Venous Multiple Sclerosis Hypothesis | CCSVI

Multiple sclerosis patients examined with perfusion magnetic resonance (MR) imaging techniques have been found to have patterns of abnormal blood flow. These include prolonged mean transit time, a trend toward decreased cerebral blood flow in the area of plaques, and decreased cerebral blood flow and prolonged mean transit time within normal-appearing white matter. In-creased cerebral blood flow and volume and decreased mean transit time (compared with the baseline values before the relapse) were found to precede the development of plaques. In addition, susceptibility-weighted imaging utilizing deoxyhemoglobin as the contrast has revealed that venous blood in cerebral veins of multiple sclerosis patients is less deoxygenated compared with healthy controls. All these findings were traditionally interpreted as a sign of local flow disturbances mediated by inflammatory and neurodegenerative processes. However, recent findings of significant stenoses in the extracranial veins that drain the brain and spinal cord shed new light on these MR results. With the assumption that a majority, if not all, of multiple sclerosis patients exhibit such extracranial venous obstacles, the perfusion MR images of multiple sclerosis patients should be reinterpreted. Perhaps ongoing MR studies with respect to extracranial venous hemodynamics may decipher some of the unsolved puzzles related to this neurologic disease.

Background: Chronic cerebrospinal venous insufficiency (CCSVI) is characterized by stenoses of the internal jugular veins or the azygous vein, or both. It has been recently reported that this condition contributes to severe dis-regulation of the physiologic mechanisms of cerebral venous outflow in patients with multiple sclerosis (MS). Endovascular treatment (EVT) was demonstrated to be a safe and effective CCSVI treatment, but only in an unblinded clinical evaluation.

Methods: We designed an open-label, magnetic resonance imaging (MRI)-blinded, two-center, randomized, EVT intervention parallel-group, 12-month study (EVTMS) after an initial cross-sectional (CVIMS) study. CIVMS enrolled 16 relapsing-remitting MS patients (8 from Ferrara, Italy and 8 from Buffalo, NY). All 16 patients who completed the CVIMS study and presented severe Doppler venous hemodynamic (VH) anomalies accepted participation in the EVT intervention prospective study (EVTMS). Half of the cohort, the early intervention group (4 from Buffalo and 4 from Italy), was randomly selected to have the EVT procedure in Italy at 3 months, whereas 6 patients comprised the delayed control intervention group (late group) at 6 months; 2 patients were followed-up without any EVT. The EVT procedure consists of selective venography complemented by balloon dilatation when significant stenoses are detected. All patients will be prospectively evaluated at 3, 6, 9, and 12 months with ultrasound imaging, MRI, and clinical examinations.

Results: For the CVIMS cross-sectional study, mean age at baseline was 36.1 ± 7.3 years, mean disease duration was 7.5 ±1.9 years, and median Expanded Disability Status Scale (EDSS) was 2.5. The mean number of gadolinium-active lesions at baseline was 0.38 ± 1.5. The mean number of T2 lesions was 27.1 ± 10.5. Median of VH of CCSVI was 4 (range, 2-5). The six MS patients investigated and none of the HCs met the VH criteria for CCSVI (P < .0001). MS patients showed significantly lower net cerebrospinal fluid flow compared with the HC (P = 0.038), which was associated with the number of anomalous VH criteria present (r = 0.79, P < .001; Fig, A) and confirmed by the strong relationship with the venous hemodynamic insufficiency severity score (r = 0.77, P < .0007). Moreover, increases in the number of anomalous VH criteria present were negatively associated with lower whole brain volume (Spearman R = –0.5; P = 0.05; Fig B). The 1-year blinded EVTMS longitudinal study will be concluded next October and results analysis completed within the Fall.

Conclusions: CCSVI is associated with abnormal cerebrospinal fluid flow dynamics and decreased brain volume. Finally, the EVTMS study should provide valuable data on preliminary efficacy of EVT for CCSVI associated with MS.

Fig. A, Net cerebrospinal fluid (CSF) flow was lower in patients with multiple sclerosis and was associated with the number of venous hemodynamic (VH) criteria present. B, Increases in the number of anomalous VH criteria present were negatively associated with lower normalized brain volume.