NeuroVoices: Shaliee Shah, MD, and Ditte Primdahl, MD, on Improving Diagnostic Accuracy in Paraneoplastic Neurologic Syndromes

Paraneoplastic neurologic syndromes (PNS) are most commonly associated with malignancies such as small cell lung cancer, thymoma, gynecologic cancers, breast cancer, and seminoma. In recent years, the use of immune checkpoint inhibitors has been accompanied by an increased recognition of autoimmune neurologic complications in patients with tumor types not traditionally linked to PNS. Although neurologic immune-related adverse events are uncommon, neuromuscular manifestations occur more frequently than central nervous system involvement, and multifocal presentations may be observed.¹

Early recognition of these syndromes may be important to limit progression and optimize outcomes in patients. Prior studies have shown that management strategies for PNS typically begin with discontinuation of immune checkpoint inhibitor therapy and initiation of high-dose corticosteroids, with escalation to additional immunosuppressive agents based on symptom severity and individual patient factors. Outcomes could be closely tied to the specific clinical presentation and individual patient factors, reinforcing the importance of timely diagnosis and specialist involvement.

In a new iteration of NeuroVoices, neuro-oncology experts Shailee Samir Shah, MD, and Ditte Primdahl, MD, both of Northwestern Medicine, discussed the clinical distinctions between PNS and other cancer-related neurologic complications. They noted that PNS often follows a more insidious and progressive course and may precede a cancer diagnosis, in contrast to treatment-related or structurally mediated neurologic symptoms that typically demonstrate a clearer temporal relationship. The duo also highlighted that improved cancer survival and expanded use of immunotherapies have increased both the incidence and recognition of PNS.

NeurologyLive: How do PNS differ from other cancer-associated neurologic complications encountered in practice?

Shailee Samir Shah, MD: Neurologic manifestations of cancer are really either treatment-related toxicities, so chemotherapy-related complications, for example, like neuropathy, or directly metastatic disease to the brain or the spinal cord. These differ in terms of complications from PNS in that there is a very clear temporal onset, often, in the case of chemotherapy-induced toxicities, a temporal onset that’s related to the administration of drugs that are known to have those complications. When we're talking about metastatic disease, anytime anybody is coming in with a new neurologic symptom, we're talking about doing some targeted imaging regardless, to make sure that there isn't any new involvement, even if that's new headaches, new weakness, or new numbness. We're certainly going to be concerned about that. Some of it may depend on the particular type of cancer, but ultimately that will be high on our differential.

Now, PNS, on the other hand, sometimes can be a little bit harder to localize, meaning they can involve multiple areas of the neurologic system. Their onset may be a little bit more insidious, and classically, actually, these will come on before the actual diagnosis of the cancer. So frequently, patients who have PNS will be diagnosed with their neurologic disease first and then, as a result of that, their cancer.

Ditte Primdahl, MD: There's also the difference of whether or not a patient is on immune therapy, like immune checkpoint inhibitors, etc., because that can change it a little bit. The prediction of whether or not the neurological symptoms might be related to the timeline of when the immune checkpoint inhibitor was started matters. Did they have anything before that? So, it can change a little bit in how we think of it and the likelihood of it being PNS.

Like Dr. Shah said, if the cancer is known, some cancers are more prone and known to have a higher risk of developing PNS, especially neuroendocrine cancers. Most people know small cell, for example. So, the pretest probability will be higher with certain types of cancer, and then adding to that risk, if you are on anything that will boost your immune system.

How has increased survival across tumor types changed the clinical relevance and complexity of PNS in neuro-oncology clinics?

Ditte Primdahl, MD: I think in a couple of ways. To your point, the incidence. The cases that we see—we see more cases. So, the incidence is increasing. Why is that increasing? I think there are multiple different reasons. One thing is more people are diagnosed with cancer, and people live longer, to your point. Also, people are being treated more with immunotherapy, which we know increases the risk of PNS. Then we're also getting better at detecting them, which is obviously one of the reasons we're doing this—the awareness of it

One piece is that people are more aware, so they will do more testing. But we're also getting better at testing, thankfully. We've come a long way in terms of detecting and finding new antibodies and ways to confirm or at least be as sure as we can be on a diagnosis, but we still have a ways to go. We'll talk about that too.

Shailee Samir Shah, MD: I agree. I think that really, as our understanding of these diseases has improved and as we've gotten better at treating these cancers, these patients are living longer. We're seeing more of these complications. We're able to follow these patients for longer. We're able to see how these patients do, and ultimately, that translates back to being able to give patients who have these diseases a better understanding, as well as giving clinicians a better understanding of what these diseases look like.

What are the most common diagnostic pitfalls neuro-oncologists see when PNS presents alongside active malignancy?

Ditte Primdahl, MD: I think one of the big problems is, if we take, for instance, the case of a patient with cancer and they're seen by oncologists in the community, even at academic centers—they are not neurologists, if we're talking about neurological symptoms and/or syndromes in particular. Symptoms can be very vague, and people who have cancer, as Dr. Shah already said, are getting a lot of toxins. Most of them are getting chemo. They have fatigue, they can have weakness that is diffuse, and they can have tingling because of neuropathy. So part of the symptoms that they might experience from a PNS standpoint could be attributed simply to chemo toxicity and adverse effects.

So, if you're not a neurologist, it can be hard to monitor and decipher—is this what we would expect, or is it more? Is it less? I think it's really important, a couple of take-home messages in PNS: typically, you'll see a progressive course. So typically, symptoms that the patient may experience—and it is true what was already said—it can affect any part of the central nervous system, the peripheral nervous system, the neuromuscular junction, and it can present with different constellations of symptoms. So basically, it can look like pretty much anything. But the time course typically is that it will progress over weeks to months.

If you start seeing that progressive course out of proportion to what you would expect from a known toxicity like neuropathy, you should really start becoming suspicious. If the patient is worsening, if there is symptom worsening, then there should be a low threshold to get a neurologist involved who can actually track things with the tools that neurologists have and just the confidence that this is what we do—neurological examinations and also the appropriate workup, which I'm sure we'll talk about as well.

Shailee Samir Shah, MD: I think that some of the other additional diagnostic pitfalls are probably related to just actually getting a patient to a neurologist quickly. Even if it's not a dedicated PNS center, if there are concerns for progressive symptoms out of proportion to chemo, out of proportion to what you'd necessarily expect, it makes sense to try to get patients to a neurologist as quickly as possible. Of course, if you have experts in neuroimmunology or neuro-oncology who can guide that at an even higher level, that's great. The other part of it, I think, is that early testing—which, again, we'll come back to with the diagnostics—early testing is key in identifying these patients early.

Transcript edited for clarity. Click here to view more NeuroVoices.

REFERENCES
1. Valencia-Sanchez C, Zekeridou A. Paraneoplastic Neurological Syndromes and Beyond Emerging With the Introduction of Immune Checkpoint Inhibitor Cancer Immunotherapy. Front Neurol. 2021;12:642800. Published 2021 Apr 9. doi:10.3389/fneur.2021.642800