{
  "cutoff": "2026-10-12",
  "note": "Selected publication milestones, not an exhaustive history or discovery priority claim.",
  "milestones": [
    {
      "pmid": "19060024",
      "year": "2009",
      "title": "Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis.",
      "doi": "10.1136/jnnp.2008.157164",
      "url": "https://pubmed.ncbi.nlm.nih.gov/19060024/",
      "interpretation": "Foundational case-control association proposes MS-specific venous abnormalities; PubMed issue year2009 follows online2008."
    },
    {
      "pmid": "19958985",
      "year": "2009",
      "title": "A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency.",
      "doi": "10.1016/j.jvs.2009.07.096",
      "url": "https://pubmed.ncbi.nlm.nih.gov/19958985/",
      "interpretation": "Open-label venoplasty reports pressure and selected RRMS changes, with high jugular restenosis."
    },
    {
      "pmid": "21803799",
      "year": "2011",
      "title": "Internal jugular thrombosis post venoplasty for chronic cerebrospinal venous insufficiency.",
      "doi": "10.1258/phleb.2011.011052",
      "url": "https://pubmed.ncbi.nlm.nih.gov/21803799/",
      "interpretation": "Objective balloon-only jugular thrombosis documents a possible procedural complication."
    },
    {
      "pmid": "24119384",
      "year": "2014",
      "title": "Prevalence of extracranial venous narrowing on catheter venography in people with multiple sclerosis, their siblings, and unrelated healthy controls: a blinded, case-control study.",
      "doi": "10.1016/S0140-6736(13)61747-X",
      "url": "https://pubmed.ncbi.nlm.nih.gov/24119384/",
      "interpretation": "Blinded sibling/control venography challenges disease-specific pathological narrowing; issue2014 follows online2013."
    },
    {
      "pmid": "24975855",
      "year": "2014",
      "title": "Prospective randomized trial of venous angioplasty in MS (PREMiSe).",
      "doi": "10.1212/WNL.0000000000000638",
      "url": "https://pubmed.ncbi.nlm.nih.gov/24975855/",
      "interpretation": "PREMiSe randomized pilot tests sham comparison and target engagement without demonstrated clinical efficacy."
    },
    {
      "pmid": "29150995",
      "year": "2018",
      "title": "Efficacy and Safety of Extracranial Vein Angioplasty in Multiple Sclerosis: A Randomized Clinical Trial.",
      "doi": "10.1001/jamaneurol.2017.3825",
      "url": "https://pubmed.ncbi.nlm.nih.gov/29150995/",
      "interpretation": "Brave Dreams finds no clinical functional benefit with incomplete flow correction; online2017, issue2018."
    },
    {
      "pmid": "30266886",
      "year": "2018",
      "title": "Safety and efficacy of venoplasty in MS: A randomized, double-blind, sham-controlled phase II trial.",
      "doi": "10.1212/WNL.0000000000006423",
      "url": "https://pubmed.ncbi.nlm.nih.gov/30266886/",
      "interpretation": "Independent Canadian sham trial finds no primary QOL or secondary clinical/MRI benefit."
    },
    {
      "pmid": "31735108",
      "year": "2020",
      "title": "Effects of Venous Angioplasty on Cerebral Lesions in Multiple Sclerosis: Expanded Analysis of the Brave Dreams Double-Blind, Sham-Controlled Randomized Trial.",
      "doi": "10.1177/1526602819890110",
      "url": "https://pubmed.ncbi.nlm.nih.gov/31735108/",
      "interpretation": "Expanded same-trial MRI analysis provides a positive lesion-free lead; online2019, issue2020."
    }
  ],
  "gaps": [
    "Validate a stable pathological-obstruction definition using independent blinded acquisition, pressure/flow and sibling/healthy controls.",
    "Separate procedural success, sustained target engagement and clinical mediation; low engagement is a limitation rather than a responder-defined rescue.",
    "Prospectively test the favorable-anatomy MRI lead against clinical outcomes and multiplicity control in an independent cohort.",
    "Clarify stage, collateral and inflammatory mechanisms without generalizing rat iron/gliosis to human demyelination.",
    "Establish objective long-term complication denominators by balloon/stent and operator setting with independent causal adjudication.",
    "Audit supplements and correction bodies unavailable in this bounded source examination; do not convert access failures to negative findings."
  ],
  "decisive_experiment": "If a scientifically and ethically justified study is contemplated, prospectively fix anatomical/pressure entry criteria and MS stage, verify sustained flow correction, randomize balloon venoplasty versus convincing sham with stable usual therapy and adequate clinical power, and test prespecified functional/relapse outcomes alongside MRI without conditioning on post-treatment responders."
}