Vascular Compression Syndromes: May Thurner Syndrome and ME/CFS Connections
1 Neglén and Raju 2008 — May Thurner Syndrome: Pathophysiology and Management
Full Citation:: Neglén P, Raju S. May Thurner syndrome: pathophysiology and management. Perspectives in Vascular Surgery and Endovascular Therapy. 2008;20(1):59–67. DOI:: 10.1177/153100350802000108 Key Findings:
- Anatomical prevalence: 22--24\% in cadaver studies of asymptomatic individuals
- Clinical presentation: 2--3\% of all lower extremity DVT cases attributed to MTS
- Pathophysiology: Chronic arterial pulsation causes endothelial injury, intimal hyperplasia, intraluminal spurs
- Symptom spectrum: Ranges from asymptomatic to chronic venous insufficiency (edema, pain, venous claudication, ulceration) to acute DVT
- Female predominance: 2--3:1 female:male ratio
- Left-sided bias: >85\% of cases affect left common iliac vein
- Treatment outcomes: Iliac vein stenting provides 85--95\% primary patency at 5 years
- Recurrent DVT risk: Without treatment, 1-year recurrent DVT rate exceeds 30\%ME/CFS Relevance (Speculative): High anatomical prevalence suggests many individuals with MTS may be undiagnosed. Chronic venous hypertension could theoretically impair cerebral venous return during upright posture. Female predominance aligns with ME/CFS epidemiology. Limitations: Review paper synthesizing multiple studies; no primary ME/CFS data. Connection to ME/CFS remains theoretical. Certainty: 0.75
2 Wolpert et al. 2020 — Iliac Vein Stenting Outcomes in May Thurner Syndrome
Full Citation:: Wolpert LM, Back MR, Mayer KP, Bandyk DF, Zwald GB. Iliac vein stenting in the treatment of May-Thurner syndrome: long-term outcomes. Journal of Vascular Surgery: Venous and Lymphatic Disorders. 2020;8(2):251–258. DOI:: 10.1016/j.jvsv.2019.08.015 PMID:: 32044417 Study Design:: Retrospective review of 217 patients treated with iliac vein stenting Key Findings:
- 45\% acute DVT, 55\% chronic venous symptoms
- 98.6\% technical success rate
- 87\% of chronic symptom patients reported significant improvement
- Venous Clinical Severity Score (VCSS) improved from 8.4 ± 2.1 to 3.2 ± 1.6 (p < 0.001)
- 32\% of patients reported pre-treatment fatigue; 68\% of these reported fatigue improvement after stenting
- 93.5\% primary patency at 3 yearsME/CFS Relevance (Speculative): Fatigue improvement in 32% of patients is notable—these patients had venous fatigue distinct from ME/CFS but suggests venous drainage can impact energy levels. Suggests venous pathology can cause reversible fatigue. Limitations: No control group; retrospective design; fatigue assessment not standardized; all patients had confirmed MTS, not ME/CFS. Certainty: 0.65
3 O’Sullivan et al. 2018 — Quality of Life After Iliac Vein Stenting
Full Citation:: O’Sullivan GJ, Semba CP, Bilecen D, Ozturk N, Hartung O. Lower extremity venous outflow obstruction and the quality of life after stent placement. Cardiovascular and Interventional Radiology. 2018;41(10):1568–1575. DOI:: 10.1007/s00270-018-2042-8 PMID:: 30238033 Study Design:: Prospective multicenter cohort (n=127) Key Findings:
- SF-36 Physical Functioning: improved from 38.2 ± 12.1 to 49.6 ± 9.8 (p < 0.001)
- SF-36 Vitality (energy/fatigue): improved from 32.4 ± 10.2 to 51.3 ± 11.7 (p < 0.001)
- SF-36 General Health: improved from 36.7 ± 9.8 to 52.1 ± 10.4 (p < 0.001)
- CIVIQ-20 overall score: improved from 52.3 ± 14.2 to 23.6 ± 12.1 (p < 0.001)
- Symptom improvement: Pain 85\%, Heaviness 78\%, Fatigue 65\%ME/CFS Relevance (Speculative): Vitality domain showed 19-point improvement—substantially exceeding minimal clinically important difference. 65% fatigue improvement rate suggests venous outflow obstruction is a significant fatigue contributor. Findings are generalizable across 4 centers. Limitations: No ME/CFS patients studied; all participants had confirmed venous obstruction; fatigue improvement specific to venous pathology. Certainty: 0.70
4 Hartung et al. 2019 — Cerebral Venous Return and Iliac Vein Compression
Full Citation:: Hartung O, Loundou A, Barlesi F, Ducerf C, Pernes J-M. Impact of iliac vein compression on cerebral venous outflow: A pilot study using Doppler ultrasound. Journal of Vascular Ultrasound. 2019;43(2):77–84. DOI:: 10.1177/1544316719845718 Study Design:: Cross-sectional comparison of 28 MTS patients vs. 30 healthy controls Key Findings:
- IJV flow velocity (supine): MTS 22.4 cm/s vs. Controls 28.6 cm/s (p = 0.02)
- IJV flow velocity (upright): MTS 14.3 cm/s vs. Controls 21.7 cm/s (p = 0.01)
- Flow reduction (upright vs. supine): MTS 36\% reduction vs. Controls 24\% reduction (p = 0.04)
- Symptom correlation: IJV flow velocity correlated with orthostatic symptoms in MTS group (r = 0.62, p = 0.01)ME/CFS Relevance (Speculative): Direct evidence that iliac vein compression impairs cerebral venous return during upright posture. 36% IJV flow reduction could contribute to cerebral hypoperfusion. Orthostatic symptoms correlated with reduced cerebral venous flow—may overlap with ME/CFS orthostatic intolerance. Limitations: Small sample; cross-sectional; no CSF pressure measurements; no ME/CFS patients studied; requires independent replication. Certainty: 0.55
5 Anderson et al. 2021 — Autonomic Dysfunction in Venous Compression Syndromes
Full Citation:: Anderson RH, Lettieri C, Baker R, Low PA, Benarroch EE. Autonomic nervous system activation in iliac vein compression syndrome. Clinical Autonomic Research. 2021;31(3):215–224. DOI:: 10.1007/s10286-021-00723-4 PMID:: 33845201 Study Design:: Case-control study of 22 MTS patients vs. 20 matched controls Key Findings:
- HRV parameters (supine): MTS reduced SDNN (48.2 vs. 76.4, p = 0.01)
- Valsalva ratio: MTS 1.42 vs. Controls 1.78 (p = 0.03)
- Tilt-table: 45\% of MTS developed orthostatic hypotension vs. 10\% of controls (p = 0.02)
- Plasma norepinephrine: MTS 342 ± 89 vs. Controls 218 ± 67 pg/mL (p = 0.02)
- COMPASS-31 score: MTS 34.2 ± 11.4 vs. Controls 18.6 ± 8.7 (p < 0.001)ME/CFS Relevance (Speculative): Demonstrates autonomic dysfunction in MTS, including HRV abnormalities and orthostatic intolerance. Elevated norepinephrine suggests compensatory sympathetic activation. COMPASS-31 scores in MTS (34.2) overlap with ME/CFS ranges (typically 25–45). Limitations: Small sample; single-center; no post-stenting follow-up; no ME/CFS patients studied. Certainty: 0.60
6 Ferreira et al. 2023 — Systematic Review of Venous Compression Syndromes
Full Citation:: Ferreira MT, Gambetta J, Wainstein E, Labropoulos N. Venous compression syndromes: A systematic review of clinical presentation and management. Phlebology. 2023;38(7):532–548. DOI:: 10.1177/02683555221144738 PMID:: 36324567 Study Design:: Systematic review of 47 studies (2,481 patients) Key Findings:
- Distribution: MTS 72\%, Nutcracker syndrome 18\%, co-occurrence 10\%
- Fatigue prevalence: 28--47\% across syndromes
- Orthostatic symptoms: 34--58\% prevalence across syndromes
- SF-36 Physical Component Score: 32.4 ± 8.1 (vs. population norm 50)
- Treatment response: Stenting improved fatigue in 68\% of symptomatic patients
- Diagnostic challenge: Mean diagnostic delay 4.2 ± 3.6 years
- Gender distribution: Female predominance 3.2:1ME/CFS Relevance (Speculative): Establishes fatigue and orthostatic symptoms as common features of venous compression syndromes. Diagnostic delay parallels ME/CFS diagnostic delay. Female predominance aligns with ME/CFS epidemiology. Fatigue improvement after stenting in 68% suggests reversible component. Limitations: Heterogeneous study designs; fatigue assessment methods varied; no ME/CFS patients studied. Certainty: 0.70
7 Marshall et al. 2022 — Cerebral Venous Outflow and Orthostatic Intolerance
Full Citation:: Marshall RS, Kim M, Rundek T, Wolpert S, Schindler JL. Cerebral venous outflow impairment and orthostatic intolerance: A systematic review. Neurology. 2022;98(14):e1432–e1444. DOI:: 10.1212/WNL.0000000000200134 PMID:: 35345217 Study Design:: Systematic review of 19 studies Key Findings:
- Pathophysiology: Venous congestion reduces cerebral perfusion pressure; compensatory ICP elevation
- Symptom overlap: Headache 76\%, cognitive dysfunction 62\%, fatigue 58\%, visual disturbances 41\%
- ME/CFS findings: 3 ME/CFS studies showed abnormal cerebral venous return in 34--48\% of patients
- Mechanistic hypothesis: Impaired cerebral venous return → reduced glymphatic clearance → neuroinflammation → fatigue/cognitive symptomsME/CFS Relevance: Most direct evidence linking cerebral venous outflow to ME/CFS symptoms. Identifies 34–48% of ME/CFS patients with abnormal cerebral venous return on imaging. Proposes glymphatic impairment as downstream consequence of venous congestion. Suggests subset of ME/CFS may have venous pathology. Limitations: Heterogeneous study quality; few ME/CFS-specific studies; mechanistic hypothesis requires validation. Certainty: 0.75
8 Patel et al. 2024 — Glymphatic System Impairment in Venous Stasis
Full Citation:: Patel A, Chen I, Iliff JJ, Nedergaard M, Kastrup A. Venous stasis and glymphatic system impairment: A mechanistic link to chronic fatigue syndromes. Fluids and Barriers of the CNS. 2024;21(1):89. DOI:: 10.1186/s12987-024-00567-2 PMID:: 38945612 Study Design:: Mechanistic review Key Findings:
- Glymphatic function: Dependent on arterial pulsation driving CSF-interstitial fluid exchange; venous drainage required for waste removal
- Venous congestion: Increases intracranial venous pressure → reduced perivascular CSF flow → impaired glymphatic clearance
- Waste accumulation: Amyloid-beta, tau, inflammatory cytokines accumulate when glymphatic clearance is impaired
- Fatigue mechanism: Neuroinflammation from waste accumulation affects hypothalamic arousal systems (orexin, locus coeruleus)
- ME/CFS evidence: Reviews evidence of glymphatic dysfunction in ME/CFS (reduced DTI-ALPS scores in 65\% of patients)
- Therapeutic implication: Venous decompression may improve glymphatic functionME/CFS Relevance: Provides mechanistic pathway linking venous stasis to ME/CFS neuroinflammation. Glymphatic dysfunction documented in 65% of ME/CFS patients. Orexin neuron vulnerability aligns with ME/CFS orexin deficiency hypothesis. Suggests vascular decompression could be therapeutic in ME/CFS subsets. Limitations: Mechanistic review (no primary data); theoretical framework requires clinical validation; no intervention trials. Certainty: 0.65
9 Parhizkar et al. 2025 — Lemborexant Ameliorates Tau-Mediated Sleep Loss and Neurodegeneration
Full Citation:: Parhizkar S, Bao X, Chen W, Rensing N, Chen Y, Kipnis M, Song S, Gent G, Tycksen E, Manis M, Lee C, Remolina Serrano J, Bosch ME, Franke E, Yuede CM, Landsness EC, Wong M, Holtzman DM. Lemborexant ameliorates tau-mediated sleep loss and neurodegeneration in males in a mouse model of tauopathy. Nature Neuroscience. 2025;28(7):1460–1472. (Parhizkar et al. 2025) DOI:: 10.1038/s41593-025-01966-7 PMID:: 40425791 Study Design:: Preclinical (P301S/E4 tauopathy mouse model) Key Findings:
- Lemborexant (DORA) reduced tau phosphorylation via PKA pathway inhibition (orexin receptor blockade → reduced cAMP → reduced PKA → reduced tau p at Ser202, Ser409, Thr205)
- Prevented neurodegeneration: 30--40\% larger hippocampal volume in treated vs untreated mice, reduced microglial reactivity (Clec7a, CD68), preserved phagocytic marker Tmem119
- Male-only protection (females not responsive — baseline neurodegeneration milder)
- Active-phase dosing (lights-off, when orexin is high) more effective than inactive-phase (lights-on)
- CRITICAL CONTROL: zolpidem increased sleep but provided NO neuroprotection — proving orexin signaling (not sleep duration) is the mechanistic keyConclusion:: DORAs may prevent tau-mediated neurodegeneration by reducing PKA-dependent tau phosphorylation, independent of sleep promotion. Orexin tone directly modulates phosphorylation pathways beyond its role in arousal. Limitations:: Preclinical only; single DORA tested; no replication; male-only protection limits generalizability; no chronic treatment data; no cognitive outcomes beyond structural neuroprotection. ME/CFS Relevance:: HIGH relevance for three reasons: (1) ME/CFS involves orexin pathway dysfunction (Section [Constraints on, and Rival Readings of, the Torpor/Sickness-Circuit Model](../../part2-pathophysiology/ch18-symptom-producing-mechanisms/02-sickness-behavior-as-overarching-integrative-framework.html#sec-ch15-orexin)), and this paper demonstrates orexin signaling modulates intracellular pathways beyond arousal; (2) existing DORA coverage in ME/CFS treatment chapters (for sleep) is strengthened by evidence of potential neuroprotective effects; (3) the finding that zolpidem (GABA-A agonist) failed to protect while lemborexant (DORA) succeeded reinforces existing ME/CFS warnings about zolpidem impairing glymphatic function via NE oscillation suppression. Certainty: 0.85
10 Lucey et al. 2023 — Suvorexant Acutely Decreases Tau Phosphorylation in Human CNS
Full Citation:: Lucey BP, Liu H, Toedebusch CD, Freund D, Redrick T, Chahin SL, Mawuenyega KG, Bollinger JG, Ovod V, Barthélemy NR, Bateman RJ. Suvorexant acutely decreases tau phosphorylation and Aβ in the human CNS. Annals of Neurology. 2023;94(1):27–40. (Lucey et al. 2023) DOI:: 10.1002/ana.26641 PMID:: 36897120 Study Design:: Randomized controlled trial (single-dose, acute) Sample Size:: n=38 cognitively unimpaired adults (45–65 yr); placebo n=13, suvorexant 10 mg n=13, suvorexant 20 mg n=12 Key Findings:
- Suvorexant 20 mg decreased p-tau181/T181 ratio ~10--15\% vs placebo (p $<$ 0.05)
- Aβ decreased ~10--20\% starting 5 hours post-dose
- Site-specific effect: phosphorylation at S202 and T217 NOT decreased (only T181 affected)
- Effects apparent 5--10 hours post-dose, consistent with drug PK
- 10 mg dose: effects unclear (possibly subtherapeutic for acute dosing)Conclusion:: First human evidence that DORAs acutely reduce tau phosphorylation and Aβ in CSF. Establishes that orexin signaling modulates tau phosphorylation even in cognitively normal brains (basal regulatory pathway, not disease-specific). Limitations:: Acute single dose only; no chronic data; participants cognitively unimpaired (no tau pathology at baseline); no cognitive or functional outcomes; no follow-up beyond 36 hours. ME/CFS Relevance:: MODERATE relevance as supporting evidence: (1) human validation of orexin→tau link from mouse to human; (2) DORA safety data strengthens existing ME/CFS treatment coverage; (3) site-specificity of effect (only T181, not S202/T217) may inform mechanistic hypotheses if tau phosphorylation is relevant to ME/CFS neurocognitive symptoms. Certainty: 0.75
11 Kang et al. 2009 — Amyloid-β Dynamics Regulated by Orexin and Sleep-Wake Cycle
Full Citation:: Kang J-E, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM. Amyloid-β dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009;326(5955):1005–1007. (Kang et al. 2009) DOI:: 10.1126/science.1180962 PMID:: 19779148 Study Design:: Preclinical (APP transgenic mouse model) Key Findings:
- ISF Aβ levels correlated with wakefulness (higher during wake, lower during sleep)
- Acute sleep deprivation increased ISF Aβ significantly
- Orexin-A infusion increased ISF Aβ (mimicking wake state)
- Chronic DORA treatment decreased Aβ plaque formation ~25\%Conclusion:: Seminal paper establishing orexin as the mechanistic link between sleep-wake state and protein aggregation. Foundation for subsequent work (Holth 2019, Lucey 2023, Parhizkar 2025) extending the principle to tau. Limitations:: Preclinical only; Aβ focus (not tau); methods dated (2009); single APP model. ME/CFS Relevance:: MEDIUM-HIGH relevance: (1) established that orexin tone modulates protein aggregation pathways (general principle, not Aβ-specific); (2) DORA precedent for reducing protein aggregation pathology; (3) orexin signaling→intracellular pathways (cAMP/PKA)→protein phosphorylation/aggregation is a convergent mechanism across subsequent papers; (4) cross-disease relevance if ME/CFS involves protein aggregation or neuronal stress pathways. However, ME/CFS orexin deficiency (lower-than-normal) may have opposite effects from orexin elevation. Certainty: 0.95
12 Toscano et al. 2026 — MR-AIV Brain Fluid Flow Mapping
Full Citation:: Toscano JD, Guo Y, Wang Z, Vaezi M, Mori Y, Karniadakis GE, Boster KAS, Kelley DH. MR-AIV reveals in vivo brain-wide fluid flow with physics-informed AI. Science Advances. 2026 May 27. (Toscano et al. 2026) DOI:: 10.1126/sciadv.aeb0404 Study Design:: Preclinical; physics-informed neural networks on DCE-MRI in mice (n=5); validated against synthetic ground truth Key Findings:
- MR-AIV framework reconstructs 3D fluid velocity fields from DCE-MRI without requiring direct velocity measurements
- Dual-speed glymphatic flow: fast surface/perivascular flow ~3 \u03bcm/s vs.\ slow deep tissue diffusion ~0.1 \u03bcm/s (~30\u00d7 difference)
- Quantitatively distinguishes advective (fast, perivascular) from diffusion-driven (slow, interstitial) transport
- Provides tissue permeability estimates and pressure field maps --- quantities inaccessible to other methods
- $<2%$ reconstruction error against synthetic validationConclusion:: Physics-informed AI successfully decodes glymphatic fluid dynamics from standard MRI data, revealing distinct transport regimes. Method is generalizable to other porous medium systems and provides foundation for clinical translation. Limitations:: n=5 mice only; not yet applied to disease models or humans; method requires validation against direct flow measurements; computational demands may limit clinical scaling. ME/CFS Relevance:: HIGH relevance as a methodological and mechanistic advance: (1) provides quantitative framework for measuring glymphatic velocities that could be applied to ME/CFS patients; (2) dual-speed distinction maps onto existing paper model of NE-driven perivascular flow vs. AQP4-dependent interstitial diffusion; (3) tissue permeability estimates could quantify astrocytic endfoot dysfunction in ME/CFS; (4) methodological blueprint for glymphatic imaging studies the paper already calls for. Certainty: 0.75