Multiple Sclerosis: A Comprehensive Spectrum of Symptoms Beyond Motor Dysfunction

Abstract

Multiple sclerosis (MS) is a chronic autoimmune-mediated neurodegenerative disease that affects young adults. The diagnosis of MS currently based on the McDonald criteria, which based on four core principles: the presence of a symptomatic demyelinating syndrome, an objective neurologic finding, the dissemination in space (DIS), and the dissemination in time (DIT). In addition, the diagnosis of MS relies on the exclusion of any alternative diagnosis. This may implicate the absence of systemic non-neurological symptoms and signs, such as rheumatological, cutaneous, or ophthalmological findings. Nevertheless, the non-neurological symptoms are commonly observed in patients with MS either at the onset of MS, which therefore can delay the diagnosis and the incrementation of a disease-modifying therapy, or during the course of the disease progression. The purpose of our review is to highlight non-neurological symptoms of MS that frequently go undiagnosed or mistakenly linked to other conditions, aiming for the more accurate and earlier diagnosis of MS.

1. Background

Multiple sclerosis (MS) is a chronic autoimmune-mediated neurodegenerative disease that affects the central nervous system (CNS) of young adults [1]. The pathophysiology of MS is related to an autoimmune destruction of the myelin sheath in the central nervous system and the failure of the myelin-producing cells to produce new sheathes. These findings can be triggered by numerous genetics and environmental factors like pollution and some viral infections [2].

The diagnosis of MS is currently based on the McDonald criteria, first introduced in 2001 with revisions in 2005, 2010, and 2017, with more revisions yet to come [3]. These criteria are made of four core principles: the presence of a symptomatic demyelinating syndrome, an objective neurologic finding (which can be clinical, on the MRI or recently on the CSF analysis), the dissemination in space (DIS: which means that the neurological damage is occurring in multiple regions of the CNS), and the dissemination in time (DIT: meaning that the attacks or relapses happened in different times clinically or in the MRI). The last but important criterion is the absence of an alternative diagnosis that can explain the symptoms [3]. The possibility of a different diagnosis can be considered with the presence of other systemic non-neurological symptoms and signs, such as rheumatological, cutaneous or ophthalmological findings.

Nevertheless, the non-neurological symptoms are commonly observed in patients with MS and have only lately been specifically explored. Patients with a definite MS diagnosis can exhibit cardiovascular symptoms, bladder dysfunction, gastrointestinal symptoms, and sexual dysfunction as autonomic symptoms during the course of their disease. Other systemic signs can be present at the onset of MS and therefore can delay the diagnosis and the incrementation of a disease-modifying therapy.

In this article, we described the different non-neurological features that can be observed at the onset of MS or during the course of the disease.

2. Musculoskeletal and Rheumatological Symptoms in Multiple Sclerosis

Musculoskeletal involvement in MS is one of the most frequent features of the disease. In fact, the impairment of the motor pathways in the cerebral hemispheres, the brainstem, and the spinal cord leads to muscular weakness and later to atrophy and spasticity, which can significantly restrict the functional capacity of the affected muscles. Herein, we will further discuss the articular and skeletal features of MS [4].

2.1. Arthralgia

The presence of joint pain, articular swelling or inflammation can be regarded as an atypical sign in the onset of the disease. They rather refer to a connective tissue disease, such as systemic lupus erythematosus and rheumatoid arthritis. Nevertheless, some very rare cases of association between MS and systemic diseases have been reported in the literature [5], making the diagnosis of MS possible in patients with arthralgias.

On the other hand, most joint pain associated with MS is often caused by other symptoms of the condition. For example, fatigue and reduced mobility can lead to deconditioning, which weakens muscles and diminishes support for the joints. Additionally, balance issues may severely alter the gait, and attempting to compensate for this can result in back or hip pain, as well as muscle spasms [6].

2.2. Osteoporosis

Osteoporosis is a condition characterized by reduced bone strength, which significantly increases the risk of fractures. Throughout life, the process of bone remodeling continuously replaces lost or damaged bone with new bone, thereby maintaining bone strength and restoring both its micro- and macro-architecture. This process relies on the regular generation, function, and longevity of osteoclasts, osteoblasts, and osteocytes [7]. However, chronic conditions like MS can severely disrupt bone remodeling and modeling, leading to bone loss, deteriorating bone quality, and an increased risk of fractures. In a recent meta-analysis, Azadvari et al. [8] reported that up to 20% of patients with MS suffer from osteoporosis, and more than a half (51%) have signs of osteopenia. They imputed this reduction of bone mass in MS to reduced mobility, the use of disease-modifying drugs, and also to MS-impaired cardiovascular autonomic nervous system function that has the potential of reducing bone mass density [8,9]. In fact, individuals with MS are more prone to low-trauma fractures and secondary osteoporosis. Factors such as gradual immobility, long-term glucocorticoid therapy, vitamin D deficiency, skeletal muscle atrophy, and the influence of various cytokines associated with MS are likely contributing to the development of osteoporosis in these patients. Additionally, long-term use of other medications that can also impact on bone density, like anti-serotonergic antidepressants, may also contribute to osteoporosis and the risk of fractures, although the pathophysiology is not yet entirely established [7]. Alongside bone loss and poor bone quality, functional limitations further increase the risk of falls, thereby heightening the likelihood of fractures among patients with MS [10].

3. Respiratory Symptoms in Multiple Sclerosis

Respiratory dysfunction is a prevalent concern among patients with advanced MS. It can present in several forms, such as acute or chronic respiratory failure, impaired breathing control, weakness in respiratory muscles, sleep-related breathing disorders, or neurogenic pulmonary edema. The underlying causes are generally associated with demyelinating plaques that impact the brain stem or spinal cord [11].

Respiratory Muscle Weakness

One of the respiratory complications associated with MS is respiratory muscle weakness. Although this weakness typically does not reach severity levels that result in respiratory failure, it can still lead to various other respiratory issues. Studies have evaluated respiratory muscle strength by measuring maximal static mouth inspiratory pressure (MIP) and maximal static mouth expiratory pressure (MEP), which offer a comprehensive assessment of inspiratory and expiratory muscle strength. Nevertheless, more specific evaluations of diaphragmatic function, with the measurement transdiaphragmatic pressure during voluntary efforts, have only been documented in a limited number of cases involving acute respiratory failure [11].

In a unique case report, Aisen et al. [12] reported that a patient with a long-standing history of MS presented with debilitating pulmonary symptoms, while exhibiting minimal disability in other areas. The clinical examination and fluoroscopy confirmed the presence of bilateral diaphragmatic paralysis. Magnetic resonance imaging revealed atrophy and extensive white matter changes in the cervical spinal cord. This case is notable because the respiratory compromise, stemming from MS involvement in the cervical spinal cord, occurred independently of any bulbar dysfunction or severe limb weakness.

4. Autonomic Nervous System Dysfunction in Multiple Sclerosis

Autonomic nervous system disorders are underestimated in MS. They may include cardiovascular, gastrointestinal, urological, sexual, and thermoregulatory disorders. Most of these symptoms are associated with some localized lesions in the CNS, especially infratentorial plaques (in the midbrain, the pons, and the medulla oblongata) or the autonomic centers in the spinal cord. Abnormal results are observed in 94% of MS patients on the Composite Autonomic Symptoms Score screening, which is a comprehensive score assessing six domains of the autonomic nervous system (orthostatic hypotension, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor functions). The most significant correlations between disease duration and the progressive phase of MS were found regarding the impairments within secretomotor, gastrointestinal, and bladder functions [13]. Due to the non-specificity of these symptoms, they are usually overlooked in patients with MS. Nevertheless, early recognition of dysautonomic features is essential for improving the quality of life of patients [14].

4.1. Cardiovascular Symptoms in MS

Cardiovascular symptoms can sometimes be part of the presentation of MS and they are generally caused by a disruption of the autonomic regulation. Several studies have attempted to explain cardiovascular autonomic dysfunction by specific lesions in the CNS, notably in the midbrain. Parasympathetic dysfunction is associated with the progression and disability of MS, while sympathetic dysfunction is linked to clinical activity and inflammation, potentially playing a role in the onset of the disease [15].

4.1.1. Postural Orthostatic Tachycardia Syndrome (POTS)

Postural orthostatic tachycardia syndrome (POTS) is a chronic condition marked by orthostatic intolerance and an abnormal increase in heart rate without hypotension when standing. This syndrome affects almost one fifth of patients with MS, a notably higher rate compared to individuals with orthostatic intolerance but no neurological impairment, which is 10% [16]. Potential mechanisms for POTS may include sympathetic or central factors, such as sympathetic overactivity, low blood volume, and possibly the disruptions in the renin–angiotensin–aldosterone system, which could explain the connection between MS and POTS [17].

4.1.2. Tako-Tsubo Cardiomyopathy

Tako-tsubo cardiomyopathy (TTC) is a severe, segmental, and transient cardiac dysfunction and electrocardiogram changes that affects the left ventricle and is not associated with coronary stenosis, pheochromocytoma, or myocarditis. Its name comes from the shape of the left ventricle “apical ballooning” that looks like the Tako-Tsubo, a type of Japanese octopus pot [18,19]. Most patients present with dyspnea, chest pain, and syncope usually triggered by acute physical or emotional stress. More serious cardiac signs such as arrhythmias, cardiac arrest, and cardiogenic shock are less common [20]. TTC has been reported to be caused by a number of neurological conditions, including subarachnoid hemorrhage, seizures, ischemic stroke, and intracerebral bleeding. Thus, MS has also been identified as a trigger for TTC [21]. Hiltz [22] has presented an exceptional case report where TTC was the first manifestation of MS. The exact mechanism remains unclear. Theories state that inflammatory lesions in the medulla oblongata may disrupt the brain–heart axis by affecting the solitary tract nuclei. This disruption could result in temporary myocardial stunning through acute overactivation of the sympathetic pathway and the resulting surge of catecholamines [21].

4.1.3. Electrocardiogram Abnormalities

Abnormalities on an electrocardiogram (ECG) are commonly observed in patients with MS. The atypical ECG patterns include a longer P wave duration, variations in the QT interval (indicating abnormal repolarization timing), prolonged cardiac repolarization, and an extended QT interval [16]. In rare cases, a Brugada sign (BrS) may also appear, characterized by an ST segment elevation of 2 mm or more in the V1 and V2 leads on the ECG [23].

4.2. Gastrointestinal Symptoms in Multiple Sclerosis

Gastrointestinal symptoms are well documented in neurological conditions, including MS [24]. In the early stages of MS, patients may experience constipation, bloating, and early satiety. With the progression of the disease, patients may exhibit a higher incidence and more severe gastrointestinal symptoms such as diarrhea and fecal incontinence, which predominantly affect the lower gastrointestinal tract [25]. This results from disruptions in the central pathways regulating sacral parasympathetic outflow, rather than cervical parasympathetic outflow. Nonetheless, non-neurological factors, such as lack of exercise, prescription side effects, and inadequate fiber and fluid intake, may also be implicated [13]. Bladder and bowel dysfunction impacts over 80% of MS patients, significantly affecting quality of life and healthcare costs, and often serve as early indicators of a poorer prognosis.

4.2.1. Dysphagia

Dysphagia refers to any difficulty with swallowing. A recent systematic review and meta-analysis found that about 43% of MS patients experience dysphagia [26]. Swallowing difficulties in MS can result from lesions in the corticobulbar tracts, cranial nerve impairment, cerebellar and brainstem disorders, or cognitive dysfunctions, and are estimated to affect roughly one-third of MS patients. Dysphagia can lead to serious complications, such as aspiration pneumonia, malnutrition, dehydration, and airway obstruction. The high prevalence of dysphagia in MS patients, along with the associated disabilities and financial strain on families and healthcare systems, underscores the importance of early diagnosis and effective treatment [26].

4.2.2. Bowel Issues

Nearly 70% of MS patients experience bowel symptoms. In MS, the signal transmission between the brain and spinal cord can be disrupted; hence, the autonomic control of the intestinal smooth muscles involved in bowel peristalsis can be impaired. Most MS patients experience constipation or slowed bowel movements, although bowel incontinence and diarrhea are also reported, though less frequently than constipation [27].

Constipation is particularly common among people with MS. Constipation is typically characterized by difficulty passing stool or infrequent bowel movements (usually fewer than three per week) and can lead to bloating, fullness, cramping, or abdominal discomfort. It can result from insufficient daily fluids, low dietary fiber intake, and limited physical activity. Medications and supplements may further contribute to constipation in patients with MS [25]. On the other hand, MS patients may also experience diarrhea, marked by frequent bowel movements and loose, watery stools due to the rapid movement of contents through the digestive tract. In the case of chronic diarrhea, it can also lead to dehydration or poor nutrient absorption [28].

Bowel incontinence can be a distressing symptom in the later stages of MS. It ranges from occasional gas and minor stool leakage to complete loss of bowel control. Bowel retraining can help establish regular bowel movements and includes steps like consuming sufficient fiber to maintain stool formation, avoiding foods that may cause loose stools, and setting a daily routine for bowel emptying [29].

Other MS symptoms can worsen these bowel problems. MS-related fatigue may reduce physical activity, slowing the movement of waste to the colon. Spasticity can lead to bladder problems and affect muscle control, which can reduce fluid intake and, in turn, worsen constipation. Conversely, MS-related bowel issues can aggravate other symptoms of the disease, such as bladder spasms [28].

4.3. Urinary and Sexual Symptoms in Multiple Sclerosis

Bladder dysfunction is found in approximately 75% of patients with MS. The most common lower urinary tract symptoms (LUTS) include nocturia, followed by urinary urgency. Urinary incontinence, urinary retention, and poor bladder emptying are less common but still significant [30]. Although urinary symptoms are relatively uncommon during the initial manifestation of MS, occurring in only 3% to 10% of cases, up to 90% of patients ultimately experience lower urinary tract symptoms, typically developing 6 to 8 years after the initial diagnosis [30,31]. Various factors can contribute, such as the disruption of the link between the sacral and pontine micturition centers by MS plaques. The specific location of these plaques can lead to distinctive patterns of LUTS. Detrusor overactivity, which is observed in 65% of MS patients for instance, is thought to arise from lesions in the cortical areas responsible for urinary control, including the medial prefrontal cortex, insula, and pons [30]. Additionally, plaques in efferent or afferent pathways can contribute to urinary retention and difficulties with bladder emptying [32].

4.3.1. Detrusor Overactivity/Hyperactivity

Detrusor overactivity is characterized by the contraction of the detrusor muscle during the bladder filling phase, particularly when the patient is attempting to suppress the urge to urinate. This contraction can occur either spontaneously or be triggered by various stimuli. Suprasacral spinal lesions are believed to contribute to detrusor overactivity by disrupting the descending inhibitory pathways that normally regulate bladder contractions. The symptoms associated with detrusor overactivity include increased frequency of urination, urgency, urge incontinence, and nocturia [30,33].

4.3.2. Detrusor Underactivity/Hypoactivity

Twenty-five percent of patients with MS experience some level of detrusor underactivity or hypocontractility. Detrusor underactivity, also known as hypoactivity, refers to a condition in which the bladder contractions are of reduced strength and/or duration. This results in prolonged or slow bladder emptying, or the inability to fully empty the bladder within a typical time frame. Lesions in the sacral cord are associated with detrusor hypocontractility. Patients experiencing detrusor underactivity often report symptoms such as straining to urinate, incontinence, and the sensation of incomplete bladder emptying [30,34].

4.3.3. Dyssynergia of the Detrusor Sphincter

Dyssynergia of the detrusor sphincter is observed in 35% of MS patients. It is characterized by the failure of coordination between the external urethral sphincter and the bladder’s detrusor muscle during urination. Damage to the reticulospinal tracts can result in detrusor-sphincter dyssynergia, which manifests as lower urinary tract symptoms. Individuals affected often experience difficulties with voiding and/or storage, leading to issues such as urinary retention, intermittent voiding, and incontinence, frequently occurring without an associated urge to void [35,36].

4.3.4. Sexual Dysfunction

A large proportion of MS patients (up to 80% of men and 72% of women) may experience sexual dysfunction. Early recognition of these symptoms can lead to better treatment in order to improve general quality of life and enhance erectile or orgasmic function in patients with MS [37].

5. Ophthalmological Features in Multiple Sclerosis

Optic neuritis is a common presenting symptom of MS, since the optic nerve is considered as an extension of the brain and it is a part of the central nervous system [38]. Nevertheless, other factors can also contribute to visual impairment in patients with MS, such as uveitis, cataract, and glaucoma. This highlights the importance of comprehensive ophthalmic assessment in the early diagnosis and management of visual disturbances associated with MS.

5.1. Uveitis

The relationship between uveitis and MS remains ambiguous. The incidence of uveitis among MS patients ranges from 0% to 26.9%, whereas the prevalence of MS in individuals with uveitis is estimated to be between 1% and 2% [39]. Reports indicate that the most common type of uveitis is intermediate uveitis, which primarily impacts the vitreous, peripheral retina, and pars plana ciliaris. Patients with intermediate uveitis may initially experience mild impairment in visual acuity, and the severity of the condition is closely linked to the visual prognosis. Notably, the most significant predictor of a visual prognosis is macular involvement, particularly post-cystoid degeneration and cystoid macular edema (CME). Additionally, patients with MS may present with symptoms such as granulomatous anterior uveitis, substantial development of posterior synechiae, and “mutton fat” keratic precipitates—all of which are indicative of other differential diagnosis like sarcoidosis [40].

Individuals diagnosed with uveitis should undergo a comprehensive neurological evaluation in addition to an ophthalmological examination.

5.2. Glaucoma

Glaucoma, which is defined by the increase in intraocular pressure, can lead to retinal nerve fiber degeneration and irreversible vision loss. Globally, there is a 3% likelihood that individuals aged between 40 and 80 will develop glaucoma. Moreover, those with MS may be at heightened risk for glaucoma due to a reduction in macular thickness and especially the long-term use of glucocorticoids [41]. In MS patients, the chronic use of glucocorticoids is a major risk of this condition. And in cases of MS-related glaucoma, early intervention with the appropriate surgical procedure may be necessary to preserve optimal vision and improve the patient’s quality of life [42].

5.3. Cataract

The clouding of the crystalline lens is the defining characteristic of cataracts, which rank among the leading causes of vision loss worldwide. As in glaucoma, the use of glucocorticoids and shared disease mechanisms may elevate the risk of cataract development in patients with MS. Calpains-proteolytic enzymes found in the lens also increase during MS relapses and may explain the underlying link between cataracts and MS [42].

6. Dermatological Symptoms in Multiple Sclerosis

Cutaneous symptoms are not typically associated with MS itself but are rather considered as side effects of certain medications used to treat or alleviate the condition. One such medication is cladribine. Rolfes et al. [43] presented a study involving 239 patients with MS who received cladribine. Seventy-seven patients (32%) experienced at least one skin-related symptom within the first month of treatment. During the initial three months following the most recent cladribine administration, hair thinning was noted in 28 patients (11.7%), while 20 patients (8.4%) developed a skin rash. In the latter group, the skin rash was described as diffuse erythema in thirteen patients (5.4%), papulopustular acneiform eruptions in five patients (2.1%), and nummular eczema in two patients (0.8%). Additionally, pruritus occurred as an isolated symptom in four patients (1.7%), with two cases where it coexisted with a rash. Moreover, 13 patients (5.4%) exhibited transient mucositis. The underlying mechanisms of the cutaneous adverse effects of cladribine are thought to be its nonhematologic toxicity and cladribine-induced immune dysregulation, which were previously known in the oncological use of the molecule [43]. There were also cases of viral infection, with 35 patients (15%) presenting a herpes virus infection. Among these, 15 patients experienced severe herpes zoster lesions. Finally, over three months after a cycle of cladribine treatment, one case of leukocytoclastic vasculitis and two cases of alopecia areata were reported in the same study [43].

Adverse dermatological effects have also been reported with daclizumab. Cutaneous signs were reported in 77% of the 31 patients included in the review of Cortese et al. [44]. Most of the patients experienced eczema patches that did not require intervention. However, six patients developed moderate to severe rashes, resulting in the discontinuation of the medication in four of them. The more severe rashes had a psoriasiform appearance. Yet, biopsies of the affected skin showed non-specific features of eczematous dermatitis [44].

7. Conclusions

In this review, we highlighted various extra-neurological signs that can be seen during the course of MS or even initiate the disease. As MS is known as the most frequent and typical inflammatory disease of the central nervous system, the non-neurological symptoms are often overlooked and underdiagnosed. Cutaneous, articular, and sexual symptoms can hinder the quality of life of patients with MS. Other manifestations can even be life-threatening, such as cardiac and respiratory symptoms. All patients with MS should regularly undergo a comprehensive screening for these non-neurological signs, in order to improve the management of the disease.