Inhibition of acetylcholine release at the neuromuscular junction by injection of botulinum toxin A [90] is the most commonly used focal pharmacological therapy for spasticity. The resultant reduction in muscle overactivity allows for stretching and lengthening and attempts restoration of the balance between antagonist muscle groups disturbed as part of the upper motor neurone syndrome [91]. Although the blockade is permanent, nerve sprouting and reinnervation means that repeat injections are usually required after 3–6 months. Patients with MS who have focal increases in spasticity in the lower limbs causing adductor spasticity, hip flexor spasticity, hip extensor spasticity, spastic talipes equinus, and striatal toe, for example, may derive particular benefit [92]. The upper limbs are less frequently targeted in MS but severe adductor spasm of the shoulder is a recognized indication [92]. Some limited studies have demonstrated efficacy of botulinum toxin A, at least in terms of tone reduction and aiding passive functions leading to ease of nursing care (reviewed in Habek et al. [93]), but emphasis is placed on the need to combine such therapy with physiotherapy if benefits are to be optimized [94]. Botulinum toxin injections are expensive treatments given the cost of the drugs, need for repeated administration and specialist training required to perform the treatment, and analyses of its cost effectiveness in spasticity due to MS and other conditions are on-going [95, 96].

Chemical neurolysis with phenol or alcohol is a potential alternative therapy for nerves with motor predominance, with the potential for postinjection sensory dysesthesia limiting its use elsewhere. Although often considered permanent, the effects may wear off after several months due to partial nerve regeneration and sprouting. Nonetheless, careful assessment and consideration must be undertaken prior to performing these more destructive procedures, which may also cause tissue fibrosis, potentially rendering any subsequent surgical intervention more difficult. A transient motor block may be performed prior to injection to give a clearer indication of potential benefit [97], and such treatments are usually reserved for patients with spasticity affecting a relatively wide region which has been resistant to other treatments [98].

Intrathecal therapy may be also useful in patients who have not responded to oral therapies and who have severe, predominantly lower limb spasticity. The high concentration of GABAergic receptors in the spinal cord allows lower doses of medication to be effective while reducing the likelihood of side effects. Intrathecal baclofen reduces both spasticity and spasms in patients with MS as well as having beneficial effects on pain and sleep [99, 100]. Long-term treatment appears to be effective and well tolerated [101, 102], although there are reports of increased seizure frequency [103] and impaired response to treatment developing with time [104]. Intrathecal phenol is an alternative intervention, but, although it has been used in the treatment of spasticity for many years [105, 106], the consequences of bowel and bladder incontinence, limb weakness, and painful dysesthesia preclude its current use in all but a minority of carefully selected (and consented) patients [107].

Many surgical procedures have been attempted in an effort to reduce spasticity. Most, including ventral rhizotomy, longitudinal myelotomy, and distal cordectomy, have been complicated by severe side effects [108]. Posterior rhizotomy has been employed for the treatment of spasticity since the beginning of the twentieth century [109], following on from the observation that decerebrate rigidity could be abolished in animals by sectioning the dorsal roots [110]. Early surgical procedures were complicated by severe sensory disturbances and the procedure was subsequently modified so that a proportion of the dorsal roots were spared in an effort to reduce the sensory disturbances – the so-called selective dorsal rhizotomy [111]. Although it is not commonly performed in patients with MS, it may be useful in a small proportion of patients [112]. Similarly, peripheral neurotomy can be undertaken in an effort to restore the normal balance between agonists and antagonists in focal spasticity [113, 114], but is rarely undertaken. Other surgical interventions are directed at correcting the consequences of spasticity and include tendon lengthening, tendon transfers, and tendotomy, as well as osteotomy and arthrodesis.

The prevalence of pain in patients with MS has been examined frequently but methodological problems have resulted in a wide variation between reported estimates (29–90%) for prevalence of pain of any description [115, 116]. However, it is undoubtedly a common problem faced by patients with MS and some have suggested that it may be the MS symptom most frequently treated pharmacologically [117]. Types of pain directly attributable to MS include persistent central neuropathic pain, painful tonic spasms, and paroxysmal sensory disturbances including trigeminal neuralgia and Lhermitte’s phenomenon. With the notable exception of the paroxysmal phenomena, pain is rarely the presenting symptom of MS (1–2% for central dysesthetic pain [118, 119]) and most studies have demonstrated an association with disability and disease duration [119–124], although the negative impact of pain early in disease course has also been highlighted [125].

Other pains frequently experienced by those with MS, but which will not be dealt extensively with here, include headache and low back pain [121, 122, 126]. Directly attributing these to MS is difficult, given that they occur widely in the general population and low back pain in particular may arise secondary to musculoskeletal problems. It is worth noting however, that mechanisms have been proposed for how headache might arise due to MS pathophysiology [127–130], and that headache may increase, perhaps temporarily, with disease-modifying treatment [121, 131].

Bowel symptoms may be particularly distressing for patients with MS and occur frequently – studies report prevalence rates of 35–54% for constipation and 29–51% for fecal incontinence [236–239]. Unsurprisingly, bowel problems are associated with impaired quality of life [240], yet despite the scale of the problem, there is relatively little published data on which to base treatment recommendations. Constipation may be due to slow colonic transit and/or abnormal rectal function; while fecal incontinence can result from impaired sensation of rectal fullness, poor contraction of the pelvic musculature, reduced rectal compliance, and weakness of the anal sphincter [233, 241]. In addition, there may be effects of medications or concomitant disease. To optimize treatment recommendations, careful assessment of the nature of bowel symptoms is therefore required [242].

Following careful medication review, general measures which are often recommended include increasing fluid and dietary fiber, as well as increasing physical exercise. However, increasing fluid intake may be poorly adhered to by patients with urinary symptoms and, while it may be helpful in those with mild symptoms, increased dietary fiber has been shown to have adverse effects in chronic constipation [243].

Behavioral techniques have been shown to have some benefit in some patients with MS, particularly those with less severe disease and involve increased awareness of rectal fullness, techniques for anal sphincter relaxation and recto-anal coordination, as well as habit training [244]. A recent pilot study of abdominal massage also suggested a positive effect [245].

A range of pharmacological agents are available but have not been tested in MS specifically. Stimulant laxatives can be very helpful, although osmotic laxatives are less likely to cause liquid stool and may therefore be advantageous if there is coexistent incontinence. Sodium docusate has both a stimulant and stool-softener effect, which may be useful. Timing of defecation may be regulated using rectal stimulants, although direct comparison of agents has been examined only in patients with spinal injury [246].

In some patients, mechanical evacuation will be required using digital evacuation [247] or transanal colonic irrigation [248]. Surgical procedures including formation of a stoma will be required in a minority of patients refractory to other interventions [242, 249]. Depending on the site of stoma formation, laxatives or irrigation may still be required due to impaired gut motility. It should also be recognized that while colostomy is frequently considered a last resort and is not without considerable risk, it has been demonstrated to improve quality of life in those with spinal cord injury [250].

Treatment interventions for fecal incontinence remain suboptimal. Following medication review and the exclusion of diarrhoea secondary to other causes including fecal overloading, anti-motility agents such as codeine and loperamide may be tried. Anal plugs can be helpful for those with impaired anorectal sensation.

Coordination problems are common in MS, occurring in up to 80% patients [251] and can occur due to cerebellar disease or impaired proprioception due to problems with sensory afferent input. Postural and intention tremors are also common symptoms, although rest and rubral tremors relatively are rare [252, 253]. MS tremor is thought to arise predominantly as a consequence of cerebellar or thalamic disease [254].

A wide variety of conservative treatment measures have been proposed and evaluated to some extent. These include limb cooling, exposure to electromagnetic fields [255], weighted bracelets [256], orthoses [257], physiotherapy [258], specialized software [259], and robot training [260]. While they may provide assistance to some patients, the need for improved treatments remains.

There is no strong evidence basis on which to guide pharmacological treatment; a 2007 Cochrane review of treatments for ataxia in MS concluded that no recommendations could be made [261] and little has changed in the interim. Benefit has been reported for the treatment of tremor with a wide range of drugs in small open-label studies or case reports including primidone [262], glutethimide [263], intrathecal baclofen [264], topiramate [265] and isoniazid [266–269]. Negative outcomes were seen in controlled trials performed with propranolol [270], isoniazid [270], ethanol [270], levetiracetam [271], and dolasetron [272], but the number of patients involved was generally very low. Some degree of improvement was observed in other controlled trials with isoniazid [273, 274] as well as with carbmazepine [275] and ondansetron [276]. Cannabinoids appear to have no beneficial effect on tremor due to MS, given the outcome of a number of well-conducted, randomized, controlled trials of cannabis extracts [277–279] or THC [277].

Surgical options for the treatment of tremor secondary to MS are being developed and the mainly retrospective, observational studies published to date have generally targeted thalamic structures with promising results (reviewed by Koch et al. [254] and Yap et al. [280]). These studies will undoubtedly be refined as microelectrode placement and gamma knife surgery are evaluated but concerns regarding the risks of the procedure including seizures [281] and adverse effects on cognition [282] will need to be addressed. Clearly, careful patient selection and consent will be required, but, encouragingly, consensus statements are already emerging [283].

Neuropsychiatric symptoms are rarely the presenting symptoms of MS but overall are common and can negatively impact upon quality of life for both patients and their caregivers [284].

Estimates of the prevalence of cognitive impairment associated with MS range from 40% to 70% [318]. Although cognitive impairment can undoubtedly occur at any stage and in any subtype of disease [319, 320], it increases with disease duration [321], is most severe in those with greatest disability [320, 322], and has an adverse effect on quality of life [323]. Speed of information processing, memory, and executive function are the domains of function most likely to be affected, while language tends to be relatively preserved [318].

Following exclusion of concurrent systemic infection and review of medication to eliminate drugs contributing to excessive sedation, formal neuropsychometry is advised to determine the relative contribution of other deficits such as depression and fatigue to cognitive dysfunction. This clearly has implication for determining not only an accurate diagnosis but also treatment options, although the interplay between these symptoms is not straightforward.

At present, there is not a strong evidence base for the use of cognitive rehabilitation in MS. A Cochrane review concluded that psychological interventions were likely to be helpful for treating depression and for both adjustment to and coping with MS, but the range of outcome measures employed made definitive conclusions impossible [295]. Trials of disease-modifying therapies have not tended to include primary outcome measures which include tests of cognitive function, possibly because longitudinal studies with relative short follow-up periods typically show little change [324, 325]. Nonetheless, the suggestion has been raised that treatment with interferon beta-1a and interferon beta-1b might confer some benefit, although this has not been definitively addressed [326–330]. A small study has been conducted to examine the effects of natalizumab on cognition in patients with relapsing–remitting MS [331]. The authors reported that natalizumab could be effective in improving cognitive dysfunction, but given that the study was not placebo-controlled or randomized and that the “quasi” control group was not matched for disease progression or disability, limited conclusions can be drawn.

The rationale behind the use of anticholinesterases in MS arises due to the possibility that diffuse cholinergic connections from the nucleus basalis of Meynert could be disrupted due to the presence of deep white matter lesions and the fact that cholinergic deficits contribute to cognitive impairments in a disease model of MS [332]. Although some trials pointed toward a possible benefit with donepezil, a larger more recent trial provided class I evidence for lack of effect [333]. Similarly, benefit was not observed following treatment with rivastigmine [334]. A trial of memantine, a noncompetitive inhibitor of N-methyl-D-aspartic acid (NMDA) receptors, for cognitive impairment in MS was limited by the emergence of reversible dose-related deterioration in neurological disability [335]. A study using a lower dose of memantine was reasonably well tolerated but benefit was not observed [336]. A number of other agents have also been associated with negative outcomes in clinical trials for cognitive impairment in MS, including amantadine, pemoline [337], and gingko biloba [338]. Although a trial of L-amphetamine sulfate showed benefit in some tests of learning and memory, improvement was not seen in the primary outcome measures and the duration of the trial was very short, so further investigation is required before L-amphetamine sulfate can be recommended [339].

Although difficult to define precisely, fatigue is one of the most commonly reported symptoms in those with MS, and has been estimated to occur throughout the course of the illness in approximately 75% patients with significant impact upon quality of life and employment [340–343], although not upon the potential for benefit from rehabilitation [344]. The underlying mechanisms may be multifactorial with possibilities including primary mechanisms such as high circulating levels of inflammatory cytokines, endocrine changes, axonal loss, and abnormal patterns of cerebral activation, as well as secondary mechanisms including coexistent medical conditions, e.g., anemia, thyroid disorders or depression, sleep disorders [345, 346], and the effect of medications [347]. Once treatable comorbidities have been excluded, lifestyle measures which should be addressed include sleep hygiene, optimization of exercise regimens, and dietary review. Both physical interventions such as cooling [348] and/or cognitive behavioral therapy may be helpful but further research is required [349, 350]. Exposure to a magnetic field showed benefit in a pilot trial [351], but a recent randomized, placebo-controlled crossover study was associated with a negative outcome [352].

A reduction in fatigue in patients on disease-modifying drugs has been reported [353, 354] and a cross-sectional case-controlled study suggested that the effect may be most marked with natalizumab [355]. Definitive conclusions regarding the benefits of disease-modifying treatment on fatigue are, however, awaited.

Specific pharmacological interventions for the treatment of fatigue may be considered, although there is little supportive evidence for their use. This reflects both the lack of highly efficacious medications and the difficulties encountered in accurately measuring fatigue. On the basis of positive outcomes in a number of RCTs, some guidelines have suggested that a trial of amantadine might be helpful [5, 356]. However, the effect size reported is small and the validity of the outcome measures has been questioned [357–359]. Benefit was reported in a small randomized, placebo-controlled trial of modafinil [360], but the primary outcome measure was not met in a more recent, larger double-blind, placebo-controlled RCT [361]. The effect of the CNS stimulant pemoline on MS-related fatigue has been examined in double-blind, randomized, crossover [362], and parallel-arm [363] studies, but a lack of effect was observed. Furthermore, liver toxicity has been reported and it has not been widely used. Aminopyridines have been associated with improvements in fatigue in some, but not all, trials [364–367] and concerns about their safety persist, notwithstanding the recent licensing of fampridine for the symptomatic treatment of walking difficulties due to MS [368]. The effects of carnitine on MS-related fatigue have been examined in a number of studies, but only one of these met the criteria for inclusion in a Cochrane review [369]. On the basis of this randomized, crossover study which compared carnitine with amantadine, there is insufficient evidence to support a recommendation [370]. The use of many complementary therapies has not been rigorously examined, although a single center, randomized, placebo-controlled trial of ginseng was not associated with benefit [371].

Sleep disorders occur with increased prevalence in MS patients [372, 373], although the precise relationship between such conditions and MS-related fatigue remains to be determined [346]. Examples of sleep disorders in MS include insomnia, circadian rhythm disorders, drug-induced sleep disorders, nocturnal movement disorders, respiratory disorders during sleep, narcolepsy, and REM sleep disorder. Treatment recommendations for MS patients are no different to those of the general population, given the current lack of disease-specific data.

Optic neuritis is a common ophthalmological problem in those with multiple sclerosis and is frequently the presenting clinical manifestation. Spontaneous improvement in visual acuity is anticipated and treatment with corticosteroids can be considered to accelerate this. Although any part of the visual pathway may be affected in MS, symptomatic retrochiasmal field defects are relatively unusual. Uveitis is approximately ten times more common in those with MS than in the normal population, yet the presence of ocular inflammation requires screening for other conditions, including syphilis, sarcoidosis, Lyme disease, tuberculosis, Behcet’s, and rheumatological disease [374, 375]. Eye movement disorders are a common problem for MS patients and this is unsurprising given the predilection for lesions to occur in the brainstem and cerebellum. Symptomatic treatments for oscillopsia include optical dampening using spectacles and contact lenses [376], as well as pharmacological options. Treatment is frequently unsatisfactory but there is some evidence to support a trial of memantine or gabapentin for pendular nystagmus [377]. A recent crossover trial included three patients with MS and showed little benefit of one drug over the other [378], and concerns have been raised regarding the association of memantine with worsening neurological symptoms in patients with MS and use of this drug will necessitate careful patient selection and dose ­titration [335]. Downbeat nystagmus may be suppressed by either 3, 4-diaminopyridine [379] or fampridine [380], although fampridine may have a greater effect at equivalent doses [381]. Clonazepam may be an alternative for the treatment of downbeat nystagmus, baclofen for periodic alternating nystagmus, and carbamazepine or acetazolamide for paroxysmal nystagmus [382]. Reports have emerged regarding the use of retrobulbar botulinum toxin A for the treatment of oscillopsia, but there is currently insufficient evidence to recommend it [383, 384]. Surgical intervention is undertaken only rarely but may be appropriate for a few, carefully selected patients [385].

Swallowing problems are common in patients with MS and should be specifically asked about as they may not always be reported by the patient [386]. Although frequently associated with brainstem and cerebellar dysfunction, there are a variety of reasons why this symptom should develop and careful assessment should be made to establish the nature of the problem which typically involves the oral and pharyngeal phases of swallow. This generally necessitates the involvement of a speech therapist. In addition to careful clinical assessment, video fluoroscopy will often be required [387] and electrophysiological studies may have a role in some patients [388]. Mild dysphagia may be managed simply by providing the patient and their carers with appropriate advice regarding attention to swallow, posture, and food consistency. With increasing severity, exercises to employ breath-holding, diaphragmatic breathing, and voluntary cough can be useful. Intermittent exacerbations may require temporary use of a nasogastric tube, although more persistent requirement for enteral feeding is best met by placement of a percutaneous gastrostomy (PEG). It should be noted, however, that citing a PEG to supply adequate caloric intake does not obviate the need to continue oral care and on-going speech and language therapy may still be required to try to preserve residual function [387]. Pharmacological therapies are not routinely available to treat dysphagia in MS. However, interest is increasing in the development of botulinum toxin A injection of cricopharyngeus to treat overactivity of the upper esophageal sphincter (either as a treatment in its own right or to identify those who might benefit from surgical myotomy [389]) and in the use of vagal nerve stimulation [390].

Communication may be impaired in patients with MS due to problems with speech production and articulation, as well as higher level cognitive impairment. The proportion of patients affected has been reported to vary between 23% and 51% [391–394], and the classical speech pattern is dysarthric (mixed spastic and ataxic), hypernasal speech. The evidence basis for intervention is weak and guidelines which encourage the early involvement of speech and language therapists have generally been established on the basis of consensus agreement between experts [5]. No pharmacological interventions are available but technological advances continue to increase the range of options available regarding communication aids [395].

Paroxysmal dysarthria resulting from brainstem dysfunction infrequently manifests as sudden onset, transient impairment of speech initiation and control which can occur very frequently throughout the day [396]. As with other paroxysmal symptoms, treatment with carbamazepine [396] or lamotrigine [397] may be helpful. Acetazolamide can be considered as an alternative, although is frequently poorly tolerated [398].

Disturbances of the autonomic nervous system may contribute greatly to urogenital and gastrointestinal symptoms as well sleep disturbances, and the symptomatic treatment of these problems has been discussed above. Orthostatic dysregulation may occur in up to 25% patients but is not an early manifestation of the disease [399]. Generally, the approach for treatment of orthostatic dysregulation in patients with MS is as per those in whom the symptoms are attributable to other conditions and include maintenance of an adequate fluid volume and sodium content, use of compression stockings, and medication to increase circulating fluid volume and vascular tone such as fludrocortisone or sympathomimetics. Thermoregulation may also be impaired in patients with MS and strategies to counter this include cooling prior to exercise (pre-cooling). Licensed medications for the treatment of heat sensitivity in MS are not available but there are anecdotal reports of 4-aminopyridines being helpful in this context which require further investigation [400].

Life expectancy may be extremely difficult to estimate even in advanced disease and, given that the terminal event is often an acute episode of sepsis, patients frequently die in hospital. However, there is increasing appreciation MS patients may have palliative care needs [401–403] which impact significantly upon both them and their caregivers. Systems to determine how these might be best met are now developing [404, 405], but there is recognition that these are likely to involve increased coordination between neurological, neurorehabilitative, and palliative care services [5, 406–408].

Some patients who retain capacity find it empowering to discuss life-prolonging measures in advance of their requirement, but if a legally binding advance directive is not in place, decisions need to be made on a “best interest” basis [409].