Hypermobility Spectrum Disorders and Migraine: Screening Matters

Connective tissue plays a crucial role in maintaining the structural and functional integrity of both the central and peripheral nervous systems. Whereas the vascular and neurologic manifestations of heritable connective tissue disorders are well documented, the broader neurologic implications, particularly those related to migraine pathophysiology, remain underrecognized. Emerging evidence links hypermobility spectrum disorders (HSDs), including hypermobile Ehlers-Danlos syndrome (hEDS), to a higher prevalence of migraine and often an altered clinical presentation. We present a practical clinical update for neurologists, highlighting when and why to screen for HSDs in individuals with migraine and outlining treatment strategies that address the complex, multisystem needs of this population.

Hypermobility Spectrum Disorders
HSDs represent a group of clinically significant conditions characterized by symptomatic joint hypermobility, often accompanied by joint instability, soft tissue fragility, and chronic musculoskeletal pain. An HSD is diagnosed when an individual has symptomatic joint hypermobility but does not meet the criteria for hEDS or any other hereditary connective tissue disorder.¹ Despite the availability of standardized diagnostic tools, HSDs remain underrecognized in many clinical settings including neurology.

The diagnosis of hEDS is guided by the 2017 International Classification, which begins with an assessment of generalized joint hypermobility (GJH) using the Beighton scoring system. This tool evaluates hypermobility across 9 joints. Age-specific cutoff scores are used to determine whether GJH is present (≥6 for prepubertal children and adolescents, ≥5 for adults up to age 50 years, and ≥4 for adults age >50 years).² The components of the Beighton score are summarized in Table 1. To fulfill the diagnostic criteria for hEDS, individuals must demonstrate GJH; have additional systemic features, such as a positive family history or musculoskeletal complications; and exhibit no evidence of another heritable or acquired connective tissue disorder.² Individuals who exhibit symptomatic hypermobility without meeting all hEDS criteria are classified as having an HSD. The 2017 diagnostic criteria for hEDS are summarized in Table 2.

In addition to musculoskeletal complaints, individuals with HSDs often report systemic symptoms including fatigue, gastrointestinal dysmotility, genitourinary dysfunction, autonomic dysregulation, and chronic pain. These symptoms frequently overlap with migraine and other headache disorders, complicating both diagnosis and treatment.^1,2

Migraine and HSDs: Clinical Associations
Several studies have demonstrated a higher prevalence of migraine in individuals with HSDs compared with the general population. In a recent population-based study, Zloof et al³ reported migraine in 6.5% of individuals with HSDs vs 3.2% in matched controls, even after adjusting for confounding factors. In addition to increased prevalence, individuals with HSDs often exhibit a distinct migraine phenotype, characterized by earlier onset (mean age 12 vs 17 years in controls), greater headache frequency (often exceeding 10–15 days per month), and higher functional disability, as measured by validated tools such as the Migraine Disability Assessment or Headache Impact Test (HIT–6).⁴

Cervical spine pathology is also more prevalent in individuals with HSDs and may contribute to migraine chronification. Conditions such as cervical spondylosis, craniocervical instability, and ligamentous laxity may exacerbate pain through mechanical instability and increased nociceptive input from cervical structures.⁵ These biomechanical factors may contribute to the higher rates of refractory migraine observed in this population and often necessitate a modified diagnostic and treatment approach.

Why Screening for HSDs Matters in Clinical Practice
Recognizing HSDs in people with migraine can substantially influence treatment outcomes. In routine neurologic practice, people presenting with chronic or refractory migraine, particularly those with early onset, musculoskeletal complaints, or autonomic symptoms, should prompt consideration of an underlying connective tissue disorder. Failure to identify an HSD may lead to delayed diagnosis, ineffective treatment plans, and unnecessary medication trials.^1,2,6

Incorporating a structured screening tool such as the Beighton scoring system into the migraine evaluation allows clinicians to identify joint hypermobility as a potential contributor to treatment resistance. A positive Beighton score should prompt further clinical assessment for coexisting conditions common in HSDs including cervical spine instability, postural orthostatic tachycardia syndrome (POTS), and mast cell activation syndrome (MCAS), all of which may exacerbate migraine through biomechanical or inflammatory mechanisms.

Emerging data support a multidisciplinary approach to the treatment of comorbidities in HSD. Studies have shown that targeted treatment of cervical spine dysfunction, autonomic dysregulation, and sleep-disordered breathing significantly improves headache outcomes in people with HSDs.⁷ In one cohort, >50% of people with HSDs who underwent cervical medial branch blocks or radiofrequency ablation reported at least an 80% reduction in headache or neck pain symptoms.⁵ These findings underscore the value of a broader diagnostic lens in people with complex migraine presentations and support the integration of connective tissue assessment into routine headache evaluation.

Proposed Mechanisms Linking HSDs and Migraine
Several interrelated mechanisms have been proposed to explain the increased prevalence and distinct clinical features of migraine in individuals with HSDs. These include dysautonomia, central sensitization, cervical spine pathology, and connective tissue–related immune and vascular dysregulation.

Dysautonomia, particularly POTS, is strongly associated with both HSDs and migraine. Studies have shown that up to 78% of individuals with an HSD exhibit signs of autonomic dysfunction, compared with ~10% of healthy controls.⁸ Aberrant sympathetic activity, excessive venous pooling, and impaired baroreflex sensitivity are believed to promote a hyperadrenergic state that contributes to migraine susceptibility and chronicity.⁹

Central sensitization is another key contributor. Repeated nociceptive input from unstable joints, ligamentous laxity, and soft tissue strain may increase excitability within the central nervous system, resulting in lowered pain thresholds and amplified pain perception. Quantitative sensory testing has demonstrated increased temporal summation and reduced pain thresholds in individuals with HSDs, mirroring changes seen in chronic migraine.¹⁰

Cervical spine pathology is particularly relevant to neurologists. Conditions such as cervical spondylosis, atlantoaxial instability, and myodural bridge dysfunction have been observed in individuals with hEDS and HSDs.¹¹ The myodural bridges are fibrous ligaments that connect the suboccipital musculature to the dura mater, anchoring the thecal sac to the bony spinal canal. Disruption or laxity of these structures may lead to increased mobility of the dura, resulting in abnormal traction forces on the brainstem, upper cervical spinal cord, and meningeal tissues.

A study by Klinge et al¹¹ used intraoperative ultrasound and tissue sampling to compare the upper cervical spinal cord anatomy of people with hEDS vs healthy controls, all undergoing decompression for Chiari malformation. The hEDS group showed significantly more collagen fibril damage within the myodural bridges, suggesting pathologic connective tissue laxity at the craniocervical junction.¹¹ This mechanical vulnerability may contribute to migraine chronification through repeated activation of the trigeminocervical complex: a key integrator of cervical and cranial nociceptive input.

Connective tissue abnormalities in HSDs may impair vascular tone, meningeal integrity, and immune regulation. Individuals with HSDs frequently exhibit features of MCAS, which can exacerbate migraine through the release of histamine, prostaglandins, and proinflammatory cytokines.¹² This proinflammatory state may promote neurogenic inflammation, sensitization of meningeal nociceptors, and increased vulnerability to migraine triggers. 

Management Strategies for Migraine in HSDs
Effective management of migraine in people with HSDs requires an individualized, multidisciplinary approach. In addition to standard migraine therapies, treatment must address underlying musculoskeletal instability, autonomic dysfunction, and central sensitization, which frequently contribute to headache chronicity and treatment resistance.

Cervical spine instability should be evaluated in people with neck pain, mechanical headache triggers, or evidence of occipital nerve involvement. Interventions may include cervical-targeted physical therapy, postural bracing, or interventional procedures such as medial branch blocks or radiofrequency ablation, which have shown benefit in select individuals with HSDs and refractory migraine pain.⁵ Physical therapy focused on joint stabilization, proprioceptive retraining, and cervical motor control has been shown to reduce musculoskeletal pain and improve function in people with connective tissue disorders.

Complementary and integrative therapies can play a supportive role, particularly in addressing autonomic imbalance and central sensitization. Modalities such as medical acupuncture, mindfulness-based stress reduction, and biofeedback have shown promise in improving pain modulation, reducing sympathetic overactivity, and enhancing self-regulation. These nonpharmacologic strategies may also reduce reliance on polypharmacy in complex cases.

Pharmacologic Considerations
Pharmacologic management in people with HSDs requires a cautious and tailored approach due to increased medication sensitivity, autonomic dysregulation, and multisystem comorbidities.

Agents such as tizanidine and baclofen may offer short-term relief for myofascial pain but can also exacerbate joint instability and hypotonia, particularly in people with substantial ligamentous laxity.¹³ These medications should be used judiciously and often in coordination with physical therapy targeting joint stabilization.

Common migraine preventives including tricyclic antidepressants, anticonvulsants, and serotonin and norepinephrine reuptake inhibitors should be used with caution in people with HSDs, as they may worsen dysautonomia, particularly in people with POTS.¹³ In contrast, agents with more favorable autonomic profiles such as calcitonin gene-related peptide monoclonal antibodies, calcitonin gene-related peptide receptor antagonists, and onabotulinumtoxinA, may be better tolerated and are often effective in people who are refractory to standard oral preventives.

Early administration of onabotulinumtoxinA has shown promise in people with HSDs and chronic migraine who are refractory to oral preventives. In a study of 55 participants with HSDs and chronic migraine, treatment with onabotulinumtoxinA reduced monthly headache days from 24.4 to 8.1—a 67% reduction. Headache severity scores also declined, but the response was more robust for headache frequency.¹⁴ In this population, injection protocols may need to be modified to minimize cervical stress, especially when targeting paraspinal or suboccipital musculature in people with suspected cervical instability.

Gastrointestinal dysmotility, including delayed gastric emptying, is common in HSDs and can impair the absorption of oral medications, contributing to inconsistent treatment responses. In such cases, nonoral formulations such as intranasal, subcutaneous, or intravenous options should be considered for acute migraine treatment. The use of prokinetic agents (eg, metoclopramide) may improve gastric transit and enhance the efficacy of oral medications.

People with suspected or confirmed MCAS may exhibit hypersensitivity reactions or histamine-mediated flares in response to certain medications. Drugs that promote mast cell degranulation such as opioids or certain NSAIDs should be avoided or used with caution. H₁ and H₂ receptor antagonists (eg, cetirizine, famotidine) may improve medication tolerability and reduce symptom burden in these individuals.

Given the high rate of polypharmacy in this population, routine medication reconciliation is essential. Neurologists should collaborate closely with other specialists, including rheumatologists, gastroenterologists, pain management specialists, and allergists/immunologists, to optimize safety and treatment efficacy in this complex population. The Figure outlines a structured clinical pathway to support screening and management of HSDs in people with migraine.

Figure. Clinical pathway outlining a stepwise approach for neurologists to identify, evaluate, and manage hypermobility spectrum disorders (HSDs) in people with chronic or refractory migraine, incorporating screening tools, comorbidity assessment, and targeted treatment strategies.
Abbreviations: GI, gastrointestinal; GJH, generalized joint hypermobility; hEDS, hypermobile Ehlers-Danlos syndrome; MCAS, mast cell activation syndrome; MSK, musculoskeletal; POTS, postural orthostatic tachycardia syndrome; PT, physical therapy; RFA, radiofrequency ablation; SNRI, serotonin-norepinephrine reuptake inhibitors; TCA, tricyclic antidepressants.

Conclusion
Routine screening for HSDs in people with migraine represents an underrecognized yet clinically valuable practice. For people with chronic or refractory migraine, particularly those with early onset, musculoskeletal symptoms, or autonomic complaints, consideration of HSDs may uncover a distinct migraine phenotype driven by mechanical, autonomic, or inflammatory mechanisms.

Identifying HSDs enables neurologists to implement more targeted, mechanism-based treatment strategies, addressing contributors such as cervical instability, dysautonomia, mast cell activation, and central sensitization. Incorporating hypermobility screening into the routine evaluation of complex headache offers a high-yield, low-cost intervention that can improve diagnostic precision and therapeutic outcomes.

Future research should focus on refining the clinical criteria and screening tools for use in neurology settings, elucidating the shared pathophysiologic pathways between HSDs and migraine, and evaluating the long-term impact of integrated, multidisciplinary care in this complex and often underserved population.