We aimed to evaluate cerebral hemodynamics and assess autonomic dysfunction in patients with MS and explore its relationship with disease status.
In our study, we compared blood pressure measurements in supine and erect positions and the incidence of postural hypotension as an indicator of cardiac autonomic dysfunction (CAD). Blood pressure test shows statistically significant difference between both groups as regards systolic and diastolic readings in the supine position. The mean value of systolic reading was 117.75 ± 4.8 mmHg in the RRMS group and 123.5 ± 9.75 mmHg in the SPMS group. Chi-square test showed significant difference as regards postural hypotension; 35% of the patients in the RRMS group had postural hypotension in comparison with 65% of the patients in the SPMS group.
These findings were in agreement with previous studies which found that orthostatic symptoms, which are among the symptoms commonly associated with CAD, were reported in 61% of 104 patients with RRMS in a study from Croatia, and in 24% of 100 MS patients in a Turkish study. Nevertheless, in both studies, the authors did not distinguish between different forms of orthostatic dysfunction such as dizziness, palpitation, or syncope [11]. This was, however, done in an Iraqi study: in 55 MS patients and 40 age-matched controls, postural dizziness was present in 67% of patients and 33% of controls [12]. In a German study (27 RRMS, 13 SPMS), 50% of the patients reported orthostatic dizziness compared with 17% of controls [13].
Also, we found that the prevalence of postural hypotension occurred more with infratentorial lesions (38.46%) followed by periventricular lesions (35%) in the RRMS study group but does not reach statistical significance; on the other hand, in the SPMS study group, the prevalence of postural hypotension occurred more with cervical lesions (66.67%) followed by periventricular lesions (65%) and infratentorial lesions (63.16%) although it does not reach statistical significance. This was in agreement with two studies reported significant association between presence of CAD and clinical (p < 0.02) and MRI (p < 0.005) evidence of brainstem lesions while a Finnish study done on 51 MS patients and 50 controls reported a significant association between the total volume of midbrain MRI lesions and impaired BP response. In contrast, an earlier study from the Netherlands was not able to find a correlation between the number and size of brainstem lesions and abnormalities in autonomic parameters [14].
As regards TCCD findings, in this study, there is statistically significant difference as regards the MCA blood flow monitoring in supine and erect positions between both groups. The percentage of decrease in mean MCA flow upon raising to upright position was more among SPMS patients as it decreased by − 1.9% (− 12.5 to 3.7%) among the RRMS group and − 5.7% (− 30.1 to 18.3%) among the SPMS group; however, it did not reach statistical significance. These findings support data by Gonul and colleagues who stated that arterial response to postural variation is a reliable method to assess cerebral autoregulation and may depend on autonomic and neurocardiogenic control systems of cerebral perfusion [15]. These results are consistent with Gonul et al.’s study conducted on 20 RRMS patients and found that the mean cerebral BFV values that were obtained upon raising to the upright position were found to be significantly lower in comparison with the recorded baseline values. The reduction of mean cerebral BFV values after being raised to the upright position was more significant in patients with MS than in control subjects especially in the subgroup with EDSS > 2. This finding suggests a potential correlation between impaired mean cerebral blood flow responses and MS [15].
In Gonul et al.’s study, they found no relationship between the lesion locations on MRI and the changes of CBFV during head up tilt in patients with MS [15]. The same in our study, there is no statistically significant correlation between site of lesions and percentage of decrease in MCA blood flow, whereas, it is noticed that the percentage of decrease in CBFV upon changing position increased as the number of lesions increased and with the presence of brain atrophy but does not reach statistical significance. The percentage of decrease in MCA blood flow in sitting position shows significant correlation with Multiple Sclerosis Severity Scale (MSSS) and duration of illness in the SPMS group, whereas the correlation between the % of change in CBFV and EDSS does not reach statistical significance in both groups. This may be explained as the MSSS is more powerful and sensitive than the other methods for detecting disease progression.
As regards assessment of cerebral vasomotor reactivity (CVR) by BHI, in this study, BHI values were 0.64 (0.28–0.95) among the RRMS group and 0.34 (0.29–0.41) among the SPMS group. There is statistically significant difference as it is impaired in 90% of cases in SPMS in comparison with only 55% of cases in the RRMS group. These results were in agreement with Lattanzi and colleagues who reported that lower values of MCA were recorded in MS patients than in healthy controls both at rest and at the end of breath holding. BHI values obtained in healthy controls and RRMS and SPMS patients were 1.15 ± 0.11, 0.87 ± 0.18, and 0.51 ± 0.20, respectively. Group-wise, patients showed decreased CVR in comparison to controls and BHI values were significantly lower in SPMS than in RRMS patients [16]. There is no statistically significant correlation between BHI and EDSS, MSSS, the duration of illness, and the number and site of lesions in MRI. In agreement with our findings, another study reported that at linear regression analysis, the disease form was significantly associated with cerebral hemodynamics being the SPMS phenotype a predictor of lower BHI values independently from age, sex, disease duration, EDSS score, and disease-modifying therapy [16]. Another study on a total of 42 patients with MS and 31 healthy controls showed that BHI was lower in patients with MS compared to healthy controls (0.70 ± 0.43 vs. 0.93 ± 0.55, P = 0.006) documenting a lower cerebrovascular response to hypercapnia. There was no correlation between patient age, EDSS, and disease duration with BHI in patients with MS [17].
As regards assessment of autonomic functions by the questionnaire, there is statistically significant difference in the autonomic questionnaire total score between both groups with mean score 2.58 ± 1.13 for the RRMS group and mean score 4.05 ± 1.04 for the SPMS group. These results are consistent with a recent study in which there is significantly higher questionnaire total scores in SPMS patients, compared with RRMS [18]. Also, in our study, all the parameters of the questionnaire are statistically significant between both groups apart from postural hypotension, sexual dysfunction, and gastroparesis. Postural hypotension and sphincteric dysfunction are the most affected parameters in the RRMS group with percentage 72.5% and 60% respectively; meanwhile, color changes and thermal abnormalities in upper and lower extremities are more affected in the SPMS group with percentage 75% and 85% respectively. This observation supports data from other studies reporting slower gastric emptying, bowel dysmotility, constipation, or fecal incontinence as common findings in MS [19].
EDSS is directly related to the total score of the autonomic questionnaire in the RRMS group, but the duration of illness shows no statistically significant correlation with the total score of the autonomic questionnaire. In another study, relative to the effects of disease factors, disease duration showed a weak to moderate correlation with questionnaire total score and moderate correlation between EDSS score and autonomic questionnaire total score (Rho = 0.32, p < 0.001) [18].
This study will open discussion for further research about the underlying vascular disturbance in MS and the disturbance preceding plaque formation aiming at the use of TCCD and other parameters such as MRI perfusion for early detection of disease progression and subsequently prompt treatment measures to improve quality of life.
The main strengths of the current study include the number of recruited participants, which was greater than the sample sizes of other investigations, the analysis of data according to disease stages, and the use of TCCD sonography for real-time CVR assessment. This technique has the advantage to be safe, low-cost, feasible, and easily to perform in clinical practice. Moreover, we studied autonomic dysfunction and its impact on quality of life by the autonomic questionnaire and TCCD as autonomic dysfunction is not uncommon in MS patients and thus non-invasive investigations of autonomic symptoms are warranted to optimize evaluation and disease management.
Our study has some limitations. First, TCD relies on an assumption of constant MCA diameter when interpreting changes in CBFV and this may not be true, especially during head up tilt. Secondly, CBFV is exquisitely sensitive to carbon dioxide levels which may change during head up tilt. Thirdly, correcting the angle of the probe after head up tilt could lead to a different angle insonation of the MCA that could adversely affect the results. Also, A missed statistical method that weighs the sensitivity and specificity of all tests used, as not all patients can do all these tests. Lastly, our study lacks control group as we depend on the standard measurements of MCA blood flow and BHI.