Defining Neuro-EDS: A Neuro-Predominant Phenotype in hEDS/HSD and Related Heritable Connective Tissue Disorders

1. Introduction

For more than two decades, multidisciplinary clinical experience, supported by parallel observations from multiple international centers with expertise in hypermobile Ehlers–Danlos syndrome (hEDS) and related heritable connective tissue disorders (HCTDs), has consistently identified a neuro-predominant phenotype that remains incompletely characterized and lacks formal clinical definition (1-6) We refer to this neuro-predominant phenotype as Neuro-EDS.(Figure 1).

These observations describe a subgroup of patients with connective tissue disorders who develop complex neurological presentations rather than presenting as isolated neurological diagnoses (4-6). Affected individuals are characterized by progressive neurologic deterioration and severe neuro-autonomic-inflammatory manifestations, arising in the setting of interacting structural pathology, physiologic dysregulation, and metabolic dysfunction (4, 6, 7) .These patients experience a disproportionately high burden of cranial, spinal and neurovascular disorders, and the severity, complexity, and multisystem nature of their disease appear disproportionate to the degree of generalized joint hypermobility and musculoskeletal involvement alone(8).

Many of these findings appear anatomically discordant, radiographically unexplained, or diagnostically fragmented when interpreted through conventional imaging paradigms or disease-specific frameworks (2, 9, 10). However, when viewed through the lens of connective tissue biology—including its effects on cranial and spinal biomechanics, cerebrospinal fluid dynamics, venous outflow, peripheral nerve vulnerability, and autonomic regulation—these seemingly disparate manifestations are understood as interconnected expressions of a common underlying disease process (11-15).

Despite increasing recognition across multiple centers that many of these individual manifestations are interconnected components of a unified clinical pattern (4-6), they continue to be evaluated largely as independent diagnoses. Consequently, affected patients remain subsumed within broad and heterogeneous hEDS/HSD populations, obscuring this clinically important subgroup (4). Continued reliance on a diagnosis-centered approach contributes to diagnostic delay, fragmented multidisciplinary care, and inconsistent referral patterns (16). It also promotes inappropriate attribution of symptoms to functional or primary psychiatric disorders, underrecognition of potentially treatable craniospinal pathology, and missed opportunities for meaningful patient stratification (4, 6, 16).

Throughout medicine, advances in disease classification have often begun with careful clinical observation. Before underlying biological mechanisms are fully understood, reproducible clinical phenotypes provide a practical means of identifying patient subgroups, organizing complex disease presentations, and guiding systematic investigation (17, 18). As biological understanding evolves, these clinically defined phenotypes can be refined into increasingly precise, mechanism-informed classifications(17, 18) .

The convergence of large clinical datasets, expanding multidisciplinary expertise and collaboration, advances in dynamic physiologic assessment, growing recognition of connective tissue–related neurological disease, increasing understanding of the biodynamic effects of hypermobility on the nervous system, and emerging molecular and cellular insights now provide a compelling rationale to formally define and systematically investigate this neuro-predominant phenotype (4-7, 12, 19-23)(4-7, 12, 19-23) .

In this position paper, we propose Neuro-EDS as a clinically recognizable neuro-predominant phenotype within hEDS/HSD and related heritable connective tissue disorders. We define its principal clinical manifestation domains, summarize the evidence supporting this proposed phenotype, and provide a rationale for its standardized characterization and systematic investigation.

This proposal is intended to complement—not replace—existing diagnostic frameworks (24). Rather than defining a new disease entity, Neuro-EDS offers a systematic approach to identifying, characterizing, and studying a clinically meaningful subgroup within the broader spectrum of heritable connective tissue disorders.

2. Network Medicine as a Conceptual Model

Current hEDS/HSD frameworks recognize the multisystem nature of heritable connective tissue disorders but do not specifically define a neuro-predominant subgroup(2, 3, 24). As a result, patients whose presentations are dominated by neurological, cranial, spinal, autonomic, neurovascular, and immune-inflammatory manifestations remain embedded within broad and heterogeneous hEDS/HSD classifications, limiting meaningful patient stratification and obscuring a reproducible pattern of disease expression (4-6).

A network medicine perspective provides a useful conceptual model for understanding this complexity. Rather than viewing symptoms and diagnoses as independent entities, it considers disease as an interconnected system of clinical features, biological processes, and treatment responses. By examining how these features cluster and interact, network medicine offers an approach to understanding complex multisystem disorders beyond traditional diagnosis-centered models (17, 25).

Applied to Neuro-EDS, this perspective allows cranial, spinal, neurological, autonomic, vascular, cerebrospinal fluid pressure–related, neuropathic, inflammatory, and connective tissue manifestations to be viewed as interconnected expressions of a broader disease process. The reproducible co-occurrence of these manifestations suggests that they are not simply unrelated comorbidities but may reflect interacting biological and physiological mechanisms involving connective tissue biology and its downstream effects on craniospinal biomechanics, cerebrospinal fluid dynamics, vascular physiology, autonomic regulation, peripheral nerve vulnerability, neuroimmune dysfunction, and metabolic homeostasis (4, 7, 12, 15, 22, 23)(Figure 2).

This perspective provides a conceptual basis for studying Neuro-EDS as an integrated disease network rather than a collection of isolated disorders.

Applied to Neuro-EDS, this approach provides a conceptual foundation for integrating clinical observation with physiological, molecular, and mechanistic investigation, enabling progressively more biologically informed disease classification.

3. Evidence Supporting a Distinct Neuro-EDS Phenotype

Evidence supporting this phenotype emerges from multiple complementary lines of evidence—including multidisciplinary clinical experience, phenotypic clustering analyses, tertiary referral cohorts, population-based studies, and dynamic physiologic assessment—that converge on a remarkably consistent pattern of disease expression (2, 4-6, 19, 20) . Collectively, these independent observations support the recognition of a reproducible neuro-predominant clinical phenotype within the spectrum of hEDS/HSD and related heritable connective tissue disorders.

Independent phenotypic clustering analyses provide quantitative support for a reproducible neurologic subgroup within the broader hEDS population. In large-scale work from the Norris laboratory encompassing more than 2,000 individuals, approximately 10–15% of patients clustered within a high-severity neurologic subgroup characterized by prominent craniospinal, autonomic, inflammatory and neurologic manifestations (4). These findings demonstrate that neurological disease expression is not uniformly distributed across hEDS/HSD but instead clusters within a distinct subset of patients with disproportionately severe multisystem involvement.

Complementary observations from tertiary referral neurosurgical cohorts further reinforce this pattern. Large-cohort clinical studies have demonstrated a high prevalence of Chiari malformation, craniocervical instability, tethered cord syndrome, styloid hypertrophy, cerebrospinal fluid leaks, dysautonomia, mast cell activation, and related neurological disorders among individuals with hEDS, with a substantial proportion ultimately undergoing neurosurgical intervention (6). The frequent co-occurrence of craniocervical instability and tethered cord syndrome further supports the concept of a unified craniospinal phenotype characterized by overlapping cervicomedullary and lumbosacral pathology (20). Together, these observations indicate that severe craniospinal pathology is enriched within a subset of patients with hEDS, consistent with the neuro-predominant phenotype identified by phenotypic clustering analyses (9).

Published clinical investigations have further demonstrated that important manifestations of this phenotype may be radiographically occult or physiologically dynamic. Radiographically occult tethered cord syndrome and dynamic craniocervical instability may evade detection using conventional static, supine imaging, underscoring the limitations of traditional structural diagnostic paradigms in this population (10, 26-28).These findings support the concept that neurological disease expression in this neuro-predominant subgroup cannot always be adequately characterized by conventional structural imaging alone and may require dynamic, physiologic, and mechanism-informed assessment, supported by reproducible symptom modulation during multidisciplinary dynamic physiologic evaluation (19, 20).

Population-based survey studies provide an additional line of evidence supporting this phenotype. Compared with large national datasets, individuals with hEDS/HSD report disproportionately increased rates of diagnosed or clinically suspected Chiari malformation, cerebrospinal fluid leaks, tethered cord syndrome, intracranial hypotension, trigeminal neuralgia, peripheral neuropathic syndromes, and related neurological disorders, providing independent population-level evidence that neurological disease is concentrated within a distinct subgroup of affected individuals (3, 5, 11).

Across multiple clinical settings, symptoms demonstrate reproducible modulation with positional change, external cervical stabilization (e.g., rigid cervical collars and halo reduction), invasive cervical traction, and targeted physiological interventions such as diagnostic nerve blocks, along with other provocative maneuvers (10, 19, 20). In patients with craniocervical instability, invasive cervical traction has demonstrated reproducible symptom improvement accompanied by objective dynamic radiographic changes during multidisciplinary evaluation for surgical candidacy, supporting the concept that important manifestations of this clinical phenotype demonstrate dynamic clinical behavior and may not be adequately characterized by static structural assessment alone (20).

These observations suggest that conventional static structural imaging may underestimate clinically important neurological pathology in selected patients and support incorporation of dynamic, physiologic, and mechanism-informed assessment into phenotype characterization.

The reproducibility of these responses across independent physiologic interventions further suggests that many manifestations of this neuro-predominant phenotype reflect interacting structural and physiological mechanisms rather than isolated anatomical abnormalities

Taken together, these independent lines of evidence support the existence of a reproducible neuro-predominant phenotype within the spectrum of hEDS/HSD and related heritable connective tissue disorders. While many of its individual manifestations have been recognized previously, their recurrent co-occurrence across independent cohorts, reproducible physiologic behavior, and quantitative phenotypic clustering support their recognition as a unified clinical phenotype rather than a coincidental aggregation of isolated comorbid conditions.

4. Clinical Manifestation Domains of Neuro-EDS

We propose to organize the Neuro-EDS phenotype into two major clinical manifestation domains: the Cranial and Spinal Domain and the Neuro-Autonomic-Inflammatory Domain. We suggest that this may optimize the practical framework for organizing the recurrent patterns of disease expression observed in this neuro-predominant subgroup while acknowledging the substantial overlap amongst clinical manifestations, associated diagnoses, and underlying pathophysiological processes.

Although presented separately for conceptual clarity, as presented above, the evidence suggests that these domains are highly interconnected. Craniospinal pathology may contribute to neurological, autonomic, vascular, and inflammatory manifestations, while systemic neuro-autonomic-inflammatory dysfunction may influence disease expression, symptom burden, treatment response, and recovery (2, 12, 14, 29, 30). Accordingly, Neuro-EDS is best understood as an integrated clinical phenotype arising from interactions between cranial and spinal structural abnormalities and neuro-autonomic-inflammatory dysfunction rather than a collection of isolated diagnoses.

5. Evidence Supporting the Cranial and Spinal Domain

The Cranial and Spinal Domain comprises a reproducible constellation of structural, biomechanical, cerebrospinal fluid (CSF), and venous disorders that occur with increased frequency and demonstrate non-random clustering in patients with hEDS/HSD and related heritable connective tissue disorders (4, 6, 11). Although historically considered independent diagnoses, accumulating clinical, imaging, physiologic, and surgical evidence supports their recognition as interconnected manifestations of a shared connective tissue disease process affecting the craniospinal axis (2, 10, 12, 13).

Foundational investigations first described Chiari-spectrum pathology, cranial settling, craniocervical instability, and broader neurological and spinal manifestations in patients with heritable connective tissue disorders, laying the foundation for recognition of a reproducible craniospinal disease phenotype associated with connective tissue insufficiency (1-3)(Figure 3).

Subsequent systematic and scoping reviews, phenotypic studies, and multimorbidity analyses have consistently demonstrated that craniospinal disorders—including craniocervical instability, complex Chiari-spectrum disorders, tethered cord syndrome, cerebrospinal fluid pressure disorders, and venous outflow abnormalities—occur with increased frequency and frequently coexist within hEDS/HSD populations (4, 6, 10, 11). Additional cohort studies further demonstrate enrichment of styloid hypertrophy necessitating styloidectomy among patients with hEDS, providing preliminary evidence that symptomatic styloidogenic pathology may also be incorporated within this Cranial and Spinal domain (6). This may reflect a broader susceptibility of ligamentous tissues to aberrant mineralization or ossification in the setting of altered connective tissue biology, with chronic mechanical loading of the stylohyoid ligament complex promoting progressive ossification and abnormal tension across the styloid–stylohyoid complex.

Rather than occurring in isolation, these disorders share overlapping clinical presentations and demonstrate substantial pathophysiologic convergence involving connective tissue insufficiency, altered craniospinal biomechanics, cerebrospinal fluid dysregulation, and venous outflow abnormalities (1, 2, 4, 6, 11-14).

Emerging molecular and cellular evidence further supports this framework by implicating abnormalities in extracellular-matrix organization and remodeling, cell–matrix interactions, fibroblast behavior, and inflammatory and immune signaling as potential contributors to disease expression and progression in hEDS/HSD (7, 22, 23).

Collectively, these observations support recognition of a reproducible Cranial and Spinal Domain that provides a biologically coherent framework for understanding the recurrent co-occurrence of these disorders and their contribution to neurological disease expression in hEDS/HSD.

6. Tethered Cord Syndrome

Tethered cord syndrome has emerged as an important manifestation of the cranial and spinal disease spectrum in hEDS and related heritable connective tissue disorders, supported by converging evidence from clinical series, systematic and narrative reviews, histopathologic studies, biomechanical studies and surgical outcome data (1, 2, 9, 11, 26, 27, 31).

Clinical series, observational studies, and review literature have documented both classic and occult tethered cord syndrome in patients with hEDS and related heritable connective tissue disorders, with occult presentations characterized by compatible clinical features despite a normally positioned conus medullaris on conventional imaging, highlighting the limitations of relying solely on structural imaging for diagnosis (2, 26, 27).

Histopathologic and biomechanical studies further support tethered cord syndrome in hEDS as a distinct connective tissue disorder–associated entity by demonstrating structural abnormalities of the filum terminale together with altered biomechanical properties adding to pathological anchoring of the spinal cord in the hypermobile spine with resulting spinal cord motion disorder, providing biologic support for the observed clinical phenotype (26, 27).

7. Craniocervical Instability

Craniocervical instability, a central component of the Cranial and Spinal Domain, is characterized by ligamentous insufficiency and altered craniovertebral biomechanics that permit abnormal motion across the craniovertebral junction and the potential for position- and load-dependent neural deformation and neurological dysfunction (1, 2).

Foundational investigations described occipitoatlantoaxial hypermobility, cranial settling, ventral brainstem compression, complex Chiari-spectrum pathology, and associated neurological dysfunction, establishing the characteristic anatomical and clinical features of CCI in connective tissue disorders (1, 2).

Subsequent clinical studies, systematic reviews, and phenotypic analyses have further characterized CCI in hEDS/HCTDs and documented its frequent co-occurrence with other craniospinal disorders. In a large phenotypic study of 2,149 individuals with hEDS, the prevalence of craniocervical or cervical instability was 31.6% (4, 9).

Unlike acute traumatic craniocervical instability, which typically follows a discrete osseoligamentous injury, CCI in connective tissue disorders develops in the setting of chronic connective tissue insufficiency and altered craniovertebral biomechanics.

Consequently, diagnostic paradigms and imaging thresholds developed for acute traumatic instability in otherwise normal connective tissue may not adequately characterize the severity or physiological impact of disease, with important implications for diagnosis, physiological assessment, and treatment (19-21, 32, 33).

8. Chiari I Malformation and Syringomyelia

Hindbrain abnormalities have long been recognized within the neurological spectrum of heritable connective tissue disorders, with Chiari I malformation among the most extensively reported cranial manifestations (1-3, 34). Dysfunction within the hindbrain and cervicomedullary region may contribute substantially to neurological disability in Neuro-EDS because these structures mediate critical autonomic, respiratory, vestibular, cerebellar, lower cranial nerve, and sensorimotor functions.

Syringomyelia is a well-established pathologic effect of Chiari-spectrum pathology and has also been documented in patients with heritable connective tissue disorders. Its occurrence reflects extension of disease beyond the hindbrain to the spinal cord, commonly in association with disturbed cerebrospinal fluid flow at the craniovertebral junction (1, 2, 35).

9. Complex Chiari Spectrum Disorders

The concept of Complex Chiari, introduced by Brockmeyer and colleagues, describes a subgroup of patients with Chiari-spectrum pathology who require interventions beyond standard posterior fossa decompression because of associated ventral brainstem compression, craniocervical instability, or other craniovertebral junction abnormalities (36, 37).

Clinical studies have consistently shown that patients with connective tissue disorders are disproportionately represented within the Complex Chiari phenotype and frequently exhibit concurrent craniocervical instability, ventral brainstem compression, cranial settling, and multisystem neurological involvement (1, 35, 38, 39).

These observations suggest that in patients with connective tissue disorders, Chiari malformation is frequently accompanied by a broader pattern of craniovertebral junction abnormalities rather than occurring as isolated tonsillar ectopia.

10. Cerebrospinal Fluid Pressure Disorders

Disorders of cerebrospinal fluid (CSF) pressure regulation represent a key physiological component of the craniospinal phenotype (12-14). Rather than representing isolated disease entities, disorders of both elevated and reduced intracranial pressure may reflect disturbances of a shared craniospinal pressure homeostasis, with these seemingly opposite clinical states existing along a continuum of dysregulated CSF pressure physiology (15, 40, 41).

11. Intracranial Hypertension

Reduced craniospinal compliance has emerged as a potential mechanism contributing to intracranial hypertension in connective tissue disorders. By limiting the ability of the craniospinal axis to accommodate normal physiological fluctuations in intracranial blood and cerebrospinal fluid volumes, impaired compliance may contribute to elevations in intracranial pressure and associated neurological manifestations (15, 42, 43). Emerging evidence suggests that intracranial hypertension in connective tissue disorders may represent part of a broader disorder of craniospinal pressure regulation involving altered connective tissue and meningeal biology, impaired craniospinal compliance, cerebral venous outflow dysfunction, and interacting cranial and spinal pathology(13, 14, 44).

12. Spontaneous Intracranial Hypotension

Published evidence suggests that spontaneous intracranial hypotension in connective tissue disorders is associated with dural fragility and connective tissue insufficiency, which may predispose to spontaneous spinal CSF leaks through multiple mechanisms that disrupt craniospinal pressure homeostasis (13, 43, 45). These include meningeal diverticula, dural defects, and the increasingly recognized CSF–venous fistulas (13, 41, 45, 46). Because classic imaging findings may be absent and clinical manifestations are frequently nonspecific, these disorders remain underrecognized and often require targeted diagnostic evaluation using advanced imaging techniques (41, 45-48) .

The discovery of CSF–venous fistulas has fundamentally expanded the understanding of spontaneous intracranial hypotension by establishing direct CSF egress into the venous system as a distinct mechanism of CSF volume depletion (45, 46, 49). Unlike leaks caused by dural tears, CSF–venous fistulas typically occur without a spinal longitudinal extradural CSF collection and may remain occult on conventional imaging, often requiring lateral decubitus digital subtraction myelography or CT myelography for localization. Although their prevalence among patients with connective tissue disorders remains incompletely defined, their identification broadens the spectrum of mechanisms underlying spontaneous intracranial hypotension and should be considered during evaluation of connective tissue disorder patients with suspected CSF pressure disorders (39, 48, 50, 51).

Modern concepts of CSF pressure disorders recognize intracranial hypertension and spontaneous intracranial hypotension as complementary manifestations of disturbed craniospinal pressure homeostasis rather than mutually exclusive disease states (13-15, 40).

The occurrence of rebound intracranial hypertension following successful treatment of spontaneous CSF leaks further supports the concept that these disorders reflect dynamic disturbances in craniospinal pressure homeostasis rather than independent disease processes(41, 47, 48) .

13. Venous Outflow Disorders and Jugular Compression

Abnormal cerebral venous drainage represents an additional physiological component of the craniospinal phenotype (52).

Increasing evidence suggests that focal internal jugular vein compression within the styloid-C1 corridor may contribute to impaired cerebral venous drainage, intracranial hypertension, and altered intracranial pressure physiology in selected patients with connective tissue disorders (14, 53-55) Advanced venographic and cross-sectional imaging studies have demonstrated focal jugular narrowing, collateral venous drainage patterns, pressure gradients, and associated neurologic manifestations consistent with disturbed craniospinal venous outflow and pressure regulation (14, 54, 55).

Emerging CTD-focused venous outflow studies further suggest that connective tissue disorder populations may be predisposed to clinically significant jugular compression phenotypes (14, 56).

14. Eagle Syndrome and Styloidogenic Neurovascular Compression

Eagle syndrome results from symptomatic styloidogenic neurovascular compression caused by an elongated styloid process or ossified stylohyoid ligament (53, 57, 58.)Although traditionally viewed as a cervicofacial pain syndrome, its clinical spectrum extends beyond local pain to include neurological, vascular, and autonomic manifestations (53, 58).

Recent analysis of a prospectively evaluated cohort of 2,003 consecutive CTD patients presenting with neurologic symptoms demonstrated that, although the prevalence of styloid hypertrophy was comparable to contemporary CT-based population estimates, approximately half of patients with styloid hypertrophy met criteria for Definite or Probable Eagle syndrome following application of a structured diagnostic framework (59).

Because this cohort was derived predominantly from patients with hEDS/HSD, these observations suggest that symptomatic styloidogenic pathology may be enriched within neurologically symptomatic connective tissue disorder populations and may represent an underrecognized contributor to the broader craniospinal phenotype.

Collectively, these observations support recognition of the Cranial and Spinal Domain as a biologically coherent pattern of interconnected structural and physiologic disease processes that contribute to neurological disease expression in the proposed Neuro-EDS phenotype.

15. Neuro-Autonomic-Inflammatory Domain

The Neuro-Autonomic-Inflammatory Domain encompasses a reproducible constellation of neurologic, autonomic, inflammatory, and systemic manifestations spanning symptoms, signs, and independently recognized diagnoses that frequently cluster across affected patients. Common features of this domain include dysautonomia, manifested by postural orthostatic tachycardia syndrome (POTS), other forms of orthostatic intolerance, gastrointestinal dysmotility, thermoregulatory dysfunction, and urinary dysfunction (30, 60-62) as well as mast cell activation syndrome (MCAS) (29, 60, 61, 63, 64) small fiber neuropathy, neuropathic pain, (30, 65, 66) headache disorders, sleep disturbance, cognitive dysfunction, chronic fatigue, exercise intolerance, and ME/CFS-like presentations (30, 67-69).

16. Clinical Overlap

Autonomic dysfunction frequently coexists with mast cell activation syndrome, small fiber neuropathy, neuropathic pain, gastrointestinal dysmotility, cognitive dysfunction, headache disorders, and chronic fatigue. Multiple cohort studies demonstrate substantial overlap among these manifestations, supporting their recognition as a recurring pattern of clinical co-occurrence rather than solely as isolated comorbidities (29, 30, 60, 64, 65, 67).

17. Relationship to Craniospinal Disease

These manifestations may not be independent of craniospinal pathology. The brainstem contains the principal autonomic nuclei regulating critical cardiovascular, respiratory, visceral, and thermoregulatory function and serves as an integration center linking peripheral organ systems with higher central nervous system networks, including the hypothalamus. Disorders affecting the structural, biodynamic and physiologic integrity of the craniospinal axis—including craniocervical instability, Chiari-spectrum pathology, tethered cord syndrome, venous outflow abnormalities, and cerebrospinal fluid pressure disorders— may therefore contribute to or amplify autonomic, neurovascular, and inflammatory symptom expression (2, 12, 14, 30).

Extrinsic venous collapse due to connective tissue insufficiency and impaired craniospinal compliance have likewise been proposed as potential contributors to neurological and autonomic symptoms in this population (14, 15, 21, 42, 43).

Severe dysautonomia is frequently reported in hEDS/HSD and may be disabling, affecting cardiovascular regulation, gastrointestinal motility, thermoregulation, and urinary function (30, 60, 62). MCAS and related mast cell disorders may co-occur and amplify symptom burden through mediator-driven inflammatory and neuroimmune pathways (29, 63, 70).

Small fiber neuropathy and neuropathic pain syndromes are also common and may contribute to peripheral pain generation, sensory dysregulation, and autonomic dysfunction, while interacting bidirectionally with central nervous system pathology (30, 65, 66). Cognitive dysfunction, headache disorders, chronic fatigue, and ME/CFS-like illness may reflect convergent effects of autonomic dysregulation, impaired cerebral perfusion, altered neurovascular coupling, neuroimmune activation, connective tissue dysfunction, and abnormal cerebrospinal fluid or venous physiology (12, 30, 67-69).

Emerging evidence further suggests that neuroimmune, inflammatory, vascular, and connective tissue mechanisms may interact with craniospinal pathology and contribute to symptom severity and disease expression, with preliminary evidence that these relationships may also influence treatment response (2, 10, 29, 30, 65).

Collectively, the consistent co-occurrence of these manifestations, their plausible shared biological mechanisms, and their relationship to connective tissue and craniospinal dysfunction support recognition of a distinct neuro-autonomic-inflammatory manifestation domain within the Neuro-EDS phenotype.

18. Discussion

Recognition of Neuro-EDS extends beyond nomenclature. It is meant to provide a framework for earlier recognition, more appropriate multidisciplinary referral, standardized phenotypic characterization across institutions, improved patient stratification, and more consistent investigation of complex neurological disease within heritable connective tissue disorders. It also establishes a common language for multicenter collaboration, prospective registries, natural history studies, and mechanism-informed research.

Recognition of clinically meaningful organ-specific phenotypes within broader multisystem diseases is well established across medicine. Neuropsychiatric systemic lupus erythematosus, neurosarcoidosis, neuro-Behçet disease, and neuro-Sjögren syndrome are recognized because they represent reproducible patterns of neurological disease expression requiring distinct approaches to diagnosis, investigation, and management. We propose that Neuro-EDS should be viewed similarly—not as a separate disease entity, but as a clinically recognizable neuro-predominant phenotype within the broader spectrum of hEDS/HSD and related heritable connective tissue disorders.

This proposal is intended to complement existing diagnostic frameworks rather than replace them. We recognize the ongoing evolution of the 2017 hEDS diagnostic criteria, which were developed primarily to standardize musculoskeletal phenotyping and facilitate genetic investigation rather than characterize neurological disease expression (71) .

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.(Figure 4)

The recognition of this patient population as Neuro-EDS may help define a reproducible neuro-predominant clinical phenotype within hypermobile Ehlers–Danlos syndrome, hypermobility spectrum disorders, and related heritable connective tissue disorders, while acknowledging that continued validation is needed.

Rather than redefining disease, recognition of Neuro-EDS may further shift the clinical paradigm from viewing neurological manifestations as isolated comorbidities to understanding them as interconnected patterns of disease expression within heritable connective tissue disorders.

As with other organ-specific phenotypes recognized across medicine, this framework provides a foundation for identifying biologically meaningful subgroups and advancing mechanism-informed research toward more precise diagnosis and patient care.