Yuval Karmon

Chronic cerebrospinal venous insufficiency in multiple sclerosis: diagnostic, pathogenetic, clinical and treatment perspectives

Chronic cerebrospinal venous insufficiency (CCSVI) was recently described in multiple sclerosis patients. CCSVI is characterized by impaired brain venous drainage due to outflow obstruction in the extracranial venous system, mostly related to anomalies in the internal jugular and azygos veins. The current CCSVI diagnosis is based on Doppler sonography of extracranial and transcranial venous hemodynamics criteria. To date, prevalence estimates of CCSVI, provided by different groups using various imaging methods of assessment, vary widely from none to 100%. There is an urgent need to define and validate the spectrum of cranial/extracranial venous anomalies and to establish reliable, diagnostic gold-standard test(s). The potential usefulness of endovascular treatment for CCSVI in multiple sclerosis patients is still unknown.

Results of stent-assisted vs non-stent-assisted endovascular therapies in 489 cerebral aneurysms: single-center experience.

BACKGROUND Whether the addition of stenting to intracranial aneurysm coil embolization results in benefit in terms of occlusion rates or additional risk in terms of periprocedural adverse events is not clear. OBJECTIVE To report retrospectively analyzed results of endovascular aneurysm treatment comparing stent-assisted coiling with coiling without stents at our hospital from 2005 to 2009. METHODS In this retrospectively reviewed case series, aneurysms were grouped as intent-to-treat or initially treated with stent-assisted coiling (A) vs coiling alone (B) or as-treated-those that ultimately received a stent (C) or not (D). Complication and occlusion rates were compared between groups. Some patients crossed from group B to C after receiving stent placement at a later treatment following the initial therapeutic modality (without a stent). RESULTS In 459 patients, 489 aneurysms were treated by group as follows: A = 181, B = 308, C = 225, and D = 264. In stent groups (A and C), there were significantly lower frequencies of ruptured aneurysms (A vs B = 11% vs 62%, P < .001; C vs D = 20.4% vs 62.5%, P < .001) and more giant aneurysms (A vs B = 7.3% vs 1.0%, P = .001; C vs D = 5.9% vs 1.1%, P < .001). There was no statistically significant difference in permanent event-related morbidity (A vs B = 4.4% vs 4.2%, P = 1.0; C vs D = 4.4% vs 4.2%, P = 1.0). Average angiographic follow-up after last treatment was 18.2 ± 15 months (median = 14). Higher rates of complete occlusion at last angiographic follow-up were observed in stented aneurysms (A vs B = 64.6% vs 49.7%, P = .001; C vs D = 62.7% vs 48.9%, P = .003). CONCLUSION Stent-assisted aneurysm treatment resulted in higher total occlusion rates than non-stent-assisted treatment, with acceptable, comparable periprocedural event rates.

The Prevalence of the Classical and Non-Classical Cardiovascular Risk Factors in Multiple Sclerosis Patients

BACKGROUND Inflammation is known to play a role in cererovascular risk. Multiple sclerosis (MS) is a neurodegenerative disease that is initially characterized by inflammatory changes in the brain. We hypothesized that due to chronic inflammation, MS patients would present with a higher levels of cardiovascular (CV) risk factors than non-MS patients. METHODS We performed a retrospective chart review on 206 MS patients and 142 control patients suffering from meningiomas and acoustic neuromas, non inflammatory, non autoimmune diseases of the brain. The obtained data included fasting lipid profiles, plasma glucose, systolic and diastolic blood pressure (BP), serum levels of homocysteine and uric acid, data on iron status, smoking habit, and list of medications. In addition, data on indicators of MS disease severity was obtained for MS patients. RESULTS MS patients had significantly higher total plasma cholesterol, p = 0.01, and plasma high density lipoprotein, P < 0.001, but lower plasma glucose, P < 0.001, and systolic BP, P = 0.001, than non-MS patients. In addition, MS patients had lower erythrocyte sedimentation rate and serum vitamin B12, but higher serum folic acid and vitamin D3 than non-MS patients. A positive correlation was observed between plasma glucose and the extended disability status scale (EDSS), P = 0.008, and between plasma glucose and the rate of clinical relapse, P = 0.001. CONCLUSION The MS pathophysiology may be among factors for the lower CV risk factors in MS patients. Future studies should examine whether the chronic use of many pharmacological agents influence CV risk factors in MS patients.

Stent-assisted coiling of paraclinoid aneurysms: risks and effectiveness

Background Stent assistance for treatment of wide-based aneurysms is becoming rapidly accepted. Methods Cases of aneurysms arising in the paraclinoid location of the internal carotid artery treated with intracranial stents and/or bare platinum coils were analyzed retrospectively from our prospectively collected database. We identified 70 aneurysms treated with stent assistance (including one stenting-alone case) and 24 aneurysms treated with coiling alone. Stenting-assisted coiling was achieved either as a one-time treatment or as a two-step maneuver with the stent placed several weeks before coiling, or stent-assisted coiling was used as a second maneuver in aneurysms that recanalized after previous coiling. Results In aneurysms treated with stent assistance, 60% had ≥95% occlusion at treatment completion, a result comparing favorably with the 54.2% rate of ≥95% occlusion associated with coiling alone. At last follow-up, 60 aneurysms treated with stent assistance had a 66.7% incidence of ≥95% occlusion, with no in-stent stenosis; 75% of patients treated with coiling alone had ≥95% aneurysm occlusion. Thrombus occurred during stent deployment in two patients, one with and one without neurologic sequelae; stent displacement occurred in one patient without neurologic sequelae. At last follow-up, 57 of 62 patients (91.9%) treated with stent-assisted coiling experienced excellent/good outcomes (modified Rankin scale score ≤2). These results compared favorably with those for the coiling-alone group in which 23 of 24 (95.8%) had good outcomes. Conclusion Stent-assisted coiling of paraclinoid aneurysms did not add significantly to morbidity; overall effectiveness was comparable to that of bare coiling of paraclinoid aneurysms. These results require confirmation by a prospective controlled trial.

Vitamin D and multiple sclerosis.

Background:Epidemiological data support a potential relationship between vitamin D deficiency and an increased risk of developing multiple sclerosis (MS). In vitro studies have expanded the potential role of vitamin D and its receptor beyond calcium modulation, regulation, and maintenance of bone mineralization, to include immune modulation. Review Summary:Whether vitamin D immunomodulatory effects can be translated into clinical benefits in MS patients is still a matter of debate. A review of the biochemistry of vitamin D and its synthesized derivatives is discussed in the context of treating vitamin D deficiency. Animal studies, which led to some human studies, are also discussed. Future studies are pending and will likely yield conclusive results as to the benefit and possible synergistic effects of vitamin D with other disease-modifying therapies of MS. Conclusions:Further prospective studies are needed to identify vitamin D levels during the various phases of MS, including relapses, remissions and progression, and to determine whether correcting vitamin D during any or all of these phases may affect the incidence or even the course of the disease.

Prospective randomized trial of venous angioplasty in MS (PREMiSe)

Objective: We report the results of the investigation of safety and efficacy of venous angioplasty in patients with multiple sclerosis (MS) with findings of extracranial venous anomalies, considered hallmarks of chronic cerebrospinal venous insufficiency (CCSVI), in a 2-phase study (ClinicalTrials.gov NCT01450072). Methods: Phase 1 was an open-label safety study (10 patients); phase 2 was sham-controlled, randomized, and double-blind (10 sham procedure, 9 treated). All study patients fulfilled venous hemodynamic screening criteria indicative of CCSVI. Assessment was at 1, 3, and 6 months postprocedure with MRI, clinical, and hemodynamic outcomes. Primary endpoints were safety at 24 hours and 1 month, venous outflow restoration >75% at 1 month, and effect of angioplasty on new lesion activity and relapse rate over 6 months. Secondary endpoints included changes in disability, brain volume, cognitive tests, and quality of life. Results: No perioperative complications were noted; however, one patient with history of syncope was diagnosed with episodic bradycardia requiring placement of a pacemaker before discharge. Doppler evidence-based venous hemodynamic insufficiency severity score (VHISS) was reduced >75% compared to baseline in phase 1 (at 1 month) but not phase 2. In phase 2, higher MRI activity (cumulative number of new contrast-enhancing lesions [19 vs 3, p = 0.062] and new T2 lesions [17 vs 3, p = 0.066]) and relapse activity (4 vs 1, p = 0.389) were identified as nonsignificant trends in the treated vs sham arm over 6 months. Using analysis of covariance, significant cumulative new T2 lesions were related to larger VHISS decrease (p = 0.028) and angioplasty (p = 0.01) over the follow-up. No differences in other endpoints were detected. Conclusion: Venous angioplasty is not an effective treatment for MS over the short term and may exacerbate underlying disease activity. Classification of evidence: This is a Class I study demonstrating that clinical and imaging outcomes are no better or worse in patients with MS identified with venous outflow restriction who receive venous angioplasty compared to sham controls who do not receive angioplasty. This study also includes a Class IV phase 1 study of safety in 10 patients receiving the angioplasty procedure.

Arterial, venous and other vascular risk factors in multiple sclerosis.

Abstract Purpose of review: This article reviews vascular risk factors with specific emphasis on lipid abnormalities reported to be associated with multiple sclerosis (MS). Recent findings: The current paradigm of MS, supported only partially by MS lesion histopathology and its animal model (experimental allergic encephalomyelitis) considers MS to be a predominantly autoimmune disease. Until recently, most of the known risk factors for MS were interpreted in the context of the autoimmune theory, which still fails to explain why genetically close populations exposed to similar pathogens and/or environmental risk factors have different incidences of MS. Therapies which partially modulate the inflammatory arm of MS pathogenesis, fail to achieve similar benefits in later disease stages, when less inflammatory lesions and more neurodegeneration are present. Several studies have reported an increased cardiovascular morbidity in MS patients and that vascular comorbidity at any time during the disease course also increased the risk of progressive disability. A condition named chronic cerebrospinal venous insufficiency provided a different perspective, on the possible association of MS with the abnormalities of the venous system. Our recent findings revealed increased prevalence of chronic cerebrospinal venous insufficiency associated with MS disease progression as well as with other neurologic disorders. On the other hand, recently emerging evidence indicates that there is an association between lipoproteins and cholesterol metabolism and MS disease progression. Expanded disability status scale worsening was associated with higher baseline low-density lipoprotein and total cholesterol, and higher serum high-density lipoprotein levels were associated with lower contrast-enhancing T1-weigthed lesion volume. It is thought that apolipoprotein A-1 and paraoxonase anti-oxidant enzyme are associated with high-density lipoprotein and contribute to its anti-oxidant and anti-inflammatory properties. A significant inter-dependence was also recently demonstrated between vitamin D, one of the best known environmental risk factors for MS and MS disease progression and the serum lipid profile. Future work in this direction is required in order to better elucidate the role of lipid metabolism and vascular pathology in pathogenesis of MS.

The role of noninvasive and invasive diagnostic imaging techniques for detection of extra-cranial venous system anomalies and developmental variants

The extra-cranial venous system is complex and not well studied in comparison to the peripheral venous system. A newly proposed vascular condition, named chronic cerebrospinal venous insufficiency (CCSVI), described initially in patients with multiple sclerosis (MS) has triggered intense interest in better understanding of the role of extra-cranial venous anomalies and developmental variants. So far, there is no established diagnostic imaging modality, non-invasive or invasive, that can serve as the “gold standard” for detection of these venous anomalies. However, consensus guidelines and standardized imaging protocols are emerging. Most likely, a multimodal imaging approach will ultimately be the most comprehensive means for screening, diagnostic and monitoring purposes. Further research is needed to determine the spectrum of extra-cranial venous pathology and to compare the imaging findings with pathological examinations. The ability to define and reliably detect noninvasively these anomalies is an essential step toward establishing their incidence and prevalence. The role for these anomalies in causing significant hemodynamic consequences for the intra-cranial venous drainage in MS patients and other neurologic disorders, and in aging, remains unproven.

Prediction of adverse outcomes by blood glucose level after endovascular therapy for acute ischemic stroke

OBJECT The authors evaluated the prognostic significance of blood glucose level at admission (BGA) and change in blood glucose at 48 hours from the baseline value (CG48) in nondiabetic and diabetic patients before and after endovascular therapy for acute ischemic stroke (AIS). METHODS The BGA and CG48 data were analyzed in 614 patients with AIS who received endovascular therapy at 7 US centers between 2006 and 2009. Data reviewed included demographics, stroke risk factors, diabetic status, National Institutes of Health Stroke Scale (NIHSS) score at presentation, recanalization grade, intracranial hemorrhage (ICH) rate, and 90-day outcomes (mortality rate and modified Rankin Scale score of 3-6 [defined as poor outcome]). Variables with p values < 0.2 in univariate analysis were included in a binary logistic regression model for independent predictors of 90-day outcomes. RESULTS The mean patient age was 67.3 years, the median NIHSS score was 16, and 27% of patients had diabetes. In nondiabetic patients, BGA ≥ 116 mg/dl (≥ 6.4 mmol/L) and failure of glucose level to drop > 30 mg/dl (> 1.7 mmol/L) from the admission value were both significant predictors of 90-day poor outcome and death (p < 0.001). In patients with diabetes, BGA ≥ 116 mg/dl (≥ 6.4 mmol/L) was an independent predictor of poor outcome (p = 0.001). The CG48 was not a predictor of outcome in diabetic patients. A simplified 6-point scale including BGA, Thrombolysis in Myocardial Infarction (TIMI) Grade 2-3 Reperfusion, Age, presentation NIHSS score, CG48, and symptomatic ICH (BRANCH) corresponded with poor outcomes at 90 days; the area under the curve value was > 0.79. CONCLUSIONS Failure of blood glucose values to decrease in the first 48 hours after AIS intervention correlated with poor 90-day outcomes in nondiabetic patients. The BRANCH scale shows promise as a simple prognostication tool after endovascular therapy for AIS, and it merits prospective validation.

Comparison of Intravascular Ultrasound with Conventional Venography for Detection of Extracranial Venous Abnormalities Indicative of Chronic Cerebrospinal Venous Insufficiency

PURPOSE To investigate prevalence of extracranial abnormalities in azygos and internal jugular (IJ) veins using conventional venography and intravascular ultrasound (IVUS) in patients with multiple sclerosis (MS) being evaluated for chronic cerebrospinal venous insufficiency, a condition of vascular hemodynamic dysfunction. MATERIALS AND METHODS PREMiSe (Prospective Randomized Endovascular therapy in Multiple Sclerosis) is a venous angioplasty study that enrolled 30 patients with relapsing MS. The patients fulfilled two or more venous hemodynamic extracranial Doppler sonography screening criteria. Phase I of the study included 10 patients and was planned to assess safety and standardize venography, IVUS, and angioplasty and blinding procedures; phase II enrolled 20 patients and further validated diagnostic assessments using the two invasive techniques. Venography was considered abnormal when ≥ 50% lumen-diameter restriction was detected. IVUS was considered abnormal when ≥ 50% lumen-diameter restriction, intraluminal defects, or reduced pulsatility was detected. RESULTS No venography-related or IVUS-related complications, including vessel rupture, thrombosis, or side effects of contrast media were recorded among the 30 study patients. IVUS-detected venous abnormalities, including chronic, organized, thrombus-like inclusions were observed in 85% of azygos, 50% of right IJ, and 83.3% of left IJ veins, whereas venography demonstrated stenosis of ≥ 50% in 50% of azygos, 55% of right IJ, and 72% of left IJ veins. Sensitivity of venography for detecting IVUS abnormalities was 52.9%, 73.3%, and 80% for the azygos, left IJ, and right IJ veins, respectively. CONCLUSIONS IVUS assessment of azygos and IJ veins showed a higher rate of venous abnormalities than venography. IVUS provides a diagnostic advantage over conventional venography in detecting extracranial venous abnormalities indicative of chronic cerebrospinal venous insufficiency.