The many faces of Parkinson’s disease

Irish Medical Times - Dr Claire Reynolds, Patrick Browne and Prof Tim Counihan examine the challenges in determining a diagnosis of Parkinson’s disease and the main treatment options available to doctors.

With a prevalence rate of around 2 per cent, most physicians in primary care can expect to encounter several patients with Parkinsonism in their practice. For the experienced clinician, recognising the symptoms and signs of Parkinson’s disease (PD) is reasonably straightforward.

The typical patient shuffles into the doctor’s surgery, slightly stooped, looking older than their years. When seated, a coarse tremor affecting one or other hand will emerge, with the hands at rest on the lap. It is this ‘pill-rolling’ rest tremor that is usually the biggest tip-off to the diagnosis. The remaining typical (Table 1) clinical features can then be elicited with more detailed examination.

Table 1: Typical features in early Parkinson’s disease

■Asymmetric tremor at rest
■Stooped posture
■Expressionless face (hypomimia)
■Low-volume monotonous voice (hypophonia)
■Micrographia
■Slowness of movements (bradykinesia)
■Shuffling gait with fragmented turning
■Cog-wheel rigidity of muscle tone
Life, however, is often not quite so simple. Up to 30 per cent of patients with PD do not exhibit tremor at the time of diagnosis. Moreover, other tremor disorders can often be confused with PD, although if the patient exhibits a clear tremor at rest, in the presence of slow movements, the diagnosis is rarely in doubt.

In a recent community-based study of PD misdiagnosis in the west of Scotland, 36 of 610 patients (6 per cent) on treatment for Parkinson’s disease had either essential tremor or vascular Parkinsonism (Newman EJ, Breen K, Patterson J et al, Mov Disord 2009;24:2379-85).

The diagnosis may be further complicated by the difficulty in recognising bradykinesia for both doctor and patient. Many patients attribute stiffness and slowness of movement to advancing age, or arthritis.

Complaints of a persistent ‘frozen shoulder’ are a common early sign of emerging Parkinsonism. One of the most useful markers of bradykinesia is to examine the patient’s handwriting; ask them to write a sentence across the page. Writing that starts reasonably clearly but becomes smaller in amplitude across the page is a reflection of true bradykinesia, distinguishing it from other causes of poor script (such as due to arthritis or other musculoskeletal ailment).

Increasing understanding of the pathological basis for PD has led to greater awareness that it is not simply a disorder of the motor symptom. In fact, non-motor symptoms can actually precede the emergence of motor symptoms by several years.

Non-motor symptoms in early PD include: constipation; loss of sense of smell; postural dizziness; REM sleep behaviour disorder; restless leg syndrome; depression; anxiety; apathy; excessive daytime somnolence; and excessive sweating.

Ensuring diagnosis
It will be seen from this list that common non-motor symptoms include affective, cognitive, autonomic and sleep-related complaints, emphasising the multi-system nature of the disease. Before concluding that the patient has PD, it is particularly important to assiduously review the patient’s list of medications to exclude drug-induced Parkinsonism, the symptoms of which are indistinguishable from idiopathic PD.

Neuroleptic antipsychotics (olanzepine, risperidone in particular) and anti-emetics (metoclopramide, prochlorperazine) are the most frequently encountered causative agents. A radio-isotope dopamine transporter (DATScan) scan may be helpful to distinguish these entities. International best practice recommends that all patients with suspected Parkinson’s disease be referred to a specialist physician with experience in managing the condition.

This should be done ideally prior to any trials of medication, so that the specialist can confirm the diagnosis and also discuss the growing treatment options with the patient.

Not everything that looks like PD turns out to be PD; up to 25 per cent of patients diagnosed with PD in the community ultimately (at necropsy) turn out to have alternative diagnoses. Making an accurate diagnosis early in the disease course is important so as not to give false expectations to patients whose Parkinsonism turns out to be treatment resistant (and hence not idiopathic PD).

A number of factors are important ‘red flags’, suggesting that the Parkinsonism may be atypical.

Should PD be diagnosed and managed entirely in the community, under the guidance of the GP? The European Parkinson’s Disease Association published a charter in 1997 that espoused the following principles that people with PD: be referred to a doctor with a special interest in PD; receive an accurate diagnosis; have access to support services; receive continuous care; and take part in managing the illness.

Bearing in mind that early, accurate diagnosis and institution of appropriate therapy in PD is associated with improved quality of life and possible improved long-term prognosis, the GP retains a vital role in the overall care of such patients.

Treatment options in early PD
It is essential to determine the degree of functional impairment that the symptoms may be causing in our patient. Several studies support the notion that patients with early PD who are left untreated have a poor quality of life. There seems little doubt that early treatment improves patients’ sense of wellbeing, irrespective of the degree of motor impairment at baseline.

Non-motor symptoms need also to be addressed early on, with particular attention to both depression and constipation. Low mood can severely hinder any improvement and needs to be treated as a separate condition. Commonly utilised anti-Parkinson’s medications are mainly absorbed via the duodenum and thus, constipation can impair this process, often leading to acute deteriorations in quality of life. Regular screening for these two possible issues is vital in maintaining a decent quality of life.

Fortunately, treatment options for significant motor impairment are plentiful (Table 5). Which agent to choose will be directed by a number of factors including the degree of functional impairment and, as mentioned earlier, patient age. It is convenient to divide treatment options into low-, medium- and high-potency drugs.

For younger patients (under 60) with mild to moderate motor deficit, it is reasonable to consider an MAO inhibitor or dopamine agonist. Although they lack the degree of efficacy of levodopa, there is a lower risk of motor fluctuations and drug-induced involuntary movements (dyskinesias) at five years. This is rarely a concern in patients 65 or older in whom the five-year risk of dyskinesias is around 20 per cent.

Moreover, dopamine agonists are associated with the potential for significant adverse effects, including sudden onset of sleep, peripheral oedema and hallucinations, as well as a variety of impulse control disorders. In the past decade, it has become apparent that anti-Parkinson’s therapy may worsen, or even be the primary cause of both motor and non-motor symptoms. Motor fluctuations and dyskinesias have been particularly well characterised.

However, a set of complex disinhibitory psychomotor pathologies that relate to aberrant or excessive dopamine receptor stimulation are being increasingly recognised. These behaviours are linked by their repetitive, reward or incentive-based natures, and include impulse control disorders (ICDs), punding, walkabout and dopamine dysregulation syndrome (DDS).

It is important for all health professionals to be able to identify these behaviours and have an understanding of their aetiology and management to limit potential harm. These potential behaviours need to be discussed with the patient and their families after diagnosis, not least due to potential legal implications.

Behaviours
Phenomenology of ICDs typically involves pleasurable behaviours that are performed repetitively, excessively, and/or compulsively, and to an extent that interferes in major areas of life functioning. These behaviours encompass a broad range of compulsive behaviours such as pathological gambling, hypersexuality, compulsive shopping, binge or compulsive eating, and compulsive reckless driving.

Morbid jealousy (Othello syndrome) is not uncommon, in the authors’ experience. Punding refers to behaviours that encompass excessive ‘hobbyism’ to prolonged, disabling, highly stereotyped ritualistic behaviour.

Activities are highly influenced by gender and, in Western societies, are reported to include: collecting or hoarding items; cleaning; repairing things; gardening; writing and categorising information; artistic drawing or craft-making; singing or playing a musical instrument; playing cards; fishing; excessive computer and internet use.

Dopamine dysregulation syndrome refers to the compulsive use of dopaminergic medications well beyond the dose needed to optimally control motor disability and in the face of a mounting number of harmful physical, psychiatric and social sequelae.

Patients may not spontaneously report these behaviours due to shame, denial or not suspecting an association with PD treatment. Direct questioning about a range of behaviours and interviewing a caregiver or informed other is often critical to ensure detection and assessment of severity of impulsive or compulsive behavioural disorders, especially due to the associated lack of insight in many patients.

Project Helps Parkinson Patients Regain Their Voices

kera - Parkinson's disease is a neurological disorder that is often associated with hands that shake uncontrollably; a loss of balance; arms and legs that become rigid and difficult to move.

There's also a less recognized symptom- a loss of understandable speech. As we mark this Parkinson's Awareness month we want to tell you about a North Texas project that is helping Parkinson patients recover their voices. Shelley Kofler reports it's also saving their lives.

Imagine thinking you are talking loudly enough to be heard, when your voice is barely a whisper. You begin a conversation only to have your words tumble out unintelligible and garbled. Your breath support grows so shallow you can't produce a full sentence.

That's what happened to Earl Duniphin as his Parkinson's disease progressed. At the age of 61 he'd spent 10 years unable to communicate. Here's how Duniphin sounded in 2009 as he described feeling alone, invisible and shut-off from his family.

Earl Duniphin: (Mumbling) I was going just downhill.

His wife Ann says Duniphin felt invisible, shut off from family and friends.

Ann Duniphin: He was just miserable as anybody would be. His own mother didn't want to try to talk to him.

Some 89 percent of people with Parkinson's suffer from problems similar to Duniphin's. Many lose their voices and the ability to swallow as their brain cells produce less dopamine which is needed to control muscles and movement.

Speech therapist Samantha Elandary says that can ultimately lead to death.

Elandary: The same muscles we use for speaking we use for swallowing. The main cause of death for people with Parkinson's is aspiration pneumonia. Food, liquid, saliva going down the wrong way to the lungs and making people sick.

Elandary says for many years therapists and doctors watched almost helplessly as their patients' voices and conditions' grew weaker.

Then Elandary discovered a breakthrough.

Elandary: I learned about a treatment that focused on teaching Parkinson's patients to speak louder, how to project their voices. It was administered in an intense manner four days a week for four weeks.

Excited about the possibilities Samantha Elandary began teaching the voice exercises at her home as she raised money and support needed to launch the non-profit Texas Voice Project.

Now after more than five years Elandary and therapists with the project have treated more than 450 Parkinson patients. Nearly all of them have regained their voices after learning how to compensate for their bodies' loss of dopamine.

Elandary: Parkinson's is characterized by reduced amplitude. You think of everything kind of smaller: smaller walking; smaller writing; smaller voice. So people with Parkinson's have to over-exaggerate all of their movements in order to compensate for the characteristic of reduced amplitude.

Two years ago Earl Duniphin entered the program and went from incoherent mumbling to having a conversation with his mother for the first time in a decade.

Earl: My mother for the first time in ten years could hear me and talk to me. My family could hear to me. The words are more concise, much clearer. They understand me. I feel like a human being.

His wife Ann says the transformation is miraculous.

Wife: It's been so long since he had any friends. He'd not had hope. There hasn't been anything like hope in so long.

Elandary says the program rejects no one with Parkinson's and there are no upfront costs. At the end of their treatment patients are asked to contribute what they can so others will be helped.

Right now the Texas Voice Project is the only program of its kind but Elandary hopes to change that. Her team in Richardson is reaching out, training speech pathologists from around the country. They're hoping to restore the voices and quality of life to more people with Parkinson's.

Elandary: It's actually very sad. If you look around the country at other places Parkinson's patients are losing their ability to speak. But it truly can be treated.

Link: http://www.texasvoiceproject.org/

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Experts Call for Stricter Regulations in Clinical Trials of New Drugs

PDtrials - Parkinson's Disease Clinical Trials

/Clinical Research News

Clinical Research News

Experts Call for Stricter Regulations in Clinical Trials of New Drugs

Mar 14 2011

When most people learn about the results of clinical trials for new medicines, it's either because something very good or very bad happened.
Last year that was illustrated when Dendreon's prostate drug Provenge was approved in April by the U.S. Food and Drug Administration because clinical trials went well, and five months later Eli Lilly infamously had to pull its Alzheimer candidate drug semagacestat because test subjects using it were actually getting worse -- putting both in the news.
"There seems to be two narratives people can handle: Experiments are dangerous and you shouldn't take part, or experimentation is the engine for the next great wonder drug," said Alex John London, an associate professor of philosophy at Carnegie Mellon University who is the co-author of an article in the current issue of the journal PLoS Medicine that looks at this and related issues with clinical trials. "What we need is a more even set of expectations."
That's important, Mr. London said, because if people believe there are only two possible outcomes at either extreme, they might not be willing to participate in clinical studies.
"If people don't participate, studies don't happen," he said.
Mr. London and his colleague, Jonathan Kimmelman, an associate professor in the biomedical ethics unit at McGill University in Montreal, co-authored the article titled, "Predicting Harms and Benefits in Translational Trials: Ethics, Evidence and Uncertainty."
But while arguing that our expectations of clinical trials need to be more realistic and informed, Mr. London and Mr. Kimmelman also believe that the trials themselves need to be proposed, and run, more rigorously.
The article -- which Mr. London sees as "taking part in a wider conversation" with researchers, funders, review boards and other stakeholders -- goes right at what they see as some of the problems in both pre-clinical animal-based trials, and the transitional, first-in-human clinical trials where so many proposed drugs fall apart.
They both point out the problems they see in clinical trials, and make proposals for how they could be corrected -- with potentially far-reaching implications in drug research.
"I thought they raised incredibly important points," said Nancy Davidson, director of the University of Pittsburgh Cancer Institute and UPMC Cancer Centers. "I think Kimmelman and London are right: This black and white, either really good or really bad theme, isn't the answer. "
The co-authors were motivated to write the article, Mr. Kimmelman said, because "only rarely do the effects seen in animal studies translate into human studies."
That is, that even though researchers regularly find success with a proposed drug during research on animals, only infrequently do researchers achieve similar success with human test subjects.
They note in their paper that one study showed, for example, that only 5 percent of proposed cancer drugs that enter trials are eventually licensed.
"Drug discovery is hard," Mr. London said. "I don't think there's any way of getting around that."
And that gets to a central theme to their work, Mr. Kimmelman said: "What we're really trying to do here is check the expectations associated with major clinical findings."
That has important implications not only for possible human test subjects -- who need to have a better understanding of potential outcomes -- but for organizations that provide research funding "and who would want to move their resources into the most promising areas," Mr. London said.
Still, they believe clinical trial outcomes might be improved were it not for two main problems they have found.
The first is that most animal studies don't use the same generally accepted methods used in human trials -- such as randomization and blinded outcome assessment ­-- to prevent bias by the researcher.
They note that one recent analysis of animal studies found that only 12 percent of those studies used random allocation -- where animals are randomly assigned to take the proposed drug or to get a placebo -- and only 14 percent used blinded outcome assessment -- where a researcher doesn't know which animals were getting the drug and which were getting the placebo.
These are important because "researchers have an inherent bias in wanting to see a positive outcome" from the studies, Mr. Kimmelman said.
Moreover, Mr. London said that the routine use of randomization and blind testing in animal studies should increase the efficiency of the drug development process, "if for no other reason than that it enables us to better distinguish effects caused by new interventions from outcomes that are simply artifacts of the way we have set up the experiment."
Sean Savitz, a stroke researcher and associate professor of neurology at the University of Texas Medical School at Houston, said: "What they're getting is what we've been trying to get at in the stroke field -- that studies with animals are not being done as well as they could be."
The second problem they worry about is that they believe that researchers don't look widely enough at other related research in making their predictions about the possible outcome once they begin human trials.
They believe that most researchers, when predicting the outcome of their study, only consider other studies involving the particular agent, or drug, they are testing. The researchers don't look at agents that might be different but that work on the same pathway, they argue. Mr. London and Mr. Kimmelman refer to this process as "evidential conservatism."
Howard Mann, a program associate in the Division of Medical Ethics at the University of Utah School of Medicine, said this point made by Mr. London and Mr. Kimmelman is troubling.
"What should be alarming is the persistent conduct of pre-clinical research that will not yield clinically relevant information because researchers are not aware of, or have not made sufficient attempts to identify, the negative results of prior completed relevant research," Mr. Mann said in an e-mail statement about the article.
As an example of this, the authors presented two tables with their article: One shows the negative outcomes of eight randomized trials of anti-amyloid drug candidates for Alzheimer's disease, similar to Eli Lilly's semagacestat; and the other shows the negative outcomes of seven randomized trials for neuroprotective agents and/or transplanted tissue strategies to combat Parkinson's disease.
"If consistently neuroprotective strategies have failed, we're suggesting that people should ratchet down their expectations," Mr. Kimmelman said.
Researchers might be doing that on their own, Mr. London said, but they should also include their findings, and lower expectations, in their proposals to the committees that have to review the results of an animal trial before allowing it to move on to human trials.
Including such information in proposals could result in some research not being funded, Mr. Kimmelman acknowledged. But it could also push researchers to "come back and explain how their work is going to overcome previous results."
Ultimately, Mr. London said: "We want to make sure we design our trials as well as possible so we can learn from them -- even if it is a failure in outcome.
"It's not that we learn from every failure, but it's that when they are well designed, we can learn much more from them."
Source Publication: Pittsburgh Post-Gazette

Neurologix Gene Therapy Helps Parkinson’s Patients Walk, Move in Study

• Clinical Research News

Neurologix Gene Therapy Helps Parkinson’s Patients Walk, Move in Study

Mar 17 2011

A gene injected deep into the brains of people with Parkinson’s disease eased their jerking motions and tendency to freeze, according to a study sponsored by Fort Lee, New Jersey-based Neurologix Inc. (NRGX)
The inserted gene acts like a factory, pumping out one of the brain chemicals lacking in people with the disorder to rebalance substances that stimulate and inhibit activity, said Michael Kaplitt, a founder of Neurologix and co-creator of the therapy. The study was published today in the journal Lancet Neurology.
The therapy appeared safe and seemed to improve motor control, compared with subjects who received a placebo through a sham surgical procedure, said Jon Stoessl, director of the Pacific Parkinson’s Research Centre at the University of British Columbia in Vancouver. Stoessl, who wasn’t involved in today’s findings, said the finding should be evaluated in larger trials.
“This is the first controlled trial to show a significant improvement in the active group of a gene therapy trial,” Stoessl said in a telephone interview. “It appears promising and merits further investigation.”
Neurologix, which has no marketed products, will apply to the FDA to begin an expanded trial next year that may be used to win regulatory approval, Marc Panoff, the company’s chief financial officer, said yesterday in a telephone interview.

Seeking Investors

The company needs to raise $30 million to $40 million to conduct the study and is talking to both investors and potential partners from the pharmaceutical industry to obtain funding, Panoff said.
Walter Liskiewicz, 60, a retired oral surgeon who has been living with Parkinson’s for 18 years, said he was in “terrible” shape before taking part in the study.
“I wiggled all the time, I had trouble walking, life sucked,” Liskiewicz said.
After being treated in July, 2009, Liskiewicz started noticing slow, steady improvement, he said in a telephone interview yesterday. Now he walks a mile or two once or twice a week and can carry groceries into his house.
“This is not a neuroprotective treatment, which would be the holy grail,” said Blair Ford, a professor of clinical neurology at Columbia University in New York. “This is aimed at ameliorating the immediate symptoms of Parkinson’s, not reversing its course.”

Gene Therapy Revival

About 1.5 million people in the U.S. have Parkinson’s, according to the Parkinson’s Disease Foundation. People with the neurological disease gradually lose neurons that make the brain chemical dopamine. The lack of dopamine leads to increasing activity in a part of the brain called the subthalamic nucleus, which influences movement.
While no gene therapy has yet been approved by the U.S. Food and Drug Administration, recent successes have revived a field that was almost ended when a patient in such a trial died in 1999. Cambridge, Massachusetts-based Bluebird Bio, a closely held company, is developing therapies for a vision disorder and blood conditions including beta thalassemia and sickle cell disease after clinical trials reported positive results. Bluebird is backed by Genzyme Corp. (GENZ), also in Cambridge, and by venture capital firms.
Early-stage Parkinson’s patients now are treated with medications including Boehringer Ingelheim GmbH’s Mirapex, GlaxoSmithKline Plc’s Requip and a generic medication called levodopa. All aim to increase dopamine in the brain.

Effectiveness Wanes

These treatments generally lose effectiveness after several years. Patients may then get a treatment called deep-brain stimulation, which shoots electrical current into the subthalamic area of the brain. While the procedure helps many patients, they must have batteries and wires installed in their bodies, said Neurologix’s Kaplitt, a neurosurgeon at Weill Cornell Medical College in New York.
In the Neurologix therapy, an ultra-thin wire is inserted through the skull and passes through brain tissue to reach the subthalamic area. The gene, carried by a harmless virus, journeys into brain cells to ramp up production of the chemical GABA, which limits excess activity to reduce abnormal movements.
The therapy was first tested in 12 patients in a 2007 study. While those findings were encouraging, no control group was used so researchers couldn’t be certain about the findings.
In the latest study, 22 patients received an injection with the gene, called GAD. For comparison, 23 people underwent a sham procedure in which surgeons pretended to drill holes in their skulls and imitated sounds of the actual procedure.

Catheter Inserted

A catheter designed by Minneapolis-based Medtronic Inc. (MDT) to lock in place after being inserted allowed patients to leave the operating room and have the gene injected in a recovery room, making the procedure less invasive and more affordable. Afterward, the catheter was removed and a small cap was used to cover the hole in the skull.
Both groups of patients showed improvement on a scale that rates stiffness, tremors, speed of motion and other symptoms. After six months, patients who got the treatment improved by 8.1 points, or 23 percent, while the placebo patients had a 4.7 point, or 11 percent, improvement, Kaplitt said yesterday in a telephone interview. Some patients did even better, he said.
“All but two of the patients in the treatment group had some improvement and half of them had dramatic improvement,” Kaplitt said. There were no serious adverse events related to the treatment, he said.
The therapy didn’t appear to alleviate the cognitive problems, depression and impaired balance many patients suffer, Stoessl said.
Gene therapy has several advantages over deep-brain stimulation, said Kaplitt.
“It’s a single operation instead of two, patients don’t need general anesthesia and no hardware is left in the brain,” he said.
Source Publication: Bloomberg