This week, on August 20, several Medicare MACs will hold a public session on the literature on alpha-synuclein tesitng for Parkinson's and related disorders (synucleinopathies).
It's an important opportunity for the neurologic community as most physicians get very little training in neurology. I suspect as few as ten percent take a full elective month in neurology (they only get a few electives) and once they're off in residency track (surgery, ER, pediatrics, immunology, etc) neurology is far in the rear view mirror. [*]
Questions for the advisory meeting have been posted:
While there may be too many questions, and some are repetitive, they seem to question whether diagnostics matter at all in neurology. Whether diagnosis affects management would usually be out of scope of a specific diagnostic study, and here, there is not one outcome (like "survival" in cancer) but diverse ones across the diverse presentation of disease. The most important metric for Patient A may be a symptom patient B doesn't even have.
Parkinson's itself has protean symptoms - what other disorder causes both visual hallucinations and foot cramps? And in between there's swallowing disorders, gastroparesis, orthostatic hypotension, constipation, bladder disorders, balance disorder with falls, restless leg syndrome, insomnia (sometimes to a toxic degree), and others. In this sense, Parkinson's has protean entry points and outputs, like lupus.
Here's some clarification from Chat GPT:
“Protean” disease is a familiar medical concept, not an argument against the importance of diagnosis. In several classic disorders, the underlying disease is critical to figure out, precisely because a patient may enter the healthcare system through very different symptoms and may require management across multiple organ systems.
Six useful comparators:
Syphilis — the archetypal “great imitator.” Depending on stage and site, it can present with dermatologic, neurologic, psychiatric, ocular, auditory, and cardiovascular disease; neurosyphilis itself ranges from meningitis and cranial neuropathies to stroke, tabes dorsalis, and general paresis. (CDC)
Systemic Lupus erythematosus. One patient may present with arthritis or rash, another with nephritis, cytopenias, seizures or cognitive problems, pleuritis, pericarditis, or vasculitis. NIH explicitly notes that manifestations vary greatly among individuals and can change over time. (NIAMS)
Sarcoidosis. Usually thought of as pulmonary disease, but it can involve lymph nodes, skin, eyes, heart, liver, salivary glands, and the nervous system. Thus two patients with the same underlying granulomatous disease can look almost unrelated clinically. (NHLBI, NIH)
Systemic vasculitis — particularly ANCA-associated disease. Depending on which vessels are involved, presentation can be sinus disease, pulmonary hemorrhage, renal disease, rash, neuropathy/foot drop, eye disease, constitutional symptoms, or gastrointestinal involvement. The very diversity of manifestations makes establishing the unifying diagnosis especially consequential. (MedlinePlus)
Systemic amyloidosis. The same protein-deposition process can manifest as cardiomyopathy, nephrotic renal disease, peripheral or autonomic neuropathy, hypotension, gastrointestinal dysfunction, hepatic disease, carpal tunnel syndrome, or combinations of these. NIDDK specifically emphasizes that different patients have different organs and tissues involved. (NIDDK)
Multiple sclerosis — a particularly useful neurologic analogy. Although confined principally to the CNS rather than being truly systemic, its clinical expression is extraordinarily heterogeneous: optic/visual disease, sensory symptoms, weakness, spasticity, gait and balance problems, pain, cognitive problems, fatigue, and bowel/bladder dysfunction can appear in different combinations and at different points in the disease course. (MedlinePlus)
The analogy to Parkinson's is quite strong. The Australian “iceberg” (pic below) is not simply an advocacy graphic making Parkinson's look complicated. It reflects the fact that PD will simultaneously be a movement disorder, autonomic disorder, sleep disorder, gastrointestinal disorder, neuropsychiatric disorder, cognitive disorder, and bulbar disorder. Hallucinations and foot dystonia [cramps] may indeed belong to the same disease as gastroparesis, orthostatic hypotension, RBD, urinary dysfunction, sudden falls, dysphagia, constipation, and bradykinesia.
That matters directly the somewhat odd premise running through the MAC questions. MACs acknowledge that synucleinopathies encompass “multiple diseases and a broad array of signs and symptoms,” yet repeatedly asks what useful outcome, if any, could follow diagnosis in the absence of curative (disease-modifying0 therapy. (And a trial could only pick one or two definitive endpoints; for synuclein diagnostics in early patients, surely that can't be 20-year survival).
In a protean progressive disease, heterogeneity is a powerful reason why diagnosis matters: identifying the unifying disease organizes otherwise disconnected symptoms, directs surveillance, anticipates complications, informs medication and referral choices, and gives meaning to new manifestations as they emerge.
Syphilis, lupus, sarcoidosis, vasculitis, amyloidosis—and PD—would all be vastly harder to manage if medicine insisted that "diagnosis had little value" until there was a curative treatment.
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[*] I have some content knowledge here. I did a two year postdoc in basal ganglia research before residency, and I spent a month at the PD iinstitute affiliated with the royal neurologic hospital - Queen's Square - in London, before getting board-certified in Neuropathology.
