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Symptom management of multiple sclerosis in adults

Symptom management of multiple sclerosis in adults
Literature review current through: Jan 2024.
This topic last updated: Oct 05, 2023.

INTRODUCTION — Multiple sclerosis (MS) is an immune-mediated, inflammatory, neurodegenerative disease of the central nervous system that is a leading cause of disability in young adults.

A range of symptomatic problems can occur in patients with MS. Cognitive dysfunction, depression, fatigue, and gait impairment are increasingly common with disease progression. Spasticity, tremor, seizures, sphincter dysfunction, and sexual dysfunction may also complicate disease progression.

Management of the comorbid problems associated with MS will be reviewed here. Other aspects of MS management are discussed separately. (See "Treatment of acute exacerbations of multiple sclerosis in adults" and "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults" and "Treatment of secondary progressive multiple sclerosis in adults".)

BLADDER DYSFUNCTION — Common symptoms of bladder dysfunction in patients with MS include urinary frequency, urgency, and nocturia. Urinary tract infections are also common in MS, particularly in women, and may increase the extent of bladder dysfunction [1]. (See "Manifestations of multiple sclerosis in adults", section on 'Bowel and bladder dysfunction'.)

Our approach in evaluating a patient with urinary symptoms involves the following steps:

Categorize the type of bladder dysfunction based upon the history (see "Manifestations of multiple sclerosis in adults", section on 'Bowel and bladder dysfunction'):

Failure of the bladder to store urine (eg, from detrusor overactivity) with symptoms such as urinary urgency, frequency, and urge incontinence

Failure of the bladder to empty (eg, from detrusor sphincter dyssynergia, inefficient bladder contractility, or bladder hypoactivity) with symptoms such as urinary retention, interrupted micturition, and increased frequency

Combinations of the above

Other causes of urinary urgency and incontinence (see "Female urinary incontinence: Evaluation")

Physical examination of the urinary system to rule out any obvious confounding local disease processes (eg, prostate hypertrophy, urethral strictures).

Urinalysis with culture and sensitivity.

Measurement of postvoid residual (PVR) urine volume; patients with high PVR (typically >100 mL) are at risk of recurrent infections, calculi, and hydronephrosis.

Urodynamic studies in selected patients in order to plan management of refractory symptoms or to identify patients at risk of future complications, particularly upper urinary tract problems.

Subjective complaints of bladder dysfunction in a case series of 297 patients with MS did not correlate with one objective measure (PVR), prompting the authors to recommend ultrasound scanning of residual volume in all patients with MS, even in the absence of subjective urinary symptoms [2]. A more restrained approach favored by other experts is to measure PVR volume in symptomatic patients prior to initiating anticholinergic therapy [3].

The management of neurogenic bladder dysfunction in patients with MS has several goals, including [4]:

Preserving renal function

Attaining social continence

Minimizing urinary tract complications

Treatment of bladder dysfunction in patients with MS involves suppressing urgency and ensuring effective urinary drainage. Initial therapy for sphincter dysfunction is adjustment of fluid intake (eg, restriction of fluids to ≤2 L a day) and regimented bathroom stops (ie, timed voiding).

For patients with the failure to store type of bladder dysfunction (eg, detrusor overactivity), anticholinergic and antimuscarinic drugs remain the primary medical treatment [5]. Oxybutynin is a first-line medication for bladder dysfunction. Dosing is 2.5 to 5 mg, one to three times per day. There is an extended-release preparation as well as a transdermal preparation (oxybutynin 3.9 mg patch twice weekly), which may have the advantage of improved compliance. Oxybutynin decreases bladder emptying and consequently increases PVR; hence, it is important to check the PVR before starting this treatment, and then again subsequently after the first few weeks of continuous therapy. Other anticholinergic drugs include tolterodine, propantheline, propiverine, fesoterodine, and solifenacin. Since these drugs increase PVR, adjunctive treatment with clean intermittent catheterization may be helpful to achieve efficient bladder emptying and continence [4]. Dual therapy is effective and well-tolerated in some patients. This may involve using medications with different mechanisms of action, such as anticholinergic agents, cholinergic agonists, alpha-adrenergic blocking agents, tricyclic antidepressants, or sympathomimetic agents. In other cases, it may involve using two agents with similar anticholinergic properties.

Adverse effects of anticholinergics include confusion; hence, they should be used with caution in older adults and those with preexisting cognitive difficulties [5]. For such patients, options include the use of antimuscarinics that do not cross the blood-brain barrier (eg, trospium chloride) or that selectively block the M3 muscarinic receptor (eg, darifenacin), which is not known to be involved in cognition. (See "Urgency urinary incontinence/overactive bladder (OAB) in females: Treatment", section on 'Medication prescribing details'.)

Botulinum toxin injection is a treatment option for patients with bladder dysfunction due to neurogenic detrusor overactivity who are refractory to or intolerant of anticholinergic/antimuscarinic therapy [6]. There is evidence from several randomized controlled trials of patients with MS or spinal cord injury that onabotulinumtoxinA injections (200 or 300 international units) into the detrusor muscle are more effective than placebo for the outcomes of reducing incontinence episodes and improving quality of life [7,8]. The most common side effects are urinary retention, often resulting in the need to initiate clean intermittent catheterization, and asymptomatic urinary tract infections. Patients selected for onabotulinumtoxinA injection should be willing and able to perform clean intermittent catheterization.

Detrusor overactivity that is unresponsive to botulinum toxin may benefit from sacral neuromodulation with electrical stimulation of the S3 nerve root as well as peripheral nerve stimulation of the dorsal penile or clitoral nerves and posterior tibial nerve. This treatment inhibits the micturition reflex [9,10].

For patients with failure to empty (eg, detrusor sphincter dyssynergia), alpha antagonist medications such as prazosin, terazosin, doxazosin, and tamsulosin may be beneficial [5]. Clean intermittent catheterization is an option for those with severely impaired emptying.

Nocturia can be effectively managed with oral or intranasal desmopressin [3,11]. Hyponatremia has been reported in about 5 percent of cases. An afternoon dose of a diuretic can lead to a reduction in nighttime frequency [12]. This may be particularly effective for patients with dependent edema. (See "Nocturia: Clinical presentation, evaluation, and management in adults".)

Patients with recurrent urinary tract infections should be investigated by ultrasound and cystoscopy to rule out any underlying predisposing abnormalities. If no cause is identified, it is reasonable to start a prophylactic course of low dose antibiotics [3]. (See "Recurrent simple cystitis in women".)

BOWEL DYSFUNCTION — Neurogenic bowel dysfunction in patients with MS may result from both upper and lower motor neuron impairment and can be divided into disorders of storage and elimination. Common problems include constipation, poor evacuation, and incontinence. (See "Manifestations of multiple sclerosis in adults", section on 'Bowel and bladder dysfunction'.)

In addition to neurogenic disorders related to MS, other causes of bowel dysfunction include decreased physical activity and mobility, which can impact bowel movement frequency, secondary medical conditions unrelated to MS, and adverse effects of medications used to treat MS-related spasticity, pain, or bladder dysfunction.

There are several interventions for constipation, including dietary changes to increase fluid and fiber intake, laxatives (table 1), and enemas [5,13]. (See "Management of chronic constipation in adults".)

Among the laxatives, we suggest bulking agents (table 1) as first-line treatments because they increase intestinal motility without causing incontinence. Common forms include psyllium, methylcellulose, calcium polycarbophil, wheat dextrin, and wheat bran; among them, we prefer wheat dextrin, which is virtually tasteless once adequately mixed in liquid.

Other laxatives can be used for patients who have a poor response to fiber or do not tolerate it. Osmotic agents (table 1) cause intestinal water secretion and thereby increase stool hydration and frequency. This class includes magnesium sulfate, magnesium citrate, polyethylene glycol, lactulose, sorbitol, and glycerin. Stimulant laxatives increase intestinal motility and secretions. Agents include bisacodyl, senna, cascara, and castor oil; senna is generally preferred over the other stimulant agents due to increased tolerability. Stool softeners include docusate sodium and docusate calcium. Docusate sodium 100 mg twice daily combined with a stimulant (eg, senna) can be effective for mild to moderate constipation. Prokinetic agents include lubiprostone and linaclotide. Bisacodyl or glycerin suppositories can be used for patients with dysphagia, nausea, or vomiting. Tap water and soapsuds enemas work quickly to soften stools and assist in expelling the contents of the rectum.

For patients with fecal incontinence, the initial management involves supportive care and medical therapy. Supportive measures including avoiding foods or activities known to provoke symptoms and addressing perianal skin hygiene. Medical therapy includes supplementing the diet with a bulking agent (eg, methylcellulose 1 to 2 tablespoons per day) to improve stool consistency, and use of the antidiarrheal agent loperamide to reduce fecal incontinence. (See "Fecal incontinence in adults: Management".)

Behavioral feedback may be effective for treatment of constipation or fecal incontinence in some patients with MS, especially if they are only mildly to moderately disabled. However, biofeedback is not indicated in patients with substantial loss of rectal sensation and/or the inability to contract the external anal sphincter. (See "Fecal incontinence in adults: Management", section on 'Biofeedback'.)

For refractory incontinence, additional evaluation with anorectal manometry and endorectal ultrasound/magnetic resonance imaging should be performed to detect functional and structural abnormalities causing fecal incontinence. Surgical intervention (such as colostomy or ileostomy) are an option in severe cases. Quality of life may improve with colostomy because bowel dysfunction can cause embarrassment, pain and discomfort, and augment spasticity. (See "Fecal incontinence in adults: Management", section on 'Refractory symptoms'.)

A separate issue involves bowel-related side effects of dimethyl fumarate, a disease-modifying treatment which may cause diarrhea, nausea, abdominal cramps, and borborygmi. Antimuscarinic agents like glycopyrrolate (1 to 2 mg twice a day) can help ameliorate these side effects in some patients.

COGNITIVE IMPAIRMENT — Frank dementia is an uncommon feature of MS, but some degree cognitive impairment is frequently present. The most frequent abnormalities are in attention, executive functioning, abstract conceptualization, short term memory, word recall, and speed of information processing. (See "Manifestations of multiple sclerosis in adults", section on 'Cognitive impairment'.)

In addition to the pharmacologic and nonpharmacologic options for cognitive impairment outlined below, we suggest evaluating for depression, abnormalities in sleep hygiene, pain syndromes, and fatigue for all patients with MS who develop cognitive impairment, since all of these problems may have some impact on the patient's experience of cognitive impairment and are amenable to treatment. In addition, the medication regimen should be scrutinized for drugs that are associated with sedative, hypnotic, or psychomotor-slowing side effects.

Pharmacologic treatment — There are no proven therapies for the treatment of cognitive impairment related to MS [14], although the effects of disease-modifying agents for MS and cholinesterase inhibitors have been examined to see if they would have a beneficial impact on cognitive function.

Although data are limited, some of the current disease modifying medications, including interferon beta-1a, interferon beta-1b, natalizumab, and fingolimod, may slow the progression of cognitive dysfunction in MS [15]. Randomized trials have established the efficacy of these drugs for reducing relapse rates and improving surrogate measures such as MRI parameters in patients with relapsing form of MS (see "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults"). However, these trials did not routinely evaluate cognition, and in the trials that did, the results were inconsistent [15]. Much of the evidence suggesting benefit for cognitive outcomes comes from studies with methodologic limitations such as a small sample size, open-label design, or lack of a control group. Therefore, the impact of these disease-modifying therapies on cognitive impairment in MS remains uncertain.

Cholinesterase inhibitors were initially developed as treatment for patients with Alzheimer disease, a condition associated with a cholinergic deficit in the cortex. There is no known cholinergic deficit associated with MS. Although one small trial suggested that donepezil was modestly beneficial for the treatment of cognitive decline in MS [16], later trials found no benefit for cholinesterase inhibitors compared with placebo [17,18].

Nonpharmacologic approaches — Nonpharmacologic approaches to the treatment of cognitive deficits in patients with MS consist primarily of support and improvement of coping strategies, particularly because the benefits of medication and rehabilitation are fairly limited. Thus, the most common strategies for managing cognitive difficulties associated with MS require the patient to compensate for these problems and to accommodate them when unable to compensate. A fair amount of assistance from family members, friends, coworkers, and caregivers is frequently needed to enable the patient to compensate and accommodate. As an example, patients often need assistance to maintain a clean and organized home environment.

There are a number of strategies that may be useful for managing specific types of cognitive problems.

The use of personal organizers, particularly those with alarms, can be helpful for patients who have difficulty with memory and organization. Written reminders, directions, and phone logs can serve the same purpose.

Pacing of activities to manage physical and cognitive fatigue can be quite helpful. For patients who wish to keep working outside the home, appropriate pacing can be crucial.

Accommodations such as telecommuting and job sharing that allow the person with MS adequate opportunities to rest can help keep patients productive in the work force.

Cognitive rehabilitation techniques are another approach [19,20], but data related to clinical application of these methods are limited. A systematic review and meta-analysis identified 20 studies of cognitive training or cognitive-behavioral interventions that included a total of 966 patients with MS [21]. Cognitive training was computer-assisted in some studies, and in others was combined with compensatory strategies including external aids such as calendars, diaries, notebooks, and lists, or internal aids such as visualization and semantic categorization. The overall quality was variable because of methodologic limitations, and there was marked heterogeneity of outcome measures. The following observations were reported [21]:

Cognitive training combined with other neuropsychologic rehabilitation methods did not lead to statistically significant improvement for most outcomes, including attention, information processing speed, immediate verbal memory, immediate visual memory, delayed memory, executive functions, verbal functions, depression, fatigue, anxiety, or quality of life.

Cognitive training did have a statistically significant benefit for three subcategories of cognitive performance: memory span, working memory, and immediate visual memory.

Despite mostly negative results from the meta-analyses of the pooled data, some evidence of benefit was noted in 18 of the 20 included studies when analyzed individually.

A subsequent randomized controlled trial of 86 patients with MS and new learning impairment found that behavioral intervention led to significant improvements in learning [22]. Further research into the application of cognitive rehabilitation techniques is clearly needed.

DEPRESSION — Depression is a common problem in patients with MS. (See "Manifestations of multiple sclerosis in adults", section on 'Depression'.)

In the general population, there is evidence that treatment of depression with both pharmacotherapy and psychotherapy is more effective than either of these treatments alone, as discussed elsewhere (see "Unipolar major depression in adults: Choosing initial treatment", section on 'Choosing a treatment regimen'). However, data are limited for the treatment of depression in patients with MS [23,24]. As an example, a systematic review published in 2011 identified only two small randomized trials of limited quality evaluating the pharmacologic treatment of depression in patients with MS [23]. (See "Unipolar major depression in adults: Choosing initial treatment" and "Unipolar minor depression in adults: Management".)

Several classes of antidepressants (table 2) are available to treat depression, and the efficacy of different antidepressants is generally comparable across and within classes. Choosing a drug is thus based upon other factors, including safety, side effect profile (table 3), comorbid conditions, concurrent medications and potential drug interactions, ease of use, patient preference, and cost.

Our approach in choosing an antidepressant medication for patients with MS, based upon clinical experience, is as follows:

For patients with concomitant pain (neuropathic pain, chronic pain syndromes) and fatigue, duloxetine is preferred.

For patients with anxiety symptoms, a selective serotonin reuptake inhibitor (SSRI) such as escitalopram, fluoxetine, or sertraline is preferred; our preference is escitalopram, given its rapid onset of action and limited required titration to achieve optimal mood stabilizing benefits.

For patients with fatigue, fluoxetine or bupropion are preferred agents.

For patients with sexual dysfunction, bupropion and duloxetine are preferred. If there is sexual dysfunction while on an SSRI, we suggest adding bupropion extended release 24-hour (XL) tablet (initially at 150 mg daily, increasing to 300 mg daily if necessary) or duloxetine without abruptly withdrawing the SSRI at first and later gradually tapering down or off of the SSRI.

For patients with urinary incontinence and nocturia, imipramine and desipramine are preferred.

For patients with excessive somnolence, venlafaxine and bupropion are preferred.

For patients lacking these symptoms, initial treatment with an SSRI is a reasonable option. (See "Unipolar major depression in adults: Choosing initial treatment".)

A small number of randomized control trials have compared the effects of exercise training versus a control condition on depressive symptoms in MS, with equivocal results [25,26]. Based upon clinical experience and limited evidence of efficacy, we suggest a combination of aerobic exercise, resistance training and (if possible) aquatic therapy for nonpharmacologic management of depression in patients with MS [26].

Identifying and effectively managing underlying psychiatric symptoms in patients with MS may improve quality of life, strengthen interpersonal relationships, and help to create conducive family and work environments [27].

FATIGUE — Fatigue is a characteristic finding in patients with MS. It is usually described as physical exhaustion that is unrelated to the amount of activity performed. (See "Manifestations of multiple sclerosis in adults", section on 'Fatigue'.)

Our approach to managing fatigue in MS is to first address factors that could mimic or exacerbate fatigue, such as depression (see 'Depression' above), anemia (eg, secondary to menometrorrhagia), sleep disturbance (see 'Sleep' below), and side effects of medications (eg, interferon beta preparations). The evaluation and management of anemia are described elsewhere. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults" and "Treatment of iron deficiency anemia in adults".)

In general, we prefer nonpharmacologic strategies to treat fatigue in MS, since the benefit of medications is unproven.

Nonpharmacologic interventions – Nonpharmacologic strategies to combat MS fatigue include sufficient physical activity and exercise, active cooling (eg, cooling vests, cooling pads, air conditioner hand-held remote control), energy conservation techniques, cognitive-behavioral therapy, and patient education.

A 2014 meta-analysis of interventions for MS-related fatigue identified 10 randomized trials of physical and exercise therapy, 8 randomized trials evaluating educational interventions such as cognitive behavioral therapy, patient education, and self-management programs, and 7 randomized trials evaluating pharmacologic agents (ie, amantadine and modafinil) [28]. There was a statistically significant positive effect for the experimental intervention in 3 of 10 trials evaluating exercise, 6 of 8 trials evaluating educational interventions, and only 1 of 7 trials evaluating medications.

Pharmacologic options – A number of oral medications can be tried if nonpharmacologic methods are ineffective. Some MS patients with debilitating fatigue may benefit from pharmacologic agents. However, data from randomized trials do not support the efficacy of medications for fatigue in MS, all of which can be associated with limiting side effects.

Modafinil (100 to 400 mg once daily in the morning) and armodafinil (50 to 250 mg once daily in the morning) are wakefulness-promoting agents used to treat narcolepsy, shift work sleep disorder, and obstructive sleep apnea.

Dextroamphetamine-amphetamine (5 to 40 mg once daily in the morning; maximum daily dose 60 mg given in one to three divided doses) is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and fatigue. An alternative is lisdexamfetamine (30 mg once daily in the morning, increasing in increments of 10 to 20 mg at weekly intervals, maximum daily dose 70 mg).

Methylphenidate, 5 to 10 mg daily in the morning, maximum daily dose 60 mg per day in two to three divided doses.

Selective serotonin reuptake inhibitors (SSRIs), in addition to treating the depressive symptoms associated with MS, have been used to treat fatigue. We suggest starting with fluoxetine 10 to 20 mg once or twice daily. A once weekly oral formulation of fluoxetine is also available.

Amantadine (100 mg twice a day) has relatively few side effects and is well tolerated by most patients [29]. Caution must be taken in patients with renal insufficiency or seizure disorders.

Any perceived benefit of these medications may be due to placebo effect [30,31]. This conclusion is supported by the results of a randomized trial that enrolled over 100 patients with MS and fatigue and compared oral amantadine, modafinil, and methylphenidate with placebo [31]. The trial used a four-sequence, four-period, crossover design so that patients would receive all four study treatments sequentially with a two-week washout period between six-week treatment periods. The primary outcome measure was the Modified Fatigue Impact Scale (MFIS), in which lower scores indicate less fatigue. On intention-to-treat analysis with data from 136 participants, the mean MFIS score at baseline was 51.3; the mean MFIS score at week 5 of each treatment period was similar for placebo (40.6), amantadine (41.3), modafinil (39.0), and methylphenidate (38.6). Thus, each active treatment led to a reduction in the MFIS score of approximately 10 points, as did placebo. The number of patients reporting adverse events was higher with the active medications — amantadine (39 percent), modafinil (40 percent), and methylphenidate (40 percent) — as compared with placebo (31 percent). Limitations to this study include a relatively high drop-out rate of 24 percent.

Earlier findings from a controlled trial with complete data for 19 patients [32] suggested that modafinil was beneficial for fatigue in MS. In contrast, a double-blind placebo-controlled trial of 115 patients with MS found that modafinil was not effective for fatigue on intention-to-treat analysis [33].

Note that the stimulant medications (dextroamphetamine-amphetamine, lisdexamfetamine, and methylphenidate) are regulated as schedule II controlled substances in the US (table 4) due to their potential for misuse, addiction, and diversion. They require monthly prescriptions, but this inconvenience is somewhat mitigated by the advent of certified electronic prescribing applications. (See "Prescription drug misuse: Epidemiology, prevention, identification, and management".)

Though seldom used for this indication, aspirin 1300 mg daily was modestly effective compared with placebo for treatment of fatigue in a small, randomized trial [34]. The benefit of aspirin requires confirmation in larger trials. In the experience of some experts, carnitine supplementation can improve fatigue in patients with MS, though sparse data from controlled trials suggest limited (if any) benefit [35,36]. Carnitine supplementation is started at 1000 mg per day in divided doses (eg, twice daily or every three to four hours throughout the day). The dose can be titrated up slowly (eg, by 500 mg increments weekly) to a maximum of 3000 mg per day in divided doses, based upon tolerance and therapeutic response.

GAIT IMPAIRMENT — Many patients with MS develop gait impairment, and some eventually require a cane or wheelchair. Gait impairment in MS can result from of a multitude of issues such as spasticity, weakness, fatigue, sensory loss, visual loss, and vestibular dysfunction. (See "Clinical presentation, course, and prognosis of multiple sclerosis in adults", section on 'Rate of worsening'.)

Leg weakness and spasticity can result from MS lesions in the descending motor tracts of the brain and spinal cord, and ambulatory imbalance can be caused by lesions involving the cerebellar pathways. (See "Manifestations of multiple sclerosis in adults", section on 'Motor symptoms' and "Manifestations of multiple sclerosis in adults", section on 'Incoordination'.)

The management of gait problems in MS consists mainly of physical therapy along with the use of mobility aids when they become necessary [37]. Mobility aids include ankle foot orthosis (AFO) to assist with dorsiflexion, canes, forearm crutches, walkers, wheelchairs, and scooters. Measures to treat spasticity and fatigue may also be helpful. (See 'Spasticity' below.)

Though untested in large randomized trials, there is evidence from preliminary studies that functional electrical stimulation devices can improve gait in select patients with foot drop [38,39]. These devices stimulate the peroneal nerve at the fibular head in conjunction with a programmable capability to transmit such signals to the tibialis anterior only upon the swing phase of walking. Nevertheless, these devices tend to be most effective when there is still adequate hip flexor strength and ankle dorsiflexion control during the swing phase of walking.

Dalfampridine — Dalfampridine (4-aminopyridine; fampridine), a potassium channel blocker, can improve walking in some patients with MS. The largest trial randomly assigned 301 ambulatory adults with any type of MS to either sustained-release oral dalfampridine (10 mg twice daily) or to placebo in a 3:1 ratio [40]. The primary outcome was responder status, with responders defined as patients who achieved faster walking speeds in at least three of four visits during the double-blind treatment period than their fastest speed during the off-treatment period.

The following observations were noted [40]:

At 14 weeks, the dalfampridine group had a significantly higher proportion of patients who met the responder criterion than the placebo group (35 versus 8 percent, odds ratio 4.75, 95% CI 2.08-10.86). In the subset of patients who were responders, the improvement in walking speed was considered clinically meaningful.

Two adverse events (anxiety and a focal seizure) were possibly or probably related to dalfampridine.

Similar results favoring benefit with dalfampridine were obtained in an unpublished 14-week randomized controlled trial with analogous design involving 239 ambulatory adults with MS [41] and in a subsequent published randomized controlled trial [42]. Nevertheless, it is unclear how the results of these trials apply to clinical practice, since the positive outcomes were determined by a responder analysis rather than by a direct comparison of dalfampridine versus placebo groups for change in walking speed [43,44]. Dalfampridine appears to help only a subset of patients with MS, leading to faster walking speed in approximately one-quarter, and enhanced walking ability in approximately one-third [45]. Improvements in the time to complete a 25-foot walk after a trial of dalfampridine may be useful in determining whether specific patients can benefit from chronic treatment [44].

Dalfampridine increases the risk of seizures so this drug should not be used in patients with a preexisting seizure disorder. Additionally this medication may trigger or exacerbate preexisting trigeminal neuralgia in patients with MS [46]. (See "Trigeminal neuralgia".)

HEAT INTOLERANCE — Transient worsening of clinical signs and symptoms as a result of elevated body temperature (Uhthoff phenomenon) is a common problem in patients with MS. (See "Manifestations of multiple sclerosis in adults", section on 'Heat sensitivity'.)

A small number of studies have reported potential benefits using cooling strategies that are convenient methods available to most patients with MS [5,47]. These include cold showers, applying ice packs, the use of regional cooling devices, and cold beverages. In a case report, treatment with 4-aminopyridine (dalfampridine) was associated with reduced sensitivity to visual impairment after exercise [48].

IMMUNIZATIONS — Supportive care for patients with MS includes the use of vaccinations against preventable diseases. Guidance is provided by a 2019 guideline from the American Academy of Neurology, which advocates for an approach that includes counseling patients, screening for infections, and appropriate use of vaccinations [49].

Counseling – Clinicians should review with patients the evidence pertaining to immunizations in MS, the risks of infections (eg, varicella-zoster virus, hepatitis B, tuberculosis) that are associated with specific immunomodulating disease-modifying therapies (DMTs) used to treat MS (eg, alemtuzumab, cladribine, dimethyl fumarate, fingolimod, natalizumab, ocrelizumab, rituximab, siponimod, teriflunomide), and the specific vaccination guidance provided by the prescribing information for individual DMTs [49].

Screen for infections – Patients should be screened and treated for latent infections (eg, tuberculosis, hepatitis B) as appropriate before starting treatment with an immune-modulating DMT [49].

Vaccinations – Considerations for patients with MS include the following points [49]:

Vaccinations for varicella-zoster virus and hepatitis B should be given as recommended at least four to six weeks before initiating immune-modulating DMT therapy.

All patients should receive the annual influenza vaccination and follow local immunization guidelines and standards in the absence of a specific contraindication.

For patients receiving immune-modulating DMTs, live-attenuated vaccines should be avoided.

For patients who are experiencing an MS relapse (ie, attack), vaccinations should be delayed until the relapse has resolved or is no longer progressive.

For patients starting B-cell depleting DMTs, vaccines should be given prior to commencing therapy.

COVID-19 vaccination – We advise coronavirus disease 2019 (COVID-19) vaccination as soon as practical for all patients with MS, in accordance with local availability and allocation priorities. (See "COVID-19: Vaccines".)

In instances when COVID-19 vaccination has to be given after DMT has been instituted, timing should be arranged for a cycle in the treatment when the immune response is likely to be maximal. The humoral response should also be tested afterwards through an assay for antibodies against the spike S protein.

Further guidance for patients with MS during the COVID-19 pandemic is provided separately. (See "Overview of disease-modifying therapies for multiple sclerosis", section on 'COVID-19 and DMTs'.)

PAIN — Pain is a common symptom in patients with MS. (See "Manifestations of multiple sclerosis in adults", section on 'Pain'.)

Several pain syndromes are associated with MS:

Trigeminal neuralgia is defined clinically by sudden, usually unilateral, severe, brief, stabbing or lancinating, recurrent episodes of pain in the distribution of one or more branches of the fifth cranial (trigeminal) nerve. The evaluation and management of trigeminal neuralgia is reviewed in detail separately. (See "Trigeminal neuralgia".)

The Lhermitte sign is a transient sensory sensation, usually lasting seconds, that resembles an electric shock radiating down the spine or into the limbs. It is most often elicited by flexion of the neck. (See "Manifestations of multiple sclerosis in adults", section on 'Lhermitte sign'.)

Lhermitte sign often resolves spontaneously without treatment [50]. In the authors' experience, glucocorticoid therapy may mitigate or abolish the pain if the Lhermitte episodes are a result of a new inflammatory spinal cord lesion (see "Treatment of acute exacerbations of multiple sclerosis in adults", section on 'Initial therapy with glucocorticoids'). Recurrent episodes of Lhermitte sign, including those unrelated to an acute spinal cord lesion, may respond to therapy with gabapentin, pregabalin, or carbamazepine. A small open label study in patients with MS reported that treatment with the sodium channel blockers lidocaine and mexiletine was associated with improvement of paroxysmal symptoms such as painful tonic spasms and Lhermitte sign [51].

The McArdle sign is characterized by stereotyped and reversible weakness induced by neck flexion in patients with MS who harbor cervical demyelinating lesions [52,53]. Limited data suggest it is specific to MS compared with other causes of cervical myelopathy [54].

The "MS hug" (also known as the "Anaconda sign") is a dysesthetic phenomenon that manifests with gripping, squeezing, constricting, or pressure-like sensations in the thoracic and abdominal regions. In some cases, there is a component of respiratory limitation or pain with breathing. The etiology is variably attributed to neuropathic pain from spinal cord involvement or to thoracic and abdominal spasticity.

For MS hug due to neuropathic pain, treatment options include amitriptyline, gabapentin, pregabalin, or topical compounded creams containing a neuropathic pain medication, a nonsteroidal anti-inflammatory drug (NSAID), and a local anesthetic. For MS hug resulting from spasticity, treatment options include baclofen, tizanidine, and gabapentin.

Persistent neuropathic pain develops in some patients with MS, perhaps intensified by central sensitization, whereby increased activity in nociceptive afferents due to peripheral noxious stimuli, tissue damage, or nerve injury leads to increased synaptic transmission at somatosensory neurons in the dorsal horn of the spinal cord (see "Evaluation of chronic non-cancer pain in adults"). Such patients may experience an increased frequency of paroxysmal pain attacks or develop various types of persistent pain syndromes, such as atypical facial pain, chronic tension-type headache, chronic migraine, plexus-related pain, and pelvic pain syndromes. The approach to the evaluation and treatment of these pain syndromes is similar to that in the general population. (See "Chronic daily headache: Associated syndromes, evaluation, and management" and "Chronic migraine" and "Chronic pelvic pain in adult females: Evaluation" and "Chronic pelvic pain in adult females: Treatment".)

PAROXYSMAL MOTOR AND SENSORY SYMPTOMS — Paroxysmal attacks of motor or sensory phenomena can occur with demyelinating lesions. Within the brainstem, lesions may cause paroxysmal diplopia, facial paresthesia, trigeminal neuralgia, ataxia, and dysarthria. Additional symptoms include, but are not limited to, pain, trunk and limb paresthesia, weakness, ataxia, pruritus, akinesia, and seizures. Motor system involvement may result in dystonia characterized by painful tonic contractions of muscles of one or two (homolateral) limbs, trunk, and occasionally the face; these only rarely occur in all four limbs or the trunk.

These paroxysmal attacks may respond to low doses of antiseizure medications such as carbamazepine and valproic acid and frequently remit after several weeks to months, usually without recurrence.

SEIZURES — Epilepsy is more common in patients with MS than in the general population, as reviewed elsewhere. (See "Manifestations of multiple sclerosis in adults", section on 'Epilepsy'.)

Seizures associated with MS are generally benign and transient and respond well to antiseizure medication therapy or require no therapy. As an example, in a study of 5715 patients with MS, 51 (0.89 percent) experienced seizure activity [55]. Generalized tonic-clonic seizures were most common (35 patients, 69 percent), followed by simple or complex partial seizures (11 patients, 22 percent). Of the 45 patients who received antiseizure medication therapy, 35 (78 percent) became seizure free, while 5 (11 percent) had intractable seizures.

SEXUAL DYSFUNCTION — Sexual dysfunction is common in patients with MS. (See "Manifestations of multiple sclerosis in adults", section on 'Sexual dysfunction'.)

Patients with MS and sexual dysfunction should be screened for depression. The selective serotonin reuptake inhibitor (SSRI) class of antidepressants frequently cause sexual dysfunction, including decreased libido, decreased arousal, anorgasmia in women, and increased ejaculation latency in men. As reviewed separately, bupropion and phosphodiesterase-5 inhibitors may reduce sexual dysfunction caused by SSRIs (see "Sexual dysfunction caused by selective serotonin reuptake inhibitors (SSRIs): Management"). When SSRI treatment leads to well-controlled depression complicated by sexual dysfunction, we will often add a daytime dose of bupropion to counteract this adverse effect.

General treatment recommendations applicable to both males and females with MS include adequately treating neuropathic or visceral pain and spasticity because both can impede sexual performance and cause fatigue. Also, energy-conserving positions are recommended. Assessment and treatment of neurogenic bladder or bowel dysfunction can be helpful [56].

The introduction of phosphodiesterase-5 inhibitors has revolutionized the treatment of erectile dysfunction in men. There is evidence from small double-blind, placebo-controlled trials that sildenafil is effective for men with MS [57,58], and there is strong evidence of efficacy for men in the general population, as reviewed elsewhere. (See "Treatment of male sexual dysfunction", section on 'Initial therapy: PDE5 inhibitors'.)

The evidence regarding phosphodiesterase-5 inhibitors for women with MS is limited. A randomized trial of 19 women with MS and sexual dysfunction found that sildenafil resulted in significant improvement in lubrication but not in quality of life, desire, or ability to achieve orgasm [59]. In the general population, phosphodiesterase-5 inhibitors generally have not proven successful in women. (See "Overview of sexual dysfunction in females: Management", section on 'Phosphodiesterase inhibitors'.)

Although supportive data are lacking, some authors of this topic have treated vaginal pain and dryness during sexual intercourse with a combination of belladonna and opium suppositories and a 12 percent formulation of gabapentin cream; this combination acts as a vaginal lubricant and analgesic. Symptoms of vaginal dryness also can be managed by regular use of vaginal moisturizing agents with supplemental use of water-soluble vaginal lubricants for sexual intercourse. (See "Genitourinary syndrome of menopause (vulvovaginal atrophy): Treatment", section on 'Initial therapy with moisturizers and lubricants'.)

Decreased sensation or difficulty to achieve orgasm can be aided with the use of vibrators and vacuum devices. In general, effective vibrator stimulation involves high-intensity, high-frequency, wall-powered devices that are applied to the region just above the clitoris in women and to the ventral aspect of the penile corona in men.

The treatment of male and female sexual dysfunction is discussed in greater detail separately. (See "Treatment of male sexual dysfunction" and "Overview of sexual dysfunction in females: Management".)

SLEEP — Common sleep disorders in patients with MS include insomnia, restless legs syndrome, and sleep-related breathing disorders. These are reviewed elsewhere. (See "Manifestations of multiple sclerosis in adults", section on 'Sleep disorders'.)

The diagnosis of restless legs syndrome should be considered for patients with MS patients who complain of insomnia and excessive daytime somnolence [60]. Restless legs syndrome is a clinical diagnosis that is made by history in patients who complain of an urge to move the legs when lying in bed or sitting down, particularly if the symptoms occur predominantly in the evening. The diagnosis does not require additional testing, except for an assessment of iron stores (ferritin being the most informative) in all patients and blood urea nitrogen and creatinine if uremia is suspected. Any potentially causative or exacerbating medications should be identified. (See "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults", section on 'Diagnosis'.)

Nocturia and pain can disrupt sleep, causing daytime somnolence and worsening fatigue as well as reducing pain threshold. The treatment of nocturia and pain are dealt in separate sections. (See 'Pain' above and 'Bladder dysfunction' above.)

The treatment of insomnia, restless legs syndrome, and sleep-related breathing disorders in patients with MS is otherwise similar to that in the general population. (See "Overview of the treatment of insomnia in adults" and "Management of restless legs syndrome and periodic limb movement disorder in adults" and "Central sleep apnea: Treatment" and "Obstructive sleep apnea: Overview of management in adults".)

SPASTICITY — Spasticity affects a majority of patients with MS and can cause functional disability by impairing ambulation, interfering with activities of daily living, and exacerbating fatigue, thereby increasing the burden of care. Tonic spasticity is characterized by resistance to movement that is rate dependent, while phasic spasticity manifests as involuntary jerks and spasms that principally affect the limbs and are more pronounced at night when attempting to sleep. (See "Manifestations of multiple sclerosis in adults", section on 'Spasticity'.)

The goal of spasticity treatment is to reduce muscle tone to the degree that function is improved, while not compromising safety by abolishing all muscle tone. Documentation of the degree of spasticity and the muscle groups involved should be quantified using the modified Ashworth scale (table 5), a subjective scoring system that ranges from grade 0, which indicates no increase in muscle tone, to grade 4, which indicates "lead pipe" rigidity.

Oral medications remain the first-line therapy for spasticity in patients with MS. A 2004 systematic review of oral agents concluded that baclofen, tizanidine, and dantrolene were effective compared with placebo, based on a level of evidence considered fair [61]. Baclofen and tizanidine were roughly equivalent in efficacy and had similar rates of adverse events; tizanidine was more often associated with dry mouth, while baclofen was more often associated with motor weakness. Dantrolene is not commonly used for treating MS spasticity due to its hepatotoxicity.

Additional options include intrathecal baclofen infusions administered through implantable pumps [62-64] and botulinum toxin injections. An evidence-based review updated in 2016 by the American Academy of Neurology (AAN) concluded that botulinum toxin is effective for reducing muscle tone and improving passive movement in adults with arm and leg spasticity [65].

Nonpharmacologic interventions for spasticity in MS include physiotherapy, structured exercise programs, transcranial magnetic stimulation, electromagnetic therapy, transcutaneous electrical nerve stimulation, and whole body vibration; none are proven effective, though the available evidence is limited and methodologically weak [66].

Given these data, we suggest baclofen, or tizanidine as initial therapy for spasticity in patients with MS. Among these choices, we prefer baclofen due to its favorable side effect profile and low cost, particularly for patients with predominant tonic spasticity. Baclofen should be initiated at low dose (generally 5 to 10 mg once daily, to twice or three times daily) and titrated slowly up to an effective dose [5]. Rapid titration and very high doses of more than 200 mg a day can be associated with confusion, coma, and seizures. Divided doses up to a total of 80 mg per day may be used, keeping in mind the possible side effects of drowsiness and hypotonicity. Patients should be warned to neither stop nor drastically reduce the dosage of baclofen abruptly. An alternate choice is tizanidine, which may be used alone or in combination with baclofen. Tizanidine is available in 2 mg and 4 mg tablets and may be used in daily divided doses up to 36 mg per day. Patients should be warned about sedation as well as pronounced weakness from excessive tone reduction.

Benzodiazepines (eg, clonazepam) can be used for patients with predominant phasic spasticity, especially when the symptoms are most prominent at night or at bedtime.

SPEECH, SWALLOW, AND RESPIRATORY FUNCTION — Brainstem-related symptoms like dysphagia, dysarthria and respiratory dysfunction (particularly poor cough and inability to clear secretions), may develop in patients with advanced MS [67,68]. These changes increase the likelihood aspiration, infection, respiratory failure, and demise. Patients who report bulbar symptoms should be assessed by a speech-language therapist to evaluate oromotor and swallowing function.

Some patients with dysphagia require a feeding tube. A nasogastric tube can be used for patients who require nutrition support for a short period of time (<30 days). For longer periods, a percutaneous endoscopic gastrostomy tube (PEG) provides a route for enteral feeding, hydration, and medication administration in patients who are likely to have prolonged inadequate or absent oral intake. (See "Gastrostomy tubes: Uses, patient selection, and efficacy in adults".)

Potential complications related to PEG placement include pneumoperitoneum, ileus, perforation of the esophagus or stomach, tube dysfunction, infection, bleeding, peristomal leakage, ulceration, gastric outlet obstruction, inadvertent gastrostomy tube removal, leakage of gastric contents or tube feeds into the peritoneal cavity, deterioration of the gastrostomy site, buried bumper syndrome, and colocutaneous fistula formation. (See "Gastrostomy tubes: Complications and their management".)

The degree of respiratory dysfunction can be evaluated by history and physical examination, pulmonary function tests, and sleep studies [68]. Preventive and supportive care includes routine vaccinations against influenza and streptococcal pneumonia [49]. (See "Seasonal influenza vaccination in adults" and "Pneumococcal vaccination in adults".).

Where needed, chest physiotherapy, cough assist devices, respiratory muscle training, and noninvasive ventilation can help to manage respiratory complications.

TREMOR — Tremor and cerebellar dysfunction in patients with MS can lead to functional disability (see "Manifestations of multiple sclerosis in adults", section on 'Incoordination'). Unfortunately, there is no useful pharmacotherapy for cerebellar tremor. The rare patient with severe intention tremor and little or no ataxia, such as sometimes occurs in MS, may be helped by deep brain stimulation of the ventral intermediate nucleus of the thalamus. (See "Overview of tremor", section on 'Treatment' and "Surgical treatment of essential tremor".)

VERTIGO — One of the most common causes of vertigo in MS patients is benign paroxysmal positional vertigo (BPPV), which is attributed to canalithiasis (calcium debris within a semicircular canal) and is therefore a coincidental condition in patients with MS. The clinical aspects and treatment of BPPV are reviewed separately. (See "Benign paroxysmal positional vertigo".)

Vertigo directly related to MS is attributed to demyelination or inflammation in the vestibular pathways, particularly when plaques occur in the cranial nerve VIII entry zone at the pontomedullary junction, and in the medullary tegmentum (a region containing the vestibular nuclear complex, the principal target for vestibular afferent inputs carried by cranial nerve VIII). There is no specific pharmacotherapy or other intervention for vertigo related to MS, but a variety of symptomatic treatments can be used to provide relief of acute vertigo. In addition, limited data suggest that vestibular rehabilitation (physical therapy) can be associated with symptomatic improvement, at least in the short-term. These issues are reviewed separately. (See "Treatment of vertigo", section on 'Symptomatic treatment' and "Treatment of vertigo", section on 'Vestibular rehabilitation'.)

VISUAL SYSTEM DISTURBANCES — Afferent visual disturbances including optic neuritis may be the presenting feature of MS and occur in a majority of patients at some point during the disease course. The manifestations and treatment of optic neuritis are discussed in detail elsewhere. (See "Manifestations of multiple sclerosis in adults", section on 'Visual symptoms' and "Optic neuritis: Pathophysiology, clinical features, and diagnosis" and "Optic neuritis: Prognosis and treatment".)

A host of efferent visual disturbances may be seen in MS, such as internuclear ophthalmoparesis, various types of nystagmus, and paroxysmal eye movements (eg, opsoclonus) (see "Manifestations of multiple sclerosis in adults", section on 'Eye movement abnormalities'). There is no proven effective treatment for most of these conditions, though dalfampridine may be beneficial for downbeat nystagmus (see "Jerk nystagmus", section on 'Downbeat nystagmus'). Many of the visual symptoms in MS worsen with heat exposure (ie, Uhthoff phenomenon), and, therefore, measures to prevent or counter elevations in body temperature should be taken. (See 'Heat intolerance' above.)

VITAMIN D — A number of studies have found an inverse relationship between sun exposure, ultraviolet radiation exposure, or serum vitamin D levels, and the risk or prevalence of MS. In addition, the same factors may be inversely related to MS disease activity. These issues are discussed separately.(See "Pathogenesis and epidemiology of multiple sclerosis", section on 'Sunlight and vitamin D'.)

In small, underpowered randomized trials, vitamin D supplementation had no benefit for reducing brain lesions on MRI or other measures of disability or disease progression in patients with MS [69,70]. Nevertheless, some authors (EF) promote monitoring the serum 25-hydroxyvitamin D (25[OH]D) concentration and using vitamin D3 (cholecalciferol) supplementation to bring serum 25(OH)D levels up to 60 to 80 ng/mL (150 to 200 nmol/L); other experts suggest a target 25(OH)D serum level of 40 to 60 ng/mL (100 to 150 nmol) [71]. Most patients can achieve this with cholecalciferol 2000 to 5000 international units daily, although some patients with low serum levels of 25(OH)D require short-term administration of cholecalciferol 10,000 international units daily or 50,000 international units once weekly [72,73]. In a single-center trial that randomly assigned 40 patients with relapsing-remitting MS (but without severe vitamin D deficiency) to receive high-dose (10,400 international units daily) or low-dose (800 international units daily) cholecalciferol for six months, the mean increase from baseline in serum levels of 25(OH)D was significantly greater in the high-dose group (34.9 versus 6.9 ng/mL) [74]. Both doses were well-tolerated; adverse events were minor with no significant differences between the two groups.

The definition, clinical manifestations, and treatment of vitamin D deficiency in adults are reviewed separately. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

COMPLEMENTARY AND ALTERNATIVE MEDICINE — To manage their symptoms, patients with MS often employ a variety of complementary and/or alternative treatments such as exercise, meditation, yoga, relaxation techniques, acupuncture, cannabis, massage, dietary modification, vitamins, herbs, and mineral supplements [75-79]. However, there are few high-quality data sets regarding the utility of these interventions [80].

A course of physiotherapy can improve mobility and enhance mood and subjective well-being in patients with chronic MS, although the effects appear to be short-lived [81].

Cannabinoids — In randomized trials, cannabinoids have failed to provide consistent improvement in MS-related outcomes, as illustrated by the following observations:

In a meta-analysis that identified 11 studies assessing spasticity due to MS with 2138 participants, cannabinoids (nabiximols, dronabinol, and tetrahydrocannabinol/cannabidiol) led to a greater average improvement on the Ashworth scale for spasticity compared with placebo, but the difference did not achieve statistical significance (weighted mean difference, -0.12, 95% CI -0.24 to 0.01) [82].

In a randomized controlled trial assessing pain due to MS with 58 participants, treatment with tetrahydrocannabinol/cannabidiol oromucosal spray compared with placebo led to a small, nonsignificant difference in the number of responders at the 30 percent improvement level in mean pain score (50 versus 45 percent, odds ratio 1.31, 95% CI 0.84-2.04) [83].

In a 36-month placebo-controlled trial (CUPID) of 498 patients with primary progressive or secondary progressive MS, dronabinol had no effect on MS progression [84].

A 12-week randomized controlled trial (MUSEC) that enrolled 279 patients with MS reported that the rate of relief from muscle stiffness was significantly greater with cannabis extract compared with placebo (29 versus 16 percent) [85]. There was no assessment regarding whether subjects were able to accurately identify active therapy.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple sclerosis and related disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Multiple sclerosis in adults (The Basics)")

SUMMARY AND RECOMMENDATIONS

Initial treatment of bladder dysfunction involves a combination of suppressing urgency and ensuring effective urinary drainage. Initial therapy for sphincter dysfunction is water restriction and regimented bathroom stops. For patients with bladder dysfunction causing failure to store urine (eg, detrusor overactivity), anticholinergic and antimuscarinic drugs remain the primary medical treatment. For patients with bladder dysfunction causing failure to empty (eg, detrusor sphincter dyssynergia), alpha antagonist medications such as prazosin, terazosin, doxazosin, and tamsulosin may be beneficial. (See 'Bladder dysfunction' above.)

There are no proven therapies for cognitive dysfunction in MS. Nonpharmacologic approaches consist primarily of support and improvement of coping strategies. (See 'Cognitive impairment' above.)

Depression is common among patients with MS, but there are few high-quality data regarding treatment. (See 'Depression' above.)

A number of medications may be helpful in treating fatigue related to MS, including amphetamines, amantadine, and methylphenidate. (See 'Fatigue' above.)

The management of ambulatory problems in MS consists mainly of physical therapy along with the use of mobility aids, when they become necessary. Measures to treat spasticity may also be helpful. Dalfampridine may improve walking speed in some patients with MS. (See 'Gait impairment' above and 'Dalfampridine' above.)

Paroxysmal attacks of motor or sensory phenomena in patients with MS may respond to low doses of antiseizure medications such as carbamazepine and valproic acid and frequently remit after several weeks to months, usually without recurrence. (See 'Paroxysmal motor and sensory symptoms' above.)

Seizures associated with MS are generally benign and transient and respond well to antiseizure medication therapy or require no therapy. (See 'Seizures' above.)

For patients with MS who have clinically significant spasticity, we suggest initial treatment with oral baclofen or tizanidine (Grade 2B). We prefer oral baclofen due to its favorable side effect profile and low cost. Additional options include benzodiazepines, intrathecal baclofen infusions, and botulinum toxin injections. (See 'Spasticity' above.)

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