In early September, the Journal of Parkinson’s Disease (based in Amsterdam), The Cure Parkinson’s Trust (based in the UK), and Parkinson’s Movement co-hosted one of their quarterly webinars on Parkinson’s Disease (PD). The topic was prodromal PD, which refers to the stage at which people do not meet the diagnostic criteria for PD but they do exhibit many of the symptoms. Those with “prodromal PD” are obviously at a higher than average risk of meeting the diagnostic criteria for PD in the future. We at Stanford Parkinson’s Community Outreach attended the webinar and are sharing our notes.
One of the panelists states that prodromal PD is “the constellation and collection of symptoms that emerge when Parkinson’s pathology is starting to accumulate in the brain.” While PD diagnostic criteria emphasize the appearance of motor symptoms, most prodromal symptoms are nonmotor and nonspecific, complicating the search for universal early screen processes. Panelists discuss various aspects of symptoms, treatment, and screening paradigms, as well as the ethics underlying care decisions in prodromal PD.
The webinar included three panelists:
Daniela Berg is the director and chair of the Department of Neurology in Kiel, Germany. Her research interests focus on PD and the onset and development of prodromal symptoms.
Philip Herbert is a retired Professor of Family Medicine at the University of Toronto. His main interest lies in medical ethics, and he brings to the table 25 years of experience living with PD.
Alastair Noyce is a consultant and neurologist in London who specializes in PD. Like Berg, his research interests concern prodromal symptoms.
You can find the webinar recording on the Journal’s YouTube channel.
Here are my notes from the webinar.
September 2, 2020
Webinar hosted by the Journal of Parkinson’s Disease and The Cure Parkinson’s Trust
Summary by Cassandra Irizarry, Stanford Parkinson’s Community Outreach
What is prodromal Parkinson’s?
Prodromal Parkinson’s is what happens to people before their diagnosis. Alastair Noyce quite aptly states that it’s “the constellation and collection of symptoms that emerge when Parkinson’s pathology is starting to accumulate in the brain up until a diagnosis can be given.”
One thing that interests me is whether the phrases “prodrome” or “prodromal” describe a single or a range of entities. There is good evidence to suggest that there are different prodromes to Parkinson’s, different routes through which people pass on their way to getting a diagnosis, just like after diagnosis there are different types of Parkinson’s disease.”
The symptoms of prodromal Parkinson’s: a complex story
Prodromal symptoms are small on their own, but over time, their burden accumulates and intensifies. The duration of prodromal symptoms differ by the individual but can span decades. In general, Daniela Berg classifies prodromal PD as an “ongoing pathological process can have wide-ranging effects on adjacent nervous systems.” Constipation, hyposmia (loss of smell), mood disorders, and REM sleep behavior disorder (RBD) are the best-characterized symptoms of prodromal PD.
In general, anything connected to the nervous system can be affected by prodromal PD. Constipation, hyposmia, urinary dysfunction, erectile dysfunction are all common signs that the autologous nervous system is being affected. Different aspects of mental health can be affected as well- for instance, depression or other slight cognitive changes may occur before motor systems.
None of these symptoms present uniformly in everyone, something that Berg says “makes the story complex.” She adds that PD is “an individual disease, in the prodromal and the clinical phase.” According to her, the highest incidence of Parkinson’s occurs in RBD, then hypothermia, constipation, and urinary dysfunction. Berg acknowledges that there are large gaps in the aforementioned scale, and that we need definitive biomarkers that show the disease in is progress.
RBD and Parkinson’s: A Preclinical Marker, or first-stage Parkinson’s?
RBD is a sleep disorder in which one physically acts out their dreams. Someone with RBD might sometimes talk and make noises and vigorous movements in their arms and legs while asleep or having a nightmare. This disorder is often noticed by an individual’s sleeping partners before anyone else.
RBD is the strongest individual prodromal feature and, according to Berg, those with RBD are around 70-80% likely to develop motor symptoms of Parkinson’s 10 to 12 years down the line. Despite these correlations, RBD alone is not a conclusive marker of prodromal PD. Noyce notes that it’s a very rare disorder in which “the biological underpinnings are unknown” and also challenging to diagnose. If an “objective handle” could be reached on screening, Noyce believes that “we could be more certain that combinations of symptoms are Parkinson’s.”
He also cautions that care must be taken when re-labeling a disease (or, in his words, a “constellation of symptoms”) without a clear neuroprotective plan. “Applying this to the general population can be potentially dangerous- a lot still needs to be done in the research, and we don’t want to spread false or misleading information.”
The Ethical Landscape of Prodromal PD: To know, or not to know
While Berg stresses that “the aim of scientists is to stop the disease beforehand, not watch it develop,” some patients are adamant about their right not to be informed of their risk of developing prodromal PD. For one, the diagnosis could be wrong, and needlessly complicate the everyday life of those who previously considered themselves healthy. Additionally, many preventative strategies for Parkinson’s (such as choosing exercising and maintaining a healthy weight) are inconclusive. Many people, as uncovered by Berg’s retrospective study on patients’ attitudes towards early disease detection, are skeptical about early risk disclosure. On the other hand, only a little less than half of the study participants still reported that they would like to know, demonstrating the myriad individual decisions that go into treating prodromal PD.
This is “an enormously important issue,” states Berg. “The thing we now need is preclinical markers- not only symptoms, but signs that the symptoms we see are symptoms of Parkinson’s, because these symptoms are nonspecific… Nowadays, we diagnose based on specific motor symptoms. But we can also [conduct a brain scan] to see how dopamine is released. Consider someone with REM sleep disorder, with no motor symptoms yet, but a reduced dopamine uptake in the brain. This is Parkinson’s, we only need to wait until motor symptoms develop. The problem is that we don’t know the timeframe- when the motor symptoms will develop.”
Philip Herbert believes that preventative methods (such as maintaining a healthy lifestyle) are important to share- even if a patient remains unaware that their nonspecific prodromal symptom may result in future PD. He elaborates: “Most people don’t want to know the diagnosis if they’re not sure of it and [if] there’s nothing that can prevent it anyway. The danger is people will look to untested therapies, and many people will turn out not to have Parkinson’s.” He also notes, however, that PD is a disease with a long clinical lead-up, and that there comes a point where a decision must be made on whether a collection of symptoms will be labeled a condition.
Ultimately, Herbert’s ethics don’t sympathize with the right not to know: “certainly [a patient] can ask to not be informed, but if there’s side effects and the patient says they don’t want to know, then you should say ‘well, I don’t think you’re ready to pursue this intervention.” He stresses that “the most important thing we can do is to be as accurate as possible in out diagnoses beforehand,” and to be “careful [that] we’re not causing more harm than good- but it’s not our job to prevent people from hearing bad news.“
All three panelists expressed support for the notion of conducting an educational awareness campaign targeting clinicians and caregivers alike and aimed towards establishing a “culture” of early diagnosis. “Once we have the education campaign for change,” says Berg, “there’s no right not to know. We have to understand that neurodegenerative disorders affect larger society, and we have to deal with it collectively.”
Both Berg and Noyce agree that clinics capable of addressing the multifaceted and individual nature of the treatment of prodromal PD should treat individuals with multiple symptoms. “We cannot only treat motor symptoms,” she says. “Constipation; urinary tract infections; depression- in prodromal patients you have to treat these symptoms as well, which also take a toll on the patient’s life. Today, I think we need clinics to treat these kinds of patients who are informed and looking for ways to treat themselves. I think we need to find out who wants to know what to do, but also need to accept a person’s right not to know.”
Looking forward: Promising approaches
The panelists agreed across the board that diagnostic and treatment methods would be different by 2040. For instance, there is technology in development that uses fine motor movements as a diagnostic tool. And RBD diagnosis (which usually requires visiting a sleep specialist) may someday be diagnosed at home. Future treatment plans, says Berg, should also account for the serious side effects of some therapies while also treating the patient’s unique prodromal PD. “We need to know the cause and address the cause. If you don’t know the [patient’s] genetic background, something else must be done. There is much to think about before we treat.”
Noyce adds that “paternalistic medicine” can be widespread” but envisions treatment that honors the proactive patient’s urge to learn more. “Going forward,” he adds, “it’s important not to conflate a patient’s appetite for knowledge with the need to jump to a screening program… On the individual level, we need to be prepared to have these discussions.”