CCSVI -- A New Phrenology?
CCSVI -- A New Phrenology?
Where does the evidence stand on CCSVI as a cause of MS?
In 2009, Paolo Zamboni, MD, a vascular surgeon, provided the first description of chronic cerebrospinal venous insufficiency (CCSVI) in a study of 65 patients with multiple sclerosis (MS) and 235 controls. Dr. Zamboni observed that CCSVI existed in 100% of those with MS, but none of the controls. Subsequent exploration of this controversial concept has provoked heated debate and consumed enormous resources of funding, research, and time.
Dr. Zamboni described 5 critical venous flow anomalies detectable by transcranial and extracranial color Doppler that could determine the existence of CCSVI.
In Dr. Zamboni's study, the presence of any of the 5 criteria was significantly more likely in patients with MS than in controls (P < .0001). None of the control patients had more than 1 of the abnormal parameters, but all of the patients with MS had at least 2 of the parameters. Venography was performed in the 65 patients with MS and revealed unilateral or bilateral stenosis of the jugular veins (91%) and abnormalities of the azygous vein (86%). Findings on venography included agenesis, annulus, atresia, closed stenosis, membranous obstruction, septum and twisting. Venography identified 4 principal patterns of CCSVI that had different types of obstruction and venous flow. The patterns correlated with the type of MS.
There was no difference in the number of extracranial venous stenoses in patients with relapsing remitting MS treated with immunosuppressant therapy (N = 37) vs those not treated with immunosuppressant drugs (N = 18). None of the control patients without MS who were scheduled for venography for other reasons had stenosis in the azygous, internal jugular, or lumbar venous territories.
Methodologic problems with the original study include a heterogeneous study group. The 65 subjects with MS included 35 with relapsing-remitting MS, 20 with secondary progressive MS, and 10 with primary progressive MS, resulting in small numbers of each type of MS. In addition, full data for each patient regarding each of the 5 venous flow parameters was not presented, the 5 parameters were not validated, and venography procedures were not blinded.
Until Dr. Zamboni's provocative paper, the study of venous function in the central nervous system had been relatively neglected. However, the possibility that intravascular stasis caused by chronic venous obstruction could lead to pericapillary iron deposition, subsequent tissue injury, and an autoimmune response resulting in MS represented an intriguing hypothesis. MS is characterized by perivenous white matter lesions, supporting the possibility of a venous etiology. Dr. Zamboni's work sparked interest in the concept of "vascular immunology" and revived interest in long-forgotten papers that suggested a link between MS and vascular pathology.
Dr. Zamboni immediately followed this study with an open-label therapeutic study of transluminal angioplasty of the stenoses identified in the same 65 patients. All of the patients survived with minimal complications. Venous pressures were similar in stenotic or normal vessels, but after treatment, venous pressures were significantly lower (P < .0001). However, restenosis in the internal jugular vein was 47% at 18 months, 16 times higher than restenosis in the azygous vein. Significantly more patients were relapse free (50%) compared with the year prior to the procedure (27%; P < .0014), but the annualized relapse rate did not change. On MRI, the number of active gadolinium-enhanced lesions decreased from 50% to 12% (P < .001). Mental and physical quality of life improved significantly in patients with relapsing remitting MS. All of the clinical and radiologic assessments were unblinded, and there was no placebo or sham-treated MS control group.
Question
Where does the evidence stand on CCSVI as a cause of MS?
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Response from Andrew N. Wilner, MD Neurohospitalist, Department of Neurology, Lawrence and Memorial Hospital, New London, Connecticut |
What is CCSVI?
In 2009, Paolo Zamboni, MD, a vascular surgeon, provided the first description of chronic cerebrospinal venous insufficiency (CCSVI) in a study of 65 patients with multiple sclerosis (MS) and 235 controls. Dr. Zamboni observed that CCSVI existed in 100% of those with MS, but none of the controls. Subsequent exploration of this controversial concept has provoked heated debate and consumed enormous resources of funding, research, and time.
The Five Criteria of CCSVI
Dr. Zamboni described 5 critical venous flow anomalies detectable by transcranial and extracranial color Doppler that could determine the existence of CCSVI.
Reflux in the internal jugular veins and/or vertebral veins in sitting and supine posture;
Reflux in the deep cerebral veins;
High-resolution B-mode evidence of proximal internal jugular vein stenosis;
Flow in the internal jugular veins and/or vertebral veins that is not detectable on Doppler; and
Reverted postural control of the main cerebral venous outflow pathways.
In Dr. Zamboni's study, the presence of any of the 5 criteria was significantly more likely in patients with MS than in controls (P < .0001). None of the control patients had more than 1 of the abnormal parameters, but all of the patients with MS had at least 2 of the parameters. Venography was performed in the 65 patients with MS and revealed unilateral or bilateral stenosis of the jugular veins (91%) and abnormalities of the azygous vein (86%). Findings on venography included agenesis, annulus, atresia, closed stenosis, membranous obstruction, septum and twisting. Venography identified 4 principal patterns of CCSVI that had different types of obstruction and venous flow. The patterns correlated with the type of MS.
There was no difference in the number of extracranial venous stenoses in patients with relapsing remitting MS treated with immunosuppressant therapy (N = 37) vs those not treated with immunosuppressant drugs (N = 18). None of the control patients without MS who were scheduled for venography for other reasons had stenosis in the azygous, internal jugular, or lumbar venous territories.
Limitations of Methodology
Methodologic problems with the original study include a heterogeneous study group. The 65 subjects with MS included 35 with relapsing-remitting MS, 20 with secondary progressive MS, and 10 with primary progressive MS, resulting in small numbers of each type of MS. In addition, full data for each patient regarding each of the 5 venous flow parameters was not presented, the 5 parameters were not validated, and venography procedures were not blinded.
Importance of Venous Flow
Until Dr. Zamboni's provocative paper, the study of venous function in the central nervous system had been relatively neglected. However, the possibility that intravascular stasis caused by chronic venous obstruction could lead to pericapillary iron deposition, subsequent tissue injury, and an autoimmune response resulting in MS represented an intriguing hypothesis. MS is characterized by perivenous white matter lesions, supporting the possibility of a venous etiology. Dr. Zamboni's work sparked interest in the concept of "vascular immunology" and revived interest in long-forgotten papers that suggested a link between MS and vascular pathology.
Dr. Zamboni immediately followed this study with an open-label therapeutic study of transluminal angioplasty of the stenoses identified in the same 65 patients. All of the patients survived with minimal complications. Venous pressures were similar in stenotic or normal vessels, but after treatment, venous pressures were significantly lower (P < .0001). However, restenosis in the internal jugular vein was 47% at 18 months, 16 times higher than restenosis in the azygous vein. Significantly more patients were relapse free (50%) compared with the year prior to the procedure (27%; P < .0014), but the annualized relapse rate did not change. On MRI, the number of active gadolinium-enhanced lesions decreased from 50% to 12% (P < .001). Mental and physical quality of life improved significantly in patients with relapsing remitting MS. All of the clinical and radiologic assessments were unblinded, and there was no placebo or sham-treated MS control group.
