Multiple sclerosis (MS) causes a range of symptoms that affect multiple aspects of physical and psychological functioning, with impacts ranging from distressing to disabling ^[1][2]. Accordingly, the appropriate diagnosis and management of these symptoms is a key element of the routine care of people with MS and has been described as an unmet clinical need in this area ^[2][3].

Other symptoms of MS that are often missed include depression, fatigue, and cognitive impairment. These common symptoms could be present at any time during the disease course, and they may fluctuate in intensity. Some symptoms may worsen during relapse. Accordingly, the management recommendations relate to MS in general, but the need for intervention may be particularly acute during a relapse, especially if its duration is prolonged.

2. Management of Common and Troublesome Symptoms of Multiple Sclerosis

2.1. Fatigue

Fatigue in MS has not been defined precisely but has been described by different authors as an overwhelming sense of exhaustion and lack of energy that is often not related to sadness or weakness and difficulty starting or maintaining voluntary effort (see the review by Mills and Young ^[3][10] for the sources of these definitions). Other studies have investigated the role of the thalamic network in the pathophysiology of MS-related fatigue ^[4][11]. Fatigue is one of the most common symptoms of MS and is reported by almost 80% of patients at some time ^[1][5][2,12]. Fatigue tends to be more common among patients with a longer duration of MS ^[1][2]. The majority of patients report fatigue as the worst symptom of MS they experience ^[5][12]. The causes of fatigue in MS are multifactorial and overlapping, and a multifaceted approach to evaluation and management is required. Medications that may be considered for the management of fatigue in this patient population include Amantadine as a first-line treatment [13] and Modafinil as a second-line treatment [14]. 

2.2. Depression

The prevalence of depression is higher in people with MS than in the general population, with a lifetime prevalence as high as approximately 50% and an annual incidence approximately three-fold higher than that in the general population ^[6][17]. A large registry in the United States of America (USA) found a self-reported prevalence of depression of any severity in about three-quarters of people with a duration of MS of 10 years or more, with depression of moderate or higher severity reported by about one-third of this population ^[1][2]. Internationally validated, evidence-based questionnaires, such as the Patient Health Questionnaire ^[7][18] and the Beck Depression Inventory ^[8][19], are available for diagnosing depression. Psychoeducational approaches and subsequent follow-ups may be effective for mild-to-moderate depression of recent onset. For more severe or prolonged depression, evidence-based antidepressants may be prescribed only by experienced neurologists. It is also recommended to refer patients to psychiatry in the case of psychotic symptoms associated with depression. A referral for psychiatric support should also be considered for patients with clear signs of depression.

2.3. Cognitive Impairment

Cognitive impairment affects 40–65% of people with MS, with the exact prevalence depending on the classification ^[9][20]. Cognitive domains most frequently affected are episodic memory, attention, information processing speed, and executive function. When assessing cognitive impairment, compounding factors that need to be eliminated include depression, anxiety, fatigue, sleep disturbance (MS symptom, obstructive sleep apnea, Restless legs syndrome), and medications (antispastics, opioids, and some agents for neuropathic pain) ^[10][21]. The United States National MS Society has recommended that the Symbol Digit Modalities Test (or an equivalent validated test for cognition) should be administered at least annually to patients with MS (aged ≥8 years) in order to confirm and quantify any cognitive deficit, to follow the course of cognitive function over time, to detect new issues with cognition, and to evaluate the effects of treatments ^[11][22]. Strategies to improve cognition that may be recommended include conservative measures (diaries and calendars), regular physical exercise, and regular social contact ^[12][23]. While no pharmacologic therapy is currently recommended for the management of cognitive impairment in patients with MS, there are serious efforts to create evidence-based guidelines for cognitive rehabilitation for MS patients ^[13][24].

2.4. Lower Urinary Tract Symptoms/Bladder dysfunction

The prevalence of LUTS is estimated as high as 80–90% in patients with MS. Detrusor overactivity includes urgency, nocturia, frequent urination, and incontinence as the most common presentation ^[14][4]. MS is a leading cause of LUTS/bladder dysfunction among patients with neurological disorders, and this has a significant negative impact on quality of life ^[15][25]. Urinary symptoms are broadly categorized into failure to storage due to overactive bladder (urgency, frequency, nocturia, or urge incontinence), urinary retention due to failure of voiding (hesitancy, double voiding, straining, or sensation of incomplete emptying), or a combination of both ^[15][25]. Not only do LUTS reduce the quality of life of patients with MS ^[15][25], but they lead to urological complications like pyelonephritis and kidney stones, among others ^[14][4]. In fact, urological complications are one of the most common causes of hospitalization among MS patients ^[16][26]. First-line management may be initiated in neurological practice, but early referral to a urology practice should be considered if any of the following red flags are present: stress urinary incontinence, hydronephrosis, renal impairment, recurrent urinary tract infection (UTI), hematuria, suspected concomitant urologic pathology (for example., prostate enlargement), pelvic pain, or symptoms refractory to first-line treatment ^[15][25]. Conservative management strategies may be considered, including fluid restriction at night, scheduled voiding, avoidance of bladder irritants (for example., caffeine, tobacco, alcohol, carbonated beverages, chilli peppers, citrus fruits, and vitamin C supplements), and pelvic floor muscle training (PFMT) ^[15][25]. If this is ineffective, patients with overactive bladder and a postvoid residual volume <100 mL may be treated with anticholinergics. The following anticholinergics may be considered as first-line options: anticholinergics (oxybutynin, tolterodine, solifenacin, and trospium) or alpha antagonists (tamsulosin) ^[15][25] (see Table 1). Note that caution is recommended with the use of anticholinergic medications, especially in elderly patients, as they may cause central nervous system adverse effects to be monitored by the treating physician should they arise; these include headache, impaired cognition/memory, anxiety, insomnia, and behavioral disturbances. For this reason, dementia is a contraindication to the use of these medications. Other side effects caused by anticholinergics to be monitored include those affecting the peripheral nervous system, such as hyperthermia, constipation, blurred vision, and narrow-angle glaucoma. Therefore, it is also contraindicated to use these medications in patients with a history of glaucoma ^[17][27]. Second-line treatments should be initiated in urological practice and may include intravesical botulinum toxin injection ^[15][25]. In cases of voiding issues, alpha-blockers can be used in addition to other strategies such as clean intermittent self-catheterization, indwelling catheters, percutaneous and transcutaneous tibial nerve stimulation, or surgical intervention ^[15][25] LUTS are likely the most common cause of hospitalization ^[18][28].

2.5. Bowel Dysfunction

Bowel dysfunction is a common problem affecting between 39–73% of MS patients ^[19][29]. Constipation is seen in nearly half of the patients, diarrhoea to a lesser extent (32%) and rarely fecal incontinence (2.5%) ^[19][20][29,30]. The treatment of bowel dysfunction remains unsatisfactory. The causes of constipation are multi-factorial due to spinal cord lesions, decreased mobility or concomitant drug use (anti-cholinergic, narcotics, anti-convulsant, and muscle relaxant). Treating constipation starts with physical exercise and dietary modification (high fiber diet and increased water intake) and eliminating causative drugs when possible. Luxates can be used when necessary and include; psyllium, lactulose, polyethylene glycol, and bisacodyl. Other second-line options include prucalopride, transanal irrigation (TAI) or sacral neuromodulation, which require referral to gastroenterology or urology. The mode of action and side effects are mentioned in Table 2. Treatment of diarrhoea and incontinence starts with conservative therapy with antidiarrheals (loperamide), a special diet, and biofeedback if failed referral to gastroenterology or urology for TAI or sacral neuromodulation is advised (see Table 2).

2.6. Sexual Dysfunction

Sexual dysfunction is present in 50–80% of patients with MS, especially in men with a higher Expanded Disability Status Scale (EDSS). In women, sexual dysfunction is often secondary to fatigue ^[21][31]. Possible contributing factors should first be addressed, for example, medications for anxiety disorders (tricyclic antidepressants, selective serotonin reuptake inhibitors) and MS-related fatigue, depression, anxiety, and spasticity. A referral to urology or gynecology is also warranted ^[22][32]. Sildenafil has been shown to be effective for sexual dysfunction for men with MS; however, its benefits were limited to improvement in lubrication among women with MS. ^[23][24][33,34]. MS or its treatments do not seem to affect male fertility ^[25][35]. Similarly, MS in females of childbearing age does not appear to affect their fertility ^[26][36]. However, data on the topic of fertility in both sexes is still sparse and non-conclusive.

2.7. Paroxysmal Symptoms

Paroxysmal symptoms can include a wide variety of transient and stereotyped symptoms that can be sensory or motor lasting between 1–90 s ^[27][37]. The most common paroxysmal symptoms are trigeminal neuralgia and Lhermitte’s sign. Tonic spasms (more with Transverse myelitis (TM) related to Neuromyelitis Optica (NMO) are less common. Uhthoff’s symptoms (worsening of MS during an increase in temperature) may also present as paroxysmal symptoms ^[15][25]. No randomized trials have been conducted to guide therapy. However, for the management of tonic spasms, carbamazepine may be considered as the first-line therapy (low dose of approximately 200 mg two times a day) ^[28][38]. Other options for the management of tonic spasms include oxcarbazepine, gabapentin, and lacosamide ^[27][37]. Carbamazepine may also be considered for the management of trigeminal neuralgia. Lhermitte’s symptoms may be treated with amitriptyline, pregabalin, gabapentin, or duloxetine ^[27][37].

2.8. Spasticity

The initial treatment involves stretching exercises and rehabilitation. Stretches should be held for at least 30 to 60 s, and patients should be counseled to stretch twice daily. First-line pharmacologic options to manage spasticity include baclofen, tizanidine, or gabapentin, in addition to physiatry consultation or physical therapy. Second-line pharmacologic options include diazepam or dantrolene. For spasticity that is not generalized or that is considered local, botulism toxin injections and intrathecal baclofen pumps are treatment options ^[29][39]. Nabiximols are also safe to use to manage spasticity in patients that failed other treatments ^[30][31][40,41].

2.9. Gait Impairment

Gait impairment in MS is multifactorial and includes spasticity, weakness, fatigue, and sensory dysfunction. The pillar of gait impairment management is physical and occupational therapy. Dalfampridine is the main pharmacologic therapy to improve walking in MS (and the only Food and Drug Administration-approved treatment) in approximately one-third of patients ^[32][42]. The 25-foot walk test should be performed before and several weeks after starting the medication. Dalfampridine should be discontinued after a 4-week trial if there is no improvement in the 25-foot walk test.

2.10. Dysphagia

It is estimated that around 30–40% of MS patients suffer from Dysphagia or difficulty swallowing ^[33][43]. It could appear in adults with mild disability levels (EDSS 2-3) and is more prevalent in patients who are moderately or severely impaired (EDSS 8-9) ^[34][44]. Given the risk of aspiration pneumonia ^[35][45], an appropriate assessment of dysphagia through history-taking is necessary ^[36][46]. Video fluoroscopy or fiberoptic endoscopic assessment of swallowing is often used for definitive diagnosis ^[37][47]. Management of dysphagia requires the cooperation of a multidisciplinary team, including neurologists, nurses, speech and occupational therapists, otolaryngologists, and dieticians, to ensure adequate and safe nutrition.