Hypercapnia and hypoxaemia due to impaired venous blood draining and significant improvement after endovascular treatment in patients with chronic cerebrospinal venous insufficiency

Introduction

It is well known that in many diseases, for example: acute mountain sickness, carbon dioxide intoxication, and chronic obstructive pulmonary disease, cerebral hypoxaemia is directly associated with cognitive disorders. It is also known that multiple sclerosis (MS) patients exhibit significant hypoperfusion of the brain [1-6]. However, it remains unclear whether cognitive disorders seen in MS patients are related to brain ischaemia, or rather to the neurodegeneration that is a hallmark of this neurological disease. Nonetheless, an observation that endovascular treatment of MS-associated extracranial venous abnormalities, so-called chronic cerebrospinal venous insufficiency (CCSVI), results in an improvement of some symptoms of MS, such as: chronic fatigue, dizziness, diplopia, dysarthria, and paraesthesia, may suggest that impairment of brain perfusion can be responsible for these symptoms of MS.
In some MS patients an improvement of clinical symptoms of MS is seen immediately after endovascular angioplasty of the narrowed veins. Given the rapid improvement of the clinical status of these patients, we suspected that this change was not due to a weakened autoimmunity, but rather due to the recovery of an easily changeable pathology, such as hypoxia and hypercapnia of the brain. A number of studies have revealed impaired functioning of the brain in the settings of hypoxia and hypercapnia [7-11]. Also, hypercapnia of the brain can result in disassembling of the blood-brain barrier [12, 13].

Aim of the study

The aim of this study was to investigate if the venous blood coming from the brain and spinal cord indeed contains abnormally low concentration of oxygen and increased concentration of carbon dioxide in comparison with individuals without CCSVI, and whether these blood gas parameters improve after successful endovascular angioplasty of abnormal veins.

Material and methods

A total of 178 patients with sonographically-proven CCSVI (using the so-called Zamboni’s criteria [14]) and clinically defined MS (95 women and 83 men) were included after signing informed consent. The study design, protocol, and methods were approved by the Local Ethics Committee. The patients were aged 41.7 ±8.8 years. They were self-referred and reported an MS diagnosis from their local neurologists. The mean value of the patients’ EDSS (Extended Disability Status Scale) was 5.1. Mean duration of the disease was 8.6 years. The majority of patients (54%) presented with relapsing-remitting clinical type of MS, while others were diagnosed with progressive forms of MS. The control group comprised 50 individuals (26 women and 24 men), aged 42.1 ±9.5 years, who underwent other diagnostic or interventional procedures negative for CCSVI and MS. These patients did not present with signs of cardiovascular or respiratory failure. The controls, similarly to MS patients, also underwent sonographic scanning of veins of the neck using the Zamboni’s criteria of CCSVI.
With the use of femoral access, in all patients from both groups, we introduced a diagnostic catheter into both internal jugular veins and the azygous vein. Through this catheter we drew blood samples from all the above-mentioned veins in the control group (from the internal jugular veins: from one side), whilst in MS patients the samples were drawn only from the veins that presented with at least 50% stenosis (343 out of 356 internal jugular veins and 163 out of 178 azygous veins). We obtained such blood samples before the endovascular procedure and five minutes after patency of the vein had been successfully restored (using balloon angioplasty or stenting). In all patients (MS patients and controls) we also drew blood samples from the access site (femoral vein). We immediately performed gas analysis of blood samples and evaluated the following gasometric parameters: partial pressure of oxygen (pO₂), partial pressure of carbon dioxide (pCO₂) and oxygen saturation (SatO₂). The study was approved by the local ethical committee.
Statistical analysis was performed using Student’s t test to verify the hypothesis that concentrations of O2 and CO2 differed significantly between CCSVI patients and controls, and that these blood gas parameters changed significantly after endovascular treatment of pathological veins. The significance of the p value was set at < 0.05.

Results

Sonographic assessment revealed the signs of CCSVI in all 178 MS patients, while none of the controls was diagnosed with CCSVI. Catheter venography demonstrated abnormalities in all assessed MS patients: in 165 patients (92.7%) in both internal jugular veins, and in 13 patients (7.3%) in one internal jugular vein. The majority of these abnormal veins (239 veins) presented with 50-80% stenosis, 104 internal jugular veins were found to be stenosed more than 80%. In addition, we found 163 stenosed azygous veins (91.6%) – there were 116 azygous veins with 50-80% stenosis and 47 veins stenosed more than 80%.
Values of gasometric parameters of blood samples obtained from control individuals are presented in Table 1. All parameters (pO₂, pCO₂ and SatO₂) were within normal ranges and there were no statistically significant differences between blood samples drawn from the femoral, azygous, and internal jugular veins (p < 0.05). Similarly, gasometric parameters of blood samples drawn from the femoral veins in MS patients were normal, and there were no statistically significant differences between controls and MS patients (Table 2).
Conversely, blood samples taken from the internal jugular veins in MS patients revealed hypercapnia and hypoxaemia, with the values significantly different from those of the controls (Table 3). Blood samples taken from the azygous veins in MS patients revealed significant hypercapnia, but not hypoxaemia (Table 4). After endovascular treatment of the stenoses most of the abnormal blood gas parameters improved significantly; in the internal jugular veins – all parameters studied (Table 5), while in the azygous vein – pCO₂ and pO₂ improved, but SatO₂ remained unchanged (Table 6).

Discussion

For the first time Zamboni et al. demonstrated in a small pilot study that there is a significant relationship between the severity of CCSVI and hypoperfusion in the brain parenchyma. The authors comment that these preliminary findings should be confirmed in a larger cohort of MS patients to ensure that they generalise to the MS population as a whole. Reduced perfusion could contribute to the known mechanisms of virtual hypoxia in degenerated axons [15].
Another working group of Utriainen used magnetic resonance imaging (MRI) as an imaging method in MS patients and CCSVI. The authors analysed vascular structure and flow as well as brain iron content. They confirmed that in MS patients there is impairment both in major vessels and in the brain. Also in that study it was suggested that the presence of high iron content may indirectly indicate progression of existing vascular pathology [5].
In our study we demonstrated hypercapnia and hypoxaemia of venous blood draining the brain and spinal cord in MS patients, and improvement of these blood gas parameters after endovascular treatment of pathologically changed veins. Of note, MS patients and controls presented with the same blood gas parameters in the femoral veins, so the difference was probably primarily due to stenoses of the internal jugular and azygous veins.
A number of studies have demonstrated an association of CCSVI with MS [1, 6, 7, 16], and it was hypothesised that impaired cerebral venous drainage may lead to local venous hypertension and dysfunction of the blood-brain barrier, which in turn may evoke autoimmune reaction and neurodegeneration [17]. Still, an association of CCSVI with MS was not confirmed by many authors, probably not only because of the different diagnostic protocols used, but primarily due to much a more complex relationship between CCSVI and MS than was initially believed [18].
We measured pO₂, pCO₂, and SatO₂ in the internal jugular and azygous veins. Therefore, we cannot rule out the possibility that altered blood gas parameters did not reflect the actual hypercapnia and hypoxaemia of the central nervous system. It is also likely that local stasis of blood in abnormal extracranial veins could be responsible. Also, it was possible that hypercapnia and hypoxaemia in blood samples drawn from the internal jugular veins were partially caused by asymmetric venous outflow from the brain [16, 19, 20]. Still, the studies utilising perfusion MRI have shown that MS patients exhibit significant hypoperfusion of the brain [1-5]. Thus, it is reasonable to suggest that MS patients present with hypercapnia and hypoxaemia of the brain and spinal cord, which are at least partially caused by CCSVI, and that this pathological condition can be improved using an endovascular approach. It is unclear, however, if this beneficial effect is long lasting and has any influence on the natural course of MS. We suggest that future research should answer these questions.

The authors declare no conflict of interest.

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