Review

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 Lancet Neurol 2005; 4: 643–52
progressive impairments and handicap. Symptoms that contribute to loss of independence and restrictions in social Department of Neurology and
activities lead to continuing decline in quality of life. Our aim is to give an updated overview on the management of Neurorehabilitation,
Rehabilitation Centre,
symptoms and rehabilitation measures in MS. Appropriate use of these treatment options might help to reduce CH-7317, Valens, Switzerland
long-term consequences of MS in daily life. First, we review treatment of the main symptoms of MS: fatigue, bladder (J Kesselring, S Beer)
and bowel disturbances, sexual dysfunction, cognitive and affective disorders, and spasticity. Even though these Correspondence to:
symptomatic therapies have benefits, their use is limited by possible side-effects. Moreover, many common Prof Jürg Kesselring, Department
disabling symptoms, such as weakness, are not amenable to drug treatment. However, neurorehabilitation has been of Neurology and
Neurorehabilitation,
shown to ease the burden of these symptoms by improving self-performance and independence. Second, we discuss
Rehabilitation Centre, CH-7317,
comprehensive multidisciplinary rehabilitation and specific treatment options. Even though rehabilitation has no Valens, Switzerland
direct influence on disease progression, studies to date have shown that this type of intervention improves personal [email protected]
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 status scale (EDSS).6 Half of the direct costs are

The many symptoms (panel 1) associated with multiple attributable to care of 17% of patients—those with the
sclerosis (MS) cause functional impairment and most severe disability of whom 6·5% live in nursing
handicap. The symptom pattern depends on the location homes.7
of lesions in the CNS, although most inflammatory foci For many patients with MS, quality of life can
do not cause symptoms. The most common symptoms deteriorate and they lose their independence and
in relapsing-remitting MS are visual (46%) and sensory become less able to participate in social activities.
disturbances (41%), whereas in primary progressive Treatment of the symptoms of MS is essential and it
forms of MS the most prevalent symptoms are gait requires a multidisciplinary approach encompassing
disorders (88%) and pareses (38%).1 Other symptoms drug therapy, psychological counselling, and
such as bladder problems and cognitive disturbances physiotherapy.
commonly develop later in the course of the disease and Rehabilitation can be defined as an active process of
can become the most noticeable. The consequences of education and enablement, which is focused on the
these functional deficits in activities of daily life are appropriate management of disability and minimising
variable. Many patients commonly view fatigue as limitation of handicap, with the goal of achieving full
having the most adverse consequences in daily life, recovery. However, with a condition such as MS in
followed by disturbances of balance, pareses, and
bladder disorders.2 MS has an early disease onset, a Panel 1: Symptoms associated with MS
progressive course, and very long duration with a
median survival time of about 40 years from diagnosis; Fatigue
thus there is a high prevalence of disabilities with Bladder and bowel dysfunction
consequences in personal as well as social domains. Cognitive and emotional problems—eg, depression
15 years after diagnosis, around 50% of patients with MS Spasticity
use walking aids and 29% need a wheelchair.3,4 During Gait disorders
the first 10 years of disease, 50–80% become unable to Visual problems
work.5 Thus, the main burden of the disease manifests Dizziness and vertigo
during the 5th and 6th decades of a patient’s life, a time Tremor
when most people are particularly active socially as well Speech and swallowing disorders
as in their careers. Socioeconomic consequences of MS Numbness
are substantial: the direct and indirect costs for one Pain
person with MS per year are estimated at around ¤50 000 Sexual dysfunction
or US$62 000, and there is a strong correlation between Seizures
costs and increasing score on the expanded disability

http://neurology.thelancet.com Vol 4 October 2005 643

 Review

which full recovery is not possible, goals become focused practice, however, the effect of amantadine is less
on achieving the best physical, mental, and social impressive, and a recent meta-analysis criticised trials
potential of patients so that they can remain, or become, for not investigating the relevance and effect on quality
integrated into a social environment that is appropriate of life.14 A randomised, double-blind cross-over trial with
for them. The longer-term benefits from management of 36 patients with MS by Tomassini and co-workers,15
symptoms and emotional status help to compensate for showed significant improvement in fatigue (rated by the
functional deficits and enable patients to adapt to their fatigue severity scale) during 3 months of treatment
circumstances more readily. with acetyl L-carnitine compared with amantadine; the
This paper provides an overview of management researchers concluded that acetyl L-carnitine was
options for each group of symptoms that accompany MS superior and better tolerated than amantadine.15 In a
and examines clinical-trial evidence that supports the non-randomised, single-blind phase II study with a
efficacy of neurorehabilitation. In 2004, a group of titration design in 72 patients with MS who had fatigue
experts in MS from Germany, Switzerland, and Austria (measured by MS fatigue scale) fatigue improved with
published a comprehensive review and consensus daily modafinil treatment (200 mg) for 9 weeks.16 Even
statement on symptomatic treatment and rehabilitation though treatment with modafil was tolerated well, long-
in MS;8 it consists of existing evidence based literature term safety and efficacy remain unclear. An alternative
and neurologists’ therapeutic experience who have dealt therapy to modafil could be methylphenidate—another
with these problems over a long time. drug with central stimulating effects—which has also
been of benefit in patients with other diseases causing
Fatigue fatigue (HIV, cancer).17,18 Aminopyridines (3-4-diamino-
Fatigue is the single symptom that patients identify as pyridine, 4-aminopyridine) work by blocking potassium
interfering most with their daily activities. The causes channels and thus improving central conduction in
are multifactorial. A poor sleep pattern, resulting from demyelinated fibres; this mechanism has been shown to
pain, nocturia, and spasticity, is commonly the cause. lead to an improvement of fatigue and other
Another equally important factor might be the symptoms.19 In a randomised, double-blind, placebo-
immunological processes of MS. Several of the cytokines controlled, cross-over trial, 54 patients with MS were
involved in the pathogenesis of MS are known to induce treated with 4-aminopyridine (32 mg daily over
sleep, especially interleukin, which affects the 6 months);20 although there was no significant
hypothalamic axis and results in reduced cerebral improvement in fatigue among the whole study group,
metabolism.9 Motor disturbances associated with patients with serum concentrations of 4-aminopyridine
spasticity are also likely to contribute to the fatigue above 30 ng/L showed significant improvement. The
syndrome. In patients with MS, the reciprocal inhibitory treatment was tolerated well in this study, however,
mechanisms are disturbed, which results in a reduced serious side-effects of aminopyridines have been
rate of motor-unit firing. Electrophysiological studies reported, making safety an important issue for future
have suggested that an impaired drive of motor impulses trials.21 Nutritional supplements such as creatine (in
to the primary motor cortex can decay the maximal combination with magnesium) might support
muscle force.10 In addition to these pathophysiological conditioning training and improve physical endurance;22
mechanisms, treatments for MS, such as beta even though the use of these supplements might be
interferons, antispastic drugs, and antidepressive useful during intensive training, no clinical trials have
agents, have also been reported to cause fatigue. investigated the benefit during rehabilitation of patients
New evidence suggests that fatigue might be linked to with MS.
disturbances in regulation of body temperature.11 There
seems to be an association between dysregulation of Bladder symptoms
body temperature and high concentrations of Bladder symptoms are particularly incapacitating in
endothelins that accompany ischaemia.12 The role of daily life. Spinal-cord disease in MS is thought to be the
endothelins as mediators in temperature regulation and main cause of pelvic-organ dysfunction. Impairment of
fatigue is currently being investigated in our clinic. bladder function is commonly characterised by urgency,
Treatment of fatigue requires a multidisciplinary which is the consequence of detrusor hyper-reflexia. The
approach; appropriate strategies include graded exercise symptom of urgency is in many cases coupled with
programmes, behaviour modification therapy, or urinary frequency resulting from reduced bladder
medication. In a comparative, double-blind randomised capacity. A few patients also have difficulty in initiating
study, 93 patients were assigned amantadine (100 mg micturition or are unable to achieve complete bladder
twice daily), pemoline (18·75–37·5 mg), or placebo for emptying. These bladder symptoms make many patients
6 weeks.13 The group assigned amantadine had a reluctant to engage in social activities. Urgency can be
significant improvement in fatigue compared with the made worse by motor disabilities that prevent the patient
placebo group. There was no difference in fatigue from reaching the toilet quickly. Apart from drug
between the pemoline and placebo groups. In clinical therapy, pelvic-floor training can help to improve

644 http://neurology.thelancet.com Vol 4 October 2005

 Review

bladder symptoms. In a controlled study of 80 patients with other chronic diseases and 13% of healthy
with MS, pelvic floor training with combined instruction controls.37 The main complaints for women are
for home programmes led to significant improvements anorgasmia or hyporgasmia, decreased vaginal
in incontinence, urgency, and frequency.23 Incomplete lubrication, and reduced libido. In men, the main
bladder voiding can be treated with an external bladder complaints are impotence or erectile dysfunction,
stimulator (Queen Square stimulator), leading to a ejaculatory dysfunction, orgasmic dysfunction, and
substantial reduction in resting urinary volume.24,25 reduced libido.37 These symptoms can have an important
Detrusor hyperactivity can be effectively treated with effect on self-esteem and relationships. Even though
physiotherapy to train the pelvic-floor muscles26 or some of these complaints can be attributed to the
bladder-training protocols, which aim to re-establish a psychological factors related to having a chronic
normal urinary frequency and increase bladder capacity disabling disease, others are a result of the dysfunction
through behavioural modification.27 Anticholinergic of neural pathways that are important for sexual activity.
agents, especially tolterodine, are effective at decreasing The association of sexual disturbances with disability,
micturition and urge incontinence.28 However, these neurological impairment, and bladder dysfunction is
pharmacological treatments commonly have typical evidence for dysfunction of these neural pathways; MRI
anticholinergic side-effects (dry mouth and thirst), data suggest an association with pontine pathology.38
which in turn can exacerbate bladder problems. Another cause of sexual dysfunction might be the use of
Management of bladder dysfunction can also be drugs (eg, intrathecal baclofen) which can affect erectile
achieved in some cases by simpler methods, such as function.39 Management for these symptoms, is again,
effective management of fluid intake and a reduction in multifactorial in nature because the problem can be
the intake of diuretic agents such as caffeine. These organic, psychological, or related to relationship
approaches can be used alongside the methods problems. The primary approach is to refer patients for
described above. Alternatively, electrostimulation psychological counselling; this approach for couples can
therapy (anal or vaginal) has been used to stimulate the improve sexual satisfaction.40 Drug treatment is mainly
pudendal nerves and inhibits the hyper-reflexia. Some limited to erectile dysfunction, which can be treated with
patients with detrusor-sphincter dys-synergy need clean oral sildenafinil.24,41 Intracavernous self-injections of
intermittent self-catheterisation, and others need vasoactive drugs are another treatment option,42
permanent catheterisation; in these cases suprapubic however, this approach can be difficult for patients with
catheters carry a lower risk of infection and advanced disability. Other treatments occasionally used
complications than intraurethral catheters.29 A new way are vacuum devices and implants.
of treating hyper-reflexia is injection of botulinum A
toxin into the detrusor muscle. In a study of 31 patients Chronic constipation
who had spinal-cord injury with severe hyper-reflexia Chronic constipation is a substantial source of distress
and who needed intermittent self-catheterisation, an for patients with chronic neurological diseases including
injection of botulinum toxin (300 units) was highly MS. Non-specific measures to control constipation
effective in restoring continence and had no side- include: body fitness programmes, dietary intervention
effects.30,31 The effects of a single dose of botulinum toxin in the form of fibre, avoidance of chocolate, and
lasted for 9 months. adequate intake of fluids. However, increased fluid
Urinary-tract infections can occur as a result of urine intake can in turn complicate co-existing bladder
retention or catheter use. Management of these problems. Pharmacological interventions are in the
infections is an important part of MS therapy, and form of laxative-type agents.43,44
patients should be monitored closely. Urinary tract
infections can be managed with antibiotics such as Cognitive deficit and affective disturbances
ciprofloxacin, sulfamethoxazole, and nitrofurantoin,32 40–65% of patients with MS have some degree of
and phenazopyridine can be used for symptom relief.33 cognitive deficit.45 These deficits can occur early in the
Methenamine hippurate can also be used course of the disease and can have long-term effects on
prophylactically to prevent infections,34 although this use patients and their families. Unemployment, social
is still controversial.35 In some patients, infection of the isolation, and the need for personal assistance at home
upper urinary tract results in severe illness and are more likely in patients with cognitive impairment
permanent damage to the kidneys. Patients with (figure 1),46 and these patients also have a high risk of
symptoms consistent with such infections and those not developing depression. Many patients with cognitive
responding to treatment should be carefully monitored. deficits, particularly early in the course of MS, have to
give up work with subsequent loss of income. This loss
Sexual dysfunction is an important part of the indirect costs of MS; loss of
Many patients with MS experience sexual dysfunction.36 earnings for both patient and carer and costs of informal
In a comparative study, sexual dysfunction was found in care account for up to 60% of the financial cost of MS.47,48
73% of patients with MS compared with 39% of those Memory is the most commonly affected function; long-

http://neurology.thelancet.com Vol 4 October 2005 645

 Review

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
Figure 1: Training activities of daily life—climbing stairs from professional psychological or psychiatric therapy
supported with drug treatment;59 group therapy can
term memory is more impaired than the short-term improve motivation, social interaction, and participation
memory. Attention is also compromised as shown by of patients in daily life.
diminished alertness, a reduction of mental processing
speed, and impaired visuospacial perception. Pain
Cognitive deficits must be recognised as early as Pain in MS can be the result of demyelination in one of
possible, enabling rehabilitation strategies to be the pain-conducting pathways. The most common form
employed to limit effects on the patient’s life. These is trigeminal neuralgia, in which the block is in the root
strategies are focused primarily on non-pharmacological entry zone of the trigeminal nerve.60 Other nerve regions
measures, such as cognitive rehabilitation, occupational are affected as a result of similar processes. The
therapy, and psychotherapy. Pharmacological measures increased pain perception is a result of abnormal
focus mainly on the control of comorbid symptoms, impulse transmission caused by demyelination and is
such as fatigue and depression. Because of the best treated with antiepileptic drugs.61 Other sources of
difficulties of undertaking clinical trials to assess the pain are indirectly related to the disease. Wheelchair use
effect of treatment on cognitive deficits, there are (figure 2) can cause secondary forms of pain resulting
currently few effective pharmacological agents approved from contractures, flexor spasm, or indirectly via
as symptomatic therapy for cognitive dysfunction in urinary-tract infections. According to published
MS.49,50 guidelines by WHO for treatment of cancer pain,62 the
Cognitive training can lead to substantial general principle of pain management in MS is to
improvement of attention and therefore a reduction in progress in a stepwise manner.
attention-associated problems in comparison with non-
specific training;51 these effects were measurable even Spasticity
several weeks after the end of treatment. Lincoln and Difficulties arising from spasticity include limitations in
colleagues52 examined the influence of detailed the range of movement and malpositioning of the joints,
neuropsychological testing with cognitive intervention commonly accompanied by pain, and limitations of
(which consisted, however, only of instruction in self- normal pursuit of movements. Individual factors and
training rather than of peforming therapy by type and distribution of spasticity must be taken into
professional neuropsychologists) compared with account in decisions on therapeutic options. Spasticity
neuropsychological testing alone. At 4 months and can initially be managed with exercise (figure 3),
8 months after neuropsychological testing, there were changes in daily activities, physiotherapy, occupational

646 http://neurology.thelancet.com Vol 4 October 2005

 Review

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
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.
Figure 2: Transfer from wheelchair to bed using skidding board The differences within and between individuals
complicate prediction of outcome even in patients with
therapy, or a combination of these methods. If these the same form of disease (primary relapsing remitting,
approaches are unsuccessful, or only partially secondary chronic progressive, primary chronic
successful, spasticity can be managed with orally progressive). Triggering factors for progression and
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 Figure 3: Training of force, endurance, and full range of movements

http://neurology.thelancet.com Vol 4 October 2005 647

 Review

comprehensive assessment of functional disturbances

Panel 2: Criteria for selection of outcome variables in and of personal needs is essential for an individualised,
neurorehabilitation studies goal-oriented treatment programme.72 Specific
Outcome therapeutic interventions are only one part of the
Impairment rehabilitation programme. Comprehensive information
Disability and handicap and instruction of patients and relatives and other non-
Quality of life specific factors are equally important.
Goal achievement The timing and mode of rehabilitation treatment in
Coping skills MS patients should be set individually, with account
Self sufficiency taken of the degree and extent of disability, and
personal and environmental factors. The need for
Criteria rehabilitation should be assessed early in patients at
Clinical usefulness risk of losing important functions, activities, or
Scientific soundness (reliable, valid and responsive) independence. Preservation of functions is much
Acceptability (appropriateness to sample) easier and more reliable than restoration of functions
that have been lost for some time. Patients with
complex functional deficits and disabilities should be
relapses are not well understood. Basic pathological admitted to the hospital for multidisciplinary
processes (inflammation, demyelination, and axonal rehabilitation treatment because outpatient treatment
damage) are heterogeneous and can be discriminated can be too difficult for logistic reasons. Even though,
only with great difficulty by conventional the best evidence for efficacy of rehabilitation came
neuroradiology.70 Furthermore, the symptom pattern from studies with patients with chronic progressive
can fluctuate as a result of various factors that may make MS, there is growing evidence that patients with
assessment of functional capacity difficult because relapsing-remitting MS can benefit from rehabilitation
different functional CNS systems are affected. The measures after an acute relapse with incomplete
consequences in terms of the kind and amount of recovery.73,74
disability, handicap, and quality of life vary.71 MRI is not Realistic goals must be laid down in collaboration with
helpful in assessment of functional capacity because patients and carers before the rehabilitation process
there is no close relation between conventional MRI starts. Features that limit comprehensive rehabilitation
findings and degree of disability.70 To achieve a treatment include severe, cognitive disturbances, which
homogeneous cohort of patients, which satisfies affect cooperation and learning capabilities, and severe
scientific criteria for assessment of effectiveness of a concomitant diseases, which limit training capacity.
medical intervention, is therefore very difficult. Perhaps Several randomised controlled trials have added
this difficulty explains why only a few studies on the evidence of efficacy of rehabilitation measures. Although
efficacy of rehabilitation in MS have been done. some studies suggest that some cortical reorganisation
Assessment of outcome by appropriate methods is not in patients with MS can occur,75 this mechanism of
only of scientific interest, it also enables comparison of recovery probably plays only a minor part in MS
efficacy of different treatment modalities and allows rehabilitation. The main effect results from improved
adaptations and development of new approaches. compensation, adaptation, and reconditioning.
Assessment systems should be related to impairment, Furthermore, information and instruction to patients
disability and handicap, quality of life, goal achievement, and carers and the use of medical and social resources
coping skills, self efficacy, and they should be clinically can improve the patient’s ability to cope with disease and
useful, scientifically sound (reliable, valid, and disability, thereby improving quality of life of patients
responsive), and acceptable (appropriate to sample).69 and their relatives. The specific effect of treatment
Panel 2 shows the range of possible measures that can modalities on functions only partly explains the
be used to assess outcomes in rehabilitation trials. Based observed long-term benefit; adaptation, improved
on our experience with patients at our centre, disability, coping strategies and better use of personal and social
handicap, and quality of life are the most important of resources are also important contributing factors.76
these measures, but a general consensus on how to
measure them is lacking. Multidisciplinary rehabilitation
In an open, non-controlled study after short duration of
Rehabilitation measures inpatient rehabilitation (15 days) in 79 patients, there
Therapeutic programmes vary widely among was a significant improvement in disability and
rehabilitation clinics, but there is a general consensus on handicap.77 This positive effect persisted for 3 months,
personnel and infrastructure requirements and essential particularly in patients with relapsing-remitting disease,
components of a rehabilitation programme.71,72 Owing to but also in progressive forms. These findings were
the broad range of symptoms and disabilities in MS, a confirmed in a randomised, controlled study by the

648 http://neurology.thelancet.com Vol 4 October 2005

 Review

same research group;78 32 patients with MS, who therapy, individual counselling) 1 day per week over
followed an inpatient multidisciplinary rehabilitation 1 year. A more recent randomised, controlled trial83
programme for 3 weeks, were compared with another examined the effect of a short multidisciplinary
group of 34 patients who were on a waiting list and treatment in patients with chronic progressive MS:
started rehabilitation later. All patients were examined at 58 patients randomly assigned individualised
the beginning of treatment and after 6 weeks; patients in multidisciplinary outpatient rehabilitation (6 weeks)
the control group had slight deterioration in disability were compared with a control group of 53 patients
and handicap, but those in the treatment group showed taking exercise at home. After 6 weeks and 12 weeks,
a significant improvement. There were no significant there was a significant improvement in disability (FIM)
changes in either group in function as measured by in the treatment group, while impairment remained
EDSS.79 In a longitudinal study on the duration of the unchanged. 32 patients in the treatment group improved
benefit of multidisciplinary inpatient rehabilitation, after by more than 2 FIM steps compared with only four
3 weeks of treatment in 67 patients with chronic patients in the control group.
progressive disease there was a significant improvement
in disability in the inpatient group compared with the Specific treatment modalities
outpatient treatment group.80 This benefit was apparent In a randomised, controlled trial, the effect of inpatient
3 months after treatment but not after 12 months. In physical therapy (two 45 min sessions per day for
another prospective, non-controlled longitudinal study, 3 weeks) in 27 ambulatory patients with MS was
50 patients with chronic progressive MS were examined examined in comparison with a control group of
every 3 months after a multidisciplinary inpatient 23 patients instructed on self training at home.84
rehabilitation treatment of 23 days; disability, handicap, Significant improvements in disability and quality of
and quality of life improved significantly over 6 months life were apparent after 3 weeks and 9 weeks, but after
and even over 9 months.76 These benefits occurred 12 weeks there was no significant difference. Both
despite progressive deterioration in function (measured groups remained unchanged in terms of functional
by EDSS),79 reflecting further progression of the disease level (EDSS). In an earlier controlled study no
process. significant improvement had been shown after
In our own study,81 a group of 90 men and 196 women inpatient physical therapy of 2 weeks duration (one
with MS were treated for a mean of 28 days (range 39 min session per day).85 In another controlled, cross-
11–92 days). These patients showed a significant over trial, 40 patients were treated in randomised order
increase in score on the extended Barthel index (EBI, over 8 weeks as outpatients in a specialised
0–64) of 0·85 points per week in patients with moderate rehabilitation clinic, by a physical therapist at home, or
disabilities (EBI, 30–39). Patients with low disability not at all.86 There was a significant improvement in
(EBI, 60–64) had a small gain (0·18 per week), possibly mobility and disability during the active treatment
owing to a ceiling effect.81 periods compared with phases without therapy. In
The effect of multidisciplinary inpatient rehabilitation addition the frequency of falls was lower. Despite the
on measures of disability and quality of life in the long lower costs for treatment at home, there was no
term was investigated in a randomised controlled study significant difference between outpatient and home
with patients on the waiting list as controls;78 this study treatment. The effect was of short duration and was no
included 66 patients with progressive MS who longer detectable after 8 weeks.
participated in a short period of inpatient rehabilitation The efficacy of aerobic training (three sessions per
(mean 20 days). At the end of the treatment period there week for 15 weeks) was studied in a randomised
were significant improvements in scores of handicap controlled trial of 54 patients; aerobic capacity and
(London handicap scale) and disability scores (functional isometric strength were significantly better during the
independence measure, FIM) compared with patients in observation period than in a control group.87 In addition,
the control group. The improvements in disability and there was transient improvement in psychological
handicap were maintained for 6 months.76 features (anxiety and depression) and fatigue. The role of
Improvements in emotional well-being lasted for aerobic training during multimodal rehabilitation
7 months and those in health-related quality of life for programmes has also been analysed in a randomised
10 months. These sustained benefits were achieved controlled study;88 with individually adapted ergometer
despite worsening neurological status. training at the aerobic threshold (30 min per day for
The influence of outpatient multidisciplinary 4 weeks), the functional capacity, aerobic capacity, and
rehabilitation of patients with MS was studied82 in a level of activity could be increased. Scores of vitality and
prospective, longitudinal, randomised study; and it social interaction also improved, and fatigue was slightly
showed a significant reduction in the frequency of but not significantly reduced. Furthermore there was a
symptoms, particularly fatigue compared with a control trend of reduced fatigue. Another important finding was
group. These patients had undergone an outpatient that the physical stress of this study had no negative
therapy programme (physiotherapy, occupational effect on the clinical course.

http://neurology.thelancet.com Vol 4 October 2005 649

 Review

rehabilitation regimens do offer benefits to patients

Search Strategy and selection criteria with MS in terms of improvements in disability,
Data for this review were identified by searches of MEDLINE handicap, and well-being. The improvements achieved
with the search terms “multiple sclerosis”, “rehabilitation”, persist for several months after the treatment period
“management”, “spasticity”, “fatigue”, “sexual dysfunction”, even though the procedures have no direct influence on
“cognitive deficits”, “incontinence”, and “pelvic organ underlying disease activity or progression; clinical
dysfunction” in April 2005, without limit on year of features that are perceived as disease progression can
publication. More recent publications, however, were simply be the result of inadequate management of the
preferred if they were of similar content. References were also patient.
identified from relevant articles and through searches of the
Authors’ contributions
authors’ files. Only papers published in English or German Both authors collaborated closely for ten years in leading the
were reviewed. 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
For occupational therapy (ergotherapy) in MS, only a trials with new immunomodulating drugs for the treatment of MS
few open, non-controlled studies have been published. (trials sponsored by Schering AG/Berlex, Serono, Biogen, Wyeth).
In a meta-analysis, a positive effect of ergotherapy (tone SB has no conflicts of interest.
modulating measures and specific training of manual References
and practical functions) on muscle function, range of 1 Beer S, Kesselring J. Die multiple Sklerose im Kanton Bern. Eine
epidemiologische Studie. Fortschr Neurol Psychiat 1988;
movement, and activities of daily living was shown.89 56: 390–97.
Because aphasia is rare in MS, specific speech therapy 2 Kraft GH, Freal JE, Coryell JK. Disability, disease duration, and
is rarely necessary. In patients with dysarthrophonia, rehabilitation service needs in multiple sclerosis: patient
perspectives. Arch Phys Med Rehabil 1986; 67: 164–68.
however, speech training and exercises in respiration
3 Weinshenker BG, Bass B, Rice GPA, et al. The natural history of
can help increase the capacity to articulate. Furthermore, multiple sclerosis: a geographically based study: I, clinical course
as for patients after strokes, training in swallowing with and disability. Brain 1989; 112: 133–46.
triggering of reflexes, training of the swallowing process, 4 Kantarci OH, Weinshenker BG. Natural history of multiple
sclerosis. Neurol Clin 2005; 23: 17–38.
compensatory measures and appropriate consistency of 5 Rao SM, Leo GJ, Ellington L, et al. Cognitive dysfunction in
food and liquids can help to improve the process of multiple sclerosis: II, impact on employment and social
swallowing and reduce the risk of aspiration.90,91 In more functioning. Neurology 1991; 41: 692–96.
6 Patwardhan MB, Matchar DB, Samsa GP, McCrory DC,
severe dysphagia, percutaneous endoscopic gastrostomy Williams RG, Li TT. Cost of multiple sclerosis by level of disability:
should be discussed. a review of literature. Mult Scler 2005; 11: 232–39.
In the most severely disabled dependent patients, in 7 Carton HR, Loos J, Pacolet K, Versieck, Vlietinck R. Utilisation and
addition to problems with swallowing and insufficient cost of professional care and assistance according to disability of
patients with multiple sclerosis in Flanders (Belgium).
respiratory functions, reduced coughing can lead to J Neurol Neurosurg Psychiatry 1998; 64: 444–50.
pulmonary infections. Respiratory training can help to 8 Multiple Sklerose Therapie Konsensus Gruppe (MSTKG).
improve respiratory functions and cough reflex.92 Symptomatische Therapie der Multiplen Skleorse. Nervenarzt 2004;
(suppl 1) 75: S2–S39.
9 Bertolene K, Coyle PK, Krupp LB. Cytokine correlates of fatigue in
Conclusions MS. Neurology 1993; 43: A356 (abstr).
Despite newer immunomodulating therapies, there is a 10 Sheean GL, Murray NMF, Rothwell JC, Miller DH, Thompson AJ.
An electrophysiological study of the mechanism of fatigue in
continuing demand for treatments that address the multiple sclerosis. Brain 1997; 120: 299–315.
negative effects of MS symptoms on daily life. 11 Humm A, Beer S, Kool J, Magistris MR, Kesselring J, Rösler KM.
Symptomatic treatment and rehabilitation are effective Altered central motor conduction time caused by change in body
temperature: a quantification of the Uhthoff phenomenon in
in this respect. There is, however, much scope for multiple sclerosis. Clin Neurophysiol 2004; 115: 2493–501.
further research on more effective and more tolerable 12 Haufschild T, Shaw SG, Kesselring J, Flammer J. Increased
drug treatments and the accurate nature and extent of endothelin-1 plasma levels in patients with multiple sclerosis.
rehabilitation techniques in MS. The main priorities are J Neuroophthalmol 2001; 21: 37–38.
13 Krupp LB, Coyle PK, Doscher C, et al. Fatigue therapy in
to define which treatment modalities are most effective multiple sclerosis: results of a double-blind, randomized, parallel
and to identify the optimum duration and frequency of trial of amantadine, pemoline, and placebo. Neurology 1995;
such interventions.69 However, the philosophies behind 45: 1956–61.
14 Taus C, Giuliani G, Pucci E, D’Amico R, Solari A. Amantadine for
rehabilitation and evidence-based medicine often fatigue in multiple sclerosis. Cochrane Database Syst Rev 2003;
conflict with one another. The main issue is that 2: CD002818.
reductionism used in clinical trials can be insensitive to 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
the individually tailored aims of rehabilitation multiple sclerosis: results of a pilot, randomised, double-blind,
medicine. The correct balance between these two aims crossover trial. J Neurol Sci 2004; 218: 1038.
must be found for elucidation of how to integrate new 16 Rammohan KW, Rosenberg JH, Lynn DJ, et al. Efficacy and safety
scientific advances into clinical practice. Despite of modafinil (Provigil) for the treatment of fatigue in multiple
sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry
these difficulties, multidisciplinary inpatient neuro-

650 http://neurology.thelancet.com Vol 4 October 2005

 Review

2002; 72: 179–83. 39 Denys P, Mane M, Azouvi P, et al. Side effects of chronic
17 Breitbart W, Rosenfeld B, Kaim M, Funesti-Esch J. A randomized, intrathecal baclofen on erection and ejaculation in patients with
double-blind, placebo-controlled trial of psychostimulants for the spinal cord lesions. Arch Phys Med Rehabil 1998; 79: 494–96.
treatment of fatigue in ambulatory patients with human 40 Foley FW, LaRocca NG, Sanders AS, Zemon V. Rehabilitation of
immunodeficiency virus disease. Arch Intern Med 2001; 161: 411–20. intimacy and sexual dysfunction in couples with multiple sclerosis.
18 Bruera E, Driver L, Barnes EA, et al. Patient-controlled Mult Scler 2001; 7: 417–21.
methylphenidate for the management of fatigue in patients with 41 Goldstein I, Lue TF, Padma-Nathan H, et al. Oral sildenafil in the
advanced cancer: a preliminary report. J Clin Oncol 2003; treatment of erectile dysfunction. N Engl J Med 1998; 338:
21: 4439–43. 1397–404.
19 Sheean GL, Murray NMF, Rothwell JC, Miller DH, Thompson AJ. 42 Vidal J, Curcoll L, Roig T, Bagunya J. Intracavernous
An open-labelled clinical and electrophysiological study of pharmacotherapy for management of erectile dysfunction in
3,4 diaminopyridine in the treatment of fatigue in multiple multiple sclerosis patients. Rev Neurol 1995; 23: 269–71.
sclerosis. Brain 1998; 121: 967–75. 43 Crayton H, Heyman RA, Rossman HS. A multimodal approach to
20 Rossini PM, Pasqualetti P, Pozzilli C, et al. Fatigue in progressive managing the symptoms of multiple sclerosis. Neurology 2004;
multiple sclerosis: results of a randomised, double-blind, placebo- 63 (11 suppl 5): S12–18.
controlled, crossover trial of oral 4-aminopyridine. Mult Scler 2001; 44 Kesselring J. Complications of multiple sclerosis: fatigue; spasticity;
7: 354–58. ataxia; pain; and bowel, bladder, and sexual dysfunction. In:
21 Solari A, Uitdehaag B, Giuliani G, Pucci E, Taus C. McDonald WI, Noseworthy JH, eds. Multiple sclerosis 2nd edn.
Aminopyridines for symptomatic treatment in multiple sclerosis. Philadelphia, Butterworth-Heinemann, 2003: 217–227.
Cochrane Database Syst Rev 2003; 2: CD001330. 45 Foong J, Ron MA. Neuropsychiatry: cognition and mood
22 Tarnopolsky MA, Beal MF. Potential for creatine and other disorders.In: McDonald WI, Noseworthy JH, eds. Multiple sclerosis
therapies targeting cellular energy dysfunction in neurological 2nd edn. Philadelphia, Butterworth-Heinemann, 2003: 115–24.
disorders. Ann Neurol 2001; 49: 561–74. 46 Gilchrist AC, Creed FH. Depression, cognitive impairment and
23 Vahtera T, Haaranen M, Viramo-Koskela AL, Ruutiainen J. Pelvic social stress in multiple sclerosis. J Psychosom Res 1994;
floor rehabilitation is effective in patients with multiple sclerosis. 38: 193–201.
Clin Rehabil 1997; 11: 211–19. 47 Whetten-Goldstein K, Sloan FA, Goldstein LB, Kulas ED.
24 DasGupta R, Fowler CJ. Bladder, bowel and sexual dysfunction in A comprehensive assessment of the cost of multiple sclerosis in the
multiple sclerosis: management strategies. Drugs 2003; United States. Mult Scler 1998; 4: 419–25.
63: 153–66. 48 Pompeii LA, Moon SD, McCrory DC. Measures of physical and
25 Prasad RS, Smith SJ, Wright H. Lower abdominal pressure versus cognitive function and work status among individuals with
external bladder stimulation to aid bladder emptying in multiple multiple sclerosis: a review of the literature. J Occup Rehabil 2005;
sclerosis: a randomized controlled study. Clin Rehabil 2003; 15: 69–84.
17: 42–47. 49 Bagert B, Camplair P, Bourdette D. Cognitive dysfunction in
26 Fantl J, Newman D, Colling J, et al. Urinary incontinence in adults: multiple sclerosis: natural history, pathophysiology and
acute and chronic management. 2nd update. Rockville, Maryland: management. CNS Drugs 2002; 16: 445–55.
Department of Health and Human Services, Public Health Service, 50 Krupp LB, Christodoulou C, Melville P, Scherl WF,
Agency for Health Care Policy and Research, 1996 (Clinical MacAllister WS, Elkins LE. Donepezil improved memory in
Practice Guideline, 96-0682.). multiple sclerosis in a randomized clinical trial. Neurology 2004;
27 Glenn J. Restorative Nursing Bladder Training program: 63: 1579–85.
recommending a strategy. Rehabil Nurs 2003; 28: 15–22. 51 Plohmann AM, Kappos L, Ammann W, et al. Computer assisted
28 Abrams P, Freeman R, Anderström C, Mattiasson. Tolterodie, a retraining of attentional impairments in patients with multiple
new antimuscarinic gent: as effective but better tolerated than sclerosis. J Neurol Neurosurg Psychiatry 1998; 64: 455–62.
oxybutinin in patients with an overactive bladder. Br J Urol 1998; 52 Lincoln NB, Dent A, Harding J, et al. Evaluation of cognitive
81: 801–10. assessment and cognitive intervention for people with multiple
29 Branagan GW, Moran BJ. Published evidence favors the use of sclerosis.J Neurol Neurosurg Psychiatry 2002; 72: 93–98.
suprapubic catheters in pelvic colorectal surgery. Dis Colon Rectum 53 Feinstein A, O’Connor P, Gray T, Feinstein K. The effect of anxiety
2002; 45: 1104–08. on psychiatric morbidity in patients with multiple sclerosis.
30 Schurch B, Stohrer M, Kramer G, Schmid DM, Gaul G, Hauri D. Mult Scler 1999; 5: 323–26.
Botulinum-A toxin for treating detrusor hyperreflexia in spinal 54 Feinstein A, Feinstein K. Depression associated with multiple
cord injured patients: a new alternative to anticholinergic drugs? sclerosis: looking beyond diagnosis to symptom expression.
Preliminary results. J Urol 2000; 164: 692–97. J Affect Disord 2001; 66: 193–98.
31 Leippold T, Reitz A, Schurch B. Botulinum toxin as a new therapy 55 Feinstein A, Feinstein K, Gray T, O’Connor P. Prevalence and
option for avoiding disorders: current state of the art. Eur Urol neurobehavioral correlates of pathological laughing and crying in
2003; 44: 165–74. multiple sclerosis. Arch Neurol 1997; 54: 1116–21.
32 Nicolle LE. Urinary tract infection: traditional pharmacologic 56 Feinstein A, O’Connor P, Gray T, Feinstein K. Pathological
therapies. Dis Mon 2003; 49: 111–28. laughing and crying in multiple sclerosis: a preliminary report
33 Zelenitsky SA, Zhanel GG. Phenazopyridine in urinary tract suggesting a role for the prefrontal cortex. Mult Scler 1999; 5: 69–73.
infections. Ann Pharmacother 1996; 30: 866–68. 57 McIvor GP, Riklan M, Reznikoff M. Depression in multiple
34 Banovac K, Wade N, Gonzalez F, Walsh B, Rhamy RK. Decreased sclerosis as a function of length and severity of illness, age,
incidence of urinary tract infections in patients with spinal cord remissions, and perceived social support. J Clin Psychol 1984;
injury: effect of methenamine. J Am Paraplegia Soc 1991; 40: 1028–33.
14: 52–54. 58 Siegert RJ, Abernethy DA. Depression in multiple sclerosis: a
35 Lee B, Bhuta T, Craig J, Simpson J. Methenamine hippurate for review. J Neurol Neurosurg Psychiatry 2005; 76: 469–75.
preventing urinary tract infections. Cochrane Database Syst Rev 59 Kesselring J, Klement U. Cognitive and affective disturbances in
2002; 1: CD003265 multiple sclerosis. J Neurol 2001; 248: 180–83.
36 Lundberg PO, Ertekin C, Ghezzi A, Swash M, Vodusek D B. Sexual 60 Kesselring J. Paroxysmale Phänomene bei Multipler Sklerose.
problems associated with neurological diseases (Neurosexology): Akt Neurol 2001; 28: 1–5.
guidelines for Neurologists. Eur J Neurol (in press). 61 Samkoff LM, Daras M, Tuchman AJ, Koppel BS. Amelioration of
37 Zorzon M, Zivadinov R, Bosco A, et al. Sexual dysfunction in refractory dysesthetic limb pain in multiple sclerosis by gabapentin.
multiple sclerosis: a case-control study. I. Frequency and Neurology 1997; 49: 304–05.
comparison of groups. Mult Scler 1999; 5: 418–27. 62 WHO. Palliative care and end-of-life care: integrated management
38 Zivadinov R, Zorzon M, Locatelli L, et al. Sexual dysfunction in of adolescent and adult illness. http://www.who.int/3by5/
multiple sclerosis: a MRI, neurophysiological and urodynamic publications/documents/en/genericpalliativecare082004.pdf
study. J Neurol Sci 2003; 210: 73–76. (accessed July 18, 2005).

http://neurology.thelancet.com Vol 4 October 2005 651

 Review

63 Paisley S, Beard S, Hunn A, Wight J. Clinical effectiveness of oral an expanded disability rating scale (EDSS). Neurology 1983;
treatments for spasticity in multiple sclerosis: a systematic review. 13: 1444–52.
Mult Scler 2002; 8: 319–29. 80 Francabandera FL, Holland NJ, Wiesel-Levison P, Scheinberg LC.
64 Rizzo MA, Hadjimichael OC, Preiningerova J, Vollmer TL. Multiple sclerosis rehabilitation: inpatient vs. outpatient.
Prevalence and treatment of spasticity reported by multiple Rehabil Nurs 1988; 13: 251–53.
sclerosis patients. Mult Scler 2004; 10: 589–95. 81 Jörger M, Beer S, Kesselring J. Impact of neurorehabilitation on
65 Snow BJ, Tsui JK, Bhatt MH, Varelas M, Hashimoto SA, Calne DB. disability in patients with acutely and chronically disabling diseases
Treatment of spasticity with botulinum toxin: a double-blind study. of the nervous system measured by the Extended Barthel Index.
Ann Neurol 1990; 28: 512–15. Neurorehabil Neural Repair 2001; 15: 15–22.
66 Grazko MA, Polo KB, Jabbari B. Botulinum toxin A for spasticity, 82 Di Fabio RP, Soderberg J, Choi T, Hansen CR, Schapiro RT.
muscle spasms, and rigidity. Neurology 1995; 45: 712–17. Extended outpatient rehabilitation: its influence on symptom
67 Ward AB. A summary of spasticity management: a treatment frequency, fatigue, and functional status for persons with progressive
algorithm. Eur J Neurol 2002; 9: 48–52. multiple sclerosis. Arch Phys Med Rehabil 1998; 79: 141–46.
68 Hyman N, Barnes M, Bhakta B, et al. Botulinum toxin (Dysport) 83 Patti F, Ciancio MR, Cacopardo M, et al. Effects of a short
treatment of hip adductor spasticity in multiple sclerosis: a outpatient rehabilitation treatment on disability of multiple
prospective, randomised, double blind, placebo controlled, dose sclerosis patients: a randomised controlled trial. J Neurol 2003;
ranging study. J Neurol Neurosurg Psychiatry 2000; 68: 707–12. 250: 861–66.
69 Kesselring J. Rehabilitation in MS: what is the evidence-base? 84 Solari A, Filippini G, Gasco P, et al. Physical rehabilitation has a
J Neurol 2004; 251, (Suppl 1); 75: 25–29. positive effect on disability in multiple sclerosis patients. Neurology
70 Miller DH, Kesselring J, McDonald WI, Paty DW, Thompson AJ. 1999; 52: 57–62.
Magnetic resonance in multiple sclerosis. Cambridge, Cambridge 85 Fuller KJ, Dawson K, Wiles CM. Physiotherapy in chronic multiple
University Press, 1997. sclerosis: a controlled trial. Clin Rehabil 1996; 10: 195–204.
71 Stucki G, Cieza A, Ewert T, Kostanjsek N, Chatterji S, Üstün TB. 86 Wiles CM, Newcombe RG, Fuller KJ, et al. Controlled randomised
Application of the International Cclassification of Functioning, crossover trial of the effects of physiotherapy on mobility in chronic
Disability and Health (ICF) in clinical practice. Disabil Rehab 2002; multiple sclerosis. J Neurol Neurosurg Psychiatry 2001; 70: 174–79.
24: 932–38. 87 Petajan JH, Gappmaier E, White AT, et al. Impact of aerobic
72 Freeman JA, Thompson AJ. Rehabilitation in multiple sclerosis. training on fitness and quality of life in multiple sclerosis.
In: McDonald WI and Noseworthy JH eds. Multiple Sclerosis 2. Ann Neurol 1996; 39: 432–41.
Philadelphia: Butterworth-Heinemann, 2003: 63–107. 88 Mostert S, Kesselring J. Effects of a short-term exercise training
73 Craig J, Young CA, Ennis M, Baker G, Boggild M. A randomised program on aerobic fitness, fatigue, health perception and activity
controlled trial comparing rehabilitation against standard therapy level of subjects with multiple sclerosis. Mult Scler 2002; 8: 161–68.
in multiple sclerosis patients receiving intravenous steroid 89 Baker NA, Tickle-Degnen L. The effectiveness of physical,
treatment. J Neurol Neurosurg Psychiatry 2003; 74: 1225–30. psychological, and functional interventions in treating clients with
74 Liu C, Playford ED, Thompson AJ. Does neurorehabilitation have a multiple sclerosis: a meta-analysis. Am J Occup Ther 2001;
role in relapsing-remitting multiple sclerosis? J Neurol 2003; 55: 324–31.
250: 1214–18. 90 Bartholome G Schluckstörungen NeuroRehabilitation. Berlin:
75 Rocca MA, Falini A, Colombo B, et al. Adaptive functional changes Blackwell Wissenschafts-Verlag, 1999, 107–124.
in the cerebral cortex of patients with nondisabling multiple 91 Prosiegel M, Heintze M, Wagner-Sonntag E, et al.
sclerosis correlate with the extent of brain structural damage. Schluckstörungen bei neurologischen patienten: eine prospektive
Ann Neurol 2002; 51: 330–39. studie zu diagnostik, störungsmustern, therapie und outcome.
76 Freeman JA, Langdon DW, Hobart JC, Thompson AJ. Inpatient Nervenarzt 2002; 73: 364–70.
rehabilitation in multiple sclerosis: do the benefits carry over into 92 Gosselink R, Kovacs L, Ketelaer P, Carton H, Decramer M.
the community? Neurology 1999; 52: 50–56. Respiratory muscle weakness and respiratory muscle training in
77 Kidd D, Thompson AJ. Prospective study of neurorehabilitation in severely disabled multiple sclerosis patients. Arch Phys Med Rehabil
multiple sclerosis. J Neurol Neurosurg Psychiatry 1997; 62: 423–24. 2000; 81: 747–51.
78 Freeman, JA, Langdon DW, Hobart JC. Thompson AJ. The impact
of inpatient rehabilitation on progressive multiple sclerosis.
Ann Neurol 1997; 42: 236–44.
79 Kurtzke JF. Rating neurological impairment in multiple sclerosis:

652 http://neurology.thelancet.com Vol 4 October 2005