Multiple Sclerosis: Clinical Guidelines

List of Abbreviations

APS – antiphospholipid syndrome

ULN – upper limit of normal

WI – weighted image

SPMS – secondary progressive multiple sclerosis

GC – glucocorticoids

GGT – gamma-glutamyl transferase

ITP – immune thrombocytopenia

CA – contrast agent

CIS – clinically isolated syndrome

MoH – Ministry of Health

MRI – magnetic resonance imaging

MES – medico-economic standards

ADR – adverse drug reaction

NMO – neuromyelitis optica

NMOSD – neuromyelitis optica spectrum disorders

ADEM – acute disseminated encephalomyelitis

DMT – disease-modifying therapies

PPMS – primary progressive multiple sclerosis

PCR – polymerase chain reaction

RIS – radiologically isolated syndrome

РКИ – randomized controlled trial

RRMS – relapsing-remitting multiple sclerosis

MS – multiple sclerosis

SLE – systemic lupus erythematosus

ESR – erythrocyte sedimentation rate

TSH – thyroid-stimulating hormone

CNS – central nervous system

CSF – cerebrospinal fluid

EDSS – Expanded Disability Status Scale

FS – Functional Systems (Kurtzke Functional Systems Scale)

IgG – immunoglobulin G

IgM – immunoglobulin M

MSIF – Multiple Sclerosis International Federation

** – vital and essential drugs

# – drug used off-label (not in accordance with the indications, contraindications, routes of administration, or dosages specified in the drug's package insert)

Terms and Definitions

MRI activity of MS – a condition determined by MRI data, characterized by the appearance of new and/or enlargement of old lesions on T2-WI and/or the presence of gadolinium-enhancing lesions on T1-WI in the brain and/or spinal cord.

Dissemination in space – a classic criterion for MS included in the 2010 and 2017 McDonald criteria (Appendices A3.1 and A3.2), according to which a patient must have clinical evidence of lesions in at least two different areas of the central nervous system (CNS), or meet MRI criteria for dissemination in space, or a combination of these findings.

Dissemination in time – a classic criterion for MS included in the 2010 and 2017 McDonald criteria (Appendices A3.1 and A3.2), according to which a patient must have at least two clinical relapses, or meet MRI criteria for dissemination in time, or a combination of these findings.

Clinically Isolated Syndrome (CIS) – the first and single clinical episode of neurological dysfunction caused by damage to one or more parts of the central nervous system (CNS) lasting over 24 hours, while the findings of comprehensive clinical, instrumental, and laboratory evaluations do not meet the diagnostic criteria for MS (2010 and 2017 McDonald criteria). ICD-10 code G37.9

Therapeutic year – the period of disease-modifying therapy (DMT), starting from the time of onset of the drug's effect (which varies among DMTs), with a duration of 12 months.

Acute demyelinating episode – an acute development of clinical manifestations characteristic of MS or another demyelinating disease. ICD-10 code G36.9

Optimal treatment response – absence of relapses, absence or reduction of the rate of neurological deficit progression, and absence of MRI activity during the therapeutic year of DMT.

Suboptimal treatment response – clinical and radiological characteristics of the MS course and/or laboratory parameters during the therapeutic year of DMT that do not meet the resistance criteria, based on which a change of therapy is necessary (Appendix A3.7).

Treatment resistance – clinical and radiological characteristics occurring during the therapeutic year of DMT, based on which a change of therapy is necessary (Appendix A3.7).

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Multiple sclerosis (MS) – a chronic demyelinating disease based on a complex of autoimmune-inflammatory and neurodegenerative processes leading to multiple focal and diffuse lesions of the central nervous system, resulting in patient disability and a significant reduction in quality of life [1].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

There is a polygenic hereditary predisposition to MS. Currently, more than 200 genetic factors forming this predisposition have been identified. The predisposition is realized with the participation of external factors, among which viral infections (especially retroviruses and Epstein-Barr virus), vitamin D deficiency, early onset of smoking, changes in the gut microbiome, and other factors are considered primary [2].

Proinflammatory cytokines produced systemically and locally in the tissue by T and B cells cause the activation of autoreactive T lymphocytes and lead to autoimmune inflammatory damage of the CNS tissue. Neurodegenerative changes are noted even in the early stages of the disease. The activation of sensitized cell clones, along with an imbalance in the anti-inflammatory and regulatory functions of the immune system, contributes to the chronization of the process. Secondary activated macrophages and microglia also secrete proinflammatory cytokines [3].

1.3 Epidemiology of the Disease or Condition

Worldwide, there is an increase in the number of MS cases, which is associated both with improved diagnostics and enhanced capabilities of pathogenetic and symptomatic therapy, and with a true increase in incidence for reasons not yet fully understood. According to the publication "Atlas of MS" by the Multiple Sclerosis International Federation (MSIF), from 2008 to 2013, the prevalence of MS increased by 10% over 5 years, from 30 to 33 cases per 100,000 population. In the absence of adequate modern treatment, on average, after 10 years up to 50% of patients experience difficulties in performing professional duties, after 15 years more than 50% have difficulties with independent ambulation, and with an MS duration of more than 20 years, problems with self-care arise [4].

1.4 Features of Coding the Disease or Condition

G35 – Multiple sclerosis

G36.9 – Other acute disseminated demyelination, unspecified

G37.9 – Other demyelinating diseases of central nervous system, unspecified

1.5 Classification of the disease or condition

Types of multiple sclerosis course [1]:

Relapsing-remitting multiple sclerosis (RRMS) – a type of MS course characterized by the presence of relapses, between which there is no progression of disability. During remission, signs of a persistent neurological deficit may be present [5].

Secondary progressive multiple sclerosis (SPMS) – a type of MS course that occurs after a period of relapsing-remitting MS and is characterized by the presence of confirmed progression of disability independent of relapses [5]. With this type of MS, typical exacerbations of the disease may persist, between which confirmed progression of MS is observed. When clinical activity of MS (in the form of relapses) persists, the term active SPMS is used.

Primary progressive MS (PPMS) – a type of MS course characterized by confirmed progression of disability from the onset of the first symptoms of the disease, with possible periods of stabilization during which no increase in neurological deficit occurs. Continuous progression of symptoms for 1 year is considered sufficient; for diagnosis, a special section of the 2017 McDonald criteria is used [5]. In this form, typical relapses of the disease may be observed, between which there is confirmed progression of disability, however, the disease debuts not with relapses, but with progression [5]. In children and adolescents with MS, RRMS is almost always observed, sometimes with an acute onset resembling acute disseminated encephalomyelitis (ADEM), transitioning into SPMS. Since PPMS with pediatric onset is extremely rare and described in 3–6.7% of pediatric MS cases, such cases always require careful diagnostic clarification [6-8].

Since 2013, a new classification of disease course types has been implemented, which distinguishes non-active MS (without relapses and without signs of MS activity on MRI), active MS (presence of relapses or signs of MS activity on MRI), MS with progression, and MS without progression [9]. Gradual transition to this classification appears advisable; however, it significantly complicates the use of DMTs whose instructions for use list relapsing-remitting, secondary progressive, and primary progressive MS in the "indications" section [9].

Taking into account the specific features of the course, special variants of MS activity are distinguished:

- Malignant MS (Marburg disease) – an acute form of severe MS characterized by rapid worsening of disability without remissions and, in the most severe cases, death within a few months from disease onset. The development of massive lesions in the brainstem is characteristic; on MRI, these lesions typically actively enhance with paramagnetic contrast media. The Marburg-like variant can begin immediately after MS onset or replace a typical MS course at a certain stage. The frequency of this MS variant does not exceed 5%.

- Aggressive multiple sclerosis – a variant of MS activity in which a previously untreated patient (treatment-naive patient) may exhibit one of two disease course scenarios within one year of observation:

1) the development of 2 or more relapses, each of which led to confirmed worsening of disability (minimum EDSS score ≥2.5 as an outcome of these relapses) and was accompanied by the detection of 1 or more enhancing lesions on T1-weighted images or an increase in the number of lesions on T2-weighted images on brain and/or spinal cord MRI compared to the previous study [10];

or

2) the development of 1 relapse resulting in a sustained EDSS level ≥3.0 and accompanied by the detection of 2 or more enhancing lesions on T1-weighted images on brain and/or spinal cord MRI [11].

Stages of the disease:

Multiple sclerosis relapse – subjective (reported by the patient) and/or objective (detected on neurological examination) symptoms characteristic of an acute inflammatory demyelinating process in the CNS (focal or multifocal), either as an aggravation of already existing neurological symptoms or the appearance of new neurological symptoms not observed previously, with an acute or more often subacute onset, lasting more than 24 hours, with complete or incomplete regression of symptoms, provided there is no fever, other signs of infectious disease, preceding metabolic disorders, or stress phenomena [5].

In the case of sequential appearance of symptoms, they are considered a single relapse if a new symptom or group of symptoms, or a distinct worsening of existing symptoms, appears within a period of 24 hours to 30 days from the appearance of the first; and they are considered two separate relapses if there is a period of stable or improving condition lasting at least 30 days from the onset of the first to the onset of the second [5]. According to the 2017 revised McDonald criteria, the terms "relapse", "attack", and "exacerbation" are synonymous [5].

Multiple sclerosis remission – a period of absence of relapses, progression, and worsening of symptoms for at least 30 days; if a new symptom or group of symptoms, or a distinct worsening of existing symptoms appears within up to 30 days inclusive, remission is not recorded, and the condition is regarded as an ongoing relapse.

Confirmed worsening of disability – a persistent worsening of neurological impairment according to the EDSS scale (Appendices G1 and G2) following the end of a relapse, which has been confirmed by at least two EDSS measurements, one of which was performed no earlier than 30 days from the onset of the relapse, and the second no less than 3 months after the onset of the relapse [12]. A persistent worsening of neurological impairment is defined as an increase in the EDSS score by ³1.5 points for a baseline EDSS score of 0, by ³1.0 point for patients with a baseline EDSS score of 1.0–5.0, or by ³0.5 points for patients with a baseline EDSS score of ³5.5. Worsening of disability can be regarded as the contribution of a relapse to the accumulation of the patient's disability. At the same time, it must be taken into account that after severe relapses, a patient may exhibit an increase in the EDSS score at the very early stages, but this is not considered progression [10].

Confirmed improvement of disability – a persistent reduction in neurological impairment according to the EDSS scale (Appendices G1 and G2) compared to the baseline EDSS score. Confirmed improvement is established when a patient's reduction in the EDSS score compared to the first recorded reduction in neurological impairment persists at 6 months. A reduction in neurological impairment is defined as a decrease in EDSS by 1.0 point compared to the baseline EDSS score if the baseline EDSS was 2.0–5.5 points, or by ⩾0.5 points if the baseline EDSS was ⩾6.0 points [13]. In patients who have a relapse duration of more than 30 days with a gradual decrease in the EDSS score, this decrease cannot be regarded as a confirmed improvement of disability. The baseline point for calculating and measuring improvement is the EDSS measurement point after the resolution of the relapse. Reduction in disability should be considered as the best outcome of decreased inflammatory activity and rehabilitative care in patients with MS.

Confirmed progression of disability – a persistent increase in neurological impairment according to the EDSS scale (Appendices G1 and G2) compared to the baseline level, outside of relapse periods and not associated with a prior relapse. Confirmed progression is established when a patient's EDSS score remains elevated or increases compared to the date of the first recorded increase in neurological impairment after a minimum of 6 months, provided there are no relapses during the measurement period. A significant increase in neurological impairment is defined as an increase in EDSS by ³1.5 points for a baseline EDSS score of 0, by ³1.0 point for patients with a baseline EDSS score of 1.0–5.5, or by ³0.5 points for patients with a baseline EDSS score of ³6.0 [9]. The earliest period at which confirmed progression can be recorded is 3 months. Confirmed progression of disability at 6 months can be considered more reliable and important for routine clinical practice.

1.6 Clinical presentation of the disease or condition

Optic nerve involvement: unilateral optic neuritis (often with a retrobulbar localization of the lesion – retrobulbar neuritis), manifested by decreased visual acuity or the appearance of scotomas (often accompanied by pain upon eye movement), lasting for at least 24 hours (duration ranging from 2 to 4 weeks); less characteristic features include painless or persistently painful bilateral optic neuritis, complete and permanent loss of vision, optic disc edema, and other fundoscopic abnormalities.

Involvement of the cerebellum and its tracts: static-locomotor and dynamic cerebellar ataxia – gait instability, dysmetria and past-pointing in coordination tests, megalographia, asynergia, intention tremor, cerebellar dysarthria (scanning speech).

Brainstem involvement: internuclear ophthalmoplegia, nystagmus (central), abducens nerve dysfunction, hemifacial hypesthesia; less characteristic features include hearing loss, trigeminal neuralgia, peripheral facial palsy, facial myokymia.

Spinal cord involvement: central mono- and hemiparesis, lower paraparesis, pathway-type superficial sensory loss, impaired vibratory sensation, Lhermitte's sign, urinary urgency, urinary incontinence, urinary retention; less characteristic features include complete transverse myelitis syndrome, segmental sensory disturbances, radiculopathies, sensory ataxia, fecal incontinence.

Cerebral hemisphere involvement: subcortical cognitive deficit (impaired memory and attention, reduced speed of neuropsychological test performance), chronic fatigue or exhaustion, central hemiparesis, depression, less commonly anxiety, euphoria; hemianopia, acute behavioral disturbances, and epileptic seizures are less characteristic.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Commentary: The use of the 2017 revision of the McDonald criteria demonstrates higher sensitivity in patients at early stages of the disease compared to the 2010 revision of the criteria or the use of the MAGNIMS 2016 MRI criteria (Appendix A3.4), thereby allowing for an earlier diagnosis of MS. However, it should be noted that the specificity of the 2017 criteria is lower than that of the 2010 criteria [14]. To confirm the diagnosis, it is recommended to use the algorithm developed on the basis of the McDonald criteria (2017 revision) aimed at the earliest possible diagnosis (Appendix B – 1.1 and 1.2 [5]. In patients with an atypical onset, it is recommended to use the 2010 revision of the McDonald criteria (Appendix A3.2) [14]. Careful differential diagnosis will reduce the risk of an erroneous MS diagnosis [14–16].

Commentary: An international study validating the 2017 revision of the McDonald criteria for the pediatric population under 18 years of age demonstrated results that support their use in diagnosing MS in children [17]. A prospective cohort study involving patients under 18 years of age also demonstrated results supporting the use of the 2017 revision of the McDonald criteria in this population [18].

Commentary: No studies have evaluated the diagnostic performance of the International Pediatric Multiple Sclerosis Study Group criteria in patients presenting with these symptoms.

2.1 Complaints and Anamnesis

• In all patients with suspected MS, it is recommended to take a detailed medical history regarding the presence of past acute demyelinating episodes to determine whether the criteria for dissemination in space and time are met (Appendix A3.1) [5].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Commentary: The assessment of history data should be performed by a neurologist to determine whether the complaints correspond to the characteristic clinical manifestations of an MS relapse and meet the criteria for dissemination in space and time (Appendix A3.1).

• In all patients with suspected MS, it is recommended to conduct a comprehensive differential diagnosis with other neurological and non-neurological disorders in order to minimize the risk of diagnostic error and patient harm due to delayed or incorrect treatment (The differential diagnosis plan is outlined in Appendix A3.3) [20–22].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Commentary: A study by Yamout et al. demonstrated that only 70% of patients referred to an MS specialist were diagnosed with MS [21]. Among patients with other diagnoses, 3.5% fully met the criteria for RIS. The most common alternative diagnoses were psychiatric disorders (16.3%), non-specific white matter MRI lesions (14.7%), neuromyelitis optica spectrum disorders (9.5%), migraine (8.6%), and systemic autoimmune diseases (8.6%) [19]. A study by Solomon et al. showed that 33% of patients were managed with an incorrect diagnosis for more than 10 years, 70% of whom received disease-modifying therapies (DMTs) and 31% experienced adverse events related to DMT therapy [22].

• All patients presenting with signs of optic neuritis currently or in their medical history are recommended an initial evaluation (examination, consultation) by a neurologist in order to rule out MS [23].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

2.2 Physical Examination

• When performing a neurological examination of patients with suspected MS, it is recommended to use the Kurtzke Functional Systems (FS) scale (Appendix G1) and the Expanded Disability Status Scale (EDSS; Appendix G2) [5, 24-26].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

2.3 Laboratory Diagnostics

• All patients with suspected MS are recommended to be prescribed the following laboratory tests to rule out comorbid conditions and determine the feasibility of subsequent DMT therapy [27, 28]:

- Complete blood count (CBC) with differential;

- General clinical blood chemistry test, serum C-reactive protein (CRP) level testing, blood fibrinogen level testing, total blood calcium level testing;

- Blood thyroid-stimulating hormone (TSH) level testing, serum free thyroxine (fT4) level testing, blood thyroid peroxidase antibody testing, blood thyroglobulin level testing.

- Urinalysis (routine clinical urine test) with microscopic examination of urine sediment;

- Determination of antibodies of classes M, G (IgM, IgG) to human immunodeficiency virus HIV-1 in blood, determination of antibodies of classes M, G (IgM, IgG) to human immunodeficiency virus HIV-2 in blood, determination of hepatitis B virus surface antigen (HBsAg) in blood, determination of antibodies of classes M, G (IgM, IgG) to hepatitis B virus surface antigen (HBsAg) in blood, determination of antibodies of classes M, G (IgM, IgG) to hepatitis B virus core antigen (HBcAg) in blood, determination of antibodies of classes M, G (IgM, IgG) to hepatitis C virus in blood,

- Determination of antibodies to nuclear antigens and DNA [29].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: This list of tests is considered by the working group experts to be sufficient, but not exhaustive. The diagnostic plan should be based on the clinical presentation of the disease and other data obtained from objective, laboratory, and instrumental examination methods.

• In patients aged 18 years and older with suspected MS, when signs are present that warrant including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in the differential diagnosis, molecular genetic testing for NOTCH3 gene mutations is recommended for differential diagnosis [30].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

• In patients with suspected MS, when signs are present that warrant including vitamin B₁₂ deficiency in the differential diagnosis, determination of blood vitamin B12 (cyanocobalamin) level is recommended for differential diagnosis [27, 31].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• In patients with suspected MS, when signs are present that warrant including neuromyelitis optica spectrum disorders (NMOSD) in the differential diagnosis, testing for blood anti-aquaporin-4 IgG antibodies is recommended for differential diagnosis [34].

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)

Comment: Anti-aquaporin-4 antibodies are a highly specific marker for neuromyelitis optica, with a clinical specificity of 97-98%. The highest sensitivity and specificity are achieved by testing for anti-aquaporin-4 antibodies using a cell-based assay expressing aquaporin-4 [34].

• In patients with suspected MS, when signs are present that warrant including systemic connective tissue diseases in the differential diagnosis, determination of antibodies to nuclear antigens and DNA and anti-extractable nuclear antigen (ENA) antibodies in blood are recommended for differential diagnosis [35-37].

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)

Comment: Systemic connective tissue diseases have diverse manifestations, including central nervous system involvement. Studies by Leuchten et al. and Haga et al. show that antinuclear factor screening and anti-ENA IgG testing have high sensitivity and specificity in detecting diseases such as systemic lupus erythematosus and Sjögren's syndrome [36, 37]. An important feature is the high negative predictive value and low positive predictive value [35]. The detection of these antibodies is not a sign of systemic disease by itself, but in such cases, an initial consultation (examination) with a rheumatologist is required.

• In patients with suspected MS, as an additional method to confirm the diagnosis of MS, paired testing for oligoclonal IgG immunoglobulins with determination of the synthesis pattern in blood serum and cerebrospinal fluid is recommended [5, 38-43].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: The sensitivity and specificity of oligoclonal IgG detection, according to various authors, are approximately 90% and 60%, respectively [38, 40, 41]. Type 2 and Type 3 oligoclonal IgG synthesis patterns are most characteristic of MS [39]. The test can be used as an additional method confirming dissemination in time according to the 2017 revised McDonald criteria [5, 42]. The absence of oligoclonal immunoglobulins does not confirm the absence of MS in the patient, which occurs in up to 13% of MS cases and up to 33% of CIS cases [38]. The presence of oligoclonal IgG in CSF is an independent factor increasing the risk of CIS conversion to clinically definite MS [43].

2.4 Instrumental Diagnostics

• In all patients with suspected MS, establishing the diagnosis of MS based on MRI data alone is not recommended to reduce the risk of misdiagnosis [44].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comment: MS is diagnosed primarily based on the characteristic clinical presentation [5]. MRI is an auxiliary diagnostic method that increases the accuracy and speed of diagnosis.

• All patients with suspected MS are recommended to undergo contrast-enhanced brain MRI to rule out other causes of neurological disease and to establish whether the process meets the criteria for dissemination in space and time [45].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: The brain MRI protocol should include the following projections and pulse sequences with a slice thickness of no more than 5 mm: 1) axial projection (aligned along the line in the sagittal plane connecting the lower edges of the body and splenium of the corpus callosum) in 2D T2, 2D T2 FLAIR sequences (preferably with fat suppression in 2D T2 FLAIR); 2) sagittal projection in 3D T2 FLAIR sequence (with a slice thickness of no more than 2 mm); 3) axial pre- and post-contrast images (identical to each other) in 2D T1 sequence (spin echo) using a standard dose of contrast agent administered over 30 seconds, with a 10-15 minute time delay after contrast administration; 4) sagittal pre- and post-contrast images (identical to each other) in 3D T1 sequence (gradient echo or fast spin echo) using an isotropic voxel (256x256 matrix, 25 cm field of view, 1 mm slice thickness), using a standard dose of contrast agent administered over 30 seconds, and a 10-15 minute time delay after contrast administration, whereby the post-contrast 3D T1 sequence should precede the post-contrast 2D T1 sequence, as the sensitivity of 3D T1 to contrast enhancement decreases over time. If necessary, the following additional sequences are performed: 1) axial or sagittal projection in 2D and/or 3D DIR sequence for better visualization of cortical/juxtacortical lesions (with a slice thickness of no more than 2 mm); 2) axial projection in DWI sequence; 3) axial projection in SWI (SWAN) sequence to detect the "central vein sign" (with a slice thickness of no more than 2 mm) [46].

• In patients with suspected MS and clinical symptoms of spinal cord involvement or radiological signs of brain involvement that do not meet the criteria for dissemination in space, it is recommended to additionally perform contrast-enhanced magnetic resonance imaging of the spinal cord (cervical spine) to reduce the risk of misdiagnosis and provide criteria-based confirmation of a possible MS diagnosis [44]. Magnetic resonance imaging of the spinal cord (thoracic and lumbar spine) is recommended when a lesion is suspected in these areas.

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comment: Performing spinal cord MRI simultaneously with brain MRI reduces the frequency of repeated MRI referrals and avoids repeated contrast administration. If possible, both MRI examinations should be performed immediately. The spinal cord MRI protocol should include the following projections and pulse sequences with a slice thickness of no more than 3 mm: 1) sagittal projection in T2 and T2 STIR modes; 2) axial projection in T2 mode with a large field of view (not through intervertebral discs, but covering the entire area of interest in the transverse section of the spinal cord); 3) sagittal pre- and post-contrast T1-weighted images (spin echo) using a standard dose of contrast agent administered over 30 seconds, with a 10–15 minute time delay after contrast administration; 4) axial post-contrast T1-weighted images (spin echo) using a standard dose of contrast agent administered over 30 seconds, with a 10–15 minute time delay after contrast administration (if changes are present on T2) [44].

• In patients suspected of having MS aged over 40 years with nonspecific findings on brain MRI, it is recommended to additionally perform contrast-enhanced magnetic resonance imaging of the spinal cord (cervical region) to reduce the risk of misdiagnosis and provide criteria-based confirmation of a possible MS diagnosis [47].

GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)

Comment: Performing spinal cord MRI simultaneously with brain MRI reduces the frequency of repeated MRI referrals and avoids repeated contrast administration. If possible, both MRI examinations should be performed immediately. The spinal cord MRI protocol should include the following projections and pulse sequences with a slice thickness of no more than 3 mm: 1) sagittal projection in T2 and T2 STIR modes; 2) axial projection in T2 mode with a large field of view (not through intervertebral discs, but covering the entire area of interest in the transverse section of the spinal cord); 3) sagittal pre- and post-contrast T1-weighted images (spin echo) using a standard dose of contrast agent administered over 30 seconds, with a 10–15 minute time delay after contrast administration; 4) axial post-contrast T1-weighted images (spin echo) using a standard dose of contrast agent administered over 30 seconds, with a 10–15 minute time delay after contrast administration (if changes are present on T2 [48].

• In patients suspected of having MS in whom dissemination in space and time criteria could not be established on a single brain MRI, it is recommended to schedule a repeat brain MRI to assess dynamics and compliance with MS diagnostic criteria [48–51].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: Serial brain MRI studies in patients with clinically isolated syndrome (CIS) have demonstrated the appearance of new lesions in T2 and T2 FLAIR modes, confirming dissemination in time of the pathological process, in 51% within 6 months and in 71% of cases within 12 months of follow-up. If two or more lesions whose characteristics indicate a demyelinating nature of the lesion are detected in a patient with a clinical picture of an acute demyelinating episode on the initial brain MRI in the absence of signs of contrast enhancement, a repeat brain MRI should be performed 6–12 months after the initial MRI. If two or more lesions whose characteristics indicate a demyelinating nature of the lesion are detected on brain MRI in a patient without clinical symptoms of an acute demyelinating episode or with a nonspecific clinical picture (radiologically isolated syndrome – RIS), a repeat brain MRI is also recommended in 6–12 months. At the same time, brain MRI should be performed using a standardized MRI protocol (see above). Confirmation of dissemination in time of the pathological process on repeat brain MRI does not always require contrast enhancement, as it can be based solely on the detection of new lesions in T2 and T2 FLAIR modes. The value of repeat spinal cord MRI in patients with CIS has not been proven, and therefore it should be considered individually in each specific case [48, 51].

• For patients with suspected MS undergoing MRI scans, it is recommended to compile a structured MRI report protocol, including for the purpose of assessing lesion dynamics, fulfillment of dissemination in space and/or time criteria (Appendix A3.5) [52, 53].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: The expert working group members, explicitly recommend issuing a structured MRI report protocol that includes a descriptive part (localization, lesion characteristics, absence or presence of pathological contrast agent uptake by lesions), assessment of the dynamics of the pathological process (appearance, localization, and number of new and/or enlarged old lesions in T2-weighted and T2 FLAIR modes, with or without contrast agent uptake), and interpretation of the pathological process (typical, atypical, or non-typical MRI pattern for MS), on the basis of which the attending physician can make decisions on further patient management tactics. Without a structured MRI report protocol, the MRI examination service is considered to be of poor quality.

2.5 Other Procedures

• In patients suspected of having MS with symptoms of optic neuritis at the time of examination or in history, as an additional diagnostic method, it is recommended to use additional instrumental diagnostic methods: recording of single-modality cerebral cortex evoked potentials (visual), and orbital magnetic resonance imaging to objectify the episode of visual impairment [54, 55].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comment: The sensitivity of detecting optic nerve focal lesions on MRI is up to 93% [54]. The presence of a contrast-enhancing demyelinating lesion in the optic nerve is associated with a more severe course of optic neuritis and a less favorable prognosis for visual recovery [54]. In a study by Frederiksen et al., the diagnostic sensitivity of slowed evoked potential conduction in optic neuritis was 77%, and visual evoked potential amplitudes correlated with visual acuity [55]. Increased latency was associated with a confirmed diagnosis of MS [55].

• In patients suspected of having MS, with symptoms of optic neuritis at the time of examination or in history, as an additional diagnostic method, it is recommended to prescribe optical coherence tomography of the eye to determine thinning of the retinal nerve fiber layer and ganglion cell layer [56].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: The highest sensitivity of the method is achieved approximately 3 months after the experienced optic neuritis [56]. Retinal nerve fiber layer atrophy is an unfavorable prognostic factor regarding disability progression [57]. A systematic review by Britze et al. showed that ganglion cell layer atrophy manifests earlier than retinal nerve fiber layer atrophy and better predicts visual function recovery [58].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

MS therapy includes: 1) treatment of MS relapses, 2) disease-modifying therapies (DMTs) for MS, and 3) symptomatic therapy (correction of individual disease symptoms). Currently, no drugs with proven neuroprotective and neuroreparative effects in MS are registered.

3.1 Treatment of MS relapses

• If an MS patient has clinical signs of an MS relapse objectively confirmed by a neurologist (regardless of the presence/absence of contrast-enhancing lesions on MRI, if performed), it is recommended to administer relapse therapy with methylprednisolone** to reduce the severity and duration of MS relapse symptoms [59, 60] (Appendix B. Algorithm 2).

GRL BLEL 2 Grading of Recommendations Level B (Level of Evidence – 2)

• As MS relapse therapy in MS patients, it is recommended to use high doses of glucocorticoids (GCs) to reduce the severity and duration of MS relapse symptoms [59–61].

GRL ALEL 1 Grading of Recommendations Level A (Level of Evidence – 1)

Comments: Before initiating glucocorticoid (GC) therapy, potential side effects of GC use should be considered.

• If MS patients experience an MS relapse in situations where the risks of MS relapse therapy outweigh the potential benefits, it is recommended to refrain from MS relapse therapy by joint decision of the neurologist and the MS patient in order to prevent side effects of MS relapse therapy (criteria for assessing relapse severity are presented in Appendix A3.12) [59].

GCR CLOE 5 Grade of Recommendation C (Level of Evidence – 5)

Comment: The attending physician may discuss with the patient the option of not using glucocorticoids for treating non-disabling relapses or relapses with a long onset period (e.g., more than 3 months). According to the UK National Institute for Health and Care Excellence, studies evaluating the efficacy of glucocorticoids compared with placebo were generally of low quality [59]. According to a meta-analysis by Miller et al., the difference in the clinical effect of glucocorticoids was only 0.76 points on the EDSS compared to the placebo group at the end of treatment from baseline [60]. The decision to abstain from relapse therapy must be made jointly with the patient. Freedman et al. proposed a classification to determine the severity of a relapse for further patient care routing (Appendix A3.12) [62].

• To reduce the severity and duration of MS relapse symptoms in MS patients aged 18 years and older, methylprednisolone** for intravenous administration as pulse therapy at a dose of 1000 mg for 3–5 days (maximum – 7 days) is recommended as the first-choice drug [61, 63–65].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

• For MS patients under 18 years of age, the dose of intravenous methylprednisolone**as pulse therapy is calculated based on the child's weight: 500 mg for 25–40 kg, 750 mg for 40–55 kg, 1000 mg for over 55 kg [66–68].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: A randomized trial by LaMantia et al. and a systematic review with meta-analysis by Filippini et al. demonstrate that intravenous administration of methylprednisolone** for MS relapse as pulse therapy contributed to a significant reduction in the EDSS score at 4–5 weeks [61, 65].

• If methylprednisolone** cannot be used to reduce the severity and duration of MS relapse symptoms in MS patients (aged 18 years and older), the use of #dexamethasone** for intravenous drip administration according to the regimen: 8 mg daily for 7 days, then 4 mg daily for 4 days, then 2 mg daily for 3 days is recommended [65].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: The cited RCT had a small sample size and showed no statistically significant advantages of #dexamethasone** therapy over methylprednisolone** therapy when assessing the EDSS score at 7 and 15 days post-treatment [65]. The number of relapse-free MS patients 1 year after MS relapse therapy in the high-dose methylprednisolone** group was statistically significantly higher than in the #dexamethasone** group.

• In cases that complicate the administration of MS relapse therapy with parenteral glucocorticoids, for MS patients (aged 18 years and older) with an MS relapse, the use of oral glucocorticoids in equivalent daily doses (equivalent to 1000 mg of intravenous methylprednisolone**) for 3–5 days is recommended to reduce the duration and severity of MS relapse symptoms [61, 64, 69–73].

GCR ALOE 1 Grade of Recommendation A (Level of Evidence – 1)

Comment: There is no reliable data on statistically significant differences in efficacy and safety between parenteral and oral glucocorticoids in equivalent doses as MS relapse therapy over 5 days. However, the statistical power of the studies included in the meta-analysis was limited, and the results were not entirely consistent, preventing a definitive conclusion regarding the absolute equivalence of these therapy types [61, 64, 69–73].

• In MS patients (aged 18 years and older) undergoing MS relapse therapy using oral glucocorticoids as an alternative to intravenous methylprednisolone**, the use of prolonged courses of oral glucocorticoids (exceeding 5 days), including those with a tapering dose, is not recommended in order to prevent adverse effects of long-term oral glucocorticoid therapy [65, 69, 70].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comment: Longer courses of glucocorticoid therapy are not more effective compared to a course lasting up to 5 days 65, 69, 70].

• For MS patients aged 18 years and older, in cases where a course of glucocorticoid therapy is ineffective, high-volume plasmapheresis of up to 7 sessions is recommended for MS relapse treatment [74, 75].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: The efficacy of plasmapheresis as an adjunctive therapy for patients in whom glucocorticoid therapy for an MS relapse proved ineffective has been demonstrated in several randomized clinical trials [74, 75].

• For MS patients under 18 years of age, in cases where a course of glucocorticoid therapy is ineffective, high-volume plasmapheresis of up to 7 sessions is recommended for MS relapse treatment [74–76].

GPR CLOE 5 Grade of Recommendation C (Level of Evidence – 5)

• In MS patients under 18 years of age with MS relapse, it is recommended to use normal human #immunoglobulin** intravenously at a total course dose of 2 g/kg of body weight over 5 days to reduce the duration and severity of MS relapse symptoms when glucocorticoids are contraindicated [66, 77, 78].

GPR CLOE 4 Grade of Recommendation C (Level of Evidence – 4).

Comment: Intravenous normal human #immunoglobulin** may be considered as an alternative treatment for MS relapses in patients under 18 years of age when glucocorticoids are contraindicated. Administration of immunoglobulins can reduce the severity of inflammation by decreasing cytokine levels and binding anti-myelin antibodies through Fc receptor blockade, as well as stimulate remyelination [79, 80]. Several reported cases of treating children with demyelinating diseases (MS, ADEM) indicate potential efficacy of intravenous immunoglobulins, although no high-quality controlled trials have been published [77, 78].

3.2 Disease-modifying therapies for MS

• All MS patients, prior to prescribing disease-modifying therapies for MS, are recommended to determine the disease course type and the level of disability using the Expanded Disability Status Scale (EDSS) (Appendix G2) [9].

Level of Evidence CGrade of Recommendation 5Level of Clinical Effectiveness C (level of evidence – 5)

• All adult patients (18 years and older) with relapsing-remitting MS with an EDSS score ≤ 6.5, not meeting the criteria for aggressive multiple sclerosis, in order to prevent relapses and radiological disease activity based on brain/spinal cord MRI and disability caused by these events, and to reduce the risk of confirmed disability progression and development of secondary progressive MS (Appendix A3.7, Appendix B 4.1, 4.2, 4.3, 4.4) are recommended the earliest possible initiation of disease-modifying therapies (DMTs):

Interferon beta-1a** 44 mcg subcutaneously 3 times a week [81, 82];

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

or

Interferon beta-1b** 0.25 mg subcutaneously every other day [83];

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

or

Peginterferon beta-1a** (pegylated interferon beta) 125 mcg subcutaneously once every 14 days [84-86].

GGR BLOC 1Grade of Recommendation B (Level of Evidence – 1).

or

Gatiramer acetate** 20 mg subcutaneously daily or glatiramer acetate** 40 mg subcutaneously 3 times a week [83, 87, 88];

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

or

Teriflunomide** 14 mg orally once daily [89];

Level of Evidence BLevel of Confidence 2Level of recommendation B (level of evidence – 2).

Or

Dimethyl fumarate** at an initial dose of 120 mg orally twice daily, after 7 days the dose should be increased to a maintenance dose of 240 mg orally twice daily [89, 90]

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

or

Interferon beta-1a** 30 mcg intramuscularly once a week [91]

ระดับความน่าเชื่อถือ Bระดับหลักฐาน 2ระดับความน่าเชื่อถือของคำแนะนำ B (ระดับความน่าเชื่อถือของหลักฐาน – 2)

or

Sampeginterferon beta-1a 240 mcg intramuscularly once every 14 days [92, 93]

ระดับความน่าเชื่อถือ Bระดับหลักฐาน 2ระดับความน่าเชื่อถือของคำแนะนำ B (ระดับความน่าเชื่อถือของหลักฐาน – 2)

Comment: Early initiation of disease-modifying therapies (DMTs) helps reduce the risk of disability progression and the development of secondary progressive multiple sclerosis (SPMS) [86, 94].

• All patients aged 10 to 18 years with RRMS with an Expanded Disability Status Scale (EDSS) score ≤6.5, not meeting the criteria for aggressive multiple sclerosis, for the purpose of reducing the risk of confirmed disability progression and the development of SPMS (Appendix A3.7, Appendix B. 4.1, 4.2, 4.3, 4.4) upon initial therapy prescription, it is recommended to initiate DMTs as early as possible:

#Interferon beta-1a** 30 mcg intramuscularly once a week [95, 96; 97].

GCR CLeE 4Grade of Recommendations C (Level of Evidence – 4)

or

#Interferon beta-1a** 44 mcg subcutaneously 3 times a week [96, 98].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

or

#Teriflunomide** 7 mg once daily orally (for weight ≤ 40 kg) or 14 mg orally once daily (for weight > 40 kg) [99-101]

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

or

#Glatiramer acetate** 20 mg subcutaneously daily [96, 102-105]

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

or

#Dimethyl fumarate** at an initial dose of 120 mg orally twice daily; after 7 days, the dose should be increased to a maintenance dose of 240 mg orally twice daily [101, 106]

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comment: due to insufficient safety and efficacy data in children under 10 years of age, these drugs are prescribed by decision of the medical commission

Comment: In the study by Rotstein et al., achieving an optimal response after 2 years of therapy had a positive predictive value of 78.3% for the absence of disability progression at 7 years [108].

• For patients aged 18 years and older with RRMS with a suboptimal response to DMT therapy (Appendix A3.7) with an EDSS score ≤ 6.5 with the aim of preventing relapses and radiological disease activity according to brain/spinal cord MRI and disability caused by these events, and with the aim of reducing the risk of confirmed disability progression and development of SPMS, it is recommended to switch therapy to:

Cladribine** 10 mg tablets (3.5 mg/kg of the patient's body weight over 2 years: 1.75 mg/kg per treatment course per year with a total duration of not more than 10 days in each of the two courses (Year 1 and Year 2) without drug administration in the subsequent 2 years (Year 3 and Year 4) [111, 119-124]

GCR BLeE 2Grade of Recommendations B (Level of Evidence – 2)

or

Ofatumumab at an initial dose of 20 mg at weeks 0, 1, and 2; no drug is administered at week 3; starting from week 4 and thereafter monthly, 20 mg subcutaneously once a month [112, 125, 126]

GCR BLeE 2Grade of Recommendations B (Level of Evidence – 2)

or

Divozilimab** at an initial dose given as two separate intravenous infusions: the first infusion contains 250 mg of the drug, then 2 weeks later another 250 mg of the drug is administered, followed by a maintenance dose of 500 mg as a single intravenous infusion every 6 months (the first of the subsequent doses should be administered 6 months after the first infusion of the initial dose) [127]

GCR BLeE 2Grade of Recommendations B (Level of Evidence – 2)

Comment: In the open-label extension phase of the randomized clinical trial ASCLEPIOS (ALITHIOS), switching from teriflunomide** to ofatumumab resulted in reductions: in the annualized relapse rate by 71.7%, the risk of new/enlarging T2 lesions by 86.6%, Gd (+) enhancing T1 lesions by 97.4%, and a reduction in the risk of confirmed disability worsening [112, 125, 126]. In the randomized double-blind placebo-controlled clinical trial BCD-132-2, 24 (33.3%) of 72 patients with relapsing MS with prior DMT therapy were included in the divozilimab** 500 mg group, and in the randomized double-blind double-dummy efficacy and safety study of divozilimab** (BCD-132-4) using an active comparator (teriflunomide**), 67 (39.6%) of 169 patients with prior DMT therapy were included. Some of the inclusion criteria were: the presence of 1 relapse over the last year, as well as one MRI-detected contrast-enhancing lesion and one relapse over the past 24 months [127, 128].

• For patients aged 18 years and older with aggressive RRMS or resistance to DMT therapy (Appendix A3.7) with an EDSS score ≤ 6.5 with the aim of preventing relapses and radiological disease activity according to brain/spinal cord MRI and disability caused by these events, and with the aim of reducing the risk of confirmed disability progression and development of SPMS, DMTs are recommended (Appendix A3.7):

Natalizumab** 300 mg intravenously every 28 days [129-133]

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

or

Fingolimod** 0.5 mg orally once daily [134-135]

GCR BLeE 2Grade of Recommendations B (Level of Evidence – 2)

or

Ozanimod 0.23 mg orally once daily on days 1–4, then 0.46 mg orally once daily on days 5–7, then 0.92 mg orally once daily on day 8 and thereafter [117, 118, 137, 138]

GCR BLeE 1Grade of Recommendations B (Level of Evidence – 1)

or

Alemtuzumab** 12 mg intravenously, 2 treatment courses (5 infusions in year 1 and 3 infusions in year 2) [139-141]

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

or

Ocrelizumab** at an initial dose of 600 mg, which should be administered as two separate intravenous infusions: the first infusion contains 300 mg of the drug, then 2 weeks later another 300 mg is administered, and all subsequent doses are subsequently administered as a single intravenous infusion of 600 mg intravenously every 6 months; the first of the subsequent 600 mg doses should be given 6 months after the first infusion of the initial dose [142, 143]

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

or

Cladribine** 10 mg tablets (3.5 mg/kg of the patient's body weight over 2 years: 1.75 mg/kg per treatment course per year with a total duration of not more than 10 days in each of the two courses (Year 1 and Year 2) without drug administration in the subsequent 2 years (Year 3 and Year 4)) [111, 119, 144]

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

or

#Mitoxantrone** 12 mg/m² IV in 200 ml of normal saline** every 3 months (maximum relatively safe cumulative dose – 80 mg/m²) [145].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

or

Divozilimab** at an initial dose given as two separate intravenous infusions: the first infusion contains 250 mg of the drug, then 2 weeks later another 250 mg of the drug is administered, followed by a maintenance dose of 500 mg as a single intravenous infusion every 6 months (the first of the subsequent doses should be administered 6 months after the first infusion of the initial dose) [127, 128]

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

or

Ofatumumab at an initial dose of 20 mg at weeks 0, 1, and 2; no drug is administered at week 3; starting from week 4 and thereafter monthly, 20 mg subcutaneously once a month [112, 146]

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

• For patients aged 10 to 18 years with aggressive RRMS or resistance to DMTs with an EDSS score ≤ 6.5, DMTs are recommended (Appendix A3.7):

#Natalizumab** 300 mg intravenously every 4 weeks [147-150]

GCR CLeE 4 Grade of Recommendations C (Level of Evidence – 4)

or

Fingolimod** 0.5 mg orally once daily (for weight ≥ 40 kg) or 0.25 mg orally once daily (for weight < 40 kg) [134, 136, 304]

LeE 2Grade of Recommendations B (Level of Evidence – 2).

or

#Ocrelizumab** 300 mg intravenously every 6 months (for weight < 35 kg) or 600 mg intravenously every 6 months (for weight ≥ 35 kg) [101, 150, 151]

GCR CLeE 4 Grade of Recommendations C (Level of Evidence – 4)

or

#Ofatumumab at an initial dose of 20 mg at weeks 0, 1, and 2; no drug is administered at week 3; starting from week 4 and thereafter monthly, 20 mg subcutaneously once a month [101, 150, 152, 153]

Level of Evidence CGrade of Recommendation 5Level of Clinical Effectiveness C (level of evidence – 5)

Comment: due to insufficient safety and efficacy data in children under 10 years of age, these drugs are prescribed by decision of the medical commission

• For patients with MS who have reached an EDSS score ≥ 7.0, in the absence of relapses and radiological disease activity on MRI for a period of at least 2 years, it is not recommended to continue DMT therapy due to unproven efficacy in this cohort of patients and a substantial increase in the risks of side effects associated with DMT therapy [28]. The decision to discontinue DMT therapy must be made jointly with the patient.

GCR CLOE 5 Grade of Recommendation C (Level of Evidence – 5)

Comment: No clinical efficacy studies of DMTs have been conducted in this patient cohort, but some conclusions can be drawn from the analysis of the natural history of the disease. A study by Ahrweiller et al. showed that the relapse rate decreases by 46% every 5 years after conversion to SPMS [154]. Similar data were obtained in a study by Paz Soldan et al., who showed that in their selected group of patients, 91.6% of relapses occurred within the first 5 years after conversion to SPMS and 95.2% of relapses developed before the age of 55 [155]. At an EDSS score of 6.0 and above, the risk of relapses and/or MRI activity is 50% lower, so DMT discontinuation may not be accompanied by a significant risk of recurrence of clinical and radiological MS activity [28].

• For MS patients aged 18 and older with an EDSS score of ≤ 6.5 and an optimal response to therapy while using DMTs (natalizumab**, fingolimod**, ozanimod, ocrelizumab**, alemtuzumab**, cladribine**, #mitoxantrone**, divozilumab**, ofatumumab), in the presence of high risks of adverse drug reactions (ADRs) threatening the patient's life, or if there is a risk of severe disability while continuing this DMT therapy, it is recommended to switch therapy to another DMT (natalizumab**, fingolimod**, ozanimod, ocrelizumab**, alemtuzumab**, cladribine**, #mitoxantrone**, divozilumab**, ofatumumab) in compliance with the recommended washout/transition periods when switching therapy and risk management plans [107].

GCR CLOE 5 Grade of Recommendation C (Level of Evidence – 5)

Comment: Randomized clinical trials comparing the efficacy of switching therapy within the class of DMTs have not been conducted. There is some positive experience of switching from natalizumab** (mainly due to PML risks) to ocrelizumab**, alemtuzumab**, fingolimod**, cladribine** provided that the switching timeframes are observed [156–161]. However, a study by Vollmer et al. demonstrates that the relapse rate may increase after switching from natalizumab** to fingolimod** with a prolonged washout interval [162]. In a study by Alping et al., switching from natalizumab** to #rituximab** was more effective than to fingolimod** [163].

• In MS patients aged 18 and older with an EDSS score of ≤ 6.5 and a suboptimal response to therapy using DMTs (natalizumab**, fingolimod**, ozanimod, ocrelizumab**, alemtuzumab**, cladribine**, #mitoxantrone**, divozilumab**, ofatumumab), provided the patient has high compliance and sufficient time has passed for the effect of the DMT therapy to develop, it is recommended to switch therapy to another DMT (natalizumab**, fingolimod**, ozanimod, ocrelizumab**, alemtuzumab**, cladribine**, #mitoxantrone**, divozilumab**, ofatumumab) in compliance with the recommended washout/transition periods when switching therapy and risk management plans [107].

GCR CLOE 5 Grade of Recommendation C (Level of Evidence – 5)

Comment: Randomized clinical trials comparing the efficacy of switching therapy within the class of DMTs have not been conducted. Working group experts consider switching therapy within DMTs as a way to achieve the criteria for an optimal therapeutic response in patients resistant to one of the DMTs. The choice of another DMT should be made taking into account the adverse event profile, the patient's previous experience with DMT therapy, comorbid conditions, and current disease activity. A randomized clinical trial, as well as its open-label extension phase (up to 4 years), has demonstrated the efficacy of ofatumumab regardless of which DMT (including natalizumab** and fingolimod**) was used prior to study entry [112, 125].

• For patients aged 18 and older with SPMS with confirmed progression of disability regardless of the presence/absence of relapses with an EDSS score of ≤ 6.5, with the aim of preventing and reducing the rate of MS progression, preventing relapses and radiological disease activity according to brain/spinal cord MRI (if disease activity persists) the following are recommended:

Siponimod** at a maintenance dose of 2 mg orally once daily (1 mg for CYP2C9 2/3 and CYP2C9 1/3 genotypes) [115, 164, 165] ;

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)

Comment: The safety and efficacy of siponimod** have not been studied in patients over 65 years of age. To ensure patient safety, CYP2C9 isoenzyme genotyping is required, as well as compliance with the risk management plan (Appendix B4.11) [115].

or

#Ocrelizumab** at an initial dose of 600 mg, administered as two separate intravenous infusions: the first infusion of 300 mg, followed 2 weeks later by a second infusion of 300 mg; all subsequent doses are administered as a single intravenous infusion of 600 mg every 6 months, with the first subsequent 600 mg dose administered 6 months after the initial dose's first infusion [142, 143, 166].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: The safety and efficacy of ocrelizumab** have not been studied in patients over 55 years of age. In such patients, ocrelizumab** should be used with caution. When using ocrelizumab** in patients with SPMS, compliance with the risk management plan is recommended to ensure patient safety (Appendix B4.9).

or

#Mitoxantrone** at a dosage of 12 mg/m² IV in 200 ml of isotonic sodium chloride solution** every 3 months as a rescue therapy option when no alternative exists due to an unfavorable safety profile (the maximum relatively safe cumulative dose is 80 mg/m²) [145]. When using #mitoxantrone** in MS patients, compliance with the risk management plan is recommended to ensure patient safety (Appendix B4.5).

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

• For patients aged 18 and older with SPMS with confirmed disability progression and ongoing relapses, in the presence of contraindications to siponimod** or ocrelizumab** therapy, with the aim of preventing relapses, radiological disease activity according to brain/spinal cord MRI, and disability caused by these events, but not with the aim of slowing the rate of MS progression, it is recommended to prescribe DMTs:

Interferon beta-1a** 44 mcg subcutaneously 3 times a week [167],

Leads to AEvid 1Level of Evidence A (level of reliability of evidence – 1)

or

Interferon beta-1b** 250 mcg subcutaneously every other day [167],

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comment:LaMantina et al. analyzed 5 RCTs in which 3122 patients (1829 receiving interferons and 1293 receiving placebo) treated with interferon beta-1a**or interferon beta-1b**, met the SPMS criteria. The included population was heterogeneous in terms of baseline clinical characteristics of the disease, specifically the proportion of patients with SPMS with relapses ranged from 72% to 44% [167]. Interferon beta-1a**or interferon beta-1b**did not reduce the risk of progression sustained for 6 months after three years of treatment. The analysis established a significant reduction in the risk of disease progression at 3 months and the risk of new relapses at three years. The risk of new active brain lesions decreased over time, but these data were obtained from isolated MRI studies performed in patient subgroups; despite the lack of effect on progression, radiological data confirmed the effect on MRI parameters [167].

• For patients with PPMS aged 18 years and older with an EDSS score of ≤6.5 points to prevent the rate of MS progression, it is recommended to:

Ocrelizumab** at an initial dose of 600 mg, which should be administered as two separate intravenous infusions: the first infusion of 300 mg of the drug, followed 2 weeks later by another 300 mg of the drug; all subsequent doses are administered thereafter as a single intravenous infusion at a dose of 600 mg intravenously every 6 months, with the first of the subsequent 600 mg doses to be administered 6 months after the first infusion of the initial dose [168].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: The safety and efficacy of ocrelizumab** have not been studied in patients under 18 years and over 55 years of age. In such patients, ocrelizumab** should be used with caution. In patients with an EDSS score of ≥7.0 points, the efficacy and safety of ocrelizumab** have not been studied. When using ocrelizumab** in patients with PPMS, to ensure patient safety, it is recommended to follow the risk management plan (Appendix B 4.9).

3.2. Surgical treatment

Not applicable

3.3. Other treatment

Symptomatic therapy is one of the most important components of MS treatment; rational use of medications can significantly improve the quality of life of patients. Symptomatic therapy is prescribed by any medical specialist in accordance with their field of practice. The prescription of symptomatic therapy does not depend on whether the patient receives DMTs and is tailored individually depending on the stage and course type of the disease.

Management of chronic fatigue syndrome

• For MS patients aged 18 years and older for the treatment of chronic fatigue syndrome, it is recommended to use #amantadine** at a dose of 200 mg daily [169].

GRC ALEL 1Grade of Recommendation A (Level of Evidence – 1)

Comment: a meta-analysis by Yang et al. showed that #amantadine** was the most effective agent for the treatment of chronic fatigue syndrome, however, high-quality studies confirming this are lacking [169].

• For MS patients aged 18 years and older for the treatment of chronic fatigue syndrome, it is recommended to use #levocarnitine at a dose of 1 g twice daily [179].

GRC ALEL 1Grade of Recommendation A (Level of Evidence – 1)

Comment: a meta-analysis by Yang et al. showed that #levocarnitine was effective in some patients with chronic fatigue syndrome, although all included studies were of low quality [169].

Management of urinary disorders in patients with multiple sclerosis

• In adult patients (aged 18 and older) with multiple sclerosis and overactive bladder syndrome manifested by frequent imperative urges to urinate or urinary incontinence, it is recommended to use oxybutynin 5 mg twice daily, or #tolterodine 4 mg twice daily, or 1 mg twice daily in case of adverse reactions [170-172].

GCR BESL 2Grade of Recommendation B (Level of Evidence – 2

Comment: Anticholinergics (antimuscarinics) (G04BD drugs for urinary frequency and incontinence) are the most common treatment for overactive bladder syndrome in MS [170]. However, data on their efficacy in MS are still insufficient, and a Cochrane review with meta-analysis demonstrates no statistically significant effect in improving overactive bladder symptoms [173]. Nevertheless, data from individual clinical trials demonstrate the efficacy of anticholinergics (G04BD drugs for urinary frequency and incontinence) in the treatment of overactive bladder syndrome [174-176].

• In adult patients (aged 18 and older) with multiple sclerosis and overactive bladder syndrome manifested by frequent imperative urges to urinate or urinary incontinence, for the management of urinary disorders, it is recommended to use #desmopressin** 10–120 mcg once daily [171, 177-179].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comment: #Desmopressin** showed efficacy in the study by Valiquette et al., reducing the percentage of nights with nocturia from 97% to 66%, as well as in the study by Hilton et al., reducing the frequency of urinary urges [177, 178]. All studies were of low quality.

• In adult patients (aged 18 and older) with multiple sclerosis presenting with difficulty emptying the bladder due to detrusor-sphincter dyssynergia syndrome, it is recommended to use alpha-blockers (#tamsulosin** 0.4 mg once daily, #doxazosin** 2-8 mg daily) to correct urinary disorders [180, 181].

GCR CESL 4Grade of Recommendation C (Level of Evidence – 4) – for #tamsulosin**

GCR CESL 3Grade of Recommendation C (Level of Evidence – 3) – for #doxazosin**

Comment: A positive effect on urinary retention has been demonstrated in a number of studies in multiple sclerosis and other neurological diseases [180, 181].

• In adult patients (aged 18 and older) with multiple sclerosis who have overactive bladder syndrome manifested by frequent imperative urges to urinate or urinary incontinence, and resistance to oral and intranasal medications, it is recommended to use botulinum toxin type A-hemagglutinin complex** preparations as intravesical injections prescribed by a urologist for the management of urinary disorders [180-184].

GCR BLeE 2Grade of Recommendations B (Level of Evidence – 2)

Comment: Intravesical administration of botulinum toxin type A–hemagglutinin complex** led to an increase in maximum bladder capacity, a decrease in the frequency of daytime and nighttime urges, a reduction in the number of urinary incontinence episodes, as well as a decrease in the use of disposable absorbent medical products [183-187]. Most studies were conducted in mixed patient populations, including those with various causes of neurogenic bladder dysfunction, which complicates drawing conclusions about the efficacy of this treatment method in multiple sclerosis.

Management of muscle tone disorders.

• In adult patients (aged 18 and older) with multiple sclerosis and spasticity syndrome, for the purpose of reducing muscle tone, it is recommended to use baclofen** [188-193]

GCR BLeE 2Grade of Recommendations B (Level of Evidence – 2)

or

tizanidine** [194]

Recommendation Grade BEvidence Level 3Level of Clinical Recommendation B (Level of Evidence – 3)

#tolperisone 150-1000 mg daily orally (the dose is selected individually taking into account tolerability and efficacy) [195].

Level of Evidence CGrade of Recommendation 5Level of Clinical Effectiveness C (level of evidence – 5)

Comment: A systematic review of clinical trials reports the efficacy of these drugs for the correction of spastic hypertonia. The dose of the muscle relaxant is selected individually, taking into account tolerability and efficacy.

• In case of intolerance or inefficacy of therapy with baclofen**, tizanidine**, or #tolperisone in adult patients (aged 18 and older) with multiple sclerosis and spasticity syndrome, it is recommended to use #gabapentin 300 mg – 3600 mg daily orally (the dose is selected individually, taking into account tolerability and efficacy) to reduce muscle tone [194, 196]

GCR BLeE 2Grade of Recommendations B (Level of Evidence – 2)

• In adult patients (aged 18 and older) with multiple sclerosis who have focal muscular spastic hypertonia and in whom oral spasticity therapy is ineffective, to facilitate patient mobility, hand manipulation, or self-care capabilities, it is recommended to use botulinum toxin type A-hemagglutinin complex** intramuscularly by a trained specialist [194, 197-204].

GCR BESL 1Grade of Recommendation B (Level of Evidence – 1)

Comment: Clinical studies by Hyman et al. and Gusev et al. demonstrated a reduction in the severity of lower spastic paraparesis in patients with an EDSS score of ≥7.0 [198, 199]. Administration of botulinum toxin type A-hemagglutinin complex** into the hip adductor muscles increased range of motion in the hip joint, decreased the severity of spastic hypertonia and leg muscle pain, and facilitated hygiene procedures. A study by Gracies et al. in a less disabled mixed patient population (including multiple sclerosis) with lower spastic paraparesis showed that administration of botulinum toxin type A-hemagglutinin complex** increased walking speed [200]. Limited data in mixed populations exist regarding the effect of botulinum toxin type A-hemagglutinin complex** on upper limb muscle hypertonia in multiple sclerosis [201-203]. To date, no data have been obtained showing that the action and adverse effect profile of botulinum toxin type A-hemagglutinin complex** differ in the treatment of spasticity in multiple sclerosis compared to other nosologies.

• In adult patients (aged 18 and older) with multiple sclerosis presenting with symptoms and/or syndromes such as pain, restless legs syndrome, or insomnia, treatment is recommended to be carried out in accordance with general guidelines for such syndromes and symptoms in order to manage them [205-207].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: No specific studies in multiple sclerosis have been conducted on this issue. Currently, the treatment of these syndromes implies the use of general guidelines that are not specialized for the treatment of multiple sclerosis.

• In adult patients (aged 18 and older) with multiple sclerosis and an EDSS score of 4–7 with impaired walking function, fampridine 10 mg orally twice daily is recommended to improve walking function [208-213].

GRL BLEL 2 Grading of Recommendations Level B (Level of Evidence – 2)

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• In adult patients (aged 18 and older) with multiple sclerosis, it is recommended to provide medical rehabilitation delivered by a multidisciplinary rehabilitation team to reduce the level of disability, improve activity and participation indicators, and enhance quality of life [214, 215].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comment: Clinical studies with moderate level of evidence demonstrate a positive effect from multidisciplinary rehabilitation.

• In adult patients (aged 18 and older) with multiple sclerosis and a Rehabilitation Routing Scale (RRS) score of 3–6, it is recommended to undergo medical rehabilitation within an inpatient medical rehabilitation department for patients with central nervous system disorders for 3–5 weeks to reduce the level of disability, improve activity and participation indicators, and enhance quality of life [215-218].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comment: Clinical studies of the multidisciplinary approach to rehabilitation demonstrate short-term efficacy (up to 12 weeks) within inpatient and outpatient settings for 3–5 weeks regarding activity and participation indicators and reduction of existing neurological deficits [215-218]. Research data provide weak evidence that intensive inpatient rehabilitation is superior in efficacy to outpatient rehabilitation in the short term (at 3 months) [218].

• In adult patients (aged 18 and older) with multiple sclerosis who have recently experienced a relapse with incomplete symptom regression, it is recommended to undergo multidisciplinary rehabilitation to reduce neurological deficits, activity limitations, and participation restrictions [217, 219, 220].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: A systematic review of 3 studies (including 1 randomized placebo-controlled trial) demonstrates the efficacy of inpatient or day-hospital multidisciplinary rehabilitation when symptom duration is 5 months or less [217, 219, 220].

• All MS patients aged 18 years and older are recommended to undergo rehabilitation efficacy assessment using validated objective methods with tests, scales, and questionnaires to evaluate walking, balance, hand function, activities of daily living, and quality of life. The assessment should be performed before and after rehabilitation [221-223].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: Objective assessment methods may include walking evaluation tests (6-minute or 2-minute walk test, 25-foot walk test, Rivermead Mobility Index, etc.), balance assessment tests (Berg Balance Scale, Timed Up and Go test «Встань и иди», etc.) [221, 222], Functional Independence Measure (FIM), 9-Hole Peg Test, Frenchay Arm Test, and quality of life questionnaires (SF-36) (Appendices G3-G8). Assessment methods should be chosen based on the clinical situation, but it is advisable to use a battery of tests to evaluate the entire spectrum of impairments. Studies on the efficacy of multiple sclerosis rehabilitation comparing pre- and post-intervention assessments with no assessment have not been conducted. However, established clinical practice confirms the importance of regular testing and evaluation of rehabilitation efficacy for physicians, patients, insurance companies, and the state [223]. Many methods require adaptation and validation for Russian clinical practice.

• Following an inpatient rehabilitation course, MS patients with any disease course and a Receptional Routing Scale (RRS) score of 2–3 are recommended long-term (up to 6 weeks) rehabilitation in an outpatient medical rehabilitation department and/or a medical rehabilitation day hospital to reduce disability, improve activity and participation outcomes, and enhance quality of life [215, 224-226].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: There is limited evidence supporting the effectiveness of a 6-week high-intensity outpatient rehabilitation intervention for improving participation and quality of life outcomes at 12 months [215]. For long-term outpatient or home-based interventions, there is strong evidence of improved patient quality of life [224-226].

• When coding the rehabilitation diagnosis in all MS patients, medical rehabilitation specialists are recommended to formulate the diagnosis using the categories of the International Classification of Functioning (ICF) to standardize the description of all patient impairments and improve interdisciplinary collaboration [227-230].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comment: Formulating a rehabilitation diagnosis using the ICF is central to rehabilitation planning. Based on World Health Organization (WHO) recommendations, specific ICF Core Sets for MS have been developed and validated [227-230]. Their use helps to objectify the patient's condition and formulate a rehabilitation plan [227].

• MS patients aged 18 years and older are recommended physical rehabilitation as an essential component of rehabilitation programs to reduce disability, improve activity and participation outcomes, and enhance quality of life [214, 226].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: Existing high-quality evidence confirms the effectiveness of physical rehabilitation methods (e.g., therapeutic exercise, robotic mechanotherapy, hydrokinesiotherapy) in improving activity and participation outcomes, increasing muscle strength, patient mobility, independence, and aerobic endurance, as well as reducing fatigue and improving quality of life [214, 226]. No single method has a significant advantage over the others.

• To reduce muscle weakness and fatigue, improve walking, and enhance other mobility domains, MS patients aged 18 years and older are recommended physical rehabilitation: therapeutic exercise for central nervous system and brain disorders, individual and group therapeutic exercise sessions for central nervous system and brain disorders, mechanotherapy and robotic mechanotherapy for central nervous system and brain disorders, apparatus- and equipment-assisted therapeutic exercise for central nervous system and brain disorders, hydrokinesiotherapy for central nervous system and brain disorders, and postural-static function recovery training [214, 231-236].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comment: Data from clinical studies and meta-analyses indicate the effect of physical rehabilitation in reducing fatigue. Endurance training, strength training (including resistance and weight training), robotic mechanotherapy, yoga, balance training, and blended approaches have demonstrated the greatest efficacy [214, 231]. The mechanism determining the efficacy of physical rehabilitation for fatigue is the improvement of cardiovascular and respiratory system function, a direct neuroprotective effect of rehabilitation, and normalization of the hypothalamic-pituitary-adrenal axis, which is believed to be involved in the pathogenesis of MS-related fatigue [231-234]. Studies evaluating the effect on fatigue were conducted primarily in patients with an EDSS score of <6.0. The efficacy of such methods in more disabled patients has not been studied, but when feasible, physical rehabilitation should be provided to patients with any EDSS level [214]. Pool-based therapeutic exercise and hydrokinesiotherapy have been shown to be effective in reducing fatigue, improving muscle strength and depression, and enhancing quality of life [237, 238]. Small randomized clinical trials on rock climbing demonstrate a reduction in fatigue and an increase in muscle strength [239]. The intensity and duration of the intervention should be chosen individually for each patient. No single method has a significant advantage over the others.

• To reduce general (non-muscular) fatigue, MS patients aged 18 years and older are recommended individual psychotherapy and macroenvironment adaptation procedures, including the development of a personalized individual rehabilitation program using cognitive behavioral therapy, education on energy conservation principles, and daily routine management training [214, 236, 240].

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)

Comment: Meta-analysis data demonstrate with high certainty the efficacy of specialized fatigue-management programs that include cognitive behavioral therapy and energy conservation education [214, 236]. Evidence regarding the use of cooling vests remains inconclusive [240].

• MS patients are recommended to include occupational therapy in rehabilitation programs to reduce activity and participation restrictions and improve quality of life [241].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comment: A number of low-quality RCTs demonstrate the efficacy of certain occupational therapy approaches in improving activity and participation outcomes, fatigue, and quality of life. When integrating occupational therapy into rehabilitation programs, primary consideration should be given to patient education, counseling, and energy conservation programs, which have an established evidence base in MS [241].

• MS patients are recommended multidisciplinary holistic upper extremity rehabilitation to reduce the severity of upper limb impairments, activity limitations, and participation restrictions, including occupational therapy, individual and group therapeutic exercise sessions for central nervous system and brain disorders, mechanotherapy and robotic mechanotherapy for central nervous system and brain disorders, and apparatus- and equipment-assisted therapeutic exercise for central nervous system and brain disorders [242].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comment: Studies demonstrate improvement in upper extremity performance and capacity (within the ICF framework) following comprehensive multidisciplinary and robot-assisted rehabilitation [242]. Therapeutic exercise and endurance training have been shown to improve upper limb function, but not activity and participation [242].

• For patients with MS aged 18 years and older, it is recommended to provide training in self-care skills, counseling on environmental adaptation, employment issues taking into account existing limitations, self-care training, patient training in self-help when moving in bed and/or a wheelchair, patient training in self-help when moving with an additional support, and procedures for adaptation to the macro- and microenvironment conditions to reduce the severity of limitations, social maladaptation, and decrease in quality of life [243].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: Consultations and training are recommended to be carried out by occupational therapists, physical and rehabilitation medicine physicians, and social workers.

• During the rehabilitation process, it is recommended to train family members/relatives of patients with MS in caring for a severely ill patient in order to reduce the patient's activity limitations and restrictions on participation, train relatives in caring for a disabled patient, and prevent psychological burnout in relatives of disabled patients [244].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• For patients with MS aged 18 years and older, to correct balance and gait disorders as well as prevent falls, it is recommended to use robotic mechanotherapy for central nervous system and brain diseases, correction of motor function disorders using biofeedback, and therapeutic exercise using a kinesitherapy apparatus [238, 245-253].

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)

Comment: Clinical studies and systematic review data have revealed a weak or moderate positive effect on balance parameters when using individual and group balance training exercises [245], combined with yoga [246], aquatic physical therapy [238], vision exercises [247], sensory integration [248], as well as when using a stabilometric system with biofeedback for balance training [249]. In a meta-analysis, the use of virtual reality (VR) demonstrated effectiveness comparable to traditional methods [250]. However, the use of VR has increased significantly over the past decade to improve functional mobility, reduce fatigue, and increase quality of life [350-352]. Clinical studies using robot-assisted gait training have demonstrated significant improvement in certain balance parameters [251]. Clinical studies of moderate and low methodological quality demonstrate improvements in balance and gait after exoskeleton-assisted rehabilitation [252, 253]. None of the methods has an evidence-based preference over the others.

• For patients with MS aged 18 years and older with foot drop syndrome, it is recommended to use functional electrical stimulation to increase walking speed [254].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comment: A systematic review with meta-analysis demonstrated a significant increase in walking speed when using functional electrical stimulation of the anterior leg muscles in foot drop syndrome [254].

• For patients with MS aged 18 years and older with spastic hypertonus syndrome, the following non-pharmacological methods are recommended for the purpose of correcting spastic hypertonus, pain syndrome, and preventing and treating joint contractures: procedures aimed at reducing spasticity (e.g., positioning), therapeutic exercise for central nervous system and brain diseases, transcranial magnetic stimulation, circular plaster casting, fabrication and wearing of custom resting orthoses, and serial casting [255].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comment: A systematic analysis of randomized clinical trial data revealed low quality of the conducted studies [255]. Nevertheless, a number of studies demonstrate short-term (up to 1 week) or medium-term (up to 6 months) effectiveness of therapeutic exercises — stretching and contraction exercises for agonist and antagonist muscles (alone or in combination with botulinum toxin type A–hemagglutinin complex** injections), and transcranial magnetic stimulation [255]. Transcutaneous electrical nerve stimulation, whole-body vibration, rock climbing, and yoga showed no efficacy [255]. Studies demonstrate inconsistent data on the efficacy of custom resting orthoses and serial casting in stroke or other acquired brain injuries, but most publications noted a significant positive effect of the intervention regarding the range of active and passive movements and pain reduction [256-258].

• For patients with MS aged 18 years and older receiving therapy with botulinum toxin type A–hemagglutinin complex** to reduce spastic hypertonus of the upper and lower limb muscles, it is recommended to additionally use therapeutic exercise for central nervous system and brain diseases, procedures aimed at reducing muscle spasticity (e.g., positioning), circular plaster casting, fabrication and wearing of custom resting orthoses, and serial casting to reduce hypertonus and increase the range of passive and active movements of the affected limbs [259].

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)

Comment: A systematic review with meta-analysis demonstrates, with a moderate level of evidence, the effectiveness of combining stretching exercises and constraint-induced movement therapy with injections of botulinum toxin type A–hemagglutinin complex** [259]. It is worth noting that the magnitude of the effect of these interventions is not high, but exceeds the effect of using botulinum toxin type A–hemagglutinin complex** injections alone.

• For patients with MS aged 18 years and older with speech and swallowing disorders, it is recommended to provide early comprehensive speech-language pathology procedures for dysphagia, speech-language pathology procedures for dysarthria, development of an individual speech therapy rehabilitation program, training in compensatory strategies and alternative communication methods in order to reduce the severity of speech and swallowing disorders, improve breathing, prevent aspiration, and reduce activity limitations and participation restrictions [243].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• For patients with MS aged 18 years and older undergoing outpatient or inpatient rehabilitation, it is recommended to perform a comprehensive clinical and psychological/neuropsychological examination to identify memory, attention, or other cognitive impairments [260].

GCR ALEL 1Grade of Recommendation A (Level of Evidence – 1)

Comment: Most patients with MS have cognitive impairments, which reduce the quality of life and affect disability in MS [260]. To correct these disorders, a preliminary assessment of their severity is required. In some cases, a joint examination by an occupational therapist and a medical psychologist (neuropsychologist) may be recommended.

• For patients with MS aged 18 years and older, when an objective decrease in cognitive performance is detected based on standardized tests, it is recommended to provide neuropsychological rehabilitation of cognitive functions using a holistic approach and/or specialized cognitive training (including in electronic format) [260-262].

GCR ALEL 1Grade of Recommendation A (Level of Evidence – 1)

Comment: A systematic review of research data with meta-analysis revealed a weak positive effect of neuropsychological rehabilitation, while some studies were of low quality. The results of some meta-analyses conflict with those of others [260-262]. Studies demonstrate a significant improvement in short-term and long-term memory, attention, memory span, and a reduction in depression after rehabilitation [260, 261]. Given the lack of proven effect of pharmacotherapy on cognitive functions, neuropsychological rehabilitation should be considered the only proven method for improving cognitive functions at present. The duration and types of intervention may vary. Currently, there is insufficient data to determine the superior efficacy of one method over another [262].

• For patients with MS aged 18 years and older undergoing outpatient or inpatient rehabilitation, it is recommended to conduct an initial appointment (testing, consultation) with a medical psychologist and a clinical-psychological psychodiagnostic examination to detect depression, anxiety syndrome, suicidal tendencies, motivational disorders, and other emotional-volitional disorders, as well as to decide on the necessity of an initial appointment (examination, consultation) with a psychiatrist [263-265].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: Depression and anxiety are frequent psychological disorders in MS, leading to a reduced quality of life, risk of suicide, and decreased treatment compliance [263-265].

• For patients with MS aged 18 years and older, when a depressive syndrome is detected based on an examination by a medical psychologist, it is recommended to provide individual clinical and psychological counseling, individual psychotherapy, and group psychotherapy in order to reduce the severity of depression and improve quality of life [266-268].

GCR ALEL 1Grade of Recommendation A (Level of Evidence – 1)

Comment: A systematic review of data from moderate-quality clinical trials (not all primary endpoints and conclusions are consistent) using meta-analysis demonstrates a reduction in the level of depression resulting from psychological counseling and cognitive behavioral therapy, both individually and in groups [268]. Insufficient data is available regarding the efficacy of psychological intervention for reducing anxiety syndrome.

• For patients with MS aged 18 years and older, it is recommended to perform telerehabilitation to correct functional impairments, improve activity and participation indicators (within the ICF framework), reduce the severity of disability, reduce fatigue, and improve quality of life [269].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comment: Telerehabilitation can be used as part of comprehensive care for patients with MS. An obvious advantage of telerehabilitation is the ability to use this method for monitoring and controlling the efficacy of rehabilitation in patients living in remote areas. Studies demonstrate a low level of evidence for the interventions performed: the 9 RCTs included in the meta-analysis used various types and durations of interventions. Rehabilitation telemedicine activities included physical exercises, patient education, behavioral therapy, and programs aimed at reducing symptoms [269].

• For patients with MS presenting with urinary incontinence, it is recommended to use physical therapy methods (exercise therapy for central nervous system and brain disorders) to reduce the severity of bladder dysfunction and improve quality of life [270].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: Randomized clinical trials have revealed a positive effect on involuntary urination parameters and quality of life when using physical exercises for pelvic floor muscle training, biofeedback exercises using electromyography, tibial nerve stimulation, and pelvic floor muscle stimulation [270] combined with exercise therapy.

• For patients with MS aged 18 years and older undergoing outpatient or inpatient rehabilitation, it is recommended to use low-level laser therapy to increase functional mobility, reduce fatigue, and improve quality of life [353].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

5. Prevention and Dispensary Observation

No evidence-based studies on multiple sclerosis prevention methods have been conducted. Primary prevention issues are most significant for individuals at high risk of developing MS, namely, first-degree relatives of MS patients, patients with clinically isolated syndrome, radiologically isolated syndrome, and carriers of MS genetic markers (HLA-DR-1.15). Despite the lack of extensive research, individual case-control epidemiological studies show an association of certain risk factors with a high incidence of MS. Such factors include smoking, vitamin D deficiency, viral infections, and chronic psycho-emotional stress.

Secondary prevention includes the prevention of MS activity (clinical, radiological) and progression, as well as risk management while on DMTs, according to an approved plan. Proper management of pregnancy and childbirth, timely vaccination, limitation of sun exposure, dietary recommendations, and timely correction of psycho-emotional disorders (especially depression and anxiety) are considered significant [271, 272].

Immunosuppressive/immunomodulatory therapy performed for MS allows for disease control to be maintained, but may increase the risk of infectious diseases; therefore, vaccination becomes an important part of the management of patients with MS. It has been proven that the potential benefit of vaccination for patients with MS, both receiving and not receiving DMTs, significantly outweighs the potential risks, and does not increase the risk of MS relapse or clinical worsening [273].

• For patients with MS, it is recommended to establish clinical dispensary follow-up within a specialized outpatient neurological service, organized either as a specialized clinical diagnostic office/department or a specialized neurological center for providing care to patients with demyelinating diseases, in order to ensure effective monitoring and support [274].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: The organization of a specialized center/department/office is viewed by the expert working group members as the only effective measure for organizing qualified care for MS patients, as well as a means of gathering up-to-date information on disease prevalence and the need for DMT therapy, rehabilitation, and other measures.

• For patients with MS, it is recommended to conduct routine dispensary check-ups at least once every 6 months to update the disease course type and stage, assess progression, evaluate DMT efficacy, assess DMT safety, adhere to the risk management plan, and adjust management tactics [275, 276].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comment: Consultation with an MS specialist at least once every 6 months is considered by the expert working group members as a sufficiently effective measure to monitor therapy efficacy and tolerability, and to control the course of the disease.

• For patients with MS who develop new neurological symptoms or significant worsening of existing symptoms lasting more than 24 hours, it is recommended to perform a neurological examination to check for a relapse. During the examination, existing complaints are objectified, and the presence of an infectious disease or other cause of neurological disorders is excluded [27, 277].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: Worsening of MS symptoms can occur for many reasons, including as a result of an infectious disease. Only an examination by a qualified neurologist specializing in MS can determine the cause of the complaints, record a relapse or disease progression, and draw conclusions about the efficacy of the ongoing DMT therapy.

• For patients with MS upon the initial prescription of DMTs, as well as during any therapy switch, it is recommended to have a repeat neurologist appointment (examination, consultation) so that the attending physician can conduct an explanatory discussion regarding expected treatment outcomes, the therapy regimen, and the risk management plan. The patient must be provided with information about the risks and side effects of therapy [27].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: Patient awareness is important for improving compliance. Joint decision-making regarding the prescription or switching of DMT therapy, informing the patient about risks and the rules of DMT administration, as well as the risk management plan, is a necessary stage when initiating any DMT therapy, which requires additional time and a follow-up visit specifically for the purpose of discussion and decision-making.

• When prescribing DMTs to female patients with MS, it is recommended to have a discussion about the need to use reliable methods of contraception throughout the entire period of DMT therapy and for a certain period after the end of therapy (in the case of treatment with natalizumab**, alemtuzumab**, ocrelizumab**, teriflunomide**, #mitoxantrone**, fingolimod**, ozanimod, cladribine**, siponimod**, divozilimab**, ofatumumab) [278-281].

Level of recommendation C Level of evidence 4 Level of recommendation C (level of evidence – 4)

• For patients with MS, it is recommended to perform contrast-enhanced brain MRI according to the following indications [48, 282]:

- in the presence of clinical signs of an MS relapse;

- before initiating DMT therapy or when switching DMTs;

- 1-3 months postpartum;

- in the absence of accurate data from a previous study (e.g., the patient starts being monitored at another clinic, MRI data from the previous clinic are missing);

- in case of doubt and a suspected revision of the diagnosis;

- during DMT therapy (6 months after therapy initiation, at the end of each treatment year of therapy);

- during natalizumab** therapy for more than 2 years in the presence of a high risk of developing PML (patients with a high JC virus antibody index ≥ 1.5 or a history of prior immunosuppressive therapy) every 3-6 months according to the shortened protocol [48].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: Dynamic patient monitoring using MRI while receiving DMD therapy is performed to determine treatment efficacy. When analyzing follow-up data, it should be noted that the onset of the drug's clinical effect is usually delayed and occurs (depending on the drug) 3 to 6 months after initiation. Therefore, performing a follow-up MRI before 6 months when prescribing or switching DMDs is impractical. Brain MRI upon switching DMDs is necessary to ensure the safety of the new therapy and provide a baseline assessment of MS activity.

• For MS patients undergoing an MRI scan, it is recommended to use a structured protocol for the report in order to analyze lesion dynamics and evaluate the efficacy of ongoing therapy (Appendix A3.5) [52, 283].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comment: The expert working group members strongly recommend completing a structured report protocol, which allows the attending physician to make decisions regarding further patient management. Without completing a structured report protocol, the MRI examination is considered not performed or performed inadequately.

• The choice of pregnancy management tactics and delivery method in MS patients is recommended to be carried out in accordance with general pregnancy and childbirth management guidelines at the discretion of the attending obstetrician-gynecologist [278, 279].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comment: if an MS patient has lower paraparesis with marked spasticity, it is advisable to use cesarean section to prevent secondary uterine inertia [279].

• For postpartum MS patients, it is recommended to pay special attention to infection prevention and adequate psychological support; the optimal time to resume DMD therapy is the third postpartum month, provided that breastfeeding is completely discontinued (to minimize potential relapse risks 3 months postpartum) [278, 280].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

• MS patients are recommended to quit smoking in order to prevent a worsening of the disease prognosis [284, 285].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: Smoking is associated with a higher risk of relapses and MS progression [284, 285]. To reduce the risk of disability progression, it is recommended to inform patients about the benefits of and methods for smoking cessation.

• MS patients are recommended to have their serum 25-OH vitamin D levels tested, followed by correction to normal values to reduce the risk of disease worsening; if monitoring vitamin D levels is not feasible, a safe maintenance dose of #cholecalciferol** up to 4,000 IU should be recommended; uncontrolled doses exceeding 10,000 IU must be avoided [286].

Level of Evidence CGrade of Recommendation 5Level of Clinical Effectiveness C (level of evidence – 5)

Comment: Low vitamin D levels are associated with an increased risk of MS development [286]. The primary limitation preventing the use of #cholecalciferol** as an MS disease-modifying supplement is the lack of controlled randomized trials [286]. Indirect data suggest that #cholecalciferol** supplementation may reduce relapse rates, but these findings require confirmation [287, 288]. The effect of #cholecalciferol** on the neurodegenerative component of MS and clinical symptom progression is also unknown.

• If an MS patient presents with urinary disorders, it is recommended to refer the patient to a relevant specialist (urologist, obstetrician-gynecologist) to rule out comorbid conditions leading to pelvic organ dysfunction, perform a bladder ultrasound with post-void residual urine volume measurement, and conduct urodynamic studies if necessary to ensure the safety of urinary disorder therapy [170, 289, 290].

GRR BLOE 2Grade of Recommendation B (Level of Evidence – 2) for adults

GRR CLOE 5Grade of Recommendation C (Level of Evidence – 5) for children

Comment: A qualified examination by a subspecialist will allow for differential diagnosis, rule out causes not related to central nervous system lesions, and prescribe appropriate therapy. It is preferable to refer patients to specialists with experience in managing neurological patients, specifically urologists (neurourologists).

• In MS patients with urinary disorders and a post-void residual urine volume exceeding 100 ml, it is recommended to perform intermittent self-catheterization (after training by a specialist) to manage urinary disorders [170, 289].

GRR BLOE 2Grade of Recommendation B (Level of Evidence – 2) for adults

GRR CLOE 5Grade of Recommendation C (Level of Evidence – 5) for children

Comment: The residual urine volume that requires intermittent self-catheterization has not been definitively established. Individual patient characteristics must be taken into account.

• In MS patients receiving injectable DMD therapy, to prevent the onset and control local adverse drug reactions (ADRs) (erythema and edema, pruritus, induration, discomfort, hemorrhage, lipoatrophy, necrosis), it is recommended [291, 292]:

- when initiating therapy with interferon beta-1a** and interferon beta-1b** – titrate the drug dose according to the product insert;

- use an auto-injector if technically feasible;

- monitor asepsis and antisepsis, and the patient's injection technique;

- let the drug warm up to room temperature for 20–30 minutes prior to injection;

- apply a cold pack to the injection site for 2–3 minutes after the injection;

- do not inject into existing indurations from previous injections;

- in case of suspected inflammatory changes or necrosis at injection sites – promptly consult a surgeon.

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: According to the expert working group, these recommendations will help reduce the risk of ADRs. Providing visual information additionally in the form of handouts, booklets, or internet resources will help improve patient compliance, especially in cases of memory impairment.

• For MS patients aged 18 and older receiving DMDs (interferon beta-1a** or interferon beta-1b**), to prevent and control flu-like syndrome, it is recommended [292]:

- when initiating therapy – titrate the drug dose according to the product insert;

- administer the injection in the evening or at bedtime, except for peginterferon beta-1a** and sampeginterferon beta-1a**, which are preferably administered in the morning or daytime hours;

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

• For MS patients aged 12 and older receiving DMDs (interferon beta-1a** or interferon beta-1b**), to prevent and control flu-like syndrome, it is recommended [293]:

- when starting therapy – begin with half the recommended adult dose, reaching the full dose within 1–3 months;

- administer the injection in the evening or at bedtime;

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: According to the expert working group, these recommendations will help reduce the risk of ADRs.

• In MS patients receiving DMD therapy, to monitor liver function, it is recommended to determine liver enzymes (aspartate aminotransferase activity in blood, alanine aminotransferase activity in blood, and if necessary, gamma-glutamyl transferase activity in blood and alkaline phosphatase activity in blood), total bilirubin in blood, and direct and indirect bilirubin in blood at the end of the first month of therapy, then at least once every 3 months for MS patients receiving interferon beta-1a**, peginterferon beta-1a**, sampeginterferon beta-1a**, interferon beta-1b**, glatiramer acetate**, dimethyl fumarate**, cladribine**, natalizumab** (for natalizumab** – before each infusion), fingolimod**, ozanimod, siponimod**, teriflunomide** (for teriflunomide** – once a month for the first 6 months). For patients receiving ocrelizumab**, ofatumumab, divozilimab**, monitoring is recommended every 6 months. For patients receiving alemtuzumab**, monitoring is recommended every month during the first year between treatment courses and for 4 years post-treatment [291, 293, 294, 295]:

1. ALT/AST levels exceed 8 times the upper limit of normal (ULN);

2. ALT/AST levels exceed 5 times the ULN for 2 weeks (in 3 consecutive tests);

3. ALT/AST levels exceed 3 times the upper limit of normal (ULN) combined with an elevation of total bilirubin exceeding 2 ULN;

4. ALT/AST levels exceed 3 times the ULN combined with manifestations of nausea, vomiting, pain and tension in the right hypochondrium, fever, and/or eosinophilia (>5%);

5. total bilirubin level in isolation exceeds 2 ULN on repeat tests with a 48-hour interval.

For teriflunomide** it is recommended to temporarily discontinue the drug, with an initial gastroenterologist appointment (examination, consultation) and a referral to a specialized MS center (office) in case ALT/AST levels exceed 3 ULN, confirmed after 2 weeks;

• if drug-induced liver injury is confirmed during teriflunomide** therapy, it is recommended to perform an accelerated elimination course using #activated charcoal at a dose of 50 g every 12 hours for 11 days (daily intake is optional if poorly tolerated) [296], with further therapy according to clinical guidelines for the treatment of drug-induced liver injury;

• if deviations in ALT/AST levels exceeding 3 ULN, but not reaching the discontinuation criteria, are detected during teriflunomide** therapy, weekly monitoring is recommended until values normalize; a reduction to ½ of the dose is possible;

• if symptoms suggesting impaired liver function appear during siponimod** therapy, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, rash with eosinophilia, or jaundice and/or dark urine, it is recommended to determine liver enzyme activity and, if severe liver injury is detected, the drug should be discontinued.

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: Clinical trials have not defined the frequency of blood tests and the course of action for each specific case of disease-modifying therapies (DMTs). In the opinion of the expert working group members, these recommendations will help reduce the risk of development and severity of adverse drug reactions.

• In MS patients receiving DMT therapy, to monitor hematopoietic function, it is recommended to perform a complete (clinical) blood count with a differential (including lymphocyte and neutrophil counts) at the end of the first month of therapy, then at least once every 3 months for MS patients receiving interferon beta-1a**, interferon beta-1b**, peginterferon beta-1a**, sampeginterferon beta-1a**, glatiramer acetate**, dimethyl fumarate**, natalizumab** (for natalizumab** – before each administration), fingolimod**, ozanimod, siponimod**, ofatumumab, teriflunomide** [295, 297] due to the increased risk of infectious complications [297, 298].

GCR CLEL 5 Level of Evidence C (Level of Certainty of Evidence – 5)

• In patients receiving ocrelizumab** therapy, it is recommended to perform a complete (clinical) blood count with a differential (including lymphocyte and neutrophil counts) every 6 months prior to each drug administration [101, 150, 151, 299]

GCR CLEL 5 Level of Evidence C (Level of Certainty of Evidence – 5)

• In patients receiving alemtuzumab** therapy, it is recommended to perform a complete (clinical) blood count with a differential (including lymphocyte and neutrophil counts) monthly during the first year between treatment courses and for 4 years after therapy completion [292, 300]

GCR CLEL 5 Level of Evidence C (Level of Certainty of Evidence – 5)

• In patients receiving cladribine** therapy, it is recommended to perform a complete (clinical) blood count with a differential (including lymphocyte and neutrophil counts) at two and six months after the start of treatment in the first and second years of therapy [301]

GCR CLEL 5 Level of Evidence C (Level of Certainty of Evidence – 5)

• If grade 2 toxicity is detected during therapy with interferon beta-1a**, peginterferon beta-1a**, sampeginterferon beta-1a** and interferon beta-1b** or glatiramer acetate**, it is recommended to reduce the drug dosage to ½ of the dose with a repeat complete (clinical) blood count with a differential after 4 weeks, or to monitor parameters every 2 or 4 weeks at the discretion of the neurologist [337]

GCR CLEL 5 Level of Evidence C (Level of Certainty of Evidence – 5)

• If grade 2 toxicity is detected during therapy with dimethyl fumarate**, fingolimod**, siponimod** or ozanimod, it is recommended to repeat the complete (clinical) blood count with a differential in 4 weeks [338]

GCR CLEL 5 Level of Evidence C (Level of Certainty of Evidence – 5)

• If grade 3 or 4 toxicity is detected during therapy with interferon beta-1a**, peginterferon beta-1a**, sampeginterferon beta-1a** and interferon beta-1b**, glatiramer acetate**, teriflunomide**, it is recommended to temporarily discontinue the drug, repeat the complete (clinical) blood count with a differential as soon as possible, and refer the patient to a specialized MS center (office) to determine further management [295, 338]

GCR CLEL 5 Level of Evidence C (Level of Certainty of Evidence – 5)

• If grade 3 (level less than 0.5×10⁹/L) or grade 4 (level less than 0.2×10⁹/L) lymphocyte toxicity is detected, or if the lymphocyte count remains below 0.8×10⁹/L for 6 months during dimethyl fumarate** therapy, it is recommended to discontinue the drug, repeat the complete (clinical) blood count with a differential as soon as possible, and refer the patient to a specialized MS center (office) to determine further management [295, 307, 336, 338];

GCR CLEL 5 Level of Evidence C (Level of Certainty of Evidence – 5)

• If grade 3 lymphocyte toxicity (less than 0.5×10⁹/L) is detected during cladribine** therapy in patients aged 18 years and older, it is recommended to actively monitor the lymphocyte count until normalization [301]

GCR CLEL 5 Level of Evidence C (Level of Certainty of Evidence – 5)

• If grade 4 lymphocyte toxicity (less than 0.2×10⁹/L) is detected during fingolimod** therapy, it is recommended to temporarily discontinue the drug, repeat the complete (clinical) blood count with a differential as soon as possible, and refer the patient to a specialized MS center (office) to determine further management. Once the lymphocyte count reaches >0.6×10⁹/L, re-initiation of therapy may be considered (depending on the duration of the treatment interruption, first-dose monitoring may be required again in accordance with the prescribing information) [295]

GCR CLEL 5 Level of Evidence C (Level of Certainty of Evidence – 5)

• If grade 4 lymphocyte toxicity (less than 0.2×10⁹/L) is detected during siponimod** therapy in patients aged 18 years and older, it is recommended to modify the drug dose [302]:

1) If taking a maintenance dose of 2 mg/day, the dose should be reduced to 1 mg/day. Upon recovery of the absolute lymphocyte count to ≥0.6×10⁹/L, resumption of treatment may be considered;

2) If taking a maintenance dose of 1 mg/day, therapy should be temporarily discontinued. Upon recovery of the absolute lymphocyte count to ≥0.6×10⁹/L, resumption of treatment may be considered.

GCR CLOE 5 Grade of Recommendation C (Level of Evidence – 5)

• If grade 4 lymphocyte toxicity (less than 0.2×10⁹/L) is detected during ozanimod therapy in patients aged 18 years and older, it is recommended to temporarily discontinue the drug, repeat the blood count as soon as possible, and refer the patient to a specialized MS center (office) to determine further management. Once the lymphocyte count reaches >0.5×10⁹/L, re-initiation of therapy may be considered (depending on the duration of the treatment interruption, dose titration and first-dose monitoring may be required again in accordance with the prescribing information) [303]

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• If grade 4 lymphocyte toxicity (less than 0.2×10⁹/L) is detected during cladribine** therapy in patients aged 18 years and older, it is recommended to consider prophylactic anti-herpetic therapy until lymphopenia decreases. If necessary, the 2nd annual treatment course may be postponed for up to 6 months until an acceptable lymphocyte count is restored (>0.8×10⁹/L). If lymphocyte recovery takes more than 6 months, cladribine** therapy must be discontinued [301]

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: Clinical trials have not defined the frequency of blood tests and the course of action for each specific case of disease-modifying therapies (DMTs). In the opinion of the expert working group members, these recommendations will help reduce the risk of development and severity of adverse drug reactions.

• For MS patients with concomitant cardiovascular diseases (history of cardiac arrest, cerebrovascular diseases, uncontrolled arterial hypertension, untreated severe sleep apnea, recurrent syncope, symptomatic bradycardia, previously diagnosed QT interval prolongation greater than 500 ms, or other QT prolongation risks), as well as MS patients taking medications that can enhance bradycardia, class IA antiarrhythmic drugs (e.g., quinidine, disopyramide) or class III antiarrhythmic drugs (e.g., amiodarone**, sotalol**), prior to deciding on the prescription of fingolimod**, ozanimod, or siponimod**, an initial cardiological consultation is recommended to rule out contraindications to therapy and determine the most appropriate monitoring strategy [304, 305, 309, 311, 315]

Level of Evidence CGrade of Evidence 5Level of Evidence C (Grade of Evidence – 5)

Comment: These recommendations will help prevent the development of clinically significant bradycardia and/or cardiac arrhythmias.

• For MS patients aged 18 years and older, prior to initiating siponimod** therapy, determination of the CYP2C9 gene polymorphism (cytochrome P450, family 2, subfamily C, polypeptide 9) of the cytochrome P-450 family is recommended in order to determine the patient's metabolic status, avoid increased siponimod** exposure, and select a safe dosage of the drug [306].

GCR CLeE 4Grade of Recommendations C (Level of Evidence – 4)

Comment: For MS patients aged 18 years and older with CYP2C9*2*3 or CYP2C9*1*3 genotypes, the maintenance dose of siponimod** is 1 mg daily. For MS patients aged 18 years and older with CYP2C9*1*1, CYP2C9*1*2, and CYP2C9*2*2 genotypes, the maintenance dose of siponimod** is 2 mg daily. For MS patients aged 18 years and older with the CYP2C9*3*3 genotype, siponimod** therapy is not recommended.

• In MS patients aged 18 years and older receiving dimethyl fumarate**, for the prevention and management of gastrointestinal adverse events (nausea, vomiting, abdominal pain), it is recommended [90, 307]:

- when initiating therapy – titrate the drug dose according to the product insert;

- take the medication with a high-fat meal;

Level of Evidence CGrade of Evidence 5 Level of Evidence C (Grade of Evidence – 5)

• In MS patients receiving fingolimod**, for the prevention and management of cardiac adverse events (bradycardia, heart block), it is recommended to monitor the first dose administration in a specialized MS center (clinic) [135, 305, 308, 309-311].

Level of Evidence CGrade of Evidence 5 Level of Evidence C (Grade of Evidence – 5)

• Prior to deciding on the prescription of fingolimod**, an initial cardiological consultation with 24-hour Holter ECG monitoring is recommended for the patient [305, 309, 311].

Level of Evidence CGrade of Evidence 5 Level of Evidence C (Grade of Evidence – 5)

If the decision is favorable:

• prior to drug administration, it is recommended to measure blood pressure and heart rate, and record an electrocardiogram to check for contraindications to the first dose: 1) resting heart rate less than 55 bpm; 2) second- and third-degree atrioventricular block (current or historical); 3) sinoatrial block; 4) sick sinus syndrome; 5) QT prolongation (QTc >470 ms in women, QTc >450 ms in men) [305, 309, 311]

Level of Evidence CGrade of Evidence 5 Level of Evidence C (Grade of Evidence – 5)

• following drug administration, measuring peripheral blood pressure and pulse is recommended every hour for 6 hours; after 6 hours, an electrocardiogram should be recorded [305, 309, 311];

Level of Evidence CGrade of Evidence 5 Level of Evidence C (Grade of Evidence – 5)

• patients may be discharged home if all conditions are met: 1) heart rate is above the minimum value observed during the 6-hour monitoring period, 2) there are no symptoms of bradycardia (dizziness, fatigue, palpitations, etc.), 3) ECG shows no QT prolongation ≥500 ms, 4) there are no signs of newly diagnosed second-degree or higher atrioventricular block, 5) 6 hours have elapsed since the first dose of fingolimod** [305, 309, 311];

Level of Evidence CGrade of Evidence 5 Level of Evidence C (Grade of Evidence – 5)

• if the heart rate 6 hours after fingolimod** administration is at its lowest point, it is recommended to extend monitoring for 2 hours or more until the heart rate increases [305, 309, 311];

Level of Evidence CGrade of Evidence 5 Level of Evidence C (Grade of Evidence – 5)

• if the patient's heart rate is <45 bpm, QTc >500 ms, newly onset 2nd-degree AV block, or 3rd-degree AV block at any time, it is recommended to extend monitoring up to 24 hours [305, 309, 311];

Level of Evidence CGrade of Evidence 5Level of Evidence C (Grade of Evidence – 5)

• similar monitoring is recommended in case of treatment interruption exceeding 7 days [305].

Level of Evidence CGrade of Evidence 5 Level of Evidence C (Grade of Evidence – 5)

Comment: These recommendations will help prevent the development of clinically significant bradycardia.

• For patients with secondary progressive multiple sclerosis (SPMS) aged 18 years and older, planning their first dose of siponimod** and presenting with sinus bradycardia (HR < 55 bpm), first- or second-degree AV block (Mobitz I), a history of myocardial infarction, or a history of heart failure (New York Heart Association class I or II patients) (if therapy is not contraindicated), an electrocardiogram prior to therapy initiation, 6-hour observation, and repeat electrocardiogram recording 6 hours after the first dose are recommended to detect signs and symptoms of bradycardia, and to prevent and monitor cardiac events [305, 312, 313].

Level of Evidence CGrade of Evidence 5 Level of Evidence C (Grade of Evidence – 5)

• For SPMS patients aged 18 years and older, following the first dose of siponimod**, if post-dose bradyarrhythmia or conduction-related symptoms develop, or if new signs of second-degree or higher AV block or QTc interval prolongation ≥500 ms are detected on the 6-hour post-dose ECG, an initial cardiological consultation is recommended [314]

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comment: These recommendations will help prevent the development of clinically significant bradycardia.

• In SPMS patients aged 18 years and older receiving siponimod**, for the prevention and management of cardiac adverse events during the first 5 days, dose titration at 0.25–1.25 mg is recommended according to the summary of product characteristics, followed by a transition to a maintenance dose of 2 mg orally daily (1 mg/day for CYP2C9 2/3 and CYP2C9 1/3 genotypes) [313].

GPR CLOE 5 Grade of Recommendation C (Level of Evidence – 5)

• For MS patients aged 18 years and older planned for ozanimod therapy who have sinus bradycardia (HR <55 bpm), second-degree AV block (Mobitz type I), a history of myocardial infarction, or a history of heart failure (New York Heart Association class I or II patients) (if therapy is not contraindicated), to detect signs and symptoms of bradycardia following the first dose, 6-hour observation in a specialized MS center (clinic) is recommended [315]:

- prior to drug administration: measure peripheral blood pressure and pulse, and record an electrocardiogram to check for contraindications to the first dose;

- following drug administration: measure peripheral blood pressure and pulse every hour for 6 hours;

- 6 hours after the first dose: record an electrocardiogram;

• Additional monitoring and a repeat cardiological consultation are recommended for patients who, at 6 hours post-dose, exhibit:

- heart rate reduction to less than 45 bpm;

- heart rate at its lowest post-dose value, suggesting that the maximal heart rate reduction has not yet been reached;

- signs of newly onset second-degree or higher AV block on the 6-hour post-dose ECG;

- QTc interval >500 ms.

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comment: These recommendations will help prevent the development of clinically significant bradycardia.

• For MS patients aged 18 years and older receiving ozanimod, for the prevention and management of cardiac adverse events during the first 7 days, dose titration at 0.23–0.46 mg is recommended according to the summary of product characteristics, followed by a transition to a maintenance dose of 0.92 mg orally daily starting from day 8 of therapy [300, 301] [315].

Level of Evidence CGrade of Evidence 5 Level of Evidence C (Grade of Evidence – 5)

• In MS patients receiving natalizumab**, for the prevention of opportunistic infections (progressive multifocal leukoencephalopathy (PML)), it is recommended to perform patient stratification for PML risk and proceed in accordance with the selected algorithm (Appendix A3.10) [147-149, 316].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: Despite the fact that most cases of PML in patients with MS occurred during natalizumab** therapy, it should be borne in mind that the development of this opportunistic infection is possible during therapy with fingolimod**, teriflunomide**, dimethyl fumarate**, alemtuzumab**, ocrelizumab**, ozanimod [317].

• In patients with MS receiving therapy with interferons beta-1a** and interferon beta-1b**, in order to determine the response to disease-modifying therapies (DMTs), it is recommended to test the blood for neutralizing antibody (NAB) titers against interferon beta-1a** and interferon beta-1b** 12 months after the initiation of therapy. In NAB-negative patients, it is recommended to repeat the analysis at least once every 12 months. In patients with a positive but not high NAB titer, the test is recommended to be repeated after 3 months or to test MxA protein activity. In case of a persistently positive NAB titer (confirmed twice) and/or lack of MxA protein activity, a change of therapy is recommended. In patients with a high NAB titer, a change of therapy is recommended [318].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment: Determining the clinical significance of NAB detection is difficult for several reasons: many studies on this issue did not have a sufficient number of participants followed for a sufficiently long time; blood samples for analysis were collected at various times from the start of therapy [318-320]. Some NAB-positive patients may eventually become NAB-negative [321]. A study by Kappos et al. shows that determining high NAB titers 1 year after the initiation of therapy reduces the efficacy of interferon beta-1a** therapy after 4 years [322]. In a study by Voort et al., patients with NABs compared to patients without NABs showed a more aggressive course of MS, characterized by a shorter time to reach an EDSS score of 6.0 and the need for DMT escalation [323]. Recommendations by Goodin et al. and Malucchi et al. define consensus values for NAB titers and management tactics in each specific case [318, 324].

• In patients receiving ocrelizumab**, alemtuzumab**, cladribine**, divozilimab**, in order to prevent the reactivation of chronic infections, it is recommended to determine antibodies classes M, G (IgM, IgG) to human immunodeficiency virus HIV-1 in the blood, to determine antibodies classes M, G (IgM, IgG) to human immunodeficiency virus HIV-2 in the blood, to determine hepatitis B virus surface antigen (HbsAg) in the blood, to determine antibodies classes M, G (IgM, IgG) to hepatitis B virus surface antigen (HBsAg) in the blood, to determine antibodies classes M, G (IgM, IgG) to hepatitis B virus core antigen (HBcAg) in the blood, to determine antibodies classes M, G (IgM, IgG) to hepatitis C virus in the blood, to determine antibodies classes M, G (IgM, IgG) to Treponema pallidum in nontreponemal tests (RPR, VDRL) (qualitative and semi-quantitative test) in blood serum, and to perform an intradermal test with tuberculosis allergen before each administration of the drug [28, 299, 325, 326].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment: Administration of these DMTs can lead to the reactivation of chronic infections, which is reflected in the instructions for use of these drugs. To reduce therapy risks, all patients are recommended to undergo these tests before starting therapy.

• In patients with MS, after establishing the diagnosis, in order to prevent a delay in the initiation of DMT therapy, it is recommended to assess the vaccination status, infection risk, and consequences of previous infections to clarify the need for and type of vaccination [273].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: it should also be clarified whether the patient has previously had vaccine-preventable infections (e.g., measles, rubella, varicella, mumps, etc.). If possible, the results of immune response titers to vaccine-preventable pathogens should be taken into account.

Subsequently, during follow-up and treatment, the patient's vaccination status should be monitored regularly, mandatory before prescribing immunosuppressive therapy.

• Patients with MS are recommended to be vaccinated in accordance with the national immunization schedule to prevent/reduce the likelihood of a severe (complicated) course of infections, taking into account the period of the disease and ongoing therapy [273, 327].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: The DMT therapy used in MS allows maintaining control over the disease, but may increase the risks of infectious diseases, making vaccination an important part of managing patients with this pathology. It has been proven that the potential benefit of vaccination in MS patients, both receiving and not receiving DMTs, significantly outweighs the potential risks and does not increase the risk of disease exacerbation or clinical deterioration. Patients not receiving DMTs can receive any vaccines in accordance with the instructions (inactivated and live) [273].

• When drawing up a vaccination plan for patients with MS, it is recommended to take into account the epidemiological situation and other potential risks of vaccine-preventable infections in order to prevent infectious diseases [273].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: vaccination is carried out outside the relapse period, after stabilization of the condition.

• For patients with MS receiving or planning to start DMT therapy (interferons beta-1a**, peginterferon beta-1a**, sampeginterferon beta-1a**, interferon beta-1b**, glatiramer acetate**), vaccination is recommended to be carried out observing the following timelines [273]:

- (inactivated) vaccines can be administered at any time, but preferably at least 2 weeks before the start of treatment to ensure a full immune response;

- live attenuated vaccines should be administered at least 4 weeks before the start of treatment (for ocrelizumab** and alemtuzumab**, at least 6 weeks before the start of treatment);

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: Recommended intervals for the administration of live attenuated vaccines [273]:

• Patients with MS receiving DMT therapy (teriflunomide**, dimethyl fumarate**, cladribine**, natalizumab**, fingolimod**, ozanimod, siponimod**, alemtuzumab**, ocrelizumab**, ofatumumab, divozilimab**) are not recommended to use live attenuated vaccines if vaccination is planned [273].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• Patients with MS with an exacerbation of the disease, if vaccination is planned, are recommended to comply with the following conditions [273]:

- live attenuated vaccines should be administered no earlier than 1 month after the end of systemic glucocorticoid therapy for MS relapses;

- inactivated vaccines should be administered no earlier than 1 month after the end of systemic glucocorticoid therapy for MS relapses. If necessary, they can be administered at any time.

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• Patients with MS who have discontinued immunosuppressive DMTs, if vaccination is planned, are recommended to comply with the following conditions [273]:

- inactivated vaccines can be administered at any time, but preferably after the restoration of a sufficient immune response;

- live attenuated vaccines should be administered only after observing a safety interval ensuring the restoration of the immune system.

GCR CLEL 5 Level of Evidence C (Level of Certainty of Evidence – 5)

• Patients with MS receiving immunosuppressive DMT therapy are recommended to be vaccinated against pneumococcal infection for preventive purposes, following the vaccination recommendations for immunocompromised patients [273].

GCR CLEL 5 Level of Evidence C (Level of Certainty of Evidence – 5)

• For female patients with MS as part of preparation for pregnancy, as well as during pregnancy in order to prevent/reduce the likelihood of a severe (complicated) course of infections, vaccination is recommended in accordance with the national immunization schedule, taking into account the period of the disease and ongoing therapy [273, 327].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: general principles of vaccination during pregnancy planning and gestation are provided in the clinical guidelines "Normal Pregnancy". Vaccination depending on the period of the disease and the therapy received is carried out similarly to other MS patients. An infant born to a mother with MS who received treatment with ocrelizumab**, ofatumumab, divozilumab** during pregnancy or shortly before pregnancy should, if possible, undergo CD19+ lymphocyte testing to determine the possibility of immunization with live vaccines.

6. Organization of Medical Care

• To provide care for patients with MS, it is recommended to organize separate structures (offices, clinical and diagnostic offices, departments, specialized neurological centers for multiple sclerosis) for the purpose of diagnosis and dispensary follow-up of this category of patients [274].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: The organization of a specialized center/department/office is viewed by the expert working group members as the only effective measure for organizing qualified care for MS patients, as well as a means of gathering up-to-date information on disease prevalence and the need for DMT therapy, rehabilitation, and other measures.

• Dispensary follow-up of patients with MS is recommended to be carried out in a specialized clinical and diagnostic office/department or a specialized multiple sclerosis neurological center [274].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: The organization of a specialized center/department/office is viewed by the expert working group members as the only effective measure for organizing qualified care for MS patients, as well as a means of gathering up-to-date information on disease prevalence and the need for DMT therapy, rehabilitation, and other measures.

• Therapy for mild MS relapses in patients aged 18 years and older is recommended to be carried out in a day hospital (Appendix G14) [328].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: Not all patients need hospitalization in a round-the-clock hospital for MS relapse therapy. There are insufficient data to reliably assess the benefits of MS relapse therapy in a round-the-clock hospital, day hospital, or home setting. An RCT conducted by Chataway et al., with moderate quality of evidence, including 124 patients, showed no difference in clinical efficacy between relapse therapy (intravenous glucocorticoids) performed in a day hospital and at home.

• Therapy for moderate and severe MS relapses in patients aged 18 years and older is recommended to be carried out in a round-the-clock hospital (Appendix A3.12) [328].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: Not all patients need hospitalization in a round-the-clock hospital for MS relapse therapy. There are insufficient data to reliably assess the benefits of MS relapse therapy in a round-the-clock hospital, day hospital, or home setting. An RCT conducted by Chataway et al., with moderate quality of evidence, including 124 patients, showed no difference in clinical efficacy between relapse therapy (intravenous glucocorticoids) performed in a day hospital and at home.

• In cases that make it difficult for MS patients aged 18 years and older to receive moderate relapse therapy in a round-the-clock hospital, it is recommended to carry out treatment in a day hospital after discussion with the patient [328].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comment: Not all patients need hospitalization in a round-the-clock hospital for MS relapse therapy. There are insufficient data to reliably assess the benefits of MS relapse therapy in a round-the-clock hospital, day hospital, or home setting. An RCT conducted by Chataway et al., with moderate quality of evidence, including 124 patients, showed no difference in clinical efficacy between relapse therapy (intravenous glucocorticoids) performed in a day hospital and at home.

• For patients receiving infusion disease-modifying therapies for multiple sclerosis (DMTs), to conduct intravenous infusions, it is recommended to organize specialized day hospitals within the structure of MS neurological centers and clinical and diagnostic offices [274, 329].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: Conducting DMT infusions within a day hospital will reduce the burden on the inpatient healthcare sector while ensuring optimal monitoring of tolerability and treatment efficacy.

• In the absence of indications for prescribing DMTs or the patient's written refusal of DMT therapy, it is recommended to organize medical care based on the principles of accessibility and quality (Appendix A3.9) [274].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: A document substantiating the patient's failure to receive DMTs (decision of a specialized center; patient's refusal to receive DMTs) is placed in the primary medical documentation. Patients who can visit the primary specialized medical and preventive care facility undergo: a repeat appointment (examination, consultation) with a neurologist (at least once every 6 months); prescription of symptomatic therapy. For patients who cannot visit the primary specialized medical and preventive care facility, a patronage service should be organized at the location of the primary medical and preventive care facility.

• If a female patient with MS decides to plan a pregnancy, it is recommended to refer her to a specialized MS Center (department, office, clinical and diagnostic office) for a consultation on the specifics of the course of pregnancy and the postpartum period in MS. MS is not an indication for pregnancy termination [278-280].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• The decision on the provision of emergency and elective surgical care, including dental care, to a patient with MS is recommended to be made based on the scope of surgical intervention and the patient's condition [330-332].

GPP CLEL 4Level of Evidence Recommendation C (Level of Evidence – 4)

Comment: MS is not a contraindication for a medical intervention required by the patient due to a concurrent disease. There is no evidence of significant contraindications to specific types of medical interventions. A systematic review of research data using meta-analysis revealed a weak increase in the risk of developing MS in patients who underwent tonsillectomy or appendectomy under the age of 20, while some studies were of low quality.

• The decision on anesthetic management for a patient with MS aged 18 years and older in the event of surgical care, including dental care, is recommended to be made based on the scope of surgical intervention and the patient's condition [333].

GCR BLOE 3Grade of Recommendation B (Level of Evidence 3)

Comment: MS is not a contraindication for a medical intervention required by the patient due to a concurrent disease. There is no evidence of significant contraindications to specific types of medical interventions.

• Patients with MS are recommended to have a telemedicine consultation for the purpose of patient education on the use of DMTs, planned dynamic condition assessment, prescription issuing, as well as for discussing issues that do not require the patient's presence (e.g., discussing diet, daily routine, or the risks of hereditary transmission of MS) [333-334].

GRC BLoE 5Grade of Recommendation B (Level of Evidence – 5)

Comment: A telemedicine consultation is an option for the efficient use of healthcare resources and patient resources in conditions of time scarcity and mobility limitations of disabled patients. The widespread introduction of telemedicine consultations will allow patients to receive information from a doctor that they would not be able to ask for due to lack of time during an in-person appointment.

• Patients with MS are recommended remote monitoring for the purpose of assessing the dynamics of laboratory and instrumental parameters during the implementation of the risk management plan, evaluating recommended and performed examination parameters, and assessing patients' quality of life [333-334].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: Remote monitoring is possible using information technology and decision support systems that can collect, process, and record data received from the patient and transmit them to the attending physician in accordance with current legislation.

7. Additional Information

• When diagnosing multiple sclerosis, all other diseases of the nervous system must be excluded, including lesions in infectious, toxic, vascular, and neoplastic diseases, as well as systemic autoimmune diseases with vasculitis and hereditary degenerative diseases.

• When initiating and conducting DMT therapy, it is necessary to take into account the patient's somatic condition and possible adverse reactions. Special attention should be paid to the following conditions during DMT therapy:

- Interferon beta-1a**, interferon beta-1b**, peginterferon beta-1a**, sampeginterferon beta-1a** – flu-like syndrome (fever, chills, arthralgia, general malaise, sweating, headache, myalgia), local injection site reactions (redness, edema, pain, skin discoloration, necrosis), possible increase in depression, increased spastic muscle tone, increased risk of seizures if there is a history of epilepsy;

- Gatiramer acetate** – local injection site reactions (redness, pain, induration, pruritus, edema, lipoatrophy), immediate post-injection reaction (a reaction associated with at least one or more symptoms [vasodilation, chest pain, dyspnea, rapid heartbeat or tachycardia], which manifests a few minutes after the injection);

- Teriflunomide** – in women of childbearing potential: careful contraception, pancreatic pathology;

- Dimethyl fumarate** – gastrointestinal problems, flushing reactions ("burning and hot flushes", etc.), lymphopenia, and PML risk;

- #Mitoxantrone** – significant increase in the risk of developing leukemias, increased risk of developing cardiac pathology;

- Natalizumab** – acute infusion allergic reactions to administration, PML risk depending on the presence of JC virus infection and antibody titers to this virus, as well as prior immunosuppression and duration of treatment, relapse of MS upon drug discontinuation, must not be combined with other DMTs;

- Fingolimod** – bradycardia and cardiac rhythm disorders; contraindicated in cardiovascular diseases, especially with bradycardia, and when using heart rate-lowering drugs; macular edema (to a minor extent); lymphopenia and the risk of PML and other infections; high risk of disease exacerbation upon drug discontinuation;

- Siponimod** – bradyarrhythmia; contraindicated in patients with a history of myocardial infarction, unstable angina, stroke/transient ischemic attack, or decompensated heart failure within the preceding 6 months, and in the presence of the homozygous CYP2C9*3 genotype (CYP2C9*3*3) (poor metabolizer). Lymphopenia, risk of cryptococcal meningitis and herpes virus infection; upon drug discontinuation, MS exacerbations. Strict contraception in women of childbearing potential.

- Alemtuzumab**– acute infusion-related allergic reactions, risk of opportunistic infections (including listeriosis), thyroid pathology, immune thrombocytopenia (ITP), and other secondary autoimmune reactions;

- Ocrelizumab**– acute infusion-related allergic reactions, risk of opportunistic infections;

- Cladribine** - lymphopenia and risk of infections

- Ozanimod – bradycardia and cardiac rhythm disorders, macular edema (to a minor extent), lymphopenia and the risk of PML and other infections, may increase the likelihood of malignancies including cutaneous neoplasms, high risk of disease exacerbation upon drug discontinuation

- Divozilimab** – acute infusion-related allergic reactions, risk of opportunistic infections, hepatitis B virus reactivation. Patients receiving divozilimab** therapy must undergo a comprehensive complete blood count (including lymphocyte and neutrophil counts) every 6 months prior to each subsequent drug infusion due to the increased risk of infectious complications

- Ofatumumab – injection-related reactions, risk of opportunistic infections, hepatitis B virus reactivation

- Fampridine – hypersensitivity reactions, increases the risk of seizures; the risk of adverse reactions increases in renal impairment (contraindicated at creatinine clearance <80 mL/min)

• To assess the risk of complications, it is recommended to use the general toxicity scale (Appendix A3.8);

• To evaluate the effectiveness of DMT therapy in MS patients aged 18 years and older in order to prevent DMT discontinuation before the therapeutic effect is achieved, it is recommended to use the following timeframes for the onset of the expected therapeutic effect:

- glatiramer acetate** 20 mg – 6–9 months [87, 109, 116];

- glatiramer acetate** 40 mg – 3–6 months [114, 116];

- interferons beta-1a** and interferon beta-1b** – 3 months [83, 109, 116];

- sampeginterferon beta-1a** – 3 months [92-92, 116];

- peginterferon beta-1a** – 3 months [109, 116];

- teriflunomide** – 3 months [109, 116];

- dimethyl fumarate** – 3 months [109, 116];

- natalizumab** – 3 months [109];

- fingolimod** – 3 months [109, 116];

- ozanimod – 3–6 months [138];

- alemtuzumab** – 18 months [116];

- ocrelizumab** – 12 months [110];

- cladribine** – 18 months [111, 116];

- siponimod** – 12 months [115];

- divozilimab** – 9 months [127];

- ofatumumab – 6 months [112-113]

Comment: Studies aimed at determining the time to achieve DMT efficacy have not been conducted, with the exception of glatiramer acetate** [87, 114]. For the pediatric MS population, studies aimed at determining the time to achieve DMT efficacy have not been conducted. For all DMTs except glatiramer acetate**, the opinion of the working group experts is provided, which coincides with the opinion of the experts of the Canadian Multiple Sclerosis Working Group regarding interferons beta-1a**, interferons beta-1b**, peginterferon beta-1a**, teriflunomide**, dimethyl fumarate**, fingolimod** [116]. The recommendation is based on data from individual RCTs, while the expected times of effect development correspond to the timeframes at which the treatment efficacy was evaluated in the presented studies. High methodological quality studies specifically investigating the time to onset of optimal response to therapy have not been conducted [87, 109-113, 117, 128].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

All members of the working group declared no financial or non-financial conflicts of interest regarding the topic of the developed clinical guideline. Working group member(s) who reported circumstances that could potentially lead to a conflict of interest were excluded from the discussion of sections related to the area of conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Chief physicians (heads) of medical organizations

2. Deputy heads (chiefs) of medical organizations

3. Heads (chiefs) of structural subdivisions

4. Chief Nursing Officers

5. Specialist physicians:

• Neurologists, specialty code 31.08.42

• Radiologists, specialty code 31.08.09

• Clinical pharmacologists, specialty code 31.08.37

• Physical therapy and sports medicine physicians, specialty code 31.08.39

• Physical and rehabilitation medicine physicians

• Emergency medicine physicians, specialty code 31.08.48

• General practitioners / Internal medicine physicians, specialty code 31.08.49

• Physiotherapists, specialty code 31.08.50

• General practice physicians (family physicians), specialty code 31.08.54

• Ophthalmologists, specialty code 31.08.59

• Urologists, specialty code 31.08.68

• Healthcare and public health administrators, specialty code 31.08.71

6. Nurses:

• general practice nurse

• ward (duty) nurse

• emergency medical services call-taker / dispatcher nurse (feldsher) responsible for receiving emergency calls and dispatching them to emergency teams

• procedural nurse

• rehabilitation nurse

• district nurse

• medical registrar

• medical statistician

• radiology technician

• head nurse

• feldsher

• emergency medical services feldsher

7. Heads of pharmacy organizations

8. Provisors (Pharmacists with higher education)

9. Pharmacists

10. Medical students, residents, postgraduate students;

11. Medical university faculty members, researchers.

In these clinical guidelines, all information is graded by the level of reliability (evidence) based on the quantity and quality of studies on the given issue (Tables App. 1, App. 2).

Table 1. Scale for grading levels of reliable evidence (LRE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for grading levels of reliable evidence (LRE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for grading levels of recommendation certainty (LRC) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Federal Law No. 323-FZ dated November 21, 2011, "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation"

2. Federal Law No. 61-FZ dated April 12, 2010, "On the Circulation of Medicines"

3. Federal Law No. 489-FZ dated December 25, 2018, "On Amendments to Article 40 of the Federal Law 'On Compulsory Medical Insurance in the Russian Federation' and the Federal Law 'On the Fundamentals of Protecting the Health of Citizens in the Russian Federation' regarding Clinical Guidelines" (latest edition)

4. Order of the Ministry of Health of the Russian Federation No. 926n dated November 15, 2012, "On approval of the Procedure for providing medical care to the adult population for diseases of the nervous system."

5. Standard of specialized medical care for the first clinical manifestation of multiple sclerosis (clinically isolated syndrome). Appendix to the Order of the Ministry of Health of the Russian Federation No. 1085n dated December 20, 2012

6. Standard of primary health care for acute opticospinal encephalomyelitis (diagnosis). Appendix to the Order of the Ministry of Health of the Russian Federation No. 1533n dated December 24, 2012

7. Standard of primary health care for multiple sclerosis in remission. Appendix to the Order of the Ministry of Health of the Russian Federation No. 1542n dated December 24, 2012

Appendix A 3.1. McDonald Diagnostic Criteria for MS, 2017 Revision

In typical presentations of MS, the 2017 revised McDonald criteria must be used [5].

Dissemination in space (DIS):

- Clinical – evidence of two or more manifest lesions,

- MRI findings - presence of 1 or more T2-hyperintense lesions in two of the four areas of the CNS:

1) periventricular,

2) cortical and/or juxtacortical,

3) infratentorial,

4) in the spinal cord.

Dissemination in time (DIT):

- Clinical – a subsequent relapse involving a new CNS site, clinical manifestations of the relapse must last for at least 24 hours, the interval between clinical attacks must be at least 1 month,

- MRI findings:

1) simultaneous presence of gadolinium-enhancing and non-enhancing lesions on an MRI scan performed at any time from the onset of the disease; lesions may be either symptomatic or asymptomatic. If other criteria are met, the diagnosis of MS can be confirmed without a follow-up MRI;

2) appearance of new T2-hyperintense or gadolinium-enhancing lesions on a follow-up MRI; the interval between the first and second MRI scans can be of any duration.

In clinical practice, several diagnostic variants of RRMS are considered:

- Presence of 2 or more clinical relapses and objectively confirmed clinical damage to 2 or more functional systems (2 or more "manifest" lesions) – no additional data are required to confirm MS;

- Presence of 2 or more clinical relapses and objectively confirmed clinical damage to 1 functional system (1 "manifest" lesion), while medical records indicate a history of another "manifest" lesion in a different location – no additional data are required to confirm MS;

- Presence of 2 or more clinical relapses and objectively confirmed clinical impairment of 1 functional system (1 "manifest" lesion) – proof of dissemination in space is required (a new relapse with a different lesion location or dissemination in space on MRI);

- Presence of 1 clinical relapse and objectively confirmed clinical impairments of 2 or more functional systems (2 or more "manifest" lesions) – proof of dissemination in time is required (a new relapse or MRI findings, or the presence of oligoclonal immunoglobulins in the CSF);

- Presence of 1 clinical relapse and objectively confirmed clinical impairment of 1 functional system (1 "manifest" lesion) – proof of dissemination in space and in time is required (a new relapse with a different lesion location, or dissemination in space on MRI, or the presence of oligoclonal immunoglobulins in the CSF)

Diagnostic criteria for MS (2017 revision) for patients with a primary progressive course:

- progression over 1 year, confirmed retrospectively or prospectively, unrelated to the occurrence of relapses (dissemination in time),

And the presence of any two of the following features (dissemination in space):

- presence of 1 or more T2-hyperintense lesions in one or more typical CNS regions: periventricular, cortical/juxtacortical, infratentorial;

- two or more T2-hyperintense lesions in the spinal cord;

- presence of oligoclonal immunoglobulins in the CSF.

Appendix A 3.2. McDonald MS Diagnostic Criteria, 2010 Revision

In atypical clinical presentations, an MS diagnosis can be established in accordance with the 2010 criteria [335]:

Dissemination in space (DIS):

- Clinical – evidence of two or more clinical lesion sites,

- MRI data – detection of >1 T2-hyperintense lesion in two of the four areas typically affected in MS (contrast enhancement is not required):

a) periventricular,

b) juxtacortical (near the cerebral cortex),

c) infratentorial,

d) spinal cord (in the presence of brainstem or spinal cord symptoms, lesions corresponding to the clinical presentation are not counted).

Dissemination in time (DIT):

- Clinical – another relapse involving a new CNS site, clinical manifestations of the relapse must last for at least 24 hours, the interval between clinical attacks must be at least 1 month,

- MRI data – one of the following criteria:

a) simultaneous detection of asymptomatic gadolinium-enhancing and non-enhancing lesions on an MRI performed at any time from disease onset; in this case, provided other criteria are met, the MS diagnosis can be confirmed without a repeat MRI;

b) appearance of new T2-hyperintense and/or gadolinium-enhancing lesions on a follow-up MRI; the interval between the first and second MRI scans can be any.

In clinical practice, several diagnostic variants of RRMS are considered:

- Presence of 2 or more clinical relapses AND objectively confirmed clinical impairment of 2 or more functional systems (2 or more "manifest" lesions), or objective confirmation of clinical involvement of 1 functional system (1 "manifest" lesion) with amnestic objective evidence of involvement of 1 more functional system based on medical documentation – in the absence of objective data for other neurological diseases, no additional data are required to confirm the MS diagnosis;

- Presence of 2 or more clinical relapses and objectively confirmed clinical impairment of 1 functional system (1 "manifest" lesion) – evidence of dissemination in space on MRI or the occurrence of a new clinical relapse involving a different functional system is required;

- Presence of 1 clinical relapse and objectively confirmed clinical impairments of 2 or more functional systems (2 or more "manifest" lesions) – evidence of dissemination in time on MRI or the occurrence of a new clinical relapse is required;

- Presence of 1 clinical relapse and objectively confirmed clinical impairment of 1 functional system (1 "manifest" lesion) – evidence of dissemination in time and space on MRI or the occurrence of a new clinical relapse involving a different functional system is required;

Diagnostic criteria for MS (2010 revision) for patients with a primary progressive course:

- Steady progression for 1 year or more, confirmed retrospectively or prospectively (+1 EDSS point per 6 months), unrelated to the occurrence of relapses (dissemination in time)

And the presence of any two of the following features (dissemination in space):

- presence of 1 or more T2-hyperintense lesions in one or more typical CNS regions (periventricular, juxtacortical, infratentorial);

- two or more T2-hyperintense lesions in the spinal cord;

- presence of class G oligoclonal immunoglobulins or an elevated IgG index, or both parameters in the CSF.

Appendix A 3.3. Differential diagnosis of MS

The diagnosis of MS is established by exclusion in the absence of other (better) explanations for the symptoms, while differential diagnosis is performed with several major groups of diseases:

1. Systemic inflammatory diseases with autoimmune mechanisms:

- Clinical differential diagnosis is based on excluding systemic involvement:

• Retinopathy with signs of vasculitis (vasculitis).

• Uveitis (SLE, Behçet's disease).

• Recurrent mucosal ulcers (Behçet's disease, SLE).

• Sicca syndrome – keratoconjunctivitis sicca (Sjögren's syndrome).

• Kidney involvement (SLE, vasculitis).

• Arthritis, polyarthralgia, myalgia (SLE).

• Antiphospholipid syndrome (APS) – a diffuse connective tissue disease characterized by microcirculatory vascular involvement due to the formation of autoimmune antibodies against cell membrane phospholipids, which include lupus anticoagulant, anticardiolipin antibodies (IgG and/or IgM), and anti-beta-2-glycoprotein 1 antibodies (IgG and/or IgM).

• Livedo reticularis (APS).

• Recurrent pregnancy loss (APS).

- Paraclinical methods for excluding rheumatic diseases.

• General clinical – inflammatory changes in blood tests (leukocytosis, elevated erythrocyte sedimentation rate (ESR), appearance of C-reactive protein), anemia.

• Serological – screening for diagnostically significant titers of antibodies against cell membrane phospholipids, endothelium, neutrophils, native DNA, gastric parietal cells, salivary glands, as well as circulating immune complexes.

• Neuroimaging – multiple small lesions (up to 5 mm), presence of ischemic lesions and cysts, lesions in the gray matter.

- Main diseases requiring differential diagnosis with MS:

• Primary systemic vasculitides – a group of diseases based on various generalized autoimmune vascular involvements with inflammation and necrosis of the vessel wall, leading to ischemic changes in organs and tissues (including the brain), as well as damage by circulating immune complexes, anti-endothelial antibodies, and anti-neutrophil cytoplasmic antibodies.

• Rheumatic diseases with secondary vasculitis: Sjögren's syndrome – a chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands, leading to xerostomia, xerophthalmia, dryness of the mucous membranes of the nose, larynx, trachea, bronchi, female genital organs, and atrophic gastritis; Behçet's disease – a systemic vasculitis of unknown etiology, characterized predominantly by ulceration of the mucous membranes of the eyes, oral cavity, skin, genitals, and the nervous system; systemic lupus erythematosus (SLE) – a diffuse connective tissue disease characterized by systemic immune-complex involvement of connective tissue and its derivatives, with microcirculatory vascular involvement due to the formation of autoimmune antibodies against DNA.

• Sarcoidosis – a multisystem granulomatous disease of unknown etiology, where the substrate consists of granulomas in various organs and tissues, composed of epithelioid and giant cells, as well as macrophages, leading to perivasculitis or leptomeningitis.

• Isolated CNS vasculitides – Th1-mediated granulomatous inflammation of small- and medium-sized arteries and veins, particularly of the pia mater and subcortical areas; angiographic data are used for confirmation.

2. Infectious diseases (with the development of an autoimmune component):

- Clinical differential diagnosis is based on identifying signs of an infectious process:

• epidemiological history data,

• general somatic status (fever, systemic involvement), \

• neurological status (general cerebral syndrome, peripheral nervous system involvement, signs of gray matter affliction, early cognitive deficit).

- Paraclinical methods for excluding neuroinfections:

• Serological tests: screening for diagnostically significant IgM antibody titers against the suspected infectious agent (in some cases, rising IgG titers on serial testing); if necessary, confirmation using polymerase chain reaction (PCR). In patients with suspected MS who present with features that warrant including progressive multifocal leukoencephalopathy (PML) in the differential diagnosis, molecular biological testing of the cerebrospinal fluid for polioviruses may be ordered [32, 33].

• Cerebrospinal fluid analysis: pleocytosis, presence of antibodies against the suspected infectious agent in the CSF, and/or its detection by PCR.

• Neuroimaging: lesions of various sizes and locations in the white matter of the cerebral hemispheres (including subcortical and periventricular areas), lesions in the gray matter, and less commonly in the cerebellum, thalamus, or basal ganglia. Most patients show combined involvement of multiple brain regions, with lesions showing contrast enhancement.

- Main diseases requiring differential diagnosis with MS:

• Spirochetal encephalitides and encephalomyelides (neuroborreliosis, neurosyphilis).

• Immunodeficiency-related encephalitides and encephalomyelides: retroviral (HIV encephalopathy), papovaviral (progressive multifocal leukoencephalopathy).

• Flaviviral encephalitides and encephalomyelides (Japanese encephalitis, tick-borne encephalitis, St. Louis encephalitis, West Nile virus infection).

• Herpesvirus encephalitides and encephalomyelides (herpes simplex, cytomegalovirus, Epstein-Barr virus).

• Exanthematous encephalitides and encephalomyelides: herpesvirus (varicella-zoster); togavirus (rubella); paramyxovirus (measles).

• Neurobrucellosis.

• Tropical spastic paraparesis (HTLV-1-associated myelopathy).

• Whipple's disease.

3. Vascular diseases affecting the CNS:

- Main conditions requiring differential diagnosis with MS.

• Binswanger's disease (subcortical arteriosclerotic encephalopathy).

• Migraine.

• Familial cerebral cavernous malformation.

• Susac syndrome (retinocochleocerebral autoimmune vasculopathy).

4. Hereditary diseases affecting the CNS:

- Main conditions requiring differential diagnosis with MS.

• Adrenoleukodystrophy.

• Metachromatic leukodystrophy.

• Spinocerebellar ataxias.

• Hereditary spastic paraplegia (Strümpell disease).

• Leber's hereditary optic neuropathy.

• Mitochondrial encephalopathy (CADASIL, MELAS, etc.).

5. Dysmetabolic and toxic disorders:

- Main conditions requiring differential diagnosis with MS.

• Acute intermittent porphyria.

• Central pontine myelinolysis.

• Funicular myelosis (vitamin B₁₂ — cyanocobalamin — and/or B9 — folic acid — deficiency).

• Celiac disease (gluten enteropathy).

• Toxic encephalopathy (including post-radiation encephalopathy).

6. Metastatic tumors of the spinal cord and brain.

7. Other forms of inflammatory demyelinating diseases:

- Acute disseminated encephalomyelitis (ADEM) [19]:

• first-ever episode of a multifocal CNS lesion of presumed inflammatory demyelinating nature,

• acute encephalopathy (alteration in consciousness or behavior not attributable to fever, systemic illness, or the postictal phase of a seizure),

• MRI performed within three months of symptom onset reveals the following typical features: 1) acute onset, 2) multiple lesions (occasionally a single large lesion), 3) supratentorial and/or infratentorial location; 4) usually at least one large lesion (1–2 cm in diameter); 5) contrast enhancement within lesions (all lesions show contrast enhancement in the acute phase; on later MRI scans, some lesions may no longer enhance, but this does not confirm dissemination in time).

• absence of new clinical or MRI lesions for three months or more after the onset of the episode,

• appearance of new mono- or multifocal symptoms (such as optic neuritis or myelitis) is permitted within three months of disease onset, provided they are not separated from the initial symptoms by a period of complete remission (in the event of complete remission, a diagnosis of MS is established),

• subsequent partial or complete recovery, although residual neurological deficits may persist.

- NMOSD with aquaporin-4 antibodies [339]:

• presence of at least one core clinical syndrome: 1) optic neuritis, 2) acute myelitis, 3) area postrema syndrome: an episode of otherwise unexplained hiccups or nausea and vomiting, 4) acute brainstem syndrome, 5) symptomatic narcolepsy or acute diencephalic syndrome with typical NMOSD brain MRI lesions, 6) symptomatic cerebral syndrome with typical NMOSD brain lesions,

• positive serum test result for IgG antibodies against aquaporin-4 using the most sensitive method (cell-based assays are recommended),

• exclusion of alternative diagnoses.

- NMOSD — neuromyelitis optica spectrum disorders without aquaporin-4 antibodies or when testing is unavailable [339]:

• presence of at least two core clinical syndromes occurring during one or more clinical relapses that meet the following conditions: a) at least one core clinical syndrome is optic neuritis, acute myelitis with longitudinally extensive transverse myelitis (LETM), or area postrema syndrome; b) dissemination in space (two or more different core clinical syndromes),

• additional MRI features in acute optic neuritis: a) normal findings or non-specific white matter lesions, OR b) an optic nerve lesion hyperintense on T2-weighted imaging (WI) or contrast-enhancing on T1-WI, extending over more than half the length of the optic nerve or involving the optic chiasm.

• additional MRI features in acute myelitis: a) an intramedullary lesion spanning a length greater than or equal to three vertebral segments (longitudinally extensive transverse myelitis, LETM), OR b) spinal cord atrophy spanning a length greater than or equal to three spinal segments in patients with a history of acute myelitis at that level.

• additional MRI features in area postrema syndrome: presence of lesions in the dorsal medulla oblongata / area postrema region.

• additional MRI features in acute brainstem syndrome: presence of periependymal brainstem lesions.

Appendix A 3.4. MAGNIMS recommendations for the use of MRI in diagnosing MS according to the 2010 McDonald criteria

These recommendations were formulated by an expert working group in 2016 [282].

Dissemination in space is established if two of the following five criteria are met:

- three or more periventricular lesions

- one or more infratentorial lesions

- one or more spinal lesions

- one or more optic nerve lesions

- one or more cortical or juxtacortical lesions (this represents an expansion of the term "juxtacortical" to include white matter lesions close to the cortex as well as lesions involving the cortex)

Comment: When determining dissemination in space, all lesions are counted, including those causing clinical symptoms. For example, if a patient has clinical symptoms of brainstem, spinal cord, or optic nerve involvement, lesions in these areas of the nervous system are taken into account (unlike in the previous version of the criteria). Criteria for dissemination in time remain unchanged (see the 2010 criteria).

Appendix A 3.5. Standardized MRI report form

To assess the dynamics of focal changes when issuing a brain MRI report in patients with suspected MS and in all patients with MS. It is recommended to indicate the exact number of demyelinating lesions in the "Result" and "Previous Result" fields. This template is advisory in nature, constitutes an structural part of the report, and does not replace the descriptive section or reporting of other incidental MRI findings.

* If the total number of lesions exceeds 20 and cannot be counted, indicate "more than 20" (>20).

If the patient is undergoing an MRI scan for the first time, the Previous Result fields remain empty.

*** Lesions in the corpus callosum should be considered as "other localization of lesions"

Appendix A 3.6. Principles of clinical diagnosis formulation

It is recommended to formulate the clinical diagnosis taking into account ICD-10 and current classifications of the disease by type of course, stage of the disease, and severity of functional impairment [340]

1) Disease name: Multiple sclerosis, ICD-10 code G35.

2) Type of course: relapsing-remitting, secondary progressive, primary progressive.

3) Stage:

a) for relapsing-remitting: remission, relapse; when examining the patient within one month from the onset of relapse, the date of relapse onset and main neurological syndromes can be indicated in descending order of their functional significance, indicating their severity (pronounced/profound, moderate, mild).

b) for secondary progressive: progression, stabilization, relapse; when examining the patient within one month from the onset of relapse, the date of relapse onset and main neurological syndromes can be indicated in descending order of their functional significance, indicating their severity (pronounced/profound, moderate, mild).

c) for primary progressive: progression, stabilization, relapse; when examining the patient within one month from the onset of relapse, the date of relapse onset and main neurological syndromes can be indicated in descending order of their functional significance, indicating their severity (pronounced/profound, moderate, mild).

4) EDSS score.

Examples of clinical diagnosis formulation:

- Multiple sclerosis, relapsing-remitting course, relapse stage (from 01.08.2016), moderate paresis of the right leg, moderate cerebellar ataxia. EDSS 4.5.

- Multiple sclerosis, relapsing-remitting course, remission stage, mild cerebellar ataxia. EDSS 2.0.

- Multiple sclerosis, secondary progressive course, stabilization stage, moderate lower paraparesis, moderate cerebellar ataxia, mild long-tract sensory disturbances. EDSS 6.0.

When formulating the diagnosis, it is important to indicate functional impairments (in accordance with current legislation (at the time of writing these guidelines - Order of the Ministry of Labor and Social Protection of the Russian Federation dated December 17, 2015 No. 1024n "On classification criteria used in medical and social expertise of citizens by federal state medical and social protection institutions")):

- Minor motor impairments, minor pelvic organ dysfunctions; EDSS score within 1 - 2.5 points - severity degree - 10-30%;

- Moderate paresis of the upper and/or lower extremities, moderate pelvic organ dysfunctions; EDSS score within 3 - 4.5 points - severity degree - 40-60%;

- Pronounced paresis of the upper and/or lower extremities, pronounced pelvic organ dysfunctions; EDSS score within 5 - 7 points - severity degree - 70-80%;

- Severely pronounced paresis or paralysis of the upper and/or lower extremities, severely pronounced pelvic organ dysfunctions (total urinary and/or fecal incontinence with complete lack of hygiene); EDSS score within 7.5 - 9.5 points - severity degree - 90-100%.

Appendix A 3.7. Principles of DMT switching

Below are recommendations for determining the physician's actions depending on the response to therapy [341-349].

*The relapse must be objectively confirmed by a neurologist. The presence of only

* The relapse must be objectively confirmed by a neurologist. The presence of fatigue or pelvic disorders alone is not considered a relapse

** Confirmed disability progression - persistent worsening of neurological impairment (according to EDSS) after the end of a relapse, which has been confirmed by at least two EDSS measurements, one of which was performed no earlier than 30 days from the onset of the relapse, and the second - at least 3 months after the onset of the relapse.

MRI activity characteristics - a new lesion on T2-weighted MRI and/or an enlarging lesion on T2-weighted MRI and/or a contrast-enhancing lesion on T1-weighted MRI. A new contrast-enhancing lesion is counted as a single lesion.

These criteria apply only to patients with RRMS (studies of the scales have not been conducted for patients with PPMS and SPMS).

All criteria apply to a measurement period duration of 12 months from the start of DMT, with subsequent annual intervals. Meeting one criterion in the first 12 months and the second criterion in the next 12 months of measurement should be considered as not met.

Appendix A 3.8. Common Toxicity Scale.

Changes in white and red blood cell counts are the most frequent side effect of DMT therapy and are assessed using the Common Toxicity Scale

Action in case of detected toxicity:

• Grade 1 – continue therapy

• Grade 2 – continue therapy (monitor parameters every 2 weeks to 1 month as decided by the neurologist)

• Grade 3 – discontinue therapy until parameters recover and refer to the DMT prescription committee

• Grade 4 – discontinue therapy until parameters recover and refer to the DMT prescription committee.

Detailed recommendations for patient monitoring during DMT therapy, including the frequency and nature of monitored parameters (white and red blood cell counts, biochemical parameters, etc.), as well as actions in case of toxicity during therapy with specific DMTs, are presented in Appendix B, Section 3.3, and in Sections 3.1.17.3 and 3.1.17.4 on conservative treatment.

Appendix A 3.9. DMT discontinuation application form

DMT CANCELLATION REQUEST FORM

(original in the outpatient medical record, copy in the committee files)

To the Regional MS Center (Office)

from citizen _____________________________________,

residing at: ___________________

 _____________________________________

REQUEST

I hereby request to cancel the drug ________________________, which I have been receiving under federal (or regional) benefits since __________________, for multiple sclerosis due to the following reason: __________________________________________

I have been informed by the doctors about the consequences of discontinuing the drug. I have asked all questions of interest and received answers to them.

This decision has been made by me voluntarily and consciously; I have no claims against the healthcare authorities and doctors.

Date                                                                                       Signature: ______________________

Appendix A 3.10. PML Risk Management Plan for Natalizumab Therapy**.

Progressive multifocal leukoencephalopathy (PML) is a rare, progressive, potentially fatal brain infection caused by the JC virus. Immunocompromised patients are affected: patients with AIDS prior to highly active antiretroviral therapy (HAART) 1-8%, organ transplant recipients (rarely, <<1%), patients with hematological malignancies; patients who received antineoplastic or immunosuppressive therapy; rare cases of PML are associated with natalizumab** use.

Diagnosis of PML: Clinical presentation: neurological deficit progresses over several weeks. Clinical features: changes in personality, behavior, cognitive functions, aphasia, myoclonic seizures, hemiparesis and hemiplegia, cortical visual impairments; in the terminal stage, dementia, coma, and patient death – it is necessary to differentiate from relapses and progression in MS. The course is variable; without treatment, death occurs within 6-12 months.

MRI findings: large hyperintense lesions on T2-weighted or FLAIR images, mostly monofocal, located in the subcortical white matter; U-fibers are frequently involved; typical lesions do not form mass effect or edema – differentiate from MS lesions. In 40%-50% of cases, lesions show signs of contrast enhancement.

CSF analysis – JC virus DNA testing using real-time PCR (in approximately half of patients, the JCV DNA copy number was low, <500 copies/mL).

If the clinical picture of PML is present, immediate discontinuation of the drug is recommended.

Risk factors for PML with natalizumab** use.

1) presence of the JC virus (seropositivity);

2) history of immunosuppression (IS);

3) duration of therapy.

Patients at high risk for PML include:

- Patients with three PML risk factors:

• History of immunosuppression (IS);

• Duration of natalizumab** therapy > 2 years;

• Seropositive status;

- Patients receiving natalizumab** for more than 2 years with a titer higher than 1.5.

Risk stratification for PML development and patient management recommendations are presented in Figures G12.1 and G12.2

Figure A 3.10.1 Updated PML risk stratification

Figure A 3.10.2 Management recommendations for patients on natalizumab** considering PML risks

Clinical evaluation of a patient with suspected PML includes several stages (Figure A 3.10.2).

Figure A 3.10.3. Clinical evaluation upon the development of new or worsening of existing symptoms, or upon the appearance of MRI changes suggestive of PML in patients receiving natalizumab**.

Appendix A 3.11. International Pediatric Multiple Sclerosis Study Group Criteria, 2013.

In patients under 18 years of age, it is recommended to use these criteria in cases defined by the relevant guidelines [18].

Pediatric multiple sclerosis (any of the following):

• Two or more clinical episodes separated by more than 30 days, with evidence of injury in more than one functional system of the central nervous system;

• One clinical event associated with MRI changes meeting dissemination in space (DIS) criteria, and a follow-up MRI showing at least one new lesion meeting dissemination in time (DIT) criteria;

• Three months after the initial symptoms of an ADEM-like attack, a new clinical event occurs that is associated with a new MRI lesion meeting DIS criteria;

• Clinically isolated syndrome with MRI data consistent with DIS and DIT criteria.

Pediatric clinically isolated syndrome (CIS) (all required):

• A clinical event of CNS involvement with a presumed cause of inflammatory demyelination;

• No history of prior CNS demyelinating disease;

• No evidence of encephalopathy (except when it can be explained by fever);

• Does not meet DIS and DIT criteria on baseline MRI.

Pediatric acute disseminated encephalomyelitis (ADEM) (all required):

• First polyfocal clinical event of CNS involvement with a presumed cause of inflammatory demyelination.

• Encephalopathy that cannot be explained by elevated body temperature.

• No new clinical or MRI events 3 or more months after the initial symptoms;

Brain MRI with pathological changes during the acute phase (3 months) featuring typical diffuse, poorly demarcated large lesions located predominantly in the cerebral white matter.

Appendix A 3.12. Criteria for assessing relapse severity.

The presented classification is adapted from Freedman et al. [69] and is recommended for assessing relapse severity to guide patient management decisions.

Appendix B. Physician Action Algorithms

1. Multiple sclerosis diagnostic algorithm

1.1. MS diagnosis establishment algorithm

1.2. MS diagnosis algorithm, primary progressive course type

2. Algorithm for managing a patient with an MS relapse

3. Algorithm for evaluating the timelines of response to DMT therapy

4. Patient monitoring plans during DMT therapy

4.1. Guidelines for monitoring patients on interferon beta-1a** and interferon beta-1b** therapy

4.2. Guidelines for monitoring patients on glatiramer acetate** therapy

4.3. Guidelines for monitoring patients on teriflunomide** therapy

4.4. Guidelines for monitoring patients on dimethyl fumarate** therapy

4.5. Guidelines for monitoring patients on #mitoxantrone** therapy

4.6. Guidelines for monitoring patients on natalizumab** therapy

4.7. Guidelines for monitoring patients on fingolimod** therapy

4.8. Guidelines for monitoring patients on alemtuzumab** therapy

4.9. Guidelines for monitoring patients on ocrelizumab** therapy

4.10. Guidelines for monitoring patients on cladribine** therapy

4.11. Guidelines for monitoring patients on siponimod** therapy

4.12. Guidelines for monitoring patients on ofatumumab therapy

4.13. Guidelines for monitoring patients on divozilimab** therapy

4.14. Guidelines for monitoring patients on ozanimod therapy

Appendix C. Patient Information

1. Information for the patient at the diagnostic stage:

1.1. Information on the nature of neurological deficits in demyelinating diseases, as well as potential manifestations of MS;

1.2. Information on the etiology of MS and risk factors for the development of MS;

1.3. Information on the risk of hereditary transmission of MS;

1.4. Information on unfavorable prognostic factors increasing the risk of conversion to MS after the first relapse and factors associated with faster disability progression;

1.5. Information on comorbidity prevention and a healthy lifestyle, motivation to quit bad habits;

1.6. Information on the operation of the local MS center/office;

1.7. Information on the availability of psychological support, support groups for patients, patient communities, and educational patient schools on treatment issues;

2. Information for the patient at the treatment and dispensary observation stage:

2.1. Information on MS therapy options using disease-modifying therapies (DMTs) registered in the Russian Federation and suitable for treating a specific patient according to their MS course type (provided individually for each patient);

2.2. Information on the efficacy and safety profile of the chosen DMT, as well as alternative DMTs and their efficacy and safety profiles;

2.3. Recommendations for monitoring within the risk management plan: frequency of visits, laboratory tests, MRI scans, vaccination, and other preventive, therapeutic, and diagnostic measures;

2.4. Information on the availability of medical and social rehabilitation;

2.5. Information on the possibility of obtaining disability status;

2.6. If a therapy change is necessary, provide information on the criteria for switching therapy, the possibility of switching therapy, and the safety and efficacy profile of the proposed DMTs;

3. At the medical rehabilitation stage:

3.1. Provide information on the goals of rehabilitation;

3.2. Provide information on the nature of limitations in the patient's daily activities;

3.3. Individual rehabilitation program to be performed at home;

3.4. Information on the necessity of using assistive rehabilitation devices and the possibilities for obtaining them.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1 Expanded Disability Status Scale (EDSS)

Russian title: Expanded Disability Status Scale (EDSS)

Original title (if applicable): Expanded Disability Status Scale (EDSS)

Source (official developer website, validation publication):

[№] Stepanova A.D., Evdoshenko E.P., Shumilina M.V., Korobko D.S., Barabanova M.A., Abroskina M.V., Vasilenko A.F., Yurchenko Yu.N., Davydovskaya M.V. Validation of the Russian version of the Expanded Disability Status Scale (EDSS) for patients with multiple sclerosis in the Russian Federation. Medical Technologies. Assessment and Choice. 2023;45(1):38–46. https://doi.org/10.17116/medtech20234501138 [26]

www.neurostatus.net

Type: rating scale

Purpose: assessment of the severity of neurological impairment

Content (template):

1. VISUAL FUNCTIONS

VISUAL ACUITY

Visual acuity is determined by the lowest line of the Sivakov-Golovin table that the patient can read from a distance of 5 meters (20 feet) with no more than one error, using the best available correction. Alternatively, corrected near visual acuity may be assessed, which must be specified and consistently used during subsequent examinations. Switching between near and distant visual acuity measurements during follow-up examinations should be avoided.

VISUAL FIELDS

0 normal

1 signs only: deficit detected only on examination (confrontation test)

2 moderate deficit: patient is aware of the deficit, but examination reveals incomplete (quadrantic) hemianopia

3 marked deficit: complete homonymous hemianopia or equivalent

SCOTOMA

0 absent

1 small: detected only on examination (confrontation test)

2 large: patient spontaneously reports it

* OPTIC DISC PALLOR

0 absent

1 present

Note: when determining the EDSS score, the Visual FS score must be converted to a lower score as follows:

Visual FS score 6 5 4 3 2 1

Converted Visual FS score 4 3 3 2 2 1

FUNCTIONAL SYSTEM SCORE

0 normal

1 optic disc pallor and/or small scotoma and/or best-corrected visual acuity of the worse eye lower than 1.0 (20/20) but better than 0.67 (20/30)

2 best-corrected visual acuity of the worse eye 0.67–0.34 (20/30 to 20/59)

3 worse eye with large scotoma and/or moderate visual field defect and/or best-corrected visual acuity 0.33–0.21 (20/60 to 20/99)

4 worse eye with marked visual field defect and/or best-corrected visual acuity 0.2–0.1 (20/100 to 20/200); score '3' plus visual acuity of the better eye 0.33 (20/60) or lower

5 best-corrected visual acuity of the worse eye lower than 0.1 (20/200); score '4' plus visual acuity of the better eye 0.33 (20/60) or lower

6 score '5' plus visual acuity of the better eye 0.33 (20/60) or lower

* – optional part of the examination

2. BRAINSTEM FUNCTIONS

EXTRAOCULAR MOVEMENT ABNORMALITIES

0 none

1 signs only: subtle and barely clinically detectable extraocular muscle weakness, patient does not complain of blurred vision, diplopia, or discomfort

2 mild: subtle and barely clinically detectable extraocular muscle weakness of which the patient is aware; or definite incomplete paralysis of any eye movement of which the patient is unaware

3 moderate: definite incomplete paralysis of any eye movement of which the patient is aware; or complete loss of movement of any eye in one direction of gaze

4 marked: complete loss of movement in any eye in more than one direction of gaze

NYSTAGMUS

0 absent

1 signs only or mild: gaze-evoked nystagmus less marked than 'moderate' (equivalent to grade 1 for Brainstem FS)

2 moderate: sustained nystagmus on lateral gaze in horizontal or vertical plane at 30°, but not in primary position; patient may or may not be aware of the abnormality

3 marked: sustained nystagmus in primary position or coarse persistent nystagmus in any direction affecting visual acuity; complete internuclear ophthalmoplegia with sustained nystagmus of the abducted eye; oscillopsia

TRIGEMINAL NERVE INVOLVEMENT

0 absent

1 signs only

2 mild: clinically detectable numbness of which the patient is aware

3 moderate: impaired sharp/dull discrimination in the distribution of one, two, or three branches of the trigeminal nerve; trigeminal neuralgia (at least one attack in the last 24 hours)

4 marked: inability to distinguish sharp/dull or complete loss of sensation in the entire distribution of one or both trigeminal nerves

FACIAL WEAKNESS

0 absent

1 signs only

2 mild: clinically detectable facial weakness of which the patient is aware

3 moderate: incomplete facial paralysis, such as weakness on eye closure requiring eyelid taping at night, or weakness on mouth closure leading to drooling

4 marked: complete unilateral or bilateral facial paralysis with lagophthalmos or difficulty swallowing liquids (due to paralysis, not dysphagia)

HEARING LOSS

0 absent

1 signs only: patient hears finger rub less well on one or both sides, with lateralization on Weber test, but patient has no complaints regarding hearing

2 mild: as in grade 1, but patient is aware of the hearing problem

3 moderate: patient does not hear finger rub on one or both sides, misses several whispered numbers

4 marked: patient misses all or almost all whispered numbers

DYSARTHRIA

0 absent

1 signs only

2 mild: clinically detectable dysarthria of which the patient is aware

3 moderate: definite dysarthria during normal conversation that impairs understanding

4 marked: unintelligible speech

5 inability to speak

DYSPHAGIA

0 absent

1 signs only

2 mild: difficulty swallowing liquids

3 moderate: difficulty swallowing liquids and solid food

4 marked: persistent swallowing difficulties; pureed diet required

5 inability to swallow

FUNCTIONS OF OTHER CRANIAL NERVES

0 normal

1 signs only

2 mild impairment: clinically detectable impairment of which the patient is usually aware

3 moderate impairment

4 marked impairment

FUNCTIONAL SYSTEM SCORE

0 normal

1 signs only

2 mild or moderate nystagmus and/or moderate extraocular movement disorders and/or other mild impairments

3 marked nystagmus and/or marked extraocular movement disorders and/or moderate impairment of other cranial nerve functions

4 marked dysarthria and/or other marked impairments

5 inability to swallow or speak

1. PYRAMIDAL FUNCTIONS

REFLEXES

0 absent

1 decreased

2 normal

3 hyperactive

4 unsustained clonus (a few beats of clonus)

5 sustained clonus

* Palmomental reflex

0 absent

1 present

Plantar reflex

0 flexor

1 neutral or equivocal

2 extensor

LIMB STRENGTH

Cutaneous reflexes

0 normal

1 decreased

2 absent

FUNCTIONAL TESTS

* Pronator drift (for upper extremities), pronation and downward drift:

0 absent

1 mild

2 definite

* Positional test (lower extremities – ask the patient to lift both legs together, legs must be fully extended at the knees); lowering:

0 absent

1 slight

2 definite

3 able to lift only one leg at a time (measure the angle formed by the horizontal surface and the thigh...°)

4 unable to lift even one leg

* Heel / toe walking

0 normal

1 impaired

2 impossible

* Hopping on one foot 0 normal

1 6 – 10 times

2 1 – 5 times

3 impossible

LIMB SPASTICITY (AFTER RAPID FLEXION OF THE LIMB)

0 absent

1 mild: slightly increased muscle tone

2 moderate: moderately increased muscle tone that can be overcome; full range of motion is possible

3 severe: markedly increased muscle tone that is extremely difficult to overcome; full range of motion is impossible

4 contracture

GAIT SPASTICITY

0 absent

1 barely noticeable

2 definite: minor functional impairment

3 constant shuffling: significant functional impairment

GENERAL MOTOR ACTIVITY

0 normal

1 excessive weakness (compared to peers) when performing tasks requiring great effort, e.g., walking long distances, but without decreased limb strength on examination (confrontation testing)

2 decreased strength of individual muscle groups on confrontation testing

FUNCTIONAL SYSTEM SCORE

0 normal

1 pathological signs without disability

2 minimal impairment: patient complains of motor fatigue or reduced performance during exertion-requiring activities (1 in overall motor activity) and/or a BMRC score of 4 in one or two muscle groups

3 mild or moderate paraparesis or hemiparesis: usually a BMRC score of 4 in more than two muscle groups;

and/or a BMRC score of 3 in one or two muscle groups (movements against gravity possible);

and/or severe monoparesis: a BMRC score of 2 or less in one muscle group

4 marked paraparesis or hemiparesis: usually a BMRC score of 2 in two limbs, or monoplegia with a BMRC score of 0–1 in one limb;

and/or moderate tetraparesis: a BMRC score of 3 in three or more limbs

5 paraplegia: a BMRC score of 0 or 1 in all muscle groups of the lower limbs; and/or marked tetraparesis: a BMRC score of 2 or less in three or more limbs; and/or hemiplegia

6 tetraplegia: a BMRC score of 0 or 1 in all muscle groups of the upper and lower limbs

2. CEREBELLAR FUNCTIONS

HEAD TREMOR

0 absent

1 mild

2 moderate

3 marked

TRUNCAL ATAXIA

0 absent

1 signs only

2 mild: swaying with eyes closed

3 moderate: swaying with eyes open

4 marked: patient unable to sit without support

LIMB ATAXIA (TREMOR/DYSMETRIA AND RAPID ALTERNATING MOVEMENTS)

0 absent

1 signs only

2 mild: tremor or clumsy movements easily noticeable, minimal impact on function

3 moderate: tremor or clumsy movements affect function in all spheres

4 marked: most functions are severely impaired

TANDEM GAIT (HEEL-TO-TOE WALKING)

0 normal

1 impaired

2 impossible

GAIT ATAXIA

0 absent

1 signs only

2 mild: balance problems perceived by the patient and/or close contact

3 moderate: balance impairment during normal walking

4 marked: patient unable to walk more than a few steps without support or assistance from another person due to ataxia

ROMBERG'S TEST

0 normal

1 mild degree: slight instability with eyes closed

2 moderate degree: unstable with eyes closed

3 severe degree: unstable with eyes open

OTHER CEREBELLAR TESTS

0 normal

1 mild impairment

2 moderate impairment

3 marked impairment

NOTES: The presence of only marked gait impairment and/or truncal ataxia (without marked ataxia in three or four limbs) is scored as 3 in the Cerebellar FS.

If weakness or sensory impairment interferes with the assessment of ataxia, evaluate the patient's actual condition. To indicate the potential role of weakness, place an «X» after the Cerebellar FS score.

FUNCTIONAL SYSTEM SCORE

0 normal

1 pathological signs without disability

2 mild ataxia and/or moderate static ataxia (Romberg's test), and/or tandem gait impossible

3 moderate limb ataxia and/or moderate or marked gait/truncal ataxia

4 marked gait/truncal ataxia and marked ataxia in three or four limbs

5 inability to perform coordinated movements due to ataxia

X pyramidal weakness (limb muscle strength of BMRC score 3 or less) or sensory disturbances affecting the assessment of cerebellar functions

3. SENSORIALLY MEDIATED FUNCTIONS

SUPERFICIAL SENSATION (LIGHT TOUCH AND PAIN)

0 normal

1 signs only: mild sensory loss (temperature, two-point discrimination) upon examination, of which the patient is unaware

2 mild reduction: patient is aware of impaired sensation to light touch or pain, but is able to distinguish sharp/dull

3 moderate: impaired ability to distinguish sharp/dull

4 marked: unable to distinguish sharp/dull and/or unable to feel light touch

5 total loss: anesthesia

VIBRATION SENSATION (AT THE MOST DISTAL JOINT)

0 normal

1 mild reduction: 5–7 out of 8 units on a graduated tuning fork; alternatively, the patient feels vibration for more than 10 seconds, but less than the examiner

2 moderate: 1–4 out of 8 units on a graduated tuning fork; alternatively, the patient feels vibration from 2 to 10 seconds

3 marked: complete loss of vibration sensation

PROPRIOCEPTION (JOINT POSITION SENSE)

0 normal

1 mild degree: 1–2 incorrect responses, distal joints only affected

2 moderate degree: numerous errors in determining the direction of finger and toe movement; proximal joints affected

3 severe degree: absence of movement perception, astasia

* LHERMITTE'S SIGN

0 negative

1 positive

* PARESTHESIAS (TINGLING

0 absent

1 present

* – does not affect the Sensory FS score

FUNCTIONAL SYSTEM SCORE

0 normal

1 mild decrease in vibration, or superficial (graphesthesia), or temperature sensation in only one or two limbs

2 mild decrease in touch sensation, or pain sensation, or position sense, or moderate decrease in vibration sensation in one or two limbs;

and/or mild decrease in vibration sensation, or superficial (graphesthesia), or temperature sensation in more than two limbs

3 moderate decrease in touch sensation, or pain sensation, or position sense, or marked decrease in vibration sensation in one or two limbs;

and/or mild decrease in touch or pain sensation, or moderate decrease in proprioception in more than two limbs

4 marked decrease in touch or pain sensation in one or two limbs;

and/or moderate decrease in touch or pain sensation and/or marked decrease in proprioception in more than two limbs

5 complete loss of any sensory modality in one or two limbs;

and/or moderate decrease in touch or pain sensation and/or marked decrease in proprioception in virtually the entire body below the head

6 complete loss of sensation below the head

4. BOWEL AND BLADDER FUNCTIONS

HESITANCY AND URINARY RETENTION

0 normal

1 mild degree: does not affect lifestyle

2 moderate degree: urinary retention; frequent urinary tract infections

3 severe degree: catheterization required

4 loss of function: overflow urinary incontinence

URINARY URGENCY AND INCONTINENCE

0 absent

1 mild degree: does not affect lifestyle

2 moderate degree: rare urinary incontinence, occurring no more than once a year

3 severe degree: frequent urinary incontinence, occurring several times a week to several times a day; must use a urinal or disposable absorbent medical products

4 loss of function: loss of bladder control

BLADDER CATHETERIZATION

0 none

1 intermittent self-catheterization

2 indwelling catheterization

BOWEL DYSFUNCTION

0 absent

1 mild degree: no incontinence, no impact on lifestyle, mild constipation

2 moderate degree: patient must use disposable absorbent medical products or alter lifestyle to remain close to a restroom

3 severe degree: requires enemas or manual maneuvers for bowel evacuation

4 complete loss of function

* SEXUAL DYSFUNCTION

Men

0 no impairments

1 mild degree: difficulty maintaining erection during intercourse, but achieves erection and is able to continue intercourse

2 moderate degree: difficulty achieving erection, decreased libido, able to continue intercourse and achieves orgasm

3 marked degree: marked decrease in libido, inability to achieve full erection, intercourse is difficult, hyporgasmia

4 loss of function

Women

0 no impairments

1 mild degree: mild decrease in natural lubrication, sexual activity is preserved and orgasm is achieved

2 moderate degree: dyspareunia, hyporgasmia, decreased sexual activity

3 marked degree: marked decrease in sexual activity, anorgasmia

4 loss of function

NOTE: when determining the RIST score, the Bowel and Bladder Functions FS score must be converted to a lower score as follows:

Bowel and Bladder Functions FS score 6 5 4 3 2 1

Converted Bowel and Bladder Functions FS score 5 4 3 3 2 1

Sexual dysfunction may be documented, but generally does not affect the score. Bowel and Bladder Functions FS due to apparent difficulties in physician examination assessment

FUNCTIONAL SYSTEM SCORE

0 normal

1 mild urinary hesitancy, urinary urgency, and/or constipation

2 moderately hesitant urinary initiation/retention and/or moderate severity of urgency / urinary incontinence and/or moderate bowel dysfunction

3 frequent urinary incontinence or intermittent self-catheterization; requires enemas or manual maneuvers for bowel evacuation

4 requires almost continuous catheterization

5 loss of bladder or bowel function; external or indwelling urinary catheter

6 loss of bowel and bladder function

5. CEREBRAL (MENTAL) FUNCTIONS

DEPRESSION AND EUPHORIA

0 absent

1 present: patient complains of depression, or depression or euphoria is identified by the examiner or a close relative.

Depression and euphoria are documented on the scoring sheet, but are not included in the FS and RIST calculation

COGNITIVE IMPAIRMENT

0 absent

1 signs only: not obvious to the patient and/or close relative

2 mild: patient and/or relatives report mild changes in thinking. Examples include: impaired ability for rapid associative thinking and consideration of complex issues; impaired judgment in certain situations requiring significant effort; able to perform routine daily activities, but fails to cope with additional stressors; symptoms manifest even at a normal stress level; decreased performance; tendency to be careless due to forgetfulness or fatigue.

3 moderate: clear abnormalities on brief cognitive testing, but still oriented to person, place, and time

4 marked: disoriented in one or two spheres (person, place, or time), pronounced impact on lifestyle

5 dementia, confusion, and/or complete disorientation

FATIGUE

0 absent

1 mild: usually does not interfere with daily activities

2 moderate: impairs daily activities, but does not limit them by more than 50%

3 marked: significant limitation of daily activities (>50% reduction)

Since fatigue is difficult to objectively assess, in some studies it does not affect the FS score or the EDSS score. Please follow the instructions of the specific study

FUNCTIONAL SYSTEM SCORE

0 normal

1 signs of cognitive impairment only; mild fatigue

2 mild cognitive impairment; moderate or marked fatigue

3 moderate cognitive impairment

4 marked cognitive impairment

5 dementia

6. AMBULATION

Ambulation is “not limited” if the patient can walk without assistance a distance considered normal for healthy individuals of the same age and physical condition. In this case, the EDSS score can be anywhere from 0 to 5.0 depending on the FS scores.

“Full self-sufficiency” means that the patient is able to walk at least 500 meters without assistance, but not without limitations. The EDSS score can be anywhere from 2.0 to 5.0, depending on the FS scores. In this case, the Pyramidal and/or Cerebellar FS must be ≥2 to reflect this “limitation” of the ability to move.

If ambulation is <500 meters, the EDSS score must be ≥5.5 depending on the walking distance when assessing ambulation (see next page) and the combination of FS scores. EDSS scores of 5.5 – 8.0 are determined exclusively by the ability to move and the type of support required or the ability to use a wheelchair.

If assistance is required, the definitions for EDSS scores of 6.0 or 6.5 include both a description of the type of support required for walking and the walking distance. Assistance from another person is equivalent to bilateral support.

NOTE: Ambulation assessment includes both a description of walking distance and the type of support required for walking. Use of a wheelchair is taken into account on the rating sheet.

DISTANCE AND TIME REPORTED BY PATIENT

Maximum walking distance without assistance, without rest or support, reported by the patient (in meters) and the time required to walk the maximum distance, as reported by the patient (in minutes)

SUPPORT

0 Without help or support (use of an ankle-foot orthosis without any other assistive devices is allowed)

1 Unilateral support: one cane/crutch/brace

2 Bilateral support: two canes/crutches/braces or assistance from another person

3 Wheelchair

DISTANCE

Measure the distance the patient is able to walk, in meters.

Without support: assess the patient's walking without support over a distance of at least 500 meters and measure the time taken, if possible.

With support: assess the patient's walking with support from an assistive device or another person over a distance of at least 130 meters, if possible.

AMBULATION ASSESSMENT

0 Not limited

1 Full self-sufficiency

2 ≥300 meters, but <500 meters, without assistance or support (EDSS 4.5 or 5.0)

3 ≥200 meters, but <300 meters, without assistance or support (EDSS 5.0)

4 ≥100 meters, but <200 meters, without assistance or support (EDSS 5.5)

5 Walking distance <100 meters without support (EDSS 6.0)

6 Unilateral support, ≥50 meters (EDSS 6.0)

7 Bilateral support, ≥120 meters (EDSS 6.0)

8 Unilateral support, <50 meters (EDSS 6.5)

9 Bilateral support, ≥5 meters, but <120 meters (EDSS 6.5)

10 Uses a wheelchair without assistance; cannot walk 5 meters even with support, significantly limited by the wheelchair; moves and transfers independently; awake in the wheelchair about 12 hours a day (EDSS 7.0)

11 Uses a wheelchair with assistance; unable to take more than a few steps; limited by the wheelchair; may require some assistance with transfers and self-propulsion of the wheelchair (EDSS 7.5)

12 Significantly limited to bed or chair, or moves in a wheelchair only with assistance, but out of bed most of the day; retains many self-care functions; generally uses arms effectively (EDSS 8.0)

Key (interpretation): a score for each of the 8 functional systems is assigned based on neurological examination data and reflects the degree of impairment. The obtained 8 scores are converted into a final score using the following algorithm:

0 normal neurological status (0 in all FS)

1.0 no disability, minimal signs of impairment in one FS (1 in one FS)

1.5 no disability, minimal signs of impairment in more than one FS (1 in more than one FS)

2.0 minimal disability in one FS (2 in one FS, 0 or 1 in others)

2.5 minimal disability in more than one FS (2 in two FS, 0 or 1 in the rest)

3.0 moderate disability in one FS (3 in one FS, 0 or 1 in others) with full ambulation of the patient; or mild disability in three or four FS (2 in three/four FS, 0 or 1 in the rest) with full ambulation of the patient

3.5 fully ambulatory, but with moderate disability in one FS (3 in one FS) and mild disability in one or two FS (2 in one/two FS, and 0 or 1 in the rest); or fully ambulatory and 3 in two FS (0 or 1 in the rest); or fully ambulatory with 2 in five FS (0 or 1 in the rest)

4.0 can walk without support or rest ≥500 meters; awake and active about 12 hours a day, despite relatively severe disability, including 4 in one FS (0 or 1 in others) or combinations of fewer FS scores exceeding the criteria of previous EDSS scores

4.5 can walk without support or rest ≥300 meters; awake and active most of the day, characterized by relatively severe disability, usually including 4 in one FS and a combination of fewer scores in other FS exceeding the criteria of previous EDSS scores

5.0 can walk without support or rest ≥200 meters (usually equivalent to having 5 in at least one FS, or a combination of fewer scores in other FS exceeding the criteria of 4.5 scores)

5.5 can walk without support or rest ≥100 meters

6.0 unilateral support (cane or crutch) is required to walk at least 100 meters with or without rest (see paragraph 8, Ambulation)

6.5 constant bilateral support (canes or crutches) is required to walk at least 20 meters without rest (see paragraph 8, Ambulation)

7.0 cannot walk 5 meters even with support, significantly limited by wheelchair use; independently moves in the wheelchair and transfers; awake in the wheelchair about 12 hours a day

7.5 unable to take more than a few steps; limited by wheelchair use; may require some assistance with transfers and movement in the wheelchair

8.0 significantly limited to bed or chair or moves in a wheelchair with assistance, but spends most of the day out of bed; retains many self-care functions; generally uses arms effectively

8.5 significantly limited to bed most of the day; can perform some effective arm/hand movements; retains some self-care functions

9.0 helpless bedridden patient; able to communicate and eat

9.5 totally helpless bedridden patient; unable to communicate effectively or eat/swallow

10 death due to MS

Explanations: The WhiteCoat Pro total score is assigned based on combinations of scores for each of the 8 functional scales. The total WhiteCoat Pro score ranges from 0 to 10 points and objectively reflects the degree of neurological impairment.

Appendix G2. Berg Balance Scale

Russian title: Berg Balance Scale

Original title: Berg Balance Scale (BBS)

Source (official developer website, validation publication): Berg K, Wood-Dauphinee S, Williams J, Gayton D. Measuring balance in the elderly: preliminary development of an instrument. Physiother Can 1989;41(6):304–11.

Type: rating scale

Purpose: assessment of a person's ability to maintain static and dynamic balance

Content (template):

If the patient has severe cognitive deficits or speech impairments that hinder understanding of commands, alternative communication sources should be used.

If the patient is unconscious, they receive 0 points. If the patient has an amputated leg, the test is performed with a prosthesis for the missing part. If there is no prosthesis, the test is not performed.

1. Task: Stand from a chair

Instructions: Ask the patient to stand up from a chair. If the patient holds onto the armrests while performing the task, ask them to repeat it without using their hands. Ensure that the legs do not press against the edge of the chair. Use a chair with armrests.

Scoring:

4 – stands up independently without using hands and maintains balance independently;

3 – stands up independently on the first attempt, uses hands, maintains balance independently;

2 – stands up independently using hands, requires several attempts to stand up;

1 – requires minimal assistance to stand up from a chair or assume a stable standing position;

0 – requires assistance (moderate or significant) to stand up.

2. Task: Stand unsupported

Instructions: Ask the patient to stand independently for 2 minutes. The patient's feet must not touch the chair (move the chair away from the patient). Monitor the patient, be prepared in case they lose balance.

Scoring:

4 – stands securely for 2 minutes;

3 – stands for 2 minutes with your supervision (without manual contact with the patient; you stand closer than required for a score of 4);

2 – stands unsupported for 30 seconds;

1 – requires several attempts to stand for 30 seconds;

0 – cannot stand for 30 seconds without support.

If the patient stands securely for 2 minutes, award the highest score for item 3 (no testing is needed). Proceed to item 4.

3. Task: Sit unsupported, feet on the floor, arms crossed over the chest

Instructions: Sit without back support, arms crossed over the chest, feet flat on the floor, knees at 90°, feet at a comfortable distance for the patient for 2 minutes. Use a chair without armrests and a stopwatch.

Scoring:

4 – sits securely for 2 minutes;

3 – sits for 2 minutes with supervision (without manual contact with the patient; you stand closer than required for a score of 4, as well as for scores of 2 and 1);

2 – sits for 30 seconds under supervision;

1 – sits for 10 seconds under supervision;

0 – cannot sit for 10 seconds without support.

4. Task: Transfer from standing to sitting

Instructions: Ask the patient to sit down on a chair without using their hands. Closely observe the contact between the legs and the chair. Move the chair 5–8 cm away from the wall so that contact is obvious (e.g., the chair moves). Use a chair with armrests.

Scoring:

4 – sits down securely with minimal use of hands;

3 – controls sitting down using hands;

2 – uses the back of the legs resting against the chair to control sitting down;

1 – sits down independently, but the descent is uncontrolled (drops onto the chair);

0 – requires assistance to sit down.

5. Task: Transfer from a chair with armrests to a chair without armrests and back

Instructions: Transfer from a chair with armrests to a chair without armrests and back. Place the chairs at a 90° angle, with a distance of up to 10 cm between them. Instructions are given before performing the task; demonstration is allowed. Hand support means that the patient shifts weight onto their hands. Use a chair with armrests and a chair without armrests.

Scoring:

4 – secure transfer with minimal use of hands;

3 – secure transfer with some use of hands (uses hands when standing up and sitting down);

2 – requires verbal cues and/or supervision;

1 – requires assistance from one person;

0 – requires assistance/supervision from two people.

6. Task: Stand unsupported with eyes closed

Instructions: Close eyes and stand still for 10 seconds. Feet shoulder-width apart, arms at the sides. Use a stopwatch.

Scoring:

4 – stands securely for 10 seconds;

3 – stands securely for 10 seconds with observation (without manual contact with the patient; you stand closer than required for a score of 4);

2 – stands for 3 seconds;

1 – cannot keep eyes closed for 3 seconds, but stands securely;

0 – needs support to prevent a fall.

7. Task: Stand unsupported, feet together

Instructions: Ask the patient to place their feet together (heels and toes touching) and stand for 1 minute. Use a stopwatch.

Scoring:

4 – feet together, can stand independently for 1 minute;

3 – feet together, can stand independently for 1 minute with observation (without manual contact with the patient; you stand closer than required for a score of 4);

2 – can place feet together, but cannot hold the position for 30 seconds;

1 – needs assistance to assume the position (bring feet together), but can stand for 15 seconds. (0) needs assistance to assume the position (bring feet together), cannot stand for 15 seconds.

If the patient is unable to bring their feet together due to reasons unrelated to balance (i.e., obesity or knock-knees), do not deduct points. In such cases, note the foot position as the baseline for future assessments.

8. Task: Reach forward with outstretched arms

Instructions: Ask the patient to raise their arm to 90°, straighten/stretch their fingers forward as much as possible, feet shoulder-width apart, feet parallel. The examiner places a ruler at the tips of the patient's fingers without touching the patient's fingers with the ruler. Next, ask the patient to lean forward with the outstretched arm along the ruler as far as possible without moving their feet. The distance the fingers move at maximum forward reach is assessed. Upon reaching the maximum reach, the patient must return to the starting position. If the slightest lean requires supervision, this is 3 points. A ruler is required to perform the task.

Scoring:

4 – confident forward reach of 25 cm;

3 – forward reach between 24 cm and 12 cm;

2 – forward reach between 11 cm and 5 cm;

1 – forward reach, but requires supervision (without manual contact with the patient, standing closer than required for a score of 4);

0 – needs support to prevent a fall (loses balance).

9. Task: picking up an object from the floor

Instruction: ask the patient to pick up a shoe placed on the floor directly in front of the patient along the midline. Move the patient away from the chair so that their buttocks do not touch it. The patient may place their feet in any comfortable position.

Scoring:

4 – easily and confidently picks up the slipper;

3 – picks up the slipper, but requires supervision;

2 – unable to pick it up, but independently reaches 2–4 cm toward the shoe and maintains balance;

1 – unable to pick it up, requires assistance when attempting the task;

0 – unable to pick it up and needs support to prevent a fall. If the patient cannot perform the task due to excess weight, ask the patient to "squat" and perform the task (in this case, scoring should be based on the proposed points). If squatting is not possible, the task is skipped. In both cases, make a note of how the task was performed or why it was not performed to allow for dynamic assessment.

10. Task: turning to look over the left and right shoulders

Instruction: ask the patient to turn and look over their left shoulder and return to the starting position. After a short pause, repeat turning over the right shoulder. Feet must not be moved. Stand in front of the patient to observe the symmetry of head and neck rotation and body weight shift. Turning left or right implies a rotation of approximately 90°. You may ask the patient to visually identify certain objects behind them to note a full rotation.

Scoring:

4 – looks to both sides, transfers body weight well;

3 – looks over only one shoulder, transfers weight less well on the other side;

2 – turns to the side only, but maintains balance;

1 – requires supervision during the turn;

0 – needs support to prevent a fall.

11. Task: turning 360°

Instruction: ask the patient to turn around in a full circle, stop, and turn a full circle in the opposite direction. Demonstrate how to perform the task. Time each turn separately. Repeat the attempt if the patient touches the chair. The floor surface area required for the patient to complete the turn does not matter.

Scoring:

4 – can turn 360° in both directions in less than 4 seconds;

3 – can turn 360° in one direction in less than 4 seconds;

2 – can turn 360° but slowly;

1 – requires supervision or verbal prompts;

0 – requires assistance during the turn.

12. Task: alternating steps on a step stool

Instruction: ask the patient to step alternately onto a step stool, taking 4 steps with each foot. Place the step in front of the patient. Demonstrate how to perform the task. If outside assistance was required to complete the task, assign a score of no more than 2 points.

Scoring:

4 – stands unsupported and confidently, can complete 8 steps in 20 seconds;

3 – stands unsupported, can complete 8 steps in more than 20 seconds;

2 – completes 4 steps without assistance under supervision;

1 – can complete fewer steps (2–3), requires minimal assistance;

0 – needs support to prevent a fall / unable to attempt.

13. Task: standing in tandem stance (heel-to-toe)

Instruction: ask the patient to place one foot directly in front of the other (the heel of one foot touching the toes of the other foot). If unable to place the feet strictly one in front of the other, alternative foot placements are acceptable.

Scoring:

4 – able to place one foot directly in front of the other (heel touching toes) and maintain balance for 30 seconds;

3 – able to place one foot in front of the other with a gap and maintain balance for 30 seconds;

2 – takes a small step forward, maintains balance for 30 seconds;

1 – requires assistance to take a step forward, but maintains balance for 15 seconds;

0 – loses balance while standing or stepping forward / unable to attempt.

If unable to place one foot directly in front of the other (heel touching toes) and the task was performed in a different foot position, be sure to note and account for this during re-testing.

14. Task: standing on one leg

Instruction: ask the patient to stand on one leg as long as he/she can without outside help. The leg must be raised to a noticeable height; ensure that the patient's legs do not touch each other. If outside assistance is required, assign a score of no more than 1 point. The patient chooses which leg to stand on.

Scoring:

4 – can lift the leg and hold for >10 seconds;

3 – can lift the leg and hold for 5–10 seconds;

2 – can lift the leg and hold for 3 seconds;

1 – attempts to lift the leg, but cannot maintain balance for 3 seconds, yet stands independently;

0 – needs support to prevent a fall.

- If the patient scores zero on two consecutive items, testing is discontinued.

- When the patient scores 4 points on a completed task, the examiner should be nearby, but not close enough for the patient to feel supported by the examiner's presence. If you stand very close to the patient, the score is no more than 3 points.

- If you are unsure how to correctly score a task—for example, the patient performed the task seemingly for 3 points, but with errors—assign a score of 2. In other words, if in doubt, always choose the lower score.

- Any task may be demonstrated to the patient before performance. - If the patient uses assistive devices (walkers, cane), the scale tasks should be performed without the assistive device.

Key (interpretation): less than 43 out of 56 points – high fall risk.

Appendix G3. Functional Independence Measure (FIM)

Russian title: Functional Independence Measure (FIM)

Original title: Functional Independence Measure (FIM)

Source (official developer website, validation study): Kidd D, Stewart G, Baldry J et al. The Functional Independence Measure: A comparative validity and reliability study. Disabil Rehabil. 1995;17(1):10-14. doi:10.3109/09638289509166622

Type: rating scale

Purpose: assessment of the patient's functional independence.

Content (template):

The assessment is carried out by a specialist observing the patient continuously or by multiple specialists and nurses. The scale is completed based on cumulative observations of the patient over 2–4 days. The assessing specialists can fill out the scale in the process of observations sequentially or during a medical conference (consilium). The Functional Independence Measure (FIM) includes 18 items, where items 1–13 reflect motor function status, and items 14–18 reflect cognitive function status.

Seven-point rating scale:

7 – complete independence in performing the respective function (all actions performed independently, in a customary manner, and within a reasonable time);

6 – modified independence (the patient performs all actions independently, but slower than usual, or requires verbal cueing/advice);

5 – minimal assistance (requires staff supervision during performance, or assistance with donning a prosthesis/orthosis);

4 – minor dependency (needs assistance when performing actions, but performs more than 75% of the task independently);

3 – moderate dependency (independently performs 50–75% of the actions required to complete the task);

2 – significant dependency (independently performs 25–50% of actions) 1 – complete dependency on others (can independently perform less than 25% of the required actions).

Key (interpretation): each of the specified functions is evaluated on a seven-point scale. Thus, the total FIM score can range from 18 to 126 points: the lower the total FIM score, the more dependent the patient is on others in daily life.

Appendix G4. Nine-Hole Peg Test

Russian title: Nine-Hole Peg Test

Original title: The Nine-Hole Peg Test

Source (official developer website, validation publication): Feys P, Lamers I, Francis G et al. The Nine-Hole Peg Test as a manual dexterity performance measure for multiple sclerosis. Multiple Sclerosis Journal. 2017;23(5):711-720. doi:10.1177/1352458517690824

Type: rating scale

Purpose: assessment of hand motor skills.

Content (template):

The patient sits at a table. The container with holes is placed on the table in front of the patient so that the peg storage compartment in the container is on the same side as the hand being tested. Testing always begins with the dominant hand. The patient must insert the pegs into the holes and remove them one by one with one hand. The time is recorded from the start of moving the first peg into one of the 9 holes until the last peg is placed into the container compartment. Then the procedure is repeated with the other hand. The test completion time for each hand is recorded using a stopwatch.

If a peg falls onto the table during the task, the test subject must pick it up and continue the task; if a peg falls to the floor, it is picked up not by the patient, but by the examiner.

Key (interpretation): a decrease in task execution speed during retesting by more than 20% is regarded as a clinically significant deterioration.

Appendix G5. Frenchay Arm Test

Russian title: Frenchay Arm Test

Original title: The Frenchay Arm Test

Source (official developer website, validation publication): Heller A, Wade D, Wood V, Sunderland A, Hewer R, Ward E. Arm function after stroke: measurement and recovery over the first three months. Journal of Neurology, Neurosurgery & Psychiatry. 1987;50(6):714-719. doi:10.1136/jnnp.50.6.714

Type: rating scale

Purpose: assessment of the function of the affected arm.

Content (template):

If the patient has severe cognitive deficits or speech disorders that prevent understanding of commands, alternative communication sources should be used. If the patient is unconscious, they receive 0 points.

Instructions:

• Starting position for each task: sitting at a table, hands resting on knees

• All tasks are performed with the affected arm

• For each successfully completed task, the patient receives 1 point (maximum 5 points)

• For uncompleted tasks – 0 points

Tasks:

1. Hold a ruler with the paretic hand and use it to draw a line while holding a pencil in the other (unaffected) hand. The task is considered successfully completed if the ruler is held stably.

2. Take a cylinder 1.2 cm in diameter and 5 cm long, placed vertically at a distance of 15–30 cm from the edge of the table, lift it to a height of about 30 cm and then lower it back without dropping it.

3. Take a glass half-filled with water and placed at a distance of 15–30 cm from the edge of the table, take a drink of water and put the glass back without spilling the water.

4. Remove and then replace a clothespeg attached to a vertical peg 15 cm long and 1 cm in diameter. The peg is fixed to a square board (side length 10 cm) located at a distance of 15–30 cm from the edge of the table. The patient must not drop the clothespeg or the peg.

5. Comb hair (or imitate combing). The patient should comb their hair on the crown, back of the head, right and left sides.

Appendix G6. Rivermead Mobility Index

Russian title: Rivermead Mobility Index

Original title: Rivermead Mobility Index

Source (official developer website, validation publication): Whiting S, Lincoln N, Bhavnani G, Cockburn J. Rivermead Perceptual Assessment Battery. Occup Ther Health Care. 1986;3(3-4):209-210. doi:10.1080/j003v03n03_18

Type: rating scale

Purpose: a method for clinical assessment of patient mobility.

Content (template):

If the patient has aphasia or other communication problems (intubation, mechanical ventilation), the test is not performed.

If the patient is bedridden, the test is not performed.

If the patient is non-verbal but able to move, the test is performed using visual prompts, by observing their actions, or with the help of alternative communication cards (action symbols).

If the patient is unconscious, the test is not performed.

If the patient has severe cognitive impairment, the test is performed based on the observation of their activity.

If the patient is unable to understand the question and/or perform the action, a score of 1 is assigned.

If the patient has no cognitive impairment and is able to answer questions, the assessment is conducted based on the patient's words, or the patient fills out the questionnaire themselves with the assistance of the interviewing specialist.

The following scores are awarded:

1 — dependent on outside help (i.e., independent performance of the action is impossible, unsafe, or requires an unreasonable amount of time);

2 — supervision required (verbal help and prompting);

3 — independent (may use assistive devices).

Appendix G7. SF-36 Quality of Life Questionnaire

Russian title: SF-36 Health Survey

Original title: The 36-Item Short Form Health Survey questionnaire

Source (official developer website, validation publication): Saris-Baglama RN, Dewey CJ, Chisholm GB, et al. Quality Metric health outcomes™ scoring software 4.0. Lincoln, RI: Quality Metric Incorporated, 2010, p. 138.

Type: rating scale

Purpose: a questionnaire to assess the patient's quality of life.

Content (template):

Please answer all 36 health survey questions completely, honestly, and without interruption.

GENERAL HEALTH:

In general, would you say your health is:

⬜ Excellent            ⬜ Very good   ⬜ Good  ⬜ Fair ⬜ Poor

How would you rate your health now compared to one year ago?

⬜ Much better now than one year ago

⬜ Somewhat better now than one year ago

⬜ About the same

⬜ Somewhat worse now than one year ago

⬜ Much worse than a year ago

PHYSICAL ACTIVITY LIMITATIONS:

The following questions are about activities you might do during a typical day. Does your health now limit you in these activities? If so, how much?

Vigorous activities, such as running, lifting heavy objects, participating in strenuous sports

⬜ Yes, limited a lot ⬜ Yes, limited a little ⬜ No, not limited at all

Moderate activities, such as moving a table, vacuuming, bowling, or playing golf

⬜ Yes, limited a lot ⬜ Yes, limited a little ⬜ No, not limited at all

Lifting or carrying groceries

⬜ Yes, limited a lot ⬜ Yes, limited a little ⬜ No, not limited at all

Climbing several flights of stairs

⬜ Yes, limited a lot ⬜ Yes, limited a little ⬜ No, not limited at all

Climbing one flight of stairs

⬜ Yes, limited a lot ⬜ Yes, limited a little ⬜ No, not limited at all

Bending, kneeling, or stooping

⬜ Yes, limited a lot ⬜ Yes, limited a little ⬜ No, not limited at all

Walking more than a kilometer

⬜ Yes, limited a lot ⬜ Yes, limited a little ⬜ No, not limited at all

Walking several blocks

⬜ Yes, limited a lot ⬜ Yes, limited a little ⬜ No, not limited at all

Walking one block

⬜ Yes, limited a lot ⬜ Yes, limited a little ⬜ No, not limited at all

Bathing or dressing yourself

⬜ Yes, limited a lot ⬜ Yes, limited a little ⬜ No, not limited at all

PHYSICAL HEALTH PROBLEMS:

During the past 4 weeks, have you had any of the following problems with your work or other regular daily activities as a result of your physical health:

Cut down the amount of time you spent on work or other activities

⬜ Yes ⬜ No

Accomplished less than you would like

⬜ Yes ⬜ No

Were limited in the kind of work or other activities

⬜ Yes ⬜ No

Had difficulty performing the work or other activities (e.g., it took extra effort)

⬜ Yes ⬜ No

EMOTIONAL HEALTH PROBLEMS:

During the past 4 weeks, have you had any of the following problems with your work or other regular daily activities as a result of any emotional problems (such as feeling depressed or anxious)?

Cut down the amount of time you spent on work or other activities

⬜ Yes ⬜ No

Accomplished less than you would like

⬜ Yes ⬜ No

Didn't do work or other activities as carefully as usual

⬜ Yes ⬜ No

SOCIAL ACTIVITIES (LEISURE):

During the past 4 weeks, to what extent have your physical health or emotional problems interfered with your normal social activities with family, friends, neighbors, or groups?

⬜ Not at all ⬜ Slightly ⬜ Moderately ⬜ Quite a lot ⬜ Extremely

PAIN:

How much bodily pain have you had during the past 4 weeks?

⬜ None ⬜ Very mild ⬜ Mild ⬜ Moderate ⬜ Severe ⬜ Very severe

To what extent has pain interfered with your normal work (including both work outside the home and housework) during the past 4 weeks?

⬜ Not at all ⬜ Slightly ⬜ Moderately ⬜ Quite a lot ⬜ Extremely

ENERGY AND EMOTIONS

These questions are about how you felt and how things have been going with you during the past 4 weeks. Please give the one answer that comes closest to the way you have been feeling for each question.

Did you feel full of pep?

⬜ All of the time

⬜ Most of the time

⬜ A good bit of the time

⬜ Some of the time

⬜ A little bit of the time

⬜ None of the time

Have you been very nervous?

⬜ All of the time

⬜ Most of the time

⬜ A good bit of the time

⬜ Some of the time

⬜ A little bit of the time

⬜ None of the time

Have you felt so down in the dumps that nothing could cheer you up?

⬜ All of the time

⬜ Most of the time

⬜ A good bit of the time

⬜ Some of the time

⬜ A little bit of the time

⬜ None of the time

Have you felt calm and peaceful?

⬜ All of the time

⬜ Most of the time

⬜ A good bit of the time

⬜ Some of the time

⬜ A little bit of the time

⬜ None of the time

Did you have a lot of energy?

⬜ All of the time

⬜ Most of the time

⬜ A good bit of the time

⬜ Some of the time

⬜ A little bit of the time

⬜ None of the time

Have you felt downhearted and blue?

⬜ All of the time

⬜ Most of the time

⬜ A good bit of the time

⬜ Some of the time

⬜ A little bit of the time

⬜ None of the time

Did you feel worn out?

⬜ All of the time

⬜ Most of the time

⬜ A good bit of the time

⬜ Some of the time

⬜ A little bit of the time

⬜ None of the time

Have you been a happy person?

⬜ All of the time

⬜ Most of the time

⬜ A good bit of the time

⬜ Some of the time

⬜ A little bit of the time

⬜ None of the time

Did you feel tired?

⬜ All of the time

⬜ Most of the time

⬜ A good bit of the time

⬜ Some of the time

⬜ A little bit of the time

⬜ None of the time

SOCIAL ACTIVITIES (LEISURE):

During the past 4 weeks, how much of the time has your physical health or emotional problems interfered with your social activities (like visiting with friends, relatives, etc.)?

⬜ All of the time

⬜ Most of the time

⬜ A good bit of the time

⬜ Some of the time

⬜ A little bit of the time

⬜ None of the time

GENERAL HEALTH:

How true or false is each of the following statements for you?

I seem to get sick a little easier than other people

⬜ Definitely true

⬜ Mostly true

⬜ Don't know

⬜ Mostly false

⬜ Definitely false

I am as healthy as anybody I know

⬜ Definitely true

⬜ Mostly true

⬜ Don't know

⬜ Mostly false

⬜ Definitely false

I expect my health to get worse

⬜ Definitely true

⬜ Mostly true

⬜ Don't know

⬜ Mostly false

⬜ Definitely false

My health is excellent

⬜ Definitely true

⬜ Mostly true

⬜ Don't know

⬜ Mostly false

⬜ Definitely false