Fatigue, one of the hallmark symptoms of MS, has been defined as a feeling of physical and emotional tiredness and lack of energy [4]. Mechanisms of MS fatigue are not completely understood but are likely related to central nervous system (CNS) inflammation and the burden of lesions affecting nerve signals along the thalamus, basal ganglia, and frontal cortex. Studies have been unable to demonstrate an association between MS-related fatigue and the level of disability, clinical disease subtype, or gender, although recent data show an association between MS-related fatigue, depression, and QoL [5].

The management of fatigue includes non-pharmacological and pharmacological modalities. Occupational therapy offers energy conservation techniques by teaching patients how to pace and prioritize activities. Physical therapy and a regular exercise plan including daily activities may boost energy. Sleep hygiene and preventing sleep disruption have a profound effect on energy level and fatigue. Pharmacological interventions include medications to increase energy level. These consist of amantadine, selective serotonin reuptake inhibitors (SSRIs), modafinil, armodafinil and, less commonly, the cautious use of stimulants such as methylphenidate or amphetamine preparations.

Sensory symptoms and pain are very common in MS. These encompass numbness, pins-and-needles sensations, itching, burning, electrical and vibrating manifestations as well as a variety of other sensory perceptions experienced by patients with MS. These sensory deficits may be intermittent, repetitive paroxysmal or persistent episodes. Often, patients will experience positive sensations such as paresthesias and increased sensitivity rather than negative symptoms such as diminished sensation.

Pain in MS may be acute or chronic. It may be a primary symptom related to signal aberrations or a secondary symptom related to posture changes resulting in joint disease or lumbosacral spine abnormalities. Pain also may be experienced as a tertiary or quaternary symptom related to the overall impact of the illness or to unnecessary treatment. Acute pain in MS may result from Lhermitte’s phenomenon (acute electrical sensation radiating down the torso or extremities when the neck is flexed in a patient with a cervical spine lesion), trigeminal neuralgia (severe acute unilateral facial pain associated with brain stem lesion), or optic neuritis (unilateral inflammation around the optic nerve). Chronic pain usually includes unpleasant (dysesthetic) tingling sensations and secondary symptoms, such as back pain.

Neuropathic pain management consists mainly of the use of anticonvulsant medications. Gabapentin, pregabalin, and carbamazepine are considered first-line treatments for neuropathic pain because of their efficacy and relatively benign side effect profile. Additionally, tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), such as duloxetine HCL, and cannabinoids may be used for neuropathic pain management [6]. Opiates are not recommended because of their addictive properties, and their effects on cognitive function and bowel function. Often, a referral to a pain specialist is recommended for patients with severe and chronic pain.

Motor symptoms include weakness, difficulty with fine and gross motor functions, and stiffness or spasticity. Static and dynamic balance issues include incoordination, ataxia, and difficulty performing activities of daily living (ADLs), such as showering, bathing, toileting, grooming, and others. Upper-extremity weakness leads to functional deficits and the inability to perform basic ADLs. Lower-extremity weakness is common in MS, leading to difficulty ambulating independently and safely. Falls are a major risk in patients with mobility deficits [7]. Many neurological deficits, such as spasticity, weakness, fatigue, sensory loss, visual loss, vestibular symptoms (i.e., vertigo and imbalance), ataxia, and incoordination contribute to gait and mobility issues in MS.

The main therapy for patients with these symptoms is rehabilitation. Referral to a physiatrist, physical therapist, and/or an occupational therapist is warranted. The physiatrist assesses the patient and then makes referrals to appropriate rehabilitation professionals (e.g., physical or occupational therapist). Physical therapy focuses on gait and balance training and orthotic fitting as needed, such as ankle-foot-orthosis (AFO) or an electrical stimulation device. Often, patients will require assistive devices such as a cane, crutches, or a walker. Occupational therapy promotes strengthening of upper extremities for ADLs, such as showering or transferring to the toilet. Physical or occupational therapy may also be used in conjunction with other therapies to promote independence and preserve daily functioning. The goal of rehabilitation is to improve flexibility and endurance, and to evaluate the need for assistive devices and durable equipment to promote proper posture, range of motion and safety while performing ADLs.

The only available pharmacological treatment for walking difficulty in MS is dalfampridine, an oral medication taken every 12 h, which is appropriate for patients who do not have a history of seizures or renal disease [8]. Dalfampridine works as a potassium channel blocker that enhances conduction in injured nerve fibers [9]. Two randomized placebo-control trials have been conducted in patients with MS. The primary measure of efficacy in the studies was walking speed as measured by the Timed 25-Foot Walk (T25FW), using a responder analysis. A significantly greater proportion of patients taking dalfampridine were responders in both trials compared to patients taking placebo: 34.8 % vs. 8.3 % in the first trial, and 42.9 % vs. 9.3 % in the second [7, 9]. Furthermore, patients with an expanded disability status scale (EDSS) (Fig. 6.4) score higher than 6.0, exhibiting spasticity, muscle weakness, and severe walking impairment including spastic paretic gait, are as likely to benefit from prolonged-release fampridine as patients with less disability, with 31–32 % of fampridine-treated patients responding, compared to 12–15 % of placebo-treated patients [10]. Common side effects with this medication include dizziness, nervousness, and nausea. More serious adverse events include urinary tract infections and seizures in some patients taking more than the recommended dose [10–13]. Gait issues in MS need to be identified, assessed, and managed early, using a multimodal approach that views gait from several vintage points [14].

Spasticity in MS is a velocity-dependent increase in muscle reflexes as a result of damage to descending motor pathways that leads to increased tone and rigidity [15]. Spasticity afflicts approximately 75 % of patients with MS [2] and is a major cause of spasms, pain, gait abnormality, and postural changes. One-third of patients with MS modify their daily activities as a result of spasticity [16]. Spasticity treatment can significantly affect QoL by reducing spasms, pain, and fatigue. This includes physical therapy, stretching exercises, oral medications, injections, and/or use of an intrathecal baclofen pump.

First-line therapies for spasticity in clinical practice include baclofen and tizanidine [6]. The rule of thumb, as with all medications, is to start a new medication at a low dose and increase it as tolerated. Often patients benefit from frequent dosing throughout the day [15]. Frequently, the anti-spasticity oral medications can lead to sedation and weakness, requiring clinicians to consider other medications. For patients with severe spasticity, the baclofen pump can provide the medication intrathecally (directly into the spinal subarachnoid space), delivering it continuously in small doses. The use of these intrathecal pumps can increase the therapeutic benefits with fewer and less severe side effects than oral anti-spasticity medications. Other oral medications include gabapentin and benzodiazepines (e.g., diazepam and clonazepam), which are considered to be second- and third-line therapies.

Other treatments for spasticity include botulinum toxin and cannabinoids. Botulinum toxin is injected into an affected muscle group to promote stretching and muscle relaxation. It may improve positioning and mobility, and alleviate pain [17]. Randomized, placebo-controlled trials of oral cannabinoid therapy detected no improvement for MS-related spasticity as measured by the Ashworth scale [18]. However, patients reported subjective benefit, raising questions about the sensitivity and validity of current instruments for measuring objective outcomes [18]. Further research is warranted to show the benefits of cannabinoids in MS. In addition, surgical procedures (e.g., selective dorsal rhizotomy) may be considered when all other anti-spasticity treatments have failed to alleviate spasticity or to prevent complications, such as contractures.

Balance, ataxia, and incoordination issues are common in patients with MS who have posterior fossa lesions. Balance and ataxia management include rehabilitation techniques and medications. Antiepileptics, beta-blockers, and benzodiazepines have been used, but with minimal effect.

Visual symptoms occurring in MS include loss of vision, blurred vision, color desaturation and, more rarely, visual field cuts. Posterior fossa lesions cause visual changes including diplopia, nystagmus, and internuclear ophthalmoplegia. Visual spatial rehabilitation and devices such as eye patches or prism glasses may improve vision.

Medical treatment for acute vision changes may include intravenous steroids, as found in the optic neuritis treatment trial (ONTT) [19]. Intravenous steroids provide a quicker recovery of vision than oral steroids, but after 1 month, there was no significant difference between intravenous and oral steroids in visual acuity, visual fields, color vision, or contrast sensitivity [19]. Similar findings have been reported in other studies. Therefore, some clinicians will use oral steroids, especially in patients with poor intravenous access. Furthermore, in clinical practice, some providers will use subcutaneous or intramuscular ACTH if corticosteroids are contraindicated or known to be inefficacious, or if patients have poor intravenous access. Chronic vision changes are treated with medications, such as gabapentin for nystagmus or others.

Bladder issues are present in 70–80 % of patients with MS [20]. Urinary dysfunction may be classified into three types: