Symptoms vs. Disease

“Society is indeed a contract. … It is a partnership in all science; a partnership in all art; a partnership in every virtue, and in all perfection. As the ends of such a partnership cannot be obtained in many generations, it becomes a partnership not only between those who are living, but between those who are living, those who are dead, and those who are to be born.”

Edmund Burke

The following is a repost, with a few edits, of a previous blog titled The Pursuit of A Cure. The reason I am reposting now is last week this topic came up during a discussion hosted by the World Parkinson’s Congress between Professors Kelvin Luk and Roger Barker on the topic modeling Parkinson’s disease in animals. It led to several discussions with many researchers, doctors and observers of the field. In my opinion, this is a debate worth having as it has ramifications from drug discovery all the way through drug development and therapeutic application.

Also, though I continue to use Parkinson’s diseases as my example, most of what I say below can be applied to many neurodegenerative and neuropsychiatric conditions.

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Parkinson’s disease does not exist. There is nothing that anyone can point to and say, ‘this is Parkinson’s’. No one has ever found it in a brain, recreated it in a dish, nor given it to any animal. What we have are people living with a clinical label that we call Parkinson’s disease. There is nothing that allows anyone to separate the disease from the people that experience it. For over two centuries the medical community has assumed that there is an underlying biology that connects most of those diagnosed, but they still have no clear signs that what they are looking for exists.

Yet, scientists, researchers and doctors, often talk about it as if it does. Medical journals are filled with references to ‘Parkinson’s models’ and ‘Parkinson’s pathology’, often without mention of the fact that we have no proof that there is anything there. They even have two distinct categories of therapies: ‘symptom modifying’ and ‘disease modifying’, as if they know the difference. And how do they claim to modify what they cannot define? Through a series of motor tests that output a single number. Generally, the longer it has been since a person’s diagnosis, the higher that number is. Disease modifying trials aim to slow, stop or reverse that number. However, those tests are a test of patients’ motor symptoms. So, since they cannot uncouple the symptoms from the disease, why the distinction?

Levodopa, the gold standard therapy for Parkinson’s disease is not considered ‘disease modifying’, yet its introduction in the 1960’s doubled life expectancy for people diagnosed with Parkinson’s and has arguably done more to help people live better lives than any other tool in the neurologist’s toolbox. Without it, I’d probably be dead by now. Much of the same can also be said about deep brain stimulation, which is itself steadily getting better and through which evidence is emerging that we can prolong healthy lifespan in certain individuals. So, again I ask, why do we try to separate the disease, which we have no way of measuring, from the symptoms patients do experience and which we have, especially today, pretty good measurements for?

The pathophysiology of Parkinson’s disease is murky at best. For decades experts have acknowledged that PD has a “multi-causal heterogenous etiology that results in a wide spectrum of disorder.” Yet, despite all that we have learned of its complexity, and the array of neurochemicals and brain regions and cell types involved, they continue to put forward therapies that target single pathways in groups of patients, acting as if all that heterogeneity converges on some unifying pathology.

So, how should we proceed? Perhaps until we know better (that is, have biomarkers that can tell us more about these diseases than our symptoms can) we should dispense with the distinction between ‘disease modifying’ & ‘symptom modifying’ while being agnostic to any claims about what Parkinson’s is. Such a shift would also give us much clearer and cleaner targets as outcome measures in clinical trials. Measuring constipation, time spent On vs. Off, choking, rate of falls, or (now) tremor and dyskinesia, are much more tangible outcomes than the amorphous ‘disease-modification’. Words like ‘disease-modifying’ and ‘neuroprotective’ are not even suitable goals for pharmacological intervention as they lack clear physiological definitions and thus are not something that can even be put on a drug label.

Finally, when it comes to any attempt at a cure, we must remember that for patients, our symptoms are the disease. We cannot feel genetic mutations, mitochondrial dysfunction, or protein build-ups; we can only feel their supposed downstream effects. Since any cure would have to ameliorate symptoms to earn the name, perhaps, until we understand the biology well enough to connect something we can measure to real symptoms patients do experience, the best way forward is to focus on the only things we can empirically measure, the symptoms, and do what we can to address each, one by one.

After all, if we get rid of the symptoms, we will have no disease to speak of.

We always hope for the easy fix: the one simple change that will erase a problem in a stroke. But few things in life work this way. Instead, success requires making a hundred small steps go right – one after the other, no slipups, no goofs, everyone pitching in.”

Atul Gawande
Not sure where this is from but if anyone can help me identify the author I’d appreciate it and credit them for it.

For anyone wondering what I have, a much more accurate way to describe it was first explained to me by Alberto Espay as nigrostriatal degeneration. That has far more explanatory power and allows me to better understand why the prescribed treatments work. If this community started describing these diseases by the networks affected (as best as possible), I believe we would do a lot more good and have much more accurate means to match existing therapies to target specific brain network dysfunctions.

7 comments

  1. Great post Ben! It does seem like when we dig into “disease modifying therapies” for things like PD what you see under the hood are therapies that people *expect* will improve the long-term trajectory of symptoms (possibly even with minimal short-term effect). This is in contrast to “symptom modifying therapies” where there is an expectation of short-term symptom improvement but with symptoms still being expected to worsen over time. And there may not always be a bright line between the two things either as you point out.

    1. Thank you Brian, greatly appreciated. Agreed. Seems to me the practical question here is, let’s say we had a hundred dollars to split however we want on PDs, how much would we spend on trying to develop DMs vs. SMs…ideally I think most people would want a 50-50 split, as you point out though, the question itself might be a silly. Still, it is one that the community has kinda already answered, not sure what the exact number is, but seems to me, if we look at the biggest funders (NIH, ASAP, MJFF), they are putting almost everything into the DM bucket.

    2. It’s an interesting read. I have never seen it in the perspective of disease modifying and symptom modifying. It reminded me of some of my experiences working on oncology projects. When designing for clinicians, it was all about treating the disease – disease modifying. However, when talking to patients, it’d often be all about the quality of life and lead to symptoms modifying. For PD, there is no cure per se, so all the focus become managing the symptoms.

  2. I liked the distinction you make between disease modifying and symptom modifying approaches. Another thing that has been gating work here is a better, more constructive regulatory framework that admits such endpoints to develop against.

    Curiously, I think that the terminology is also somewhat idiosyncratic across disorders. Multiple Sclerosis has many “disease modifying therapies” that are approved for use. However, none of these agents actually cure MS – they help reduce the inflammatory response which causes MS. The frontier in MS is around “remyelination therapies” that can have impact on reversing course of the disease in some patients. There are similar efforts at regeneration under way in PD with gene therapy and stem cells – but to your point the time horizon here is longer.

    1. Interesting Ro’ee, thank you for that. So do the MS DMs actually modify the disease itself? How do we know that they do that? Is there a good biomarker in MS for it?

  3. Well put Ben. This reminds me of many peoples’ experiences with dopamine agonists. What good is a disease or symptom modifier that comes with terrible side effects that destroy a person’s life and relationships? Patients need symptom modifiers that don’t come with costs that outweigh their benefits.

    1. Could not agree more Gina, we need therapies that target specific known pathways, not guesses made by the upteenth neurologist we see that then leads to a host of side effects, some of which are worse than the “disease” itself.

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