Episode 446 – Spaced Learning Series: Edema and Eosinophilia

(upbeat music) - Welcome back clinical problem solvers, Maddie and Yusuf here. At CP Solvers, our mission is to make clinical reasoning accessible to learners worldwide. We invite you to join us for our live virtual morning reports where we break down cases and sharpen our diagnostic reasoning together. Now over to you Yusuf. - Thanks Maddie, just a quick reminder, this podcast is for educational purposes only and is not a substitute for medical advice. Patient details haven't modified to protect their privacy and the views expressed to our own, not those of our employers. Now let's dive into the case. - Enjoy the show. (upbeat music) - Welcome back clinical problem solvers. We're excited to be back for another episode of the Space Learning Series with our group. Since our first recording, we have an amazing new member. Let's get to know her. - Yeah, hi everyone. My name is Lira and I'm one of the CP Solvers Academy members. I'm currently first-year internal medicine resident in St. Petersburg and also an officially full-time personal detainer from our cat. Very, very excited to join the team. - Hey everyone and welcome Lira. My name is Ethan and I'm also one of the CP S Academy member, currently based in Taiwan and doing my postgraduate general medicine trainings. Long time no see everyone since our first episode and very happy to be back on this stage and discuss another case with you all today. - Hello, hello everyone. My name is Kai Risa. I'm thrilled that Lira joined us. I'm also a CP S Academy member and I'm also a post at focusing on cancer research based in New Haven. Well, lately with everything happening in the board, I've been holding onto a deep hope for peace. So happy to be here with you all today. - Hey team, my name is Alkazai. Also a CP Solvers member and currently a hospitalist in Houston, Texas. Just been busy with my two kids and with life on the words but I'm pumped for the case today. Let's swing it over to Mengyuan. I hear it's an amazing one. - Hey, I look yes. Hi everyone, my name is Mengyuan and I also I'm a CP Solvers member and currently a hospitalist important origam. Yeah, it's been a while and life has been hectic but I'm very happy to be back sharing a case with you today. So let's start with the case. We have a 45 year old lady who presented to the hospital with six weeks of progressive swelling. She was feeling well until six weeks prior to admission when she noted swelling at her ankles, which was new to her. Since then she had progressive swelling. At first involved her legs and knees, then progressed to involve her wrists and arms as well as her abdomen and even her face fell swollen. She felt this intense swelling was stretching her skin and giving her a lot of discomfort and even pain. This also gave her joint stiffness to the point that she was having hard time bending her knees or typing at work. There was no preceding injuries or illnesses. She tried to keep a low-salt diet and try to wear compression stockings and neither helped. She endured some fatigue but otherwise denied short and sub-press, orthopnea, chest pain, abdominal pain, nausea vomiting, fever, nice sweats or any change in urine. She reported that she had a rash that she described as hypes on the right forearm of a couple weeks ago prior to this admission which resolved quickly within a day or so and otherwise denies any skin change. She had seen her primary care with these concerns at some workup was started. But I'm gonna pause here and see what initial thoughts you all have about this progressive slow-body swelling. - Wow, man, you would an incredible start. So to summarize, we have a little age woman presenting with subacute progressive edema without clear localizing or systemic symptoms. The rash was transient, so I'm just gonna set that aside for now, but if it comes back, we could definitely revisit it as a clue in our evolving problem representation. So the question I have right now is how should we approach edema? Like many of us, my first instinct is to think through the organ systems that one dysfunctional are most likely the cause of edema, the heart, deliver and kidneys. Fundamentally, edema arises when our blood vessels lose their homeostatic balance and fluid escapes into the interstitium. But what does that really mean? So we're gonna break it down thinking about the blood vessel in three parts, the inside, the wall and the outside. So inside the vessel, imagine the inside of a blood vessel like the inside of our garden hose. It contains not just blood but also pressure. In heart failure, poor forward flow leads to venous conjection, pressure backs up into the veins and capillaries, increasing hydrostatic pressure and pushing fluid outward. It's like stepping on a hose, it turning the water all the way up. Eventually, it leaks out wherever it can. Similarly, venous obstruction when acute, like a DVT or chronic, like venous stasis, can produce the same effect. On the other hand, in cirrhosis or nephrodic range partneria, there's a loss of reduced synthesis of plasma proteins, lowering on codic pressure. With fewer proteins holding fluid inside the vessels, fluid allows the favorable osmotic gradient and shifts outward into the interstitial. The vessel wall. Now, what if we poked holes in that hose? Water would leak out and that's capillary leak. This can happen with allergic or inflammatory stasis, angiodema, sepsis or certain infections. The vessel wall becomes permeable, letting fluids seep into the surrounding tissues. And now, what about outside the vessel? Surrounding our blood vessels and distributed throughout nearly every tissue in the body is interstitial. A protein-rich gel-like matrix that acts as a shock absorber and plays a key role in maintaining fluid balance. Think of it as the space between the microscopic compartment that lies between capillaries and cells. It's filled with extracellular matrix components like collagen and glycosodamina glycans, which hold water, electrolytes, protein, and is traversed by lymphatic channels that normally drain excess fluid back into the circulation. When the lymphatic system is damaged or obstructed, for example, by malagency, surgery, radiation or certain parasitic infections, that drainage system can back up, fluid accumulates in the interstitium and produces what we call lymphedema. Even though we can't directly see the interstitium, it'd eat contact with the skin and musketialto system, which we can see and feel. So diseases that directly involve the interstitium or these superficial structures through infiltration, inflammation, or fibrosis can also manifest as edema. - Wow, Alex, that was brilliant. What a comprehensive approach to edema. I'm curious now, how do your approach change if the edema is non-pitting versus pitting? - Oh, great question, menu. I was definitely taught to differentiate pitting versus non-pitting, but often felt non-pitting was overlooked or forgotten. So let's try and break it down. When we press on a dentist issue, we're really testing the structure of that interstitial space. If it's been diluted by fluid as an heart failure or high-ball bumenemia, it's like pressing on wet mud, easy to leave a pit. But if the interstitium is filled with proteins, fibrosis or inflammatory cells, such as in mixidema, lymphidema, or fasciitis, it resistant indentation, kind of like dried mud, it becomes non-pitting. So most of the edema we see comes from increased hydrostatic pressure, decreased oncotic pressure, or capillary leak, causing pitting. Of course, patients often have multiple contributing mechanisms, but this framework helps us think about the systematically. - That was so well explained, Alex. How about the distribution of edema? How does that influence your differential? - Yeah, another great question. Finally, let's think about the distribution. So a deemacanthine to the lower extremities is common. Gravity helps pull the fluid there. But when swelling extends to the upper extremities or phase, we really have to think differently. By the time the edema reaches the upper extremities, if the heart and liver are primary drivers, the absence of other symptoms would be quite atypical. The kidneys of the three organ system tends to be the sneakiest. However, if the lack of systemic signature continues to be hold true, disorders of the lymphatic system or pathology within the interstitial, I'm definitely right to the top of the differential. So amazing case so far, man, you are learning a ton and I can't wait to see where this case goes next. - Wow, wonderful discussion, Alex. So continuing with the case, her post-metall history includes hypertension, hyper-lippidemia. She was not on any medication previously. Just recently started on GABA pen10 as needed for pain and sleep. And also, LASIX, or Phyrosamite, 20 milligram daily for the swelling. She has no now allergies. Her social history is somewhat interesting. She had a recent travel to Egypt three months ago. She stayed there for a couple of weeks and had had a few mosquito bites during the trip. She had an excursion to the Nile River where she got splashed with the water while bolting on the river. But otherwise stayed in the city. She ate some fish from the river, but they were fully cooked. She only drank bottled water. Upon returning from the trip, she did have some diarrhea illness for about 10 days for which she was treated with azizromycin with resolution of her symptoms. The patient was evaluated in her primary care clinic a couple of weeks into her symptoms and had a very last testing. Reportedly all were okay. Besides a CBC with a Y count of 10, Himagobin 13.1, platelet count in the 400s, and some ill-cinophilia with an absolute ill-cinophil count of 800, which increased to a thousand on a repeat check. What do you think now with the additional history and the initial labs? - All right, Dr. Mengu. Looks like we've got a very interesting story here and some equally interesting labs. Often the times that the problem really hides in the patient's history, but when we actively search for clues there and gather all the possibility tells, it can get quite overwhelming. It's in time soon misleading. So it's always helpful to analyze the patient's history with some primary hypothesis in mind. So for now let's focus on something more objective, like using anophilia. And first, remove the fill's anophilia before even building a differential, confirm that it's real and not a red herring. And first, trust only the absolute use in the fill count, not the relative percentage, and also repeat the testing if needed because using the fill's are very sensitive cells and follow with circadian rhythm. As you can see, Dr. Mengu already double checked absolute use in the fill count so we can start to dig deeper. And the second rule of using the fill, don't underestimate the cells. Look not just for causes, but also for the consequences because yeah, in 80% of cases using the fills are just a response to damage. But even then they can also be a source of the damage themselves. Why? Using fills are not only sensitive. They're also very introverted cells. Why? Even other normal conditions, most of them leafing tissues were there 100 times more abundant than in blood. Multiply that number and the potential fetish damage becomes real. And the key locations to watch are organs that are exposed to the outside world like skin, lung, or GI tract. Also organs that we just can't afford to miss. Namely the heart was central and peripheral nervous systems. And also don't forget about trombotic and trombone-bolic complications associated with using a fill, yeah. Okay, now that they've talked about consequences, you're probably wondering how many more words starting with C we can squeeze into this approach. So here we go. For causes, we're thinking of three things that can be helpful. First one is crannicity because the template is one of the most powerful diagnostic variables. Next one is count. And this is especially helpful when we're dealing with hypereusnephilia, which is defined as moderate or severe euenaphilia with absolute euenaphil count more than 1500 because its signals are still beyond common allergic conditions and drug reactions. Although in our case, the euenaphilia actually was mild. So more than 500, but still less than 1500. And this doesn't significantly narrow down our differential. Now what we're on to the next one is context. Remember when I said that history would help us? Now it's time to use it. And when approaching this part, I'd like to ask a few simple questions. First one is who is the patient? And specifically, whether they're immune status. For example, HIV testing should be considered in all patients presented with euenaphilia because it increases suspicion for euenaphilia associated diseases that we don't typically see in immunocompetent patients. And also maybe there is any notable past medical history like the evidence of atopie or other immunity. The next one is where is the patient? And it's probably one of the most important questions we can ask when dealing with euenaphilia found out origin. Because some diagnosis need to be prioritized, purely based on their prevalence in the given context. For example, residents of resource limited countries and travelers are more likely to develop parasitic helmet infections. And given the patient's recent travel to Egypt, they are definitely on the table. And two, SS, just as a mice and strontally dices, are the most compressive causes of euenaphilia in a returning traveler. In contrast, in high income countries and patients without a significant travel history, allergic and drug induced causes of euenaphilia take the lead. With this patient's history of highs and some new medications, this is something we definitely need to consider. For example, gubapensin carries a risk for dress syndrome. Though this usually develops two to six weeks after starting the medication. And now, last but not least, what is the syndrome? Approach in euenaphilia in isolation can be very frustrating. So you need to define the other features as clearly as possible. And you can actually pause here and try to define the problem by yourself. Ready? OK, so for now, it looks like we're dealing with subacute anasarca alongside isolated mild euenaphilia. Now, my courage to preset a breakdown this very interesting combination. But first, of course, excited to hear more from Dr. Mangu. Wow, I love your deep dive analysis of euenaphilia, Lara. And here's our next aliquat. Due to persistent and progressive symptoms, patient was advised to go to the emergency room for more expedited workup, including imaging. So in the ED, the patient was a 5-brow with a heart rate of 100 blood pressure, 140s or 70s, respiratory rate 18, and with a saturation of 98% on room air. She has a BMI of 28. On exam, she was well appearing and then in no acute distress. Her heart had regular rate and rhythm, no murmurs or gallops, and no GVD was a visualized on exam. Her lungs were clear to oscultation bilaterally. Her abdomen was soft, non-tender, her extremities were warm and well perfused. There was the fused edema, however, in bilateral lower extremities extending beyond the knees, as well as edema in lower abdominal wall. Vialateral hands and forms, I would say, is largely non-pitting. Does not leave a clear indentation after pressing for a few seconds. There was not much facial edema at this time. She was alert and fully oriented and had no molter or sensory deficits. Her CBC demonstrated a white count of 10.8, including 11.4% of ocenophils, with an absolute ocenophile count of 1,230. Himalobin 11.4, which is downtrended from the typical baseline around 13. Plaitlite is 543. The complete metabolic panel was only remarkable for a albuming of 3.3, otherwise normal kidney and liver functions. Her TSS and 3T4 were within normal limits. BMP was normal at 44, and Himalobin 11.4 was also normal. Her urine dipstick and microscopy were within normal limits three times during the course of workup, no protein, or rep-glass cells. Her urine protein crann in ratio was normal at 0.2. IR was also normal, and CK was normal at 15. She does have an elevated inflammatory markers with the CRP of 116 and ESR of 26. She had an echo down that was normal for LV and RV function and size. There was no precargue fusion, and inferior vinyl cavals also normal. The CT chest f-ten pelvis with IV contrast was obtained in the ED due to some report of abdominal discomfort. So it was ordered to rule out concern for intraplaminal process or malignancy, and was only notable for diffuse anasarca and bodywild edema. There was no suspicious adenopathy or acides or any plurifusion. So I'm curious at this time, how do you reframe your differential diagnosis with these additional objective data? Thank you so much, Mangio, very interesting case. After that, I would like to encore us directly on physical examination, especially the presence of non-pity edema. Even though Mangio told us it is non-pity edema, but I would like to rule out the non-mystal diagnosis of edema generally, and I would like to use Alex for an award for edema. Looking inside the vessels and considering pressure and protein, we need to think about how to live there and keep new failures. With this BMP and the normal echo and albuming level, we could stay with confidence that none of these organs are malfunctioning, so we could rule out the repulavs of pitting edema. Moving to the assessor's wall problems, I do not see any sign of increased prempermeability, anything so far as sepsis or anaphylaxis. So these two buckets are also out. Now we need to think about problems outside of all vessels. The classic cause of the non-pity edema is always impaired lymphatic drainage. It is now not lymphatic edema. We have not seen any lymphedinopathy or masses obstructing lymphatic drainage under CTS scan. So we need to think what we are left with. If you recall Alex points about the distribution, the pattern we are seeing here, it is not gravity dependent, so I'll link it in legs only. This patient has edema in upper and lower extremity and also in her abdominal wall, which points us away from the pressure dependent pattern and really pushes us to interstitial problems. The other critical point here is the nature of the edema, which is non-pitying and we learned that it is like pressing undrived mud. But it tells us, it's telling us the underlying tissue has some infiltration or replacement of something that should not be in the interstitial normally. If you expand upon the etiologies for non-pity edema, involving the interstitial problem, we could put them in three different buckets. The first bucket referring to the all the positional problem, meaning that there are abnormal substance accumulating in this space. The first and foremost is mix edema, which is accumulation of mucopolisoccharides in this space. But looking at her TSH and that is normal, we could rule that out. The second one is escalaromic edema, which is coming from the position of their malmucines in the space. But that condition requires monocolonal gamma pacy underlying. And the other one is lipidema, which typically spares the feet, but our patient has extremity edema. The second bucket here are pointing to fibrosis, which is collage and replacement in normal tissue. We could divide them in two different buckets. The first one are escalarot dermaispectral, or something like systemic escalarosis, but we also able to rule that out because our patient lacks any rain notes or escalarotactyl. And then the second section refers to all escalarot derma mucares, something like morphia, which is specifically localized block formation, and something like nephrogenic systemic fibrosis, which happens when the patient has underlying renal failure. The last bucket in this category are inflammatory and inflammation theology. This is where immune cells are transforming the tissue and having the high CRP might also encorring us to this bucket. The other interesting point in this article is a high level of the air in a film. Lira already warned us that we need to repeat the lab to ensure that ozone failure is real. We have that data now. It's been constantly elevated across multiple checks. We also have to remember that ozone failure loves tissue. The cells we see in the blood, they are usually just tip of the iceberg. Deep in the tissue, they are not just acid bystanders. They are actively architecting their underlying pathology, meaning that they are releasing fibrogenic proteins that directly drive tissue remodeling. This is really a specific branching point in this article because we need to merge these two big clues together. We look at them as a syndrome. We have a non-pidding edema aligned with ozone failure. Let's filter our differential through these lines. The most common cause of non-pidding edema, like mix edema, a scalloradema, or lipidema, usually do not come with ozone failure. But there is a small family of non-pidding edema where ozone failure are the primary driver, of course, inflammation and fibrosis. The first one is ozone failure and myalgia syndrome. But we do not have any evidence of muscle environment where CK is normal. The second one is toxic oil syndrome. These patients usually have solid environments or exposure to oil. And the last but not least, there are specific disorders involving the connective tissue. If I want to wrap up, but we said, "Well, now we have non-pidding edema, which chronic ozone failure, with no major organ involvement and no muscle environment." It's a can't wait to learn from you, but should we do next? Mind you, please keep us informed. That was beautiful discussion, Parisa. Here are some additional workup. So the HIV and hepatitis panel were negative. The GI parasitic panel were negative, as well as the stool over and parasite. Strong similarities and system miceysrologies as requested before were also negative. In a rheumatoid factor, an anti-CCP were also normal, as well as end-cost radiologies. Lastly, SPAP and free light chains were also negative. We also obtained flow cytometry of peripheral blood, which was negative for colonoscals. The patient felt the latex diuretics actually improved her swelling somewhat and preferred to be discharged with a close-out patient follow-up. And she was subsequently referred to dermatology. Over the week or two following this charge, the patient developed some hardening of her arms and legs, recent concern for scleroderma by primary care doctor. And when she saw dermatologist, it was described as firm and oody induration. Similar findings were noted in bilateral lorxgermities from mid-back to the ankle. Additionally, the patient noted some puckering and indentation of her forearms. The dermatologist described it as poldalhont changes. There was no sclerodactylal ulcers or evidence of calcium-nose scutus and the naopholes were grossly normal. A skin biopsy of the forearm was obtained and showed subtle, superficial and deep dermatitis. There was no definitive sclerosis and the positive of musin is against scleridema. They suggest the carolate clinically. I will pause here and hear what does you have, Ethan. - Yeah, thanks so much, Wang Yu. And the slira already beautifully elaborated. The big pivot point evaluating persistent eosinophilia is to first rule out secondary causes. And at this juncture, the extensive infectious autoimmune and geomatological workup, including a negative HIV and hepatitis panel, a negative strong geoloidus and schistosomalysis, serologies, normal ancai and RNA, and negative flow-stab cytometry have basically ruled many of the classic secondary causes. Yet, the patient's eosinophil accounts remains elevated and the clinical picture continues to evolve. The CT findings of the fused bodyroidema without other significant organ involvement together with the wooden and firm texture of her skin, making the center of gravity of the case being a fibrosin inflammatory process, predominantly involving the skin and subcutus with a fingerprint of eosinophilia. And maybe we can talk about the second buckets that Parisa mentioned in last eloquence or the scroll thermodynamics and why they are less likely here. First is that eosinophilia is prominent in this case, which is not a feature of scroll thermo. And secondly, a Parisa already mentioned the hallmarks features of scroll thermo or as mimics like brain nodes phenomenon, telling ectectias or internal organ involvement were not present here. Now we can talk about the disease processes that present with eosinophilia with isolated skin involvement, which is the case here. And eosinophilic fasciitis is the archetype here. The inflammation begins in the deep fascia often after physical exertion or immune activations and radiates outward creating a pond-dorange surface and grooves sign whilst staring the fingertips. The grooves are caused by inward tethering of the skin by fascia fibrosis. In the same spectrum, or we can call them the name-bursts of eosinophilic fasciitis, including eosinophilic cellulitis, which is the epi-center in the thermos and clinically presents with arithminus, plyx, the beginning infections, and eosinophilic peniculitis, which the epi-center is the subcutaneous fat and presents with tender nodules mimicking everything on the odorsum. Oh, in all, the combinations of persistent and likely primary eosinophilia and isolated skin involvements make the differential diagnosis very narrow. And the last point I want to talk about is the utility of skin biopsy here. So for the diagnosis of eosinophilic fasciitis, we need a full thickness skin biopsy containing the fascia and muscle tissues. Otherwise, the histology findings may show similarities to other conditions. For example, like Morphea, which is the localized form of scleroterma. And skin biopsy may not be able to differentiate. Second is that the eosinophilic in a deep fascia may be transient if previously treated with systemic steroids or immunosuppressive drugs. Teach us, Mingyu. - You all nailed it, my friends. So as Ethan said, I learned that a full thickness biopsy down to the muscle service is needed. Because if we try to visualize the layer of the skin, you have to go through the epidermis, the dermis, the fat layer of the hypodermis before you hit the superficial fascia. And then you go through even more fat layer before you finally hit the deep fascia, which sits right against the muscle. Both superficial and deep fascia can be involved in eosinophilic fasciitis, although a deep fascia is felt to be the primary target and the origin. The pathologist did also suggest potential additional sampling to include fascia, given that was the clinical concern. So basically, based on these clinical findings, the diagnosis was made clinically, and treatment was initiated at her first dermatology visit. Eventually, no further biopsy was pursued, but patient underwent MRI of bilateral lorxgemiteach, which showed bilateral superficial and deep fascia edema and mild fascial enhancement. So this further confirmed the diagnosis of eosinophilic fasciitis. Patient was treated with full dose prednisone and later methotrexic and mancoventilate or added to a lusteroid taper, as well as IVIG. She felt it was only after the IVIG was started, that she began to feel significantly improved. Along with analgisics and physical therapy for symptomatic care, she had gradual improvement of symptoms to the point that it felt back to normal over the next eight months or so. So this case really stayed with me and left me with a lot of learning and reflections. It's a powerful reminder that while we are taught to look for the wooden skin and the classic group sign, catching the stagnosis early requires a robust illness grip that starts way before the skin hardens. To help us all recognize it sooner, let's walk through the illness script for eosinophilic fasciitis through the CPSAURAS format. After why, who, what, how do diagnoses and how to treat? The why or the pedophiliology is still a bit of mystery. In about 30 to 50% of cases, patients report a trigger like strenuous exercise or physical stress. We also see some links to certain infections, autoimmune or hematologic disorders, but most cases are idiopathic. Essentially, inflammatory cells, specifically eosinophils infiltrate the fascia. As they degranulate, they release toxic, fibrogenic proteins. In terms of the who, just like in our patient, patients are typically adults in their 40 to 50s, affecting men and women equally. But keep in mind, this is a zebra, we're talking about a prevalence of roughly one in every 100,000. The what is where the diagnostic delay usually happens. As highlighted in this case, in the early phase, it starts with acute or subacute symmetrical, non-pitting edema of extremities and the trunk, and it can be painful. Our patient described it as if her body or squizzed by an outside force. It has a unique distribution in that it generally spares the hands and the feet. Faces also usually spared in most cases. Although it was described in this patient's initial course, patient later did not recall prominent face swelling when I called her to clarify. And as the disease progresses to a later phase, the skin progressed to a wooden injury and was taken with puckering that gives the skin a poldahunch texture. This leads to the hallmark groove sign. When the patient raises their limb, you'll see a visible indentation along the superficial veins. As Ethan mentioned, it is because the skin or the veins stay flexible and both inward while the surrounding fascia is stiff and frozen. And here's a pro tip for differentiating from scleroderma, which is to look at the hands. Eucenophilic fasciitis almost always spares the fingers and feet and lacks the sclerodactyl scene in scleroderma. From a pathophysiology standpoint, the two differs in that eucenophishitis moves from the deep fascia outward, whereas scleroderma starts in the dermis and moves inward. Of course, the other prominent feature is the lap. Early on, you often see peripheral eucenophilia, though it's often transient and doesn't actually correlate with how severe it is with the disease. Half of the patients will also have elevated inflammatory markers. So how do we prove the diagnosis? An MRI is very helpful to confirm fascia inflammation where you will see an increased T2 signal and enhancement on fat-surprised T1 images. The ghost standard, of course, is the full-signive skin biopsy, as we mentioned earlier, all the way down to the muscle surface. Early on, you'll see fascia infiltrated with lymphocytes and eucenophils later on the inflammation phase and is replaced by a thickened sclerotic fascia. And in terms of the treatment, the reason early diagnosis so vital is the treatment response. Patients in that early etymantes face usually show a prompt resolution with cortical steroids. Once the late stage fibrosis and the wooden skin satin, the response with therapies often incomplete. We have a narrow window to prevent permanent contractures. Fortunately, despite developing some of the later findings, our patient made a full recovery by 12 months and she expressed gratitude for the care she received. Reflecting on the case, it is clear that rare diagnoses often hide behind more common presentations. The seemingly benign initial cores and workup can be deceptive. We are so primed to consider generalized edema as a symmetric process involving the organs or vessels rather than what turned out to be the early stage of a rare, diffused, sleigh infiltrating skin disorder. Solving this time-sensitive puzzle in its early stage would require familiarity with the nuanced details of a less known manuscript or perhaps a robust and broadened differential of generalized edema as Elic has elegantly laid out. Specifically recognizing the unique nature of non-pitting edema and the underlying mechanisms. I also appreciate you, Lara, Perista, and Ethan for walking us through how to connect the dots with its inner fillet and recognizing its infiltrating nature, the mimics and how to make progress. Although the past of the correct diagnosis took more time than any of us would have liked, the process highlighted the incredible partnership between the patient and her primary care team, which was essential in finally reaching clarity as soon as the condition was on full display. And also I wanted shout out to my colleague Zach, our nocturnist for considering the diagnosis. Above all, I owe a depth of gratitude to the patient for her grace as her care team navigated these challenges together and her generosity in sharing her story with all of us. As we wrap up, I'd love to hear if you have any reflections and what is one thing you will take away from this case. - Yeah, absolutely. My biggest takeaway would be that the case reminded us of one very helpful and often overlooked test, which is the test of time. And what I mean by that is, of course, our goal is always to recognize the diagnosis as early as possible, especially those where we have the window for treatment that is limited, such as in this case. But when the problem is not crystal clear and there is no emergency, we didn't see the full picture can be productive as well. And I deeply appreciate the opportunity to witness the full disease evolution with the full range of its manifestations. Mercy Dr. Mingur and I especially appreciate the beautiful French that you give the test with. - I love this case, Mingur. Thank you so much for taking us on this journey. I think my biggest takeaway is that when we do not find any footprint of internal organs and muscle environment and there is nothing obvious on the skin, we just need to zoom out and ask ourselves, okay, what lies in between of these compartments? This also reminds me that face-shack and harbor profound inflammation, while it could be a silent reservoir of the pathology, many things might happen there. And thank you for all of you for this learning opportunity. - I love all your thoughts. And thank you again, thank you for the amazing case. My biggest takeaway is the classic CPS average. First, we need to define the problem before trying to solve it. And in this case, the problem is an isolated skin disease with persistent eels in the philia. The most precise we define the problem, the narrower the differential diagnosis becomes, and the better our pre-test probability when ordering diagnostic tests, allowing for empirical treatments or targeted confirmations, rather than just generating unnecessary diagnostic noise. - You guys are amazing. And what a case presentation, Mingur. I have nothing to add, except really to emphasize the diagnostic clarity and the patient's happiness and health or Yin-in-Yang. You can't have one without the other. So happy CPS solving everyone, until next time. - That's a wrap, everyone. Thanks for tuning in. - If you enjoyed this episode and wanna be part of our community, join us for our live virtual morning report, where we can present the case or discuss with us. Visit our website for details. You would love to have you.