Feasibility of high-frequency percussions in people with severe acquired brain injury and tracheostomy: an observational study.

People with severe acquired brain injury (pwSABI) frequently experience pulmonary complications. Among these, atelectasis can occur as a result of pneumonia, thus increasing the chance of developing acute respiratory failure. Respiratory physiotherapy contribution to the management of atelectasis in pwSABI is yet poorly understood. We conducted a retrospective analysis on 15 non-cooperative pwSABI with tracheostomy and spontaneously breathing, hospitalized and treated with high-frequency percussion physiotherapy between September 2018 and February 2021 at the Neurological Rehabilitation Unit of the IRCCS "S.Maria Nascente - Fondazione Don Gnocchi", Milan. Our primary aim was to investigate the feasibility of such a physiotherapy intervention method. Then, we assessed changes in respiratory measures (arterial blood gas analysis and peripheral night-time oxygen saturation) and high-resolution computed tomography lung images, evaluated before and after the physiotherapy treatment. The radiological measures were a modified radiological atelectasis score (mRAS) assigned by two radiologists, and an opacity score automatically provided by the software CT Pneumonia Analysis® that identifies the regions of abnormal lung patterns. Treatment diaries showed that all treatments were completed, and no adverse events during treatment were registered. Among the 15 pwSABI analyzed, 8 were treated with IPV® and 7 with MetaNeb®. After a median of 14 (I-III quartile=12.5-14.5) days of treatment, we observed a statistical improvement in various arterial blood gas measures and peripheral night-time oxygen saturation measures. We also found radiological improvement or stability in more than 80% of pwSABI. In conclusion, our physiotherapy approach was feasible, and we observed respiratory parameters and radiological improvements. Using technology to assess abnormal tomographic patterns could be of interest to disentangle the short-term effects of respiratory physiotherapy on non-collaborating people.

The key role of depression and supramarginal gyrus in frailty: a cross-sectional study.

Background: The age-related decrease in reserve and resistance to stressors is recognized as frailty, one of the most significant challenges identified in recent years. Despite a well-acknowledged association of frailty with cognitive impairment, depression, and gray matter morphology, no clear data are available regarding the nature of this relationship. This cross-sectional study aims to disentangle the role of the behavioral, neuropsychological, and neural components as predictors or moderators of frailty. Methods: Ninety-six older adults (mean age = 75.49 ± 6.62) were consecutively enrolled and underwent a clinical and MRI (3 T) evaluation to assess frailty, physical activity, global cognitive level, depression, wellbeing, autonomy in daily living, cortical thickness, and subcortical volumes. Results: Results showed a full mediation of depression on the link between cortical thickness and frailty, while the cognitive level showed no significant mediating role. In particular, left supramarginal thickness had a predicting role on depression, that in turn impacted frailty occurrence. Finally, handgrip weakness was an early key indicator of frailty in this study's cohort. Conclusion: These data substantiate the role of depression in mediating the link between neural integrity of the supramarginal gyrus and frailty. In the complexity of frailty, handgrip weakness seems to be an early key indicator. These results are relevant for the design of rehabilitation interventions aimed at reversing the frail condition.

Tailored repetitive transcranial magnetic stimulation for depression and addictions.

Transcranial magnetic stimulation (TMS) has been widely applied for evaluation of the cortical eloquence through creation of the temporary "virtual lesion" allowing assessment of the evaluated function within the targeted region, which may be also employed for management of mental symptoms or modification of the abnormal behavior. It is believed that this non-invasive neuromodulation modality has a double impact on neurons-primary modulation of electrical activity and stimulation of neuroplasticity; the latter can be facilitated by repeated administration of TMS during multiple sessions over sufficiently long periods of time to induce consolidation of treatment effects through their recall at psychological, physiological, and cellular levels. These principles were employed in our data-driven, tailored strategy based on the modifications of TMS protocol and its adaptation to newly appearing changes of the clinical situation along with administration of prolonged and/or repeated courses of therapeutic stimulation, which showed high efficacy resulting in complete relief of depressive symptoms or substance use in 75% of treated patients at 1-year follow-up. Such results justify application of repetitive TMS for management of psychiatric disorders and warrant additional evaluation of its efficacy in further clinical studies.

Consistent Cerebral Blood Flow Covariance Networks across Healthy Individuals and Their Similarity with Resting State Networks and Vascular Territories.

Cerebral blood flow (CBF) represents the local blood supply to the brain, and it can be considered a proxy for neuronal activation. Independent component analysis (ICA) can be applied to CBF maps to derive patterns of spatial covariance across subjects. In the present study, we aimed to assess the consistency of the independent components derived from CBF maps (CBF-ICs) across a cohort of 92 healthy individuals. Moreover, we evaluated the spatial similarity of CBF-ICs with respect to resting state networks (RSNs) and vascular territories (VTs). The data were acquired on a 1.5 T scanner using arterial spin labeling (ASL) and resting state functional magnetic resonance imaging. Similarity was assessed considering the entire ASL dataset. Consistency was evaluated by splitting the dataset into subsamples according to three different criteria: (1) random split of age and sex-matched subjects, (2) elderly vs. young, and (3) males vs. females. After standard preprocessing, ICA was performed. Both consistency and similarity were assessed by visually comparing the CBF-ICs. Then, the degree of spatial overlap was quantified with Dice Similarity Coefficient (DSC). Frontal, left, and right occipital, cerebellar, and thalamic CBF-ICs were consistently identified among the subsamples, independently of age and sex, with fair to moderate overlap (0.2 < DSC ≤ 0.6). These regions are functional hubs, and their involvement in many neurodegenerative pathologies has been observed. As slight to moderate overlap (0.2< DSC < 0.5) was observed between CBF-ICs and some RSNs and VTs, CBF-ICs may mirror a combination of both functional and vascular brain properties.

Cerebrovascular reactivity and its correlation with age in patients with multiple sclerosis.

We assessed cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) within gray matter (GM), normal appearing white matter (NAWM) and white matter (WM) lesions in a group of multiple sclerosis (MS) patients. Furthermore, correlations between CBF, CVR and age were investigated. 31 MS patients and 25 healthy controls (HC) were examined on a 1.5 T MRI scanner, using pseudo-continuous arterial spin labeling MRI. MS vs HC CBF and CVR differences were assessed in GM regions of interest (i.e. resting state networks and vascular territories), and within WM. Correlations between CBF/CVR and age were then computed for MS and HC groups. Whereas no significant CBF and CVR differences were observed between MS and HC in any of the considered brain areas, significantly lower CBF was found in WM lesions with respect to NAWM (p < 0.001) in MS patients. Furthermore, CVR was significantly correlated with age in HC, but not in MS patients. The relatively low-grade of inflammation of our MS cohort may be associated with the observed lack of significant CVR differences between MS patients and HC. The loss of correlation between CVR and age in the MS group suggests that CVR may be influenced by MS-related factors.

Dissociative identity as a continuum from healthy mind to psychiatric disorders: Epistemological and neurophenomenological implications approached through hypnosis.

The topic of multiple personality, redefined as Dissociative Identity Disorders (DIDs) in the DSM-5, is an intriguing and still debated disorder with a long history and deep cultural and epistemological implications, extending up to the idea of possession. Hypnosis is an appealing and valuable model to manipulate subjective experience and get an insight on both the physiology and the pathophysiology of the mind-brain functioning; it and has been closely connected with DIDs and possession since its origin in 18th century and as recently proved the capacity to yield a loss of sense of agency, mimicking delusions of alien control and spirit possession. In this study we report on five very uncommon "hypnotic virtuosos" (HVs) free from any psychiatric disorder, spontaneously undergoing the emergence of multiple identities during neutral hypnosis; this allowed us to check the relationship between their experience and fMRI data. During hypnosis the subjects underwent spontaneous non-intrusive experiences of other selves which were not recalled after the end of the session, due to post-hypnotic amnesia. The fMRI showed a significant decrease of connectivity in the Default Mode Network (DMN) especially between the posterior cingulate cortex and the medial prefrontal cortex. Our results and their contrast with the available data on fMRI in DIDs allows to draw the hypothesis of a continuum between healthy mind - where multiple identities may coexist at unconscious level and may sometimes emerge to the consciousness - and DIDs, where multiple personalities emerge as dissociated, ostensibly autonomous components yielding impaired functioning, subject's loss of control and suffering. If this is the case, it seems more reasonable to refrain from seeking for a clear-cut limit between normality (anyway a conventional, statistical concept) and pathology, and accept a grey area in between, where ostensibly odd but non-pathological experiences may occur (including so-called non-ordinary mental expressions) without calling for treatment but, rather, for being properly understood.

Are Cerebral Perfusion and Atrophy Linked in Multiple Sclerosis? Evidence for a Multifactorial Approach to Assess Neurodegeneration.

BACKGROUND: Grey Matter (GM) atrophy has been extensively described in Multiple Sclerosis (MS) patients, while cerebral hypoperfusion has been less consistently reported. Since hypoperfusion might be related to atrophy, we evaluated the presence of both damages. OBJECTIVE: We aimed to assess if the regions of altered perfusion and atrophy overlapped with one another and if the two parameters were locally related. METHOD: 3D-T1 weighted and arterial spin labelling sequences were acquired using a 1.5T Magnetic Resonance Imaging scanner from 26 relapsing remitting MS patients and 26 Healthy Controls (HC). GM volume and Cerebral Blood Flow (CBF) differences and their correlation were tested with a voxel-wise approach. RESULTS: MS patients (41.4±12.5 years; 14 females) had a median [25th-75th percentile range] Expanded Disability Status Scale of 1.0[1.0-2.4] and a median [25th-75th percentile range] disease duration of 8.0 [4.0-16.5] years. HC were age- and sex-matched (43.9±17.4 years; 11 females). GM atrophy was detected for MS group in the right parahippocampal gyrus, thalami and left caudate (pFWE≤0.05). Areas of significant (after family-wise error -FWE- correction for multiple comparisons) (pFWE≤0.05) hypoperfusion were found for MS in the anterior cingulate and paracingulate gyri, supplementary motor cortex, precentral and superior frontal gyrus. GM volume and CBF showed a significant correlation (pFWE≤0.05) in the right lateral occipital cortex and precuneus in the MS group. CONCLUSIONS: GM atrophy and hypoperfusion in MS were located in different areas. Perfusion estimate might be used as a further marker of tissue damage, in addition to GM volume.

Serum iron concentration is associated with subcortical deep gray matter iron levels in multiple sclerosis patients.

Iron deposition has been noted widely in the subcortical deep gray matter (SDGM) of multiple sclerosis (MS) patients. Recent evidence suggests that serum iron may cross the blood-brain barrier and might be associated with SDGM iron deposition. The aim of the current study was to assess whether an iron-sensitive MRI measure is related to serum iron concentrations. This was a retrospective, cross-sectional study of 22 MS patients and 24 healthy controls (HCs), group matched for age and sex. Participants were imaged on a 1.5-T MRI scanner. High-resolution T1-weighted images and susceptibility-weighted images were acquired for assessing SDGM volumes and iron deposition within the SDGM, respectively. All participants also had blood drawn for the measurement of serum iron concentrations. MS and HC groups were compared with respect to SDGM tissue volumes and iron content. Partial correlations, controlling for age, sex, and structural volume, were used to assess the relationship between serum iron and SDGM iron content. MS patients presented with significantly smaller SDGM tissue volumes of the caudate, globus pallidus, putamen, and thalamus (all P≤0.0001). With respect to HCs, increased iron content was observed for MS patients in the globus pallidus (P=0.009) only. In MS patients only, there was a significant relationship between serum iron and putaminal iron volume (partial r=0.449, P=0.041), whereas trends were evidenced for the caudate (partial r=0.396, P=0.078) and the globus pallidus (partial r=0.410, P=0.065). Serum iron content in MS patients may be related to SDGM iron content. These results warrant confirmation in a larger study of MS patients.

Cardiac, Respiratory and Postural Influences on Venous Return of Internal Jugular and Vertebral Veins.

It is known from physiology that heartbeat and respiration influence venous return, but little is known regarding the extent to which these two factors affect flow. In this study, we estimated the prevalence of cardiac- and breathing-induced venous flow modulations in the internal jugular vein (IJV) and vertebral vein (VV) and the effects of posture. In 19 healthy patients, neck vein flow was examined with pulsed wave Doppler. Electrocardiogram and respiratory signals were simultaneously acquired. In supine position, heart contraction always influenced venous flow, whereas breathing influenced 68% of IJV and 34% of VV flow. In sitting position, heart contraction influenced 74% of IJV and 42% of VV flow; breathing influenced 68% of IJV and 61% of VV measures. Thus, cardiac influence is greatly present in supine position, whereas breathing influence prevails in the VV while sitting. This setup allowed us to observe that in some patients, expiration may cause an unexpected increase in venous flow.

Hypnotism as a Function of Trance State Effects, Expectancy, and Suggestibility: An Italian Replication.

Previous research using stepwise regression analyses found self-reported hypnotic depth (srHD) to be a function of suggestibility, trance state effects, and expectancy. This study sought to replicate and expand that research using a general state measure of hypnotic responsivity, the Phenomenology of Consciousness Inventory: Hypnotic Assessment Procedure (PCI-HAP). Ninety-five participants completed an Italian translation of the PCI-HAP, with srHD scores predicted from the PCI-HAP assessment items. The regression analysis replicated the previous research results. Additionally, stepwise regression analyses were able to predict the srHD score equally well using only the PCI dimension scores. These results not only replicated prior research but suggest how this methodology to assess hypnotic responsivity, when combined with more traditional neurophysiological and cognitive-behavioral methodologies, may allow for a more comprehensive understanding of that enigma called hypnosis.

White Matter Tract Injury is Associated with Deep Gray Matter Iron Deposition in Multiple Sclerosis.

BACKGROUND AND PURPOSE: With respect to healthy controls (HCs), increased iron concentrations in the deep gray matter (GM) and decreased white matter (WM) integrity are common findings in multiple sclerosis (MS) patients. The association between these features of the disease remains poorly understood. We investigated the relationship between deep iron deposition in the deep GM and WM injury in associated fiber tracts in MS patients. METHODS: Sixty-six MS patients (mean age 50.0 years, median Expanded Disability Status Scale 5.25, mean disease duration 19.1 years) and 29 HCs, group matched for age and sex were imaged on a 1.5T scanner. Susceptibility-weighted imaging and diffusion tensor imaging (DTI) were used for assessing high-pass filtered phase values in the deep GM and normal appearing WM (NAWM) integrity in associated fiber tracts, respectively. Correlation analyses investigated the associations between filtered phase values (suggestive of iron content) and WM damage. RESULTS: Areas indicative of increased iron levels were found in the left and right caudates as well as in the left thalamus. MS patients presented with decreased DTI-derived measures of tissue integrity in the associated WM tracts. Greater mean, axial and radial diffusivities were associated with increased iron levels in all three GM areas (r values .393 to .514 with corresponding P values .003 to <.0001). Global NAWM diffusivity measures were not related to mean filtered phase values within the deep GM. CONCLUSIONS: Increased iron concentration in the deep GM is associated with decreased tissue integrity of the connected WM in MS patients.

Combined DTI-fMRI Analysis for a Quantitative Assessment of Connections Between WM Bundles and Their Peripheral Cortical Fields in Verbal Fluency.

Diffusion tensor imaging (DTI) tractography and functional magnetic resonance imaging (fMRI) are powerful techniques to elucidate the anatomical and functional aspects of brain connectivity. However, integrating these approaches to describe the precise link between structure and function within specific brain circuits remains challenging. In this study, a novel DTI-fMRI integration method is proposed, to provide the topographical characterization and the volumetric assessment of the functional and anatomical connections within the language circuit. In a group of 21 healthy elderly subjects (mean age 68.5 ± 5.8 years), the volume of connection between the cortical activity elicited by a verbal fluency task and the cortico-cortical fiber tracts associated with this function are mapped and quantified. An application of the method to a case study in neuro-rehabilitation context is also presented. Integrating structural and functional data within the same framework, this approach provides an overall view of white and gray matter when studying specific brain circuits.

An anatomy-based lumped parameter model of cerebrospinal venous circulation: can an extracranial anatomical change impact intracranial hemodynamics?

BACKGROUND: The relationship between extracranial venous system abnormalities and central nervous system disorders has been recently theorized. In this paper we delve into this hypothesis by modeling the venous drainage in brain and spinal column areas and simulating the intracranial flow changes due to extracranial morphological stenoses. METHODS: A lumped parameter model of the cerebro-spinal venous drainage was created based on anatomical knowledge and vessels diameters and lengths taken from literature. Each vein was modeled as a hydraulic resistance, calculated through Poiseuille's law. The inputs of the model were arterial flow rates of the intracranial, vertebral and lumbar districts. The effects of the obstruction of the main venous outflows were simulated. A database comprising 112 Multiple Sclerosis patients (Male/Female = 42/70; median age ± standard deviation = 43.7 ± 10.5 years) was retrospectively analyzed. RESULTS: The flow rate of the main veins estimated with the model was similar to the measures of 21 healthy controls (Male/Female = 10/11; mean age ± standard deviation = 31 ± 11 years), obtained with a 1.5 T Magnetic Resonance scanner. The intracranial reflux topography predicted with the model in cases of internal jugular vein diameter reduction was similar to those observed in the patients with internal jugular vein obstacles. CONCLUSIONS: The proposed model can predict physiological and pathological behaviors with good fidelity. Despite the simplifications introduced in cerebrospinal venous circulation modeling, the key anatomical feature of the lumped parameter model allowed for a detailed analysis of the consequences of extracranial venous impairments on intracranial pressure and hemodynamics.

Cerebrospinal fluid flow dynamics in multiple sclerosis patients through phase contrast magnetic resonance imaging.

We studied cerebrospinal fluid (CSF) flow dynamics at the cervical level in association with internal jugular veins (IJV) flow for 92 patients with multiple sclerosis (MS). Phase contrast magnetic resonance imaging was used to quantify flow of the CSF and major vessels (including the IJV and the carotid arteries) at the C2-C3 level in the neck. Contrast enhanced MR angiography and time-of-flight MR venography were used to subdivide MS patients into stenotic (ST) and non-stenotic (NST) populations. We evaluated: IJV flow normalized by arterial flow; CSF peaks; CSF outflow duration and its onset from systole. We tested if these variables were statistically different among different MS phenotypes and between ST and NST MS patients. The delay between the beginning of beginning of systole and the CSF outflow was higher in ST compared to NST MS. Less IJV flow was observed in ST vs NST MS. None of the measures was different between the different MS phenotypes. These results suggest that alterations of IJV morphology affect both IJV flow and CSF flow timing but not CSF flow amplitude.

Determinants of disability in multiple sclerosis: an immunological and MRI study.

Multiple sclerosis (MS) is characterized by a wide interpatient clinical variability and available biomarkers of disease severity still have suboptimal reliability. We aimed to assess immunological and MRI-derived measures of brain tissue damage in patients with different motor impairment degrees, for in vivo investigating the pathogenesis of MS-related disability. Twenty-two benign (B), 26 secondary progressive (SP), and 11 early, nondisabled relapsing-remitting (RR) MS patients and 37 healthy controls (HC) underwent conventional and diffusion tensor brain MRI and, as regards MS patients, immunophenotypic and functional analysis of stimulated peripheral blood mononuclear cells (PBMC). Corticospinal tract (CST) fractional anisotropy and grey matter volume were lower and CST diffusivity was higher in SPMS compared to RRMS and BMS patients. CD14+IL6+ and CD4+IL25+ cell percentages were higher in BMS than in SPMS patients. A multivariable model having EDSS as the dependent variable retained the following independent predictors: grey matter volume, CD14+IL6+ and CD4+IL25+ cell percentages. In patients without motor impairment after long-lasting MS, the grey matter and CST damage degree seem to remain as low as in the earlier disease stages and an immunological pattern suggestive of balanced pro- and anti-inflammatory activity is observed. MRI-derived and immunological measures might be used as complementary biomarkers of MS severity.

Effects of Bacille Calmette-Guerin after the first demyelinating event in the CNS.

OBJECTIVE: To evaluate Bacille Calmette-Guérin (BCG) effects after clinically isolated syndromes (CIS). METHODS: In a double-blind, placebo-controlled trial, participants were randomly assigned to receive BCG or placebo and monitored monthly with brain MRI (6 scans). Both groups then entered a preplanned phase with IM interferon-ß-1a for 12 months. From month 18 onward, the patients took the disease-modifying therapies (DMTs) that their neurologist considered indicated in an open-label extension phase lasting up to 60 months. RESULTS: Of 82 randomized subjects, 73 completed the study (33 vaccinated and 40 placebo). During the initial 6 months, the number of cumulative lesions was significantly lower in vaccinated people. The relative risks were 0.541 (95% confidence interval [CI] 0.308-0.956; p = 0.03) for gadolinium-enhancing lesions (the primary endpoint), 0.364 (95% CI 0.207-0.639; p = 0.001) for new and enlarging T2-hyperintense lesions, and 0.149 (95% CI 0.046-0.416; p = 0.001) for new T1-hypointense lesions. The number of total T1-hypointense lesions was lower in the BCG group at months 6, 12, and 18: mean changes from baseline were -0.09 ± 0.72 vs 0.75 ± 1.81 (p = 0.01), 0.0 ± 0.83 vs 0.88 ± 2.21 (p = 0.08), and -0.21 ± 1.03 vs 1.00 ± 2.49 (p = 0.02). After 60 months, the cumulative probability of clinically definite multiple sclerosis was lower in the BCG + DMT arm (hazard ratio = 0.52, 95% CI 0.27-0.99; p < 0.05), and more vaccinated people remained DMT-free (odds ratio = 0.20, 95% CI 0.04-0.93; p = 0.04). CONCLUSIONS: Early BCG may benefit CIS and affect its long-term course. CLASSIFICATION OF EVIDENCE: BCG, as compared to placebo, was associated with significantly reduced development of gadolinium-enhancing lesions in people with CIS for a 6-month period before starting immunomodulating therapy (Class I evidence).

Atlas-based versus individual-based fiber tracking of the corpus callosum in patients with multiple sclerosis: reliability and clinical correlations.

BACKGROUND AND PURPOSE: In multiple sclerosis (MS), the presence of lesions and normal-appearing white matter damage may affect the reliability of diffusion tensor (DT) magnetic resonance imaging (MRI)-based tractography. We compared the performance of an individual-based method for corpus callosum (CC) fiber tracking in MS with those of two atlas-based methods. METHODS: Brain DT MRI scans were acquired from 35 patients with MS and 18 age-matched healthy volunteers (HV). DT-derived metrics from the CC-the mean diffusivity (MD) and fractional anisotropy (FA)-were calculated using an individual-based and two atlas-based methods with different types of subject registration (linear and nonlinear) to a CC atlas. Customized termination criteria were applied to stop the tracking algorithm when using the individual-based method. RESULTS: All the methods were able to distinguish between MS patients and HV. Using the individual-based method, stronger relationships were found between CC DT-derived metrics and the subjects' clinical condition. CONCLUSION: CC DT tractography using an individual-based method is more sensitive than the atlas-based ones to tract-specific alterations related to MS disability. An atlas-based method with nonlinear registration can be a valid alternative when an automated postprocessing is warranted, such as in the case of high volumes of data.

A novel approach of fMRI-guided tractography analysis within a group: construction of an fMRI-guided tractographic atlas.

Diffusion Tensor Imaging (DTI) tractography and functional Magnetic Resonance Imaging (fMRI) investigate two complementary aspects of brain networks: white matter (WM) anatomical connectivity and gray matter (GM) function. However, integration standards have yet to be defined; namely, individual fMRI-driven tractography is usually applied and only few studies address group analysis. This work proposes an efficient method of fMRI-driven tractography at group level through the creation of a tractographic atlas starting from the GM areas activated by a verbal fluency task in 11 healthy subjects. The individual tracts were registered to the MNI space. Selection ROIs derived by GM masking and dilation of group activated areas were applied to obtain the fMRI-driven subsets within tracts. An atlas of the tracts recruited among the population was obtained by selecting for each subject the fMRI-guided tracts passing through the high probability voxels (the voxels recruited by the 90% of the subjects) and merging them together. The reliability of this approach was assessed by comparing it with the probabilistic atlas previously introduced in literature. The introduced method allowed to successfully reconstruct activated tracts, which comprehended corpus callosum, left cingulum and arcuate, a small portion of the right arcuate, both cortico-spinal tracts and inferior fronto-occipital fasciculi. Moreover, it proved to give results concordant with the previously introduced probabilistic approach, allowing in addition to reconstruct 3D trajectories of the activated fibers, which appear particularly helpful in the detection of WM connections.

Chronic cerebrospinal venous insufficiency in multiple sclerosis: clinical correlates from a multicentre study.

BACKGROUND: Chronic cerebrospinal venous insufficiency (CCSVI) has recently been reported to be associated with multiple sclerosis (MS). However, its actual prevalence, possible association with specific MS phenotypes, and potential pathophysiological role are debated. METHOD: We analysed the clinical data of 710 MS patients attending six centres (five Italian and one Canadian). All were submitted to venous Doppler sonography and diagnosed as having or not having CCSVI according to the criteria of Zamboni et al. RESULTS: Overall, CCSVI was diagnosed in 86% of the patients, but the frequency varied greatly between the centres. Even greater differences were found when considering singly the five diagnostic criteria proposed by Zamboni et al. Despite these differences, significant associations with clinical data were found, the most striking being age at disease onset (about five years greater in CCSVI-positive patients) and clinical severity (mean EDSS score about one point higher in CCSVI-positive patients). Patients with progressive MS were more likely to have CCSVI than those with relapsing-remitting MS. CONCLUSION: The methods for diagnosing CCSVI need to be refined, as the between-centre differences, particularly in single criteria, were excessively high. Despite these discrepancies, the strong associations between CCSVI and MS phenotype suggest that the presence of CCSVI may favour a later development of MS in patients with a lower susceptibility to autoimmune diseases and may increase its severity.