CCSVI monthly update: February 2013

Epub: Imperiale et al. Chronic cerebrospinal venous insufficiency in multiple sclerosis: A sonographer-blinded case-control study. Clin Neurol Neurosurg. 2013. doi:pii: S0303-8467(13)00018-8. 10.1016/j.clineuro.2013.01.003.

OBJECTIVE: To evaluate the presence of chronic cerebrospinal venous insufficiency (CCSVI) and cerebral venous anomalies in a consecutive series of patients with multiple sclerosis (MS), other neurologic diseases (NEU) and healthy controls (HC).

METHODS: A consecutive series of 80 MS patients, 41 HC and 40 NEU cases underwent a transcranial and extracranial echo-color Doppler (ECD) evaluation of cerebrospinal venous return in a sonographer-blinded fashion. According to the original Dr. Zamboni's protocol, CCSVI was diagnosed in presence of ≥2 ECD venous criteria.

RESULTS: We did not observe any association between CCSVI and MS. CCSVI was detected in 17.5% of MS cases, 7.3% of HC and 11.5% of NEU patients (p=0.333). The prevalence of internal jugular vein stenosis (IJV) and the proportion of patients with any positive ECD criterion differed significantly among groups, being higher in MS cases versus HC (67.5% and 76.2% versus 48.8% and 41.5%, respectively; p=0.005 and p=0.006). No relationship between CCSVI and MS type and severity was evidenced.

CONCLUSIONS: The present study argues against a positive link between CCSVI and MS risk or severity. Interestingly, a weak association between venous ECD anomalies (in particular IJV stenosis) and MS was observed in our population. This finding should be interpreted with caution due to the possible confounders and needs to be confirmed in large controlled studies.

More negative evidence for a causal role of CCSVI and MS, but more vascular problems in MSers

Epub: Barreto et al. 
Chronic cerebrospinal venous insufficiency: Case-control neurosonography results. Ann Neurol. 2012 Dec . doi: 10.1002/ana.23839.

OBJECTIVE: Chronic cerebrospinal venous insufficiency (CCSVI), has been implicated in the pathophysiology of multiple sclerosis (MS). We sought to determine if neurosonography (NS) provides reliable information on cerebral venous outflow patterns specific to MS.

METHODS: Single center, prospective case-control study of volunteer MS and non-MS participants. A neurosonologist, blind to the subject's diagnosis, used high resolution B-mode imaging with color and spectral Doppler to systematically investigate, capture and record extracranial and intracranial venous drainage. These neuroimaging results were evaluated and scored by an expert blinded to subject's information and with no interactions with the participants.

RESULTS: Altogether 276 subjects were studied: 206 with MS and 70 non-MS. MS patients were older than non-MS subjects (48.3±9.9 vs 44.3±11.8 years, p<0.007), with durations from first symptoms and diagnosis of 13.7±10 and 9.9±7.8 years, and EDSS 2.6±2.0. Overall, 82 subjects (29.7%) fulfilled one of five NS criteria proposed for CCSVI; 13 (4.7%) fulfilled two criteria required for diagnosis, none fulfilled >2 criteria. The distribution of subjects with 0, 1 or 2 criteria did not differ significantly across all diagnostic groupings, between MS and non-MS subjects, or within MS subgroups. CCSVI was present in 7.14% of non-MS and 3.88% of MS patients (p=0.266). No significant differences emerged between MS and non-MS subjects for extracranial or intracranial venous flow rates.

INTERPRETATION: NS findings described as CCSVI are much less prevalent than initially reported, and do not distinguish MS from other subjects. Our findings do not support the hypothesis that CCSVI is causally associated with MS.

The interpretation says it all.
Epub: Leone et al. Chronic Cerebrospinal Venous Insufficiency Is Not Associated with Multiple Sclerosis and Its Severity: A Blind-Verified Study. PLoS One. 2013;8(2):e56031. Epub 2013 Feb.

BACKGROUND: Chronic Cerebrospinal Venous Insufficiency (CCSVI) has been associated with multiple sclerosis (MS) with a risk ranging from as high as two-hundred-fold to a protective effect. However, not all studies were blinded, and the efficacy of blinding was never assessed.

OBJECTIVE: To evaluate the association of CCSVI with MS in a cross-sectional blinded study and look for any association of CCSVI with the severity of MS.

METHODOLOGY/PRINCIPAL FINDINGS: The Echo-color Doppler examination was carried out in accordance with Zamboni's five criteria in 68 consecutive MS patients and 68 healthy controls, matched by gender and age (±5 years). Four experienced neurosonologists, blinded to the status of cases and controls, performed the study and were then asked to guess the status (case or control) of each participant. The number of positive CCSVI criteria was similar in the two groups. CCSVI, defined as the presence of two or more criteria, was detected in 21 cases (30.9%) and 23 controls (33.8%), with an OR of 0.9 (95%CL = 0.4-1.8, p = 0.71). The prevalence of CCSVI was related to age in cases (OR increasing from 0.2 to 1.4), but not in controls. CCSVI positive (N = 21) and negative (N = 47) MS patients were similar in clinical type, age at disease onset, disability, and fatigue. Disease duration was longer (16.5±9.8 years) in CCSVI positive than negative patients (11.5±7.4; p = 0.04). The operators correctly guessed 34/68 cases (50%) and 45/68 controls (66%) (p = 0.06), indicating a different success of blinding.

CONCLUSIONS/SIGNIFICANCE: CCSVI was not associated with MS itself, nor its severity. We cannot rule out the possibility that CCSVI is a consequence of MS or of aging. Blinding of sonographers is a key point in studying CCSVI and its verification should be a requisite of future studies.

The conclusions say it all, Surely there is now enough evidence to say CCSVI is not the cause of MS?
Epub: Lanzillo et al. Chronic cerebrospinal venous insufficiency in multiple sclerosis: a highly prevalent age-dependent phenomenon. BMC Neurol. 2013 13:20.

BACKGROUND: This study aimed to investigate the prevalence and clinical relevance of chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis (MS) patients and healthy controls using extra- and intracranial colour Doppler sonography.

METHODS: We examined 146 MS patients, presenting with a clinically isolated syndrome, relapsing-remitting, secondary progressive, or primary progressive MS, and 38 healthy controls. Sonographic examination was performed according to Zamboni's protocol and was performed by three independent sonographers. The results of sonographic examination were compared with clinical and demographic characteristics of the patients.

RESULTS: CCSVI, defined as the presence of at least two positive Zamboni's criteria, was found in 76% of MS patients and 16% of control subjects. B-mode anomalies of internal jugular veins, such as stenosis, malformed valves, annuli, and septa were the most common lesions detected in MS patients (80.8%) and controls (47.4%). We observed a positive correlation between sonographic diagnosis of CCSVI and the patients' age (p=0.003). However, such a correlation was not found in controls (p=0.635). Notably, no significant correlations were found between sonographic signs of CCSVI and clinical characteristics of MS, except for absent flow in the jugular veins, which was found more often in primary (p<0.005) and secondary (p<0.05) progressive patients compared with non-progressive patients. Absent flow in jugular veins was significantly correlated with patients' age (p<0.0001).

CONCLUSIONS: Sonographically defined CCSVI is common in MS patients. However, CCSVI appears to be primarily associated with the patient's age, and poorly correlated with the clinical course of the disease.

Well this study finds a high frequency of CCSVI in Msers, which is more related to age than disease. There is clearly controversy in the air still, but is the phenomenon more a consequence of disease and age than causal.
Epub: Ghezzi et al. Adverse events after endovascular treatment of chronic cerebro-spinal venous insufficiency (CCSVI) in patients with multiple sclerosis. Mult Scler. 2013 Feb.

Although it is debated whether chronic cerebro-spinal venous insufficiency (CCSVI) plays a role in multiple sclerosis (MS) development, many patients undergo endovascular treatment (ET) of CCSVI. A study is ongoing in Italy to evaluate the clinical outcome of ET. Severe adverse events (AEs) occurred in 15/462 subjects at a variable interval after ET: jugular thrombosis in seven patients, tetraventricular hydrocephalus, stroke, paroxysmal atrial fibrillation, status epilepticus, aspiration pneumonia, hypertension with tachicardia, or bleeding of bedsore in the remaining seven cases. One patient died because of myocardial infarction 10 weeks after ET. The risk of severe AEs related to ET for CCSVI must be carefully considered.
As we have always said there can be consequences of having the CCSVI procedure, it is not high but it is not trivial and the question remains, it is an unproven therapy.
The American Academy of Neurologists Meeting 2013 Abstracts are Published. 

I was not going to publish abstracts but these add to the mix.

[P05.177] Fox R et al. An Assessment of Chronic Cerebrospinal Venous Insufficiency in MS

OBJECTIVE: To conduct an independent assessment of chronic cerebrospinal venous insufficiency (CCSVI) in MS. 

BACKGROUND: CCSVI is a hypothesis of MS pathogenesis related to venous outflow from the head, with conflicting results from different studies. Recent studies have found a very low prevalence of CCSVI, suggesting that those investigators were performing ultrasound assessments differently than the original reports. 

DESIGN/METHODS: After obtaining formal training in CCSVI ultrasound techniques, we performed ultrasound assessments on a group of 61 MS subjects (4 CIS, 28 RRMS, 19 SPMS, 10 PPMS; 42 females) and 20 non-MS controls (15 healthy and 5 other neurological diseases; 10 female). Ultrasonographers were blinded to diagnosis, and separate research staff positioned subjects prior to ultrasonographer arrival. Assessments were performed using a Biosound MyLab25, equipped with Quality Doppler Profiles (QDP) technology, and traditional transcranial Doppler. Two published interpretations of CCSVI Criteria were utilized: Narrow Criteria did not include either B-mode intraluminal abnormalities or QDP technology for deep cerebral vein reflux, while Broad Criteria included both of these. 

RESULTS: Using either Narrow Criteria or Broad Criteria, there were no significant differences between MS subjects and controls (p>0.5 for both comparisons). In both groups, there was a doubling of the proportion of subjects meeting CCSVI criteria when using the Broad Criteria.

CONCLUSIONS: Using trained and blinded ultrasonographers and QDP technology, we observed no difference in the proportion of MS subjects meeting CCSVI criteria compared to non-MS controls. Different interpretations of CCSVI criteria altered the proportions of subjects meeting CCSVI criteria, highlighting the importance of criteria interpretations when comparing the prevalence of CCSVI between studies. These observations do not support a significantly increased prevalence of CCSVI in MS and suggest against a pathogenic role of CCSVI in MS.

You can read the conclusions!

[P05.183] Met L et al. Chronic Cerebrospinal Venous Insufficiency and Multiple Sclerosis: Changes in Treatment Patterns and Opinions in a Province-Wide Study.

OBJECTIVE: We aimed to describe the population of Multiple Sclerosis (MS) patients reporting chronic cerebrospinal venous insufficiency (CCSVI) treatment and to describe the change in treatment patterns and opinions over time.

BACKGROUND: The CCSVI hypothesis has been of great interest to MS patients. Many Albertans have travelled out-of-country for venous angioplasty. 

DESIGN/METHODS: Initiated in July 2011, The Alberta Multiple Sclerosis Initiative is a longitudinal observational study that uses online questionnaires to collect patient-reported information about the safety, experiences, and outcomes following CCSVI treatment. All Albertans with MS have been encouraged to participate, irrespective of treatment status. Enrollment is ongoing. 

RESULTS: This analysis included 733 participants. Mean (SD) age was 47.9 (11.2) years, 76.5% were female, and 63.8% had relapsing remitting MS; 152 participants (20.7%; 95% CI: 17.9-23.9%) reported having CCSVI treatment, beginning in March 2010. Participants were more likely to have undergone treatment in 2010 (66.4%; 95% CI: 58.3-73.9%, n=101) than in 2011 (30.9 %; 95% CI: 23.7-38.9%, n=47), even after controlling for the period of enrolment. Between January and June 2012 only four participants had CCSVI treatment (2.6%; 95% CI: 0.7-6.6%). Older age, male sex, a progressive course, and greater disability were more common in those who had CCSVI treatment. 

CONCLUSIONS: The number of participants reporting CCSVI treatment is declining. This may indicate that patients who wanted and could afford out-of-country treatment went soon after the CCSVI hypothesis was widely publicized. However, this may also reflect declining patient interest after they observed the outcomes in this earlier group of patients. The sociodemographic and clinical characteristics of participants who received CCSVI treatment will be compared to those who did not receive treatment. Factors that influenced participants' opinions for or against having CCSVI treatment will be compared over time

You can read the conclusions!

[P01.182] Baharnoori M et al. Treatment for Chronic Cerebrospinal Venous Insufficiency in Patients with Multiple Sclerosis: Patient-Reported Outcomes (PRO).

OBJECTIVE: To assess changes in multiple sclerosis (MS) associated symptoms and disability scores (EDSS) in patients with MS after endovascular treatment (ET). 

BACKGROUND: The chronic cerebrospinal venous insufficiency (CCSVI) hypothesis has been proposed as the causal factor for MS. Contradictory data on the association between CCSVI and MS have been reported to date. CCSVI was defined as impaired extra cranial cerebrospinal venous drainage which leads to the accumulation of cerebral iron deposits causing inflammation and degeneration. 

DESIGN/METHODS: 82 eligible patients completed a questionnaire regarding changes in their MS symptoms after ET including fatigue, sensory deficits, impairments in mobility, coordination, bladder control and cognition. First, we examined symptom changes within 2 weeks after treatment compared to before. For longitudinal assessment, we divided patients to 3 groups; patients who had ET 1) within past 6 month 2) 6-12 months or 3) more than 12 months. Changes at the time of interview were compared to those before the ET. Their EDSS score was measured before and after ET and analyzed using student t test. 

RESULTS: Within 2 weeks after treatment, 70% (56/79) reported decreased fatigue. About two-thirds reported improvement in cognition (38/65), mobility (51/79) and perceived warming in their limb temperature (40/63). Half of patients reported improvement in bladder control (34/73), coordination (37/73) and sensory deficits (28/61). Longitudinal assessment of symptoms revealed that initial reported improvement in most symptoms greatly diminished over time. Furthermore, we did not find any significant difference between EDSS scores before and after the ET (P=0.828). 

CONCLUSIONS: Our findings indicate that ET procedures for CCSVI are associated with subjective reports of improvement of various symptoms by many patients without any corresponding objective change in neurological evaluations as measured by neurologist-derived EDSS scores. These uncontrolled and unblinded observations do not provide any credible evidence of a true benefit from ET for MS. 
You can read the conclusions!

However remember the cannabinoid trials there were subjective improvements reported by MSers, but no objective benefits in spasticity scales. They changed the way they do trials listened to MSers and Sativex was born

However I wonder whether the writing is on the wall with regard to the results of the blinded trials?

Pryse-Phillips W, Stefanelli M, Murphy-Peddle K, Barrett B. 
An Observational Study of Venoplasty in Patients with Multiple Sclerosis. Can J Neurol Sci. 2013;40(2):203-209.
Rationale: It is estimated that some hundreds of Canadian patients with multiple sclerosis (MS) have journeyed abroad to avail themselves of 'liberation therapy' (venoplasty) following the initial report by Zamboni et al in 2009. That study also led to public pressure upon Departments of Health in Canadian Provinces to fund the procedure. The present study was done in order to advise the Government of Newfoundland and Labrador as to whether or not it should do so.

Methods: We conducted an observational study of 30 MS subjects who had submitted to venoplasty, using objective, semi-objective and subjective measures.

Results: Significant subjective improvement was reported by half of the subjects at three months, although the degree of perceived improvement was less at 12 months. The objective and semi-objective tests employed did not indicate improvement in any area over the one-year follow-up period. Seven of the 29 subjects in whom CT venography was performed at the end of the study year were found to have uni- or bilateral occlusion or >50% stenosis of at least one cervical draining vein, but they showed no deterioration in their clinical status compared to those in whom no venous occlusion nor stenosis was found.

Conclusion: No objective improvement was found at one year in thirty MS subjects who had undergone venoplasty, although many reported a degree of subjective benefit.

This study offers some encouragement in that some improvements are felt after venoplasty but the effect was largely transient and was not seen by the neuro. Restenosis was common. However is this a disaster zone for the Brave Dreams trials? This I think is set to run that are set to run over 12 months.
Epub: Pullman et al. "Media, politics and science policy: MS and evidence from the CCSVI Trenches" BMC Med Ethics. 2013 Feb (1):6.

BACKGROUND: In 2009, Dr. Paolo Zamboni proposed chronic cerebrospinal venous insufficiency (CCSVI) as a possible cause ofmultiple sclerosis (MS). Although his theory and the associated treatment ("liberation therapy") received little more than passing interest in the international scientific and medical communities, his ideas became the source of tremendous public and political tension in Canada. The story moved rapidly from mainstream media to social networking sites. CCSVI and liberation therapy swiftly garnered support among patients and triggered remarkable and relentless advocacy efforts. Policy makers have responded in a variety of ways to the public's call for action.

DISCUSSION: We present three different perspectives on this evolving story, that of a health journalist who played a key role in the media coverage of this issue, that of a health law and policy scholar who has closely observed the unfolding public policy developments across the country, and that of a medical ethicist who sits on an expert panel convened by the MS Society of Canada and the Canadian Institutes of Health Research to assess the evidence as it emerges.

SUMMARY: This story raises important questions about resource allocation and priority setting in scientific research and science policy. The growing power of social media represents a new level of citizen engagement and advocacy, and emphasizes the importance of open debate about the basis on which such policy choices are made. It also highlights the different ways evidence may be understood, valued and utilized by various stakeholders and further emphasizes calls to improve science communication so as to support balanced and informed decision-making.

An interesting read, it is open source so I will not spend time commenting on this but take a few quotes as food for thought.

"In the end, one thing that journalism and science—two disparate professions—have in common is that they are self-correcting over time. It’s not always a pretty process but it is a necessary and informative one".

"The rapidity with which new findings, whether speculative or proven, make their way into the public sphere has undergone a paradigm shift such that the process in which “evidence” is manufactured may be changing irrevocably."

"Gone are the days when researchers and clinicians can rely on a few hours of “media training” to prepare them for the off-chance they might be interviewed about some aspect of their work........ the advent of the internet and social media mean the ivory tower of academia might be stormed at any moment by an interested, enthusiastic, and motivated public. Researchers and clinicians must learn how to utilize these resources to ensure the message that emerges is both balanced and informed."

This reminds me of the debate that Prof G lost on whether Academia should engage with the Social Media!