Vaccination and Multiple Sclerosis - Current Situation.

Active immunization of patients with autoimmune diseases is a current challenge. Vaccination of patients with multiple sclerosis (MS) has been shown not to be associated with increased risk of exacerbation. A personalized approach to immunization of this group of patients is required, taking account of ongoing therapy and the nature of the course of illness. MS is not an absolute contraindication for vaccination against the new coronavirus infection. Vaccination can be with any of the currently authorized immunoformulations.

[Results of a multicentre double-blind randomised placebo-controlled clinical trial evaluating the efficacy and safety of Mexidol in the treatment of Attention Deficit Hyperactivity Disorder in Children (MEGA)]. / Rezul'taty mnogotsentrovogo dvoinogo slepogo randomizirovannogo platsebo-kontroliruemogo klinicheskogo issledovaniya po otsenke effektivnosti i bezopasnosti preparata Meksidol v lechenii sindroma defitsita vnimaniya s giperaktivnost'yu u detei (MEGA).

OBJECTIVES: To evaluate the efficacy and safety of two dosing regimens of Mexidol film-coated tablets, 125 mg («RPC «PHARMASOFT¼ LLC Russia), compared with placebo in children with attention deficit hyperactivity disorder (ADHD) aged 6 to 12 years. MATERIAL AND METHODS: A multicenter randomized, double-blind, placebo-controlled study in 3 parallel groups was conducted in 14 clinical centres of the Russian Federation to assess efficacy and safety of Mexidol film-coated tablets, 125 mg («RPC «PHARMASOFT¼ LLC Russia) in the treatment of attention deficit hyperactivity disorder (ADHD) in children 6-12 years old with different dosing regimens. The study involved 333 boys and girls aged 6 to 12 years with a confirmed diagnosis of ADHD established in accordance with ICD-10 and DSM-5 criteria. After screening (up to 14 days) the patients were randomised into 3 treatment groups in a 1:1:1: Mexidol 125 mg 2 times daily, Mexidol 125 mg daily+placebo and the placebo group. The duration of treatment in all groups was 42 days. 332 children completed the study. ADHD and comorbid disorders assessment scales were used. RESULTS: There were statistically significant changes in the sum of the total scores on the SNAP-IV inattention and hyperactivity/impulsivity subscales after 6 weeks of therapy in all three study groups (p<0.05). There were statistically significant differences between the Mexidol 125 mg and placebo groups and between the Mexidol 125 mg 2 times daily and placebo groups (for the PP population: p=0.000308 and p=0.000024, respectively; for the FAS population: p=0.000198 and p=0.000024, respectively), indicating that Mexidol therapy is superior to placebo. Statistically significant differences (p<0.05) were also obtained for most of the secondary efficacy criteria (average change in SNAP-IV inattention subscale score, average change in SNAP-IV hyperactivity/impulsivity subscale score, average change in SNAP-IV subscale score - Conners index, average change in ADHD-RS-IV score, change in CGI-ADHD-S scores, change in CGI-I score - the Clinical Global Impressions Scale - Improvement) when comparing Mexidol therapy with placebo. The results of statistical analysis of the incidence of adverse events, laboratory values, physical examination show no significant differences between the compared groups in the main safety parameters. CONCLUSIONS: The regimen of Mexidol, 125 mg film-coated tablets twice daily has been shown to be superior to the regimen of Mexidol, 125 mg film-coated tablets once daily and placebo. The safety profiles of the studied dosing regimens of Mexidol and placebo were comparable.

[Vaccination and multiple sclerosis at the present stage]. / Vaktsinatsiya i rasseyannyi skleroz na sovremennom etape.

Immunization of the patients with autoimmune diseases is rising a lot of concerns. It was previously demonstrated that vaccination in MS patients was not associated with an increased risk of exacerbations. A personalized approach is needed to define the immunization schedule. A decision should be made based on the course of the disease and the treatment used. Multiple sclerosis is not an absolute contraindication to vaccination. Any authorized vaccine can be used in MS patients.

[Clinical observation experience of a pediatric patient with primary progressive multiple sclerosis in the Moscow office for the treatment of children and adolescents with multiple sclerosis]. / Opyt kuratsii pediatricheskogo patsienta s pervichno-progressiruyushchim rasseyannym sklerozom v usloviyakh kabineta po lecheniyu detei i podrostkov s rasseyannym sklerozom Departamenta zdravookhraneniya goroda Moskvy.

OBJECTIVE: To demonstrate the experience of a personalized approach to the treatment of pediatric patients with multiple sclerosis using the example of the Moscow patient population. MATERIALS AND METHODS: The authors describe the clinical follow-up of 79 pediatric patients with demyelinating diseases of the nervous system during 2019, including 39 patients with multiple sclerosis, including one patient with a primary progressive course of the disease (clinical case). RESULTS: The experience of the Moscow office for the treatment of multiple sclerosis in children and adolescents demonstrates the effectiveness of the personalized approach to the treatment of pediatric cases confirmed by the case report of biological therapy by recombinant humanized monoclonal antibody directed against CD20-expressing B-cells for early treatment of the adolescent patient with primary progressive multiple sclerosis. CONCLUSION: The identification of patient's groups with different levels of disease activity and different risks of disability progression is highly relevant in the pediatric population of patients with multiple sclerosis, especially in the context of expanding therapeutic opportunities.

[Therapy of perinatal brain injury outcomes: results of a multicenter double-blind placebo-controlled randomized study of tenoten for children (liquid dosage form)]. / Terapiya posledstvii perinatal'nogo porazheniya tsentral'noi nervnoi sistemy: rezul'taty mnogotsentrovogo dvoinogo slepogo platsebo-kontroliruemogo randomizirovannogo klinicheskogo issledovaniya zhidkoi lekarstvennoi formy preparata Tenoten detskii.

OBJECTIVE: To evaluate the efficacy and safety of tenoten for children (a novel liquid pediatric formulation) in the treatment of perinatal brain injury (PBI) outcomes. MATERIAL AND METHODS: The multicenter double-blind placebo-controlled randomized trial enrolled 184 children (aged 29 days-9 months) with the total score 12-27 according to Djurba-Mastukova scale and the level of physical development 25-75 centiles. Patients were randomized into tenoten (10 drops per day) and placebo groups. Treatment period was 12 weeks ± 5 days. Percentage of patients with ≥4 points improvement according to Djurba-Mastukova scale (responder rate) was used as a primary efficacy endpoint. RESULTS AND CONCLUSION: Patients in the tenoten group had a significant result on primary efficacy endpoint: 77.5% of participants responded to therapy (p=0.02 vs. placebo). In addition, the safety of tenoten for children in the treatment of PBI outcomes is shown. Tenoten for children (a novel liquid pediatric formulation) has been shown to be an effective medication in treatment of PBI outcomes that helps to achieve therapeutic results with minimal side-effects, good tolerability and the high level of adherence to therapy.

[Clinical cases of multiple sclerosis in children with cerebral palsy]. / Klinicheskie sluchai rasseiannogo skleroza u detei s detskim tserebral'nym paralichom.

The careful differential diagnosis is very important in pediatric cases of multiple sclerosis (MS). It has special difficulties, if MS started in patients with residual neurological pathology. Two cases of development of MS in children with cerebral palsy (CP) are presented. The clinical features and diagnostic difficulties in such comorbid situations are discussed .

[Experience of application of Russian biosimilar of interferon beta-1b for treatment of pediatric multiple sclerosis]. / Opyt primeneniya rossiiskogo bioanaloga interferona beta-1b v lechenii detskogo rasseyannogo skleroza.

AIM: To evaluate efficacy and safety of biosimilars of interferon beta-1b (Infibeta) in patients aged 14 to 17 years. MATERIAL AND METHODS: Interferon beta 1b (Infibeta) was appointed 9 children and adolescents (4 boys and 5 girls) between the ages of 14 to 17 years (mean age of onset of therapy 16.22±1.09). RESULTS: In the course of therapy there was a significant decrease in the annualrelapse rate (ARR) to 0.33±0.5 (from 0 to 1, r≤0,0001) and the of regression of neurological deficit on the EDSS scale up to ±1.94±0.68 (1.5 to 3, p≤0.05). No cases of cancellation was not recorded due to poor tolerability or inefficiency. CONCLUSION: Although numerically small so far, but quite successful results on the use of Russian interferon beta-1b biosimilar (Infibeta) in children, we can recommend this treatment as sufficiently safe and effective.

[Disease-modifying drugs in pediatric patients with multiple sclerosis]. / Preparaty, izmenyayushchie techenie rasseyannogo skleroza, u detei i podrostkov.

The vast majority of therapies are being evaluated and introduced for the treatment of adult multiple sclerosis (MS). A role of these drugs in the management of pediatric MS has yet to be defined both in Russia and in the whole world. Despite the fact that today the study of new drugs in the pediatric population have included in routine practices of the big pharmaceutical agencies, such as FDA and EMA, recommendations for the treatment of pediatric patients with MS are based not so much on a long period of systematic clinical research, but on professional consensus of international expert associations, in particular, the International pediatric multiple sclerosis study group (IPMSSG). The clinical trials include the small number of patients which is not comparable to those conducted in adults. Therefore, there is a need for study designs for assessment of efficacy and safety of the drugs for MS treatment in children and adolescents. The authors present the IPMSSG concept on the treatment of pediatric MS taking into account peculiarities of the Russian legislation and experience of national experts.

[Differential diagnosis of multiple sclerosis with pediatric onset: the experience of the Moscow Division for treatment of children and adolescents with multiple sclerosis].

The diagnosis of multiple sclerosis in children and adolescence should be differentiated from a group of rare white matter diseases, with fuzzy diagnostic criteria. Some of these conditions require modern diagnostic techniques and wide knowledge of the doctor. The Moscow Division for treatment of children and adolescents with multiple sclerosis is a specialized advisory structure, which has specialists with experience in the differential diagnosis of multiple sclerosis with pediatric onset. The emphasis on the clinical aspects in differential diagnosis of early onset multiple sclerosis can reduce the time for the diagnosis and help to avoid diagnostic mistakes.

[Management of cognitive impairment in children and adolescents with cerebral palsy treated with pantocalcin].

A randomized study on the efficacy and safety of the hopantenic acid preparation (pantocalcin) and its effect on cognitive functions in children with cerebral palsy (CCP) has been carried out. The positive effect of pantocalcin on the visual memory and attention concentration, activity and fatigability has been shown. At the same time, there was a decrease of anxiety in children and adolescents with CCP. No evidence for the effect of the drug on visual-motor skills has been found. The results of the study have demonstrated the high safety profile of pantocalcin when used in pediatric practice.

[Assessment of the size of the thalamus as a method for the evaluation of the activity of neurodegenerative process after the treatment with cerebrolisin in young patients with multiple sclerosis].

The aim of the study was to describe the atrophy of the thalamus in young patients with active relapsing multiple sclerosis (MS) treated with cerebrolysin. Eighteen MS patients (mean age 20.10±0.45 years) with disease onset in childhood or adolescence were studied. Neurological examination using the EDSS, neuropsychological testing and MRI were used. At baseline, MRI revealed the hypotrophy of the thalamus that was not correlated with the performance on neuropsychological tests. After treatment with cerebrolysin, there was the decrease in the level of atrophy that suggested the neuroprotective effect of this drug. This effect was more prominent in younger patients with the high frequency of previous relapses.

[The comparative study of efficacy and tolerability of intramuscular introduction of beta-interferon-1a in adults and adolescents with remitting multiple sclerosis].

The experience of the treatment of patients with remitting multiple sclerosis (MS) with intramuscular introduction of beta-interferon-1a (avonex) is presented. Seventeen children and adolescents, aged from 11 to 18 years, and 55 adults, aged over 55 years, were treated for at least one-year period. Results revealed a significant reduction of exacerbations in both groups (from 1.35 to 0.06 in average in adolescents and from 0.86 to 0.17 in adults). The changes were accompanied by the stabilization of MS severity index: EDSS scores have decreased in 23.6% of adults and in 17.6% of adolescents. In both groups, good tolerability of the treatment was noted. There was a low probability of side-effects with the exception of increased frequency of a flu-like syndrome (47% cases) in patients younger than 18 years that demands special attention from children neurologists. The high efficacy and good tolerability and safety profile of beta-interferon-1a give grounds for administering this drug to children and adolescents with MS.

[Family's adherence to treatment of the child with a neurological pathology].

Neurological diseases, mental disorders and inherited developmental abnormalities held a prominent place in the structure of primary children disability. Children cerebral palsy is the main cause of children disability, its prevalence reaching 2-3.5 cases per 1000 children. This disease has the noticeable negative consequences (both clinical and economic). Adherence to treatment means patient's compliance with doctor's orders including taking medicines as prescribed, sticking to diet and changing life style habits. While the adult patient plays an active role in doctor-patient alliance, the child patient interacts with the doctor together with his/her family. The authors consider the effect of different factors on the adherence basing on the analysis of 270 questionnaires completed by persons involved in the treatment of minor patients.

[Children cerebral palsy and epilepsy: approaches to treatment and rehabilitation].

Epilepsy is one of the most frequent and difficult for treatment co-morbid disease of cerebral palsy. In therapeutic aspect, the difficulty of the problem is defined by the necessity to combine the active restoration of motor disorders with a regime of antiepileptic treatment. It leads frequently to stopping the restoration process and aggravation of patient's motor disability. The diagnosis of epilepsy in the child with cerebral palsy should in no way discontinue the rehabilitation measures, albeit in case of the concomitant pathology a plan of rehabilitation scheme should be adjusted. The pharmacological control of epileptic seizures should be the first step of the new rehabilitation scheme. Epileptologists usually conduct the selection of multi-component antiepileptic treatment in patients with drug resistant epilepsy, however a neurologist of an outpatient clinics who follows up the patient in different stages of development and rehabilitation should play a key role. The authors suggest the general treatment tactics for children with cerebral palsy and epilepsy by the neurologist of the polyclinics.

[Lipids of neocortex after X-ray irradiation of the rat head at a dose of 200 Gy].

X-ray irradiation at a dose of 200 Gy with local exposure of the rat head induced the change of the lipid content in the neocortex tissue. The amount of phosphatidylinositol was decreased, the amount of free fatty acids, diglycerols, sphingomyelin was increased, and the amount of cholesterol had a growth trend in 2 h after X-ray exposition. The results testify in favor of participation of phosphatidylinositol- and sphingomyelin-relating signal systems and cholesterol in early stages of the cerebral radiation syndrome. We suggest that the change of the lipid content in early periods after the effect of a super-high dose of X-ray irradiation indicates the lipid dependence in the elimination of motion damages and the restoration of the functions of nerve cells. Effects on the lipid metabolism in the nerve tissue are promising for correcting the cerebral radiation syndrome.

Family Analysis of Linkage and Association of HLA-DRB1, CTLA4, TGFB1, IL4, CCR5, RANTES, MMP9 and TIMP1 Gene Polymorphisms with Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS). Proteins of the immune system, as well as proteins that are involved in the infiltration of activated immune cells in the CNS, play an important role in the pathogenesis of MS. We investigated the association and linkage with MS of the following immune-system genes polymorphisms: HLA-DRB1,CTLA4,TGFB1,IL4,CCR5 andRANTES, as well as of the matrix metalloproteinase 9 (MMP9) and tissue inhibitor of metalloproteinase  1 (TIMP1) genes polymorphisms. For this purpose we used the transmission disequilibrium test (TDT). The group investigated was comprised of 100 nuclear families of Russian ethnicity, each consisting of an affected offspring and his nonaffected parents. It was found that HLA-DRB1*15alleleandMMP9*-1562C allele were transmitted from healthy heterozygous parents to affected children more frequently than alternative alleles (p  =  0.02 andp  =  0.04, respectively). Another family-based method, AFBAC (affected family-based control), showed MS association with HLA-DRB1*15, but not with theMMP9*-1562C allele.

Lipids of nuclear fractions from neurons and glia of rat neocortex under conditions of artificial hypobiosis.

Lipid contents were studied in tissue and nuclei isolated from neurons and glia of neocortex of rats under conditions of normothermia and in the state of artificial hypobiosis caused by hypothermia-hypoxia-hypercapnia. Compared to the neocortex tissue, both nuclear fractions were fivefold impoverished in phospholipids and cholesterol and strongly enriched with mono- and diglycerides and fatty acids. The nuclear fractions from neurons and glia contained similar amounts of phospholipids, and only the cardiolipin content in the neuronal nuclei was lower than in the glial nuclei. The state of artificial hypobiosis in rats led to an increase in the cholesterol/phospholipids ratio (mol/mol) in the nuclei from the neurons and glia; amounts of cholesterol and sphingomyelin in the nuclei from the glia were increased. The increases in the cholesterol and sphingomyelin contents and in the cholesterol/phospholipids ratio suggest an involvement of lipid-dependent signaling systems of the nuclei in the functional response of mammalian neocortex cells to artificial hypobiosis.

[Analysis of linkage and association of alleles of proinflammatory cytokines genes IL-6, IFNg and TNF with multiple sclerosis using transmission disequilibrium test (TDT)].

Proinflammatory cytokines Interleukin-6 (IL-6), Interferon-gamma (IFNg) and Tumor necrosis factor (TNF) are known as participants of inflammation and play an important role in pathogenesis of multiple sclerosis (MS). Based on literature data about influence of SNPs G(-308)A of TNF gene, A(+874)T of IFNG gene and G(-174)C of IL-6 gene on production of these cytokines, we investigated association of these polymorphic sites with MS. Linkage and association of alleles of these genes with MS was analyzed by transmission disequilibrium test (TDT). In investigated group of 104 nuclear families of Russian ethnicity it was found that TNF* (-308)A allele transmitted from healthy heterozygous parents to affected children more frequently (p = 0.01). Linkage/association of IFNG and IL-6 alleles with MS was not revealed. Thus, data obtained indicate the participation of TNF gene in MS susceptibility in Russians.

[Effective treatment of multiple sclerosis with rebif-22 mcg in children and adolescences: results of a long-term study].

Management from an early age and availability of new treatment options have changed the outcome of paediatric patients with multiple sclerosis (MS). Currently available for treatment of MS in adults, such drugs as interferons beta and copolymer-1 are not widely used in paediatric neurological practice. The present long-term study of the effect of interferon beta la (rebif-22 mcg) included 20 children with MS from Moscow population. The data of this open-label study were compared with our previously reported data from the prospective population-based study of 67 ethnically-matched children with MS. The results revealed early formation of stable neurological deficit at late-onset treatment, high therapeutic efficacy when the drug was timely used and good tolerability of the treatment. So, it is necessary to use immunomodulating therapy with these drugs in children and adolescents as early as possible.