Nash Moawad, MD - Endometriosis Is a Nerve Disease—So Why Are We Still Treating It Like a Gynecologic One?

Well, first, I want to thank you, Tamra, for inviting me for this inspiring conference. And I've learned a lot and I put a lot of what I learned into this presentation. This is an interesting topic for me because I'm a surgeon, as Tamer said, and this topic is sort of deviating away from surgery a little bit. This kind of summarizes what we're talking about. This is where I practice in the University of Florida in Gainesville. I started there, started the division 16 years ago, and we have built it into a center of excellence in minimally invasive surgery, as well as complex endometriosis care. I put this here as a disclosure that I am a surgeon because if I critique our system in any way, I am part of that system and I'm the first to admit that some change is necessary.

So those are my objectives. And part of this will summarize yesterday's talks for those who are not here. So don't feel bad that you missed it. I'll put it all here in a small package for you. We know there's a very long delay in diagnosing endometriosis, seven to 10 years, totally unacceptable. It's a system failure in my mind, and you can see this multiple studies showing the same thing. It's a nerve-centric disease, as we've learned in the last few talks. 10% of reproductive age women have endometriosis, and we think it's actually more, but this is what we can see from the literature. And this is the same like diabetes and Crohn's disease, but it doesn't get the same attention. Somebody said yesterday that the agent in the airport, she was a female, she didn't know what endometriosis is, but everybody knows what diabetes is. Central sensitization evidence from 2019, we know from functional MRIs that the brain is affected with this chronic pain condition, and there's a discrepancy between the pain and the lesions.

Patients with stage one endometriosis, couple tiny spots have severe pain, and patients with stage four endometriosis may not have pain at all. It's accidentally discovered during surgery.

There's a neuroimmune integration that happens. So the lesions will secrete inflammatory markers, and the inflammatory markers bring all the immune response here. The lesions are responsive to hormones, but they also make their own hormones, the estrone. The inflammatory markers secrete a lot of factors like substance B, CGRP, histamine. Those produced nerve fibers nearby, and the nerve fibers themselves create more issues, and it becomes a bidirectional loop that keeps going. And it's not just the lesion, it's not just a hormonally responsive endometriotic lesion. Neuroangiogenesis is the topic of this meeting, and we've heard quite a bit about it. This is the cycle. Again, it starts with the inflammatory response to the tissue, and it sends a signal to build more nerves. The nerve secrete CGRP, and it goes to ramp one receptors, and the sacro repeats itself, and the macrophages are a big part of that as well.

This is a study from endometrium of patients with endometriosis, and you can see the nerve fibers there in the endometrium. So they're different in patients with endometriosis than from others. So in general, nerve involvement is a key driver of pain. It's not only the lesions in the pelvis, and the pain is not a side effect of the inflammatory lesions, it's nerve related. So there's dense nerve fibers in the lesions, there's neurogenic inflammation as we showed, and there is spinal cord and CNS impact of all this is happening. This is a very interesting study from mice. It's a mouse model that they created endometriosis in it. And you can see that the endometriosis induced widespread glyal cell activation. The glial cells, the inflammatory cells, and the tissue in the spinal cord and the central nervous system. So it's not only in the pelvis. So the endometriosis related pain may involve central mechanisms, including CNS neuroinflammation, not just inflammation in the pelvis.

So neuropathic pain is part of endometriosis-related pain. It's not just the inflammation near the lesions. Those are some screening tests, validated screening test pain detect and DN4. And they found that those patients have some features that are nerve type pain, the throbbing, the sharp pain, the neuropathic pain that sometimes it's not discovered. 30 to 40% of women with endometriosis will show those neuropathic features, and it's very important to phenotype the patient when we see them. What is causing their pain? Is it all inflammatory, hormonal response? Is it dyspneoria? And the rest of the month is fine. There's no nerve-related types of pain, or is it central sensitization? Those are all different types of pain that we have to phenotype the patient when we see them. Those patients have allodynia and hyperalgesia on exam, and that shows peripheral nerve sensitization. And there is risk of misclassification.

So if you see a patient with central sensitization, you keep operating on them, that's not going to help. So we want to differentiate between those three different types of pain, nociceptive, neuropathic, and nociplastic. Nociceptive is where the lesions are, inflammation, and this is how we've been treating endometriosis. Neuropathic is peripheral and central. So the nerves themselves become a problem. The nerves themselves peripherally become sensitized, and that causes burning, electric, stabbing pain, radiating pain. And nociplastic mechanism, this is a central sensitization where you have those spinal tracts firing constantly. If you think of phantom leg after amputation for crush injury, that's the same exact thing. And frequently, it's a mixed phenotype, but it's important to break it down into what's causing this patient's pain. This is quickly and held recovered this nicely, quickly the nerve pathways covering the sensation from the pelvis with the inferior hypogastric nerve plexus, the hypogastric nerve, then the superior hypogastric nerve plexus, and so on and so forth to the spinal thalamic tracts.

So why lesion removal? We know that lesion removal, not always. It's not always successful, and we all do the surgery, and most of the time patients feel great, but sometimes they don't. And why is that? It's 20 to 40% patients of patients will have pain recurrence at five years. Is this a recurrence of endometriosis? Is it a recurrence of pain? Or is there something else we haven't treated? So there's persistent dorsal horn sensitization due to sustained spinal excitability. Even after the excision, you have stuff happening in the brain, the anterior singular cortex and frontal lobe are impacted. And Susie Asani showed this beautifully in 2019 with the functional MRI.

This is a patient who had surgery before for pelvic pain, and she was told everything looks great. Normal looking uterus, tubes, and ovaries. I don't see anything. And she was told it's not endometriosis. Keep going. Well, I listened to her, examined her. Obviously findings on an imaging is all fine, but I took her back for laparoscopy and from far away it looks fine. But when you get really close, you can see so many subtle lesions. I think there was Tamar yesterday who said there is no phenotype for endometriosis. Endometriosis is abnormal peritoneum. Any peritoneum that's not normal is abnormal. So it doesn't have to be brown or white or yellow or any of those things. So anything that doesn't look right, we excise and we see what the pathologist says. You can see her some subtle adhesions with the ovary. You can see some bands, you can see some windows.

So when you put it all together, you really give the patient the benefit of the doubt, then you do a complete excision. Again, mindful of the nerves. So you see here, the nerves are all preserved. We don't go digging for them. We don't have to show beautiful pictures if we don't have to, so we just preserve them. But anything that doesn't look right is excised. And some of you may think this is excessive, but guess what? This is the pathology. So this is the right thing to do for this patient. So before we say, okay, surgery did not help, we got to make sure we do the right thing for the patient and we'll do the right and complete excision procedure. Excision that's mindful of the nerves. Here's on the flip side, a patient who's 32-year-old, she had stage one endometriosis and she had eight out of 10 non-cyclic pain.

She had three laparoscopies within six years and nothing is showing up. The first time, yes, there was stage one, but three laparoscopies after that, nothing. Ultrasounds, MRIs, they're all fine. But what do we do? Well, you got your diagnosis here, central pain diagnosis, centralized pain diagnosis. So central sensitization. It's we need to stop operating on this patient because we're just perpetuating this problem. We'll just keep going like this. The problem is patients will keep shopping for another doctor who would take them, and that creates more issues. So this is what happens in the central nervous system, the wind up phenomena with repetitive C-fiber stimulation leading to temporary summation in the dorsal horn where the sensations go initially, and then that goes up to the second order neurons going up to the brain. And so increased excitability on the opposite side, decreased inhibition from the brainstem.

And when you add those two things together, that creates central sensitization. And functional MRI, like I said earlier, showed findings in the singular and the prefrontal cortex. So it's real. It's not just imagination, it's real. There's gray matter volume changes. I showed you from the mouse study earlier, the glial tissue all over the central nervous system. And this is very similar to what happens with fibromyalgia. It's the same exact mechanism. There's a lot of overlap with other conditions. So IBS has similar background, fibromyalgia, migraines. And when you put all this together, neuroimaging shows overlapping insular and anterior singular cortex and the frontal cortex sensitivity.

Other issues that have to do with the pain, it's not just the lesions, it's not only central sensitization. There are so many other factors that go into it. So pain catastrophizing, increased pain intensity and functional impairment in those patients with endometriosis. HPA access dysregulation. So chronic stress, when we talk about stress reduction, we're not just brushing up and it's like, there's nothing we can do to help. Stress reduction does help because it does decrease the cortisol, it does decrease the inflammation and so forth. And anxiety and depression play an important role. They increase the central sensitization and they make our surgical outcomes poorer. So when you have a patient who is severely depressed, you don't think you're going to do surgery and fix all her pain. History of sexual abuse, unfortunately, it's not uncommon and it's important to uncover and discuss and address with the patient if she's open and willing to address it.

So it's not a psychogenic issue. It's not what I'm trying to say. It's a neurobiologic issue, but our psyche plays a very important role in that and we can't ignore it.

So what happens with repeated surgery? Every time we do surgery, regardless how you do it, there is increased perineural fibrosis. So those nerve fibers, they have to heal somewhere and we heal with fibrosis with scar tissue. They can be peripheral nerve injury, whether it's the hypogastric or any other nerve like the obturator, pedendal, depending on where you go sacral nerve roots. There's reinforcement of the central pathway. So you reactivate that peripheral input every time and you strengthen the established central sensitization circuits. And every time you do surgery, what do you do? Most of us will give a few pills of opioids. So the patient gets exposed to opioid, and that's a whole other talk, but we're part of it.

So this is the historical GYN system, the paradigm that we need to change, the paradigm shift that we're promoting. So we always say you have a lesion, it's localized estrogen dependent model, and this is what's causing the pain. Let's do surgery to remove the lesions and life should be good. We have to look at the surgical staging we have. It doesn't correlate to the pain. So what do we do? Pain is always secondary outcomes. Let's do surgery and see how you feel. That's not how it works. Let's figure out what's causing your pain first. Plan for management according to your pain etiology and take it from there. And hopefully with this approach, we can achieve better care for our patients. So hormonal suppression is limited. Decreasing the inflammation and the hormonal stimulation does not affect the peripheral or the central neurosensitization. There's relapse after this continuation.

We can keep patients on hormones or generate agonist or antagonist forever. There is a good number of patients who don't respond to hormones. There's a number of patients who have side effects, and the problem is the neuropathic and nociplastic type of pain. How about ablation? We need to avoid ablation altogether. Ablation should be removed, erased off the map of endometriosis. So where would you ablate any of those patients? Lesions on the bowel, lesions on the ureter, deep infiltrating lesions, stage four endometriosis with posterior culturecycle obliteration and the ovary stuck here and the ureters underneath. There's no room for ablation here. Where would you ablate this? This patient had surgery. She was told, "Oh, you have fitcardis from chlamydia." She has endometriosis all over her diaphragm. There's no room for ablation here. So when we ablate, we burn the tip of the iceberg. So if you go ablate here, you're missing all this big rectal nodule.

So we need to abandon ablation.

So we need to switch. It's a paradigm shift from let's cut lesions out. Let's do excision surgery for every patient who walks into the door to a multimodal, multidisciplinary. So we'll talk about multidisciplinary care in the OR when you have patient with rectal involvement, nerve involvement, bladder involvement, ureter involvement, thoracic endometriosis, but we need to also think of multidisciplinary care before the OR, outside of the OR. What does that involve? What involves everybody else in the care for the whole patient. So neurology, pain management, physical therapy, psychology, integrative medicine, and then the surgical disciplines we just discussed. So we need to change our system. We need to change our referral patterns. We need to change our insurance reimbursement. We need to change our training for residents and fellows.

So the team model, you need a mixed surgeon at the middle of all this because somebody needs to orchestrate all the care. Nobody else is more qualified than a mix surgeon. You need to involve your pelvic floor physical therapists. You need to really involve the integrative medicine. There's a lot of things they can offer that we don't think about. You need the pain psychology that's really critical. Those are physicians or PhDs who take care, and we talked about this yesterday. It was an amazing talk about the endometrial panic. That's a big deal. That was a great talk. So we really need to address this. And like I mentioned earlier, history of sexual abuse needs to be addressed to the fullest. PMNR, physical medicine, rehab, pain management, nerve blocks. All those things are very important in looking at the patient as a whole and addressing all the causes of pain.

CBT is very important. It reduces pain catastrophizing and improves function. Mindful-based stress reduction. Again, we talked about stress and its impact on pain and pain perception and coping mechanisms. And there are a lot of drugs that can be used. Again, we may not be the best experts, but we have experts we can refer to. So SNRIs, the tricyclics, the gabapentinoids, and all of those target the descending inhibitory pathways and the dorsal horn. The anti-CRCGRP, that's a promising new field, the medications for migraine, and they have been shown to decrease the size of endometriotic lesions in my studies so that can be explored further. Initiating the multimodal central sensitization management early, not 10 years into it will help us prevent the sensitization from happening. This is the goal. Once synthitization sets in, it's very hard to go back from there. This is a quick look at that study I was talking about where the anti-CGRBs decrease the size of the lesions in mice.

Other things we can do put on the nerve blocks or pelvic floor trigger point injections, sacral neuromodulation. The spinal cord stimulation, we talked about this yesterday. The vagal nerve stimulation that was very exciting and promising. Obviously, we need more data, but there's a lot of things that we can do, we can focus on rather than just always talking about the surgery, the excision surgery, the excision surgery. Very important when we do surgery to be nerves bearing. So the hypogastric plexus, look for the nerves. As Hilder said, with current laparoscopy and robotic surgery, we can see a lot of things we never used to see. And laparoscopic neural navigation and EMG during the surgery will allow you to see what you're dealing with. This is a patient who had surgery in another university by another mixed surgeon, unfortunately. So we need to go back and look at our fellowships.

How are we training people? And this is her nine months after surgery. So what do we do with her? We would take care of her. We open all this, still nerve sparing, excise all the lesions, but still nerve sparing. And we got to do this before we say, okay, it's a failure. It didn't work because at that point she had surgery and it was a failure.

This is a quick video showing nerve sparing. So this is a excision of the pelvic side wall and you can see all the nerves underneath. So the hypogastric nerve and the pelvic splanking nerve plexus here, getting parasympathetic from the S2, 3-4 deeper than the uterine vein. And you have your spaces. And those are areas we have to identify first before we excise. Just like the ureter, you find the ureter first before you go cutting. So we need early multimodal therapy, avoid unnecessary repeat surgeries as much as possible. Just work with your patient, partner with the patient, and routine pain screening at diagnosis. We need to phenotype what's causing the pain before we do surgery. This is a provocative last slide here. Who has dental abscess who wait seven to 10 years? This will get seen the same day or the next day. You have the maxillary nerve here and you have a dental abscess here.

This gets taken care of right away, but endometriosis, not the same. Patient with a spinal cord herniation here, disc herniation causing nerve compression, they don't wait. So we got to change our mindset. With this, I invite you to join us in November at the AGL meeting. We'll continue the conversation and we'll try to include some of the things that we highlighted here in this talk. Thank you very much for your attention. Thank you for having me.