Dr. Cindy Xi at the 2023 Cedars-Sinai Intracranial Hypotension Conference
Dr. Cindy Xi, Clinical Assistant Professor of Medicine and Section Head of Allergy & Immunology at Keck Hospital of USC in Los Angeles, CA, presented this talk on “Headache in Mast Cell Activation Syndrome: Differential Diagnosis or Comorbidity” at the 2023 Cedars-Sinai Intracranial Hypotension Conference on July 8, 2023. The conference was hosted by Cedars-Sinai with generous support from the Spinal CSF Leak Foundation in Kohala Coast, Hawaii.
Slides from the talk
View a PDF of Dr. Xi’s slides here.
Transcript
Dr. Cindy Xi on “Headache in Mast Cell Activation Syndrome: Differential Diagnosis or Comorbidity”:
[00:00:09] So I’ll be talking about mast cell activation syndrome. The main takeaway is when to recognize this condition, and to gain an awareness that there are some things we can do in the perioperative management that can improve outcomes in these patients. And there’s really a lot that we don’t know.
[00:00:38] So I’ll start with some nomenclature. So mast cell disorders can be divided into two big categories, clonal versus non-clonal. Clonal means systemic mastocytosis, or monoclonal mast cell activation syndrome. And these are defined by elevations in serum tryptase, presence of KIT mutation, atypical morphology or density in either a bone marrow biopsy or an extracutaneous site.
[00:01:04] Most commonly a GI biopsy or expression of these CD markers that they should not be expressing. And that’s differentiated from most mast cell disorders, which includes allergic conditions, chronic urticaria, and much more common than monoclonal conditions is idiopathic mast cell activation syndrome, which is really gonna be the focus of this talk. And this can present in a wide range of ways. But these different presentations really stem from dysfunctional behavior of mast cells, which so far we haven’t been able to characterize with specific genetic markers. So, mast cell activation syndrome comes from dysfunctional behavior of mast cells.
[00:01:47] So what is it that mast cells, are supposed to be doing? What’s their normal function? They’re antigen-presenting cells, they’re a part of the innate immune system, and they sit in the tissue, so they’re in the skin, the airway, the gastrointestinal tract, and they’re, they’re in the meninges, they’re in the brain, and they’re sitting very close to blood vessels and nerves.
[00:02:09] And it’s their job to interact with everything foreign that we interact with and decide: is this foreign and dangerous and warrants an immune response, or is this something that’s foreign and benign and we should leave it alone? And when individuals have dysfunctional mast cell behavior, that might mean increased number or severity of infection.
[00:02:30] It might mean inflammation, in the absence of infection, and it can mean allergy symptoms. So classic allergies involve mast cells and specific IgE antibodies. So a classically allergic person, a peanut-allergic person, let’s just say, should have specific IgE antibodies that bind to peanut. And that’s what we’re looking for when we’re doing our allergy testing, either by skin or by blood. So these IgEs sit on the surface of mast cells everywhere in the tissues, and if that peanut-allergic person eats peanut, there’s a very specific interaction between the peanut protein and the IgE that binds to peanut and that causes mast cells to become activated and release mediators like histamine, but really hundreds of different mediators. Leukotrienes, prostaglandins, tryptase, which go on to cause symptoms like hives, swelling, trouble breathing, nausea, vomiting, diarrhea, changes to heart rate and blood pressure. And that should happen very consistently, very reproducibly. So treating that problem, treating IgE mediated allergy is really about avoidance and having a rescue plan.
[00:03:44] So the problem in mast cell activation syndrome is that there are lots of ways that mast cells can become activated in a non–IgE dependent way. There are G-protein surface receptors, toll-like receptors, growth factor receptors that can result in mast cell activation. And so you end up having symptoms due to dysfunctional or aberrant mast cell mediator release, possibly related to triggers, especially the stacking of multiple triggers, but often in an inconsistent and non-reproducible way.
[00:04:22] And it’s really impossible to practice only trigger avoidance. It’s impossible to avoid stressors or have any control over what the weather is and activity and so on. And so treating this problem, the paradigm for managing this condition is about trying to raise the threshold for mast cell activation to allow someone to be more tolerant and less sensitive.
[00:04:48] So mast cell activation syndrome can present in many different ways. By definition, this is a multi-system condition where you need to have at least two systems involved. And often there are skin symptoms like flushing, hives, often itchiness with or without any apparent skin lesions, upper and lower respiratory symptoms, various GI symptoms. There’s often a diagnosis of irritable bowel syndrome, GI dysmotility different kinds of pain, bone pain, muscle pain, nerve pain, joint pain. I share a large population of patients with our pain team. And same with headache. There can really be every type of headache.
[00:05:31] Cognitive dysfunction mood disturbances, dizziness, tinnitus, vertigo. They’re all very common in this population. And then there’s the dysautonomia symptoms. There can be dysregulation of heart rate, blood pressure temperature, gastrointestinal motility, and so on. And there’s an association with connective tissue issues.
[00:05:54] So often there is a triad of MCAS, dysautonomia, connective tissue disorder. There can be a pentad of GI dysmotility and immune dysregulation. So when should one suspect MCAS? I’m an allergist and so, you know, patients will come to me with idiopathic urticaria, flushing pruritus, and you know, I’ll always do a review of systems to look for other system involvement along list of drug allergies.
[00:06:25] Atypical reactions to foods and medications, meaning a food doesn’t necessarily just cause itchiness or stomach issues, but maybe it causes joint pain, or a fragrance, you would expect it to cause respiratory symptoms. But it causes GI symptoms when there’s autoimmunity and allergic conditions. Sometimes the, the term undifferentiated connective tissue disorder often means a variety of symptoms where there isn’t quite a specific diagnosis, but the individual doesn’t feel well. There’s often multiple “functional” disorders, functional in quotations, plus allergic conditions, and again, pain plus allergic conditions. And there’s often a significant family history, although individuals in the family may have different presentations.
[00:07:15] On exam they might be flushing, they might have erythema, especially of the face, the neck, the upper chest, dermatographism, this mottled skin appearance. They may or may not demonstrate obvious joint hypermobility. The hands and feet might be red or, or purple or blue. And on exam, on my lung exam, they might start feeling dizzy, lightheaded.
[00:07:39] If I’m suspicious, I’ll check for mast cell mediators. We can measure blood levels of tryptase, histamine, and prostaglandin D2. The way that you handle the specimens is really important in getting an accurate result. They have to be immediately placed on ice. And they need to be refrigerated throughout, including during centrifugation, and most labs aren’t equipped to do that.
[00:08:04] And we might get falsely negative results. These levels are only reflective also of just what the levels are in that person in that moment. And so if they’re not particularly having symptoms, these levels might be normal and they do not rule out this diagnosis. Theoretically, 24-hour urine metabolite studies are a more sensitive measure since you’re measuring metabolites over a longer time period.
[00:08:32] But in reality this is a very laborious. It’s a process for the patient. It exchanges hands multiple times in transport before it gets to the lab where potentially you have false negative results. And so clinically I don’t find that it’s more sensitive. And depending on the history, I may perform a typical allergy and immunology evaluation.
[00:08:56] A lot of symptoms of MCAS are non-specific, so how do you make the diagnosis? There are two major criteria. One from comes from the American Academy of Allergy, asthma, and Immunology. And it requires that there are recurrent and acute episodes involving at least two systems. And during these episodes, there need to be increases in levels of mast cell mediators above baseline with tryptase being the far preferred mast cell mediator.
[00:09:30] There needs to be some response to anti-mediator therapy, meaning antihistamines and mast cell stabilizers need to reduce the severity or frequency of these episodes. So you have to start treating before you can conclude the diagnosis. Logistically it’s not so easy to capture these elevations in mast cell mediators.
[00:09:51] So this is a more inclusive criteria called the Global Consensus 2 criteria, where you need one major criterion and one minor. The major criterion is symptoms affecting at least two systems, and they can be chronic or acute, not necessarily acute. And the systems can include neurologic symptoms, which aren’t mentioned in the other criteria.
[00:10:15] The minor criteria include evidence of above normal levels of mast cell mediators, response to therapy, and then there are some pathology findings, although I would say that this is more controversial. So just one of these, not both of these. And so, I really rely on this set of criteria more.
[00:10:36] And I, I think that sometimes people worry too much about whether they fit the criteria, and I think it’s more important to, to look at the symptoms. The initial therapies are very low-risk, and just empirically treating, I think there’s, there’s very low risk to doing that. So I’ll attempt to review some of the reasons that individuals can develop this condition.
[00:10:59] So I, I like this schematic of mast cells, their cell surface receptors. All the downstream pathways that can lead to mast cell degranulation. You know, we talk a lot about antigen and receptors as a trigger for mast cell degranulation, but there are agents such as C3a that can induce mast cell activation independently of antigen.
[00:11:25] There are agents that can alter the threshold for mast cell activation. And theoretically if you have genetic variants for any one of these receptors or downstream pathways which potentially could increase the threshold for mast cell activation. And it’s probably the case that individuals with, you know, multiple hits, so to speak, that are more likely to have disease or more likely to have severe disease. And there are times when I perform whole genome sequencing in these patients often in challenging cases. And I ask for help from geneticist, Dr. Richard Bowles. He’s a specialist in channelopathies and, and mitochondrial dysfunction, and the variants that he’s often looking for, and, and that we find in this patient population involve variants in calcium channels and sodium channels, and they all result in this overactivity, or a lack of filter or an amplified signal that can present with symptoms of pain, migraine fatigue, visceral hyperalgesia, GI symptoms, excessive or inappropriate fight or flight.
[00:12:40] In the drug allergy world the MRGPRX2 receptor has been really important in the last five or so years. This is expressed on the surface of mast cells and it’s directly activated by drugs like vancomycin and morphine. And so there is literature that upregulation of this receptor can present clinically with inappropriate mast cell activation in conditions such as chronic urticaria.
[00:13:09] And so this receptor may be involved in the pathogenesis in some individuals. There’s the idea that autoimmunity may be the cause of MCAS in some individuals. In 2019 this study was published on 55 patients with POTS, and 50 of them—so 90%—had presence of autoantibodies to adrenergic or muscarinic receptors.
[00:13:35] And so this really suggested that POTS can be an autoimmune condition. The major criticism to this study was that there was no control group. So, theoretically these autoantibodies could be present in healthy controls and not actually be causing disease. But clinically there are individuals that really respond to immune modulating therapies to IVIG and there’s an ongoing clinical trial for IVIG as a treatment.
[00:14:05] In POTS clinically, I see this where a lot of our typical therapies don’t really work, but IVIG does. For both POTS and for MCAS, mast cells express the same receptors. And so, again, that could be an explanation for, for what we’re seeing clinically. There are IgG antibodies to the high affinity IgE receptor on mast cells, which potentially is a target for mast cell activation as well.
[00:14:35] So why, why does the triad go together? Why does the pentad go together? There are some potential explanations for that. So we know that mast cell proteases can induce abnormal remodeling of the extracellular matrix, meaning they might actually increase connective tissue weakness. And clinically, some patients will report when their MCAS symptoms are really flaring, they’re extra hypermobile, they’re more likely to dislocate joints.
[00:15:07] On the flip side, a weakened barrier function may actually allow for abnormal penetration or excessive penetration of antigen, and therefore mast cell activation and their downstream effects. So this is like the idea, the hypothesis for why very young children with eczema are more likely to develop food allergy.
[00:15:31] The idea is that if they have leaky skin, if they have a innate barrier defect, and food antigen is introduced through the skin before it’s introduced through the gut, there’s more likely to be, there’s a higher chance that there’s going to be an abnormal immune response and development of food allergy.
[00:15:51] Extracellular matrix stretch is actually capable of inducing mast cell degranulation. And we know that in at least my population of patients that undergo whole genome sequencing, it’s not uncommon at all that we see variants in the gene encoding for tenocyn and the collagen genes. I mentioned mast cells are very closely located next to blood vessels and nerve endings.
[00:16:18] Mast cells are capable of forming direct membrane to membrane contact with nerve cells in vivo. They can release mediators that acutely modulate nerve function and cause tachycardia, bradycardia, hypertension, hypotension. Mast cells mediators can alter the excitability of a nerve and vice versa. So, there was an elegant study looking at platelet activating factor and how it was capable of stimulating histamine release from mast cells in intact human skin, but not in dispersed human skin, uh, mast cells in vitro. Suggesting that PAF actually activates nerve cells that then activate mast cells that then release histamine. After allergic stimulation, nerves can undergo phenotypic changes that can have longer term effects even after the resolution of those mediators.
[00:17:17] And that might be an explanation for small fiber neuropathy or even autonomic neuropathy. Mast cell mediators can stimulate receptors that are expressed on afferent nerve terminals. Those neurons can then send signals to the central nervous system and release neuromodulators, which then further stimulate mast cell activation.
[00:17:38] And that’s, you know, probably why there is so much pain involved. In patients with MCAS and, and sometimes controlling the MCAS can really help control the pain. Drugs that work on the nervous system can also affect typical MCAS symptoms. And of course, mast cells can recruit other inflammatory cells.
[00:18:01] So I wasn’t able to find literature on the role of mast cells specifically in CSF leak, but there is a significant body of literature on the role of mast cells in neuroinflammation. So I’ll discuss the role that mast cells play in several CNS conditions, starting with multiple sclerosis. So I mentioned that mast cells can release cytokines and chemokines, they can recruit and activate T-cells and macrophages.
[00:18:29] Mast cells being antigen presenting cells, they can present myelin antigen to T cells. Mast cells can disrupt the blood-brain barrier, allowing T cells and other cells to infiltrate and target myelin basic protein. In vitro mast cell proteases can degrade myelin protein. Myelin is capable of directly stimulating mast cell degranulation.
[00:18:54] So there’s quite a lot of literature on the role of mast cells and multiple sclerosis, and there’s an ongoing clinical trial for Clemastine, which is an antihistamine for the treatment of multiple sclerosis. This was a really compelling set of studies on mast cells and intracranial aneurysm.
[00:19:15] Mast cells have been detected in human intracranial aneurysm tissues, and so this was a mouse study where aneurysms, intracranial aneurysms, were induced with systemic hypertension and elastase, and they studied the role of cromolyn, which is a mast cell stabilizer; CD48/80, which is a mast cell activator; and mice that are genetically lacking mast cells on aneurysm formation and rupture. So in mice treated with cromolyn versus controls, there was no difference in the incidence of aneurysm, but the cromolyn treated group had a significant reduced rupture rate, and the mice treated with cromolyn had significantly reduced expression of tryptase compared to controls.
[00:20:06] Mice treated with mast cell activator, again, had no change as far as the rate of aneurysm formation, but a significantly increased rupture rate. And the investigators quantified the mRNA of inflammatory cytokines and enzymes released from mast cells to try to understand if there’s a particular agent that’s responsible for the high rupture rate, and they found no difference in the activator, the mast cell activator treated versus control group. Genetically mice without mast cells they again had no significant difference in the formation of aneurysms compared to wild type mice, but they had a significantly lower rate of aneurysm. So, to summarize, the presence of mast cells and increased mast cell activation had no effect on formation of aneurysm, but they did increase the rate of rupture, and the authors hypothesized that it’s the cytokines and chemokines released by mast cells that can be responsible for this promotion of aneurysm.
[00:21:13] There’s literature on the role of mast cells and, and stroke. Mast cells are on the brain side of the blood-brain barrier and the lepto meninges. They communicate with neurons, astrocytes, microglia, the extracellular matrix and blood vessels. They can increase vascular permeability and disrupt the blood brain barrier.
[00:21:34] Early on in stroke, mast cells can release preformed VA vasoactive and neuroactive mediators that promote damage to the blood-brain barrier edema, prolonged extravasation and hemorrhage, and then following ischemic injuries. Cerebral mast cells can amplify and prolong the endothelial expression of adhesion molecules that continue the breakdown of the blood-brain barrier.
[00:22:00] So again, there was a, a rat study that used cromolyn, a mast cell stabilizer, before and after hypoxia and ischemia. They looked at mast cell migration into the CNS and brain damage by quantifying dying neurons. And the, the rats treated with cromolyn had far less mast cell migration and brain damage compared to controls.
[00:22:23] And so, I, you know, don’t have the data, but think what we do know about the role of mast cells and these CNS conditions suggest that they probably do play a role in the pathogenesis of CSF leak as well. And fortunately this is a treatable condition. There are a lot, a lot of things that we can do to get this condition under control.
[00:22:45] So far, nothing is FDA approved for the specific indication of mast cell activation syndrome. So we borrow what we know is safe and effective from the allergy world and at times from rheumatology and hematology oncology. So, we always start with lower-risk therapies like over-the-counter histamine one and histamine two blockers, montelukast, cromolyn, ketotifen.
[00:23:13] These are used to treat hay fever, chronic urticaria, asthma. Supplements sometimes can make a big difference. And then more advanced therapies include omalizumab, which is an anti IgE monoclonal antibody. Other monoclonal antibodies used to treat asthma and allergic conditions potentially can also be beneficial.
[00:23:37] Imatinib is used to treat CML and systemic mastocytosis and can be beneficial for MCAS. I mentioned IVIG and immune suppression. A number of JAK inhibitors have become available and FDA approved to treat atopic dermatitis, and it’s gonna be very exciting to see their effect on mast cell activation syndrome.
[00:24:01] Another very low risk therapy, low-dose naltrexone, sometimes makes a big difference in, in MCAS dysautonomia pain and so on. Perioperatively, so, surgery, trauma: these are times where there are a lot of potential ways that mast cell activation syndrome can become exacerbated. And I typically write some recommendations prior to surgery, any surgery.
[00:24:28] And this comes from literature in systemic mastocytosis. So these are anesthetics that are more and less likely to cause mast cell activation. Premedication can go a long way. IV solumedrol and IV diphenhydramine unless there’s a previous intolerance. Maintenance fluids since dysautonomia is almost always present, and I often suggest increasing baseline medications leading up to and after surgery.
[00:25:01] And you know, oftentimes opioids and NSAIDs can be triggering, but there often are formulations that are well tolerated. So when it comes to procedures and surgery, there are number of potential triggers starting with the antiseptic, the agent itself, but also the application of it. The anesthetics, the excipients, the trauma itself, the adhesives, the topical ointments.
[00:25:26] And then there are things that are not specific to the procedure but fragrances, room temperature, emotional stress; they’re quite individualized. And so I, I would say that it really is important to listen to the patient and their previous experience. And it’s not uncommon that patients have had, you know, a negative experience with the previous surgery, either with anesthesia or the recovery or the healing.
[00:25:51] And just with some extra precautions, some extra medications, they do much better with subsequent surgeries. So in summary, to try to address, should it be in the differential or, or can it be a comorbidity? I would say that both can definitely be true. There’s a very wide spectrum of presentation, laboratory data, and response to therapy.
[00:26:15] And oftentimes we rely on the response to therapy. You know, we empirically treat, and we see what happens. And when it comes to things like headache, dizziness, often these things are part of the picture and often they improve with therapy. Of course it doesn’t rule out other causes.
[00:26:34] This is probably a common condition and again, quite treatable and worth addressing. So, I thank Dr. Schievink very much for including me in this conference, and all of you for your very kind attention. Thank you.