Roberto Galeotti

Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis

Background: The extracranial venous outflow routes in clinically defined multiple sclerosis (CDMS) have not previously been investigated. Methods: Sixty-five patients affected by CDMS, and 235 controls composed, respectively, of healthy subjects, healthy subjects older than CDMS patients, patients affected by other neurological diseases and older controls not affected by neurological diseases but scheduled for venography (HAV-C) blindly underwent a combined transcranial and extracranial colour-Doppler high-resolution examination (TCCS-ECD) aimed at detecting at least two of five parameters of anomalous venous outflow. According to the TCCS-ECD screening, patients and HAV-C further underwent selective venography of the azygous and jugular venous system with venous pressure measurement. Results: CDMS and TCCS-ECD venous outflow anomalies were dramatically associated (OR 43, 95% CI 29 to 65, p<0.0001). Subsequently, venography demonstrated in CDMS, and not in controls, the presence of multiple severe extracranial stenosis, affecting the principal cerebrospinal venous segments; this provides a picture of chronic cerebrospinal venous insufficiency (CCSVI) with four different patterns of distribution of stenosis and substitute circle. Moreover, relapsing-remitting and secondary progressive courses were associated with CCSVI patterns significantly different from those of primary progressive (p<0.0001). Finally, the pressure gradient measured across the venous stenosies was slightly but significantly higher. Conclusion: CDMS is strongly associated with CCSVI, a scenario that has not previously been described, characterised by abnormal venous haemodynamics determined by extracranial multiple venous strictures of unknown origin. The location of venous obstructions plays a key role in determining the clinical course of the disease.

A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency

OBJECTIVE Chronic cerebrospinal venous insufficiency (CCSVI) is characterized by combined stenoses of the principal pathways of extracranial venous drainage, including the internal jugular veins (IJVs) and the azygous (AZY) vein, with development of collateral circles and insufficient drainage shown by increased mean transit time in cerebral magnetic resonance (MR) perfusion studies. CCSVI is strongly associated with multiple sclerosis (MS). This study evaluated the safety of CCSVI endovascular treatment and its influence on the clinical outcome of the associated MS. METHODS Sixty-five consecutive patients with CCSVI, subdivided by MS clinical course into 35 with relapsing remitting (RR), 20 with secondary progressive (SP), and 10 with primary progressive (PP) MS, underwent percutaneous transluminal angioplasty (PTA). Mean follow-up was 18 months. Vascular outcome measures were postoperative complications, venous pressure, and patency rate. Neurologic outcome measures were cognitive and motor function assessment, rate of MS relapse, rate of MR active positive-enhanced gadolinium MS lesions (Gad+), and quality of life (QOL) MS questionnaire. RESULTS Outpatient endovascular treatment of CCSVI was feasible, with a minor and negligible complication rate. Postoperative venous pressure was significantly lower in the IJVs and AZY (P < .001). The risk of restenosis was higher in the IJVs compared with the AZY (patency rate: IJV, 53%; AZY, 96%; odds ratio, 16; 95% confidence interval, 3.5-72.5; P < .0001). CCSVI endovascular treatment significantly improved MS clinical outcome measures, especially in the RR group: the rate of relapse-free patients changed from 27% to 50% postoperatively (P < .001) and of MR Gad+ lesions from 50% to 12% (P < .0001). The Multiple Sclerosis Functional Composite at 1 year improved significantly in RR patients (P < .008) but not in PP or SP. Physical QOL improved significantly in RR (P < .01) and in PP patients (P < .03), with a positive trend in SP (P < .08). Mental QOL showed significant improvement in RR (P < .003) and in PP (P < .01), but not in SP. CONCLUSIONS PTA of venous strictures in patients with CCSVI is safe, and especially in patients with RR, the clinical course positively influenced clinical and QOL parameters of the associated MS compared with the preoperative assessment. Restenosis rates are elevated in the IJVs but very promising in the AZY, suggesting the need to improve endovascular techniques in the former. The results of this pilot study warrant a subsequent randomized control study.

The value of cerebral Doppler venous haemodynamics in the assessment of multiple sclerosis

Iron stores in the white and deep grey matter in course of multiple sclerosis (MS) have never been explained and could be related to abnormalities in venous drainage, but this possibility has never before been investigated. From an initial cohort of 320 subjects, after application of exclusion criteria, we selected 109 patients affected by MS, and 177 controls respectively composed by age- and sex-matched, healthy aged, and patients affected by other neurological diseases. They blindly underwent transcranial and extracranial Color-Doppler sonographic examination (TCCS-ECD), aimed at investigating five parameters related to normal cerebral venous outflow haemodynamics. Overall we analyzed 1430 TCSS-ECD parameters. In controls we found 861 normal parameters of cerebral venous return vs. 24 anomalous, whereas in MS 288 parameters were normal and 257 anomalous, respectively. Consequently, each of the considered Doppler haemodynamic parameters, when compared to revised McDonald criteria as a gold standard of MS diagnosis, showed separately a highly significant sensitivity and a noteworthy specificity. However, the detection >or=2 parameters in the same subject, never observed in controls, perfectly overlapped the diagnosis of MS (value, 95%CI: sensitivity 100%, 97-100; specificity 100%, 98-100; positive predictive value 100%, 97-100, negative predictive value 100%, 98-100; p<0.0001). Moreover, this study demonstrates a significant impairment of cerebral venous drainage in patients affected by MS, a mechanism potentially related to increased iron stores.

Intracranial Venous Haemodynamics in Multiple Sclerosis

In multiple sclerosis (MS) plaques are known to be venocentric; in addition, MS lesions and peripheral venous disorders share a number of key features. To date, however, despite the anatomical relationship between MS lesions and the venous system, no information on the intracranial venous haemodynamics of MS is available. Eighty-nine consecutive MS patients (58 relapsing-remitting, 31 secondary progressive) matched with 60 controls underwent transcranial color-coded duplex sonography (TCCS). We assessed, in supine as well as in sitting positions, the direction of flow at the activation of the thoracic pump in the deep middle cerebral veins (dMCVs), and in the transverse sinus (TS). In the dMCVs, we also measured peak systolic velocity (PSV), peak diastolic velocity (PDV), as well as the resistance index (RI). Reflux/bidirectional flow rate was significantly higher in the MS population determining also significant differences in PDV, characterized by negative values (16.2+/-1 cm/sec in controls vs. -1.3 +/-2.6 cm/sec in MS, respectively, p<0.0001). Consequently, RI was dramatically increased in the MS group, affecting impedance of cerebral venous drainage (0.48+/-0.04 in controls vs. 1.1 +/-0.08 in MS, respectively p<0.0001). Therefore, the detection of reflux directed toward the subcortical grey matter was significantly associated to highest disability scores (p < 0.0001). Our study of MS patients demonstrated significant haemodynamic alterations detected in veins anatomically related to plaque disposition. Our findings should contribute towards understanding the role of altered venous flow and tissue drainage in the MS inflammatory chain, as well as in the neurodegenerative process.

Venous Collateral Circulation of the Extracranial Cerebrospinal Outflow Routes

A new nosologic vascular pattern that is defined by chronic cerebrospinal venous insufficiency (CCSVI) has been strongly associated with multiple sclerosis. The picture is characterized by significant obstacles of the main extracranial cerebrospinal veins, the jugular and the azygous system, and by the opening of substitute circles. The significance of collateral circle is still neglected. To the contrary, substitute circles are alternative pathways or vicarious venous shunts, which permit the drainage and prevent intracranial hypertension. In accordance with the pattern of obstruction, even the intracranial and the intrarachidian veins can also become substitute circles; they permit redirection of the deviated flow, piping the blood toward available venous segments outside the central nervous system. We review the complex gross and radiological anatomy of collateral circulation found activated by the means of EchoColor-Doppler and selective venography in the event of CCSVI, focusing particularly on the suboccipital cavernous sinus (SCS), the condylar venous system, the pterygoid plexus, the thyroid veins, and the emiazygous-lumbar venous anastomosis with the left renal vein.

The chronic cerebrospinal venous insufficiency syndrome

Chronic cerebrospinal venous insufficiency (CCSVI) is a syndrome characterized by stenosies of the internal jugular and/or azygous veins (IJVs-AZ) with opening of collaterals and insufficient drainage proved by reduced cerebral blood flow and increased mean transit time in cerebral MRI perfusional study. The present review is aimed to give a comprehensive overview of the actual status of the art of the diagnosis and treatment of this condition. As far as the origin of venous narrowing is concerned, phlebographic studies of the IJVs and AZ systems demonstrated that venous stenoses were likely to be truncular venous malformations; mostly, they are intraluminal defects such as malformed valve, septa webs. CCSVI condition has been found to be strongly associated with multiple sclerosis (MS), a disabling neurodegenerative and demyelinating disease considered autoimmune in nature. In several epidemiological observations performed at different latitudes on patients with different genetic backgrounds, the prevalence of CCSVI in MS ranges from 56% to 100%. To the contrary, by using venous MR and/or different Doppler protocols, CCSVI was not detected with the same prevalence. Two pilot studies demonstrated the safety and feasibility in Day Surgery of the endovascular treatment of CCSVI by means of balloon angioplasty (PTA). It determines a significant reduction of postoperative venous pressure. Restenosis rate was found out elevated in the IJVs, but negligible in the AZ. However, PTA seems to positively influence clinical and QoL parameters of the associated MS and warrants further randomized control trials.

Venous Angioplasty in Patients with Multiple Sclerosis: Results of a Pilot Study

OBJECTIVES Chronic cerebrospinal venous insufficiency (CCSVI) is associated with multiple sclerosis (MS). The objective of the study was to see if percutaneous transluminal angioplasty (PTA) of duplex-detected lesions, of the internal jugular and/or azygous veins, was safe, burdened by a significant restenosis rate, and whether there was any evidence that treatment reduced MS disease activity. DESIGN This was a case-control study. MATERIALS We studied 15 patients with relapsing-remitting MS and duplex-detected CCSVI. METHODS Eight patients had PTA in addition to medical therapy (immediate treatment group (ITG)), whereas seven had treatment with PTA after 6 months of medical therapy alone (delayed treatment group (DTG)). RESULTS No adverse events occurred. At 1 year, there was a restenosis rate of 27%. Overall, PTA was followed by a significant improvement in functional score compared with baseline (p < 0.02). The annualised relapse rate was 0.12% in the ITG compared with 0.66% in the DTG (p = NS). Magnetic resonance imaging (MRI) blindly demonstrates a trend for fewer T2 lesions in the ITG (p = 0.081), corresponding to a 10% decrease in the ITG compared with a 23% increase in the DTG over the first 6 months of the study. CONCLUSIONS This study further confirms the safety of PTA treatment in patients with CCSVI associated with MS. The results, despite the significant rate of restenosis, are encouraging and warrant a larger multicentre double-blinded, randomised study.

Changes of cine cerebrospinal fluid dynamics in patients with multiple sclerosis treated with percutaneous transluminal angioplasty: a case-control study.

PURPOSE To investigate characteristics of cine phase contrast-calculated cerebrospinal fluid (CSF) flow and velocity measures in patients with relapsing-remitting (RR) multiple sclerosis (MS) receiving standard medical treatment who had been diagnosed with chronic cerebrospinal venous insufficiency (CCSVI) and underwent percutaneous transluminal angioplasty (PTA). MATERIALS AND METHODS This case-controlled, magnetic resonance (MR) imaging-blinded study included 15 patients with RR MS who presented with significant stenoses (≥50% lumen reduction on catheter venography) in the azygous or internal jugular veins. Eight patients underwent PTA in addition to medical therapy immediately following baseline assessments (case group) and seven had delayed PTA after 6 months of medical therapy alone (control group). CSF flow and velocity measures were quantified over 32 phases of the cardiac cycle by a semiautomated method. Outcomes were compared between groups at baseline and at 6 and 12 months of the study by mixed-effect model analysis. RESULTS At baseline, no significant differences in CSF flow or velocity measures were detected between groups. At month 6, significant improvement in flow (P<.001) and velocity (P = .013) outcomes were detected in the immediate versus the delayed group, and persisted to month 12 (P = .001 and P = .021, respectively). Within-group flow comparisons from baseline to follow-up showed a significant increase in the immediate group (P = .033) but a decrease in the delayed group (P = .024). Altered CSF flow and velocity measures were associated with worsening of clinical and MR outcomes in the delayed group. CONCLUSIONS PTA in patients with MS with CCSVI increased CSF flow and decreased CSF velocity, which are indicative of improved venous parenchyma drainage.

High output heart failure due to an iatrogenic arterio-venous fistula after lumbar disc surgery

SummaryVascular injury is a rare but not uncommon complication of spinal surgery and associated with dramatic consequences. Congestive heart failure secondary to a hyperkinetic circulation can occur in systemic diseases and in arterio-venous fistulae.A 57-year-old man was admitted to hospital complaining of dyspnoea and oedema of the left leg. Eight days previously he had undergone a discectomy at L4–L5. On auscultation a systolic-diastolic murmur was noted over the entire abdomen. An echocardiogram demonstrated an enlarged right atrium, severe mitral and tricuspid regurgitation and increased pulmonary artery pressure. An abdominal CT demonstrated irregular dilatation of the left common iliac vein and through a fistula and simultaneous opacification of the right common iliac artery; subsequently, this was also confirmed by angiography.The patient underwent an emergency endovascular stent-graft of the right common iliac artery with normalization of the venous return pressure and quick resolution of the heart failure.It is important for the physician involved in clinical work to keep in mind all the possible post-surgical complications that can occur in symptomatic patients who have recently undergone an intervention.

Efficacy and safety of venous angioplasty of the extracranial veins for multiple sclerosis. Brave dreams study (brain venous drainage exploited against multiple sclerosis): study protocol for a randomized controlled trial

BackgroundMultiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system with a disabling progressive course. Chronic cerebrospinal venous insufficiency (CCSVI) has recently been described as a vascular condition characterized by restricted venous outflow from the brain, mainly due to blockages of the internal jugular and azygos veins. Despite a wide variability among studies, it has been found to be associated with MS. Data from a few small case series suggest possible improvement of the clinical course and quality of life by performing percutaneous balloon angioplasty (PTA) of the stenotic veins.Study design and methodsThis is a multicenter, randomized, parallel group, blinded, sham-controlled trial to assess the efficacy and safety of PTA. Participants with relapsing remitting MS or secondary progressive MS and a sonographic diagnosis of CCSVI will be enrolled after providing their informed consent. Each participant will be centrally randomized to receive catheter venography and PTA or catheter venography and sham PTA. Two primary end points with respect to efficacy at 12 months are (1) a combined end point obtained through the integration of five functional indicators, walking, balance, manual dexterity, bladder control, and visual acuity, objectively measured by instruments; and (2) number of new brain lesions measured by T2-weighted MRI sequences. Secondary end points include annual relapse rate, change in Expanded Disability Status Scale score, proportion of patients with zero, one or two, or more than two relapses; fatigue; anxiety and depression; general cognitive state; memory/attention/calculus; impact of bladder incontinence; and adverse events. Six hundred seventy-nine patients will be recruited. The follow-up is scheduled at 12 months. Patients, treating neurologists, trained outcome assessors, and the statistician in charge of data analysis will be masked to the assigned treatment.DiscussionThe study will provide an answer regarding the efficacy of PTA on patients’ functional disability in balance, motor, sensory, visual and bladder function, cognitive status, and emotional status, which are meaningful clinical outcomes, beyond investigating the effects on inflammation. In fact, an important part of patients’ expectations, sustained and amplified by anecdotal data, has to do precisely with these functional aspects.Trial registrationClinicaltrials.gov NCT01371760