Autonomic dysfunction in multiple sclerosis

Multiple sclerosis (MS) is the leading cause of neurological disability in young adults. Since the pathophysiology of MS is characterized by dissemination in space, as well as in time, the autonomic nervous system is inevitably damaged in the course of the disease in many patients and the proportion of affected patients increases with disease duration. Autonomic dysfunction (AD) in MS is explained by lesions in regions responsible for autonomic regulation such as nuclei in the periventricular region of fourth ventricle in the brainstem as well as medullar lesions. Reports about frequency of AD in MS patients vary notably between groups. Nevertheless its impact on quality of life is substantial but, unfortunately, often overlooked. The aim of this article is to present a concise review of various symptoms and signs of autonomic system dysfunction in MS.     

Prevalence of bowel dysfunction in patients with multiple sclerosis and bladder dysfunction

Urinary dysfunction is common in cases of multiple sclerosis (MS). The close proximity of those neural pathways which control the bladder to those which control anorectal function might be expected to lead to a high coexistence of bladder and bowel symptoms. Seventy-seven consecutive patients with clinically definite MS attending a uroneurology clinic were interviewed about their bowel function. All patients had clinical evidence of spinal cord disease with varying degrees of impaired mobility and sufficiently severe disturbance of bladder control to seek medical advice. Thirty-six per cent of these patients had constipation. Twenty per cent had current incontinence, although another 30% had had at least one episode of faecal incontinence more than 3 months previously. Some patients had both constipation and faecal incontinence. A total of 52% currently had at least one bowel symptom. The pattern of bowel symptoms did not correlate with the pattern of urinary disturbance, or the duration of MS, or the degree of disability. Bowel symptoms are common in patients with MS, but even in those with urinary dysfunction are not universal. Whereas bladder dysfunction in MS is clearly related to spinal cord disease, the neurological basis for the bowel dysfunction is less clear.     

Urinary, faecal and sexual dysfunction in patients with multiple sclerosis

The prevalence and nature of bladder and bowel dysfunction were examined in a population-based study of 221 patients with multiple sclerosis who returned postal questionnaires. This preliminary investigation was supplemented by personal review which also provided information on sexual dysfunction in 174 and laboratory and urodynamic tests in 152 participants. Thirty of 221 (14%) currently used an indwelling catheter, and 84 of the remainding190 (44%) reported symptoms of urinary dysfunction, of which the most common were urgency and frequency. Thirteen of 144 (9%) patients had biochemical evidence of renal dysfunction, and 40 of 132 (30%) had infected urine samples. Eleven of 54 patients in whom investigation of upper urinary tract was thought to be appropriate demonstrated abnormalities. Sixty-four of 221 (29%) patients had experienced faecal incontinence, and 120 of 221 (54%) were constipated. Fifty-six of 68 (82%) men and 55 of 106 (52%) women reported a deterioration in sexual activity, the commonest symptoms being erectile failure in men and fatigue in women. Received: 21 August 1998 Received in revised form: 27 April 1999 Accepted: 16 June 1999     

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.     

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.     

Urinary dysfunction in multiple sclerosis

We aimed to determine the prevalence of urinary symptoms and complications in multiple sclerosis (MS) and to investigate the correlation of these symptoms and complications with urodynamic findings and disease characteristics (primary progressive, relapsing–remitting and secondary progressive). Fifty-two patients with MS were enrolled in the study. Patients were divided into three clinical types: primary progressive, relapsing–remitting and secondary progressive. Urological symptoms and complications were recorded. Each patient underwent a urodynamic investigation. Patients were evaluated for overall disability using the Expanded Disability Status Scale (EDSS). We found that 22 patients had primary progressive, 18 patients had relapsing–remitting and 12 patients had secondary progressive MS. Urgency was the most frequent urinary symptom (65%). Urinary infection was the most frequent urinary complication (15%). Detrusor hyperreflexia was found to be the main bladder dysfunction (27%). Detrusor sphincter dyssynergia was found in 25% of patients, and detrusor hyporeflexia was detected in 6%. No relationship was found between urinary symptoms and urodynamic abnormalities (p > 0.05) and between urinary complications and urodynamic findings (p > 0.05). No significant correlation was found between disease characteristics and urinary symptoms, urinary complications or urodynamic findings (p > 0.05). We suggest that the assessment of urological symptoms and urodynamic evaluation is critical for evaluating quality of life in MS.     

Cardiovascular autonomic dysfunction in multiple sclerosis: correlation with orthostatic intolerance

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. Received: 18 September 1998 Received in revised form: 28 December 1998 Accepted: 3 January 1999     

Mechanisms and current treatments of urogenital dysfunction in multiple sclerosis

The majority of patients with multiple sclerosis (MS) suffer from lower urinary tract symptoms and sexual dysfunction at some stage of the disease. This has a negative impact on the quality of life of patients as well as causing concern to caregivers and family. Neurologists can now treat most of these symptoms by a number of pharmacological and non-pharmacological methods. This review presents the neuroanatomy, neurophysiology, neuropharmacology and pathophysiology of the urinary bladder and sexual organs, and the biological mechanisms underlying urogenital dysfunction in MS patients. Current treatment options for urinary and sexual dysfunction are reviewed. As most urogenital symptoms of MS can now be treated by conservative means, expert urological or gynaecological consultation should be requested only if more aggressive diagnostic or therapeutic measures are needed. Received: 24 July 2001, Accepted: 25 July 2001     

Relationship between urinary symptoms and disease-related parameters in multiple sclerosis

Objective To find the prevalence of voiding dysfunction in patients with multiple sclerosis and to examine the relationship between the voiding dysfunction and various parameters of the disease (disease severity, disease duration, lesion site, age and sex). Methods Using the International prostate symptom score, lower urinary tract symptoms were quantitatively evaluated in all patients with multiple sclerosis who had visited our neurological department during three months. The lesion site in the central nervous system was determined by a combination of neurological and magnetic resonance imaging findings. Results Of the 47 patients who had completed the questionnaire, 25 (53 %) were considered to have symptomatic voiding dysfunction. Even at early stage of the disability, 6 of 19 (32 %) patients were symptomatic. Eight (17 %) patients had irritative urinary symptoms alone, whereas 9 (19 %) patients had obstructive urinary symptoms alone. The irritative and obstructive symptoms were concomitant in 10 (21 %) patients. Compared with reports from Western countries, the ratio of obstructive symptoms to irritative symptoms was high in Japan. The degree of irritative symptoms was well correlated with the disease severity, whereas the correlation of obstructive symptoms with the disease severity was less significant. Irritative symptoms also showed a weak correlation with the disease duration, but obstructive symptoms did not. Among the lesion sites in the central nervous system, only the presence of the spinal cord lesion was related to the degree of urinary symptoms. Urinary symptoms were not significantly influenced by the age or the sex. Quality of life was disturbed by urinary symptoms, and this disturbance paralleled the disease severity. Conclusion Urinary symptoms, especially irritative symptoms, reflect the condition of the disease. Thus, the quantified urinary symptoms may assist neurological diagnosis. Received: 5 September 2001 Received in revised form: 28 January 2002 Accepted: 1 February 2002     

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.     

Symptomatic management in multiple sclerosis

The development of immunomodulatory therapies for multiple sclerosis (MS) has had significant impact in altering the natural history of the disease. Although these agents reduce relapse rate and MRI-associated disease activity, they are only partially effective and do not ameliorate irreversible axonal injury, which produces much of the symptomatic burden of MS. Treatment of MS-associated symptoms remains an essential cornerstone of comprehensive care of patients with MS and, arguably, more favorably enhances quality of life than do the disease-modifying medications. This article reviews strategies of symptom management in patients with MS.     

Sexual dysfunction in male multiple sclerosis patients in relation to clinical findings

Seventy-seven consecutive male patients with clinically definite or laboratory supported definite multiple sclerosis were submitted to a questionnaire and a clinical interview in order to assess the frequency, the nature of sexual dysfunction and its relationship with clinical findings. Twenty-six patients (35%) complained of erectile dysfunction: the defect was partial and inconstant in 11 patients (14%), complete and fixed in 15 (21%). Six patients complained of premature ejaculation, in three of whom the symptom was already present before the onset of the disease. Taking the series as a whole, sexual life was poor or not satisfying at all in 34 patients. Erectile dysfunction was associated with the presence and severity of bladder dysfunction and with disability. The relationship with sensory impairment of legs was slight, no relationship was found with motor involvement of legs, type of course, age and disease duration.     

Oxcarbazepine for treating paroxysmal painful symptoms in multiple sclerosis: a pilot study

Oxcarbazepine (OXC) is an anitepileptic medication recently approved as monotherapy for partial onset seizure and demonstrated to be useful in the treatment of several neuropathic pain. We performed an open-label pilot study of OXC (dosage 600–1200 mg/day) in 12 multiple sclerosis (MS) patients suffering painful paroxysmal symptoms. Eight subjects were female and 4 male, with a mean age of 43.6 years, mean disease duration of 7.3 years and mean score at the EDSS of 3.2. Ten patients had a relapsing-remitting disease course, 1 had secondary progressive and 1 had primary progressive course. Painful paroxysmal symptoms (PPS) were defined as transient painful symptoms in any area of the body, with abrupt onset, brief duration, from a few seconds to a few minutes, with repetitive and stereotyped features. The subjective level of the PPS was scored using a three-point scale (0–3). The mean dosage of OXC was 1033 mg daily. Nine patients experienced a complete and sustained recovery within 1 month from treatment initiation (T0 vs. T1, p>0.05). Two patients dropped out of the study due to adverse effects: 1 case of nausea and dizziness, 1 case of C. hyponatraemia. The medication was well tolerated in the majority of the subjects. The study results provide a new possibility for treating painful symptoms in MS, but efficacy on PPS must be confirmed in a larger study.     

Choreoathetosis in multiple sclerosis

Extrapyramidal symptoms are extremely rare in multiple sclerosis. We examined a patient with a ten year history of multiple sclerosis, who developed choreoathetoid movements of both upper extremities. To our knowledge this is the second case report of this association.     

The mediating role of processing speed in the relationship between depressive symptoms and cognitive function in multiple sclerosis

Introduction: Although disorders of mood and cognition are frequently observed in multiple sclerosis, their relationship remains unclear. We aimed to investigate whether this mood–cognition relationship is mediated by inefficient processing speed, a deficit typically associated with mood symptomatology in the psychiatric literature and a common deficit observed in multiple sclerosis patients. Method: In this study, comprehensive cognitive data and self-reported mood data were retrospectively analyzed from 349 patients with relapsing remitting multiple sclerosis. We performed a bootstrapping analysis to examine whether processing speed provided an indirect means by which depressive symptoms influenced cognitive functioning, specifically memory and executive function. Results: We observed that processing speed mediated the relationship between depressive symptoms and measures of memory and executive function. Interestingly, exploratory analyses revealed that this mediational role of processing speed was specific to MS patients who were younger, had a lower disability level, and had fewer years since MS diagnosis. Conclusions: Together, these findings have implications for mood and cognitive intervention with multiple sclerosis patients.     

Hypermetabolism in multiple sclerosis patients

Hypermetabolism, which can lead to wasting syndrome, is well recognized in diseases such as AIDS, cancer, rheumatoid arthritis, sepsis and burns. In these conditions proinflammatory cytokines are thought to be essentially involved. In experimental allergic encephalitis (EAE), which is regarded as an animal model of multiple sclerosis (MS), wasting syndrome and elevated levels of cytokines have also been reported. The aim of this study was to investigate whether hypermetabolism does occur in MS patients. After a 3-day standard diet the basal metabolic rate (BMR) was measured by indirect calorimetry in 20 MS patients and 10 healthy controls. Body composition was assessed using an impedance analyser and lean body mass (LBM) was calculated. Other metabolic disturbances and infectious disease were ruled out by clinical examination and various laboratory tests. Tested by analysis of variance (ANOVA), the BMR corrected for LBM was increased by an average of 6% in the patients group (p < 0.05) as compared to the controls. As far as we know this is the first study demonstrating the presence of hypermetabolism in MS.     

Rehabilitation challenges in multiple sclerosis

While current immunomodulating drugs aim to reduce multiple sclerosis (MS) exacerbations and slow disease progression, rehabilitation aims to improve and maintain the functional abilities of patients in the face of disease progression. An increasing number of journal articles are describing the value of the many rehabilitation interventions that can be used throughout the course of the disease, from the initial symptoms to the advanced stages. An integrated team of healthcare professionals is necessary to address a myriad of problems to reduce impairments, disabilities, and handicaps. The problems may be related to fatigue, weakness, spasticity, mobility, balance, pain, cognition, mood, relationships, bowel, bladder, sexual function, swallowing, speech, transportation, employment, recreation, and activities of daily living (ADL) such as dressing, eating, bathing, and household chores. The team can help prevent complications and secondary disabilities, while increasing patient safety. Improving neurologically related function, maintaining good relationships, and feeling productive and creative adds enormously to the quality of life of people with MS and their families. Rehabilitation is more than an ‘extra’ service that is given after medical therapies; it is an integral part of the management of the diverse set of problems encountered throughout the course of the disease. An interdisciplinary team may have many members, including physicians, nurses, physical therapists, occupational therapists, speech and language pathologists, psychotherapists, social workers, recreational therapists, vocational rehabilitation therapists, patients, families, and other caregivers.     

A case of multiple sclerosis with an onset mimicking the Kleine-Levin syndrome

A 20 years old patient is described, who presented two episodes of day-time hypersomnia, orthostatic hypotension and psychotic behavior. Compulsive masturbation and abnormalities of the eating habits were also present. Both episodes cleared up spontaneously in about one week. From the clinical point of view a Kleine-Levin syndrome, was suspected. However a CSF examination showed IgG oligoclonal bands and an increased IgG index. A NMR showed multiple area of increased signal intensity, suggestive of a demyelinating disease. On these elements a final diagnosis of MS was made, in spite of a normal neurological examination. This case was compared to other cases of MS in which the disease begins with acute remitting psychiatric symptoms. However cases of MS with complex episodes as observed in our patient were not found in the Literature.

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Sommario Viene descritto il caso di un paziente di 20 anni che presentava 2 episodi caratterizzati da ipersonnia diurna, ipotensione ortostatica e sintomi psicotici. Erano anche presenti masturbazione compulsiva e anomalie dell’alimentazione. Ambedue gli episodi si risolvevano spontaneamente in circa una settimana. Gli aspetti clinici degli episodi erano suggestivi di una sindrome di Kleine-Levin. Tuttavia l’esame del LCS dimostrava la presenza di bande oligoclonali IgG e un aumento dell’IgG index. Una Risonanza Magnetica Nucleare dimostrava aree multiple di segnale aumentato, suggestive di un processo demielinizzante. Sulla base di tali dati veniva posta diagnosi di SM, malgrado l’esame neurologico fosse completamente normale. Tale caso viene discusso in relazione ad altri casi di SM in cui la malattia iniziava con episodi psichici acuti remittenti. Dall’esame della letteratura, tuttavia, non venivano riscontrati casi caratterizzati da episodi complessi, simili a quello descritto.

     

Treatment of neurogenic bladder dysfunction in multiple sclerosis by ultrasound-controlled bladder training

Summary Neurogenic bladder dysfunction, the main cause of chronic urinary tract infections in multiple sclerosis (MS), is efficiently treated by bladder training with ultrasound control of the residual urine. However, the beneficial effects of bladder training in the hospital are often lost within a short time when the patient returns to his home. Reexamination at home of 97 MS patients with increased residual urine and/or chronic urinary tract infections showed that the group which claimed to continue bladder training at home had significantly less residual urine at home than the group which did not continue bladder training at home. The residual urine decreased from 210 ml on average to almost normal while the patients did bladder training in the hospital, but the volume nearly doubled within a short time at home. Thus, more decentralized rehabilitation by family members, volunteer personnel or local nurses is necessary. Decentralized symptomatic therapy is the most efficient treatment of MS at present. Family members, volunteers, and local nurses, however, need training. Without these improvements in decentralized rehabilitation the hospital treatment of MS is of little benefit because urinary tract infection quickly recurs at home. For efficient bladder training the patient needs feedback regarding the residual urine; this can be provided with minimum risk by ultrasound sonocystography. In those rare cases in which bladder training does not work, intermittent catheterization must be carried out by the patients or their families, volunteer personnel or a local nurse. A continuous indwelling catheter should not be used. Antibiotic treatment should be applied only on the basis of a precise bacteriological diagnosis.     

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.