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Disclaimer: The views expressed here are my own and do not represent my employer or any affiliated organization.

I recently brought up the topic of a “neuro” type of Ehlers-Danlos syndrome. While not formally recognized as a subtype, it is frequently discussed in the EDS community. Studies have shown elevated rates and clustering of complex neurological manifestations in patients with hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD). Until now, there have been no formal publications describing this subpopulation within hEDS and HSD. A preprint “concept paper” was just released titled “Defining Neuro-EDS: A Neuro-Predominant Phenotype in hEDS/HSD and Related Heritable Connective Tissue Disorders”. This publication has yet to be peer reviewed, but presents a framework of two clinical manifestations of neuro-EDS: a cranial and spinal domain, and a neuro-autonomic-inflammatory domain.

The authors propose this as a working framework, and not diagnostic criteria or it’s own subtype at this time, and they acknowledge the ongoing diagnostic criteria efforts for hEDS and HSD. For those that might be new to the discussion of neuro phenotypes in EDS, let’s review some of the recent literature.

In a 2,149 patient cohort, self reported symptoms based on a questionnaire identified three clusters of clinical presentation, with one having a strong neuro presentation. In this cluster, chiari, craniocervical instability (CCI), tethered cord and MCAS had a higher prevalence than the other two clusters.

A 2017 literature review discussed neurological and spinal manifestations of the Ehlers-Danlos syndromes. Spinal instabilities, ligament laxity at the craniocervical junction, early disc degeneration, and nerve entrapments are covered and considered structural consequences of connective tissue laxity. Migraine, idiopathic intracranial hypertension, Tarlov cysts, tethered cord syndrome, chiari and dystonia are also highlighted co-occuring presentations in EDS patients.

These conditions often require intervention. Tethered cord syndrome may require surgical intervention for release of the filum terminale. In another study at a neurosurgical center, researchers performed a retrospective chart review and found that out of 460 hEDS patients, 404 had surgical intervention and 73% of those had a cranio-cervical fustion for CCI. And it’s not uncommon for patients to present with both tethered cord and CCI.

So what does this preprint propose?

The authors suggest “Neuro-EDS” as a clinically recognizable neuro-predominant phenotype within hEDS/HSD and related heritable connective tissue disorders. The main issue highlighted is that neurological manifestations in hEDS and HSD are looked at as separate diagnoses which leads to fragmented care. They specify two interconnected domains: a cranial spinal domain and a neuro autonomic inflammatory domain.

Cranial and Spinal Domain: CCI, Chiari I malformation, complex Chiari spectrum, syringomyelia, tethered cord syndrome, intracranial hypertension, spontaneous intracranial hypotension/CSF leaks, internal jugular venous outflow disorders, and Eagle syndrome. Interestingly, the authors discuss intracranial hypertension and spontaneous intracranial hypotension as two opposite ends of a dysregulated CSF pressure homeostasis, rather than separate conditions. They also emphasize that pathologies like occult tethered cord and CCI can be missed on standard imaging and may require other diagnostic assessments.

Neuro-Autonomic-Inflammatory Domain: POTS/dysautonomia, MCAS, small fiber neuropathy, GI dysmotility, neurogenic bladder, cognitive dysfunction, headache, sleep disturbance, and ME/CFS. The preprint emphasizes that these may not necessarily be independent of craniospinal pathology, and that structural disease could drive or worsen dsyautonomia and inflammatory changes.

One of my favorite arguments this position paper mdae, is that Neuro-EDS should be viewed similarly to other organ-specific phenotypes recognized in multisystem diseases such as neuropsychiatric lupus or neuro Sjögren’s disease.

So where does this leave things?

As I mentioned in the previous post, I feel strongly that subtyping should eventually rest on biological mechanism, not clustered symptoms. The authors shared a similar viewpoint, so I’ll leave you with a excerpt of the preprint directly:

“This position paper should foster future efforts to focus on refinement and validation of the proposed phenotype through standardized terminology, multicenter prospective registries, longitudinal natural history studies, consensus-based clinical characterization, and multidisciplinary collaboration. As these frameworks eventually mature, integration of clinical phenotyping with advanced imaging, physiological testing, molecular profiling, and other mechanism-linked verifiers may facilitate identification of biologically meaningful endotypes, improve patient stratification, and support precision diagnostic and therapeutic strategies within Neuro-EDS”

As someone who has more manifestations in this paper than I’d like to admit, I am excited for the direction of this research and appreciate the efforts of those working to care for and understand these patients. And as someone who works directly in the biology in this space, I am hopeful for the future. Check out the full text here.

Researchers just proposed a framework for "neuro EDS"

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