Cognitive impairment and “invisible symptoms” are not associated with CCSVI in MS

Multiple sclerosis (MS) is an inflammatory-mediated demyelinating disease of the Central Nervous System (CNS), characterized also by axonal damage in the brain and spinal cord [1] and cortical lesions [2]; its pathogenesis is still unknown, but it is most likely caused by a complex interplay between polygenetic and environmental factors [3, 4].

Recently, it was hypothesized that extra-cranial venous abnormalities, named chronic cerebrospinal venous insufficiency (CCSVI), might play a role in the pathogenesis of MS [5, 6]. CCSVI has been described to interfere with venous drainage from the CNS, which contributes to the development and progression of MS; moreover, when the stenotic lesions in the internal jugular and azygos veins were treated with balloon angioplasty, rapid and often dramatic symptomatic improvement in many patients has been reported [7]. However, a number of studies have showed controversial data (ranges from 0% to 100%) about the frequency of CCSVI in MS patients so far see in review, [8]. Recently, our group found that CCSVI was present in 18.9% of MS patients [9], but one more recent study did not find any association between CCSVI and MS [10]. Although several studies have recently evaluated the effects of CCSVI endovascular treatment on subjective aspects of MS, such as fatigue, patients clinical status and their quality-of-life [7, 11‐14], to date no studies have investigated the possibility of an association between CCSVI and symptoms of MS.

MS determines not only motor symptoms and signs which are responsible for the so-called physical disability, but it is also responsible for a number of non-motor, self-reported symptoms and signs so-called “invisible symptoms” [15]. Among them, in recent years, much attention has been focused on bladder and sexual disorders, visual symptoms, fatigue, pain, depression and anxiety, and especially, on cognitive disorders.

Cognitive impairment (CI) is a well-recognized symptom of MS, occurring in about half of all patients; it is a disabling symptom which contributes to the poor quality of life in MS patients [16]. CI is a common finding in brain vascular diseases also; however, because of evolving definitional criteria, the precise frequency of vascular CI is difficult to assess [17]. The cerebral flow reduction, which is a key feature of brain vascular diseases, has been recently investigated in MS [18]. A widespread cerebral hypo perfusion seen in MS [18], leading to brain atrophy, could be the result of the venous outflow obstructions secondary to CCSVI [19].

We aimed to investigate whether CCSVI may be associated with CI in MS patients. Bearing in mind that CI could be a direct effect of MS or an effect of the cerebrovascular hypo perfusion, we sought to investigate the presence of a possible association between CCSVI and CI in MS patients.

Out of the 30 patients (28 MS and 2 CIS) CCSVI positive identified in the previous population-based case–control study, 27 (25 MS and two CIS) were enrolled in the study. Out of the 138 MS and CIS patients without CCSVI, identified in the previous study, using a frequency matching, 34 similar in terms of age (± 5 years), sex, mean EDSS, mean disease duration and disease course were enrolled in the study as control group.

Demographic and clinical characteristics of patients with and without CCSVI are reported in Table 1.

The most common venous abnormalities found in our patients are detailed in Table 2.

CI was present in 13/27 CCSVI positive MS-patients and in 16/34 CCSVI negative MS-patients (48.1% and 47.0%, respectively). At univariate analysis presence of CCSVI was not associated with presence of CI (OR 1.04; 95% CI 0.37-2.87; p-value = 0.9). A close association (OR 0.90; 95% CI 0.23-3.53; p-value = 0.8) was found performing a multivariate analysis and adjusting by age sex and EDSS considered as a priori confounders and included in the model regardless the p-value threshold.

According to multiple linear regression analysis only increasing age (p-value 0.01), followed by higher EDSS (p-value 0.08), proved to be positively correlated with the severity of cognitive dysfunction defined as the number of test failed as shown in Table 3.

The most frequently impaired tests found in CI patients were SDMT, 3′ PASAT and 2′ PASAT, SRT-D and ST (see Figure 1a). For the cognitive profile, no significant difference was found between the two groups (see Figure 1b). Regarding the self-reported measures of fatigue, depressive symptoms, bladder/sexual disturbances and quality of life not significant differences between CCSVI positive and CCSVI negative patients were found (see Table 4).

Our study, performed in a well-defined MS population, showed that CI was not associated with CCSVI. We found about the same prevalence of CI between CCSVI-positive (48.1%) and CCSVI-negative patients (47.0%). Moreover, a similar prevalence of other frequent reported MS-symptoms, such as fatigue, depression and bladder/sexual disturbances, was found between the two groups. These findings suggest that CCSVI is not correlated to the cognitive status and other MS symptoms investigated, at least in our well-selected MS population.

Our study is the first evaluating the possible association between CCSVI and one of the most disabling MS symptoms such as CI. In the few years, a number of studies were carried out to evaluate the possible association between CCSVI and MS; most of them reported higher frequency of CCSVI among MS patients and suggested a possible pathogenic role of CCSVI in determining specific symptoms and signs [5, 8]. Although our recent population-based study [9] demonstrated that CCSVI was associated with MS, especially with progressive forms of the disease, there is no agreement about the exact frequency of CCSVI in MS, its putative pathogenic role and its contribution, if any, on MS symptoms [5, 8, 42‐45]. CI is one of the most common and disabling symptom of MS, occurring in about half of all MS patients. Literature data show that the most common cognitive deficits in MS patients are memory and speed of information processing, concentration and executive functions [16, 46]. However, the mechanisms underlying CI in MS has not been fully elucidated. Several cross sectional studies demonstrated that the pathogenesis of CI in MS patients might not depend just on the extent and severity of the pathological process in the brain lesions, but also on the pathological changes affecting the normal appearing brain tissue [47‐49]. Considering that, we could take into account the possible vascular hypothesis as a possible contribute to the presence of a spread or regional brain atrophy, which is one of the strongest factor correlated with the CI in MS [50‐52]. Impaired cerebral perfusion seems to be related to CI [18] and a widespread cerebral hypo perfusion in MS, described as a potential cause of brain atrophy [50‐52], could be the result of the venous outflow obstructions as seen in the CCSVI [19]. Although there is no strong evidence suggesting that CCSVI is a cause of MS, there is some evidence that a slower cerebral venous flow in patients with MS might be secondary to the reduced cerebral blood flow [19].

Our results do not support the hypothesis that CCSVI might be responsible for the appearance or worsening of CI in MS.

This study represents the first population-based case control-study looking at the possible association between CCSVI and CI in MS.

The population-based design represents the main strength of our study reducing the risk of a possible selection bias. Nevertheless such design has led to a small study size allowing us to enrol just a limited number of cases and controls. Consequently the lack of association between CCSVI and CI in MS patients could be due to a lack of power (type II error). Furthermore the retrospective nature of the study did not allow us to establish the exact sequence of the events. In order to exclude a number of conditions which might have influenced the NPS performance, we evaluated subjective fatigue and depressive symptoms, excluding that these symptoms could be correlated with CCSVI.

CI was detected by a single trained Neuropsychologist in order to avoid any inter-rater disagreement.

Although the role of CCSVI in MS pathology is still unknown and the previous evidence are controversial so far, further prospective studies are needed to withdraw the hypothesis that CCSVI might play a role in determining CI or other invisible symptoms in MS.

Our findings suggest a lack of association between the presence of CCSVI with CI and others “invisible symptoms” in patients with MS.