thomson

1182 www.thelancet.com/neurology Vol 9 December 2010

Review

Lancet Neurol 2010; 9: 118299

Department of Brain Repair and Rehabilitation, UCL Institute of Neurology,

University College London, London, UK

(Prof A J Thompson FRCP, A T Toosy PhD, O Ciccarelli PhD)

Correspondence to:Dr Olga Ciccarelli, UCL Institute

of Neurology, University College London, Queen Square, WC1N 3BG London, UK

[email protected]

Pharmacological management of symptoms in multiple sclerosis: current approaches and future directions Alan J Thompson, Ahmed T Toosy, Olga Ciccarelli

Management of symptoms in multiple sclerosis (MS) has received little attention compared with disease-modifying treatments. However, the eff ect of these symptoms on quality of life can be profound. Clinical trials of pharmacological drugs to treat symptoms of MS have often been underpowered and have used inappropriate measures of outcome. Many currently used symptomatic drugs were introduced decades ago, when study quality was considerably below current standards. Therefore, the evidence base on which to make clinical decisions is less than adequate. Interest in pharmacological treatment of symptoms in MS has increased in recent years, and several large randomised controlled trials have been reported. Pharmacological strategies are a core component of the treatment of these symptoms, but it is imperative to remember that a multidisciplinary rehabilitation approach is needed for eff ective management.

IntroductionMultiple sclerosis (MS) has a substantial economic and social burden. The total fi nancial cost per patient per year has been estimated at about US$48 000 in the UK in 2007, with a lifetime cost of $12 million.1 People with this disorder can have many disabling symptoms that result in high emotional, psychological, and physical burden for the patients and carers. Therefore, the eff ective management of symptoms of MS is crucial, since it can improve quality of life, reduce the eff ect of disability on daily activities, and help patients to continue employment or education.

Pharmacological treatment is an essential component in the management of symptoms of MS and a patient-centred approach is central to its success. Physicians need to educate patients appropriately, discuss their priorities and expectations, and help them to select the right treatment to optimise compliance, especially with invasive interventions. Symptoms can change during the course of the disease; hence serial monitoring helps to optimise interventions. With oral drugs, the initial dose should be low and increased slowly according to response and tolerability. If one drug is insuffi cient because it is partially eff ective or has intolerable side-eff ects, then a combination of drugs, perhaps at lower doses, is advisable.

In this Review, we will describe pharmacological treatments for these symptoms, which represent an important component of a multidisciplinary approach to improve quality of life, ease care, and ensure independence. Surgical interventions will also be covered where relevant, but rehabilitation approaches such as physiotherapy are beyond the scope of this Review and are mentioned only briefl y. Some recent large and well conducted trials that have assessed the effi cacy of symptomatic medications such as fampridine2 and cannabinoids3 represent a clear improvement in the quality of trial design. Future trials of good quality should provide a strong evidence base for identifi cation of optimum treatments. In the meantime, in this Review, we provide an update on the available evidence for optimum treatment of symptoms in MS, discuss the

issues that need to be addressed before starting treatment, and provide recommendations for the most appropriate drug treatments.

For the management of individual symptoms, we group the wide range of symptoms of MS, beginning with mobility-related symptoms, such as spasticity, ataxia, and impaired ambulation. We then discuss bladder, bowel, and sexual dysfunction. The next group, which is often overlooked despite being very disabling for patients, consists of fatigue, cognitive dysfunction, and mood disturbance. These symptoms can interact, as can their treatments. This is also true for pain, another overlooked symptom discussed here. Finally, we will briefl y discuss symptoms resulting from visual and brainstem involvement.

Mobility-related symptomsSpasticitySpasticity is seen in more than 60% of patients with MS. This increased muscle tone (or hypertonia) results from injury to the corticospinal system and unmodulated activity of local spinal neurons and sensory aff erent pathways. If not well managed, it can lead to pain, spasms, reduced mobility, limited range of movement, and contractures.

General managementAt the outset, several issues need to be considered. First, is spasticity localised or generalised? Localised spasticity is amenable to physiotherapy and stretching of specifi c muscles, splinting, and botulinum toxin. Conversely, for generalised spasticity, oral drugs and, at a later stage, intrathecal interventions are commonly considered. Second, are there features that could aff ect the patients function, such as spasms (which can be painful), clonus, muscle shortening, and tendon or soft tissue contractures? Third, is spasticity masking underlying muscle weakness and ataxia? Individuals might rely on spasticity to walk or stand. Increased weakness and deterioration of tremor and coordination are sometimes reported side-eff ects of anti-spasticity medications, resulting from the reduction in muscle tone. Fourth, are

www.thelancet.com/neurology Vol 9 December 2010 1183

Review

there aggravating factors? Urinary and bowel dysfunction, poor posture or positioning, and pressure sores can exacerbate spasticity. Pain of diff erent origins (central pain, back pain, pain originating from unrecognised fractures) also needs to be considered. Addressing these factors is essential before pharmacological treatments are considered. Fifth, which drug treatments are appropriate? If drug therapy has already started, optimisation of its dosage or timing of administration might be necessary. Finally, are physiotherapy and nursing interventions available? The physiotherapist works with the patient to follow a mutually agreed, goal-oriented programme with the aim of improving patient function and quality of life. In cases of acute deterioration after a relapse, or of rapid progression, physiotherapy input is often needed to reduce spasticity and improve mobility and independence. Nursing intervention is essential to tackle precipitating and aggravating factors, such as pressure sores and ingrown toenails.

Pharmacological treatmentsThe evidence base for drugs commonly used to treat spasticity in MS is poor; trials are rare and many are underpowered, are unblinded, and use poorly validated measures (table 1). Trials generally use the Ashworth scale as the primary outcome measure of spasticity, but this has limitations14 such as poor reliability, validity, and responsivenessall potential disadvantages of one-item scales.

Baclofen, benzodiazepines (ie, diazepam and clonazepam), and tizanidine seem to have similar eff ects in reduction of stiff ness and spasms,4,13 but tizanidine seems to be the best and diazepam the worst tolerated.15 Although baclofen has been extensively investigated, its effi cacy has not been well proven (table 1). The initial dose should be low and increased slowly, although high doses tend to be tolerated reasonably well.16 In clinical practice, baclofen is recommended as the fi rst choice, especially in patients with spinal cord-related spasticity. Tizanidine can also be used as a fi rst-line treatment, although both well designed positive5,6 and negative7 trials have been published (table 1); side-eff ects are dose-dependent.6 Clonazepam can help reduce spasms and stiff ness. This drug should be prescribed at night because of drowsiness, and alone or in combination with baclofen or tizanidine; this strategy increases its tolerability.

Second-line drugs include gabapentin and dantrolene. The use of gabapentin in treatment of spasticity and spasms in MS is increasing, despite weak evidence of its effi cacy from small trials (table 1);9 it is well tolerated and can be particularly useful when central pain coexists (table 1). Dantrolene can be eff ective in treatment of spasms and clonus rather than stiff ness; however, it has a poor safety profi le (table 1) and data on its effi cacy are scarce, with only a few very small studies. Another possible second-line drug is tolperisone, although it has

been tested only in patients with spasticity after stroke.17 The results of this randomised double-bind placebo-controlled trial17 in 120 patients showed that tolperisone reduces spasticity eff ectively, as measured by the Ashworth scale, and is well tolerated.

Cannabinoids are the most innovative drugs for spasticity and, after improving spasticity and tremor in animals,18 they were tested in patients with MS in a large placebo-controlled trial3 with 1-year follow-up10 (table 1). These trials3,10 were aff ected by the limitations of the Ashworth scale, diffi culties with blinding attributable to the psychoactive side-eff ects, and a strong placebo eff ect. More studies are needed to confi rm the potential benefi ts of cannabinoids with better validated spasticity scales, incorporating the patients perspective.19 From a pragmatic point of view, cannabinoids can be helpful when spasticity is associated with central pain. An oromucosal spray (Sativex; GW Pharmaceuticals, Wiltshire, UK) containing dronabinol (delta-9 tetra-hydrocannibinol) and cannabidiol (CBD), has become available for use as an add-on treatment for MS-related spasticity that is not adequately controlled with other available treatments; if there is no benefi t at 4 weeks, the treatment can be stopped.20

Intrathecal baclofen is recommended for patients with severe spasticity that is diffi cult to manage with oral drugs. It is given through a catheter that releases the drug directly into the intrathecal space from a programmable pump in the abdominal wall. Thus, very high concentrations can be achieved without systemic side-eff ects. Benefi cial eff ects are seen with spasticity and muscle spasms,21 life comfort, pain,22 sleep time, and periodic leg movements.23 The dose of baclofen needs empirical calibration and adjustment at regular intervals. Interestingly, after a period of clinical stabil-ity, paradoxical unresponsiveness to baclofen with increased dose has been described.24 The most common complications relate to pump malfunction and technical problems with the catheter; an increased risk of epileptic seizures and non-convulsive status epilepticus in treated patients compared with matched controls has also been described.25 Intrathecal baclofen seems to be safe in pregnancy, and possibly safer than oral baclofen for the newborn.26 When severe pain remains a problem despite treatment with intrathecal baclofen, then morphine can be added.27 Intrathecal phenol is an eff ective alternative to intrathecal baclofen in patients with severe spasticity to improve spasms and pain, but it can aff ect urinary and bowel continence.28 In our experience, this drug can be used to improve care and posture in severely disabled patients who have lost bowel and bladder function and have absent sensation in the lower limbs.

Botulinum toxin A is recommended to induce muscle relaxation and prevent contractures in distal muscles and in selected proximal muscles such as hip adductors.29 In general, larger muscles are treated, which means that


Review

there is no need for electromyographic guidance. The treated muscle is paralysed by neuromuscular transmission block.30 The advantages of this therapy include minimum systemic side-eff ects and the non-

daily regimen. However, its eff ect disappears after 36 months, depends on the target muscle and injected dose, and has a high cost. Its benefi t is enhanced if combined with a physiotherapy and stretching exercise

Study design Main outcome measures Main results Action Daily doses in clinical practice (minmax)

Most common side-eff ects in clinical practice

Baclofen

Shakespeare et al4 Cochrane review (26 placebo-controlled studies and 13 comparative studies)

Ashworth scale (15 studies); spasms, other symptoms, and overall impression

3 of 8 placebo-controlled trials showed a signifi cant diff erence between groups

Binds the GABAB receptor, causing inhibition of the excitatory activity of spinal refl exes

10120 mg Sedation, drowsiness, muscle weakness, paraesthesia, gastrointestinal symptoms, hallucinations, and seizures

Tizanidine

UK Tizanidine Trial5 Double-blind randomised placebo-controlled study; 187 patients

Ashworth scale; activities of daily living

Tizanidine reduces spasticity compared with placebo; no improvements in activities of daily living

Exact mechanism of action remains unknown; its main activity is thought to occur at a presynaptic level by reducing release of excitatory aminoacids

636 mg Fatigue, tiredness, somnolence, dizziness, drowsiness, dry mouth, postural hypotension, and liver function abnormalities, which improve after discontinuation; these side-eff ects increase with increasing drug concentrations in plasma6

Nance et al6 Double-blind randomised placebo-controlled dose-response study; 142 patients

Ashworth scale; knee-swing amplitude using pendulum test

Positive eff ect of tizanidine on spasticity related to plasma drug levels

See above See above See above

Smith et al7 Multicentre double-blind randomised placebo-controlled study; 220 patients

Ashworth scale; type and frequency of muscle spasms (patients diaries)

No diff erences in spasticity between groups; greater reduction in spasms in treated group compared with placebo group


Gabapentin

Mueller et al8 Double-blind placebo-controlled crossover study; 15 patients

Ashworth scale; Kurtzke disability scale; visual faces scale rating, quantitative surface electromyography, clonus and refl ex withdrawal, Babinski response

Signifi cant diff erences on the Ashworth scale, visual faces scale, and Kurtzke disability scale between groups

Decreases glutamate concentrations released from presynaptic terminals

300 mg3600 mg

Drowsiness, somnolence, dizziness, and gastrointestinal symptoms

Cutter et al9 Double-blind placebo-controlled crossover study; 22 patients

Modifi ed Ashworth scale; expanded disability status scale; clonus scale, deep tendon refl exes, plantar stimulation response, spasm frequency and severity scales, interference with function scale, painful spasm scale, and global assessment scale

Signifi cant diff erences on the Ashworth scale, plantar stimulation response, spasm severity scale, interference with function scale, painful spasm scale, and global assessment scale between groups


Cannabinoids

Zajicek et al3 Multicentre double-blind randomised placebo-controlled study; 630 patients

Ashworth scale; other secondary outcome scales; patient-reported spasticity and pain

No diff erence on the Ashworth scale between groups; improvements in patient-reported spasticity and pain in the treated group

Probably interacts via cannabinoid receptor type 1 expressed in CNS, leading to inhibition of neurotransmitter release

NA NA

Zajicek et al10 Double-blind 1-year follow-up study; 502 patients

Ashworth scale Signifi cant eff ect on spasticity on the Ashworth scale in the group treated with dronabinol

See above NA NA

Wade et al11 Double-blind randomised placebo-controlled study; 160 patients

Ashworth scale; visual analogue scale score for spasticity (subjective measure recorded in patients diaries)

No diff erence in spasticity on the Ashworth scale between groups; signifi cant improvement on the visual analogue scale score for spasticity

See above NA NA

(Continues on next page)


Review

programme.31 A trend exists towards increased effi cacy and duration of eff ect, with increasing doses.29 However, the dose that can be injected can reach a maximum, after which the patient is at greater risk of developing systemic botulinum toxicity. Botulinum toxin can be combined with other treatment modalities, such as oral baclofen and physiotherapy under expert clinical guidance.

Ataxia and tremorLittle evidence exists for the treatment of ataxia and tremor, which are symptoms that remain very challenging to manage. Up to 80% of patients with MS have tremor or ataxia in the duration of their disease.32 Ataxia consists of a reduction in coordination in one (or more) limb, trunk and gait, and can be caused by dysfunction of the cerebellum (cerebellar ataxia) or sensory system (ie, caused by impaired proprioception). Cerebellar ataxia is often associated with tremor, which usually occurs during voluntary movements or during the maintenance of a position. Tremor is a frequent symptom of MS, and has been detected in more than half of patients attending specialist MS clinics.

Pharmacological treatmentsClinical trials have been small, limited by inadequate design and outcome measures, and essentially negative (table 2).32 Although recommendations are diffi cult to make for the treatment of ataxia and tremor, we have used propanolol,35 clonazepam, levetiracetam,40 isoniazid33,34 (limited by side-eff ects), and carbamazepine.41 Other drugs tested include ondansetron (reported to improve tremor in the fi rst trial36 but not in a subsequent open-label study37), dolasetron,38 cannabinoids,39 and glutethimide.42 Larger randomised controlled trials of interventions that

address these disabling symptoms with scientifi cally sound outcome measures are urgently needed.

Surgical interventionsCarefully selected patients with localised tremor with minimum disability could benefi t from stereotactic thalamotomy, which targets the nucleus ventralis lateralis and nucleus ventralis intermedius, or deep brain stimulation, which targets the nuclei ventralis lateralis and nucleus ventralis intermedius, ventralis oralis posterior nucleus, and zona incerta.4345 Stereotactic thalamotomy seems to be more eff ective for intractable tremor, but the consequent functional improvement is variable and the intervention is associated with a higher risk of neurological defi cit. Deep brain stimulation is likely to improve tremor, but the eff ect might be reduced over time. Functional improvement is more often reported after deep brain stimulation than after stereotactic thalamotomy, and deep brain stimulation can be better tolerated. However, the choice between interventions should be made on an individual basis in consultation with the specialist neurosurgical team. In our experience, distal tremor with good proximal stability and limb function are particularly responsive to deep brain stimulation. However, larger trials that compare these two interventions and assess the effi cacy of gamma-knife thalamotomy46,47 are needed.

Impaired ambulationPhysiotherapy input should always be considered when ambulation disability develops after a relapse or when it is associated with rapid progression. The aminopyridines have been extensively investigated in the context of this symptom. Initial studies did not convincingly show benefi cial eff ects on ambulation.48 However, recent

Study design Main outcome measures Main results Action Daily dose (minmax)

Most common side-eff ects

(Continued from previous page)

Comparative trials

Eyssette et al12 Multicentre randomised double-blind study of tizanidine vs baclofen; 100 patients

Functional status (walking distance), patients state in bed and in a chair, fl exor spasms, stretch refl ex, angle at which contracture occurs

No diff erence between the two drugs

NA NA NA

Groves et al13 Meta-analysis of 10 double-blind randomised studies of tizanidine vs baclofen (7 studies) or diazepam (3 studies); 270 patients*

Ashworth scale; muscle strength and global tolerability to treatment rating

All three drugs had a similar eff ect on spasticity; tizanidine seemed to be better tolerated

NA NA NA

This table includes studies that were considered to be important in terms of results and are characterised by acceptable study designs, in accordance with the scope of this Review. Preference was given to more recent trials. The information given on action, dose, and side-eff ects is based on all the articles read for the preparation of this Review, on the drug leafl ets, and on the authors own experience. Clonazepam (0252 mg; generally one dose at night) and dantrolene (25400 mg) can also be used for treatment of spasticity but evidence for their effi cacy is weak. Side-eff ects for clonazepam include drowsiness, fatigue, sedation, reduced attention, poor concentration, memory problems, dependence, and withdrawal; side-eff ects for dantrolene include gastrointestinal symptoms, CNS symptoms, muscle weakness, and hepatotoxicity, which is important to remember. Min=minimum. Max=maximum. NA=not applicable. *Also included patients with cerebrovascular diseases.

Table 1: Selected studies and reviews of anti-spasticity drugs in MS


Review

studies of long-acting 4-aminopyridine (fampridine) have shown positive results for this drug on walking ability in a proportion of patients.2 In a large double-blind controlled phase 3 trial,49 229 patients were treated with sustained-release oral fampridine 20 mg a day, which was previously shown to be the safest dose, and 72 patients were treated with placebo. A higher proportion of responders, as defi ned on the basis of repeated

standardised assessments of the timed 25-foot-walk test,50 was seen in the fampridine group than in the placebo group.2 Additionally, timed-walk responders showed reduced self-assessed ambulation-related disability, as measured by the 12-item MS walking scale,51 compared with non-responders. However, the proportion of timed-walk responders was only 35% (vs 8% in the placebo group), and walking speed improved by only 25% in the

Study design Main outcome measures Main results

Isoniazid

Hallett et al33 Double-blind placebo-controlled crossover trial; 6 patients

Self-rating scales, quantitative tremor recording, blinded ratings of videotapes

All patients improved on at least one outcome measure

Duquette et al34 Open-label study; 13 patients with MS and tremor Patient assessment, blinded rating of videotapes

10 patients showed improvement

Propanolol and ethanol

Koller35 Double-blind placebo-controlled randomised crossover study of propanolol, ethanol, and isoniazid; 3 patients with MS and 3 patients with idiopathic cerebellar tremor

Writing tasks, self-assessment, clinical examination, accelerometry

No eff ect for any treatment

Ondansetron

Rice et al36 Double-blind placebo-controlled randomised crossover study; 20 patients with tremor (16 with MS)

Writing tasks, self-assessment, nine-hole peg test

12 of 16 patients with MS showed tremor reduction

Gbadamosi et al37 Open-label prospective study; 14 patients with MS and tremor

Writing tasks, self-assessment, nine-hole peg test

No treatment eff ect

Dolasetron

Monaca-Charley et al38 Double-blind placebo-controlled randomised crossover study; 34 patients with MS and tremor

Nine-hole peg test, ataxia scores No treatment eff ect

Cannabinoids

Fox et al39 Double-blind placebo-controlled randomised crossover study; 14 patients with MS and upper limb tremor

Tremor rating scale No treatment eff ect

Levetiracetam

Feys et al40 Double-blind placebo-controlled randomised crossover study; 18 patients with MS and intention tremor

Fahns tremor rating scale A and B No treatment eff ect

Carbamazepine

Sechi et al41 Single-blind placebo-controlled randomised study; 10 patients with tremor (7 with MS)

Tremor rating scale, accelerometry All 7 patients with MS improved

Glutethimide

Aisen et al42 Open-label study; 8 patients with tremor (6 with MS) Computer-assisted tracking task, blinded assessment by occupational therapist

5 of 6 patients with MS improved

Thalamic stimulation or surgical thalamotomy

Bittar et al43 Comparative study of thalamotomy vs thalamic DBS; 20 patients with MS and intractable tremor

Clinical tremor rating scale Postural tremor improved by 78% for thalamotomy vs 64% for DBS (p>005); intention tremor improved by 72% for thalamotomy vs 36% for DBS (p


Review

responder group. Clinically, it might not be easy and feasible to identify the responders.52 Nonetheless, the absence of any comparable drug in this area will encourage its use in patients who do not have a history of seizures (or epileptiform activity on a screening electroencephalogram, EEG),52 despite the relatively high cost of this drug. Future trials should clarify the benefi t of this drug on impaired ambulation.

Bladder, bowel, and sexual dysfunctionBladder dysfunctionAbout three-quarters of patients with MS have bladder symptoms.53 The key CNS regions involved in the regulation of micturition include the periaqueductal grey matter, pontine micturition centre, medial frontal cortex, hypothalamus, and sacral micturition centre.54 In MS, bladder symptoms arise mainly from interruption of connections between the pontine and sacral micturition centres caused by spinal cord pathology.

General managementAn initial assessment should establish whether urinary symptoms are due to bladder ineffi ciency (incomplete emptying, residual urine, and frequency), bladder over-activity (urgency, frequency, and urge incontinence), detrusor-sphincter dyssynergia (hesitancy, interrupted stream, and incomplete emptying) or a combination of two or more of these causes. We recommend that residual bladder volume after micturition is measured and that urinary tract infection is excluded before treatment is considered. Urodynamics can aid assessment in more complex situations.55

A fl uid intake of 12 L per day should be ensured. A 25% reduction in fl uid intake leads to improved urgency, frequency, and nocturia in patients with bladder overactivity.56 Pelvic fl oor exercises, perhaps with neuromuscular stimulation57 and regular bowel emptying,55 should be considered. Finally, increased intake of cranberry juice can be suggested because, although not studied in MS, it reduces the recurrence of urinary tract infection in healthy women58 and in patients with spinal cord injury (in tablet form).59

Pharmacological treatmentsFor bladder ineffi ciency (table 3), blockers can be considered, although only one small randomised trial60 showed an improvement in urinary fl ow rate. However, if the postmicturition residual volume is more than 100 mL, the treatment of choice remains clean inter-mittent self-catheterisation. If this is not suffi cient to control symptoms, permanent catheterisation might be advisable after urological consultation.

For bladder overactivity, results from a few small studies of oral antimuscarinic drugs have shown benefi cial outcome (table 3), although details on randomisation and blinding were incomplete.63 Never-theless, drugs such as oxybutynin are usually used as

fi rst-line treatment. Oxybutynin decreases bladder emptying with consequent increased residual volume; hence it is important to check the postmicturition residual bladder volume before starting this treatment. Increasing confusion can be seen in patients with cognitive impairment, which is not surprising given the anticholinergic eff ect of this drug. Therefore, we recommend that this drug is used with caution in elderly patients and those with pre-existing cognitive impair-ment. Tolterodine is a useful alternative, as a long-acting preparation. Other drugs include trospium, propan-theline, propiverine, and fesoterodine. Pair combinations of oxybutynin, tolterodine, and trospium have been used in patients with neurogenic detrusor dysfunction, without inducing substantial side-eff ects.66 The most recently tested antimuscarinic drugs showing benefi cial eff ects are solifenacin and darifenacin, although they have not been assessed in MS.79,80

Intranasal desmopressin spray is very useful for nocturia. It reduces the number of voiding episodes and increases the period of uninterrupted sleep,70,81 and it is usually well tolerated. Hyponatraemia has been reported in about 5% of cases.81 In a randomised placebo-controlled trial,71 cannabinoids reduced the number of urge incontinence episodes in MS, based on patient diaries. Results from a recent large randomised placebo-controlled trial82 showed little diff erence in the number of daily urinary incontinence episodes between the group treated with an oromucosal spray containing dronabinol and cannabidiol and the placebo group, but a high proportion of secondary endpoints (including patients perception of bladder symptom severity) were in favour of the drug.

Intravesical injection of botulinum toxin A is an eff ective treatment for symptoms of bladder over-activity, with benefi cial eff ects on incontinence episodes, urinary leakage, reduced bladder capacity, maximum detrusor pressure, and quality of life,6769 and is available in major centres. The mean duration of eff ect is almost 10 months, after which the treatment can be repeated.69 However, not enough robust data on its effi cacy and safety exist, mainly because of the inconsistent use of comparison interventions, and whether effi cacy increases with higher doses is unclear. The intravesical vanilloid capsaicin and its analogue resiniferatoxin have been shown to have benefi cial eff ects in small controlled trials on incontinence frequency and bladder capacity in patients with MS.72 Pelvic pain and fl ushing are frequent side-eff ects, and these drugs are not given regularly to patients with the disorder.

Surgical treatmentsSacral neuromodulation with electrical stimulation of the S3-nerve root can be considered in detrusor overactivity unresponsive to botulinum toxin, especially in milder forms of MS.55 This treatment inhibits the micturition refl ex. Although the total number of patients


Review


Bladder ineffi ciency

Indoramin (1 blocker)

ORiordan et al60 Randomised placebo-controlled trial; 18 patients Flow rates, residual volumes Mean 41% improvement in peak fl ow rate

Vibrating device

Dasgupta et al61 Open-label study; 36 patients (29 with MS); mean follow-up 115 months

Flow rates, residual volumes; patient questionnaires

Symptom improvement in 70% of patients; mean residual volume reduced from 175 mL to 68 mL

Prasad et al62 Randomised controlled crossover study; 28 patients with MS Residual volumes, patient questionnaires

Signifi cant eff ect of vibration on residual volumes but not incontinence episodes or micturition frequency

Bladder overactivity

Antimuscarinics

Nicholas et al63 Cochrane review (3 of 33 trials selected as suitable) Bladder volumes, urological symptoms Evidence too weak to advocate use of antimusarinics

Gajewski and Awad64 Randomised prospective study of oxybutynin vs propantheline; 34 patients with MS

Urological symptoms, urodynamics Oxybutynin superior to propantheline

Fader et al65 Randomised double-blind crossover trial of intravesical atropine vs oral oxybutynin; 64 patients with MS

Bladder capacity, urological symptoms Intravesical atropine at least as eff ective as oxybutynin with fewer side-eff ects

Amend et al66 Randomised unblinded comparative study of combination dual therapy (two of oxybutynin, tolterodine, trospium); 27 patients (2 with MS)

Urodynamics, urological symptoms Benefi cial eff ects of dual therapy without signifi cant side-eff ects

Intravesical botulinum toxin A

Duthie et al67 Cochrane review (8 randomised studies included); participants had neurogenic, overactive bladders

Urodynamics,urological symptoms Most studies reported superiority to placebo; overall, they showed promise for therapy of overactive bladder; optimum dose not known

Ehren et al68 Randomised placebo-controlled double-blind trial; 31 patients with neurogenic detrusor overactivity (6 with MS)

Cystometry, quality of life Signifi cant benefi ts of one dose of botulinum toxin on cystometry and quality of life

Kalsi et al69 Open-label study; 43 patients with MS and detrusor overactivity

Cystometry, urological symptoms Signifi cant improvements on outcome measures; 98% needed self-catheterisation

Desmopressin

Bosma et al70 Meta-analysis from 1990 to 2003 (5 randomised double-blind placebo-controlled crossover trials); 115 patients with MS and urinary symptoms

Urinary frequency and volume; patient questionnaire

Moderate reduction in voiding frequency; large eff ect on urine volume 6 h after dose but small eff ect 24 h after dose; serum sodium and osmolality not signifi cantly aff ected

Cannabinoids

Freeman et al71 Part of CAMS study3 (630 patients with MS); three arms: oral cannabis extract, dronabinol, and placebo

Incontinence diaries All three groups showed signifi cant benefi t: oral cannabis 38%, dronabinol 33%, placebo 18%; both active treatments showed signifi cant eff ects over placebo

Intravesical vanilloids

MacDonald et al72 Systematic review; 10 randomised trials of 288 patients (43% with spinal cord injury; 52% with MS); capsaicin, 6 trials; resiniferatoxin, 4 trials; botox, 2 trials

Incontinence diaries Capsaicin superior to placebo; resiniferatoxin similar to capsaicin

Peripheral nerve stimulation

Fjorback et al73 Open-label study of acute posterior tibial nerve stimulation; 8 patients with MS

Cystometry No acute eff ect of posterior tibial nerve stimulation on bladder contractions

Kabay et al74 Open-label study; 12 weeks of posterior tibial nerve stimulation; 19 patients with MS

Urodynamic studies Signifi cant improvements in cystometric capacity, fl ow rate, and detrusor pressure with stimulation

Sacral nerve neuromodulation

Wallace et al75 Retrospective case series of 28 neurological patients (13 with MS) with urinary dysfunction

Urological diaries Large improvements in urological measures after implantation

Sexual dysfunction

Sildenafi l

Fowler et al76 Double-blind randomised placebo-controlled trial; 217 men with MS and erectile dysfunction; 12-week duration

Patient questionnaires (international index of erectile function, global effi cacy, quality of life)

Very signifi cant benefi ts with sildenafi leg, 89% of patients treated with sildenafi l reported improved erections compared with 24% treated with placebo

Safarinejad77 Double-blind randomised placebo-controlled study; 203 men with MS and erectile dysfunction; 24 doses given

International index of erectile function questionnaire; sexual encounter profi le diary

Small but signifi cant eff ects; improved erections reported by 33% of patients given sildenafi l and 18% of patients given placebo (p=004)

Dasgupta et al78 Double-blind randomised placebo-controlled crossover trial; 19 women with MS and sexual dysfunction

Validated questionnaires; pudendal and tibial evoked potentials

Signifi cant improvement only in lubrication domain of sexual function with sildenafi l; no improvement in quality of life

This table includes studies that were considered to be important in terms of results and are characterised by acceptable study designs, in accordance with the scope of this Review. Preference was given to more recent trials. MS=multiple sclerosis.

Table 3: Selected studies or reviews of treatments for bladder ineffi ciency and overactivity and sexual dysfunction in MS


Review

studied is low, results are very encouraging in terms of improvement in bladder symptoms and urodynamic parameters.75 Other surgical procedures, such as urinary diversion or bladder augmentation, can be off ered to patients with intractable urge incontinence or irrever-sible complications from long-term catheters.55

Peripheral nerve stimulation of the dorsal penile or clitoral nerves73 and posterior tibial nerve74 can be eff ective in suppression of detrusor contractions in MS, but confi rmation from larger trials is awaited.

Bowel dysfunctionBowel dysfunction manifesting as constipation or faecal incontinence, despite being present in more than 50% of patients with MS, is poorly studied compared with bladder dysfunction.83 General management includes dietary and mobility advice and review of drug side-eff ects and concurrent medical problems (eg, obstetric injury).84 Pharmacological and other therapies can then be considered.

ConstipationAlthough increasing fl uid and fi bre intake is advised for constipation, few studies have focused specifi cally on patients with MS.85 Similarly, bulking drugs (which increase faecal mass and stimulate peristalsis), stool softeners, osmotic laxatives (which increase fl uid retention within the bowel; eg, lactulose), and stimulant laxatives (eg, senna and bisacodyl) are often recom-mended, although no specifi c evidence exists for their effi cacy in MS. As they increase intestinal motility without causing incontinence,86 they are often the fi rst-line treatments.

Rectal stimulants (such as glycerol and bisacodyl suppositories)87 can be used to manage the timing of defecation. Behavioural feedback is eff ective for treat-ment of constipation or faecal incontinence in some patients with MS, especially if they are mildly to moderately disabled.88 This treatment improves spontaneous bowel-emptying frequency and reduces abdominal pain, bloating, and the concomitant use of oral laxatives in patients with idiopathic chronic consti-pation.89 If these measures fail, surgical intervention (such as colostomy or ileostomy) can be considered, usually in severe cases. Transanal colonic irrigation has also been studied with benefi cial results in patients with spinal cord injury and other neurological diseases.90

Faecal incontinenceFaecal incontinence is a very diffi cult symptom to manage. Although no evidence base exists for their use in MS, antimotility agents (such as codeine phosphate and loperamide) and rectal stimulants represent the main treatments, because they help to regulate discharge and reduce the frequency of incontinence episodes. Rectal stimulants are favoured when timing of defecation needs to be planned. Biofeedback has also been reported

to be eff ective.88 End stoma, dynamic graciloplasty, artifi cial bowel sphincter,91 sphincter repair, and sacral nerve stimulation92 (in cases of structural anal sphincter damage) are surgical treatments for faecal incontinence but have not been investigated in MS.

Sexual dysfunctionThe main complaints in male patients with MS are reduced libido, erectile impotence, and premature ejaculation; 84% of 31 men with MS had one of these symptoms in one study,93 with a signifi cant eff ect on quality of life. For women, research interest in this area has grown, both for diagnosis and treatment. The main complaints in female patients with MS are reduced libido, diffi culties in achieving orgasm, and decreased vaginal lubrication; 85% of 78 women with MS had one of these symptoms, aff ecting their quality of life.93 Sexual dysfunction is less frequent in newly diagnosed female patients with low disability than in women at a later stage of the disease.

Table 3 shows treatments for sexual dysfunction that have been studied or reviewed in MS. For men, sildenafi l was the fi rst phosphodiesterase-5 (PDE5) inhibitor to be tested in this disease. It enhances the erectile response through the inhibition of the breakdown of cyclic guanosine monophosphate (cGMP). Positive results were reported in two double-blind randomised placebo-controlled trials in patients with MS (erections improved in 89%76 and 33%77 of patients treated with sildenafi l compared with 24%76 and 18%77 of patients on placebo). However, in both trials, the patients studied had relatively low levels of disability, which suggests mild spinal cord involvement, and were young, which makes extrapolation diffi cult to older patients with more severe disease. An eff ect of unblinding might also have been present, because adverse eff ects for sildenafi l were more frequent than for placebo. However, the drug was generally well tolerated. Encouraging results have recently been shown for other PDE5 inhibitors, such tadalafi l and vardenafi l, in several disorders other than MS. Only one open-label study94 showed a possible benefi t for tadalafi l in MS. Sublingual apomorphine can be used as an alternative to sildenafi l,53 although no evidence of its effi cacy in MS has been described. Alprostadil (prostaglandin E1) can be given as intracorporeal injection or transurethrally and has been shown to be eff ective in a large sample of patients with organic erectile dysfunction, without local adverse eff ects such as priapism or fi brosis.95

In women, results from a small but well designed study assessing sildenafi l78 showed poor benefi t. Generally, defi nitive evidence to support its routine use remains weak96 because trials have included small sample sizes, inappropriate statistical tests, and assessment techniques that are not validated. Androgen hormone therapy (methyltestosterone) in combination with oestrogen can be helpful,53 although specifi c trials in MS have not been done.


Review

Fatigue, cognitive impairment, and mood disturbanceFatigueFatigue is a complex symptom that defi es defi nition and measurement. Patients complain of diff erent types of fatigue, such as relapse-related fatigue, excessive tiredness after exercise, and excessive daytime sleepiness. It is present in up to 74% of patients with MS97 and is often described as their most disabling symptom.

General measuresThe patients daily routine should be reviewed and activities rearranged to minimise the eff ect of fatigue. The sleep pattern should also be reviewed to consider, for example, whether nocturnal spasms or nocturia contribute to poor sleep. Mood should be assessed to establish coexistent depression. Other conditions should be considered, such as anaemia or hypothyroidism. The patient should maintain a healthy diet and regular physical activity.98 Pharmacological treatments can be considered when fatigue remains a disabling symptom despite the introduction of fatigue management programmes, which attempt to minimise the eff ect of this symptom on daily activities, and the provision of advice on work simplifi cation techniques. Alternative medicines and cooling therapy99 have captured interest but not enough scientifi c evidence exists to support their use.

Pharmacological treatmentsDrug treatment has not been very successful in alleviating fatigue (table 4). Amantadine has been studied,101103 but defi ciencies in clinical trial design limit the interpretation

of the results. Despite preliminary and encouraging results obtained with open-label104 and single-blind105

studies, modafi nil was ineff ective for treatment of fatigue in 115 patients at doses ranging from 100 to 400 mg per day.106 However, results from a randomised double-blind trial107 suggested that modafi nil 200 mg per day could improve fatigue, concentration, and upper limb function, although the sample size was small. Pemoline has been reported to be ineff ective103 and poorly tolerated.108 Small positive eff ects on fatigue, although subjective, have been described for aminopyridines.48,109,110 A possible eff ect of levocarnitine on fatigue has been shown in patients treated with disease-modifying drugs,111 and increased benefi t compared with amantadine has been reported,112 although this evidence is preliminary because of the small sample size (n=36) of this study. An improvement in self-reported fatigue has been described in association with disease-modifying treatments, including glatiramer acetate97,113 and natalizumab,114 but the results need confi rmation in more focused, randomised, double-blind trials.

Cognitive dysfunctionCognitive impairment is common (4070%) in patients with MS115 and occurs in all phenotypes.116 Several cognitive domains, especially memory, speed of information processing, mental fl exibility, and executive functions, are aff ected. Further methodologically sound research needs to be done before diff erent cognitive rehabilitative interventions can be recommended in MS.117 Very few studies have examined the eff ect of disease-modifying drugs with cognition as the primary outcome (table 5). Incomplete evidence exists that interferon beta-1b and interferon beta-1a might improve or stabilise cognitive scores on various assessments, including the Wechsler memory scale visual reproduction-delayed recall test,128 the Wisconsin card sorting test129 for frontal lobe function, and more comprehensive neuropsychological batteries.118 Results from a recent large observational study in patients with MS treated with interferon beta-1a showed a 32% lower risk of cognitive impairment with high doses of interferon than with low doses, but these results might have been confounded by the low-dose group having greater cognitive impairment at baseline than the high-dose group.119 Additionally, the mechanisms of action are speculative.

Large, double-blind randomised placebo-controlled clinical trials in MS are needed to clarify whether acetylcholinesterase inhibitors have an eff ect on cognition in this disorder. A possible benefi cial eff ect for donepezil on memory function and cognition has been reported120,121 with tolerable side-eff ects, which included abnormal dreams, in patients with MS who had impaired verbal memory. However, this trial did not include patients with a mini-mental state examination score lower than 26, clinical depression, or severe disability, and the two groups were not balanced for phenotype, sex, and

Action Daily dose (minmax)

Most common side-eff ects

Amantadine Cholinergic, dopaminergic, adrenergic, and glutamatergic eff ects on the CNS

200600 mg Numerous side-eff ects: anorexia, nausea, insomnia, visual hallucinations, blurred vision, gastrointestinal symptoms, livedo reticularis, peripheral oedema, dry mouth, urinary retention

Modafi nil Amphetamine-type action

100400 mg Dose-dependent side-eff ects: restlessness, loss of appetite, insomnia, nervousness, dizziness, headache, nausea, asthenia

Pemoline Stimulant of the CNS 2060 mg Insomnia, irritability, anorexia, weight loss, tremor, tachycardia, increased risk of seizures

Aminopyridine Blocks potassium channels, resulting in improved conduction; possible modulator of brain activity100

560 mg Dizziness, insomnia, paraesthesias, asthenia, nausea, headache, tremor, light-headedness, epileptic seizures (with doses of 30 or 35 mg twice a day), anxiety

Carnitine Cellular component with a role in cellular metabolism

16 g Insomnia, nervousness, gastrointestinal symptoms

DMTs Possible eff ect on fatigue via the drugs anti-infl ammatory mechanism

Standard doses of specifi c DMTs

Side-eff ects vary depending on specifi c DMT

The information given on action, dose, and side-eff ects is based on all the articles read for the preparation of this Review, on the drug leafl ets, and on the authors own experience. DMTs=disease-modifying treatments.

Table 4: Drugs used for treatment of fatigue in MS


Review

disability. Additionally, the treating physician also did the assessment and, although the primary outcome favoured donepezil, the eff ects were not signifi cant on an overall composite cognitive score or on specifi c areas such as word fl uency, spatial recall, or executive function. A second larger study is currently underway.130 No signifi cant diff erences have been seen between rivastigmine and placebo in terms of memory function.122

Memantine, an NMDA receptor, was tested in a small, double-blind placebo-controlled trial that was curtailed when nine of 19 patients with MS complained of a deterioration in their neurological symptoms at 30 mg per day.123 These symptoms were reversed when memantine was discontinued (table 5). Another larger, placebo-controlled study compared memantine 10 mg twice a day with placebo in 126 patients with MS and showed no signifi cant treatment eff ect on cognitive performance. Adverse events were infrequent and mild, although fatigue and neurological eff ects were

more common with memantine than with placebo (table 5).124

Studies of amantadine and pemoline125 and gingko biloba126 have shown disappointing results. In a double-blind placebo-controlled randomised trial,127 L-amphetamine sulfate was associated with improved learning and memory and was well tolerated. However, in this large trial (n=151), the primary outcomes were not signifi cant, although the secondary outcomes did reach signifi cance. Additionally, the duration of treatment was short (the maximum treatment dose was maintained for 14 days), and changes in mood during or after the trial were not examined, making it impossible to ascertain the long-term eff ectiveness, tolerability, and eff ect on mood of the drug.

Psychiatric and psychological dysfunctionPsychiatric disorders such as major depression, bipolar disorder, pseudobulbar aff ect, and psychosis are known to have a higher prevalence in patients with MS compared


Interferon beta-1a

Fischer et al118 Randomised placebo-controlled study; 161 patients with relapsing remitting MS; 2-year duration

Comprehensive neuropsychological battery Signifi cant benefi t of active treatment on information processing and learning/memory; benefi cial trend for visuospatial ability and problem solving

Patti et al119 Observational 3-year study of 459 patients with relapsing remitting MS naive to treatment; 318 patients followed up

Raos brief repeatable battery; Stroop colour-word task; Hamilton depression rating scale; quality of life questionnaires; conventional MRI

32% lower risk of cognitive impairment with high dose (44 g) than with low dose (22 g; p=001), but baseline cognitive impairment was higher in low-dose group

Acetylcholinesterase inhibitors

Krupp et al120 and Christodoulou et al121

Double-blind placebo-controlled randomised study of donepezil; 69 patients with MS and cognitive impairment

Selective reminding test (verbal learning and memory) Signifi cant improvement in memory performance with treatment (66% of patients treated with donepezil vs 32% on placebo); abnormal dreams reported as a side-eff ect of donepezil

Shaygannejad et al122 Double-blind placebo-controlled randomised study of rivastigmine; 60 patients with MS and cognitive impairment

Wechsler memory scale Slight but signifi cant memory improvement in both groups; no diff erences between rivastigmine and placebo

Memantine

Villoslada et al123 Double-blind placebo-controlled randomised crossover study; 19 patients with MS and cognitive impairment

Brief repeatable battery Trial stopped after neurological worsening in 9 patients (eg, with blurred vision, fatigue, headache, muscle weakness, walking diffi culties); eff ects reversed after treatment was stopped

Lovera et al124 Double-blind placebo-controlled randomised study; 126 patients with MS and cognitive impairment; 4-week titration then 12-week maintenance period

Paced auditory serial addition test; California verbal learning test-II; long delay free recall test

No diff erence for cognitive eff ects; patients given memantine had more fatigue (6 vs 4, not signifi cant) and neurological side-eff ects (17of 58 vs 6 of 58; p=0003), including anxiety, confusion, dizziness, spasticity, and somnolence

Amantadine and pemoline

Geisler et al125 Placebo-controlled randomised study of amantadine, pemoline, and placebo; 45 patients with MS and severe fatigue

Neuropsychological tests of multiple domains (attention, verbal and non-verbal memory, motor speed)

Signifi cant improvements on neuropsychological tests for all three arms; no diff erences between amantadine, pemoline, and placebo

Gingko biloba

Lovera et al126 Double-blind placebo-controlled randomised study; 38 patients with MS and cognitive impairment

Several neuropsychological tests including California verbal learning test-II, paced auditory serial addition test

Overall, no signifi cant improvement in cognitive function

L-amphetamine sulfate

Morrow et al127 Double-blind placebo-controlled randomised study; 151 patients with MS and cognitive impairment

Subject global assessment of change; single-digit modalities test

No signifi cant diff erences in main outcomes; some benefi ts for secondary outcomes testing learning and memory; fi ndings need replication

This table includes studies that were considered to be important in terms of results and are characterised by acceptable study designs, in accordance with the scope of this Review. Preference was given to more recent trials. MS=multiple sclerosis.

Table 5: Selected studies and reviews of treatment of cognitive dysfunction in MS


Review

with the normal population.131133 Importantly, depression can exacerbate cognitive dysfunction in MS.134 Overall, not enough well designed and scientifi cally sound trials of pharmacotherapy or psychotherapy in MS exist, and, therefore, management of these disorders follows the recommendations of general psychiatry. Several thera-peutic trials in depression have specifi cally recruited patients with MS. Cognitive behavioural therapy has been reported to be helpful,135 as well as fl uoxetine,136 sertraline,137 and moclobemide,138 a reversible monoamine oxidase A inhibitor, all with good tolerability.

For pseudobulbar aff ect or involuntary emotional depression disorder, dextromethorphan with quinidine (DMq) has been shown to have a benefi cial eff ect on the number of episodes of laughing and crying and quality of life in patients with MS in two studies.139,140 In the fi rst study,139 a randomised controlled trial of 150 patients, a relatively high dropout rate was noted (2729%), but the sensitivity analyses showed that the assessment of effi cacy was not biased.139 In the second study,140 a randomised double-blind trial comparing placebo with DMq at 30/10 mg and 20/10 mg, 283 of 326 patients (87%) completed the trial.140 The frequency of episodes of pseudobulbar aff ect was 469% (p


Review

abnormalities at the maximum pain site were included, whether other types of central pain such as those related to spasms might benefi t from the same drug remains unknown. An oromucosal spray that contains equal amounts of dronabinol and cannabidiol (Sativex) has provided encouraging results in one study.159 Another study reported negative results11 but used diff erent doses and outcome measures and the two reports are therefore not comparable. Pain reduction was maintained during 2 years of treatment, without induction of tolerance, and with only mild to moderate side-eff ects in a further study.160 Finally, nabilone, a synthetic cannabinoid, was eff ective in reducing otherwise uncontrollable pain, but not spasticity, in a double-blind placebo-controlled trial of spasticity-

related pain in MS.161 This study lasted for only 9 weeks and only 11 of the 13 patients completed it; one of the dropouts was attributable to an exacerbation of weakness in the lower limbs, possibly due to nabilone.

The evidence for non-pharmacological treatments in patients with MS with neuropathic pain is weak and is based on small open-label trials and case-reports. Therefore, when pharmacological relief of neuropathic pain is insuffi cient, recent guidelines173 from the European Federation of Neurological Societies (EFNS) on neurostimulation therapy for neuropathic pain can be followed.

In MS specifi cally, intrathecal infusions of baclofen and morphine, or both,27 might be benefi cial in severe cases. Transcutaneous electrical nerve stimulation


Trigeminal neuralgia

Carbamazepine

Hooge and Redekop146 Observational study of 35 patients with MS and TN; 27 treated with carbamazepine

Pain scores and symptoms 10 of 27 patients had complete pain relief; 10 of 27 patients had partial relief; 4 of 27 patients stopped because of side-eff ects

Lamotrigine

Lunardi et al147 Small open-label study; 5 patients with MS and TN Pain scores and symptoms All 5 patients with MS had symptomatic relief

Gabapentin

Solaro et al148 Small open-label study; 11 patients with MS and TN intolerant or refractory to carbamazepine or lamotrigine

Pain scores and symptoms Good pain control in all but one patient when given gabapentin combined with lowered doses of carbamazepine or lamotrigine

Topiramate

Zvartau-Hind et al149 Small open-label study; 6 patients with MS and refractory TN

Pain scores and symptoms Complete resolution of pain in all 6 patients; one patient needed topiramate with carbamazepine to maintain relief

Misoprostol

DMKG Study Group150 Small open-label study; 18 patients with MS and refractory TN

Pain scores and symptoms 14 of 18 had a more than 50% reduction in attack frequency and intensity

Microvascular decompression

Broggi et al151 Observational study; 35 patients with MS and medically intractable TN

Imaging and operative fi ndings; pain scores and symptoms

Neurovascular compression found in 46% of patients; long-term outcome excellent in 39% and poor in 39% of patients; overall results less satisfactory than for idiopathic TN

Gamma-knife radiosurgery

Zorro et al152 Observational study; 37 patients with MS and TN Pain scores and symptoms Reasonable pain control in 83% of patients at 1 year and 54% at 5 years; 40% of patients had a second procedure for ongoing pain

Persistent neurogenic pain

Gabapentin

Houtchens et al153 Open-label study; 25 patients with MS and neuropathic pain

Pain scores and symptoms Excellent to moderate pain relief in 15 patients

Lamotrigine

Cianchetti et al154 Open-label study; 21 patients with MS and burning paraesthesias, paroxysmal or continuous limb pain, and painful tonic spasms; lamotrigine used as adjunct

Pain scores and symptoms 8 of 9 patients had improvements in burning paraesthesia; 1 of 6 patients had improvements in continuous limb pain; 5 of 8 patients had improvements in painful tonic spasms

Breuer et al155 Double-blind randomised placebo-controlled crossover trial; 12 patients with MS and central neuropathic pain

Brief pain inventory, neuropathic pain scale, quality of life questionnaire

No signifi cant diff erences between lamotrigine and placebo

Levetiracetam

Rossi et al156 Single-blind randomised placebo-controlled trial; 20 patients with MS and central neuropathic pain

Visual analogue pain scale, expanded disability status scale, Hamilton depression scale, quality of life questionnaire

Signifi cant benefi t of levetiracetam for all study outcomes

(Continued on next page)


Review

(TENS) might be benefi cial for chronic low-back pain.162 However, these fi ndings were not signifi cant when corrected for multiple comparisons, and the patient group was heterogeneous, including patients with probable MS. Results from another randomised trial163 showed that the eff ect of TENS on pain and sensory complaints in the upper limbs was similar to that of nortriptyline163 in a small group of patients over a short time period (8 weeks); however, no placebo group was included in this study. Therefore, evidence for effi cacy of self-applied TENS remains poor. Spinal cord stimulation can provide long-term pain relief in patients with MS and low-back pain.164

Visual and brainstem symptomsVisual dysfunctionNystagmus results from the disruption of mechanisms that control foveation. Management of nystagmus in MS is challenging with a poor rate of treatment response.174 A few trials with small numbers of patients with MS have been done. These trials focused on acquired

pendular nystagmus, which includes quasi-sinusoidal oscillations thought to result from defi ciencies in feedback circuits between the brainstem and cerebellum.175 Memantine (mainly an NMDA glutamate antagonist) and gabapentin have both been eff ective in treatment of acquired pendular nystagmus in randomised, but small, studies that included patients with MS.176,177 The most recent trial177 was a blinded, crossover, therapeutic study of gabapentin (1200 mg per day) versus memantine (40 mg per day) for acquired nystagmus in ten patients, of which three had MS.177 The heteregenous characteristics of nystagmus in such a small group makes extrapolation of benefi ts to the whole population with MS diffi cult, but gabapentin can be recommended as a fi rst-line treatment for nystagmus in this disorder since it is well tolerated. Memantine has been reported to cause deterioration of cognitive symptoms in MS.123 Practically, it might be possible to use memantine for nystagmus in this disorder, selecting patients without signifi cant cognitive impairment and cautiously titrating the dose. Further studies are ideally


(Continued from previous page)

Cannabinoids

Zajicek et al3 Randomised placebo-controlled trial of oral cannabis extract and dronabinol; 630 patients with MS and spasticity

Ashworth spasticity scale; pain-related scale

No improvement on spasticity scale but improvements in patient-reported spasticity and pain

Iskedjian et al157 Meta-analysis; 7 studies of central neuropathic pain syndromes including MS; randomised placebo-controlled blinded designs; 298 patients pooled

Pain-related scales Pain signifi cantly better with cannabinoid (Sativex, cannabidiol, dronabinol) treatment (p


Review

warranted to clarify its safety profi le. Second-line drugs include clonazepam and antimuscarinics, although their use might be limited by side-eff ects.174

Brainstem-related symptomsBrainstem-related symptoms include dysphagia, speech and respiratory dysfunction, and vertigo (if of central origin), which are not uncommon in MS, especially in more advanced cases. Management of mild dysphagia and dysarthria requires the input and support of speech and language therapy. More advanced cases of dysphagia (eg, with frequent or severe choking) should be assessed with videofl uoroscopy, which is used to establish function of the anterior pharyngeal segment (ie, laryngeal dysmotility) and posterior segment (ie, pharyngeal constrictor dysmotility).178 If the aspiration risk is high and food intake becomes insuffi cient, then percutaneous gastrostomy might be needed. For severe dysarthria, communication aids might be useful.

Respiratory training can improve inspiratory179 and expiratory180 muscle strength in patients with MS; however, these studies were done in patients with mild to moderate disability and, therefore, whether these interventions might help patients with more severe disability and greater respiratory impairment remains unknown. Additionally, both studies recruited a low number of patients, the treatment was short, and only one study179 included a control group. Respiratory impairment seems to occur in patients with MS even if they do not complain of specifi c respiratory symptoms.181

Not enough evidence exists for treatment of vertigo in MS. Measures generally recommended for patients with vertigo also apply to patients with MS, who are most commonly aff ected by benign positional paroxysmal vertigo, followed by vertigo secondary to brainstem involvement.182 Other brainstem-related symptoms include paroxysmal phenomena such as painful spasms, paroxysmal dysarthria,183 and dysarthria-ataxia syndrome,184 which are associated with demyelinating midbrain lesions. In clinical practice, these syndromes seem to respond to the antiepileptic drugs discussed for paroxysmal pain in this Review.

Search strategy and selection criteria

We searched PubMed for articles published from 1970 to September, 2010, with the search term multiple sclerosis combined with specifi c search terms that constituted the subheadings (eg, spasticity, ataxia, bladder dysfunction, fatigue). References from identifi ed studies were also checked and included if felt appropriate. Articles published in English were considered. References from our own fi les were also searched. More recent publications (within the past 10 years) were preferentially selected, although older references that were considered important were also included.

ConclusionsA diverse and wide range of symptoms can occur in MS. Optimum management requires a multidisciplinary approach, and is focused on the needs of the patients and their priorities. For most treatments, however, the supporting evidence for their use in MS is weak and often relies on evidence provided by other disciplines (eg, general psychiatry, and urology). This restricted evidence base is attributable not only to the paucity of trials done so far and their methodological limitations, but also to the diffi culty in assessing the eff ect of treatments in a chronic condition such as MS, in which impaired functions often interact (eg, impaired cognition, mood disturbance, and fatigue). The key to the success of future research into symptom management in MS must be based on improved understanding of the underlying pathological mechanisms and translation of this knowledge into development of appropriate therapies. Additionally, symptomatic treatments need to be assessed rigorously in well designed trials in which clinical outcome measures focus on symptoms and in which the patient perspective is incorporated.14

Finally, the use of surrogate measures that focus on underlying pathological processes should be considered in future trials. For example, brain atrophy, which is a marker of axonal loss, has been reported to predict cognitive dysfunction in MS; therefore, neuroprotective treatments could be tested to investigate whether they induce cognitive improvement in patients with MS.

The development of more innovative therapies (eg, cannabinoids for spasticity and donepezil for cognitive function), better designed treatment trials (large random-ised double-blind trials that are powered to detect the desired eff ect), and use of patient-related outcome measures (which must be fi t for purpose14) off er some encouragement for the future. Further well designed trials are needed before any new treatments can be recomm ended in clinical practice. These trials need to address practical issues, such as optimum length of treatment, whether rebound eff ects or withdrawal eff ects occur after a treatment is interrupted, the cost-eff ectiveness of new treatments, and the side-eff ect profi le in the long term.ContributorsAll authors contributed equally to the preparation of this Review. AJT was involved in the conception, writing, critical reviewing, and revision of the manuscript. OC and ATT were involved in writing, critical reviewing, and revision of the manuscript.

Confl icts of interestAJT serves on advisory boards for Novartis and Eisai. He has received honoraria and support for travel from Schering, Serono Symposia, LaRoche, Novartis, and Teva. ATT and OC have no confl icts of interest.

AcknowledgmentsOC is a Wellcome Trust Clinical Advance Fellow. ATT is funded by the Higher Education Funding Council for England. This work was done at UCLH/UCL, which received a proportion of funding from the Department of Healths National Institute for Health Research Biomedical Research Centres funding scheme.


Review

References1 Trisolini M, Honeycutt A, Wiener J, Lesesne S. Global economic

impact of multiple sclerosis. Multiple Sclerosis International Federation 2010. http://www.msif.org/en/resources/msif_resources/msif_publications/global_economic_impact_of_ms/index.html (accessed Aug 10, 2010).

2 Goodman AD, Brown TR, Krupp LB, et al. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. Lancet 2009; 373: 73238.

3 Zajicek J, Fox P, Sanders H, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 2003; 362: 151726.

4 Shakespeare DT, Boggild M, Young C. Anti-spasticity agents for multiple sclerosis. Cochrane Database Syst Rev 2003; 4: CD001332.

5 United Kingdom Tizanidine Trial Group. A double-blind, placebo-controlled trial of tizanidine in the treatment of spasticity caused by multiple sclerosis. Neurology 1994; 44 (11 suppl 9): 7078.

6 Nance PW, Sheremata WA, Lynch SG, et al. Relationship of the antispasticity eff ect of tizanidine to plasma concentration in patients with multiple sclerosis. Arch Neurol 1997; 54: 73136.

7 Smith C, Birnbaum G, Carter JL, Greenstein J, Lublin FD, for the US Tizanidine Study Group. Tizanidine treatment of spasticity caused by multiple sclerosis: results of a double-blind, placebo-controlled trial. Neurology 1994; 44 (11 suppl 9): 3442.

8 Mueller ME, Gruenthal M, Olson WL, Olson WH. Gabapentin for relief of upper motor neuron symptoms in multiple sclerosis. Arch Phys Med Rehabil 1997; 78: 52124.

9 Cutter NC, Scott DD, Johnson JC, Whiteneck G. Gabapentin eff ect on spasticity in multiple sclerosis: a placebo-controlled, randomized trial. Arch Phys Med Rehabil 2000; 81: 16469.

10 Zajicek JP, Sanders HP, Wright DE, et al. Cannabinoids in multiple sclerosis (CAMS) study: safety and effi cacy data for 12 months follow up. J Neurol Neurosurg Psychiatry 2005; 76: 166469.

11 Wade DT, Makela P, Robson P, House H, Bateman C. Do cannabis-based medicinal extracts have general or specifi c eff ects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Mult Scler 2004; 10: 43441.

12 Eyssette M, Rohmer F, Serratrice G, Warter JM, Boisson D. Multi-centre, double-blind trial of a novel antispastic agent, tizanidine, in spasticity associated with multiple sclerosis. Curr Med Res Opin 1988; 10: 699708.

13 Groves L, Shellenberger MK, Davis CS. Tizanidine treatment of spasticity: a meta-analysis of controlled, double-blind, comparative studies with baclofen and diazepam. Adv Ther 1998; 15: 24151.

14 Hobart JC, Cano SJ, Zajicek JP, Thompson AJ. Rating scales as outcome measures for clinical trials in neurology: problems, solutions, and recommendations. Lancet Neurol 2007; 6: 1094105.

15 Beard S, Hunn A, Wight J. Treatments for spasticity and pain in multiple sclerosis: a systematic review. Health Technol Assess 2003; 7: iii, ixx, 1111.

16 Smith CR, LaRocca NG, Giesser BS, Scheinberg LC. High-dose oral baclofen: experience in patients with multiple sclerosis. Neurology 1991; 41: 182931.

17 Stamenova P, Koytchev R, Kuhn K, et al. A randomized, double-blind, placebo-controlled study of the effi cacy and safety of tolperisone in spasticity following cerebral stroke. Eur J Neurol 2005; 12: 45361.

18 Baker D, Pryce G, Croxford JL, et al. Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 2000; 404: 8487.

19 Hobart JC, Riazi A, Thompson AJ, et al. Getting the measure of spasticity in multiple sclerosis: the Multiple Sclerosis Spasticity Scale (MSSS-88). Brain 2006; 129: 22434.

20 Wade DT, Collin C, Stott C, Duncombe P. Meta-analysis of the effi cacy and safety of Sativex (nabiximols), on spasticity in people with multiple sclerosis. Mult Scler 2010; 16: 70714.

21 Zahavi A, Geertzen JH, Middel B, Staal M, Rietman JS. Long term eff ect (more than fi ve years) of intrathecal baclofen on impairment, disability, and quality of life in patients with severe spasticity of spinal origin. J Neurol Neurosurg Psychiatry 2004; 75: 155357.

22 Boviatsis EJ, Kouyialis AT, Korfi as S, Sakas DE. Functional outcome of intrathecal baclofen administration for severe spasticity. Clin Neurol Neurosurg 2005; 107: 28995.

23 Bensmail D, Quera Salva MA, Roche N, et al. Eff ect of intrathecal baclofen on sleep and respiratory function in patients with spasticity. Neurology 2006; 67: 143236.

24 Cooper JA, Ridley B. Response of intrathecal baclofen resistance to dose reduction. Neurology 2006; 67: 149596.

25 Schuele SU, Kellinghaus C, Shook SJ, Boulis N, Bethoux FA, Loddenkemper T. Incidence of seizures in patients with multiple sclerosis treated with intrathecal baclofen. Neurology 2005; 64: 108687.

26 Dalton CM, Keenan E, Jarrett L, Buckley L, Stevenson VL. The safety of baclofen in pregnancy: intrathecal therapy in multiple sclerosis. Mult Scler 2008; 14: 57172.

27 Sadiq SA, Poopatana CA. Intrathecal baclofen and morphine in multiple sclerosis patients with severe pain and spasticity. J Neurol 2007; 254: 146465.

28 Jarrett L, Nandi P, Thompson AJ. Managing severe lower limb spasticity in multiple sclerosis: does intrathecal phenol have a role? J Neurol Neurosurg Psychiatry 2002; 73: 70509.

29 Hyman N, Barnes M, Bhakta B, et al. Botulinum toxin (Dysport) treatment of hip adductor spasticity in multiple sclerosis: a prospective, randomised, double blind, placebo controlled, dose ranging study. J Neurol Neurosurg Psychiatry 2000; 68: 70712.

30 Dolly JO, Aoki KR. The structure and mode of action of diff erent botulinum toxins. Eur J Neurol 2006; 13 (suppl 4): 19.

31 Giovannelli M, Borriello G, Castri P, Prosperini L, Pozzilli C. Early physiotherapy after injection of botulinum toxin increases the benefi cial eff ects on spasticity in patients with multiple sclerosis. Clin Rehabil 2007; 21: 33137.

32 Mills RJ, Yap L, Young CA. Treatment for ataxia in multiple sclerosis. Cochrane Database Syst Rev 2007; 1: CD005029.

33 Hallett M, Lindsey JW, Adelstein BD, Riley PO. Controlled trial of isoniazid therapy for severe postural cerebellar tremor in multiple sclerosis. Neurology 1985; 35: 137477.

34 Duquette P, Pleines J, du Souich P. Isoniazid for tremor in multiple sclerosis: a controlled trial. Neurology 1985; 35: 177275.

35 Koller WC. Pharmacologic trials in the treatment of cerebellar tremor. Arch Neurol 1984; 41: 28081.

36 Rice GP, Lesaux J, Vandervoort P, Macewan L, Ebers GC. Ondansetron, a 5-HT3 antagonist, improves cerebellar tremor. J Neurol Neurosurg Psychiatry 1997; 62: 28284.

37 Gbadamosi J, Buhmann C, Moench A, Heesen C. Failure of ondansetron in treating cerebellar tremor in MS patientsan open-label pilot study. Acta Neurol Scand 2001; 104: 30811.

38 Monaca-Charley C, Stojkovic T, Duhamel A, De Seze J, Ferriby D, Vermersch P. Double-blind crossover study with dolasetron mesilate, a 5-HT3 receptor antagonist in cerebellar syndrome secondary to multiple sclerosis. J Neurol 2003; 250: 119094.

39 Fox P, Bain PG, Glickman S, Carroll C, Zajicek J. The eff ect of cannabis on tremor in patients with multiple sclerosis. Neurology 2004; 62: 110509.

40 Feys P, Dhooghe MB, Nagels G, Helsen WF. The eff ect of levetiracetam on tremor severity and functionality in patients with multiple sclerosis. Mult Scler 2009; 15: 37178.

41 Sechi GP, Zuddas M, Piredda M, et al. Treatment of cerebellar tremors with carbamazepine: a controlled trial with long-term follow-up. Neurology 1989; 39: 111315.

42 Aisen ML, Holzer M, Rosen M, Dietz M, McDowell F. Glutethimide treatment of disabling action tremor in patients with multiple sclerosis and traumatic brain injury. Arch Neurol 1991; 48: 51315.

43 Bittar RG, Hyam J, Nandi D, et al. Thalamotomy versus thalamic stimulation for multiple sclerosis tremor. J Clin Neurosci 2005; 12: 63842.

44 Schuurman PR, Bosch DA, Bossuyt PM, et al. A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor. N Engl J Med 2000; 342: 46168.

45 Schuurman PR, Bosch DA, Merkus MP, Speelman JD. Long-term follow-up of thalamic stimulation versus thalamotomy for tremor suppression. Mov Disord 2008; 23: 114653.

46 Niranjan A, Kondziolka D, Baser S, Heyman R, Lunsford LD. Functional outcomes after gamma knife thalamotomy for essential tremor and MS-related tremor. Neurology 2000; 55: 44346.

47 Mathieu D, Kondziolka D, Niranjan A, Flickinger J, Lunsford LD. Gamma knife thalamotomy for multiple sclerosis tremor. Surg Neurol 2007; 68: 39499.


Review

48 Solari A, Uitdehaag B, Giuliani G, Pucci E, Taus C. Aminopyridines for symptomatic treatment in multiple sclerosis. Cochrane Database Syst Rev 2003; 2: CD001330.

49 Goodman AD, Cohen JA, Cross A, et al. Fampridine-SR in multiple sclerosis: a randomized, double-blind, placebo-controlled, dose-ranging study. Mult Scler 2007; 13: 35768.

50 Goodman AD, Brown TR, Cohen JA, et al. Dose comparison trial of sustained-release fampridine in multiple sclerosis. Neurology 2008; 71: 113441.

51 Hobart JC, Riazi A, Lamping DL, Fitzpatrick R, Thompson AJ. Measuring the impact of MS on walking ability: the 12-Item MS Walking Scale (MSWS-12). Neurology 2003; 60: 3136.

52 Thompson A, Polman C. Improving function: a new treatment era for multiple sclerosis? Lancet 2009; 373: 69798.

53 DasGupta R, Fowler CJ. Bladder, bowel and sexual dysfunction in multiple sclerosis: management strategies. Drugs 2003; 63: 15366.

54 Fowler CJ, Griffi ths D, de Groat WC. The neural control of micturition. Nat Rev Neurosci 2008; 9: 45366.

55 Fowler CJ, Panicker JN, Drake M, et al. A UK consensus on the management of the bladder in multiple sclerosis. Postgrad Med J 2009; 85: 55259.

56 Hashim H, Abrams P. How should patients with an overactive bladder manipulate their fl uid intake? BJU Int 2008; 102: 6266.

57 McClurg D, Ashe RG, Lowe-Strong AS. Neuromuscular electrical stimulation and the treatment of lower urinary tract dysfunction in multiple sclerosisa double blind, placebo controlled, randomised clinical trial. Neurourol Urodyn 2008; 27: 23137.

58 Guay DR. Cranberry and urinary tract infections. Drugs 2009; 69: 775807.

59 Hess MJ, Hess PE, Sullivan MR, Nee M, Yalla SV. Evaluation of cranberry tablets for the prevention of urinary tract infections in spinal cord injured patients with neurogenic bladder. Spinal Cord 2008; 46: 62226.

60 ORiordan JI, Doherty C, Javed M, Brophy D, Hutchinson M, Quinlan D. Do alpha-blockers have a role in lower urinary tract dysfunction in multiple sclerosis? J Urol 1995; 153: 111416.

61 Dasgupta P, Haslam C, Goodwin R, Fowler CJ. The Queen Square bladder stimulator: a device for assisting emptying of the neurogenic bladder. Br J Urol 1997; 80: 23437.

62 Prasad RS, Smith SJ, Wright H. Lower abdominal pressure versus external bladder stimulation to aid bladder emptying in multiple sclerosis: a randomized controlled study. Clin Rehabil 2003; 17: 4247.

63 Nicholas RS, Friede T, Hollis S, Young CA. Anticholinergics for urinary symptoms in multiple sclerosis. Cochrane Database Syst Rev 2009; 1: CD004193.

64 Gajewski JB, Awad SA. Oxybutynin versus propantheline in patients with multiple sclerosis and detrusor hyperrefl exia. J Urol 1986; 135: 96668.

65 Fader M, Glickman S, Haggar V, Barton R, Brooks R, Malone-Lee J. Intravesical atropine compared to oral oxybutynin for neurogenic detrusor overactivity: a double-blind, randomized crossover trial. J Urol 2007; 177: 20813.

66 Amend B, Hennenlotter J, Schafer T, Horstmann M, Stenzl A, Sievert KD. Eff ective treatment of neurogenic detrusor dysfunction by combined high-dosed antimuscarinics without increased side-eff ects. Eur Urol 2008; 53: 102128.

67 Duthie J, Wilson DI, Herbison GP, Wilson D. Botulinum toxin injections for adults with overactive bladder syndrome. Cochrane Database Syst Rev 2007; 3: CD005493.

68 Ehren I, Volz D, Farrelly E, et al. Effi cacy and impact of botulinum toxin A on quality of life in patients with neurogenic detrusor overactivity: a randomised, placebo-controlled, double-blind study. Scand J Urol Nephrol 2007; 41: 33540.

69 Kalsi V, Gonzales G, Popat R, et al. Botulinum injections for the treatment of bladder symptoms of multiple sclerosis. Ann Neurol 2007; 62: 45257.

70 Bosma R, Wynia K, Havlikova E, De Keyser J, Middel B. Effi cacy of desmopressin in patients with multiple sclerosis suff ering from bladder dysfunction: a meta-analysis. Acta Neurol Scand 2005; 112: 15.

71 Freeman RM, Adekanmi O, Waterfi eld MR, Waterfi eld AE, Wright D, Zajicek J. The eff ect of cannabis on urge incontinence in patients with multiple sclerosis: a multicentre, randomised placebo-controlled trial (CAMS-LUTS). Int Urogynecol J Pelvic Floor Dysfunct 2006; 17: 63641.

72 MacDonald R, Monga M, Fink HA, Wilt TJ. Neurotoxin treatments for urinary incontinence in subjects with spinal cord injury or multiple sclerosis: a systematic review of eff ectiveness and adverse eff ects. J Spinal Cord Med 2008; 31: 15765.

73 Fjorback MV, Rijkhoff N, Petersen T, Nohr M, Sinkjaer T. Event driven electrical stimulation of the dorsal penile/clitoral nerve for management of neurogenic detrusor overactivity in multiple sclerosis. Neurourol Urodyn 2006; 25: 34955.

74 Kabay S, Kabay SC, Yucel M, et al. The clinical and urodynamic results of a 3-month percutaneous posterior tibial nerve stimulation treatment in patients with multiple sclerosis-related neurogenic bladder dysfunction. Neurourol Urodyn 2009; 28: 96468.

75 Wallace PA, Lane FL, Noblett KL. Sacral nerve neuromodulation in patients with underlying neurologic disease. Am J Obstet Gynecol 2007; 197: 9695.

76 Fowler CJ, Miller JR, Sharief MK, Hussain IF, Stecher VJ, Sweeney M. A double blind, randomised study of sildenafi l citrate for erectile dysfunction in men with multiple sclerosis. J Neurol Neurosurg Psychiatry 2005; 76: 70005.

77 Safarinejad MR. Evaluation of the safety and effi cacy of sildenafi l citrate for erectile dysfunction in men with multiple sclerosis: a double-blind, placebo controlled, randomized study. J Urol 2009; 181: 25258.

78 DasGupta R, Wiseman OJ, Kanabar G, Fowler CJ, Mikol DD. Effi cacy of sildenafi l in the treatment of female sexual dysfunction due to multiple sclerosis. J Urol 2004; 171: 118993.

79 Cardozo L, Hessdorfer E, Milani R, et al. Solifenacin in the treatment of urgency and other symptoms of overactive bladder: results from a randomized, double-blind, placebo-controlled, rising-dose trial. BJU Int 2008; 102: 112027.

80 Chapple C, Steers W, Norton P, et al. A pooled analysis of three phase III studies to investigate the effi cacy, tolerability and safety of darifenacin, a muscarinic M3 selective receptor antagonist, in the treatment of overactive bladder. BJU Int 2005; 95: 9931001.

81 Cvetkovic RS, Plosker GL. Desmopressin: in adults with nocturia. Drugs 2005; 65: 99107.

82 Kavia R, De RD, Constantinescu C, Stott C, Fowler C. Randomized controlled trial of Sativex to treat detrusor overactivity in multiple sclerosis. Mult Scler 2010; 16: 134959.

83 Chia YW, Fowler CJ, Kamm MA, Henry MM, Lemieux MC, Swash M. Prevalence of bowel dysfunction in patients with multiple sclerosis and bladder dysfunction. J Neurol 1995; 242: 10508.

84 Preziosi G, Emmanuel A. Neurogenic bowel dysfunction: pathophysiology, clinical manifestations and treatment. Expert Rev Gastroenterol Hepatol 2009; 3: 41723.

85 Cameron KJ, Nyulasi IB, Collier GR, Brown DJ. Assessment of the eff ect of increased dietary fi bre intake on bowel function in patients with spinal cord injury. Spinal Cord 1996; 34: 27783.

86 Wiesel PH, Norton C, Glickman S, Kamm MA. Pathophysiology and management of bowel dysfunction in multiple sclerosis. Eur J Gastroenterol Hepatol 2001; 13: 44148.

87 House JG, Stiens SA. Pharmacologically initiated defecation for persons with spinal cord injury: eff ectiveness of three agents. Arch Phys Med Rehabil 1997; 78: 106265.

88 Wiesel PH, Norton C, Roy AJ, Storrie JB, Bowers J, Kamm MA. Gut focused behavioural treatment (biofeedback) for constipation and faecal incontinence in multiple sclerosis. J Neurol Neurosurg Psychiatry 2000; 69: 24043.

89 Chiotakakou-Faliakou E, Kamm MA, Roy AJ, Storrie JB, Turner IC. Biofeedback provides long-term benefi t for patients with intractable, slow and normal transit constipation. Gut 1998; 42: 51721.

90 Faaborg PM, Christensen P, Kvitsau B, Buntzen S, Laurberg S, Krogh K. Long-term outcome and safety of transanal colonic irrigation for neurogenic bowel dysfunction. Spinal Cord 2009; 47: 54549.

91 Tan EK, Vaizey C, Cornish J, Darzi A, Tekkis PP. Surgical strategies for faecal incontinencea decision analysis between dynamic graciloplasty, artifi cial bowel sphincter and end stoma. Colorectal Dis 2008; 10: 57786.

92 Jarrett ME, Dudding TC, Nicholls RJ, Vaizey CJ, Cohen CR, Kamm MA. Sacral nerve stimulation for fecal incontinence related to obstetric anal sphincter damage. Dis Colon Rectum 2008; 51: 53137.


Review

93 Tepavcevic DK, Kostic J, Basuroski ID, Stojsavljevic N, Pekmezovic T, Drulovic J. The impact of sexual dysfunction on the quality of life measured by MSQoL-54 in patients with multiple sclerosis. Mult Scler 2008; 14: 113136.

94 Lombardi G, Macchiarella A, Del Popolo G. Effi cacy and safety of tadalafi l for erectile dysfunction in patients with multiple sclerosis. J Sex Med 2010; 7: 21922200.

95 Padma-Nathan H, Hellstrom WJ, Kaiser FE, et al, for Medicated Urethral System for Erection (MUSE) Study Group. Treatment of men with erectile dysfunction with transurethral alprostadil. N Engl J Med 1997; 336: 17.

96 Brown DA, Kyle JA, Ferrill MJ. Assessing the clinical effi cacy of sildenafi l for the treatment of female sexual dysfunction. Ann Pharmacother 2009; 43: 127585.

97 Hadjimichael O, Vollmer T, Oleen-Burkey M. Fatigue characteristics in multiple sclerosis: the North American Research Committee on Multiple Sclerosis (NARCOMS) survey. Health Qual Life Outcomes 2008; 6: 100.

98 Stroud NM, Minahan CL. The impact of regular physical activity on fatigue, depression and quality of life in persons with multiple sclerosis. Health Qual Life Outcomes 2009; 7: 68.

99 Schwid SR, Petrie MD, Murray R, et al. A randomized controlled study of the acute and chronic eff ects of cooling therapy for MS. Neurology 2003; 60: 195560.

100 Mainero C, Inghilleri M, Pantano P, et al. Enhanced brain motor activity in patients with MS after a single dose of 3,4-diaminopyridine. Neurology 2004; 62: 204450.

101 The Canadian MS Research Group. A randomized controlled trial of amantadine in fatigue associated with multiple sclerosis. Can J Neurol Sci 1987; 14: 27378.

102 Cohen RA, Fisher M. Amantadine treatment of fatigue associated with multiple sclerosis. Arch Neurol 1989; 46: 67680.

103 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: 195661.

thomson

Documents