Tamer Seckin MD - Why is Endometriosis is a Nerve-centric Disease

Frank has been a very strong supporter of me in my career at Lenex Health, even though we met before his departure, he's been my chief for many years, and I appreciate it. I also want to welcome to the 17th meeting of ours. This is not easy and I am humbled to get going in New York City. I want to thank for those who made today possible, particularly Rudin family who opened their homes. This is their facility. I want to thank Madeline Rudin, my board member who's been supporting us for good. I also recognize my mentors in the room, Dr. Dan Martin, Dr. Harrich, and others scientists. This is going to be the scientist day first. And we have wonderful visitors from speakers from Germany, from Europe, from everywhere from Mexico. I think we will bring a tasteful balance of what we can talk today. I picked this topic, nerve-centric endometriosis, because it was challenging.

It was never done before. Not really that. There's an area in our specialty that we cannot keep our hands on, like removing sick tissue in surgery. This is a part of care that we give so slippery as Dr. Martin says that. Endo is like a jelly. You cannot nail it on the tree, really. But this issue with nerve-centric, especially for a sympathetic and sympathetic system, particularly involving vagus, we have vagus scientists here today that they're going to talk from Feinstein. It's an amazing topic. I think I'm opening a Pondora box here. Everybody will follow what you're going to see because neuropathiology, which I'm going to get in my present a little bit, has also opened that door and we have to recognize Mark Passover for that. So this is, as you know, I've been practicing for many years. This is our 17th meeting. And what makes this foundation different is I think you have to understand, we brought initially scientists and surgeons together concept, but we put the patient right in the middle.

And I thought without patients, we would not go anywhere. This foundation became from whatever, however it started 2006 actually, when we got originally filed and get going with Padmalakshmi joining me. If it wasn't for the patient, we wouldn't be here. And the revolution and the change will be within from the patients. The doctors have their own world. They will never be listened to the point that the patient's voice could make difference in the future. So we got to get going. I'm humbled. I'm not going to talk about the lab much, but this lab happened not because of my choice. And I honestly did not even ask my name to be put there, but there was issue that they pushed for it. So it's a $20 million endowment. We already have, it's four million going in eight months. And I'm hoping with your support, we will get more.

And we continue to support other research initiatives. We gave over up to $2 million to others. So you can really consider there's six million we gave away for research. It's unheard from a privately founded public charity to give this kind of thing. So why neurocentric disease? Actually, the rhetoric has changed. Endometriosis is not simply anymore just no longer an ectopic tissue outside the uterus. It involves incredible association of inflammation. It's a inflammation fibrosis immune science behind it that affects the whole body. It's a systemic disease. And the nociceptive and noxious feelings from the peritonium makes this disease very special because it's the non-specific symptoms starts from the adolescence that these women get lost and nobody knows what to do. Look at this. This is what we are faced today. Women can come all of these and the doctors are blank. They don't know what to say.

And I'm one of them too. I'm as perplexed as everybody else. And that's why I'm doing this because I want to accept responsibility and humild here because I was one of those people that when I could understand uterine pain, I could understand leg pain. I could understand NDA. I never understood anything beyond pelvis that's happening in the mind. It's all happening. It's all happening because of our neuropathy. And this is me, really. I mean, this is me for still it's me. I do this. What am I going to do? It's a big challenge. So there are two books that also got me there here. I'm not sure if she's here, but one is Kat Bohannon. This is the evolution of female mind, femaleness under this effect of this. Is cat here? She's not here. So she will be here, hopefully. But the bottom line is, for 200 million years, our mammalian nervous system has gone through evolution and men and women are different.

And there's 200 million estrogen dependent evolution of women, 200 million years versus men. And all the nervous system from brain to periphery, our animal brain, even before that, is under the effect. So the complexity is immense. So this book really explains that on other issues. And the other is the Kevin Tracy book, Great Nerve. I never thought Wagus put Wagos' role, even though we know there's some connections, but we never recognize that. So Kevin has proven that stimulating vagus nerve, effective vagus nerve, can decrease inflammation in the body. And there's been proven and others in rheumatoid arthritis, especially cytokines are with increasing wago stone, decreases, and it's been shown by so many. And this is a very promising area I think we are going to face in the future. There's already things going on. So the vagus has 200,000 nerve fibers

And 80% of them are afferent, constantly sensing the peritonium and lower abdomen. Imagine that's how this ... And it is not under your control, all autonomic. And this slide demonstrates an earlier experiments in 1999, vagus nerve conduct sensory information from the uterus to the brainstem. And this is an alternative sensory pathway directly to the brain. They injected with retrograde tracer, fluorogold and Saudi Arabias virus to uterus and cervix. They popped out all the way at the nodose ganglion and nucleus tractus in the midbrain. And these were estrogen positive. So there is direct connection, direct connection out of our spinal cord from uterus all the way to the brain. This is an alternate pathway, rarely, rarely appreciated.

And that was the animation of that. So this visual really shows that there's a brain activation in five women with complete spinal cord injury. Their spinal are gone, they're paralyzed, they are doing self-stimulation and orgasm is achieved without direct stimulation to the brain without any spine involved. So that says a lot, right? So similarly, this is the focus MRI responses in those women. Immediately, you can see activity in the nucleus tractor solitary and in those areas in the brain. So this is interesting. Does anybody know what birthgasm is? Who knows birthgasm? I learned, I didn't know. This is a midwife stuff. It's a female orgasm that reportedly occurs during childbirth. This is sometimes referred as an orgasmic childbirth. Some women use sexual stimulation to ease contraction instead of anesthesia. More than 85% of the midwives testify this, and it's been really practice in midwifery world, it's been acknowledged.

This is interesting. So let's not be shy about understanding things. Man never understands a lot of things with women, and I am still learning. I just learned this. I didn't know this.

But in reality, for all practicality, this is what happens in symplistic terms. In menage, the first period, the resistance of cervix, the power of uterine pain causes a lot of things to women. I mean, first of all, she doesn't know what's going on, what's going down there, pain, discomfort, panic maybe, right? But before that cervix probably opens up, probably in these women, there's significant retrogradeness of that debris goes backward. We assume this, but we do see this all the time. When I do surgery during adolescents during their periods, with endometriosis patients, there's significant blood inside. I have so many pictures of them. This is one of them, but there's also some other things happening at bowels work. There's ovulation there. This blood causes significant discomfort. Many women knows us as endobelly. Endobelly is bloating gas. Later as it goes further, it becomes constipation, painful bowel movement, and vomiting.

So it's all peritoneal. It's different than uterine pain that comes with cramps, completely different. And peritoneal pain later localized, woman can say, "It's more on my right side, more on my left side," or ovalation pain constantly on one side, that becomes permanent. These are the things that when women say this, I know they have endo immediately. So this slide depicts the neural network of spine, sympathetic change, which is different than peritoneal pain in a way. The WAGUS carries differently. Perietal peritonium and pelvic peritoneum is different. I'm not going to go into details with this, but I want you to know how my mind as a surgeon really works. Obviously, there's rectal pain, there are painful sex. They all have a way of ... We ask these questions, we all have a way of processing these before the surgery, but painful sex and painful bowel movements means a lot because that means there's disease in cul-de-sac.

It doesn't have to be deep disease that you see here. Even 10 peritoneal implant can cause the same effect. So the lesions, size and severity does not correlate with pain. So I say to my patients and to everyone, you cannot stage pain. Pain is pain. Pain is perceived here and everybody has their own private life. But one thing is very bad is horrific, horrendous, incredible. This is one of my patient drawdi. She has incredible drawings of ... She had sciatic pain and amazing drawing she came up. These patients have so much on the patient. They use hot water bottle to the point that they burn themselves. They also take a lot of pain medication. They may not feel the pain, but as soon as the pain medication eases away, and they end up with colostomy. Many surgeries lead to serious injuries. So this is not an easy field to be in.

Terrible when you see one of your patients call, but you can't help it. It does happen. When it comes to sciatic pain, I have to acknowledge Dr. Mark Passover. Mark Possover, like Harry, like Dan Martin, we honored him years ago. It's been seven years now at the Explorer Clubs. He's a true Maverick that really opened this neuropaviology. And truthfully, I didn't go to those areas.

There was a guy named from Australia, Terry Wankyl, Harry. You remember Terry? Terry Wankyl called this area of ... Terry Wankar called this area of sciatic as Tigerland, but he would approach from medium and I never saw him exploring Vargas. No, but I've seen his videos. But now this area is ... I declare this area should be lion land before Mark Passover. I hope he hears this. And I'm being so nice to him. So I'm going to present a little video of ... I hope it's little, but basically this is a targeted excision of a deep nerve endometriosis with two masses, as you see, and it's right on top of the sciatic. So we went to do these-

Beltsein nerve mapping for endometriosis involving the sciatic and pudendal nerves. The patient-

Somebody tells-

... For publication and distribution of the video, including on social media, the journal's website, and scientific databases. Endometriosis involving the sacral plexus and its component nerves has been largely unexplored. Fully infiltrating endometriosis can affect pelvic nerves such as the sciatic obturator, pudendal and presacral nerves. It is more frequently found on the right side. These nerves are not examined during routine procedures. Therefore, its true incidence remains unknown. The sciatic nerve runs from the pelvis down the heels, powering hamstrings and lower leg muscles. Sciatic nerve involvement causes sharp pain, tingling, or weakness radiating down the thigh and calves. The pudendal nerve controls sensation to the perineum in genitals and pelvic floor muscles for continence. Pudendal neuralgia can cause paresthesias, numbness, sexual dysfunction, or urinary and bowel issues. Opturator nerve controls adductor muscles and sensation in the medial thigh. When injured or compressed, patients may develop groin pain, thigh numbness, and difficulty crossing the legs.

To reach these nerves, then the surgeon must navigate dense arterial and venous networks that surround the lumbosacral and presacral spaces. These vessels and nerves often show significant anatomical variations

And

Whenoperative neurotic monitoring is-

I'm sorry. So basically-

Despite-

I just want to say you cannot dive to these areas without understanding it's very dangerous and you really have to be trained. So this is a patient 36-year-old that came with demonstrable mass there. And so we went in with a vascular surgeon and I hope-

There's an hysterectomy for adenomyosis for symptoms persisted.

Do you hear the voice? The

Patient underwent a comprehensive multi-

Turn the voice up a little bit. So the patient had a neurology consult and before, and we have everything ready for ... Prior to surgery, you didn't see that. Prior to surgery, we basically put the sensors all over from leg to bladder to sciatic, all these appropriate areas that we are going to provoke during the procedure. So when we looked at it, we did not see any endo other than just the tip of the iceberg there. There's little fibrosis on the rectum. So we basically first tried the medial approach. We did our typical urotherolysis and moved forward. Sorry. So my apologies. I lost the sound there. I don't know why, but ... Huh? All right. So I cannot pass forward this.

Despite prior endometriosis excision and striking me for adenomyosis, her symptoms persisted. Following, the patient underwent a comprehensive multidisciplinary preoperative evaluation, including neurology, vascular surgery, and neurophysiology consultation. Pelvic MRI revealed a fibrotic endometriotic nodule along the right pelvic sidewall compressing the sciatic nerve roots. While there was no direct nerve invasion, its location revealed nerve entrapment. The surgery was led by an experienced endometriosis surgeon with a vascular surgeon assisting to safely manage major pelvic vessels and reduce complications. On entry into the pelvis, peritoneal implants were seen on the left pelvic sidewall and a pigmented lesion was appreciated on the right. With imaging, we knew this to be the tip of the iceberg of a concealed deeply infiltrative nodule. We begin with the medial approach to retroperitoneal dissection, performing careful ureterolysis to the parametrium supported by retroperitoneal hydrodissection. Next, we used a lateral approach to access the ileal lumbar fossa, working lateral to the external iliac vessels and medial to the psoas muscle.

The dissection proved a safe corridor to these lumbosacral nerves. We proceeded caudally with identification of the sciatic nerve, which was verified with the ball tip-

This is the probe we're using. We're touching immediately we see it to sciatic pudendal obturator. This is reassuring for the crouto. Medical legally, it's also important in New York City when you practice anywhere. So, but medially because of the mass, we had to transect major vessels to approach here.

I can carefully dice-

This is the first mass.atic

Tissue and adjacent.

This was medial to the obturator.

Subsequently, the obturator lymph nodes were removed from the surgical field to allow for clear visualization of the endometriotic nodule.

There's something very interesting coming at the end of this case when we removed these lymph nodes.

After completing the lymphadenectomy, the mass was visualized with invasion of the umbilical artery. The umbilical artery was clipped and cut. Dissection continued to the vaginal cuff completing perimetrial ureterolysis. The inferior medial portion of the nodule displayed arterial invasion at its face and marked adherence to surrounding neurovascular structures. Perimetrial dissection was continued by identifying the vaginal artery and vein, both of which were involved with the endometriotic mass. The vascular components of the mass were clipped and cut medially. Then attention was turned to the base of the-

So you have to pay attention how dry it is. So you have to have this precision. Otherwise, I see a lot of cautery being used all over.

Dissected from the sacral nerves, parametrial vessels in an inferior medial direction.

This is the second mass coming out.

The distal extension of the mass trapped along the sciatic nerve and pudendal trunk towards the femoral canal. We continued our decompression caudally of the sciatic nerve trunk under direct visualization. We clearly exposed the obturator pudendal sciatic and superior gluteal nerves along with the superior vertebral pudendal arteries. The pudendal nerve was identified using neurophysiologic monitoring. The final portion of the mass was found to abut the pudendal neurovascular bundle. Careful dissection was performed to preserve both the artery and the nerve. After separating the mass from the pudendal nerve and artery, the distal part of the mass was successfully excised using a ligature. Following excision, the pudendal nerve was explored through Alcox canal and neurophysiologic monitoring confirmed intact sciatic and pudendal nerve function. No complications were observed and deep pelvic nerve function was successfully preserved during surgery. Histopathologic analysis confirmed deeply infiltrative endometriosis with lymphatic invasion into the obtrader lymph nodes.

Interestingly, pathology also demonstrated direct vascular invasion in the vessels abutting sciatic nerve. Surgery involving deep pelvic nerves is highly complex and carries a significant risk of postoperative complications, such as numbness, hypersensitivity, or neuropathic pain.

So we have close to 30 cases right now. And truthfully, there is always some degree of neural new symptoms pop out. Even though their sciatic symptoms disappear, there is edibity, numbness, this, that, because you're directly navigating around these nerves and you don't really see quite a few nerves that are microscopic and everything. So this is important to note, but working very dry is a very non-burning technique is very important. I irrigate a lot to get the clean capillary oozings in my view. This is how the baby is born. This is a interesting ... Sorry about this. How the baby, the first lesion pops out. I call this, this is how the baby's born. This is not going to be a good baby. This is going to be nasty son of a bitch coming. So this is the one who's going to destroy that uterus, that woman's life, that lesion.

And that lesion has some genetic markers in it that we have no idea what they are and we're working on it. So these lesions grow that like a little mass of blood in it, like placenta or whatever. And you see the angiogenesis, how is this intricate network of vessel? But trust me, there are nerves in that we never see. And these protrude, really, endometrials never come from retrograde blood implanting. Well, Samsung thought like that. Samsung lived like a hundred years ago. He didn't know any of these today. But now endo actually comes out like a tomato from a pothole. So you put the season, it starts coming out. That's where the secret of this disease lies. And I say that with confidence because ... Oops. Okay. So you see how beautiful these pictures are.

But these are all places that it bled. Whenever bleeding happen, it destroys them as a tellium. This is how these lesions really swim underwater. If I stimulate that, you're going to see them swimming like buds. I mean, when I discovered this, it was amazing for me to always think. So this is a nerve that's been surrounded by inflammation, and we know it by ... This is an adhesion 430 times enlarged with Mason's Tricom with calcitonin gene related peptide. You see the nerve in green, the vessel is here, capillary. Similarly, this one is 1,500 times enlarged, again, in how the nerve and vessel travel together. And this is the same thing on electron microscopy. The non-myelinated, which is the peritoneal nerves are this, which is right next to the vessel. So this is an interesting case. Years ago, 15 years ago, this patient from California, very famous person, who's getting estrogen all over.

She's 65 years old. She's blasting estrogen from every part of her body, from vagina, skin, orally. So she comes to the emergency room, massive hemoperitonium. She's been on menopause for 10 years before, and she started this recently, and huge hemoperitonium. And this is the findings we had. This is why I did my blue dye. Peritonium was thick like a leather. And you cut this peritonium. I have more cuts of this, but this is her, I think, Dr. Ihan, to do all these. She's here right now. This is her staining. You see gland stroma, but you see inflammation all over, and you see the nerves all over. So there's not only nerves, there's also mini muscle tissue coming there. And you see them. It's histologically multiple systems are activated, most likely from stem cells. So this is what we really think. This is mesothelium, transmesothelial migration of ER cells, Dr. Iyon did.

So we see in this middle one, we see the estrogen receptor on the mesothelium. In the second one, you see it is under the mesothelium, again, estrogen sensitive staining positive cells. Again, another example of the inflammation where must cells, you're going to hear from a lot of researchers today, I'm sure from must cells. But this is what happens. When you look at this peritonium, you really see a normal peritonum. There's nothing wrong. And a lot of doctors get fooled by this because I can't blame that. That's the blinding effect of the bright light. Beautiful peritonium, nothing there. I don't see an endo there. Anybody see Zenda, experience endosurgeons? You do. Where is it?

Okay.

I honestly ... Yeah, there is something there, but I didn't irrigate. Maybe it's something else. But there's something here maybe, but there's star lesion there because still given, but more importantly, you see massive destruction of that peritonium. Okay? This peritoneum, you don't see the holes. That peritonium sick all over. That peritoneum sick all over. This is where this fresh blood comes maybe in touch with underlying nerves. That's where the pain is probably. We don't know. These are, I call these potholes. This is where next blood will come and like a pothole is going to see there and going to flourish. And this is another one. Before that, I see only this guy there, two of them, but you don't see the other guys that are so ... I mean, these are distinct holes here, but these holes are real. When I push from water from, look at how mechanically it's open to outside.

And my theory is, look, this is rectum, this is uterus, this cul-de-sac is closed. This is an advanced endo. Look at the peritoneum right next to the rectum holes, lesions. Trust me, the speritonium that covers the rectum, the whole intestine is exposed to this very toxic, corrosive, menstrual debris. But I swear to, I did a case yesterday, endo all over. I did the blue. There was no holes in this case, but endo was. So there is a difference between corrosive mestrial debris versus non-corrosive menstrual debris. This is metalloprexidizer, whatever, destroying the basement membrane in these cases. And I think it also is responsible for diaphragm endometriosis because I see these, there's the same holes and it goes on in central tendon. There are holes that develops in these patients. So what causes thoracic endo is probably in some patients, they're propensity to destroy that there are enzymes most likely.

That's my thing. That's chest pain. So this is my hypothesis. I think whatever pores is also responsible for these holes. So also chest pain and this is all covered by peritonium. There is phrenic nerve is vagus again. And this is our survey. We did more than 51 cases of these. Almost all of them, in our cases, we never found anything on the left side. Everybody came with right-sided endometriosis. We removed so many specimens from these. And more of these are not glands. They're all mostly stroma. Mostly stroma. You don't see glands there much. But what is important is more than almost 90% of them had stage four endo downblow. So there is a very wild endometriosis down below. And many of them had positive family history and their age was all 37. So endo is a progressive disease. It doesn't pop out in 17 years old.

I never seen one. The youngest I saw was 29 in my series, but most of them are older. Same thing with sciatic. On the average, it is 37, 35, 35. So the head of the snake is really coming from the pelvis. So that's the definitive. So we do approach these as dual compartment. We go with the thoracic surgeon together. So we talk about nerve sparing surgery. The most important nerve to be spared in the body is the brain. This is El Sani, beautiful work that was published 10 years ago. This is what happens to the brain. The brain loses its volume 15% to 10% all over. And this is something that's been published by my psychologist and myself. I send some patients for psychoanalysis prior surgery. Not psychoanalysis, but some sort of a consult with the psycho, even though they have their own. They don't mind.

They rush. And many of these cases, you come to understand their life has been nothing but panic initially. Anxiety. Their journey often starts with pain not being believed. They are constant fight for epistemic authority. They want to be believed. When they wake up from the surgery, the first question they ask, did I have endo?

99% asked this question. The depression pain cycle emerges from years of chronic pain symptoms and repeated misdiagnosis, lost trust to the doctors. That it was including me in the old times. So psychological retreat becomes a natural defense. This is also called withdrawing into psychology scores, and I like this term, psychic dead zone. They retreat. They become silent within. Listen, this is a very dangerous dead zone because this is where substance abuse abuse start. This is where you see suicide or overdosing. A lot of other things happen in this psychological lens. So early diagnosis, early intervention, not by just surgery, by psychological help and understanding. I tell my patient, out of maybe 500 patients, I said, "There is only two or three patients came back. Why did you send me to this guy?" You know who they were? They were both psychoanalysts themselves. They didn't like the questions.

So there's three to five times elevated rates of major depressive disorder on these women. So I'm coming to the end. Thank you for your time, but WAGA stimulation may offer something for these patients. This is invasive, but it could increase waggle tone and decrease inflammation. There's been studies that's been performed for epilepsy, migraine, with some promising results. So the question comes, is endo next? Maybe. Maybe the right way. We're going to hear from someone very interesting. I'm not going to say because it's very exciting what I heard from Wagu scientists, from Starrus. Starros here is not here. Surprise. You're going to see him here. So

Exercise is the key. I think for men and women, exercise would decrease your inflammation in the body. So I think that's something positive. We can promote exercise. In that sense, this guy is swimming somewhere. I think I'm increasing my waggle tone here, but it's more than that. This is adventure for me. This is excitement. And I think adrenaline is coming from different direction from my mind. So I am sailing, sailing somewhere that you cannot ... Some people notice, obviously. I am sailing right in the middle of Atlantic Ocean. I crossed the Atlantic two years ago. It's my most memorable time from Miami all the way to Portugal. In the middle, we stopped and I did this swimming. It was 6,500 meters down. And I thought about that. I just thought about that. So I hope you could do something exciting for yourself. I'm a risk taker.

So thank you.