Significant advances have been made in recent years in terms of disease-modifying treatment of multiple sclerosis. A large number of new treatments are now available. These can prevent clinical relapses, new lesions on imaging, and evidence suggests, significant delay time to progressive disease.¹

However, treatments frequently only have a minimal effect on the broad range of existing symptoms affecting patients and have no role in progressive multiple sclerosis. As people with longstanding multiple sclerosis and significant disability have difficulty attending for outpatient appointments, they often turn to local health professionals for help in managing their symptoms. 

Fatigue, cognitive difficulties, pain, spasticity, bowel difficulty, urinary issues, sexual dysfunction, depression, anxiety, and mobility problems are all common in multiple sclerosis. Even people who are physically well can have hidden symptoms associated with the condition.²

Fatigue 

This one of the most common and invisible symptoms that affects MS patients, even those with minimal physical disability.³ Treatment can be challenging and often has a limited impact on the symptoms. Thorough evaluation of fatigue is a good place to start. In taking the history, establish if the patient is getting sufficient sleep overnight. MS patients often have nocturia, visiting the toilet multiple times each night with subsequent impact on sleep. Sleep may also be impacted by spasticity or pain. Again, these should be treated in the first instance. 

Comorbid conditions that are more frequent in MS such as thyroid dysfunction and sleep apnoea should be considered. Previous studies have established a strong relationship between depression and fatigue. Depending on the clinical situation, careful evaluation of mood and treatment if necessary may be appropriate.³

Fatigue management has a three-pronged approach: education, exercise and medication. In a recent review article, studies using exercise for fatigue management had the most positive outcome. Aquatics, climbing and resistance training were all highlighted.⁴ Education-based interventions including mindfulness and cognitive behaviour therapy (CBT) are also beneficial. 

Pharmacological intervention trials demonstrated the smallest effect size. Modafinil and amantadine are prescribed off-licence for MS patients, but the evidence is weak and inconclusive.⁵ Clinically, only a small proportion of patients have a significant improvement in fatigue with these medications. Patients are counselled carefully regarding potential side-effects such as insomnia and aggravation of mood symptoms. A trial of medication may be warranted, but a plan for discontinuation should be made if no benefit is demonstrated. 

Cognitive impairment

Cognitive impairment is a common manifestation of MS in adults. The most frequent deficits may include problems with attention, word recall, speed of processing information, short-term memory and executive functioning. The degree of cognitive decline correlates to the severity of cerebral pathology and lesion load on MRI. Brain atrophy of the corpus callosum and thalamus is also associated with impairment.⁶

Brief assessment tools such as the Montreal Cognitive Assessment (MOCA) and Mini-Mental State Examination (MMSE) can be useful to ascertain the degree of dysfunction and monitor/measure the rate of decline. Referral to a clinical neuropsychologist to assess cognition and mood, and to help the patient make sense of what they may be experiencing is important. 

It will also help pinpoint any areas of difficulty and provide support, strategies, and techniques to help the patient to live well with any cognitive difficulties they may be experiencing. Depression is known to have a negative effect on cognition particularly memory, attention, and concentration.⁶

Pain 

Pain associated with MS can stem from neurogenic and non-neurogenic sources. Neurogenic pain includes paroxysmal pain, persistent pain, and intermittent neuropathic pain (eg. burning or ice-cold dysesthesias of the feet, hands, limbs, and trunk). Musculoskeletal and soft tissue pain may be caused by paralysis, immobility or spasticity.⁷

Paroxysmal pain of motor and sensory nature can occur with MS. These symptoms are characterised by brief, frequent events, often triggered by movement or sensory stimuli. They are likely caused by ephaptic transmission of nerve impulses at the sites of previous disease activity. This is not considered an exacerbation of MS.⁷

Trigeminal neuralgia is a sudden onset of pain of the fifth cranial nerve. Typically, this is a unilateral, transitory, severe, or stabbing type of pain. These episodes usually respond to low doses of carbamazepine and often stop within weeks to months.⁷

Lhermitte’s sign is a transient sensory symptom, described as an electric shock radiating down the spine on flexion of the neck. Often it will resolve spontaneously but can be managed with gabapentin or pregabalin effectively.⁷

‘MS hug’ or anaconda sign may be attributed to neuropathic pain or spasticity of the thoracic and abdominal muscles. It is described as a gripping, tightening pressure around the torso and can be painful. If neuropathic in nature it may be treated with gabapentin, pregabalin or amitriptyline; if spasticity- related it can be effectively treated with baclofen, tizanidine and gabapentin.

Spasticity 

Spasticity results from damage to the upper motor neurones of the corticospinal tracts and affects about 34% of patients.^8,9 It is characterised by increased muscle tone and weakness, pain, and sudden involuntary movements (spasms). If severe, contractures can occur. Spasticity can worsen in the context of illness, such as urinary tract infections. 

Optimum management requires a multidisciplinary team, including nurse, physiotherapist, neurologist, and rehabilitation consultant. This involves a combination of non-pharmacological and pharmacological approaches. Mild spasticity can be managed with physiotherapy initially and use of a single medication. 

A recent review of this field evaluated the medication treatment options. Centrally-acting medications such as baclofen, a GABA analogue, and tizanidine, a short-acting muscle relaxant, are good first-line options. Tizanidine is more commonly associated however with elevated hepatic transaminases. 

Doses should be commenced at low levels and titrated slowly, to a maximum of 100mg of baclofen and 36mg of tizanidine. Much lower doses are often therapeutic at an early stage. Side-effects include drowsiness, weakness, and dry mouth. Gabapentin can be considered as a second-line medication. However, it is often required at higher doses of 2,700-3,600mg daily to have a therapeutic effect. 

Nabiximols is an oromucosal spray of cannabis extract containing THC and CBD. However, it is not currently available in Ireland. Therapy usually involves a titration period leading up to maximum of 12 sprays per day dosing. There is class 1 evidence on its efficacy, particularly as an add-on therapy.¹⁰ However, only about 50% of people are responders to the medication so close monitoring is required in the initial treatment period. Side-effects include dizziness and worsening cognitive function. 

If spasticity is isolated to a single limb, referral for botulinum toxin injection can be beneficial.¹¹ For patients with more severe symptoms of generalised spasticity, who are not responding to increased dosing of anti-spasmodic medication, the intrathecal baclofen pump can be considered. This allows much higher concentrations in the spinal fluid while minimising potential side-effects. 

Prior to implantation, the patient requires admission for assessment of the effects of baclofen through an intrathecal catheter. Studies have shown efficacy, but careful patient selection is key, given the potential for surgical morbidity and pump-related complications. 

Neurogenic bowel dysfunction 

This may result from both upper and lower motor neuron impairment. Common problems include constipation, poor evacuation, and incontinence. There are several interventions for constipation, including dietary changes, exercise, increase in fluid and fibre intake and laxatives. 

Bulking agents are recommended as first-line treatment because they increase intestinal motility without causing incontinence (Fybogel/Ispaghula husk). Osmotic agents increase stool hydration and frequency (Lactulose). Stimulant laxatives increase intestinal motility and secretions (senna).⁷

Due to the sensitive nature of bowel dysfunction it can be extremely embarrassing for patients, especially if they have incontinence or excessive flatulence. Referral to physiotherapy for a pelvic floor exercise programme or to gastroenterology, as they treat conditions of the GI tract including the bowel, may be required.

Urinary dysfunction

Up to two-thirds of MS patients will experience moderate to severe urinary dysfunction over the course of the disease.¹² Symptoms are rarely present at diagnosis but approximately 50% are affected at 18 years. The most common symptoms are suggestive of lower urinary tract dysfunction and include urgency, frequency, incontinence, hesitancy and retention.¹³ Upper urinary tract dysfunction is uncommon in MS.

Cortical lesions of the medial prefrontal cortex, insula and pons can impact on urinary tract regulation and result in detrusor overactivity. Spinal cord lesions can also have a similar impact as they can cause damage to the descending inhibitory tracts. 

Urinary symptoms have a significant impact on quality of life and can result in severe fatigue and social isolation. Comorbidities such as stress incontinence from pelvic floor dysfunction related to childbirth, and benign prostatic hypertrophy can aggravate existing symptoms. Studies have suggested that they are undertreated, partly due to a lack of knowledge of the most effective medications 

In making clinical decisions, treatment should be chosen according to patient mobility, disease phase, manual dexterity, social support, comorbidities and symptoms.¹³ The focus should be on improving quality of life by reducing incontinence, improving bladder emptying and avoiding urinary tract infections. Assessment of post-void residual at least, and full urodynamics testing is generally advised prior to proceeding to pharmacotherapy. 

Anticholinergics are a commonly used first-line medication for detrusor overactivity in multiple sclerosis. Oxybutynin, solifenacin, trospium and tolterodine have all shown positive results in clinical trials. However, anticholinergics can be problematic with potential aggravation of cognitive impairment and drowsiness. Mirabegron is also commonly prescribed, with a less marked side-effect profile. 

Alpha blockers may be considered for patients with detrusor underactivity, but the evidence in multiple sclerosis patients is sparse. No pharmacological agents selectively relax the external urinary sphincter. 

Botulinum toxin treatment, in particular intradetrusor injection, is considered to be the most effective treatment to reduce neurogenic detrusor overactivity. Again data is sparse, and repeat injections every few months will be required. One study has suggested increased need for intermittent catheterisation in this treatment cohort. 

Intermittent catheterisation (IC) is the preferred management strategy for patients with detrusor overactivity and voiding difficulties. However, it is often not a favoured initial choice of patients. Its use in patients with progressive MS has to be carefully considered given the manual dexterity required. 

Discreet, easy to use catheters, particularly for women, allow for better integration of IC into the daily life of MS patients. Judgement on the timing to initiate IC should involve patient preference as well as PVR, recurrent UTIs, and continence. Suprapubic catheterisation is a treatment option, particularly for patients with advanced disease. This is preferable to long-term indwelling urinary catheters due to the reduced risk of potential complications. 

While clearly some of the above treatments can be initiated locally, often specialist evaluation by the urology service and input from urology specialist nursing is required. Access, particularly in the public system, can be challenging and early referral is advised. 

Sexual dysfunction

Sexual dysfunction in MS is common and undertreated. Sexual dysfunction is defined as being unable to participate in or desire a sexual relationship. It impacts between 30-70% of both men and women with multiple sclerosis.¹⁴ It is also a multifactorial problem, and can be due to a combination of direct physical impact of multiple sclerosis on the brain and spinal cord, secondary to other physical symptoms such as spasticity or medication side-effects, or related to cultural ideology and psychosocial factors.¹⁵  Sexual dysfunction is underdiagnosed. Aside from specialist centres it is often not routinely discussed at clinic visits, either by the patient or the physician.

Primary sexual dysfunction is due to direct damage of multiple sclerosis on the brain and spinal cord. Symptoms affecting women include delayed orgasm, difficulty achieving orgasm, genital hypersensitivity, reduced sensation and loss of libido. Men describe erectile dysfunction but also commonly delayed ejaculation. Reduced libido is also common in men with multiple sclerosis. 

Secondary sexual dysfunction occurs as a result of other MS problems such as cognitive dysfunction, bladder dysfunction, spasticity, motor weakness and fatigue. Centrally acting medications such as SSRIs, tricyclic antidepressants and baclofen can all reduce libido. 

Tertiary sexual dysfunction is a biopsychosocial phenomenon. Disability can result in increased dependence on others, changing the roles in a relationship and reducing privacy. Both patients and partners may lack the language to discuss the changing nature of the sexual relationship resulting in withdrawal.

Treatment starts with careful evaluation of the nature of the difficulty as outlined above. Depending on the issue, treatment may begin with the GP, urologist, urology specialist nurse, MS nurse specialist, physiotherapist, gynaecologist, sexual health therapist, occupational therapist with an interest in sexual function and disability or CNS in sexual function and disability. 

Pharmacological and device-related treatment options are frequently effective. For women, pelvic floor muscle training and water based lubricants have been demonstrated to improve arousal and satisfaction. Alternatives to intercourse can also be explored. 

Advice around bladder function and spasticity management in the context of sexual function – improving bladder function, suggesting alternative positions and reducing medications if necessary can all result in increased sexual functioning. The MS Society and MS Trust UK are patient organisations that offer advice on sexual functioning specific to men and women, and provide workshops, lectures and online resources in this area

With the advent of novel and highly effective therapies, the consultation in MS clinics frequently focuses on disease activity, MRI, disease-modifying treatment choice and side-effects and the increased monitoring that is required. This allows little time for discussion of issues that may be having a more direct impact on the daily life of the MS patient. 

Symptomatic intervention by any practitioner involved in the patient’s care can result in improved quality of life at every stage of the disease. Multidisciplinary involvement, rehabilitation and pharmacological approaches offer the best opportunity for improved outcomes. 

References

1. Giovannoni G, Turner B, Gnanapavan S, Offiah C, Schmierer K, Marta M. Is it time to target no evident disease activity (NEDA) in multiple sclerosis? Mult Scler Relat Disord 2015;4:329-333
2. Barin L, Salmen A, Disanto G, et al. The disease burden of Multiple Sclerosis from the individual and population perspective: Which symptoms matter most? Multiple Sclerosis and Related Disorders 2018;25:112-121
3. Ayache SS, Chalah MA. Fatigue in multiple sclerosis – Insights into evaluation and management. Neurophysiologie Clinique / Clinical Neurophysiology 2017;47:139-171
4. Asano M, Finlayson ML. Meta-analysis of three different types of fatigue management interventions for people with multiple sclerosis: exercise, education, and medication. Multiple sclerosis international 2014;2014:798285-798212
5. Miller P, Soundy A. The pharmacological and non-pharmacological interventions for the management of fatigue related multiple sclerosis. Journal of the Neurological Sciences 2017;381:41-54
6. Olek M, Narayan R, Frohman E, Frohman T. Manifestations of multiple sclerosis in adults. UpToDate 2020, Dashe, J
7. Olek M, Narayan R, Frohman E, Frohman T. Symptom management of multiple sclerosis in adults. UpToDate 2020, Dashe, J
8. Otero-Romero S, Sastre-Garriga J, Comi G, et al. Pharmacological management of spasticity in multiple sclerosis: Systematic review and consensus paper. Multiple Sclerosis Journal. London, England: SAGE Publications, 2016: 1386-1396
9. Pozzilli C. Overview of MS Spasticity. European Neurology 2014;71:1
10. Giacoppo S, Bramanti P, Mazzon E. Sativex in the management of multiple sclerosis-related spasticity: An overview of the last decade of clinical evaluation. Multiple Sclerosis and Related Disorders 2017;17:22-31
11. Bensmail D, Josseran L, Baptiste C, Karam P. Medical management of spasticity using botulinum toxin in France: Etiologies and evolution of practices. Annals of Physical and Rehabilitation Medicine 2017;60:e23-e23
12. Aharony SM, Lam O, Corcos J. Evaluation of lower urinary tract symptoms in multiple sclerosis patients: Review of the literature and current guidelines. Journal of the Canadian Urological Association 2017;11:61-64
13. Aharony SM, Lam O, Corcos J. Treatment of lower urinary tract symptoms in multiple sclerosis patients: Review of the literature and current guidelines. Journal of the Canadian Urological Association 2017;11:E110-E115.
14. Delaney KE, Donovan J. Multiple sclerosis and sexual dysfunction: A need for further education and interdisciplinary care. NeuroRehabilitation 2017;41:317-329
15. Young CA, Tennant A. Sexual functioning in multiple sclerosis: Relationships with depression, fatigue and physical function. Multiple Sclerosis Journal 2017;23:1268-1275

Useful websites:

https://www.mstrust.org.uk

https://www.ms-society.ie