Subclinical autonomic disturbances in multiple sclerosis

We compared results from non-invasive autonomic testing [sympathetic skin responses (SSR), heart beat variation during deep breathing, and orthostatic manoeuvre with transcranial Doppler monitoring in 22 patients] with motor and somatosensory evoked potentials (MEP and SEP) in 30 unselected patients with multiple sclerosis. We found a similarly high yield of pathological results for SSR, MEP and SEP (66.7%, 65.5%, and 69%, respectively). When analysed for each limb (n = 120), SSR were highly correlated with MEP and SEP (for bothP < 0.001). Heart beat variation was reduced in only 3 patients. In 4 of 22 patients orthostatic manoeuvre induced a pathological decrease in cerebral blood flow velocity despite normal systemic blood pressure being maintained. We conclude that SSR may be a useful additional diagnostic tool in patients with multiple sclerosis. Cerebral dysautoregulation is a rather frequent finding, although its significance is not known.     

Measurement of autonomic dysregulation in multiple sclerosis

OBJECTIVE: Patients with definite multiple sclerosis (MS) were tested for autonomic nervous system (ANS) dysfunction using clinical symptomatology criteria and non-invasive laboratory testing. Exactly 45.45% of patients exhibited subjective symptoms of autonomic dysfunction and 42.42% of patients had abnormal laboratory tests results. METHODS: The sympathetic ANS tests were abnormal in 30.3% of MS patients and the parasympathetic ANS tests were abnormal in 18.18% of MS patients. The most sensitive test for the presence of autonomic dysfunction was the sympathetic skin response. CONCLUSION: Autonomic dysfunction was often subclinical and we conclude that it is preferable to combine several tests for a more thorough and accurate evaluation of the ANS impairment in MS.     

Cardiac autonomic function during sleep and wakefulness in multiple sclerosis

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 brain stem. The findings of our study suggest that autonomic nervous system evaluation during sleep could show impairment earlier than the traditional autonomic tests during wakefulness.     

Determinants of heart rate variability during deep breathing: Basic findings and clinical applications

The measurement of heart rate variation during forced breathing (HR_DB) is a well-known clinical test of parasympathetic function. It is known that normal values of HR_DB are strongly dependent on age. However, little is known about other physiological factors that may lead to reduced HR_DB values that may mimic parasympathetic failure. Thirty-two normal subjects (age 56.7±12.4 years) and 32 neurological patients with pathological autonomic test findings (age 57.9±10.2) were studied. Oscillations in heart rate and in mean arterial blood pressure were recorded in the supine position during forced breathing (6 cycles/min) using the Finapres monitor. Amplitudes of heart rate and blood pressure waves at 6 cycles/min (HR₆ and ABP₆) as well as gain values (Gain₆=HR₆/ABP₆) and phase differences ({ie131-1}) between HR and ABP waves were calculated by means of spectral analysis. The mean (±SD) HR₆ in normal subjects was 6.34±3.36 cycles/min with a mean ABP₆ of 5.11±2.49 mmHg. HR₆ correlated significantly with age (r=–0.426) and with ABP₆ (r=0.602). No significant correlation was found between HR₆ and mean blood pressure, mean heart rate or sex. From 24 patients with pathological findings in the classical HR_DB value, only nine could be classified as pathological when the effect of ABP₆ was considered. In conclusion, ABP variations significantly influence the amplitude of heart rate variations during forced breathing. We interpret these findings in terms of a baroreflex mechanism of HR_DB including both vagal and sympathetic efferents. Normal reference value tables for clinical HR_DB studies should not only consider age but also the amplitude of blood pressure variations.     

Fatigue,sleep disturbances and circadian rhythm in multiple sclerosis

The aim of this study was to investigate whether fatigue and sleep disturbances in multiple sclerosis (MS) patients might be due to disrupted circadian sleep wake regulation. Actigraphy and a multiple sleep latency test (MSLT) were performed in 16 MS patients with both prominent sleep complaints and fatigue. Actigraphy scores did not differ from control values, whereas sleep onset latency values were altered in subgroups of MS patients. No evidence was found for a generalized circadian disturbance in MS patients.     

Personality aspects in multiple sclerosis

To test the claim that peculiar personality bias is detectable in multiple sclerosis (MS) we used the Szondi test to investigate the psychodynamic aspects of 110 MS patients in comparison with 200 healthy subjects. MS patients appeared to have a greater need for love in a passive form than normal people, rigid defense mechanisms, difficulty in resolving their inner conflicts either by sublimation or by internalization of satisfactory new emotional experiences, feelings of autoaggressiveness, and many symptoms of depression. Some of these aspects correlate with the severity of the disease, others seem to date back to early childhood as peculiar personality patterns. An investigation of childhood events in 110 controls confirmed that MS patients had had many more unhappy experiences in childhood than might commonly be expected. Further, the oft-reported psychiatric troubles preceding MS clinical onset suggest that at least in some MS patients there are specific gaps in personality structure dating back to early phases of their development

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Sommario Con lo scopo di verificare se esistono delle peculiarità psicologiche nei pazienti con sclerosi multipla (SM), sono stati sottoposti al test di Szondi 110 casi con diagnosi certa e i risultati sono stati analizzati in rapporto a quelli di 200 persone sane di controllo. Nei soggetti con SM sono stati riscontrati un bisogno affettivo passivo più elevato che nei normali, meccanismi di difesa rigidi, difficoltà a tirarsi fuori dai propri conflitti intrapsichici sia attraverso la sublimazione che mediante la introiezione di nuove esperienze affettive, sentimenti autoaggressivi e una forte componente depressiva. Alcuni di questi aspetti sono risultati correlabili con la gravità della malattia, altri invece sono apparsi indipendenti e, dato che i soggetti con SM avevano avuto più esperienze frustranti nella prima infanzia rispetto alle persone di controllo, potrebbero essere indizio di screzi particolari della personalità. Ciò darebbe tra l'altro ragione delle reazioni psicopatologiche che spesso precedono o accompagnano la manifestazione clinica della malattia.

     

Progressive multiple sclerosis patients have a higher burden of autonomic dysfunction compared to relapsing remitting phenotype

Objective

To determine autonomic dysfunction (AD) differences in patients with relapsing remitting multiple sclerosis (pwRRMS) and progressive MS (pwPMS).

Neuroinflammation responses and neurodegeneration in multiple sclerosis

Diffuse neurodegeneration is now considered to be the main cause of irreversible neurological disability in multiple sclerosis (MS). Demonstration of a diffuse inflammatory reaction in the MS brain led to the assumption that diffuse neuroinflammation induces diffuse neurodegeneration. Macrophages/microglia accumulate throughout the MS brain and are, therefore, considered the main culprits implicated in the development of neurodegeneration. However, recent advances in the understanding of macrophage/microglia functions and origins have now challenged that view. This report is a summary of these advances, and discusses their contribution to the perception of macrophage/microglia functions in MS-associated neurodegeneration.     

Peripheral nerve conductions in relapsing remitting multiple sclerosis (RRMS) patients

PurposeThe purpose of this study was to investigate with Elektromioneurografija (EMNG) whether there is any affection on peripheral nerves in (RRMS) patients.Material and MethodMotor and sensory nerve conductions were studied in the control group including 33 RRMS patients and 25 healthy individuals. Expanded Disability Status Scale (EDSS) scores, mean annual attack frequency, duration of disease and treatments of RRMS patients were recorded.ResultsThere was a statistically significant (p < 0.05) elongation in motor distal latency of the right peroneal nerve, slowing in the left peroneal nerve conduction velocity, and an elongation in the F-wave response in the RRMS group compared to the control group. It was observed that motor nerve conduction velocities were slower, albeit not statistically significant, and F wave latencies were longer than control group.ConclusionThere are studies in the literature related to the association between MS and peripheral neuropathy. In this study, we found demyelinating type changes, differing significantly from the control group, in motor nerve conductions in RRMS patients. There may be demyelinating type affection in peripheral nervous system with common autoimmune mechanism in MS, a demyelinating disease of the central nervous system.     

Central defects of autonomic function in secondary progressive multiple sclerosis: observations based on cardiovascular and growth hormone responses to clonidine

The haemodynamic, autonomic and hormonal effects of the centrally acting sympatholytic drug clonidine have been studied in 10 patients with secondary progressive multiple sclerosis (MS) and 10 age- and sex-matched normal subjects (controls). Detailed physiological studies, previously described in these 10 MS patients, indicated that none had postural hypotension or an abnormal Valsalva manoeuvre; six, however, had impaired responses to a range of pressor tests, suggestive of a central autonomic abnormality. In the controls after clonidine, there was a fall in blood pressure and superior mesenteric artery vascular resistance. Finger temperature and growth hormone levels rose. In the MS patients after clonidine, the haemodynamic responses varied. In five out of ten MS patients, as in the controls, there was a fall in blood pressure and superior mesenteric vascular resistance, while finger temperature rose. There was no haemodynamic response to clonidine in the other five MS patients. In eight out of ten MS patients there was no rise in plasma growth hormone levels after clonidine. The abnormal haemodynamic responses to clonidine, taken in conjunction with the previous physiological studies, suggest involvement of central sympathetic interconnections in five of the MS patients, probably as part of the demyelinating process. The impaired growth hormone response to clonidine occurred in a greater number of patients and may indicate lesions in the hypothalamus. These observations in MS patients, without overt clinical evidence of autonomic failure, indicate that the haemodynamic and growth hormone responses to clonidine may be an early indicator of autonomic dysfunction involving central autonomic centres and pathways.     

Abnormal heart rate and blood pressure responses to baroreflex stimulation in multiple sclerosis patients

Abstract Cardiovascular autonomic neuropathy has been previously reported in patients with multiple sclerosis (MS) using standard reflex tests. However, no study has separately evaluated both parasympathetic and sympathetic cardiovascular autonomic regulation. We therefore assessed the baroreflex-mediated vagal and sympathetic control of the heart rate and sympathetic control of the blood vessels in MS patients using sinusoidal neck stimulation.We studied 13 multiple sclerosis patients aged 28–58 years and 18 healthy controls aged 26–58 years. The carotid baroreflex was stimulated by sinusoidal neck suction (0 to –30 mmHg) at 0.1 Hz to assess the autonomic control of the heart and blood vessels, and at 0.2 Hz to assess the vagal control of the heart. Continuous recordings were made of blood pressure, electrocardiographic RR-interval and respiration, with breathing paced at 0.25 Hz. Spectral analysis was used to evaluate the magnitude of the low frequency (LF, 0.03–0.14 Hz) and high frequency (HF, 0.15–0.50 Hz) oscillations in RR-interval and blood pressure in response to the sinusoidal baroreceptor stimulation. Responses to the applied stimulus were assessed as the change in the spectral power of the RR-interval and blood pressure fluctuations at the stimulating frequency from the baseline values.The increase in the power of 0.1 Hz RR-interval oscillations during the 0.1 Hz neck suction was significantly smaller (p<0.01) in the MS patients (4.47±0.27 to 5.62±0.25 ln ms²) than in the controls (4.12±0.37 to 6.82±0.33 ln ms²). The increase in the power of 0.1 Hz systolic BP oscillations during 0.1 Hz neck suction was also significantly smaller (p<0.01) in the MS patients (0.99±0.19 to 1.96±0.39mmHg²) than in the healthy controls (1.27±0.34 to 9.01±4.10mmHg²). Neck suction at 0.2 Hz induced RR-interval oscillations at 0.2 Hz that were significantly smaller (p<0.05) in the patients (3.22±0.45 ln ms²) than in the controls (5.27±0.29 ln ms²). These results indicate that in MS patients, baroreflex dysfunction is not only restricted to the cardiovagal limb of the baroreflex, but that the sympathetic modulation of the blood vessels is also affected.     

Sympathetic skin responses in multiple sclerosis

Objectives – This study assessed the sympathetic skin responses (SSRs) and their correlation with brain lesion volumes in patients with multiple sclerosis (MS). Materials and methods – The SSRs were measured in 27 patients with MS and 27 healthy controls. The volumes of the proton density‐weighted MS lesions in the brain were measured using MRI. Results – The SSRs were abnormal in 52% of the patients with MS, but absent only in clinically severe MS. The total lesion volume in the whole brain correlated significantly with both the severity of MS expressed by the EDSS score (P < 0.001) and the decreased SSR amplitudes in the feet (P < 0.01). Focal lesion volumes in the temporal lobe (P < 0.01), in the pons (P < 0.01) and in the cerebellum (P < 0.01) were also separately associated with abnormal SSR reflexes. Conclusions – Sudomotor regulation failure in MS is associated with certain focal MS lesions.     

Tests of autonomic dysfunction in patients with multiple sclerosis

Autonomic dysfunction is frequent in patients with multiple sclerosis (MS). The sympathetic skin response (SSR) and the R-R interval variation (RRIV) are simple electrophysiologic tests for the assessment of central and peripheral autonomic disturbances. Both tests were performed in 60 patients with clinically definite MS and 30 controls. The SSR was recorded simultaneously from both upper and both lower limbs. In all volunteers normal responses were recorded from the four limbs, but 39 patients (65%) showed abnormal responses in at least one limb. The reduction in amplitude of the response was correlated with patients' EDSS. In individual limbs, the SSR amplitude correlated with weakness, spasticity and cerebellar dysfunction, but was not sufficiently related to the deep sensory loss. The RRIV was abnormal in 48 MS patients (80%), as compared to the controls, but showed no significant relationship either to the EDSS or to the SSR. The sensitivity of SSR and RRIV is high and comparable with that of visual and somatosensory evoked potentials.     

Physiological assessment of aspects of autonomic function in patients with secondary progressive multiple sclerosis

A detailed non-invasive study of systemic and regional haemodynamic responses to a range of autonomic tests which assess sympathetic and parasympathetic pathways (mental arithmetic, cutaneous cold, isometric exercise, deep breathing, Valsalva manoeuvre and head-up tilt) were performed in ten patients with secondary progressive multiple sclerosis and ten age- and sex-matched healthy normal subjects (controls). 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 Valsava 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. Detection of these abnormalities, which may be clinically silent, may help in the prognostic and diagnostic evaluation of patients with multiple sclerosis.     

Western and Asian features of multiple sclerosis in Mexican Mestizos

OBJECTIVES: The objective of this study was to compare the clinical expression of MS in Mexican Mestizos with that of patients of European or Asian descent; as well as to compare the annual frequency of new cases with that observed in the previous decades. PATIENTS AND METHODS: All patients with diagnosis of definite MS seen at the National Institute of Neurology and Neurosurgery of Mexico from January 1993 to December 2003 were studied (n=312). Sociodemographic and clinical characteristics were compared with reports of patients from either Western or Asian origin; the long-term disability score was analyzed according to gender, age of onset of MS and the initial symptom. RESULTS: The clinical expression of MS in Mexican Mestizos shares some characteristics with both, Asian and Western forms of MS indicating that the genetic composition of Mexican Mestizos participates in the clinical expression of the disease. Also, at the prevalence date, the mean age of patients and the duration of the disease were lower in our patients than in MS patients from endemic countries suggesting a true increasing incidence in recent times, rather than only improved case ascertainment. CONCLUSIONS: Clinical expression of MS in Mexican Mestizos shows the coexistence of some features common in European and in Asian cases.     

Pathophysiological background and clinical characteristics of sleep disorders in multiple sclerosis

Sleep disorders in multiple sclerosis (MS) are more common than in general population and are considered to be one of the important etiological factors in development of fatigue, most common and debilitating symptom of MS. Although almost all of the major subgroups of sleep disorders such as insomnia, sleep disordered breathing, REM sleep behavior disorder, narcolepsy and restless legs syndrome have been described in the MS patients their higher prevalence in MS population than in healthy controls in some of the sleep disorders is not fully elucidated. Immunological background in disease development in both multiple sclerosis and sleep disorders have been proposed as possible common pathophysiological mechanism and recent findings of disrupted melatonin pathways in MS patients suggest multi-level causative mechanism of the development of sleep disorders in MS.     

Decreased heart rate variability in amyotrophic lateral sclerosis

Autoregressive spectral analysis of heart rate variability (HRV) was performed in 29 patients with amyotrophic lateral sclerosis (ALS) and 33 age-matched healthy subjects to evaluate the involvement of the autonomic nervous system. HRV analysis provides a means to recognize low (LF) and high (HF) frequency components, respectively mediated by sympathetic and parasympathetic heart control. An increase in the mean heart rate at rest (P < 0.001), a decrease in standard deviation of R-R interval as well as in PNN50 (P < 0.001), and an increase in the LF/HF component ratio (P < 0.01) were found in the ALS patients, indicating a vagal–sympathetic imbalance. These alterations were not related to the clinical features and to the duration of the disease. Our results suggest a subclinical involvement of the autonomic nervous system in ALS, particularly affecting parasympathetic cardiovascular control. © John Wiley & Sons, Inc.     

Heart rate variability in multiple sclerosis during a stable phase

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. Material and 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 frequency of relapse in multiple sclerosis

Summary The authors analyze the course of 245 cased of multiple sclerosis. The mean annual frequency of attacks is 0.66 for all the patients (remittent forms and progressive forms). Although it is usually suggested that this frequency decreases with the years, this has not been found in our study. Our results also indicate that we would have to follow 590 patients over 1 year or 190 over 2 years before being able to attest the effectiveness of a treatment decreasing the frequency of attacks by 25%.Ingénieur I.N.S.E.R.M.