Treatment and Disease Management

Vascular Ehlers Danlos Syndrome (vEDS) is a disorder of Type III Collagen, a crucial component of connective tissue. The disease is initiated by a mutation that causes malformation of collagen fibrils, which are a major component of ligaments, tendons, intestines, and, most importantly, blood vessels. Major blood vessels, especially large arteries like the aorta and femoral artery, become weakened and fragile due to the lack of functional collagen, and are at increased risk of rupturing, causing a life-threatening internal hemorrhage.

There is currently no curative treatment available for the disease, and treatment has largely been limited to surgical intervention to fortify, or repair, weakened organs and arteries. Since breakage of major arteries is almost always fatal due to massive internal bleeding, closely monitoring major vessels and identifying weaknesses is essential to patient survival. Vessel weaknesses generally present as aneurysms, a small budge in a blood vessel, or as dissection, in which the inner, but not the outer, wall of the aorta tears. Such vessel abnormalities can be detected via basic medical imaging techniques, like MRI, CT scan, or ultrasound; these tools are all non-invasive, which is now considered preferable because interventional methods may inadvertently further damage blood vessels (Busch et al, 2014). In many cases, such arterial abnormalities are detected accidentally during medical scans for a different condition.

Grafts and Stents

When weaknesses of the vessels are detected, they can be treated with either surgery or stents. Surgical treatment, or “open” repair is highly invasive, as the physician makes a large incision near the aneurysm, and then stops blood flow to the area (Coselli, Bozinovski, and LeMaire, 2007). Blood flow to this region can then be stopped using endovascular embolization (blockage caused by intentional blood clotting), as this is one of the few methods that do not cause excess pressure on the surrounding vessels, which might cause further breakage in vEDS patients (Nakanishi, et al 2014). For small aneurysms, it may also be possible to clamp (rather than remove) the aneurysm, which prevents blood from entering the aneurysm and thus relieves pressure, decreasing the likelihood that it will burst. In most cases, though, this is insufficient, and the surgeon will need to completely resect the aneurysm, and then cover this section with a graft, which serves as a patch to physically close the artery. Alternatively, a small vein from the leg could be used to close the aneurysm instead of a synthetic graft. This type of surgery, though, is generally considered high-risk, and may result in postoperative infection and major scarring at the site of incision.

graft
Picture of a synthetic graft being placed around an aneurysm in an artery. In this case, the vessel has an area of weakness, and the surgeon is sowing over the aneurysm to prevent it from bursting in the future. (Source: Google Images)

 

Therefore, the second method of treatment, endovascular stent graphs, is rapidly becoming the preferred method of treatment for aneurysms and other vessel weaknesses; this treatment uses endovascular surgery with small incisions, rather than traditional open surgery with large incisions, where there is a greater risk of infection and damage to surrounding tissue. An endovascular stent is inserted near the groin and moved through the blood vessels to the location of the aneurysm, where it is inflated. The stent then serves as a tunnel through which the blood can move through; the blood thus puts pressure on the walls of the stent, rather than on the walls of the artery itself. This thus reduces the stress on the artery and drastically decreases the likelihood of future vessel rupture. This stent minimizes the likelihood of future vascular complications, and has been shown to be highly successful (Nakagowa et al, 2014).

Both methods of surgical treatment are still relatively common and effective. Fixing aneurysms is a relatively common procedure for surgeons, and is generally successful. vEDS patients, though, are high risk patients due to the weaknesses in the blood vessels, and have a much higher mortality rate; the weakened blood vessels are at increased risk of rupture or injury during surgery, sometimes resulting in a fatal hemorrhage. Both endovascular and open surgery can be used upon detection of a vessel weakness, but open surgery is likely required after the artery has burst. In many cases, the rupture of a major artery, like the aorta, is immediately fatal, and surgery is not able to save the patient.

TGF
Pathway involving TGF, and how it upregulates the production of collagen through a signal cascade pathway. The collagen can then serve its normal functions, such as helping with wound healing or the formation of tendons and ligaments. (Source: Google Images) 

Surgical Repair of Organ Rupture

Surgery also features prominently in the repair of other symptoms of vEDS. Sadly, organ rupture is also a relatively common procedure that requires surgical correction, in which a tear in the organ is physically stitched closed. This is extremely common in the intestines and reproductive organs, as these organs use large amounts of collagen to maintain both strength and flexibility. This is particularly problematic during pregnancy, where uterine rupture is a common symptom due to pressure from the growing fetus (Murray et al, 2014). The fetus can also damage neighboring organs, resulting in a massive hemorrhage. In cases of vessel or uterine perforation, emergency surgery is usually required in which the baby is removed via C-section and the vessel is repaired. In some cases, these problems can be fatal.

 Elective Surgeries for minor symptoms

The musculoskeletal abnormalities that result in a long, thin nose and pursed lips can be fixed electively using cosmetic surgery, if desired (Byers et al, 1979). These symptoms, though, are not particularly drastic, and many choose not to undergo surgery, particularly because surgery is so high risk. Varicose veins, which are enlarged, spider-like veins, are also extremely common in these patients. While these veins do not rely heavily on collagen for strength (and thus are not at increased risk of perforation), they do rely on collagen to maintain their normal, straight shape. Endovenous surgery using lasers, though, has been shown to be useful to treat this problem (Whiteley and Holdstock, 2014). It is important to note that these musculoskeletal symptoms do not greatly affect the health of the patient, and any surgical treatment is purely elective.

Celiprolol

Until recently, surgical intervention was the only treatment available for vEDS patients. Recently, though, Celiprolol, a medication previously prescribed for patients with high blood pressure, has shown to be effective at reducing the incidence of vascular rupture in vEDS patients over a five-year double blind clinical trial (Ong et al, 2010). Although the mechanism has not yet been proven, it is believed that Celiprolol works by upregulating the beta-androgenic receptor, which then activates a downstream transforming growth factor (TGFB), a protein that controls a wide variety of biosynthetic pathways during growth; TGFB is previously known to upregulate the production of both Type I and III collagen. The newly synthesized collagen could then be incorporated into the walls of blood vessels and organs, making them much less likely to burst. Since the rupture of these structures is often fatal, this treatment method is revolutionary for vEDS patients.

All types of treatment, though, is somewhat high-risk, as surrounding blood vessels and organs are extremely weak, and frequently accidentally damaged during surgery. Therefore, it is generally recommended that all types of surgery be minimized in vEDS patients, except in cases where the risks of not doing the surgery outweigh the risks involved with the surgery. For this reason, it is recommended that, whenever possible, physicians use non-invasive methods when attempting to diagnose and treat any medical concerns in patients with vEDS. Thus, the development of Celiprolol, a non-surgical treatment method, is seen as an exciting breakthrough in the field.

Ehlers Danlos Syndrome, Vascular Type

History and Metabolic Context

Molecular Basis of the Disease

Conclusions and Proposals for Future Work

4 Replies to “Treatment and Disease Management”

  1. This is a very well-written and informative page. Regarding the surgical options to treat EDS, I was wondering if the general procedures that are used to treat EDS are involved in other types of surgeries. In other words, does the type of surgery overlap with surgeries possibly in the cardiac field? It would seem unlikely for surgeons to develop special techniques to treat a disease that affects only 1 in 200,000 people.

    1. Hi Zach,
      Yes, you are definitely right. All of the surgeries that are used to repair blood vessels and organs are not specific to vEDS. Symptoms like aortic aneurysms are surprisingly common, particularly among the elderly, and the same surgical techniques can be used between vEDS and non-vEDS patients. Surgery, though, is much more high risk in vEDS patients, as the risk of death during and after surgery is remarkably high. Due to the weakness of surrounding tissue, it is very easy for a surgeon to accidentally damage an organ or a tissue, resulting in a fatal hemorrhage. Such damages may require a second surgery to repair, only worsening the problems and creating a never-ending cycle. Physicians thus try to minimize surgery whenever possible, and the development of drugs like Celiprolol to reduce the risk of some of the effects of vEDS may be life-changing for many patients.

  2. Hello hello again friend. From what I can gather, you would recommend Celiprolol as the best treatment available… From a five year trial I am assuming the authors concluded that the treatment was relatively safe… Are there side effects that are of immediate concern? Or compared to the disease state are they negligible?

    Can you tell me a little more about the stent option?? You said it is quite effective following an aneurysm, but must we wait that long until we insert them? Can stents be proactive instead of reactive? If blood vessels are ubiquitously weakened throughout the body, wouldn’t it seem imperative to reinforce more than a single area, or would this be too extensive of a procedure? Could it be feasible to stent a little area every so often, say once a month? Or even not the whole body, but we could image and determine those areas most affected and stent those specifically before they burst open??

    Once again, well organized and clear-headed discussion. I like the way you work.

    1. Hi Ryan,

      Thanks for your questions, and compliments! The Celiprolol trial was actually a remarkable success, and the only reported side effect was fatigue. The trial was somewhat small due to the rareness of the disease (n=53), but only about 5% of patients experienced fatigue, which was classified as mild to severe. While this would certainly be annoying as a patient, this is a relatively minimal trade-off for vastly decreased risk of death.

      Yes, the stent is definitely a useful option. I’m sorry if that was unclear, but stents can be used both proactively and reactively. In many cases, stents are successfully inserted once an aneurysm is detected, which greatly decreases the risk of rupture.

      While blood vessels are weakened in vEDS, it seems that only the major arteries are greatly affected, and pose the largest risk. I only found reports of problems in the aorta, carotid, and femoral arteries, but not in any of the other vessels throughout the body; it is possible that other vessels are also weakened exist, but this may only affect a small subset of patients. These three arteries are all particularly large and under immense pressure from the pumping of the heart, so they seem particularly vulnerable to rupture, even at rest. Large arteries also have more collagen than smaller arteries, which naturally makes them more vulnerable to rupture because they lack the requisite structural support.

      The process of inserting a stent used to be major surgery, although with the development of minimally invasive surgery, the incisions are smaller and the surgery is no longer quite as high risk for healthy persons. However, in vEDS patients with weakened blood vessels, surgery can be particularly dangerous and carries high mortality rates during and post operation. For that reason, stenting very frequently would probably carry unacceptable risks. Stents are also relatively small, so it is only really practical to stent areas that show visible weaknesses, not an entire vessel. Therefore, it would definitely make sense to use CT scans or ultrasound to determine weaknesses in blood vessel, and stent those specific areas. Since all surgeries carry risks, it may be better to insert several stents at once, but it is important for the surgeon to weigh the likelihood of vessel rupture versus the very real chance of a major surgical complication.

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