Neurosarcoidosis: Complexities in its Differential Diagnosis

Podcast Transcript

Intro: Neuro Pathways, a Cleveland Clinic podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab, and psychiatry.

Glen Stevens, DO, PhD: Sarcoidosis is a complex disease with many faces and the clinical manifestation and course of neurosarcoidosis are particularly variable. Although neurosarcoidosis occurs in approximately 5% of the sarcoid patients, post-mortem studies reveal that 10% of the sarcoid cases have neurologic conditions. In today's episode of Neuro Pathways, we're discussing neurosarcoidosis and the complexity in its differential diagnosis.

I'm your host Glenn Stevens, neurologist, neuro-oncologist in Cleveland Clinic's Neurological Institute. I'm very pleased to have Brandon Moss join me for today's conversation. Dr. Moss works in the Sarcoidosis Center in Cleveland Clinic's Respiratory Institute, and as a neurologist in the Mellen Center for Multiple Sclerosis in Cleveland Clinic's Neurological Institute. Brandon, welcome to Neuro Pathways.

Brandon Moss, MD: Thanks for having me.

Glen Stevens, DO, PhD: So Brandon, before we start, how'd you get interested in neurosarcoid?

Brandon Moss, MD: I started actually with a neuro immunology fellowship at the Mellen Center for Multiple Sclerosis. And I was primarily focused on multiple sclerosis treatment and management, but I had an interest in other inflammatory conditions that affected the central nervous system. I reached out to the Sarcoidosis Clinic and asked if I could see some patients over there. Spoke with Jinny Tavee, who was our sarcoidosis expert at the time. And when she left to do other things, I assumed that role and I've been grateful to be able to do it.

Glen Stevens, DO, PhD: Well, we appreciate your doing it. So in terms of neurosarcoid, I mentioned in the intro that it's a small percentage of patients that have sarcoid actually develop neurologic manifestations, but discuss the prevalence of sarcoid itself in the population and the typical patient population that is affected.

Brandon Moss, MD: The best estimates globally about the prevalence of sarcoidosis or somewhere on the order of 20 per 100,000 people. And it's important to remember that there is a lot of variability between different racial and ethnic groups. So for example, in the United States, African-Americans are three times more likely to have sarcoidosis than Caucasians are, somewhere on the order of 36 per 100,000 people. Worldwide, there's also a higher incidence in people who are Scandinavian, and that's somewhere on the order of five to 40 per 100,000 people. Generally, there's a female predominance and peak incidence is somewhere in the thirties for most people, although there's a second peak in the fifties, particularly for people of African descent.

Glen Stevens, DO, PhD: So do we know why there's racial differences?

Brandon Moss, MD: We don't. There could be a variety of factors, some of which could be genetic, but others, which could be environmental. And it's been hard to tease out exactly what the underlying cause of the differences are.

Glen Stevens, DO, PhD: So how is the typical sarcoidosis patient diagnosed?

Brandon Moss, MD: It depends on the manifestation of the disease. So for neurologic complications of sarcoidosis, the neurologic manifestation is often the presenting symptom. And depending upon what area of the nervous system is affected, that's the manifestation that you'll see. While sarcoidosis is notorious for being able to involve any aspect of the nervous system, there are some common manifestations that we see from the neurologic side. The most common would be a cranial neuropathy and sometimes polycranial neuropathy. Probably the next most common would be a meningitis. And then there can be a variety of other presentations, including mass lesions within the brain. You can present with spinal cord lesions. There are a variety of peripheral neuropathies that people can have. Myopathy can be seen. And it's not uncommon to have neuroendocrine involvement or seizures as a manifestation and presentation as well.

Glen Stevens, DO, PhD: And if we're looking at the differential diagnosis, what's your usual suspect list?

Brandon Moss, MD: Yes, so it really depends on the manifestation that they're presenting with. So someone who has spinal cord disease, that's going to be a differential diagnosis than someone who has a chronic meningitis. But there are some key players that come up again and again, almost regardless of which manifestation of the disease you have. So other infiltrative diseases are really high on the differential diagnosis when you're considering sarcoidosis. Those would include things like mycobacterial diseases, fungal diseases, lymphoma, and other cancers.

Glen Stevens, DO, PhD: So diagnosis, what's the gold standard for diagnosing?

Brandon Moss, MD: So right now I think the most established are the Neurosarcoidosis Consortium Consensus Criteria for the Diagnosis of Sarcoidosis. And it's largely based on Zajicek criteria, which have been around for a much longer period of time. But essentially, everybody needs to have a clinical presentation and diagnostic evaluation that suggests neurosarcoidosis. And the diagnostic evaluation should include studies that are pertinent for that disease manifestation, whether it's MRI, spinal fluid studies, EMG nerve conduction studies. There should be a thorough workup for mimics for everybody as well, to make sure that you're not missing some of these key players, which could be also in the differential diagnosis. And then after that, really the diagnosis is dependent upon biopsy. And so there are various levels of certainty depending upon whether or not you can get a biopsy showing granulomatous disease and where the biopsy is. So people with possible sarcoidosis do not have biopsy evidence of granulomatous disease. People with probable neurosarcoidosis have biopsy evidence of sarcoidosis in a non-neural organ system. And people with definite neurosarcoidosis have biopsy proof of granulomatous disease within the nervous system.

Glen Stevens, DO, PhD: So when I'm in the hospital with the residents and someone has some mild enhancement on the scan, sarcoid often comes up in the differential diagnosis and somebody will say, "Get an ACE level," and then someone says, "No, that's not a very good test or very sensitive test. There's a newer blood test we can use." What do you think about checking an ACE level?

Brandon Moss, MD: So biomarkers are controversial. There's no doubt about that. And I would say that for ACE levels, the CSF ACE is particularly controversial in that it's not always the most sensitive and not always the most specific for sarcoidosis. Although a recent, very large key series came out and suggested that CSF ACE may be helpful as a tie breaker when you're considering different things and don't have definitive evidence otherwise. I would say serum ACE is generally thought of as being somewhat more reliable than the CSF ACE. And there have also been some other studies looking at alternative biomarkers, like soluble IL-2 receptor, which have shown some promise in terms of their ability to distinguish sarcoidosis in particular from multiple sclerosis when looking at the CSF. But they can be elevated in a variety of disorders as well, including other inflammatory disorders and including certain infectious disorders.

Glen Stevens, DO, PhD: Are the biomarkers helpful at all for treatment response? Can you monitor them for treatment or no?

Brandon Moss, MD: They have been looked at somewhat for treatment response, but don't have the best track record. So we don't use the biomarkers for looking at treatment response. I would say really the way we use biomarkers is if you really can't decide between sarcoidosis and an alternative inflammatory disorder, you might use those biomarkers as a tie breaker. I think soluble IL-2 receptor in the CSF is particularly valuable and there may be some value to a serum ACE level as well.

Glen Stevens, DO, PhD: What's the problem with the ACE in the CSF? Why is that less sensitive?

Brandon Moss, MD: It's not clear exactly why that's the case. What I suspect is going on is that the serum ACE is actually detecting systemic disease from sarcoidosis. And it's very often the case, although not with initial presentation necessarily, that people have other systemic disease. So after a period of time, close to 80 to 90% of people with neurologic complications have evidence of systemic disease, but at presentation that may only be 50%.

Glen Stevens, DO, PhD: And I've been told that you can sometimes see spontaneous remission with neurosarcoidosis. Have you ever seen it?

Brandon Moss, MD: Yes, there are cases that I consider to have had spontaneous remission from neurosarcoidosis. Although I would say the majority of patients that I see, and maybe that's in part because of referral bias, have more often a chronic inflammatory presentation that really doesn't go away until it's treated with an immunotherapy.

Glen Stevens, DO, PhD: So we have the diagnosis, let's go into the treatment a little bit. What's your standard treatment regimen?

Brandon Moss, MD: Really the approach to treatment depends a little bit on the severity of the disease manifestation. So the more the severe disease manifestation, the more likely you are to start someone on a TNF-alpha inhibitor from the very beginning, which is one of the most potent therapies for sarcoidosis and has some of the most evidence to support it. I would say the first line and generally the cornerstone of all treatment is glucocorticoids because they're fast acting and generally worked very well for treating sarcoidosis.

The problem is the long-term side effects. So to minimize those, we'll often add cytotoxic agents for people with moderate to severe disease to limit the dose and duration of treatment with glucocorticoids. For people with more severe manifestations, so those would include things like intraparenchymal brain lesions, spinal cord lesions, intractable seizures, polycranial neuropathies, we're often going to start multiple things at the same time. So we would do generally a three to five day course of high dose IV steroids followed by daily prednisone. We would do a cytotoxic agent at the same time, usually that's going to be methotrexate. And we would try and get, as quickly as possible, a TNF-alpha inhibitor, typically infliximab, on board to help control the disease long-term.

Glen Stevens, DO, PhD: And the general prognosis in the population, what's the breakdown for how patients do?

Brandon Moss, MD: So for the more severe disease manifestations, you're going to have a somewhat worse prognosis. But really it appears that most of the injury that happens in sarcoidosis is related to active, ongoing inflammatory disease. So once we get the inflammatory disease under control, we don't have expectation that they're going to have worsening symptoms.

Glen Stevens, DO, PhD: So I'm going to ask you a true or false here, based on what I was told many, many years ago when I was young and impressionable. And that was that if someone doesn't have, or has very limited systemic sarcoid, it'd be unlikely that they would have a significant CNS manifestation of their sarcoid. True or false?

Brandon Moss, MD: So I would say that's not necessarily the case. So it's important to keep in mind that when people initially present, they initially present with their neurologic manifestation. And about half of those people who present don't have evidence of systemic disease. Now eventually, we're talking about five or 10 years down the road, 80 to 90% of people should have systemic evidence of sarcoidosis. But there is still a minority of people who do not. And provided that their clinical course, their diagnostic evaluation and all of their other diagnostic studies are consistent with sarcoidosis and they're responding as we expect to treatment, I wouldn't have any doubts about that.

Glen Stevens, DO, PhD: And long-term prognosis, average life expectancy for neurosarcoid patients, is it decreased versus the regular normal population?

Brandon Moss, MD: It's probably slightly decreased. You might be talking about five years difference. But I would say the majority of patients do really well, especially now that we have highly effective treatments available for sarcoidosis and neurosarcoidosis, in particular. The main complications that limit life expectancy in sarcoidosis are the neurologic complications, especially those severe disease manifestations, the cardiac complications, and then pulmonary fibrosis from the pulmonary complications.

Glen Stevens, DO, PhD: Any role for radiation therapy?

Brandon Moss, MD: So radiation therapy has been studied historically, and there are case reports where they've suggested that people have improved. I think that it's not something that we use in routine clinical practice, and we've got much better therapies that have more evidence to support them now.

Glen Stevens, DO, PhD: And the major side effects of the TNF-alpha inhibitors?

Brandon Moss, MD: Yes, so the main thing that I get concerned about when I'm treating people with long-term immunosuppression with the TNF-alpha blockers is really the possibility of developing fungal infections later on down the road. So one of the main things you have to be a little bit careful about if someone is on a TNF-alpha inhibitor, they've had an appropriate response, and then they have some kind of recurrence of inflammation, especially if it's not in the area where it was previously, you have to consider, well, is there something going on in terms of a fungal infection? I have had patients with fungal meningitis who were on a TNF-alpha inhibitor, and those can be very severe complications of the disease.

I would say apart from that, it tends to be pretty well tolerated, but there are other manifestations that you have to look out for. For infliximab, which is an infusion therapy, when you first start therapy, people can be at risk for hypersensitivity reactions. That's why it's generally best to administer it in a hospital setting so that you can treat that quickly and appropriately. But there are other manifestations as well. So it increases the risk for demyelinating disease. So sometimes you can see people with MS-like presentations after they've started infliximab or adalimumab. In association with azathioprine is associated with a rare, but very aggressive hepatosplenic T-cell lymphoma. So that's another consideration when you're thinking about adjunct therapies with a TNF-alpha inhibitor.

Glen Stevens, DO, PhD: And what's the average age of diagnosis of a neurosarcoid patient?

Brandon Moss, MD: Generally, there's a peak incidence in the thirties for the majority of people. And then there's a second peak in the fifties, and that's more for people with African descent.

Glen Stevens, DO, PhD: So it could be on medication for a long, long time?

Brandon Moss, MD: That's a great question, so the optimal duration of therapy is not really clear. At this point in time, when we were looking at the evidence for infliximab and they were doing a lot of the case series, the multi-institutional case series, they saw that around 50% of people when they stopped treatment with infliximab did not have disease recurrence. And you might say that 50% of them did, but that means that 50% of people don't need to be on long-term immunosuppression with infliximab or adalimumab that sometimes have serious complications.

So one approach to treatment is to try and stop the infliximab or adalimumab therapy after a couple of years and see if the disease comes back. Again, it can be successful in, in 50% of patients then they don't require long-term immunosuppressive therapy. The other thing to keep in mind is that sarcoidosis as a whole, usually people go into remission the longer their disease course is. So after several years, you're talking about generally about half of people who don't have recurrence of disease. And then at longer periods of time, after somewhere around 10 years, two thirds of people don't have recurrence of ongoing inflammatory disease. So it's very possible to get people off of therapy, eventually.

Glen Stevens, DO, PhD: Can you develop antibodies against the treatments?

Brandon Moss, MD: You absolutely can. And so, it's not common, even when infliximab is used as a monotherapy. But oftentimes, our practice is to treat concurrently with another cytotoxic drug, usually methotrexate, to try and prevent the development of neutralizing antibodies. Neutralizing antibodies can also develop with adalimumab, although they're less likely. So if someone develops neutralizing antibodies with infliximab, adalimumab may be an alternative therapy if they've had a good response.

Glen Stevens, DO, PhD: Do you ever treat people with pulsed treatment?

Brandon Moss, MD: So we typically don't treat them with pulse steroids. And part of the reason is the minute you stop the steroids, when they go below a certain threshold, you often get disease recurrence. And so you have to have something on board to prevent the disease from coming back until someone has been on therapy for a long enough time to be able to go into remission.

Glen Stevens, DO, PhD: So talk to us a little bit about the Sarcoid Center, because obviously there's treatment of a lot of pulmonary related issues as well. So talk to us about the multidisciplinary center you work in.

Brandon Moss, MD: Absolutely. The most common manifestations are pulmonary manifestations, skin manifestations and ocular manifestations. And the Sarcoidosis Center is great, it's multi-disciplinary. A lot of pulmonologists, but we work with cardiologists, ophthalmologists and rheumatologists as well. It's really great in terms of having one place where people can see all of the specialists who focus on this particular disease. I think it allows for great coordination of care. And in addition to that, there's a lot of interdisciplinary collaboration with a lot of things, with treatment, with research, and we have learning multidisciplinary sarcoidosis conferences as well.

Glen Stevens, DO, PhD: Excellent. So before we leave, anything new and exciting on the horizon that you know of, treatment or diagnostically?

Brandon Moss, MD: Yeah. I would say that from a treatment standpoint, one of the main concerns is what do you do with someone who doesn't have a complete response to infliximab? And that's a really challenging problem in sarcoidosis. I would say the first thing is always to make sure that you've got the diagnosis correct, that you've got the dose and frequency of treatment with infliximab correct. And make sure that you don't have any neutralizing antibodies. But there are cases where people don't have a complete response. There are now some alternative therapies that have shown most of their promise really in pulmonary sarcoidosis, but there have been some case reports of improvement in neurologic complications of sarcoidosis as well. One of those is tofacitinib, which is a Janus kinase enzyme inhibitor. And the other is tocilizumab, which is an IL-6 inhibitor. So those have shown some promise.

Glen Stevens, DO, PhD: I know they've used gallium scans over the years. Do you use it? Is utility helpful? Does it help within the brain itself or is there some other scan or marker?

Brandon Moss, MD: Really where that comes into play, more than anything else, is when you are doing a systemic evaluation to find a biopsy target. And this is something that I didn't really touch on that much before, but that is absolutely essential when you're trying to make a diagnosis of sarcoidosis. As they say, tissue is the issue. And so the main job that you have is to try and get biopsy proof of granulomatous disease. You generally start by doing something like chest imaging. If the chest x-ray is negative, it's often important to go ahead and proceed with a CT scan of the chest. If that doesn't show anything, it's often important to do a CT of the abdomen and pelvis. Again, you're looking for any lymphadenopathy that could be biopsied to give you the answer.

If CT chest, abdomen, pelvis don't show anything, an FDG-PET scan is helpful in looking for FDG avid lymph nodes, which could establish the diagnosis. And it's more sensitive than a gallium scan. So that's generally the reason why it's done. The challenge is that it's sometimes difficult to get insurance approval to proceed with the test. But whenever possible, if you suspect sarcoidosis and can't find a good biopsy target, then that would be the recommended study to do.

Glen Stevens, DO, PhD: Either of them helpful for the brain?

Brandon Moss, MD: So not so much for the CNS manifestations of sarcoidosis. While they can certainly show FDG avid lesions within the spinal cord or the brain, generally MRI is going to be more sensitive and more helpful from a diagnostic standpoint.

Glen Stevens, DO, PhD: Well Brandon, thank you very much for joining us today. It's been very insightful and I appreciate your time. Thank you.

Brandon Moss, MD: Thank you so much.

Outro: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's consultQD.clevelandclinic.org/neuro, or follow us on Twitter, @CleClinicMD, all one word. And thank you for listening.