Ehlers-Danlos Syndrome Linked to Small-Fiber Neuropathy

Charles E. Argoff, MD


September 29, 2016

This feature requires the newest version of Flash. You can download it here.

This is Dr Charles Argoff, professor of neurology at Albany Medical College and director of the Comprehensive Pain Center at Albany Medical Center in Albany, New York.

Recently, we've seen several individuals at our center who have Ehlers-Danlos syndrome (EDS), a known connective tissue disorder associated with, among other things, hyperelasticity. Although there are several types of EDS, that's not the focus of today's blog post.

People have been referred to us who have severe and chronic pain of uncertain etiology. Although it's been well documented that people with EDS do experience chronic pain of varying quality, other conditions, fatigue, and pain- and fatigue-related disability, overall this syndrome has been poorly understood.

Uncovering a New Link in EDS

We saw a 47-year-old gentleman who had been experiencing severe headaches and abdominal pain for almost a decade. In fact, he stopped working in his profession because it became unbearable. Nevertheless, he participated in his life activities as a parent and spouse, but was very much looking for a solution or a reduction in his pain. He had previously been evaluated at multiple other specialty centers outside of the Albany area, as well as locally. We went through several steps to evaluate him, and did what we could before deciding that we wanted to probe deeper into what might be causing some of his more generalized pain.

We also recently saw an 18-year-old female with EDS who at one point during her high school years couldn't function because of her chronic widespread pain. She was quite disturbed by the lack of ability of anyone to figure out why she was experiencing pain. That is understandable, given that this 18-year-old wasn't able to function in a normal manner.

In each of these individuals, we elected to carry out diagnostic 3-mm skin punch biopsies. This actually wound up confirming a diagnosis of small-fiber neuropathy in both patients, on the basis of the reduction of intraepidermal nerve fiber densities that were established. We thought this was quite interesting, and so we went to "write it up." Of course, we found we were not the only ones to have recently identified this.

So the real purpose of this blog post is to highlight to others who might be seeing patients with EDS the presence of small-fiber neuropathy in these individuals.

Mounting Evidence in the Literature

Recent published evidence of this in the peer-reviewed literature is found in a 2016 case report by Pascarella and colleagues[1] in Clinical Neurophysiology. The authors noted that chronic pain, fatigue, headache, and dysautonomia had been previously reported to be important symptoms in individuals with EDS.

They saw a 41-year-old male with burning feet as well as chronic fatigue, who also had a history of postprandial abdominal discomfort, constipation, gastroesophageal reflux, headache, and fatigue. They performed routine electrophysiologic studies looking for large-fiber neuropathy, which was not present. They then elected to perform 3-mm skin punch biopsies at multiple locations.

The investigators found evidence for a non–length-dependent small-fiber neuropathic process. Findings consistent with intraepidermal nerve fiber density reduction were seen in the thigh, but not in the distal lower extremity.

In a second just-published study in the journal Neurology, Cazzato and colleagues[2] reported on a series of patients with EDS who underwent clinical nerve physiologic assessment as well as skin biopsy assessment. In addition, their sensory symptoms were recorded to determine whether or not they had neuropathic features according to the Douleur Neuropathique 4 (DN4) [instrument], a very quick and very easy, relatively sensitive, and specific questionnaire that can be used to help identify whether a person's pain is neuropathic or not.

Skin biopsies in this analysis were performed at the distal leg, and intraepidermal nerve fiber density testing was also performed. Patients were, of course, compared with sex- and age-matched normal control databases.

Twenty adults in this study had typical hypermobility EDS, three had vascular EDS, and one had classic EDS. Upon evaluation, it was found that all but one patient had neuropathic pain complaints according to the DN4. Pain intensity was moderate in eight patients and severe in 11 patients. Sural nerve conduction studies, which are used for large-fiber testing, were normal in all 24 patients. All patients showed a decrease in intraepidermal nerve fiber density consistent with the diagnosis of small-fiber neuropathy, regardless of the type of EDS they had.

In conclusion, this is fascinating, because here is a condition that many of us have seen without really understanding the underlying mechanism. Of course, knowing that the diagnosis of small-fiber neuropathy is now reported in an increasing number of published studies, and simply observed in patients with EDS, doesn't give us all the answers. What it does tell us, though, is that this may have an impact on how we treat people. It certainly tells us that small-fiber neuropathy may be a common associated feature of EDS. It may explain many or at least some of the symptoms.

Also, it tells us that further studies are certainly needed to address these observations, so that we can eventually help people with EDS experiencing chronic pain and other symptoms that adversely affect their quality of life.

I am Dr Charles Argoff, professor of neurology at Albany Medical College and director of the Comprehensive Pain Center at Albany Medical Center. I thank you for viewing this blog post, and hope that you have enjoyed seeing it.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: