still be an option for PD patients with significant motor fluctuations, as long as they do not have dementia.

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So, we still need more treatment options! What about stem cells?

Current therapies do improve motor symptoms, but they become less effective with time, and do not address the non-motor features of the disease, including dementia, speech and swallowing difficulties, and the gait/balance problems.

In the hope of finding a better treatment, investigators have been trying to replace dopamine deficiency in the brains of PD patients by introducing embryonic stem cell transplants since the 1980s. Some patients improved, but results were very variable, with many patients showing no benefit, and others developing uncontrolled dyskinesias.

One of the problems is that these foreign transplanted cells are attacked by the PD patient’s immune system. There is also a concern that the implanted embryonic stem cells may undergo a transformation in the PD patient’s brain and grow into cancerous tumors.

However, there’s a brand new study about to start at the Scripps Research Institute in La Jolla California: 8 PD patients have undergone removal of small patches of their own skin, which have been turned into a new kind of stem cell that acts like embryonic stem cells, called induced pluripotent stem cells (IPS), and can then be injected back in to the brain.  The main advantage of IPS cells over embryonic stem cells is that they are less prone to rejection by the patients’ immune systems, because the transplanted cells come from the individuals themselves.

Ultimately, the hope is that implanted the stem cells will replace the degenerated cells in the patients’ brains, and start producing dopamine in a more physiologic way, treating all of the effects of PD without the side effects of oral medications.

Only time will tell if this IPS treatment is effective, or if we need some other stem cell strategy to treat PD.  We do know that a lot of PD patients and their families and friends are waiting with baited breath.

Find out more about the IPS for PD study here.

Find out more about stem cell therapy for PD from the Michael J. Fox Foundation.

DaTscan for Parkinson’s Disease

Parkinson’s disease has always been a clinical diagnosis.

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And most patients who present with the typical unilateral rest tremor, associated with cogwheeling and rigidity are easily distinguished from essential tremor on clinical grounds (click here to review the differences).

However, some atypical cases can cause diagnostic uncertainty.   A 2009 study from the UK found that almost 50% of patients with tremor who were taking Sinemet (a medication used for Parkinson’s) prescribed by their primary care physicians, when examined by an experienced neurologist actually had essential tremor or some other diagnosis.

Autopsy studies have shown that almost 1/3 of patients diagnosed with Parkinson’s by neurologists during life actually had alternate pathological diagnoses at autopsy such as progressive supranuclear palsy or Cortico Basal Gangionic degeneration.

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A new radiological study, may help end some of this diagnostic uncertainty in difficult cases.

The DaTscan uses single-photon emission computed tomography (SPECT) after an injection of Ioflupane I-123 to demonstrate abnormal dopamine uptake in the basal ganglia in patients with Parkinson’s disease:

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On the left an essential tremor patient showing symmetric dopamine uptake. On the right, a Parkinson’s patient showing asymmetrically reduced dopamine uptake.

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Here’s a patient we recently saw, with a right sided rest and re-emergent postural tremor. On the right half of the screen we have shown an image from his DaTscan, showing reduced dopamine uptake in the left basal ganglion, and confirming the diagnosis of Parkinson’s.

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So who should get a DaTscan?

If you have already received a diagnosis of Parkinson’s from an expert, and are responding well to dopaminergic therapy, a DaTscan would not add any new information and would therefore be unnecessary. However, if the expert is not sure of the diagnosis – is it essential tremor or Parkinson’s, for example– or where a potentially risky procedure is being considered (e.g. deep brain stimulation surgery), it may be reasonable for your doctor to recommend a DaTscan.

DaTscans are now available through the radiology department at Monmouth Medical Center.

Extreme Gait Apraxia – Parkinson’s Patient Can’t Walk But Can Ride a Bike!

Apraxia is a disorder of motor planning leading to the loss of ability to carry out a learned purposeful movement, despite having the desire and the physical ability to perform that movements.

For example, patients with dressing apraxia, which can be caused by stroke or dementia, can move their limbs normally, but cannot figure out how to put their clothes on properly:

Patients with gait apraxia, caused by Parkinsonism, NPH or frontal lobe dysfunction, have particular difficulty initiating gait and making turns, often with a tendency to freeze, but a relative preservation of straight-line gait once initiated:

A newspaper article from the UK reported the case of a 58-year-old man with Parkinson’s and severe “gait freezing”. He required visual guides to help him move one foot in front of the other and was unable to turn while walking. After a few steps he would lose his balance and then require his wheelchair.  However, he could still ride his bicycle, flawlessly:

This is extreme gait apraxia – he is able to move his legs and control he balance enough to ride a bike, and yet is unable to do so for the (much easier) task of walking.

Click here to read the full article.

Click here to see more funny walks.