Chronic cerebrospinal venous insufficiency in multiple sclerosis: a highly prevalent age-dependent phenomenon

Version vom 24. Februar 2013, 12:41 Uhr

Quelle: http://www.biomedcentral.com/content/pdf/1471-2377-13-20.pdf

RESEARCH ARTICLE Open Access

Chronic cerebrospinal venous insufficiency in multiple sclerosis: a highly prevalent age-dependent phenomenon

Chronisch cerebospinale venöse Insuffizienz bei Multipler Sklerose: Ein weitverbreitetes, altersabhängiges Phänomen

Roberta Lanzillo (1,5†), Marcello Mancini (2,3†), Raffaele Liuzzi (2,4*†), Orlando Di Donato (4), Elena Salvatore (4), Valentina Maglio (4), Giovanni Vacca (4), Luca Amato (1), Gennaro D’Anna (4), Arturo Brunetti (4) and Vincenzo Brescia Morra (1)

Abstract

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.

Ziel dieser Studie war es, die Prävalenz und klinische Relevanz der chronischen venösen Insuffizienz (CCSVI) bei Patienten mit Multipler Sklerose (MS) und bei gesunden Kontrollpersonen mit extra- und intrakraniellen Farb-Doppler-Sonographie zu untersuchen.

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.

Wir untersuchten 146 MS-Patienten, entweder mit einem klinisch isolierten Syndrom, schubförmiger, sekundär progredienter oder primär progredienter MS und 38 gesunden Kontrollpersonen. Die Ultraschalluntersuchung wurde nach dem Zamboni-Protokoll durchgeführt und von drei unabhängigen Untersuchern durchgeführt. Die Ergebnisse der Sonographie wurden mit klinischen und demographischen Charakteristika der Patienten verglichen.

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).

CCSVI, definiert durch Anwesenheit von mindestens zwei positive Zambonis Kriterien, wurde bei 76% der MS-Patienten und 16% der Kontrollpersonen gefunden. B-Modus-Anomalien der internen Jugular-Venen, wie Stenose, missgebildete Venenklappen, annuli und Septen waren die häufigsten Läsionen, die bei MS-Patienten (80,8%) und bei Kontrollpersonen (47,4%) nachgewiesen wurden. Wir beobachteten eine positive Korrelation zwischen der sonographischen Diagnose von CCSVI und dem Alter des Patienten (p = 0,003). Solch eine Korrelation wurde aber nicht in der Kontrollgruppe gefunden (p = 0,635). Insbesondere wurden keine signifikanten Korrelationen zwischen sonographischen Zeichen der CCSVI und klinischen Charakteristika der MS gefunden, außer für die Abwesenheit von Fluss in den Jugularvenen, welche häufiger bei primär progressiven (p<0,005) und sekundär progressiven (p<0,05) Patienten im Vergleich zu nicht-progressiven Patienten. Keine Strömung in den Jugularvenen war signifikant korreliert mit dem Alter der Patienten (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.

Sonographisch festgestellte CCSVI ist bei MS-Patienten häufig. Jedoch scheint CCSVI in erster Linie mit dem Alter des Patienten in Verbindung zu stehen, und kaum mit dem klinischen Verlauf der Erkrankung.

Keywords:

Multiple sclerosis, Venous insufficiency, Ultrasonography

Background

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by inflammation, demyelination, and neurodegeneration [1]. However, neuropathological studies have underlined the presence of a subset of patients with a pattern that closely mimics tissue alterations found in the early stages of white matter ischemia [2]. Moreover, cerebral perfusion studies have shown diffuse hypoperfusion in patients with MS compared with age-matched controls with a greater cerebral blood flow decrease in primary progressive (PP) MS compared with relapsing-remitting (RR) MS [3]. Recently, a strong correlation between MS and a vascular condition called chronic cerebrospinal venous insufficiency was reported [4].

Multiple Sklerose (MS) ist eine Autoimmunerkrankung des zentralen Nervensystems (ZNS), charakterisiert durch Entzündung, Demyelinisierung und Neurodegeneration [1]. Allerdings haben neuropathologische Untersuchungen das Vorhandensein einer Untergruppe von Patienten gezeigt mit einem Muster, bei denen Ersatzgewebe gefunden wurde in einem frühen Stadium der Zerstörung der Weißen Substanz. Darüberhinaus haben zerebrale Durchfluß-Studien diffuse Minderperfusion bei Patienten mit MS gezeigt, verglichen mit gleichaltrigen Kontrollpersonen, mit einer größeren Verminderung der Hirndurchblutung bei primär progredienter (PP) MS verglichen mit schubförmiger (RR) MS [3]. Kürzlich wurde eine starke Korrelation zwischen MS und einer vaskulären Erkrankung, namens chronische venöse Insuffizienz, rapportiert [4].

Chronic cerebrospinal venous insufficiency (CCSVI) is characterized by anomalies of the main extracranial cerebrospinal venous routes. CCSVI is detected by selective venography [4-10] and extracranial venous echo-colour Doppler (ECD) [4,9-12] with higher sensitivity and specificity than magnetic resonance venography (MRV) [9]. The prevalence of CCSVI in MS patients is highly variable [4,10,11,13]. The largest study conducted to determine the prevalence of CCSVI in patients with MS, those with clinically isolated syndrome (CIS), those with other neurological diseases, and healthy controls (HCs), using echocolor Doppler (ECD), showed an increased prevalence of CCSVI in MS [14]. This finding suggests that CCSVI does not have a primary causative role in the development of MS. However, perfusion studies have shown a decrease in cerebral perfusion in MS subjects and HCs with CCSVI [15,16].

To date, there are only few studies regarding the relationship between venous abnormalities, phenotype, and the clinical course of MS [17-19], with different and sometimes conflicting results.

This study aimed to investigate the prevalence of CCSVI in a representative MS population and HCs using ECD. We also investigated the clinical relevance and correlations of CCSVI with MS disease parameters.

Methods

Patients
This single-centre, cross-sectional study included 171 consecutive MS patients and 41 sex- and age-matched HCs. Inclusion criteria were diagnosis of MS, according to the McDonald criteria [20], including RR, secondary progressive (SP) MS, and PPMS, as defined by Lublin [21], and diagnosis of CIS. The HC group included relatives of MS patients and healthy volunteers. For all patients, exclusion criteria were the presence of relapse and steroid treatment in the 30 days preceding study entry and, for HCs, a history of cerebral congenital vascular malformations and pre-existing medical conditions known to be associated with brain pathology (e.g., cerebrovascular disease and a positive history of alcohol abuse).

Study assessment
All of the participants underwent a clinical examination and intra- and extracranial ECD of the neck in the same week. Biochemistry was performed to exclude haematological or other medical conditions that could affect haemorheology. Standard demographic and clinical information on all participating subjects were acquired. This included, but was not limited to age, sex, familial history, detailed medical history of vascular risks with particular emphasis on venous diseases, age at disease onset, age at diagnosis, time interval between first and second relapses, annualized relapse rate, and current and previous therapy information. Disease onset symptoms were retrospectively recorded and classified into five categories according to the Expanded Disability Status Scale (EDSS) functional system involved: visual, pyramidal, sensory, subtentorial (cerebellar and brain-stem), and spinal symptoms. Actual disease phenotype was also assessed and divided into the same five categories, according to the most disabled functional system at the time of evaluation. A physical examination was performed with measurement of blood pressure, and EDSS [22] and single EDSS functional systems scores, and Multiple Sclerosis Severity Scale (MSSS) [23] scores were calculated, and disease subtype was classified.

Standard protocol approvals, registrations, and patient consents
This study was approved by the “Carlo Romano” ethics committee of the Federico II University of Naples, and informed consent was obtained from all subjects.

Colour Doppler sonography evaluation
Colour Doppler sonography was performed by the same radiologist (MM with greater than 20 years of vascular ultrasound experience) with the iU22 Ultrasound System (Philips, Amsterdam, The Netherlands) equipped with a 3.0–9.0 MHz linear wide-band transducer, a 5.0–8.0 MHz microconvex probe, and a 1.0–5.0 MHz phased array transcranial probe.

Intracranial and extracranial venous outflow were evaluated according to the Zamboni criteria, based on the detection of five criteria as previously described [4]. A subject was considered CCSVI-positive if two or more Zamboni criteria were fulfilled. The radiologist that performed ECD was not blinded to the disease status of patients.

The images were stored and anonymously coded with an identification number. A further evaluation was performed off-line and independently repeated twice by two blinded radiologists (OD, VM) who reviewed all the images. The CCSVI diagnosis was considered valid only if the findings of the three radiologists agreed for each single criterion.

Statistical analysis
Continuous data are reported as mean and standard deviation or median and range, and categorical data as percentages. For descriptive statistics and estimates of prevalence, the t-test, the U-test (Mann–Whitney), Fisher’s exact test, and the χ2 test were used. Despite the fact that diagnosis of MS is not a gold standard test to diagnose CCSVI, sensitivity, specificity, and relative odds ratios (ORs) between HCs and patients with MS were calculated, using direct computation from 2 × 2 tables, to obtain results easily comparable with previous studies [4,14]. Prevalence rates for each of the five Zamboni criteria, as well as for different CCSVI presence groups, were calculated. Residual analysis was performed to assess differences in the distribution of these venous criteria among MS subtypes. Logistic regression techniques were used to evaluate correlations between CCSVI presence and clinical parameters. Significance was denoted when p was <0.05