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Symptomatic therapy and neurorehabilitation in multiple sclerosis Jürg Kesselring, Serafin Beer
Multiple sclerosis (MS) is associated with a variety of symptoms and functional deficits that result in a range of progressive impairments and handicap. Symptoms that contribute to loss of independence and restrictions in social activities lead to continuing decline in quality of life. Our aim is to give an updated overview on the management of symptoms and rehabilitation measures in MS. Appropriate use of these treatment options might help to reduce long-term consequences of MS in daily life. First, we review treatment of the main symptoms of MS: fatigue, bladder and bowel disturbances, sexual dysfunction, cognitive and affective disorders, and spasticity. Even though these symptomatic therapies have benefits, their use is limited by possible side-effects. Moreover, many common disabling symptoms, such as weakness, are not amenable to drug treatment. However, neurorehabilitation has been shown to ease the burden of these symptoms by improving self-performance and independence. Second, we discuss comprehensive multidisciplinary rehabilitation and specific treatment options. Even though rehabilitation has no direct influence on disease progression, studies to date have shown that this type of intervention improves personal activities and ability to participate in social activities, thereby improving quality of life. Treatment should be adapted depending on: the individual patient’s needs, demands of their surrounding environment, type and degree of disability, and treatment goals. Improvement commonly persists for several months beyond the treatment period, mostly as a result of reconditioning and adaptation and appropriate use of medical and social support at home. These findings suggest that quality of life is determined by disability and handicap more than by functional deficits and disease progression.
Introduction The many symptoms (panel 1) associated with multiple sclerosis (MS) cause functional impairment and handicap. The symptom pattern depends on the location of lesions in the CNS, although most inflammatory foci do not cause symptoms. The most common symptoms in relapsing-remitting MS are visual (46%) and sensory disturbances (41%), whereas in primary progressive forms of MS the most prevalent symptoms are gait disorders (88%) and pareses (38%).1 Other symptoms such as bladder problems and cognitive disturbances commonly develop later in the course of the disease and can become the most noticeable. The consequences of these functional deficits in activities of daily life are variable. Many patients commonly view fatigue as having the most adverse consequences in daily life, followed by disturbances of balance, pareses, and bladder disorders.2 MS has an early disease onset, a progressive course, and very long duration with a median survival time of about 40 years from diagnosis; thus there is a high prevalence of disabilities with consequences in personal as well as social domains. 15 years after diagnosis, around 50% of patients with MS use walking aids and 29% need a wheelchair.3,4 During the first 10 years of disease, 50–80% become unable to work.5 Thus, the main burden of the disease manifests during the 5th and 6th decades of a patient’s life, a time when most people are particularly active socially as well as in their careers. Socioeconomic consequences of MS are substantial: the direct and indirect costs for one person with MS per year are estimated at around ¤50 000 or US$62 000, and there is a strong correlation between costs and increasing score on the expanded disability http://neurology.thelancet.com Vol 4 October 2005
Lancet Neurol 2005; 4: 643–52 Department of Neurology and Neurorehabilitation, Rehabilitation Centre, CH-7317, Valens, Switzerland (J Kesselring, S Beer) Correspondence to: Prof Jürg Kesselring, Department of Neurology and Neurorehabilitation, Rehabilitation Centre, CH-7317, Valens, Switzerland
[email protected]
status scale (EDSS).6 Half of the direct costs are attributable to care of 17% of patients—those with the most severe disability of whom 6·5% live in nursing homes.7 For many patients with MS, quality of life can deteriorate and they lose their independence and become less able to participate in social activities. Treatment of the symptoms of MS is essential and it requires a multidisciplinary approach encompassing drug therapy, psychological counselling, and physiotherapy. Rehabilitation can be defined as an active process of education and enablement, which is focused on the appropriate management of disability and minimising limitation of handicap, with the goal of achieving full recovery. However, with a condition such as MS in Panel 1: Symptoms associated with MS Fatigue Bladder and bowel dysfunction Cognitive and emotional problems—eg, depression Spasticity Gait disorders Visual problems Dizziness and vertigo Tremor Speech and swallowing disorders Numbness Pain Sexual dysfunction Seizures
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which full recovery is not possible, goals become focused on achieving the best physical, mental, and social potential of patients so that they can remain, or become, integrated into a social environment that is appropriate for them. The longer-term benefits from management of symptoms and emotional status help to compensate for functional deficits and enable patients to adapt to their circumstances more readily. This paper provides an overview of management options for each group of symptoms that accompany MS and examines clinical-trial evidence that supports the efficacy of neurorehabilitation. In 2004, a group of experts in MS from Germany, Switzerland, and Austria published a comprehensive review and consensus statement on symptomatic treatment and rehabilitation in MS;8 it consists of existing evidence based literature and neurologists’ therapeutic experience who have dealt with these problems over a long time.
Fatigue Fatigue is the single symptom that patients identify as interfering most with their daily activities. The causes are multifactorial. A poor sleep pattern, resulting from pain, nocturia, and spasticity, is commonly the cause. Another equally important factor might be the immunological processes of MS. Several of the cytokines involved in the pathogenesis of MS are known to induce sleep, especially interleukin, which affects the hypothalamic axis and results in reduced cerebral metabolism.9 Motor disturbances associated with spasticity are also likely to contribute to the fatigue syndrome. In patients with MS, the reciprocal inhibitory mechanisms are disturbed, which results in a reduced rate of motor-unit firing. Electrophysiological studies have suggested that an impaired drive of motor impulses to the primary motor cortex can decay the maximal muscle force.10 In addition to these pathophysiological mechanisms, treatments for MS, such as beta interferons, antispastic drugs, and antidepressive agents, have also been reported to cause fatigue. New evidence suggests that fatigue might be linked to disturbances in regulation of body temperature.11 There seems to be an association between dysregulation of body temperature and high concentrations of endothelins that accompany ischaemia.12 The role of endothelins as mediators in temperature regulation and fatigue is currently being investigated in our clinic. Treatment of fatigue requires a multidisciplinary approach; appropriate strategies include graded exercise programmes, behaviour modification therapy, or medication. In a comparative, double-blind randomised study, 93 patients were assigned amantadine (100 mg twice daily), pemoline (18·75–37·5 mg), or placebo for 6 weeks.13 The group assigned amantadine had a significant improvement in fatigue compared with the placebo group. There was no difference in fatigue between the pemoline and placebo groups. In clinical 644
practice, however, the effect of amantadine is less impressive, and a recent meta-analysis criticised trials for not investigating the relevance and effect on quality of life.14 A randomised, double-blind cross-over trial with 36 patients with MS by Tomassini and co-workers,15 showed significant improvement in fatigue (rated by the fatigue severity scale) during 3 months of treatment with acetyl L-carnitine compared with amantadine; the researchers concluded that acetyl L-carnitine was superior and better tolerated than amantadine.15 In a non-randomised, single-blind phase II study with a titration design in 72 patients with MS who had fatigue (measured by MS fatigue scale) fatigue improved with daily modafinil treatment (200 mg) for 9 weeks.16 Even though treatment with modafil was tolerated well, longterm safety and efficacy remain unclear. An alternative therapy to modafil could be methylphenidate—another drug with central stimulating effects—which has also been of benefit in patients with other diseases causing fatigue (HIV, cancer).17,18 Aminopyridines (3-4-diaminopyridine, 4-aminopyridine) work by blocking potassium channels and thus improving central conduction in demyelinated fibres; this mechanism has been shown to lead to an improvement of fatigue and other symptoms.19 In a randomised, double-blind, placebocontrolled, cross-over trial, 54 patients with MS were treated with 4-aminopyridine (32 mg daily over 6 months);20 although there was no significant improvement in fatigue among the whole study group, patients with serum concentrations of 4-aminopyridine above 30 ng/L showed significant improvement. The treatment was tolerated well in this study, however, serious side-effects of aminopyridines have been reported, making safety an important issue for future trials.21 Nutritional supplements such as creatine (in combination with magnesium) might support conditioning training and improve physical endurance;22 even though the use of these supplements might be useful during intensive training, no clinical trials have investigated the benefit during rehabilitation of patients with MS.
Bladder symptoms Bladder symptoms are particularly incapacitating in daily life. Spinal-cord disease in MS is thought to be the main cause of pelvic-organ dysfunction. Impairment of bladder function is commonly characterised by urgency, which is the consequence of detrusor hyper-reflexia. The symptom of urgency is in many cases coupled with urinary frequency resulting from reduced bladder capacity. A few patients also have difficulty in initiating micturition or are unable to achieve complete bladder emptying. These bladder symptoms make many patients reluctant to engage in social activities. Urgency can be made worse by motor disabilities that prevent the patient from reaching the toilet quickly. Apart from drug therapy, pelvic-floor training can help to improve http://neurology.thelancet.com Vol 4 October 2005
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bladder symptoms. In a controlled study of 80 patients with MS, pelvic floor training with combined instruction for home programmes led to significant improvements in incontinence, urgency, and frequency.23 Incomplete bladder voiding can be treated with an external bladder stimulator (Queen Square stimulator), leading to a substantial reduction in resting urinary volume.24,25 Detrusor hyperactivity can be effectively treated with physiotherapy to train the pelvic-floor muscles26 or bladder-training protocols, which aim to re-establish a normal urinary frequency and increase bladder capacity through behavioural modification.27 Anticholinergic agents, especially tolterodine, are effective at decreasing micturition and urge incontinence.28 However, these pharmacological treatments commonly have typical anticholinergic side-effects (dry mouth and thirst), which in turn can exacerbate bladder problems. Management of bladder dysfunction can also be achieved in some cases by simpler methods, such as effective management of fluid intake and a reduction in the intake of diuretic agents such as caffeine. These approaches can be used alongside the methods described above. Alternatively, electrostimulation therapy (anal or vaginal) has been used to stimulate the pudendal nerves and inhibits the hyper-reflexia. Some patients with detrusor-sphincter dys-synergy need clean intermittent self-catheterisation, and others need permanent catheterisation; in these cases suprapubic catheters carry a lower risk of infection and complications than intraurethral catheters.29 A new way of treating hyper-reflexia is injection of botulinum A toxin into the detrusor muscle. In a study of 31 patients who had spinal-cord injury with severe hyper-reflexia and who needed intermittent self-catheterisation, an injection of botulinum toxin (300 units) was highly effective in restoring continence and had no sideeffects.30,31 The effects of a single dose of botulinum toxin lasted for 9 months. Urinary-tract infections can occur as a result of urine retention or catheter use. Management of these infections is an important part of MS therapy, and patients should be monitored closely. Urinary tract infections can be managed with antibiotics such as ciprofloxacin, sulfamethoxazole, and nitrofurantoin,32 and phenazopyridine can be used for symptom relief.33 Methenamine hippurate can also be used prophylactically to prevent infections,34 although this use is still controversial.35 In some patients, infection of the upper urinary tract results in severe illness and permanent damage to the kidneys. Patients with symptoms consistent with such infections and those not responding to treatment should be carefully monitored.
Sexual dysfunction Many patients with MS experience sexual dysfunction.36 In a comparative study, sexual dysfunction was found in 73% of patients with MS compared with 39% of those http://neurology.thelancet.com Vol 4 October 2005
with other chronic diseases and 13% of healthy controls.37 The main complaints for women are anorgasmia or hyporgasmia, decreased vaginal lubrication, and reduced libido. In men, the main complaints are impotence or erectile dysfunction, ejaculatory dysfunction, orgasmic dysfunction, and reduced libido.37 These symptoms can have an important effect on self-esteem and relationships. Even though some of these complaints can be attributed to the psychological factors related to having a chronic disabling disease, others are a result of the dysfunction of neural pathways that are important for sexual activity. The association of sexual disturbances with disability, neurological impairment, and bladder dysfunction is evidence for dysfunction of these neural pathways; MRI data suggest an association with pontine pathology.38 Another cause of sexual dysfunction might be the use of drugs (eg, intrathecal baclofen) which can affect erectile function.39 Management for these symptoms, is again, multifactorial in nature because the problem can be organic, psychological, or related to relationship problems. The primary approach is to refer patients for psychological counselling; this approach for couples can improve sexual satisfaction.40 Drug treatment is mainly limited to erectile dysfunction, which can be treated with oral sildenafinil.24,41 Intracavernous self-injections of vasoactive drugs are another treatment option,42 however, this approach can be difficult for patients with advanced disability. Other treatments occasionally used are vacuum devices and implants.
Chronic constipation Chronic constipation is a substantial source of distress for patients with chronic neurological diseases including MS. Non-specific measures to control constipation include: body fitness programmes, dietary intervention in the form of fibre, avoidance of chocolate, and adequate intake of fluids. However, increased fluid intake can in turn complicate co-existing bladder problems. Pharmacological interventions are in the form of laxative-type agents.43,44
Cognitive deficit and affective disturbances 40–65% of patients with MS have some degree of cognitive deficit.45 These deficits can occur early in the course of the disease and can have long-term effects on patients and their families. Unemployment, social isolation, and the need for personal assistance at home are more likely in patients with cognitive impairment (figure 1),46 and these patients also have a high risk of developing depression. Many patients with cognitive deficits, particularly early in the course of MS, have to give up work with subsequent loss of income. This loss is an important part of the indirect costs of MS; loss of earnings for both patient and carer and costs of informal care account for up to 60% of the financial cost of MS.47,48 Memory is the most commonly affected function; long645
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Figure 1: Training activities of daily life—climbing stairs
term memory is more impaired than the short-term memory. Attention is also compromised as shown by diminished alertness, a reduction of mental processing speed, and impaired visuospacial perception. Cognitive deficits must be recognised as early as possible, enabling rehabilitation strategies to be employed to limit effects on the patient’s life. These strategies are focused primarily on non-pharmacological measures, such as cognitive rehabilitation, occupational therapy, and psychotherapy. Pharmacological measures focus mainly on the control of comorbid symptoms, such as fatigue and depression. Because of the difficulties of undertaking clinical trials to assess the effect of treatment on cognitive deficits, there are currently few effective pharmacological agents approved as symptomatic therapy for cognitive dysfunction in MS.49,50 Cognitive training can lead to substantial improvement of attention and therefore a reduction in attention-associated problems in comparison with nonspecific training;51 these effects were measurable even several weeks after the end of treatment. Lincoln and colleagues52 examined the influence of detailed neuropsychological testing with cognitive intervention (which consisted, however, only of instruction in selftraining rather than of peforming therapy by professional neuropsychologists) compared with neuropsychological testing alone. At 4 months and 8 months after neuropsychological testing, there were 646
no significant differences between the groups. The group assigned neuropsychological testing without cognitive intervention reported a reduction of quality of life after 8 months. Therefore, isolated neuropsychological testing without therapeutic intervention should be avoided. In addition to loss of cognitive function, the lifetime frequency of affective disorders (25–50%) is three times higher among patients with MS than in the general population.53,54 An estimated 73% of patients with MS have difficulty in controlling their emotions (for example, irritability, anger, and crying).55 Emotional instability occurs in 10% of patients and impairs social interaction. Uncontrollable crying is more common than uncontrollable laughing;56 such symptoms might be related to lesions in the anterior part of the limbic system, which are common in MS. The psychological problems of MS commonly cause more distress than the physical effects. Some, studies have shown that there is a positive association between depression and physical disability.57 Since these subsyndromes of affective disability respond well to antidepressants, detection and treatment offer the opportunity of substantially reducing one important part of morbidity associated with MS.58 Some patients with depressive symptoms can benefit from professional psychological or psychiatric therapy supported with drug treatment;59 group therapy can improve motivation, social interaction, and participation of patients in daily life.
Pain Pain in MS can be the result of demyelination in one of the pain-conducting pathways. The most common form is trigeminal neuralgia, in which the block is in the root entry zone of the trigeminal nerve.60 Other nerve regions are affected as a result of similar processes. The increased pain perception is a result of abnormal impulse transmission caused by demyelination and is best treated with antiepileptic drugs.61 Other sources of pain are indirectly related to the disease. Wheelchair use (figure 2) can cause secondary forms of pain resulting from contractures, flexor spasm, or indirectly via urinary-tract infections. According to published guidelines by WHO for treatment of cancer pain,62 the general principle of pain management in MS is to progress in a stepwise manner.
Spasticity Difficulties arising from spasticity include limitations in the range of movement and malpositioning of the joints, commonly accompanied by pain, and limitations of normal pursuit of movements. Individual factors and type and distribution of spasticity must be taken into account in decisions on therapeutic options. Spasticity can initially be managed with exercise (figure 3), changes in daily activities, physiotherapy, occupational http://neurology.thelancet.com Vol 4 October 2005
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striking deterioration in mobility. Furthermore, in every syndrome of spasticity provoking triggers should be sought and treated if found (eg, urinary tract infections and pain from other causes).44 Of all the symptoms of MS, ataxia and tremor are least susceptible to drug treatement. Benzodiazepines (eg, clonazepam), the tuberculostatic drug isoniazid, or ondansetron can relieve symptoms in single cases; the use of such therapies is limited, however, because of intolerable side-effects.44
Neurorehabilitation Evidence-based research on the effectiveness of neurorehabilitation69 is compromised by difficulties in trial design. There are no specific guidelines on the duration of treatment or its intensity. Controlled studies are rare owing to the justifiable reluctance, on ethical grounds, to withhold therapy judged to be the best. Moreover, masking of treatment blinding is never possible, although masking of observers might be possible.
Measurement of effectiveness
Figure 2: Transfer from wheelchair to bed using skidding board
therapy, or a combination of these methods. If these approaches are unsuccessful, or only partially successful, spasticity can be managed with orally administered drugs; there is good evidence to support use of agents such as baclofen or tizanidine.63,64 Some patients with severe spasticity who are unable to walk and do not respond to oral medication benefit from intrathecal baclofen. Botulinum toxin is also effective in the management of spasticity.65,66 Pharmacological management of spasticity should always be accompanied by physiotherapy. In tetraspasticity, an oral antispastic is used first (baclofen, tizanidine, dantrolene, diazepam). The disadvantage of these medications is a general lowering of muscle tone also in muscle groups with an already reduced tone (eg, trunk muscles). Furthermore, other possible side-effects, such as fatigue and vertigo, reduce physical fitness and cooperation. In severe paraspasticity, if a trial intrathecal injection is successful, implantation of an intrathecal baclofen pump can be a good alternative; advantages of this treatment are the very low dose needed, the absence of systemic side-effects, optimum dosing, and limitation of the effect on the legs.67 Regional spasticity (especially adduction spasticity of the legs) can be improved by botulinum-toxin injections.68 In some patients, standing and walking are only possible because of the spastic increase in muscle tones; this feature must be taken into account in decisions on treatment of spastic syndromes, because reduction of spasticity, by drugs can lead to http://neurology.thelancet.com Vol 4 October 2005
Assessment of the effectiveness of rehabilitation is particularly difficult in MS. First, the activity and the course of the disease are difficult to measure reliably. The differences within and between individuals complicate prediction of outcome even in patients with the same form of disease (primary relapsing remitting, secondary chronic progressive, primary chronic progressive). Triggering factors for progression and
Figure 3: Training of force, endurance, and full range of movements
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Panel 2: Criteria for selection of outcome variables in neurorehabilitation studies Outcome Impairment Disability and handicap Quality of life Goal achievement Coping skills Self sufficiency Criteria Clinical usefulness Scientific soundness (reliable, valid and responsive) Acceptability (appropriateness to sample)
relapses are not well understood. Basic pathological processes (inflammation, demyelination, and axonal damage) are heterogeneous and can be discriminated only with great difficulty by conventional neuroradiology.70 Furthermore, the symptom pattern can fluctuate as a result of various factors that may make assessment of functional capacity difficult because different functional CNS systems are affected. The consequences in terms of the kind and amount of disability, handicap, and quality of life vary.71 MRI is not helpful in assessment of functional capacity because there is no close relation between conventional MRI findings and degree of disability.70 To achieve a homogeneous cohort of patients, which satisfies scientific criteria for assessment of effectiveness of a medical intervention, is therefore very difficult. Perhaps this difficulty explains why only a few studies on the efficacy of rehabilitation in MS have been done. Assessment of outcome by appropriate methods is not only of scientific interest, it also enables comparison of efficacy of different treatment modalities and allows adaptations and development of new approaches. Assessment systems should be related to impairment, disability and handicap, quality of life, goal achievement, coping skills, self efficacy, and they should be clinically useful, scientifically sound (reliable, valid, and responsive), and acceptable (appropriate to sample).69 Panel 2 shows the range of possible measures that can be used to assess outcomes in rehabilitation trials. Based on our experience with patients at our centre, disability, handicap, and quality of life are the most important of these measures, but a general consensus on how to measure them is lacking.
Rehabilitation measures Therapeutic programmes vary widely among rehabilitation clinics, but there is a general consensus on personnel and infrastructure requirements and essential components of a rehabilitation programme.71,72 Owing to the broad range of symptoms and disabilities in MS, a 648
comprehensive assessment of functional disturbances and of personal needs is essential for an individualised, goal-oriented treatment programme.72 Specific therapeutic interventions are only one part of the rehabilitation programme. Comprehensive information and instruction of patients and relatives and other nonspecific factors are equally important. The timing and mode of rehabilitation treatment in MS patients should be set individually, with account taken of the degree and extent of disability, and personal and environmental factors. The need for rehabilitation should be assessed early in patients at risk of losing important functions, activities, or independence. Preservation of functions is much easier and more reliable than restoration of functions that have been lost for some time. Patients with complex functional deficits and disabilities should be admitted to the hospital for multidisciplinary rehabilitation treatment because outpatient treatment can be too difficult for logistic reasons. Even though, the best evidence for efficacy of rehabilitation came from studies with patients with chronic progressive MS, there is growing evidence that patients with relapsing-remitting MS can benefit from rehabilitation measures after an acute relapse with incomplete recovery.73,74 Realistic goals must be laid down in collaboration with patients and carers before the rehabilitation process starts. Features that limit comprehensive rehabilitation treatment include severe, cognitive disturbances, which affect cooperation and learning capabilities, and severe concomitant diseases, which limit training capacity. Several randomised controlled trials have added evidence of efficacy of rehabilitation measures. Although some studies suggest that some cortical reorganisation in patients with MS can occur,75 this mechanism of recovery probably plays only a minor part in MS rehabilitation. The main effect results from improved compensation, adaptation, and reconditioning. Furthermore, information and instruction to patients and carers and the use of medical and social resources can improve the patient’s ability to cope with disease and disability, thereby improving quality of life of patients and their relatives. The specific effect of treatment modalities on functions only partly explains the observed long-term benefit; adaptation, improved coping strategies and better use of personal and social resources are also important contributing factors.76
Multidisciplinary rehabilitation In an open, non-controlled study after short duration of inpatient rehabilitation (15 days) in 79 patients, there was a significant improvement in disability and handicap.77 This positive effect persisted for 3 months, particularly in patients with relapsing-remitting disease, but also in progressive forms. These findings were confirmed in a randomised, controlled study by the http://neurology.thelancet.com Vol 4 October 2005
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same research group;78 32 patients with MS, who followed an inpatient multidisciplinary rehabilitation programme for 3 weeks, were compared with another group of 34 patients who were on a waiting list and started rehabilitation later. All patients were examined at the beginning of treatment and after 6 weeks; patients in the control group had slight deterioration in disability and handicap, but those in the treatment group showed a significant improvement. There were no significant changes in either group in function as measured by EDSS.79 In a longitudinal study on the duration of the benefit of multidisciplinary inpatient rehabilitation, after 3 weeks of treatment in 67 patients with chronic progressive disease there was a significant improvement in disability in the inpatient group compared with the outpatient treatment group.80 This benefit was apparent 3 months after treatment but not after 12 months. In another prospective, non-controlled longitudinal study, 50 patients with chronic progressive MS were examined every 3 months after a multidisciplinary inpatient rehabilitation treatment of 23 days; disability, handicap, and quality of life improved significantly over 6 months and even over 9 months.76 These benefits occurred despite progressive deterioration in function (measured by EDSS),79 reflecting further progression of the disease process. In our own study,81 a group of 90 men and 196 women with MS were treated for a mean of 28 days (range 11–92 days). These patients showed a significant increase in score on the extended Barthel index (EBI, 0–64) of 0·85 points per week in patients with moderate disabilities (EBI, 30–39). Patients with low disability (EBI, 60–64) had a small gain (0·18 per week), possibly owing to a ceiling effect.81 The effect of multidisciplinary inpatient rehabilitation on measures of disability and quality of life in the long term was investigated in a randomised controlled study with patients on the waiting list as controls;78 this study included 66 patients with progressive MS who participated in a short period of inpatient rehabilitation (mean 20 days). At the end of the treatment period there were significant improvements in scores of handicap (London handicap scale) and disability scores (functional independence measure, FIM) compared with patients in the control group. The improvements in disability and handicap were maintained for 6 months.76 Improvements in emotional well-being lasted for 7 months and those in health-related quality of life for 10 months. These sustained benefits were achieved despite worsening neurological status. The influence of outpatient multidisciplinary rehabilitation of patients with MS was studied82 in a prospective, longitudinal, randomised study; and it showed a significant reduction in the frequency of symptoms, particularly fatigue compared with a control group. These patients had undergone an outpatient therapy programme (physiotherapy, occupational http://neurology.thelancet.com Vol 4 October 2005
therapy, individual counselling) 1 day per week over 1 year. A more recent randomised, controlled trial83 examined the effect of a short multidisciplinary treatment in patients with chronic progressive MS: 58 patients randomly assigned individualised multidisciplinary outpatient rehabilitation (6 weeks) were compared with a control group of 53 patients taking exercise at home. After 6 weeks and 12 weeks, there was a significant improvement in disability (FIM) in the treatment group, while impairment remained unchanged. 32 patients in the treatment group improved by more than 2 FIM steps compared with only four patients in the control group.
Specific treatment modalities In a randomised, controlled trial, the effect of inpatient physical therapy (two 45 min sessions per day for 3 weeks) in 27 ambulatory patients with MS was examined in comparison with a control group of 23 patients instructed on self training at home.84 Significant improvements in disability and quality of life were apparent after 3 weeks and 9 weeks, but after 12 weeks there was no significant difference. Both groups remained unchanged in terms of functional level (EDSS). In an earlier controlled study no significant improvement had been shown after inpatient physical therapy of 2 weeks duration (one 39 min session per day).85 In another controlled, crossover trial, 40 patients were treated in randomised order over 8 weeks as outpatients in a specialised rehabilitation clinic, by a physical therapist at home, or not at all.86 There was a significant improvement in mobility and disability during the active treatment periods compared with phases without therapy. In addition the frequency of falls was lower. Despite the lower costs for treatment at home, there was no significant difference between outpatient and home treatment. The effect was of short duration and was no longer detectable after 8 weeks. The efficacy of aerobic training (three sessions per week for 15 weeks) was studied in a randomised controlled trial of 54 patients; aerobic capacity and isometric strength were significantly better during the observation period than in a control group.87 In addition, there was transient improvement in psychological features (anxiety and depression) and fatigue. The role of aerobic training during multimodal rehabilitation programmes has also been analysed in a randomised controlled study;88 with individually adapted ergometer training at the aerobic threshold (30 min per day for 4 weeks), the functional capacity, aerobic capacity, and level of activity could be increased. Scores of vitality and social interaction also improved, and fatigue was slightly but not significantly reduced. Furthermore there was a trend of reduced fatigue. Another important finding was that the physical stress of this study had no negative effect on the clinical course. 649
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Search Strategy and selection criteria Data for this review were identified by searches of MEDLINE with the search terms “multiple sclerosis”, “rehabilitation”, “management”, “spasticity”, “fatigue”, “sexual dysfunction”, “cognitive deficits”, “incontinence”, and “pelvic organ dysfunction” in April 2005, without limit on year of publication. More recent publications, however, were preferred if they were of similar content. References were also identified from relevant articles and through searches of the authors’ files. Only papers published in English or German were reviewed.
For occupational therapy (ergotherapy) in MS, only a few open, non-controlled studies have been published. In a meta-analysis, a positive effect of ergotherapy (tone modulating measures and specific training of manual and practical functions) on muscle function, range of movement, and activities of daily living was shown.89 Because aphasia is rare in MS, specific speech therapy is rarely necessary. In patients with dysarthrophonia, however, speech training and exercises in respiration can help increase the capacity to articulate. Furthermore, as for patients after strokes, training in swallowing with triggering of reflexes, training of the swallowing process, compensatory measures and appropriate consistency of food and liquids can help to improve the process of swallowing and reduce the risk of aspiration.90,91 In more severe dysphagia, percutaneous endoscopic gastrostomy should be discussed. In the most severely disabled dependent patients, in addition to problems with swallowing and insufficient respiratory functions, reduced coughing can lead to pulmonary infections. Respiratory training can help to improve respiratory functions and cough reflex.92
Conclusions Despite newer immunomodulating therapies, there is a continuing demand for treatments that address the negative effects of MS symptoms on daily life. Symptomatic treatment and rehabilitation are effective in this respect. There is, however, much scope for further research on more effective and more tolerable drug treatments and the accurate nature and extent of rehabilitation techniques in MS. The main priorities are to define which treatment modalities are most effective and to identify the optimum duration and frequency of such interventions.69 However, the philosophies behind rehabilitation and evidence-based medicine often conflict with one another. The main issue is that reductionism used in clinical trials can be insensitive to the individually tailored aims of rehabilitation medicine. The correct balance between these two aims must be found for elucidation of how to integrate new scientific advances into clinical practice. Despite these difficulties, multidisciplinary inpatient neuro650
rehabilitation regimens do offer benefits to patients with MS in terms of improvements in disability, handicap, and well-being. The improvements achieved persist for several months after the treatment period even though the procedures have no direct influence on underlying disease activity or progression; clinical features that are perceived as disease progression can simply be the result of inadequate management of the patient. Authors’ contributions Both authors collaborated closely for ten years in leading the Neurorehabilitation Centre in Valens and contributed equally in writing the review. Conflicts of interest JK has been or is a member of independent advisory boards for several trials with new immunomodulating drugs for the treatment of MS (trials sponsored by Schering AG/Berlex, Serono, Biogen, Wyeth). SB has no conflicts of interest. References 1 Beer S, Kesselring J. Die multiple Sklerose im Kanton Bern. Eine epidemiologische Studie. Fortschr Neurol Psychiat 1988; 56: 390–97. 2 Kraft GH, Freal JE, Coryell JK. Disability, disease duration, and rehabilitation service needs in multiple sclerosis: patient perspectives. Arch Phys Med Rehabil 1986; 67: 164–68. 3 Weinshenker BG, Bass B, Rice GPA, et al. The natural history of multiple sclerosis: a geographically based study: I, clinical course and disability. Brain 1989; 112: 133–46. 4 Kantarci OH, Weinshenker BG. Natural history of multiple sclerosis. Neurol Clin 2005; 23: 17–38. 5 Rao SM, Leo GJ, Ellington L, et al. Cognitive dysfunction in multiple sclerosis: II, impact on employment and social functioning. Neurology 1991; 41: 692–96. 6 Patwardhan MB, Matchar DB, Samsa GP, McCrory DC, Williams RG, Li TT. Cost of multiple sclerosis by level of disability: a review of literature. Mult Scler 2005; 11: 232–39. 7 Carton HR, Loos J, Pacolet K, Versieck, Vlietinck R. Utilisation and cost of professional care and assistance according to disability of patients with multiple sclerosis in Flanders (Belgium). J Neurol Neurosurg Psychiatry 1998; 64: 444–50. 8 Multiple Sklerose Therapie Konsensus Gruppe (MSTKG). Symptomatische Therapie der Multiplen Skleorse. Nervenarzt 2004; (suppl 1) 75: S2–S39. 9 Bertolene K, Coyle PK, Krupp LB. Cytokine correlates of fatigue in MS. Neurology 1993; 43: A356 (abstr). 10 Sheean GL, Murray NMF, Rothwell JC, Miller DH, Thompson AJ. An electrophysiological study of the mechanism of fatigue in multiple sclerosis. Brain 1997; 120: 299–315. 11 Humm A, Beer S, Kool J, Magistris MR, Kesselring J, Rösler KM. Altered central motor conduction time caused by change in body temperature: a quantification of the Uhthoff phenomenon in multiple sclerosis. Clin Neurophysiol 2004; 115: 2493–501. 12 Haufschild T, Shaw SG, Kesselring J, Flammer J. Increased endothelin-1 plasma levels in patients with multiple sclerosis. J Neuroophthalmol 2001; 21: 37–38. 13 Krupp LB, Coyle PK, Doscher C, et al. Fatigue therapy in multiple sclerosis: results of a double-blind, randomized, parallel trial of amantadine, pemoline, and placebo. Neurology 1995; 45: 1956–61. 14 Taus C, Giuliani G, Pucci E, D’Amico R, Solari A. Amantadine for fatigue in multiple sclerosis. Cochrane Database Syst Rev 2003; 2: CD002818. 15 Tomassini V, Pozzilli C, Onesti E, et al. Comparison of the effects of acetyl L-carnitine and amantadine for the treatment of fatigue in multiple sclerosis: results of a pilot, randomised, double-blind, crossover trial. J Neurol Sci 2004; 218: 1038. 16 Rammohan KW, Rosenberg JH, Lynn DJ, et al. Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry
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