Hypermobile Ehlers-Danlos Syndrome <-> Migraine

Comorbidity UNKNOWN CANDIDATE

Migraine is one of the most commonly reported comorbidities of hEDS and of the associated dysautonomia/POTS and mast cell activation syndrome (MCAS) spectrum. A large propensity-matched cohort found migraine in 19.7% of EDS patients versus matched controls (OR 2.5), and a dedicated review describes migraine as bidirectionally comorbid with POTS, hypermobility spectrum disorders, and MCAS. Directionality is UNKNOWN. No ICEES KG signal exists for this pair: hEDS (MONDO:0007523) is not a node in the ICEES KG snapshot at all (confirmed while curating the hEDS-POTS comorbidity entry).

Disease A

Hypermobile Ehlers-Danlos Syndrome

Slug:Hypermobile_Ehlers-Danlos_Syndrome

Disease B

Migraine

Slug:Migraine

Causal Mechanism Graphs

Hypermobile Ehlers-Danlos Syndrome

graph LR
    Sleep_disturbance["Sleep disturbance"]
    Joint_instability_and_recurrent_soft_tissue_injury["Joint instability and recurrent soft-tissue injury"]
    Candidate_extracellular_matrix_remodeling_abnormalities["Candidate extracellular matrix remodeling abnormalities"]
    Myofibroblast_like_fibroblast_transition["Myofibroblast-like fibroblast transition"]
    Chronic_pain["Chronic pain"]
    Arthralgia["Arthralgia"]
    Joint_dislocation["Joint dislocation"]
    Joint_hypermobility["Joint hypermobility"]

    Candidate_extracellular_matrix_remodeling_abnormalities --> Myofibroblast_like_fibroblast_transition
    Joint_instability_and_recurrent_soft_tissue_injury --> Joint_dislocation
    Joint_instability_and_recurrent_soft_tissue_injury --> Chronic_pain
    Joint_instability_and_recurrent_soft_tissue_injury --> Arthralgia
    Joint_hypermobility --> Joint_instability_and_recurrent_soft_tissue_injury
    Chronic_pain --> Sleep_disturbance

    style Sleep_disturbance fill:#fef3c7
    style Joint_instability_and_recurrent_soft_tissue_injury fill:#dbeafe
    style Candidate_extracellular_matrix_remodeling_abnormalities fill:#dbeafe
    style Myofibroblast_like_fibroblast_transition fill:#dbeafe
    style Chronic_pain fill:#fef3c7
    style Arthralgia fill:#fef3c7
    style Joint_dislocation fill:#fef3c7
    style Joint_hypermobility fill:#fef3c7

Migraine

graph LR
    Ditans_Lasmiditan["Ditans (Lasmiditan)"]
    CGRP_Pathway["CGRP Pathway"]
    Trigeminovascular_Activation["Trigeminovascular Activation"]
    Vestibulo_Thalamo_Cortical_Dysfunction["Vestibulo-Thalamo-Cortical Dysfunction"]
    Vestibular_CGRP_Signaling["Vestibular CGRP Signaling"]
    PACAP_Pathway["PACAP Pathway"]
    Vestibulo_Cerebellar_Integration_Failure_and_Compensation["Vestibulo-Cerebellar Integration Failure and Compensation"]
    Dietary_Triggers["Dietary Triggers"]
    Anti_PACAP_Ligand_Monoclonal_Antibody["Anti-PACAP Ligand Monoclonal Antibody"]
    Trigemino_Vestibular_Pathway["Trigemino-Vestibular Pathway"]
    Headache["Headache"]
    Vertigo["Vertigo"]
    Cortical_Spreading_Depression["Cortical Spreading Depression"]
    Central_Sensitization["Central Sensitization"]

    Cortical_Spreading_Depression --> Trigeminovascular_Activation
    Trigeminovascular_Activation --> PACAP_Pathway
    Trigeminovascular_Activation --> CGRP_Pathway
    Trigeminovascular_Activation --> Trigemino_Vestibular_Pathway
    CGRP_Pathway --> Central_Sensitization
    CGRP_Pathway --> Vestibular_CGRP_Signaling
    Trigemino_Vestibular_Pathway --> Vestibulo_Thalamo_Cortical_Dysfunction
    Vestibulo_Thalamo_Cortical_Dysfunction --> Vertigo
    Vestibulo_Cerebellar_Integration_Failure_and_Compensation --> Vertigo
    Vestibular_CGRP_Signaling --> Trigemino_Vestibular_Pathway
    PACAP_Pathway --> Central_Sensitization
    Dietary_Triggers --> Headache
    Ditans_Lasmiditan --> Trigeminovascular_Activation
    Anti_PACAP_Ligand_Monoclonal_Antibody --> PACAP_Pathway

    style Ditans_Lasmiditan fill:#fce7f3
    style CGRP_Pathway fill:#dbeafe
    style Trigeminovascular_Activation fill:#dbeafe
    style Vestibulo_Thalamo_Cortical_Dysfunction fill:#dbeafe
    style Vestibular_CGRP_Signaling fill:#dbeafe
    style PACAP_Pathway fill:#dbeafe
    style Vestibulo_Cerebellar_Integration_Failure_and_Compensation fill:#dbeafe
    style Dietary_Triggers fill:#dcfce7
    style Anti_PACAP_Ligand_Monoclonal_Antibody fill:#fce7f3
    style Trigemino_Vestibular_Pathway fill:#dbeafe
    style Headache fill:#fef3c7
    style Vertigo fill:#fef3c7
    style Cortical_Spreading_Depression fill:#dbeafe
    style Central_Sensitization fill:#dbeafe

Association Signals

Signal 1

Population:TriNetX research network, retrospective propensity-matched analysis (2005-2023), 59,128 matched pairs of EDS patients (excluding Marfan syndrome) versus controls.

Signal IDs: MONDO:0007523 dismech -> MONDO:0005277 dismech

Temporal: A before B: , B before A: , Same time:

PREVALENCE: 19.7

CI: -

FDR:

Migraine prevalence in the EDS cohort.

OR: 2.5

CI: 2.4 - 2.6

p: 0.001

FDR:

Odds ratio for migraine in EDS versus propensity-matched controls. Reported by the source as p < 0.001, an upper bound, not a point estimate.

PMID:41432355 (SUPPORT)

Source: HUMAN_CLINICAL

"Systemic comorbidities included postural orthostatic tachycardia syndrome (13.2%, OR 899.7, 95% CI 483.8-1673.0, p < 0.001), chronic pain (7.9%, OR 7.0, 95% CI 6.4-7.6, p < 0.001), migraines (19.7%, OR 2.5, 95% CI 2.4-2.6, p < 0.001) and fibromyalgia (9.5%, OR 1.7, 95% CI 1.6-1.8, p < 0.001)."

A large propensity-matched cohort quantifies elevated migraine prevalence and odds ratio in EDS patients.

Hypotheses

Hypothesis: migraine in hEDS shares pathophysiology with the broader dysautonomia/POTS and MCAS spectrum rather than arising independently -- autonomic dysregulation of cranial vascular tone and mast-cell-mediated neurogenic inflammation are both proposed contributors, on top of any direct connective-tissue effect on cranial/cervical vasculature and dural structures.

PMID:37847487 (SUPPORT, review synthesis)

Source: HUMAN_CLINICAL

"Migraine is one of the most common comorbidities of POTS, HSD, and MCAS; conversely, these conditions are also prevalent in patients with migraine, especially in those with multiple systemic symptoms, such as chronic dizziness, lightheadedness, orthostatic intolerance, joint pain, and allergic symptoms."

A dedicated review establishes migraine as bidirectionally comorbid with the dysautonomia/hypermobility/MCAS spectrum that hEDS sits within, rather than being an isolated, mechanistically unrelated comorbidity.

PMID:37847487 (SUPPORT, review synthesis)

Source: HUMAN_CLINICAL

"Numerous studies indicate a significant overlap and shared pathophysiology in migraine, dysautonomia, HSD, and MCAS."

States that the overlap reflects shared pathophysiology rather than coincidental co-occurrence.

Pathophysiology:

Autonomic and mast-cell-mediated cranial nociceptive sensitization: Proposed convergent mechanism: autonomic dysregulation of cranial vascular tone, combined with mast-cell-mediated neurogenic inflammation, sensitizes trigeminovascular nociceptive pathways, contributing to migraine in the context of hEDS-associated dysautonomia and MCAS.

Biological processes:

Raw YAML

Show YAML

name: com_Hypermobile_Ehlers-Danlos_Syndrome__Migraine
creation_date: '2026-09-18T02:40:05Z'
curation_status: CANDIDATE
notes: >-
  Migraine is one of the most commonly reported comorbidities of hEDS and of
  the associated dysautonomia/POTS and mast cell activation syndrome (MCAS)
  spectrum. A large propensity-matched cohort found migraine in 19.7% of EDS
  patients versus matched controls (OR 2.5), and a dedicated review describes
  migraine as bidirectionally comorbid with POTS, hypermobility spectrum
  disorders, and MCAS. Directionality is UNKNOWN. No ICEES KG signal exists
  for this pair: hEDS (MONDO:0007523) is not a node in the ICEES KG snapshot
  at all (confirmed while curating the hEDS-POTS comorbidity entry).

disease_a:
  slug: Hypermobile_Ehlers-Danlos_Syndrome
  preferred_term: Ehlers-Danlos syndrome, hypermobility type
  term:
    id: MONDO:0007523
    label: Ehlers-Danlos syndrome, hypermobility type

disease_b:
  slug: Migraine
  preferred_term: migraine disorder
  term:
    id: MONDO:0005277
    label: migraine disorder

directionality: UNKNOWN

hypotheses:
- description: >-
    Hypothesis: migraine in hEDS shares pathophysiology with the broader
    dysautonomia/POTS and MCAS spectrum rather than arising independently --
    autonomic dysregulation of cranial vascular tone and mast-cell-mediated
    neurogenic inflammation are both proposed contributors, on top of any
    direct connective-tissue effect on cranial/cervical vasculature and dural
    structures.
  evidence:
  - reference: PMID:37847487
    reference_title: "Dysautonomia, Hypermobility Spectrum Disorders and Mast Cell Activation Syndrome as Migraine Comorbidities."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Migraine is one of the most common comorbidities of POTS, HSD, and MCAS; conversely, these conditions are also prevalent in patients with migraine, especially in those with multiple systemic symptoms, such as chronic dizziness, lightheadedness, orthostatic intolerance, joint pain, and allergic symptoms."
    explanation: >-
      A dedicated review establishes migraine as bidirectionally comorbid
      with the dysautonomia/hypermobility/MCAS spectrum that hEDS sits
      within, rather than being an isolated, mechanistically unrelated
      comorbidity.
  - reference: PMID:37847487
    reference_title: "Dysautonomia, Hypermobility Spectrum Disorders and Mast Cell Activation Syndrome as Migraine Comorbidities."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Numerous studies indicate a significant overlap and shared pathophysiology in migraine, dysautonomia, HSD, and MCAS."
    explanation: States that the overlap reflects shared pathophysiology rather than coincidental co-occurrence.
  pathophysiology:
  - name: Autonomic and mast-cell-mediated cranial nociceptive sensitization
    description: >-
      Proposed convergent mechanism: autonomic dysregulation of cranial
      vascular tone, combined with mast-cell-mediated neurogenic
      inflammation, sensitizes trigeminovascular nociceptive pathways,
      contributing to migraine in the context of hEDS-associated
      dysautonomia and MCAS.
    biological_processes:
    - preferred_term: sensory perception of pain
      term:
        id: GO:0019233
        label: sensory perception of pain

association_signals:
- source: LITERATURE
  method: LITERATURE_ASSOCIATION
  signal_disorder_a_id: MONDO:0007523
  signal_disorder_b_id: MONDO:0005277
  population: >-
    TriNetX research network, retrospective propensity-matched analysis
    (2005-2023), 59,128 matched pairs of EDS patients (excluding Marfan
    syndrome) versus controls.
  directionality: UNKNOWN
  statistics:
    metrics:
    - metric_type: PREVALENCE
      metric_value: 19.7
      notes: Migraine prevalence in the EDS cohort.
    - metric_type: OR
      metric_value: 2.5
      metric_ci_lower: 2.4
      metric_ci_upper: 2.6
      p_value: 0.001
      notes: Odds ratio for migraine in EDS versus propensity-matched controls. Reported by the source as p < 0.001, an upper bound, not a point estimate.
    evidence:
    - reference: PMID:41432355
      reference_title: "Comprehensive Risk Profile of Gastrointestinal and Extra Articular Comorbidities in Ehlers-Danlos Syndrome: A Propensity-Matched Analysis of 118,256 Individuals."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Systemic comorbidities included postural orthostatic tachycardia syndrome (13.2%, OR 899.7, 95% CI 483.8-1673.0, p < 0.001), chronic pain (7.9%, OR 7.0, 95% CI 6.4-7.6, p < 0.001), migraines (19.7%, OR 2.5, 95% CI 2.4-2.6, p < 0.001) and fibromyalgia (9.5%, OR 1.7, 95% CI 1.6-1.8, p < 0.001)."
      explanation: A large propensity-matched cohort quantifies elevated migraine prevalence and odds ratio in EDS patients.

Source:GitHub