Kinesiotherapeutic Possibilities and Molecular Parameters in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a chronic and incurable neurological disease of the central nervous system. Three main forms of the disease have been distinguished: relapsing–remitting form (RRMS), secondary progressive form (SPMS), and primary progressive form (PPMS). Currently, in patients with MS, in addition to pharmacotherapy, neurorehabilitation is indicated to improve the motor function of the body and action in the most physiological movement patterns possible. In this therapy, work on lost or incorrect functions is used to provide the patient with self-sufficiency in everyday life. Kinesiotherapy is used as part of neurorehabilitation. This therapy for MS includes coordination exercises aimed at facilitating movement, strengthening exercises and resistance training, balance exercises, improving stability during everyday activities stretching and relaxation exercises, improving tissue elasticity, reducing tension, and breathing exercises. In this article, we present various possibilities for using kinesiotherapy in patients with MS at various stages of disease development. Moreover, we would like to draw attention to the benefits of physical activity leading to a significant improvement in the quality of life in MS patients. We believe that a regular exercise program should be part of the neurorehabilitation program in these patients in the future.

1. Introduction

Multiple sclerosis (MS) affects about 2.2 million individuals worldwide [1]. MS is an autoimmune demyelinating disease. It involves the destruction of myelin sheaths in the central nervous system (CNS). Demyelinating changes in the course of MS appear at different times and in different locations (they are spread over time and space), both in the brain and the spinal cord, which is associated with rich symptomatology and high variability of symptoms. These include spasticity, pain, fatigue, visual disturbances, urination and defecation disorders, ataxia, and mental disorders. It is the most common disease leading to disability among young adults [2]. It is usually diagnosed in people between 20 and 40 years of age [3]. Three forms of MS are usually distinguished: relapsing–remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS). Some authors also distinguish the primary progressive relapsing form (PRSM). The most common form is relapsing–remitting [4,5].

Most patients require symptomatic treatment as the disease progresses, but in an increasing number of MS patients, it is also possible to include treatment modifying the course of MS [6]. Until recently, only the RRMS form could be qualified for such therapy, but in 2017 ocrelizumab was registered in the USA, the first drug also used in the PPSM form [7].

Synaptic plasticity is a fundamental property of the nervous system, which is not only able to restore function, but also to repair systemic disorders, and above all to respond to learning and memory. Synaptic plasticity occurs in response to various internal and external factors, including behavioral training, trauma, neurodegenerative diseases, autoimmune diseases, and pharmacological treatment [8].

Brain plasticity can be demonstrated in many ways. Physiological conditions include developmental plasticity, learning and memory, compensatory plasticity, and repair of the adult brain. Pathological conditions include plasticity after trauma, removal of a brain tumor, stroke, and other neurological diseases such as MS. In addition, synaptic plasticity at the molecular and cellular level occurs as short-term plasticity (STP), also called dynamic synapses, long-term potentiation (LTP), and long-term depression (LTD). It is known that repair of brain damage depends on the degree and extent of central damage. It is important to implement neurorehabilitation and treat CNS disorders [8,9]. Kinesiotherapy, exercise rehabilitation, massage, and hydrotherapy are all forms of physiotherapy that are used as part of rehabilitation. Early evaluation of MS patients by a physiotherapist is recommended to develop a personalized training program and/or exercise regimen tailored to their lifestyle [10]. Exercise therapy is one of the most promising treatment strategies for MS. In this article, we present an up-to-date review of the role of kinesiotherapy in the activation of MS patients. Recent findings in MS suggest that exercise may have neuroprotective and disease-modifying effects [11].

Moreover, progress in MS treatment can be measured with the Multiple Sclerosis Index, which allows for the assessment of the state of systemic care for MS patients. The document was created based on 18 measures in three assessment parameters: daily functioning, diagnostics and treatment results, and patient support and treatment management. However, there are increasing reports supporting pharmacotherapy in MS with kinesiotherapy. Such works are published in the USA, Italy, UK, Canada, Finland, Germany, Poland, Spain, Chile, France, and other countries.

It seems that understanding the mechanisms of synaptic plasticity may contribute to more effective therapy and improve the quality of life of MS patients.

2. Clinical Features and Pharmacotherapeutic Possibilities of Multiple Sclerosis

MS is characterized by a variety of symptoms that can present in different patterns due to demyelinating lesions occurring in various parts of the CNS. In most cases, the disease begins with a clinically isolated syndrome (CIS) [12]. Extraocular optic neuritis characterized by monocular visual impairment—typically presenting with central glare and color vision disturbances—is a common manifestation of CIS. There is usually a spontaneous improvement in visual acuity within 7–21 days; however, in up to 25% of cases, the symptoms do not resolve completely and, in some instances, fail to improve at all. To detect subclinical forms of optic neuritis, visually evoked potentials (VEP) testing can be used, with a characteristic finding being the prolongation of wave latencies [13]. Demyelinating lesions detected on magnetic resonance imaging (MRI) during an episode of optic neuritis indicate a very high probability of developing full-blown MS in the following years. After experiencing CIS, the course of MS can differ depending on the form of the disease. Acute relapses, progressive deterioration, or a combination of both may occur.

2.1. Clinical Forms of Multiple Sclerosis

The following forms of the disease are distinguished: RRMS, SPMS, and PPMS, where a steady progression of the disease is observed from the outset without distinct relapses. RRMS is the most common form [5]. The most common symptoms occurring in the course of MS include muscle weakness, sensory disturbances, coordination disorders, bladder disorders, fatigue syndrome, double vision, visual acuity disorder, muscle spasms, dysarthria, dizziness and balance disorders, bowel control disorders, and dysphagia [2].

In patients with RRMS, the dominant initial symptoms in the preliminary stages of the disease are visual disturbances and signs of brainstem or spinal cord damage. These symptoms completely resolve in the early stages of the disease, but as the disease progresses, they leave permanent neurological deficits and increasing disability. After approximately 10 years of disease progression, 40–50% of patients with RRMS transition to SPMS.

Analyses have shown that from the onset of the progressive phase, significant progression of motor disability occurs after approximately five years. In PPMS, progressive involvement of the spinal cord is more common, manifesting as increasing spastic weakness of the lower limbs (in about 83% of cases). In the advanced stages of the disease, tetraparesis is often present. In PPMS visual disturbances, brainstem syndrome, and cognitive dysfunction may develop. The progression of symptoms in PPMS is significantly faster than in RRMS [5].

2.2. Clinical Symptoms of Multiple Sclerosis

Common neurological symptoms in MS include pyramidal weakness, which may manifest as paraparesis, tetraparesis, and less frequently as hemiparesis. In the affected patients, increased muscle tone of spastic type is usually observed. Superficial sensory disturbances affecting various areas of the body are another common symptom. Patients often report paresthesias in the form of unpleasant sensory sensations, such as tingling, pricking, and numbness. Lhermitte’s sign is a pathognomonic symptom of MS [14]. It involves an “electrical” sensation that runs down the spine upon passive or active flexion of the neck. In 46–52% of patients, sensory disturbances are the first manifestation of the disease. The presence of a sharp boundary of sensory disturbances is more likely to suggest a different etiology for the symptoms. Patients often present with symptoms suggesting brainstem and cerebellar damage. Disorders of brainstem and cerebellar function are characterized by a wide range of symptoms. A pathognomonic sign involves damage to the medial longitudinal fasciculus, which results in impaired adduction of the eye on the side of the lesion and nystagmus in the abducting eye, on the opposite side of the lesion. This damage can be either unilateral or bilateral. It is common to see isolated damage to the oculomotor nerves (most frequently the oculomotor and abducens nerves), which manifests as double vision. As a result of damage to the cerebellum and its connections with the brainstem, coordination disorders, balance problems, and dizziness occur. The affected patients often exhibit nystagmus, and their speech may be scanned or dysarthric [2].

In the case of demyelinating lesions affecting the spinal cord, in addition to limb weakness, bladder dysfunction occurs, manifesting as urinary urgency, increased frequency of urination, nocturnal micturition, and, in more severe cases, urinary incontinence. Bladder dysfunction is often associated with frequent urinary tract infections. It is also important to mention sexual dysfunction, which is present in approximately 70% of male patients and 50% of female patients.

A dynamic assessment of patients regarding their functional abilities is crucial throughout the course of the disease. The progression of disability is assessed using the 10-point Expanded Disability Status Scale (EDSS), which includes eight functional systems (FS) that evaluate the visual, brainstem, pyramidal system, cerebellar, sensory, and cerebral functions. A score of 0 points describes a patient with no symptoms; 5 points, a patient able to walk without aid or rest for 200 m whose disability is severe enough to impair daily activities; 6 points, a patient who requires a walking aid; and 10 points indicates death [15].

When discussing the clinical picture of MS, cognitive dysfunctions must not be overlooked, as they occur in all disease phenotypes and at every stage. They are more pronounced in patients with a long disease duration.

2.3. Diagnosis of Multiple Sclerosis

To confirm the diagnosis of MS, the following tests are performed: MRI, cerebrospinal fluid analysis, evoked potentials, optical coherence tomography (OCT), visual evoked potentials (VEP), and other evoked potentials, including brainstem and somatosensory potentials. Head MRI without and with gadolinium contrast is performed using the following sequences: T1, T2, and FLAIR. Additionally, an MRI of the cervical and sometimes thoracic spinal cord is conducted to assess demyelinating lesions. In head MRI, brain atrophy is also assessed. A cerebrospinal fluid analysis is performed to determine whether oligoclonal immunoglobulin G (IgG) bands (so-called oligoclonal bands) are present. These bands are found only in cerebrospinal fluid and are absent in blood serum. In OCT, the focus is on assessing the thickness of the retinal nerve fiber layer (RNFL), as its thinning correlates with the number of brain lesions seen on MRI and with brain atrophy. In VEP, there is an extension of the P100 wave latency and a reduction in the amplitude of P waves. These tests are not only used to assess disease progression but also serve as a helpful tool in guiding therapy [4,16].

2.4. Pharmacotherapeutic Possibilities of Multiple Sclerosis

Pharmacological treatment of MS involves managing disease relapses as well as disease-modifying therapy. The gold standard for treating a relapse is the intravenous administration of methylprednisolone at a dose of 0.5–1.0 g per day for 3–5 days, sometimes up to 7 days. In the case of steroid therapy ineffectiveness, plasmapheresis can also be performed every other day, with a total of five sessions [6,16].

Disease-modifying treatment is a long-term therapy aimed at achieving disease stability and preventing its further activity. If, during treatment, a relapse occurs 6 months after its initiation, or if there is a significant worsening of disability (by at least 1 point on the EDSS), or if a Gd (+) lesion appears on MRI, or if there are two new lesions or enlarging lesions in T2 or FLAIR sequences, the medication should be changed. Recently, it has been recommended to start treatment with highly effective drugs, which include anti-CD20 monoclonal antibodies, S1P receptor modulators, natalizumab, or with induction therapies such as cladribine, alemtuzumab, and mitoxantrone. Before starting treatment with anti-CD20 antibodies, hepatitis B virus carrier status should be excluded by testing for HBs Ag, anti-HBs, and anti-HBc. Anti-CD20 antibodies include: ocrelizumab (administered intravenously every 6 months; it can also be used in PPMS), ofatumumab (administered subcutaneously every month), and ublituximab (administered intravenously every 6 months). S1P receptor modulators include: fingolimod, a non-selective modulator taken orally every day (treatment with this drug should be initiated under EKG monitoring, as it may cause bradycardia, as well as under ophthalmic monitoring to assess the macula); ozanimod, a selective modulator of S1P1 and S1P5 receptors with a more favorable safety profile; ponesimod, a selective modulator of the S1P1 receptor; and siponimod, a selective S1P receptor antagonist, used for treating certain forms of SPMS. Natalizumab is also an S1P receptor modulator, administered once a month either intravenously (IV) or subcutaneously (SC). Patients who are seropositive with elevated levels of anti-JCV titers should not be treated for more than two years due to the risk of developing progressive multifocal leukoencephalopathy (PML) [6,17].

Drugs used for induction treatment include: alemtuzumab, administered intravenously once a year in two cycles, and cladribine, taken orally in two cycles during the first and second years. Other drugs in this group include fumarates, interferon beta, glatiramer acetate, and mitoxantrone [17].

In addition to disease-specific treatment, symptomatic medications, and rehabilitation play a vital role. Only comprehensive treatment can bring a positive therapeutic effect.

3. Molecular Factors Important for Pathogenesis of Multiple Sclerosis

The identification of reliable biomarkers in MS is critical for advancing our understanding of the disease’s underlying pathomechanisms and for enabling precise monitoring of its progression. Such biomarkers are also essential for improving the accuracy of diagnostics and tailoring interventions to individual disease dynamics. Among the various mechanisms involved in MS, synaptic plasticity has emerged as a key compensatory process, facilitating neural reorganization and functional recovery in response to damage. This section focuses on biomarkers of synaptic plasticity and their potential role in elucidating the adaptive processes underlying disease progression.

Brain-derived neurotrophic factor (BDNF) is a critical neurotrophin involved in the regulation of neuronal survival, differentiation, and plasticity in the adult human brain. Its role in synaptic plasticity is essential for the induction and maintenance of LTP, a cellular mechanism underlying learning, memory, and adaptive neural processes. Through the activation of its high-affinity receptor, tropomyosin receptor kinase B (TrkB), BDNF initiates intracellular signaling pathways that enhance synaptic strength and promote the recruitment of glutamate receptors (e.g., α-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) and N-methyl-D-aspartate (NMDA)) to the postsynaptic membrane. BDNF also increases intracellular calcium levels in key brain regions, including the cortex and hippocampus, playing a crucial role in synaptic plasticity and cognitive functions. This process is mediated through the activation of TrkB receptors and the phospholipase C-γ (PLC-γ) signaling pathway. Upon activation by BDNF, PLC-γ hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP₂) into inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG). IP₃ binds to its receptors on the endoplasmic reticulum, triggering the release of calcium ions (Ca²⁺) into the cytoplasm. This rise in intracellular Ca²⁺ activates key signaling molecules such as calcium/calmodulin-dependent protein kinase II (CaMKII), which are critical for LTP and the formation of new synaptic connections. Simultaneously, DAG contributes to the activation of protein kinase C (PKC), further enhancing signaling cascades that promote synaptic remodeling [18]. Through these mechanisms, BDNF facilitates adaptive changes in the nervous system, including synaptic reorganization, dendritic spine growth, and stabilization, which are essential for learning, memory, and recovery from neural damage. Moreover, BDNF exerts a modulatory effect on neurotransmitter release, influencing both excitatory (glutamate) and inhibitory (gamma-aminobutyric acid (GABA)) systems, thereby maintaining the delicate balance of neural activity required for optimal function [19]. In the context of neuroinflammation, BDNF assumes a neuroprotective role, providing trophic support that enhances neuronal resilience and supports neurogenesis [20]. A growing body of evidence indicates that BDNF levels are significantly reduced in individuals with MS, which may compromise the brain’s capacity for compensatory synaptic plasticity and exacerbate functional impairments [21]. These findings underscore the importance of BDNF as both a biomarker for disease progression and a potential target for therapeutic interventions aimed at enhancing neuroprotection and promoting neural repair.

Interleukins are critical biomarkers of synaptic plasticity, particularly in the context of neuroinflammation. During the active phase of MS, levels of pro-inflammatory interleukins (IL), including IL-1β, IL-2, IL-4, IL-6, IL-13, IL-17, IL-21, IL-22, and IL-33, are significantly elevated. This increase is strongly associated with cognitive decline and hippocampal dysfunction, largely due to the disruption of LTP, a fundamental mechanism underlying synaptic strengthening, learning, and memory [22]. Moreover, elevated levels of interleukins suppress BDNF activity, thereby impairing the brain’s capacity for neural adaptation, repair, and functional reorganization in response to injury [23]. The inflammatory response in MS is further amplified by tumor necrosis factor-alpha (TNF-α), which exhibits a synergistic relationship with interleukins such as IL-1β and IL-6. TNF-α plays a dual role in the disease; its soluble form exacerbates neuroinflammation and neuronal damage, whereas its membrane-bound form may exert neuroprotective effects, reflecting a complex interplay of inflammatory mediators in MS pathophysiology. Additionally, interleukin-driven inflammation significantly influences the polarization of microglial cells, the resident immune cells of the central nervous system. Pro-inflammatory cytokines, such as IL-1β and TNF-α, promote the M1 microglial phenotype, characterized by the release of reactive oxygen species and pro-inflammatory mediators that exacerbate synaptic dysfunction and neuronal injury [24]. In contrast, cytokines such as IL-10 play a pivotal role in promoting the polarization of microglia towards the M2 phenotype, which is associated with anti-inflammatory signaling, tissue repair, and the clearance of cellular debris. However, in patients with MS, the levels of IL-10 are typically reduced, thereby impairing the microglial-mediated resolution of inflammation and repair processes [25]. The balance between M1 and M2 microglial states is a critical determinant of the progression or resolution of neuroinflammation, underscoring their potential as therapeutic targets in MS.

Serotonin (5-HT) plays a critical role in modulating both immune system activity and synaptic plasticity, which are particularly relevant in the context of MS. In acute inflammatory conditions, 5-HT facilitates the recruitment of innate immune cells to sites of inflammation, aiding in the regulation of immune responses. A reduction in 5-HT levels, however, may impair the immune system’s ability to effectively resolve inflammation, potentially contributing to chronic neuroinflammation and exacerbating neuronal damage [8]. In the realm of synaptic plasticity, 5-HT serves as a key neuromodulator, influencing the formation of new synaptic connections and strengthening existing ones. Through the activation of 5-HT receptors, 5-HT supports mechanisms such as LTP and the structural remodeling of dendritic spines, processes essential for neural adaptation and repair. In MS, 5-HT levels are reduced, largely due to diminished availability of the serotonin transporter (SERT) and tryptophan, its biochemical precursor. Pro-inflammatory cytokines, including IL-1, TNF-α, and IFN-γ, which are markedly elevated during the active phases of MS, upregulate the activity of the enzyme indoleamine 2,3-dioxygenase (IDO). This enzymatic induction shifts tryptophan metabolism away from 5-HT biosynthesis and towards the kynurenine pathway, resulting in a significant reduction in serotonin availability [26]. Research suggests that restoring 5-HT levels may not only slow disease progression but also enhance synaptic plasticity by promoting neuronal reorganization in response to damage [27]. This dual role in immune modulation and neuroplasticity highlights serotonin as both a biomarker of synaptic plasticity and a potential therapeutic target in MS, offering prospects for mitigating disease impact through improved immune regulation and neural repair.

Synaptic plasticity plays a pivotal role in compensating for demyelinating damage and facilitating functional adaptation. Consequently, biomarkers of synaptic plasticity hold significant promise for advancing therapeutic strategies in the treatment of MS.

4. Genetic Factors in Multiple Sclerosis

MS is a chronic autoimmune disease with a complex etiology involving interactions between genetic, environmental, and neurobiological factors. Among the most critical areas of research are genetic factors and synaptic plasticity mechanisms, which play a pivotal role in the disease’s pathogenesis and the nervous system’s ability to adapt and compensate for damage caused by demyelination and neurodegenerative processes [28].

Genetic factors are fundamental to susceptibility to MS. The strongest genetic association has been observed in the major histocompatibility complex (HLA), particularly the HLA-DRB115:01 allele, which significantly increases the risk of developing MS. The HLA complex is essential for presenting antigens to immune cells, a process critical in autoimmune diseases such as MS [29]. The HLA-DRB115:01 variant enhances T lymphocyte activity against myelin antigens, leading to heightened inflammation and nervous system damage [30]. Conversely, other HLA variants, such as HLA-A*02:01, may exert protective effects, reducing the risk of disease. Genetic studies reveal that polymorphisms in the HLA region profoundly influence disease progression, impacting symptom severity and treatment response [31].

Additionally, numerous genes outside the HLA region have been identified as influencing MS susceptibility and disease course. The IL7R gene encodes a receptor for interleukin 7, a cytokine critical for the development and function of T and B lymphocytes. Polymorphisms in IL7R can alter receptor activity, disrupting immune homeostasis and increasing autoimmunity risk [32]. Similarly, the IL2RA gene, encoding the interleukin 2 receptor, is crucial for regulating regulatory T cells, which suppress autoimmune responses. Mutations in IL2RA can impair regulatory T cell function, promoting MS pathogenesis [33].

Another gene linked to MS is TYK2, which encodes a kinase protein involved in cytokine signaling pathways, including those of interferons and interleukins. Polymorphisms in TYK2 may modify immune cell responses to inflammatory stimuli, directly influencing neuroinflammatory processes [34]. Genes associated with vitamin D metabolism, such as CYP27B1, are also significant in MS, as vitamin D is a potent modulator of the immune response. Mutations in these genes can impair vitamin D activation, correlating with an increased risk of MS, particularly in populations with limited sun exposure [35].

Genes encoding proteins related to blood–brain barrier function, such as ICAM-1 and VCAM-1, are also relevant. Increased expression of these proteins facilitates immune cell migration into the central nervous system, exacerbating inflammation and contributing to the formation of demyelinating lesions [36].

Synaptic plasticity mechanisms the nervous system’s ability to reorganize and adapt in response to environmental changes or damage constitute another critical component in MS. Demyelination and neurodegeneration disrupt neural signal conduction, leading to neurological deficits. However, synaptic plasticity enables partial compensation for such damage through increased synaptic connections, altered synaptic efficacy, or activation of alternative neural pathways [37].

At the molecular level, synaptic plasticity is regulated by factors such as neurotrophins, including BDNF. BDNF plays a crucial role in neuronal survival, synaptogenesis, and regeneration [38]. In MS, reduced BDNF expression in damaged areas can limit the nervous system’s regenerative capacity. Additionally, altered functioning of synaptic receptors, such as AMPA and NMDA receptors, may affect neuronal signaling and adaptation [39,40]. These processes occur at various levels of nervous system organization, including individual synapses, neuronal networks, and entire brain regions.

Synaptic plasticity encompasses both short-term mechanisms, such as postsynaptic potentiation (PSP), and long-term mechanisms, such as LTP and LTD. These activity-dependent mechanisms enable modifications in synaptic strength in response to experiences or damage. For instance, when axons are damaged in MS, neighboring neurons can strengthen their synaptic connections, partially preserving function [41].

The role of glial cells, particularly astrocytes and microglia, in synaptic plasticity is increasingly recognized. Astrocytes regulate the synaptic environment by controlling ion and neurotransmitter concentrations, crucial for synaptic transmission efficiency. Microglia, on the other hand, prune unused synapses, promoting adaptive reorganization of neuronal networks [42]. In MS, microglial activation and inflammatory processes can either support or hinder synaptic plasticity, depending on the context.

Genetic factors and synaptic plasticity are intricately connected. Genetic polymorphisms affecting the expression of neurotrophins and other plasticity-related proteins may influence the nervous system’s adaptive capacity in MS. For example, the Val66Met polymorphism in the BDNF gene affects BDNF secretion and is associated with differences in brain regenerative potential [43]. Inflammatory processes characteristic of MS also impact synaptic plasticity. Pro-inflammatory cytokines, such as TNF-α and IL-1β, can disrupt synaptic function and lead to degeneration, limiting the brain’s adaptability [44].

Understanding the interplay between genetic factors and synaptic plasticity is critical for developing effective therapeutic strategies in MS. Interventions aimed at enhancing synaptic plasticity, such as neurophysiological rehabilitation or drugs modulating BDNF activity, may improve neurological function and quality of life [43]. Gene therapies hold promise for reducing genetic risk and supporting nervous system adaptability. Moreover, identifying biomarkers related to plasticity and genetic factors could aid in predicting disease progression and treatment response.

5. Kinesiotherapy in Multiple Sclerosis

Kinesiotherapy is a part of physiotherapy, alongside physical therapy, manual therapy, and special rehabilitation methods. Numerous analyses have shown that kinesiotherapy training in a group of patients with MS improves aerobic capacity and muscle efficiency [45,46], reduces symptoms of fatigue [46], improves endurance and gait quality, assessed using the 6MWT [47], and significantly affects balance, especially in people with mild or moderate disability [48]. Studies show a small, but statistically significant reduction in depression symptoms, and a small improvement in quality of life, depending on the functional status of the patient [49]. Exercise is an effective symptomatic treatment (tertiary prevention). More recent analyses assess the disease-modifying effects (secondary prevention), as well as the impact on the risk of developing MS (primary prevention), explaining why exercise and physical activity have been suggested as a “cure for MS” [48]. Significant statistical benefits of physical activity also apply to the structure of brain tissue. The recommended activity level is moderate-to-vigorous physical activity (MVPA).

Moderate physical activity based on a treadmill walking training program leads to potential improvement in memory and learning [50]. Another very important advantage of moderate physical activity is its effect on some cytokines that reduce inflammatory processes. In the presented analysis, IL 6 neither increased nor decreased, but TNF-α in the blood of physically active patients with people with multiple sclerosis (PwMS) showed an anti-inflammatory effect [51]. Light resistance training plays an important role in modeling pro-inflammatory cytokines and BDNF [52]. Higher BDNF levels are associated with improved memory, the dysfunction of which is observed in patients with MS [53]. Studies have shown the effectiveness of exercise as a symptomatic treatment in patients with MS [54].

Physical activity, apart from the health benefits documented in many studies, also reduces mortality in people with MS [55]. Both physical activity as a lifestyle and rehabilitation in this group of patients with multiple sclerosis must be adapted to the level of disability, which is assessed using the EDSS 0–4.5; 5.0–6.5; 7.0–9.0. Patients diagnosed with MS, as studies show, are much less active than people without neurological diseases and without dementia, and considering the chronic nature of the disease, activity should be necessary and continued regularly [49].

MS patients rarely engage in moderate and vigorous activity, which has documented health benefits for both the general population and the disabled [56,57]. However, physical activity in this group of patients is not only safe but also effective and, most importantly, is not associated with an increased risk of disease escalation [58]. Promoting a healthy lifestyle has been considered a priority as one of the aspects facilitating coping with the disease and its consequences [45,46].

Recently, a systematic review has been published analyzing the modern approach to assisting in the implementation of physical activity and programmed rehabilitation for MS patients. The assessment was made by incorporating a telerehabilitation system in the home environment. The analysis of scientific reports suggests that telemonitoring of physical activity is safe and effective, similar to traditional forms of classes. The potential of telerehabilitation is emphasized, allowing for flexible adjustment to the time and place of the training program, as well as the possibility of long-term implementation of physiotherapy recommendations without visiting a rehabilitation center [54,59]. Thanks to the widespread availability of the Internet and the development of information technologies, telerehabilitation is increasingly used in the rehabilitation of patients after stroke [60] and, with very good results, in cardiac rehabilitation, even in patients with advanced heart failure, in which improving muscle efficiency and performance, similarly to MS patients, is a key goal of rehabilitation programs based on physical activity [56,61,62]. Patient monitoring is performed using various methods, through consultations with a doctor, mobile applications and digital platforms, or remote monitoring of devices worn on the patient’s body, e.g., motion sensors. Such a system allows for greater effectiveness of activity, and thus improvement of well-being in long-term care [63]. Analyses conducted to date suggest the safety and effectiveness of exercises performed under the supervision of telerehabilitation. However, a small number of scientific analyses do not allow for the full determination of the efficiency, safety, and effectiveness of this form of monitoring, indicating the need for further research in this area [64].

In 2020, recommendations were issued supported by the Multiple Sclerosis Treatment Centers Consortium regarding an active lifestyle for every person with MS as beneficial and safe [57]. It was emphasized that functional classification is necessary before starting the activity so that the programmed effort does not lead to excessive muscle fatigue causing conduction blockage and allows for continuous progression of effort. Taking into account comorbidities in SM patients and their variable well-being, the recommended physical activity should be at least 150 min per week. It is clearly recommended that the mentioned 150 min per week (30 min per day) should be performed as a leisure time activity, promoting activity related to lifestyle [45,56,65,66]. Physical training and physical activity are essential elements of the procedure in dealing with the consequences of the disease [67].

Similar recommendations apply to primary prevention of cardiovascular diseases: at least 150–300 min of moderate-intensity physical activity per week or 75–150 min of high-intensity physical activity per week. Elderly people are particularly distinguished, with interval physical activity recommended, even for <10 min. Such exercise results in reduced overall mortality and mortality due to cardiovascular causes [68,69].

In patients diagnosed with MS, lifestyle-related physical activity differs from typical rehabilitation activities, which are defined as regaining or maintaining optimal physical fitness, promoting functional independence, preventing complications, and improving the overall quality of life [70].

When verifying rehabilitation and physical activity, the Borg Rating of Perceived Exertion (RPE) is recommended for the subjective assessment of effort intensity [71].

Recommendations regarding rehabilitation exercises as secondary prevention and physical activity as part of lifestyle concern patients with EDSS 1–6, and sometimes even 7, and >18–65 years of age, occasionally up to 70 years of age. The duration of studies also varies greatly, usually from 4 to 14 weeks [51,72,73,74,75,76,77,78,79]. The exceptions are a pilot study where observation was conducted for 2 weeks [80] and a study in which observation was conducted for 48 weeks and concerned the early stage of the disease (

Table 1. Depending on the expanded disability status scale (EDSS), different forms of exercise are recommended.

EDSS	Aerobic Exercise
0–4.5	Frequency and duration	Intensity	Type of activity	Evaluation of effects
	2–3 times/week 10–30 min	From 40 to 60% (VO2 peak) or (HRpeak), Max 11–13 RPE [56,67,75,82,83]	Arm cycling, leg cycling, treadmill or overground walking, rowing, running, aquatic activities	6MWT, TUG (static and dynamic balance) [56,67,73,75,77,84]
	Advanced, aerobic exercise prescription
	Frequency and duration	Intensity	Type of activity	Evaluation of effects
	5 times/week up to 40 min., extend the time gradually, 1 time/week	70% VO2 peak, or 80% HRpeak [45,76] can approach a 15 on the 20 RPE scale, increase the intensity gradually five 30–90 s intervals at 90–100% maximum HR effort (e.g., 80–95% maximal HR) recovery (e.g., 40–50% maximal HR), RPE, 14 [85]	The same as the general guidelines but may be extended to running, road cycling, and Nordic walking, HIIT, cycle ergometer	6MWT, TUG (static and dynamic balance), [56,67,73,75,77,84] RPE, assessed every minute after warm-up until completion during CPET and all HIIT, VO2 peak
	Resistance training
	Frequency and duration	Intensity	Type of activity	Evaluation of effects
	2–3 times/week, 2–4 sets for each exercise, 8–15 repetitions/set, rest for 1–2 min between each set and exercise, from 4 to 16 weeks	Intensity from 40% to 80% 1-RM [76,79]	FVCRT, fast-velocity concentric resistance training, free weights, elastic resistance bands, or bodyweight exercises [74,75]	Lower limb—the maximum isometric voluntary contraction (MVIC) during knee extension; upper limb, hand grip strength, isometric handgrip strength measure for d 5; gait speed, 10 MTW, 10 m walk test; walking Endurance, 6-MWT; Fatigue (FSS) [75,77]
	Flexibility
	daily, 2–3 sets of each stretch, hold 30–60 s/stretch; exercises 10 min warm-up 20 min 10 min cool-down [56,86]	30–50% of maximum CPT cardiopulmonary test 15–30 1RM, 12 repetitions at a load equivalent to 30% of 1-RM, rest 2–3 min between sets [45,76]	Aerobic-gait training which included forward, sideways, and backward walking, integrated with 90 and 180 turning and tandem gaitstrength training, stretching exercises for upper and lower limbs and trunk muscles relaxation, postural control, and spine mobility exercises followed by post-stretching, including yoga [56,86]	GPS, GVS, ROM, hip, knee, and ankle joints [56,86]
	Balance training
	Frequency and duration	Intensity	Type of activity	Evaluation of effects
	8 week period plus [48,86]	2 min of high resistance pedaling, 40% of the tolerated maximum workload, 15 sets ofrepetitions each session, 30–35 min training (warmup walking, balance exercises and stretching) [48,86]	ACSM-based resistance training periods in combination with simultaneous electrostimulation [86,87], cycling, progressive resistance training, home-based exercise program to improve lower limb muscle strength and balance [48,86]	Timed get up and go, timed 25 foot walk, two-minute walk test, functional reach and Rivermead Mobility Index, FES, DGI [86,87] TUG, FR (cm), DGI (0–24), FES [81,83]
5–6.5	Same as above. ✓ Additionally, implement exercises that reduce the risk of falls [56,88] ✓ Reduce intensity wg RPE ✓ Adapt rehabilitation equipment (e.g., hand cycle)
7–7.5	Frequency and duration	Intensity	Type of activity	Evaluation of effects
	Up to 20 min/day, 3–7 days/week Every second day, 1 time/day 3 times/week, 3 sets, 10 repetitions/set or 10 sets, 3 repetitions/set 3–5 times/week 30 min 3 times/week, 30 min, 2–5 times/week, 30–60 min 2 times/day, 4–5 3–5 min/day [1,42] Every 1–2 h	3 sets, 10 repetitions ≥30–60 s, Six 3-min intervals at 70% target HR	Breathing exercises with resistance training equipment, flexibility, hold/stretch, upper extremities, lower extremities, power assist cycling standing [53], walking on the treadmill, core, repetitions of seated isometric abdominal muscle per 10–15 s, moving or stationary seated balance posture exercises, hold for 10–15 s	AMCA, Amended Motor Club Assessment) [56,89]

FVCRT, fast-velocity concentric resistance training; 1-RM, one repetition maximum; TUG, timed up and go test; 10 MTW, 10-m walk test; 6-MWT, 6-min walk test; FSS, fatigue; HIIT, high-intensity interval training; VO₂ peak, peak oxygen consumption; GPS, gait profile score; GVS, gait variable score; ROM, range of motion; CPT, cardiopulmonary test; FES, falls efficacy scale; ACSM, American College of Sports Medicine; DGI, Dynamic Gait Index; FR, functional reach; AMCA, Amended Motor Club Assessment.

) [81].

In order for each patient to benefit from exercise and physical activity, taking into account individual differences at each level of disability, a number of options have been presented. Each should be individually adapted to the patient’s level, taking into account the EDSS. People with mild disabilities obviously have much greater opportunities to use different forms of exercise, which allows for more effective improvement in selected physiological and functional parameters [53,56,67,72,73,74,77,82,83,84,88,90].

A significant element of rehabilitation of patients with MS is walking training, the basis for the assessment of EDSS, positively verified and assessed in a number of works by the team of researchers under the direction and with the participation of Motl et al. [55,67,91]. On the other hand, the TUG (timed up and go) test, DGI (Dynamic Gait Index), 2MWT (2-min walk test), and 6MWT (6-min walk test) have strong predictive properties for assessing the effects of walking training, described in detail by the team of Bennett et al. [92].

Resistance training appears to be a very promising form of training for MS patients, as it not only improves muscle strength, which is necessary for efficient and safe functioning in everyday life, but also plays a significant role in reducing pro-inflammatory cytokine factors, improves cognitive functions, increases BDNF levels, lowers EDSS levels, and thus improves the quality of life [51,52,74,75,85]. In 2022, a very important study was presented indicating the benefits of high-velocity concentric resistance training of the lower limbs. The study included 30 people with MS. It was shown that fast concentric resistance training accelerates the rate of development of strength, mobility, and quality of life and is more beneficial than eccentric training [74]. Another study, much earlier, assessed the torque of the quadriceps and biceps muscle groups. The assessment was made using the KIN-COM II isokinetic dynamometer during concentric and eccentric contractions. The study showed that a strengthening program that places greater emphasis on concentric exercises may be more effective in treating muscle deficits [87,92].

Another study that proved the superiority of high-velocity concentric resistance training (FVCRT) in improving both lower and upper limb strength was the work of Andreu-Caravaca et al. [74] The training group included 18 patients with EDSS from 1 to 6.2. Training was conducted three times a week for 10 weeks. The study hypothesis assumed improvement of lower and upper limb strength, which has not been assessed in MS patients so far without the use of targeted training to improve upper limb muscle endurance.

Lower limb strength was assessed using an isokinetic dynamometer, and upper limb strength using an electronic handheld dynamometer. In addition, gait speed (10-MWT-10 m walk test), walking endurance (6MWT), and fatigue using the fatigue severity scale (FSS) were assessed. The study showed an improvement in hand grip strength by 12.53% in the right hand and by 32.41% in the left hand. An important conclusion from the presented analysis is the influence of only FVCRT training on both the strength parameters of the lower and upper limbs, as well as the parameters improving the quality and efficiency of gait [78].

Hand grip strength (HGS) has an impact on functional disability and all-cause mortality. It is associated with poor health outcomes and chronic diseases [76]. Another important study evaluating HGS is the assessment of cognitive function in older adults. It has been shown that exercise to improve HGS may delay cognitive function [93,94], and since long-term assessments of cognitive function show significant decline [95], the use of exercise to improve HSG becomes doubly important because of its impact on both gait and cognitive function.

A very important study for the rehabilitation of patients with MS is the study by Hubbard et al. [85], which assessed the physiological effects of single sessions of HIIT (high-intensity interval training) and CON (continuous training). The research group included 20 people aged >18 to 64 years old with ESDD 4.0–6.5. The qualification for endurance training and its effects were assessed based on VO₂ peak (peak aerobic capacity) in the CPET (cardiopulmonary exercise test), RER (respiratory exchange ratio), and respiratory exchange ratio RPE. It was hypothesized that HIIT training produces more beneficial physiological effects than CON. The hypothesis turned out to be correct. It was feared that HIIT would lead to an increase in core temperature. This hypothesis proved to be incorrect. Core temperature did not increase, which is perceived favorably [78]. Greater effectiveness of HIIT training was also noted in a study from 2011, which included 61 patients (55 completed). The training program lasted 12 weeks (2x a week) and consisted of cycloergometric cycling training conducted using three methods: high-intensity interval training, continuous training, and a combination of both methods. Greater objective benefits were achieved in the group of patients using high-intensity training (90% peak load power). The basis for verifying the effects of the rehabilitation was the 2-min walk test and timed up and go test (TUG) [76].

Campbell et al. [78] wrote about the greater effectiveness and safety of high-intensity training in their literature review.

6. Kinesiotherapy and Diagnostic, and Prognostic Factors in Multiple Sclerosis

Rehabilitation in MS is a crucial process aimed at supporting patients in achieving and maintaining optimal physical, psychological, social, and vocational potential. A vital element of this rehabilitation is physiotherapy, particularly kinesiotherapy. The main goal of kinesiotherapy is to restore lost functions or to guide compensatory processes in such a way as to maximize the patient’s adaptive capabilities. Encouraging physical activity is important at every stage of the disease.

In the initial phases of MS, kinesiotherapy should be based on exercises preferred by the patient. As the disease progresses, movement therapy becomes increasingly focused on improving specific motor dysfunctions; however, it remains crucial to include activities that previously brought the patient satisfaction [96,97].

Physiotherapy, including kinesiotherapy, is used in symptomatic treatment and supports pharmacotherapy, impacting all motor disorders associated with the disease. Kinesiotherapy not only reduces primary and secondary symptoms but also enables the creation of functional compensations. Exercise training is considered safe for MS patients. Patients show expected physiological responses to submaximal aerobic exercise. Heart rate, blood pressure, and oxygen uptake increase proportionally with increasing workload. Individuals with minimal or moderate dysfunctions usually tolerate physical activity best, emphasizing the importance of early introduction of kinesiotherapy [98].

When planning kinesiotherapy, MS phenotypes can be considered, or the exercise program can be adjusted to the stage of disease progression. The use of appropriate scales and functional assessment tests is key in choosing therapy. The EDSS is commonly used to assess progress in locomotion. Other scales used to assess the patient’s functional status include the MSIS-29 (MS Impact Scale), the Functional Independence Measure, the Barthel Index, and the Lovett Scale [99].

The oxidative capacity of muscles in MS patients indicates significant impairments, such as reduced maximal oxygen uptake, smaller cross-sectional area of type I skeletal muscle fibers, lower succinate dehydrogenase activity, and complex I deficiency in skeletal muscle mitochondria compared to healthy individuals. These findings suggest reduced muscle oxidative capacity, which should be considered when programming kinesiotherapy at various disease stages.

6.1. Diagnostic Factors

Electrophysiological and neuroimaging studies reveal both spontaneous and physiotherapy-stimulated plastic changes in the nervous system. Research is ongoing to find correlations between physical activity and the recovery of motor and cognitive functions in MS patients. BDNF seems to play a significant role in this context. BDNF is a key neurotrophic factor involved in neuronal survival, proliferation, and regenerative processes. Increased BDNF levels have been observed as a result of systematic physical activity. Briken et al. [100] highlighted that BDNF is strongly induced during intense exercise, even in patients with progressive MS and advanced disability. However, the long-term effects of exercise programs on biological parameters seem less pronounced. The literature suggests that kinesiotherapy may support regenerative processes in the CNS. This conclusion, however, requires further verification in studies with larger patient groups [100,101,102,103,104].

It is important to note that secondary symptoms in patients with progressive MS progress faster than in those with RRMS. In patients with progressive forms of MS, spasticity significantly impairs daily functioning. Kinesiotherapy alone often fails to sufficiently reduce muscle stiffness, necessitating a combination of physiotherapy and pharmacotherapy. Electrostimulation, such as using the Exopulse Mollii Suit (EMS), is also being explored. For progressive muscle weakness leading to limb paresis and chronic fatigue, exercises aimed at increasing muscle strength can yield beneficial results, especially in aquatic therapy [105].

Physiotherapy selection must be closely tied to the individual needs of the patient, considering their overall health, symptoms, functional capacity, age, and psychological condition. The variability of symptoms makes effective therapy selection difficult, emphasizing the importance of understanding the patient’s challenges.

Kinesiotherapy, as an integral part of MS treatment, aims to alleviate symptoms, improve motor function, and support adaptation to the disease. With proper planning and customization to individual needs, it can significantly improve quality of life.

The McDonald criteria are used to confirm an MS diagnosis. These guidelines rely on demonstrating dissemination in time (DIT) and space (DIS) of demyelinating lesions. Evidence of neurological symptoms from different brain areas at different times is required. These symptoms may include vision problems, sensory disturbances, muscle weakness, and coordination difficulties. Diagnosis requires clinical evaluation and additional tests such as MRI and cerebrospinal fluid (CSF) analysis. MRI assesses inflammatory lesions, requiring at least one lesion in two typical demyelinating areas with evidence of multiphasic disease. These lesions are typically irregular, asymmetric, and of varying size (>3 mm). Spinal cord MRI often reveals lesions, especially in the cervical region (>75%). In CSF, the presence of oligoclonal bands of IgG without serum oligoclonal bands, and elevated IgG index, significantly increases the likelihood of an MS diagnosis (up to 97%). It is crucial to exclude other diseases with similar presentations [106,107,108,109].

6.2. Prognostic Factors

The prognosis for MS patients has improved significantly in recent decades due to disease-modifying therapies (DMTs). However, predicting long-term outcomes with DMTs is challenging due to the limited time these treatments have been available. A 16-year study showed that 18% of patients with RRMS transitioned to SPMS, and 11% developed sufficient disability requiring mobility assistance. The estimated quality of life loss is 13.1 adjusted life years per patient. Modifiable risk factors associated with disease progression include low vitamin D levels and smoking. Progressive MS forms tend to have an earlier onset of irreversible disability, with most patients experiencing mild to moderate disability at diagnosis. Risk factors for progression from RRMS to SPMS include older age at onset, male sex, high initial relapse rate, longer disease duration, higher initial disability score, greater lesion burden on imaging, and smaller brain volume. Despite advances in RRMS treatment, options for progressive MS remain limited [110,111,112,113]. The prognosis for MS is complex and depends on multiple factors affecting disease course and symptoms (see table below,

Table 2. Prognostic factors in multiple sclerosis [111,113].

Factors Favoring a Better Prognosis	Factors Indicating a Worse Prognosis
Caucasian Race	Non-Caucasian Race
Female	Male
Younger Age at Onset	Older Age at Onset
Monofocal Onset (single symptom onset)	Multifocal Onset (multiple symptom onset)
First Symptom: Optic Neuritis or Isolated Sensory Disturbances	First Symptoms: Motor, Cerebellar, or Sphincter Disturbances
Long Remission After First Relapse	Short Remissions Between Relapses
Minimal Cortical Plaque Involvement	Early Cortical Plaque Involvement
Low Relapse Frequency in the First 2–5 Years	High Relapse Frequency in the First 2–5 Years
Mild Relapse	Severe Relapse
No or Minimal Disability After 5 Years	Disability After 2 or 5 Years
Low Number of Demyelination Lesions on MRI	High Number of Demyelination Lesions on MRI
Early Treatment Initiation	Delayed Treatment Initiation
Absence of Oligoclonal Bands of IgG and IgM	Presence of Oligoclonal Bands of IgG and IgM
Higher Income and Education, Higher Health Literacy, and Positive Disease Perception	Lower Income and Education, Lower Health Literacy, and Negative Disease Perception

).

In the case of MS patients, it is also necessary to mention health inequalities [112]. MS has a diverse clinical picture. Patients may be affected by the disease to a different extent. For example, they may use a wheelchair or be fully functional in terms of physical fitness. The symptoms they experience may be limited to physical (mobility, physiological symptoms), but may also include intellectual difficulties (problems with memory, concentration, impaired cognitive functions) and mental (low mood, depression, psychotic disorders). This diversity of clinical symptoms causes patients to assess the disease both as suffering or a burden and as a challenge. This cognitive assessment has a huge impact on the choice of ways to cope with MS, and as a result, the effectiveness of this process may depend on it to a significant extent. Moreover, there is evidence that social determinants of health (SDOH) influence health outcomes across ethnic and racial groups. Recently, SDOH has been shown to influence the development of MS in select racial groups. Greater health disparities in autoimmune diseases have also been found in individuals with lower income and education, lower health literacy, and negative disease perceptions [113].

7. Conclusions

MS is a chronic neurological disease of unknown etiology, which significantly reduces the quality of life with this neurological disease. In the course of MS, the body’s immune response is disturbed, and synaptic plasticity processes are disturbed. Synaptic plasticity is a dynamic and complex process critical for the nervous system’s adaptation to damage and changes associated with MS. Understanding its mechanisms and modulators offers new therapeutic opportunities to support regeneration and enhance the quality of life for patients with MS.

Kinesiotherapy in MS is a complementary method to pharmacotherapy. Before starting the rehabilitation process, an in-depth diagnostic assessment of the patient’s condition should be carried out and the patient’s mental state, neurological state, and consciousness should be taken into account. The physical activity program (kinesiotherapy) in MS assumes a gradual transition from basic movements to more complex ones until global functions are achieved. It seems that physical activity, regardless of the stage of the disease, will increase the functional capabilities of all body systems and thus may contribute to improving the health of patients with MS and improving their quality of life.