The authors have declared that no competing interests exist.
Increased neurovascular (NV) reactivity has been shown in patients with relapsing-remitting multiple sclerosis (RRMS) during the acute exacerbation period. However, the NV reactivity after several attacks is not known. We, therefore, have investigated the patients by transcranial Doppler (TCD) using simple visual stimulation after the repeated attack periods.
Thirty patients (22 females and eight males, mean age 40 years) with RRMS were examined at least two times. The average TCD examination interval was 26.7 months (range 4-120 months). Mean attack number was 3.8 (range 2-8 times), average disease duration was 57 months (range 4-124 months), and average Expanded Disability Status Scale (EDSS) value was 2.5 (range 1-5.5). We performed transcranial Doppler recordings from the P2-segments of both posterior cerebral arteries simultaneously during simple visual stimulation. The NV reactivity was defined as a relative increase of the blood flow velocities during visual stimulation.
The NV reactivity to simple visual stimulation was significantly lower in the second test on both sides (31.5±9.2% and 29.2±7.2%; right and left side, respectively) from those of the first test (38.3±11.9% and 36.0±11.9%; right and left side, respectively) (p<0.001).
The present study is the first study examining neurovascular reactivity in patients with RRMS during repeated attacks using the transcranial Doppler to our best knowledge. Our results suggest patients with RRMS after repeated exacerbation periods have less reactive neurovascular units in the occipital cortex. The possible explanation might be the repeated demyelination, and insufficient remyelination with longer disease duration may lead glial dysfunction resulting neurovascular unit impairment. If so, functional TCD may be useful for the determining of the disease progression. However, the exact cut-off point is not known.
Multiple sclerosis (MS) is a chronic disease containing the inflammatory, demyelinating, and degenerative processes of the central nervous system
There is a physical relationship between the neuronal activity and regional cerebral blood flow (CBF) related to the metabolic demand
Thirty patients (22 females and eight males, mean age 40.1±8.7 years) with RRMS who were admitted to our Neurosonology laboratory during an exacerbation period of the disease were examined at least two times. An exacerbation was defined as a rapid worsening of the symptoms lasting for more than one day in a particular area. The diagnosis of RRMS was determined according to McDonald criteria
All patients were examined clinically, and haematological investigations were performed on all of them. The Expanded DisabilityStatus Scale (EDSS) was also routinely calculated for all the patients
The TCD examination was performed within the first three days of an acute exacerbation and before any treatment. All TCD and Duplex Sonography examinations were done by the same person (NU), and the same machine was used in this study. The examiner was blinded to disease characteristics of the patients and to study timeline at the time of the examination. Caffeine and nicotine use before TCD examination was not allowed. Although cardiovascular risk factors were not estimated according to the Framingham Cardiovascular Risk Score
The simple visual stimulation was performed with a black and white checkerboard. The full instrumentation of the simple visual stimulation has been published elsewhere
The analysis of the visually evoked flow response was performed offline. NV reactivity was defined as a relative increase of the blood flow velocities as a percentage change of the baseline values NVR = 100*(Vs. Where Vs indicates the maximum velocity at stimulation (eyes open and stimulus on); the Vr, the minimum velocity at rest (eyes closed) (Figure 1). They are calculated by the special software of the TCD system that allows trigger-related blood flow velocity is averaging
The mean number of the attacks were 3.8 (range 2-8 times), and the mean disease duration was 57 months (range 14-124 months) at the date of the Doppler examination. The EDSS values of the patients were 2.5 (range 1.0–5.5). Twenty patients had mono or hemiparesis, 2 had paraparesis, 8 had ataxia, 22 had sensory disturbances, 7 had optic neuritis, and 2 had diplopia. A combination of more than two symptoms was present in most patients. NV reactivity to simple visual stimulation of patients with optic neuritis only (2 patients) was not significantly different from those of other patients, and therefore, this data was not excluded in the analysis.
A paired t-test for the samples was applied for statistical analysis, where appropriate, and p < 0.05 was accepted as the statistical significance.
The visual stimulation led to a significant blood flow velocity increase (NVC) on both sides (p < 0.001) in all the subjects. All Doppler data for the visual stimulation group is given in
| First test | Second test | P value | |
| Right-hand side | |||
| Maximum velocity (cm/s) | 49.6±12.0 | 45.4±10.2 | 0.086 |
| Minimum velocity (cm/s) | 36.2±9.9 | 34.8±8.9 | 0.478 |
| Reactivity (%) | 38.3±11.9 | 31.5±9.2 | 0.001 |
| Left-hand side | |||
| Maximum velocity (cm/s) | 47.9±10.0 | 46.4±8.4 | 0.352 |
| Minimum velocity (cm/s) | 35.4±7.9 | 35.9±6.9 | 0.618 |
| Reactivity (%) | 36.0±11.9 | 29.2±7.2 | 0.001 |
Values are mean±SD, paired sample t-test
The NV reactivity to simple visual stimulation was significantly lower in the second test on both sides (31.5±9.2% and 29.2±7.2%; right and left side, respectively) from those of the first test (38.3±11.9% and 36.0±11.9%; right and left side, respectively) (p<0.001).
Normal brain activity is subject to a continuous supply of oxygen and glucose, and local brain activity has to be gone together with an increase in local CBF. The signalling from the neurones to the local vessels are necessary for the local CBF to increase. Also, glial activation plays a role in the neurovascular coupling; especially visual stimulation
Also, neurovascular reactivity can be affected by different concomitant factors
The cerebrovascular reactivity can be measured by TCD, which allows for the real-time investigation of the velocity changes after the breath holding test
The results of the previous studies assessing NV reactivity in MS patients have shown hyperactivity to visual stimulation during an attack and just after a high-dose of intravenous corticosteroid treatment
To our best knowledge, the present study is the first one examining neurovascular reactivity in patients with RRMS after repeated attacks using the transcranial Doppler. However, the small number of cases and the variation of the second test whether about the number of attacks or relation to the disease duration are the important limitations of our study. Nonetheless, our results suggest patients with RRMS after repeated exacerbation periods have less reactive neurovascular units in the occipital cortex. The possible explanation might be the repeated demyelination, and insufficient remyelination with longer disease duration may lead not only neuronal dysfunction but also the impaired glial dysfunction. Due to limitations of the present study, we recommend a larger study with an adequate number of patients to support our explanation.