Table 1 Inclusion and exclusion criteria for trial participants

(1) Age 18–65 years

(1) Patients who have previously undergone an extracranial venous angioplasty

(2) Patients who have received care for at least 2 years at the enrolling center

(2) Patients treated with natalizumab, fingolimod, cladribine or laquinimod within 3 months prior to screening

(3) MS defined according to McDonald’s criteria [40] with relapsing- remitting (RRMS) or secondary progressive (SPMS) course

(3) Patients treated with botulinum toxin within 3 months prior to screening

(4) At least one relapse in the 2 years before inclusion for RRMS

(4) Patients with implanted infusion pumps or neurostimulators within 3 months prior to screening

(5) CCSVI diagnosed by ECD according to the Zamboni criteria [12]

(5) Use of experimental drug or participation in a clinical trial within 3 months prior to screening

(6) EDSS from 2 to 5.5

(6) Contraindications to venography: documented thrombophilia, previous adverse reactions after administration of iodized contrast medium or presence of pathological conditions that could favor reactions to the introduction of contrast medium, that is, severe renal insufficiency, hepatic insufficiency, cardiac insufficiency, Walderstrom’s paraproteinemia or multiple myeloma

(7) Disease duration from diagnosis to study inclusion ≤10 years for RRMS and ≤15 years for SPMS

7) Contraindications to MRI and/or its contrast medium

(8) Stable neurological condition without relapse for at least 30 days

(8) Hemoglobin value ≤9 g/dl, leukocytes >11,000/μl, thrombocytes <70.000/μl

(9) Patient not undergoing therapy, or undergoing disease- modifying therapies without modification for at least 6 months

(9) Prothrombin time, activated partial thromboplastin time, creatinine values outside laboratory reference ranges

(10) Written informed consent.

(10) Monoclonal gammopathy or hypergammaglobulinemia (>21%)

(11) History of congenital or ischemic cardiopathy, arrhythmias, conditions that can cause changes in motor and/or vision and/or bladder and/or cognitive functions

(12) Current or previous radiotherapy performed for any reason

(13) Female subjects pregnant or lactating

(14) Patients unable to comply with the follow-up