Were it not for the eventual verdict of the Court of Appeal, Holmes v Poeton may well have been a landmark case for Parkies. Or so claims the (ex) Judge, Nicholas Mostyn, who serves as the guide in today's episode, where the Movers & Shakers look into some thorny questions: what causes Parkinson's? And who, if anyone, is to blame? Our guide is Professor Yoav Ben-Shlomo from the University of Bristol, who dissects the evidence – from controversial twin studies to a contaminated Marine encampment – and delivers his verdict on the balance of probability.
By Podot
Each week Rory Cellan-Jones guides us between the laughs and moans in the pub. To read Rory's summary of this week's episode click here.
A note from...
Professor Yoav Ben-Shlomo
As a Professor of clinical epidemiology, I spend a lot of my time considering risk factors for Parkinson’s disease (PD), be they genetic or environmental. Over the last decade there has been a real momentum to try and prove that PD is caused by pesticides or other environmental neurotoxins. When I started my academic career, this hypothesis was already around but the quality of evidence mainly based on retrospective self-reported exposure was poor. Over time the research literature has become far stronger with evidence from prospective cohorts as well as record linkage studies that assign exposure based on mandatory reporting of crop spraying to residential histories (in the USA), though there still remains debate about whether such associations are truly causal or not.
In this podcast, we discussed in some detail the very important study by Goldman and colleagues (JAMA Neurology 2023) about a natural experiment where US marines based at Camp Lejeune were accidentally exposed to TCE and other volatile organic compounds. Using routine follow-up data, those stationed at Lejeune had on average a 70% higher risk of being diagnosed with Parkinson’s disease (PD) than similar marines stationed at Camp Pendleton. This is powerful evidence of a possible causal link but there was one major caveat. In 2017, the US Congress and Veterans Administration (VA) informed the marines formerly based at Lejeune that they may be at greater risk of developing PD because of these toxic exposures, and they were thereby eligible for additional benefits. Hence these ex-marines may have been more concerned, or have presented sooner to a health care professional, than the marines at the other camp if they were concerned that they were developing PD.
In epidemiology, this issue is known as “ascertainment bias” when an exposure (being a marine based at Camp Lejeune) increases the likelihood of being ascertained as a case (PD) than those not exposed and it will create an artefactual positive association even if the exposure is not causally related to the outcome. The research team were fully aware of this potential bias and did several additional analyses to their credit. We discussed the results of one of these on the show but ran out of time to discuss another approach which they undertook namely the creation of what is known as a prodromal PD risk score. This is a probabilistic risk that someone without PD will go on and develop it in the future based on current features (‘prodromal’ describes the condition where one or more symptoms signals the impending onset of disease or illness.)
It is well recognised that PD begins well before the classic motor symptoms (tremor, slowness of movement, stiffness) are experienced and it may have a prodromal period of between 10 to 20 years. No one really knows the true duration and it is likely to vary depending on what has triggered the process that leads to clinical PD. The research team calculated two risk scores and, in both cases, ex-marines from Camp Lejeune scored worse and were more likely to be in the top 1% of the score. This further supports the possible causal role of trichloroethylene (TCE) or other neurotoxins as being causal.
However, the score was derived from data routinely collected from VHA and Medicare files and the most common features were anxiety, erectile dysfunction and depression. Tremor, though rare (1.5%) was also 19% more common for the Lejeune marines. Whilst these data do not rely on self-report, which is a great strength, they may still be biased by ascertainment as in the case of tremor, or may have been more common for some of the Lejeune marines as a secondary consequence deriving from the uncertainty that they may develop PD in the future. Further follow-up of both cohorts of marines may help resolve the current uncertainty.
To conclude, the research by Goldman and colleagues, in my view, provides the best available evidence of a causal link between TCE and/or other neurotoxins and the risk of PD but whether this is sufficiently robust in a court of law will need to await future legal hearings.
Despite one or two invitations, I have never acted as an “expert witness” for a legal case and hence the invitation by Sir. Nicholas Mostyn, retired High Court Judge to discuss the case of “Holmes vs Poeton” was both intriguing and as it turned out really interesting and enjoyable. Nick provided me with a wonderful summary of the legal background as well as the report of an American court case (about paraquat) where the “expert witness” was quite justifiably torn to shreds by a very erudite judges who demonstrated excellent understanding of epidemiological concepts.
Unfortunately for Mr. Holmes the best evidence suggesting a causal link between TCE and PDs was published after his case and was not reviewed by the appeal court. Who knows if the judgment might have differed if the excellent study by Goldman and colleagues of US Marines accidentally exposed to TCE (and other neurotoxins) was available at the time. However, even this had some caveats as we discussed on the podcast. Overall, it was wonderful to meet the whole team behind “Movers and Shakers” including the production team and see what amazing educational and entertaining outputs can be produced so simply sitting at the back of a noisy pub. Congratulations to all of you on this wonderful endeavour, and, who knows, perhaps I might be invited again in the future.
Read more about the "Risk of Parkinson's Disease Among Service Members at Marine Corps Base Camp Lejeune" here.
This article post-dates the judgment of HHJ Harrison in Holmes v Poeton (see below) but was not considered by the Court of Appeal when it heard the appeal on 25 and 26 July 2023.
Read more about "The Epidemiology of Parkinson's Disease" here.
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Prof Ben-Shlomo sets out very clearly a summary of the history and current understanding of the epidemiology of PD (20 January 2024).
Guest Biography
Michael Holmes
Michael Holmes is 58 years old and hails from Cardiff in Wales. He is happily married to Shin Ru, originally from Taiwan, whom he met whilst she was studying in Cardiff. Michael has four children Alex Louise, Teagan-Coel, Elisha & Jacob who he loves, but not sure if they are killing him off slowly or keeping him on his toes!
Michael is happy to say that he was brought up in a happy atmosphere in Splott and admits he was a spoilt child as being the youngest and the only boy, having four older sisters. That said he didn’t mind hand me down’s i.e. a Chopper bicycle, but is thankful he didn’t have to share their clothes.
At the very young age of 6 through to16 years of age, each weekend and during the school holidays, Michael enjoyed working as a bread boy - delivering and stacking bread for his brother-in-law across many stores around Cardiff. In 1982, at the age of 16, he left school and started as a trainee metal finisher, working at Poeton (Cardiff) Ltd. He worked his way up through various supervisory roles until becoming the General Manager for the last 20 years of his employment. Poeton (Cardiff) became a great success due to the tremendous team in place who made vast improvements to site and profits. In April 2020 after 38.5 years service (all his working life), he reluctantly had to take early retirement due to his health, having being diagnosed with Parkinson’s Disease in 2014.
Listen to the full recording of Sir Nicholas Mostyn's conversation with Mr Michael Holmes and Dr Ray Dorsey here.
Read more from "Trichloroethylene: An Invisible Cause of Parkinson’s Disease?" here.
This article by Dr Dorsey and others of 14 March 2023 post-dates the judgment of Judge Harrison but was not considered by the Court of Appeal when it heard the appeal on 25 and 26 July 2023.
Used the chemical in my twenties whilst working for MOD, process was uncontrolled. Diagnosed PD Iin my seventies, symptoms in my early forties?