Wednesday, October 5, 2016

Ehlers-Danlos syndrome linked to small-fiber neuropathy

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…

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…

Recent published evidence of this in the peer-reviewed literature is found in a 2016 case report by Pascarella and colleagues  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…

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 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.


  1. Cazzato D, Castori M, Lombardi R, Caravello F, Bella ED, Petrucci A, Grammatico P, Dordoni C, Colombi M, Lauria G. Small fiber neuropathy is a common feature of Ehlers-Danlos syndromes. Neurology. 2016 Jul 12;87(2):155-9.

    To investigate the involvement of small nerve fibers in Ehlers-Danlos syndrome (EDS).
    Patients diagnosed with EDS underwent clinical, neurophysiologic, and skin biopsy assessment. We recorded sensory symptoms and signs and evaluated presence and severity of neuropathic pain according to the Douleur Neuropathique 4 (DN4) and ID Pain questionnaires and the Numeric Rating Scale (NRS). Sensory action potential amplitude and conduction velocity of sural nerve was recorded. Skin biopsy was performed at distal leg and intraepidermal nerve fiber density (IENFD) obtained and referred to published sex- and age-adjusted normative reference values.
    Our cohort included 20 adults with joint hypermobility syndrome/hypermobility EDS, 3 patients with vascular EDS, and 1 patient with classic EDS. All except one patient had neuropathic pain according to DN4 and ID Pain questionnaires and reported 7 or more symptoms at the Small Fiber Neuropathy Symptoms Inventory Questionnaire. Pain intensity was moderate (NRS ≥4 and <7) in 8 patients and severe (NRS ≥7) in 11 patients. Sural nerve conduction study was normal in all patients. All patients showed a decrease of IENFD consistent with the diagnosis of small fiber neuropathy (SFN), regardless of the EDS type.
    SFN is a common feature in adults with EDS. Skin biopsy could be considered an additional diagnostic tool to investigate pain manifestations in EDS.

  2. Pascarella A, Provitera V, Lullo F, Stancanelli A, Saltalamacchia AM, Caporaso G, Nolano M. Evidence of small fiber neuropathy in a patient with Ehlers-Danlos syndrome, hypermobility-type. Clin Neurophysiol. 2016 Mar;127(3):1914-6.

    From the article:

    The pathomechanisms of chronic pain and dysautonomia in JHS/EDS-HT are still unknown. Both “nociceptive/inflammatory” and “neuropathic/neurogenic” pain subtypes are supposed to be involved. Despite the evidence of high prevalence of neuropathic symptoms in JHS/EDS-HT patients, standard neurophysiological and ultrasound evaluations rarely demonstrate signs of focal or generalized nerve involvement. It has been suggested this might be due to the presence of a small fiber neuropathy which could be also responsible for the dysautonomic symptoms reported by JHS/EDS-HT patients.

    To our knowledge this is the first description of cutaneous innervation involvement in JHS/EDS-HT. The morphological evaluation revealed abnormalities of sensory free and corpusculated nerve endings paralleling a functional impairment of C, A-delta and A-beta-mediated sensory modalities with mixed aspects of loss (increased sensory thresholds) and gain (mechanical allodynia) of function. Neurophysiological tests selectively investigating A-delta fibers were unavailable in our laboratory and therefore the assessment of such fiber population was based on psychophysical sensory testing. Nerve conduction velocity study revealed normal large fiber function although the neurological and psychophysical examination pointed toward their involvement. However electrical stimuli don’t explore mechanoreceptors, last endings of large myelinated fibers, and this may be a possible explanation for the discrepancy between clinical and neurophysiological findings. We previously observed similar findings in patients with small fiber neuropathies. The prolonged hypomobility due to chronic pain may play a role in the reduced strength and muscle bulk in our patient.