Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, and is the leading cause of nontraumatic disability in young adults. Prevalence varies between 50 to 200 per 100,000 people.1–3 Despite recent therapeutic advances that have led to improvements in disease control in relapsing-remitting MS, the majority of individuals with MS experience significant symptomatic problems which may have an negative impact on quality of life.4 These symptomatic problems may include fatigue, pain, spasticity, depression, bowel and bladder dysfunction, balance and gait problems, or sexual dysfunction. Specific therapies targeting these symptoms may help to improve quality of life. This review aims to discuss these therapies.
Fatigue
Fatigue may affect up to 80 % of patients with MS.5–9 Multiple scales for fatigue in MS are currently in use, including the Fatigue Severity Scale (FSS),10 Modified Fatigue Impact Scale (MFIS),11 Visual Analogue Scale for Fatigue,12 the MS Fatigue Scale, and the Neurological Fatigue Index (NFI-MS).13 The pathophysiology of fatigue in MS is incompletely understood, but proinflammatory cytokines, lesion burden, axonal injury, and endocrine functions may play a causative role in fatigue.14,15 Functional magnetic resonance imaging (fMRI) studies have suggested greater activation in the motor-attentional network when performing motor tasks.16 In addition, structural brain changes have been found in patients with MS fatigue: atrophy of the sensorimotor cortex was greater in MS patients with fatigue than controls and MS patients without fatigue, despite no differences between MS patients in overall brain atrophy.17 Baseline disability (Expanded Disability Status Scale [EDSS]), mood, and pain predicts the presence of ongoing fatigue after one year.9,18 Exacerbating factors include heat and humidity.19–21
Pharmacologic and nonpharmacologic treatment options for MS-related fatigue have been well described. Agents that have been investigated for MS fatigue include: (1) amantadine, an agent whose specific mechanism of action in treating MS fatigue is unknown, but which has properties including contributing to the release of dopamine and norepinephrine in the brain, and weak antagonism of NMDA receptors; (2) modafinil, whose mechanism of action is unknown, but is thought to act by increasing hypothalamic histamine levels and increasing levels of extra-synaptic dopamine; and (3) stimulants (amphetamines), including methylphenyldate, pemoline, and lisdexamphetamine.
Two randomized controlled trials (RCTs) have been conducted on modafinil in MS fatigue. In one phase II study of 72 patients with MS, modafinil led to a significant improvement in fatigue compared with placebo at a dose of 200 mg/day, but not at 400 mg/day.22 Similarly, another study of 115 MS patients with fatigue did not show a significant difference between the use of 400 mg/day of modafinil and placebo. No information on response at 200 mg/day was available for this study.23
In a multicenter RCT, amantadine, pemoline, and placebo were compared in 93 MS patients with fatigue. In this study, amantidine-treated patients showed a significant decrease in fatigue as measured by the MS-Fatigue Scale in comparison to pemoline or placebo.24 Evidence for efficacy of stimulants in MS fatigue is limited. For example, methylphenidate leads to improvement of fatigue in patients with chronic fatigue syndrome,25 but no placebo-controlled trials have been conducted on its effect on MS fatigue. Lisdexamphetamine (70 mg/day) was evaluated in a placebo-controlled trial of 63 patients with MS, and although improvements were seen in processing speed and memory, no improvements were seen in fatigue.26
Nonpharmacologic strategies to improve fatigue include cooling, cognitivebehavioral therapy (CBT), and aerobic exercise. Cooling therapy, consisting of a cooling suit applied for 45 minutes two times a day, was found to have beneficial effects on fatigue and strength in an open-label series of six MS patients preselected for heat sensitivity.27 In a single-dose, double-blind randomized, sham-treatment controlled trial of cooling, 84 MS patients with heat sensitivity showed modest improvement in disability with ‘highdose’ cooling, as well as persistent improvements in fatigue as measured by daily recordings and the MFIS.28
In addition, CBT may improve fatigue. An RCT of 72 individuals with MS randomized to CBT or relaxation therapy (RT) showed improvements with both CBT and RT (effect size 3.03 [2.22–3.68] versus 1.83 [1.26–2.34]). The effect was persistent 6 months after treatment.29 More recently, internetbased CBT (MS Invigor8) has been investigated in 40 patients with MS fatigue who were randomized to either the intervention or standard therapy. A large treatment effect was seen in fatigue severity.30
Group exercise in any form may have a positive effect on MS fatigue. In a study of 99 MS patients randomized to group exercise or ‘wait list,’ significant improvements in the FSS were seen in patients randomized to ‘group exercise.’31 In another study comparing routine care (n=71) to physiotherapy-led exercise (n=80), yoga (n=77), or fitness instructorled exercise (n=86) in MS patients with fatigue, all interventions led to improvements in the MFIS in comparison with routine care.32 Other studies have shown similar results with yoga and exercise classes in comparison with controls.33 Group aquatic exercises have also been shown to lead to significant improvements in MS fatigue in comparison to routine care.34
Whether the effect of these exercises on fatigue is related to the group setting, or is due to the exercise itself is difficult to discern from the aforementioned studies. Several other studies focusing on specifically on aerobic training have evaluated its benefit on fatigue. Petajan et al. published a study of 54 patients who were randomized to a 12-week intervention of three 40-minute aerobic exercise sessions/week or no exercise, and although they found improvement in areas such as depression (see below), no effect was seen on fatigue in either group.35 However, in a case series of 21 MS patients with fatigue, elliptical training led to significant improvement in the FSS.36
Pain
Pain accounts for almost one-third (30 %) of symptomatic therapy that is prescribed for MS patients37 and is experienced by almost half (43 %) of MS patients.38 Pain associated with MS may be classified into four categories: continuous central neuropathic pain, intermittent central neuropathic pain, musculoskeletal pain and mixed neuropathic, and nonneuropathic pain.39
Continuous central neuropathic pain, which may described as a burning sensation or deep, aching pain, occurs in about 40–50 % of MS patients.40,41
Although central neuropathic pain is thought to be due to demyelinating lesions in areas of pain perception, a study comparing MS patients with and without pain did not show a correlation between pain and lesion localization.42 Antiepileptic medications (e.g. carbamazepine, lamotrigine, gabapentin, pregabalin, and levetiracetam), tricyclic antidepressants, opioids, intrathecal baclofen, anesthetics, and cannabinoids have been described for MS-related pain in this category. Although several studies have shown antiepileptic drugs to be effective against pain, the rate of discontinuation of these medications due to adverse side effects is high.43,44 Tricyclic antidepressants such as clomipramine, amitryptiline, and nortryptiline are frequently used in the treatment of central pain, although guidelines regarding optimal dose scheduling are lacking.45
The highest level of evidence for pharmacologic intervention in MS pain is in the use of cannabinoids. A double-blind, placebo-controlled crossover trial (n=24) showed a modest decrease in pain using an oral agent, delta-9-tetrahydrocannabinol dronabinol (maximum 10 mg/ day).46 Another large RCT whose primary endpoint was improvement in spasticity scores, but had change in pain as a secondary endpoint (n=630), showed cannabinoids (oral cannabis extract [CE], n=211, delta9- tetrahydrocannabinol [D9THC], n=206, and placebo, n=213) to be more effective than placebo for pain in MS.47
Results of studies of oromucosal tetrahydrocannabinol/cannabidol (THC/CBE) in MS pain have been mixed. Researchers found oromucosal THC/CBE (n=66) to be efficacious for pain in MS in a five-week RCT,48 and further, found sustained effect in an open-label extension study (n=28).49
However, another large, randomized, open-label controlled trial of THC/ CBE oromucosal spray versus placebo as add-on therapy after failure with other pain medications (n=339), showed no difference between the treatment group and placebo after 14 weeks of treatment. On the other hand, statistically significant differences favouring the THC/CBE group were seen in time-to-treatment failure, as well as the secondary endpoints of pain upon withdrawal of medication and sleep quality.50 It is possible that the lack of effect seen in the second trial was due to patient selection, as only patients who had failed conventional pain therapies participated in this trial.
Intermittent central neuropathic pain frequently occurs in the form of trigeminal neuralgia (1.9–6.3 %) in MS patients.38,51 Descriptions of successful treatment of this entity in MS using anticonvulsants, such as topiramate,52 gabapentin,53 lamotrigine,54 and carbamazepine55 have been published, although no randomized-controlled studies have been performed on these interventions in the MS population. Multiple surgical interventions for medically refractory cases have been described, including gamma knife surgery, percutaneous balloon compression, microvascular decompression, and percutaneous radiofrequency rhizotomy.56 A recent meta-analysis suggests little difference in acute pain control related to these procedures, but higher recurrence rate for percutaneous balloon compression.56
Musculoskeletal pain in MS is usually related to painful tonic spasms that occur in the context of spasticity or immobility. These spasms usually happen at night, affect the lower limbs and may be elicited by sensory stimuli.38 Treatment of spasticity-related pain should be oriented toward treatment of the underlying spasticity (see ‘spasticity’ below).
Spasticity
Spasticity occurs in 60 % of MS patients.57 It may manifest as gait disturbance, and affects the lower extremities to a greater extent than the upper extremities in most MS patients. Demyelinating lesions and axonal loss cause upper motor neuron dysfunction, leading to spasticity.58 Painful spasms may result from tonic contractions of both agonists and antagonists due to insufficient descending inhibition at the segmental level of the spinal cord.59
Nonpharmacologic options, such as stretching, may control mild spasticity,60 but the effect of stretching on moderate to severe spasticity is less clear. Medications used in the treatment of spasticity influence the GABAergic system (baclofen, gabapentin, benzodiazepines), the α2 adrenergic system (tizanidine), and calcium release in the muscles (dantrolene).61 Several RCTs have been performed evaluating tizanidine and baclofen in MS spasticity,62–64 the largest of which suggests functional benefit in the majority of patients (80 and 76 %, respectively), with a good tolerability profile at doses up to 24 mg (tizanidine) and 60 mg (baclofen).62 Caution is indicated in discontinuing baclofen, as immediate withdrawal can lead to encephalopathy and seizures.
Several reports suggesting benefit of dantrolene sodium for the treatment of spasticity in MS are available,65–68 but concern regarding its effects on the liver limit its use. Diazepam has been evaluated in an open-label crossover trial comparing it with dantrolene,69 and a double-blinded trial comparing it with baclofen.70 In both studies, diazapem was equally effective to the other agent. Sedation was noted to be a frequent side effect.
In a placebo-controlled, double-masked, crossover trial, gabapentin (900 mg TID) was found to improve impairment related to spasticity without worsening concentration and fatigue.71 It may therefore be considered as an alternative to the abovementioned agents. Finally, cannabinoid extract may be of mild to moderate benefit in MS spasticity. In the large RCT noted above comparing CE and D9THC to placebo, Zajicek et al. found improvements the Ashworth scale in both treatment groups in comparison to placebo (CE versus placebo, 0.32 (95 % confidence interval [CI] –1.04 to 1.67); D9THC versus placebo, 0.94 (-0.44 to 2.31). Patient-reported improvement in spasticity was 61 % and 60 % in the treatment groups, respectively, in comparison to 45 % in the placebo group. In another large RCT, Zajicek et al. compared oral E (n=144) to placebo (n=135), and found it to be effective for spasticity in approximately 29 % of patients in comparison with almost 16 % of placebo-treated patients.72 Importantly, there are concerns regarding the long-term effects of CE on cognition and behavior.73,74
Intrathecal baclofen, in the form of a baclofen pump, is a well-established therapeutic modality for the treatment of patients with spinal-cord related spasticity.75 It was reported to be effective for the management of pain due to spasticity in a case series of four MS patients with spinal cord lesions.76 A retrospective study of its use in 64 patients with MS spasticity suggests benefit in improving comfort in nonambulatory patients with severe spasticity.77 Another retrospective analysis of its long-term use in MS spasticity suggests tolerability and effectiveness that may last up to 12 years.78 Finally, botulinum toxin has been shown to be effective compared with placebo in MS-related spasticity, but it is only indicated in focal spasticity.79,80
Depression
Depression occurs in approximately 50 % of MS patients, three times higher than in the general population.7,81,82 Depression may have a negative impact on cognitive function, relationships, treatment adherence, and quality of life.83–86 Pharmacologic and nonpharmacologic strategies have been evaluated in the treatment of depression in MS patients.87
Several studies of MS-related depression have suggested benefit of fluvoxamine (200 mg),88 sertraline,89 and fluoxetine.90 As for nonpharmacologic interventions, CBT has shown promising results. In a study comparing CBT to supportive expressive therapy and sertraline, CBT sertraline showed equal efficacy. Both were superior to supportive expressive therapy. The effect was sustained after a time period of 6 months.91
Exercise has been reported to have a positive effect on mood in MS. In the 1996 randomized trial of exercise versus no exercise by Petjan et al. discussed above (n=54), significant improvements were seen in the exercise group in depression and anger scores after 5 and 10 weeks of intervention.35 In addition, in one study of female MS patients (n=25), exercise had immediate effects on total mood disturbance, with greater effect seen in patients with high levels of baseline anxiety.92 Progressive resistance training (i.e. strength training), improved mood in a RCT (control group [n=15] or treatment group [n=16]). This benefit was sustained 12 weeks after the intervention was completed.93 Finally, a mindfulnessbased intervention has been shown to be effective for depression when compared with placebo in a study of 67 MS patients.94
Bladder Dysfunction
Over half of patients with MS will experience bladder dysfunction at some point during their disease course due to damage to central autonomic pathways.87 Bladder dysfunction can be related to urinary frequency or urgency, urinary retention or a combination of both due to dyssynergia of the detrusor and sphincter muscles. Untreated, bladder dysfunction leads to complications in over 50 % of cases. These complications include urinary tract infections, urolithiasis, hydronephrosis, and kidney failure.95,96 Nonpharmacologic, pharmacologic, and surgical options can be offered for bladder dysfunction in MS.
Nonpharmacologic bladder rehabilitation programs include a selection or combination of behavioral treatment, pelvic floor muscle training, electromyography biofeedback, and neuromuscular electrical stimulation.97 A study assessing pelvic floor muscle training alone showed a decrease in storage and voiding symptoms and improvement in quality of life in MS patients with bladder dysfunction using standardized questionnaires.98 Another study reported effectiveness of an individual bladder rehabilitation program in a RCT assessing bladder impairment, activity limitation, and quality of life.99 In the event that incomplete voiding and high post-void residuals occur, regular clean intermittent self-catheterization may prevent further complications.100
Anticholinergics are major pharmacologic interventions used in the treatment of bladder dysfunction in MS.101 They reduce urinary frequency, urgency, and incontinence. The side-effect profile includes dry mouth, constipation, cognitive problems, and nausea, leading to a high rate of discontinuation of therapy. According to one study, after 6 months, fewer than 30 % of MS patients continue to be on treatment.102 A valid option for some patients is once-a-day treatment in combination with self-catheterization to reduce urologic complications and reduce incontinence.103 Desmopressin has a positive effect on urine volume and urinary frequency during the first 6 hours after treatment and may be offered on occasion for social occasions or travel.104
Surgical options include bladder augmentation, sacral neuromodulation, and botulinum toxin injections. Augmentation cytoplasty has been shown to be effective in the treatment of refractory urgency, urinary incontinence, or detrusor overactivity.105 Sacral neuromodulation may be used in patients with MS-related bladder dysfunction. A case series of four patients with MS-bladder dysfunction reported improvement in leakage from an average of four episodes/day to 0.3/day, with two of these patients completely dry for 24 hours.106 Long-term follow up (average 43 months, range 7–72 months) of nine women who received this procedure for detrusor hyperreflexia showed sustained benefit in all patients.107
Botulinum toxin injections may be used to treat detrusor-sphincter dyssynergia. The effect lasts approximately 6–12 months, and over 70 % of patients treated successfully with botulinum toxin are able to use reduced anticholinergic therapy. On the other hand, caution is warranted, as botulinim toxin injections may lead to increased post-void residual and therefore increase the need for self-catheterization.108–110
Bowel dysfunction in MS consists of constipation, bowel urgency, or incontinence and can be highly embarrassing for the patient. The pathophysiology of bowel dysfunction in MS patients is not fully understood, but is thought to be due to dysfunctional extrinsic autonomic control of bowel function.111 Bowel dysfunction may worsen due to medications used for other MS symptoms, such as anticholinergics, antidepressants, or medications used for spasticity.111 A conservative approach is recommended as a first step in MS-related constipation. Dietary modifications are recommended, including increasing fluid and fiber intake. In more severe cases, laxatives such as lactulose syrup or polyethylene glycol may be used, as can enemas, but they carry the risk of dependence.112 Patients resistant to standard therapies may benefit from bowel biofeedback therapy.113 Approximately 50 % of the patients evaluated in a study of bowel biofeedback therapy showed improvement in standardized bowel and depression scores.113
Sexual Dysfunction
Sexual dysfunction is common in women and men with MS, but patients may be hesitant to discuss it with their physicians. It may affect patients at any time during the disease course. Female complaints may include decreased vaginal lubrication and loss of libido, whereas men often suffer from erectile and ejaculatory dysfunction. Both genders have been reported to have anorgasmia.114–116 The first step in treatment of sexual dysfunction in MS is to identify potentially aggravating therapies such as antidepressants, anticonvulsants, or anticholinergics. If possible, adjustment in these medications should be attempted. Lubrication can be improved by using synthetic lubricants or phosphodiesterase inhibitors in women.112 Sildenafil has been shown in randomized placebo-controlled trials to lead to significant improvement of erectile dysfunction in male MS patients.117,118 Sildenafil has been shown to improve quality of life in MS in one study,117 whereas another study did not demonstrate significant differences in quality of life compared with placebo.118
Gait Abnormalities—Balance and Falls
Mobility and balance are important areas of concern in the MS population. Multiple cross-sectional studies have shown that approximately half of patients with MS experience falls.119,120 Of MS patients with falls, 79 % will experience recurrent falls.119 Much attention has focused on prevention of falls in this population; risk factors include older age, greater disability, use of an assistive device, decreased walking coordination/endurance, and poor balance.119
Improvements in balance have been explored using computer-based interventions, such as Wii Fit©, but the results of a randomized study (n=84) have suggested no difference between controls and those randomized to Wii Fit©, in the timed-up-and-go, a measure of balance and mobility.121 Group exercise classes, such as group kick-boxing, may be of benefit. One open-label pilot study of patients with MS with mild to moderate disability (n=15) demonstrated improvements in gait speed and some measures of balance after a 5-week group kick-box intervention.122 Finally, assistance in proprioceptive input may be of benefit: preliminary data on MS patients (n=15) has suggested that the use of kinesio-taping on the ankle may improve postural control.123
In another study, MS patients (n=40) and controls (n=12) were randomized to receive a six-week visuo-proprioceptive feedback training program; improvements were seen in walking speed and fall risk.124
Gait training, in the form of robot-assisted gait training (n=15), has been found to be equivalent to conventional walking treatment (n=17) in a group of MS patients with severe motor impairment (EDSS 5-7).125 Importantly, neither of these interventions had a lasting effect: patients returned to baseline 3 months after the intervention.125 This underlines the need for ongoing rehabilitative efforts in this population.
One pharmacologic intervention has been approved by the US Food and Drug Administration (FDA) for the improvement of walking speed in MS, 4-aminopyridine (dalfampridine; Fampyra©). This therapy has been evaluated in a phase III, randomized, double-blind, controlled trial (n=229 on dalfampridine 10 mg BID, n=72, on placebo) and shown to result in a greater proportion of patients responding to therapy than in the placebo group (35 % versus 8 %), as well as a 25 % increase in walking speed in responders.126 A second phase III, double-blind RCT (intervention n=120, placebo n=119) showed similar results (responders 43 % versus nonresponders 9 %; improvement in walking speed in responders 24.9 %).127
Summary
Patients with MS suffer from many comorbidities, including fatigue, depression, pain, bowel and bladder dysfunction, sexual dysfunction, and balance and gait difficulties. A variety of therapies targeted specifically at these symptoms have been evaluated, and in some cases, have shown efficacy in ameliorating these symptoms. As these pharmacologic or nonpharmacologic interventions have the potential to improve the quality of life of patients with MS, they should be considered and offered to MS patients on a regular basis.
