CardioVascular Autonomic Dysfunction In Multiple Sclerosis

Autonomic Dysfunction is frequently observed in patients with Multiple Sclerosis (MS), but clinical studies disagree on the frequency and type of abnormalities in Autonomic function tests.

Orthostatic Dizziness (OD) has been reported in up to 49% of patients, but the pathophysiological mechanisms are poorly understood.

This study investigated CardioVascular reflex tests and their association with OD in patients with MS in order to examine the hypothesis that the Sympathetic Nervous System is specifically involved in these patients.

Forty patients with clinically active Relapsing/Remitting (n = 27) and Secondary/Progressive MS (n = 13), aged 35.0+/-8.5 years, were studied by ParaSympathetic (Heart rate responses to the Valsalva Maneuver, Deep Breathing, and active change in posture) and Sympathetic function tests (Blood Pressure Responses to active change in posture and sustained handgrip), and by Spectral analysis of Heart rate variability during rest and during standing.

Results were compared to those obtained in 24 healthy volunteers, aged 29.4+/-7.2 years. A standardized questionnaire was used to evaluate symptoms of Orthostatic intolerance.

Abnormal responses on at least one CardioVascular reflex test were observed in 40% of MS patients, compared to 17% of the control group, with a statistically significant involvement of the Sympathetic VasoMotor System.

Orthostatic intolerance was reported in 50% of patients (controls: 14%, P<0.006). Subgroup comparison of patients with and without OD suggests that Orthostatic intolerance results from impaired Sympathetic VasoConstriction.

These results provide further evidence that the Sympathetic Nervous System is involved in patients with MS.

Objectives
Multiple Sclerosis (MS) frequently causes disturbances of Autonomic functions. CardioVascular DysAutonomia has been studied by classic Autonomic tests and, recently, by Heart rate variability analysis in some isolated periods.

Multiple authors recommended performing Heart rate variability analysis with a 24 h ECG recording to increase its sensitivity.

Materials & Methods
We analyzed the Heart rate variability in time and frequency domains in 34 MS patients and 24 age and sex-matched healthy control subjects.

In order to evaluate the effects of MS on Sympathetic and ParaSympathetic CardioVascular regulatory functions measured from 24-h electrocardiogram.

Results
Low frequency power (0.01) and low frequency/high frequency power (0.01) were significantly higher in Multiple Sclerosis patients independently, all together or in subgroups.

Very low frequency (0.01) and high frequency (0.001) power were higher in less affected Multiple Sclerosis patients. Variability in time domain (0.05) were lower in most affected Multiple Sclerosis patients.

Conclusions
These results suggest that Multiple Sclerosis causes CardioVascular Autonomic dysregulation manifesting as impaired Heart rate variability.

This illness seems to cause an increase in Sympathetic CardioVascular tone; the ParaSympathetic tone is most variable and depends on clinical and paraclinical findings, but the illness progression seems to provoke a decrease in it.

The purpose of this study was to determine whether patients with Multiple Sclerosis (MS) would show attenuated Heart rate and/or Pressor Responses to isometric handgrip exercise.

Patients with MS (30 males, 74 females, aged 23-61 yr) and control subjects (9 males, 16 females, aged 25-47 yr) performed isometric handgrip exercise at 30% of maximal voluntary contraction (MVC) to fatigue.

Systolic, Diastolic, and Mean Arterial Pressure (MAP) increased linearly in both groups, but were significantly lower (P < 0.05) in patients with MS at 20%, 40%, 60%, 80%, and 100% of exercise duration.

Mean change in MAP at fatigue was +47.9 mm Hg for controls and +28.2 mm Hg for patients with MS, with 18 patients with MS between -6 mm Hg and +15 mm Hg.

Heart rate increased normally in patients with MS. To predict change in MAP at fatigue in patients with MS, stepwise regression analysis using six variables yielded an R2 of 0.26.

These data suggest that in some patients MS lesions exist in areas of Autonomic CardioVascular control that result in attenuated Pressor Responses to exercise. In 17% of patients tested, attenuation was profound.

Data also suggest an abnormal dissociation between the Heart rate and Pressor Response to static work in patients with MS.

In Multiple Sclerosis (MS) Autonomic CardioVascular Dysfunction is an uncommon, but potentially dangerous event, to which studies of Spectral analysis of Heart rate variability have not been applied, yet.

Material & Methods
We studied 16 patients with definite MS (11 women and 5 men, mean age 30.3 +/- 7.4 yrs., mean EDSS 2.06 +/- 1.42) and 16 sex- and age-matched healthy controls.

Besides CardioVascular reflex tests (Valsalva Manoeuvre, Deep Breathing, lying to standing, Blood Pressure response to standing and sustained handgrip).

Each underwent Spectral analysis of the R-R interval short-term variability at rest and after tilting, to detect three components: very low frequency (VLF), low frequency (LF) and high frequency (HF).

A recent Brain MRI was obtained from patients, to compare plaque characteristics with Spectral parameters.

Results
At CardioVascular reflexes, only four patients (25%) showed an impairment, mostly of a mild degree.

VLF and LF at rest were lower in MS subjects than in controls (p < 0.01). No significant correlation was found between Spectral parameters and lesion area or localization as detected on MRI.

Conclusions
Spectral analysis could usefully flank reflex tests to detect Autonomic subclinical CardioVascular abnormalities.

The aim of the study was ElectroPhysiologic assessment of SudoMotor function and some aspects of CardioVascular System function in patients with Multiple Sclerosis and an attempt of referring assessed variables to duration of the disease and EDSS score.

The study included 24 patients with clinically definite, Relapsing/Remitting Multiple Sclerosis and 22 healthy, age-matched controls.

Autonomic functions were evaluated by means of clinical examination, Heart rate variability tests, measures of blood pressure in supine and standing position and Skin Sympathetic response examination.

Clinical symptoms in patients with Multiple Sclerosis were scarce. ElectroPhysiologic tests showed no abnormalities in Heart rate variability and Blood Pressure response to standing in studied group.

The majority of patients presented with subclinical dysfunction of SudoMotor System, indicated by an abnormal Sympathetic Skin response, which did not correlate with duration of the disease or EDSS score.

Sympathetic Skin response examination proved to be a sensitive indicator of Autonomic Disturbances in patients with Multiple Sclerosis.

Several studies have shown various degrees of Autonomic Dysfunction in patients with Multiple Sclerosis. Longitudinal follow-up studies are remarkably scarce up to now.

We assessed Autonomic Dysfunction twice with an interval of 1 year in 20 Relapsing/Remitting and 26 Secondary/Progressive MS-patients.

Autonomic function was assessed by the Heart rate response during deep breathing, standing up and Valsalva manoeuvre.

Only the maximum change in Heart rate after standing up (in ms and beats/min) and the Max/Min ratio after standing up showed significant worsening over 1 year.

The changes in EDSS scores also documented gradual deterioration of the neurological condition over the study period.

We conclude that there is progression of Autonomic Dysfunction in MS over 1 year and that this could correlate with progression in clinical disability.

In this study blood pressure (BP) and Heart rate (HR) responses to standing and HR responses to deep breathing were assessed in 34 patients with Clinically Definite Multiple Sclerosis (MS) and 63 healthy subjects.

Normal ranges, which were clearly age related for both HR responses, were obtained. The BP response to standing was abnormal in 13% of the MS patients, these patients demonstrating significant postural hypotension.

The HR response to standing was abnormal in 28% of the MS patients, with a normal initial increase in Heart rate and a significantly reduced reflex Bradycardia.

On deep breathing 36% of MS patients showed abnormal HR changes.

The resting HR did not differ between both groups. Abnormalities of one or more tests were found in 53% of the MS patients.

No relationship was found between abnormal CardioVascular Autonomic responses and the symptoms, duration, severity and progression of the disease.

Based on clinical and Magnetic Resonance Imaging findings, no indications were found for localization of the Autonomic disturbances in the BrainStem.

It is suggested that at least a part of the CardioVascular Autonomic lesions in MS is located outside the BrainStem, i.e. in SupraMedullary Reflex Pathways or in the Spinal Cord.

Some studies in Multiple Sclerosis (MS) patients have shown evidence of Autonomic Dysfunction involving the CardioVascular System.

However, the findings in these studies have not been completely consistent. The discrepancy may be related to the limits of the traditional Autonomic tests during wakefulness.

In our study, after the investigation of the CardioVascular reflexes during wakefulness, Heart rate (HR) variations were considered during sleep in order to avoid the limits of cooperation and the emotional state of the patient.

We evaluated tonic (vagal activity) HR modifications in relation to the deepening of sleep, as well as phasic (Sympathetic activity) HR modifications in relation to spontaneous body movements during sleep, in 25 MS patients and 25 age-matched controls.

No difference was found between the two groups in Autonomic function during wakefulness.

A reduced ParaSympathetic activity was observed in MS subjects during both Rapid Eye Movement (REM) and non-REM sleep, while no difference was found in Sympathetic function between patients and controls.

No significant correlation was found between cardiac Autonomic data during sleep and MRI lesion load in the InfraTentorial areas and, in particular, of the BrainStem.

The findings of our study suggest that Autonomic Nervous System evaluation during sleep could show impairment earlier than the traditional Autonomic tests during wakefulness.

The Autonomic CardioVascular System was studied by means of Autonomic tests and Heart rate variability related to body movements during sleep, in 20 patients with Relapsing/Remitting Multiple Sclerosis in a stable phase and in 9 normal subjects.

Responses to Autonomic tests in Multiple Sclerosis and control subjects were similar. Heart rate variability, instead, showed a lower degree of adaptability in patients with Multiple Sclerosis than in controls during sleep, because of Sympathetic System Dysfunction.

No significant correlation between Magnetic Resonance lesions and CardioVascular sleep indexes was found.

An impairment in the Autonomic function has been demonstrated in patients with Multiple Sclerosis (MS) using ElectroPhysiological, Pupillary and BioChemical tests.

Particularly evident were alterations in the CardioVascular reflexes, Cutaneous Sympathetic response and LymphoMonocyte Adrenergic binding. Electrophysiological and biochemical findings in MS patients have only occasionally been compared.

Among the peripheral markers of the Autonomic system, NeuroPeptide Y (NPY) and Dopamine-ß-Hydroxylase (DBH) have been singled out as reliable indices of Sympathetic function.

The former is a Peptide with a strong VasoConstrictive action, which is released from Adrenergic endings together with NorAdrenaline following Sympathetic activation.

The latter is the Enzyme which catalyses the conversion of Dopamine to NorEpinephrine. It is located both in Sympathetic Endings and the Chromaffin granules of Adrenal Medulla.

To verify a failure in Autonomic function in the course of MS, a battery of CardioVascular tests (assessing Sympathetic and ParaSympathetic functions) was performed on 25 MS patients.

The results were compared with a group of 20 age- and sex-matched control individuals. The Plasma levels of NPY and the Serum DBH activity were also determined in both groups.

52% of patients showed an impairment in Sympathetic function in one or more tests (sustained handgrip, Postural Hypotension, cold face test).

48% of the patients had abnormal values in deep breathing test, indicating a failure of the ParaSympathetic function.

44% of patients showed also a Paroxysmal Tachycardia after cold face test, indicating an abnormal function of the Vagal-Cardiac and Sympathetic-Vascular Smooth Muscle pathways of the Trigeminal Nerve.

In ten patients with Secondary/Progressive Multiple Sclerosis and ten age- and sex-matched healthy normal subjects (controls), a detailed non-invasive study of systemic and regional HaemoDynamic responses to a range of Autonomic tests.

To evaluate Sympathetic and ParaSympathetic pathways (Mental Arithmetic, Cutaneous Cold, Isometric Exercise, Deep Breathing, Valsalva Manoeuvre and Head-Up Tilt) were performed.

Blood pressure rose in controls during the Pressor Tests and was maintained during tilt. In six out of ten patients with Multiple Sclerosis blood pressure was unchanged during one or more of the three Pressor Tests, but was maintained in all during tilt.

In the controls, Superior Mesenteric Artery blood flow fell during Pressor Tests and head-up tilt.

In Multiple Sclerosis patients, Superior Mesenteric Artery blood flow did not change during Pressor Tests but fell during tilt.

Cardiac index rose during isometric exercise and fell during head-up tilt in controls. Forearm blood flow rose during mental arithmetic in the controls only, but fell during tilt in both groups.

Individual analysis indicated that of the ten Multiple Sclerosis patients, four had responses during the Pressor Tests similar to controls.

Responses to deep breathing and to the Valsalva manoeuvre in controls and Multiple Sclerosis patients were similar.

We conclude that some patients with an aggressive and disabling form of Multiple Sclerosis have selective Autonomic Dysfunction, in particular involving Pressor Responses, despite the lack of Postural Hypotension.

The Autonomic abnormality is likely to involve Central Autonomic InterConnections rather than afferent or Sympathetic efferent pathways. Further clarification of the nature, site and progression of these lesions is needed.

• Comment in: J Neurol 1994 Mar;241(5):348-9

Traditional assessments of Autonomic Nervous System function have depended on invasive and complex procedures.

Vagal power, which is the Respiratory component of Heart Rate Variability (HRV) is an alternative and non-invasive measure for indexing Autonomic Nervous control of the Heart.

In the current study, 18 Multiple Sclerosis (MS) and 20 healthy subjects matched with respect to age, education and intelligence served as subjects.

The MS group showed significantly lower Vagal power during natural and paced breathing than healthy subjects. Importantly, Heart rate did not differ between the two groups.

If MS patients exhibit abnormalities in mechanisms mediating Cardiac ParaSympathetic control, the impact on quality of life and vulnerability to adverse Cardiac events need to be further evaluated.

The results of this study may have implications with respect to the feasibility of using HRV as both a diagnostic and prognostic tool for evaluating ParaSympathetic Nervous System Dysfunction and in providing valuable information for developing more effective treatment and rehabilitation strategies.

The Autonomic Nervous Function of the CardioVascular System was investigated by non-invasive methods in 30 Multiple Sclerosis patients between 20 and 50 years of age.

The results were compared to those of 30 healthy controls in the same age group. Minor abnormalities of ParaSympathetic and Sympathetic function occurred.

Heart rate variation at deep breathing was reduced and more than half of the patients had abnormal responses during an Orthostatic procedure, mainly as an increased rise in Heart rate.