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. 2025 Jul 18:14:100111.
doi: 10.1016/j.ajmo.2025.100111. eCollection 2025 Dec.

Hypermobile Ehlers-Danlos Syndrome: Cerebrovascular, Autonomic and Neuropathic Features

Peter Novak  1   2 , David M Systrom  3   2 , Sadie P Marciano  1 , Alexandra Witte  1 , Arabella Warren  3   2 , Donna Felsenstein  4   2 , Matthew P Giannetti  3   2 , Matthew J Hamilton  5   2 , Jennifer Nicoloro-SantaBarbara  6   2 , Mariana Castells  5   2 , Khosro Farhad  1   2 , David M Pilgrim  1   2 , William J Mullally  1   2 , Mark C Fishman  7   2 , Jeff M Milunsky  8 , Aubrey Milunsky  8 , Joel Krier  9
Affiliations

Hypermobile Ehlers-Danlos Syndrome: Cerebrovascular, Autonomic and Neuropathic Features

Peter Novak et al. Am J Med Open. .

Abstract

Background: Hypermobile Ehlers-Danlos syndrome (hEDS) affects multiple systems, but comprehensive evaluations of a larger sample of hEDS patients are lacking. The objective of this study was to describe cerebrovascular, autonomic, and neuropathic features of hEDS.

Methods: This retrospective case-control study was conducted at Brigham and Women's Faulkner Hospital between 2016-2023. Data from hEDS patients who completed autonomic testing and skin biopsies were analyzed. Outcome measures include validated surveys (Survey of Autonomic Functions, Neuropathy Total Symptom Score-6 (SAS)) and autonomic function testing (Valsalva maneuver, deep breathing, head-up tilt and sudomotor), cerebrovascular (cerebral blood flow velocity (CBFv) in the middle cerebral artery), respiratory (capnography), and neuropathic (skin biopsies for assessment of small fiber neuropathy) testing and inflammatory/ autoimmune markers.

Results: Total 270 hEDS patients were analyzed and compared to 29 healthy controls. Common hEDS complaints (prevalence > 90% ) were orthostatic sudomotor, vasomotor, gastrointestinal, and pain. Orthostatic cerebral blood flow velocity was reduced in 79% of hEDS and correlated with orthostatic dizziness. The head-up tilt test revealed postural tachycardia syndrome (prevalence 33%), hypocapnic cerebral hypoperfusion (22%), orthostatic cerebral hypoperfusion syndrome (18%), and neurogenic orthostatic hypotension (9%). Widespread but mild autonomic failure was present in 90% of hEDS patients on autonomic testing. Small fiber neuropathy using structural criteria was detected in 64%, and using combined structural and functional criteria in 82%.

Conclusions: This study provided evidence of cerebrovascular dysregulation with reduced orthostatic cerebral blood flow velocity associated with symptoms of cerebral hypoperfusion, frequent small fiber neuropathy, and widespread but mild autonomic failure in hEDS.

Keywords: Autonomic; Cerebral blood flow; Dysautonomia; Ehlers-Danlos; POTS; QASAT; Small fiber neuropathy; hEDS.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Image, graphical abstract
Graphical abstract
Figure 1
Figure 1
A flowchart diagram of the study.
Figure 2
Figure 2
QASAT results. (A) Absolute scores, mean ± sd (B), Relative scores in percent, mean ± sd (C), Percentage of patients in which the QASAT score was abnormal (> 0). CBFv = cerebral blood flow velocity in the middle cerebral artery; ET-CO2 = end-tidal CO2; AF = autonomic failure; Cardiov = cardiovagal, Adren = adrenergic; OH = orthostatic hypotension; OT = orthostatic tachycardia (orthostatic heart rate increment ≥ 30 BPM); Sudo = sudomotor; SFN = small fiber neuropathy; ENFD = epidermal nerve fiber density; SGNFD = sweat gland nerve fiber density; SFN-mixed=noth ENFD and SGNFD are abnormal; SFN-any-b=SFN with ENFD or SGNFD abnormal; SFN-any-b+=SFN with ENFD or SGNFD or sudomotor abnormality.
Figure 3
Figure 3
The head-up tilt test shows hemodynamic variables at supine baseline and at every minute of head-up tilt, mean ± conf.int. (A) heart rate; (B) systolic blood pressure; (C) mean blood pressure; (D) diastolic blood pressure; (E) systolic cerebral blood flow velocity (CBFv), (F) mean CBFv; (G) diastolic CBFv; (H) end-tidal CO2. CBFv = cerebral blood flow velocity in the middle cerebral artery.
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