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Dr Charles Brantigan (Denver, Colo). I'd like to know how you made the diagnosis of the various types of Ehlers-Danlos. Was the diagnosis based on genetic testing, or was it based on clinical presentation? If you're faced with a patient with what looks like Ehlers-Danlos syndrome that might need a vascular procedure, what further diagnostic tests are needed?

Dr Brooke. When vascular surgeons are referred patients with Ehlers-Danlos, there is usually a lot of confusion as to how to distinguish the different subtypes. However, most patients can be reliably diagnosed solely on clinical grounds using the revised diagnostic criteria from the nosology of Villefranche. If a diagnosis of vascular type Ehlers-Danlos needs to be confirmed, skin biopsies can be obtained to assay the amount of type III collagen levels from dermal fibroblasts. Alternatively, PCR analysis may also be employed to look for collagen III mutations. Finally, it always helps to consult a trained medical geneticist to assist with making the diagnosis.

Dr B. Timothy Baxter (Omaha, Neb). I have a fair experience with these patients. I just have a couple comments and questions.

I think that the older the patients are at the time they present, the less I worry. I think their tissues are going to be better if they present at an older age. The young patients are the ones that the tissues can be more difficult. Can you comment on this?

My other question is about surveillance in these patients. One of the problems that you pointed out is that most of these are women. I am reluctant to do frequent CT scans in these patients because of the radiation risk especially associated with breast cancer. I have followed them with MRI.

The last question is, do you routinely do any intracranial scanning to look for intracranial aneurysms or associated pathology that might need to be addressed?

Dr Brooke. There is not a clear genotype-phenotype correlation with Ehlers-Danlos syndrome, and patients of all ages and subtypes can behave very differently in an operative setting. Older patients with EDS who haven't experienced a major vascular complication may indeed have good tissue characteristics for elective procedures, but this is hard to generalize.

In our cohort, some of the oldest patients underwent the endovascular procedures. Conversely, we worry that younger patients who present with vascular complications at an early age are going to have poor tissue characteristics and may be at higher risk for poor outcomes. We recognize that better methods are needed for stratifying Ehlers-Danlos patients' operative risk based on variables including their age, comorbidities, family history, tissue typing, and other biomarkers.

With regard to your second question about surveillance, we employ a similar strategy that includes CT angiography, MRI/MRA in special circumstances, and occasionally, ultrasound for transcranial assessment.

We routinely assess intracranial imaging in patients when the diagnosis of Ehlers-Danlos is in question. Patients with a similar connective tissue disease known as Loeys-Dietz syndrome have a propensity for arterial tortuosity within their vertebral and carotid vasculature. Hence, this radiographic finding can help establish the diagnosis of Loeys-Dietz versus the vascular type of Ehlers-Danlos.

Dr Ronald Dalman (Palo Alto, Calif). I noticed that most of your patients that were treated were treated with embolization. I'm curious how you approach more complex problems that don't necessarily lend themselves to embolization. For example, I have one patient with distal internal carotid artery aneurysms fairly close to the base of the skull plus a large renal artery aneurysm with a history of spontaneous bleeding in the past. So if you're not going to use covered stents for those patients, what type of approaches do you use in these more complex reconstructions, if you do consider them?

Dr Brooke. We certainly try to use embolization or other minimally invasive procedures in Ehlers-Danlos patients whenever they are practical and amenable. Nevertheless, some patients are only going to be candidates for an open repair due to their specific anatomic variation or constrictions. Each operative approach is dependent on the individual patient.

Dr Timothy Kresowik (Iowa City, Iowa). My first comment relates to your suggested prohibition against the use of stent grafts in Ehler-Danlos patients when you are treating a spontaneous disruption rather than performing an aneurysm repair. If you have a spontaneous disruption of a nonaneurysmal vessel, with good landing zones, it seems like the stent graft is a much less invasive and potentially more attractive approach.

Also, in your discussion of endovascular access, you talked about the use of pledgets or other adjunctive reinforcements for vessel repair. Are you implying that you always use an open approach rather than a percutaneous approach? Do you think the risk of complications is lower with an open approach or could it be higher?

Dr James Black (Baltimore, Md). Let me clarify something about the prior questions. I think in general, we agree that the endovascular safety profile is quite good. I think a lot of that speaks to lower-profile devices. The prior reports of mortality rates of 20% to 40% even for a diagnostic arteriogram probably were related to very large sheath sizes. So for Dr. Dalman's question, I think that the advent of newer technologies might open up an arena where we can have wiggle room for endovascular technologies.

Now, on the other side of that, puncture site complications are very common, and so it's been our approach that particularly for the patients that you know are quite fragile, multiple aneurysms, very frequent rate of presentation with aneurysms, that we do cut down on those femoral vessels. Most of those procedures, as you might guess, are done under general anesthesia for all the concerns about accessing those vessels and manipulating them.

And just to echo the prior issues of genotype-phenotype, we have also appreciated that patients as they age, not necessarily that they remain suitable for surgery, particularly on the vascular EDS types, their average survival is only 48 years. So while they might have handled the surgery very well at age 20 or 30, when they come in again at age 40 and 50, well, they might be at the end of their life expectancy, and their tissues could be more fragile. So again, going back to the idea of a skilled medical geneticist evaluating their tissues is clearly an important part of our treatment paradigm.

Dr Gustavo Oderich (Rochester, Minn). One of your conclusions was that we should be more liberal in the treatment indications of aneurysms in patients with vascular EDS. And as you pointed out, this is a very heterogenous group, and there are patients with more vascular fragility than others. So what would you leave as a message for everybody here, what should be the indications?

I also have another question regarding the patients that you didn't treat, how many patients are you following with surveillance only, and what is the fate of the aneurysms in those patients?

Dr Black. Well, I think in general the study such as this, when you talk about patients who are treated or not treated, we suffer with the referral bias. And for genetic conditions in particular, referral bias is a double-edged sword. Patients who have mild forms of the disease, of course, are never referred at all, or they're handled in their local institution with relatively little morbidity, versus patients who are tremendously affected and who probably aren't referred at all for the conception that they're going to have a very high rate of morbidity. So there is a group of patients that I think we would have a hard time defining, referring to your question, Gustavo.

And the other is just in general, a take-home message that obviously this is – I don't need to preach to the audience about doing emergent procedures – but emergent procedures are inherently more difficult. Your options become limited. Our treatment will focus on patients who have an arterial abnormality that is changing, such as growing. Our results speak to a high percentage of patients done electively versus the prior reports from the Mayo Clinic where 70% of the patients were done urgently. And I think that the differences between our report and that report that's available in the Journal of Vascular Surgery are clearly related to that.

So I don't think we want to ever defer an intervention on a patient with EDS. If that aneurysm is growing, those patients, given the window of time, can have a proper genetic evaluation, get a sense about what the options are. As I said, with the advent of better technologies, lower-profile, perhaps less traumatic, more flexible stent grafts, maybe there will be some wiggle room in the future to consider stent-graft therapy, but that has not been our approach.

From the standpoint of stent-graft therapy for connective tissue disorders, there is a pretty strong consensus statement. Consensus statements actually carry some medical-legal weight. So it's a very tricky ground to be traveling to say we're going to put a lot of stent grafts in these patients.