RU2686083C1 - Method of selecting a therapeutic approach to patients with muscular dystonia - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention refers to medicine, namely neurology, and can be used in treating patients with muscular dystonia. That is ensured by complex clinical examination of the patient and prescribing botulinotherapy. Prior to injection, 2 ml of venous blood is taken in the patient to determine RCEPM, ASI and NI. One month after the botulinum toxin injection, the RCEPM, ASI and NI are examined, if the obtained RCEPM values are less than 1.00 mcm×cm/V×s, the ASI is more than 0.5 standard units and NI in range greater than 0.15 and less than 0.35 standard units prescribing anxiolytic preparations, and when RCEPM is less than 1.00 mcm×cm/V×s, ASI is lower than 0.45 standard units or NI is higher than or equal to 0.35 standard units prescribing preparations of metabolic action. Three months after the injection, the RCEPM, ASI and NI are examined, if the RCEPM, ASI and NP correspond or approximate as compared to the initial values to a physiological norm and there is no hyperkinesis, then a decision is made to postpone the next injection of botulinum toxin two months later than previously planned.EFFECT: method enables higher stability of the therapeutic effect and prolongs remission in the patients.1 cl, 4 ex

Description

The present invention relates to the field of medicine, to drug therapy, and can be used in the treatment of patients with muscular dystonia.

Dystonia is a movement disorder manifested by sustained muscle contractions that lead to disabling violent movements and the formation of pathological poses. Among movement disorders, dystonia ranks third in frequency after essential tremor (ET) and Parkinson's disease (PD) (Collaborative Croup Epidemiology study of Dystonia Europe (ESDE). A prevalence study of dystonia in eight European countries. J Neurol 2000; 247: 787-792.). The high prevalence of dystonia among people of working age, a significant decrease in the functional capabilities of patients and their quality of life determines the medical and social significance and relevance of the problem.

The etiology of dystonia is unknown, however, there are more and more assumptions about the multifactorial origin of dystonia, which is the result of genetic predisposition, manifested in the conditions of influence of various environmental factors (stress, surgery, forced position of body parts, etc.). Researchers discuss the impact of previous stressful events in the debut of the disease (Loginova N.V., Karakulova Y.V. Comorbidity of pain syndrome and emotional disorders in patients with spastic torticollis. Modern problems of science and education. - 2015. - № 6. https: // www .science-education.ru / ru / article / view? id = 23088).

The role of stress in the formation of the clinical picture of focal muscular dystonia was previously reported (Suvorova V.A. The role of stress in the formation of the clinical picture of focal dystonia / Suvorova V.A., Antipenko E.A., Dyachkova M.S., Serdtseva D.V. , Deryugina AV, Gustov AV. //– Medical Almanac - 2017; 5; 89-91), a chronological connection was established between the onset of the disease and stress in 88% of patients. Indicators of electrophoretic mobility of erythrocytes, reflecting the level of stress reactions of the hypothalamic-pituitary-adrenal system, indicated a state of chronic stress with depletion of adaptation reserves in the majority of patients with focal dystonia.

It is known that the electrophoretic mobility of erythrocytes (EFES) is an integral indicator that comprehensively characterizes the homeostasis of the organism, since any pathology or stress is realized under the conditions of the whole organism indirectly through the cell membrane systems. The definition of EPPE is widely used in predicting and evaluating treatment results, in particular for evaluating the function of the adrenal cortex (RF Patent No. 2466410), differential diagnosis of diseases of oncological and non-oncological genesis (RF Patent No. 2593015), for predicting purulent postoperative complications (RF Patent No. 2293325 ), determining the tactics of transfusion therapy in patients with post-hemorrhagic anemia (RF patent №2542507), the choice of tactics in patients suffering from chronic cerebral ischemia (RF patent №23 71193).

So, in the first phase of stress, associated with the activation of the sympatho-adrenal system, there is a decrease in EFFE, while in the second phase, the resistance phase of the organism, EFFE increases and with the development of maladjustment (characterized by depletion of the body's reserves in the third phase), there is a repeated decrease in EFFE.

Also as an indicator of adaptation reactions, leukocyte indices are known: the adaptation stress index (INA) according to L.Kh. Garkavi (1978) and the nuclear index (GI) GD Dashtayants (1978).

INA reflects the ratio of the number of lymphocytes to the number of segmented neutrophils in the leukocyte formula, i.e. relationship of cellular and humoral immunity, assessment of stress. This index can be considered as an indicator of the balance of the response of blood cells.

YI is the ratio of the total number of monocytes and stab neutrophils to the level of segmented. The index characterizes the rate of regeneration of neutrophils and monocytes, as well as the duration of their circulation in the bloodstream (Dynamics of cellular indicators of the erythrocyte system when adapting to acute experimental hypoxia of the brain depending on the level of stress tolerance / Pakhrova O.A. [and others.]. Successes of modern science - 2016; 12; 99-104).

According to the Primary Health Care Standard for Dystonia (Order of the Ministry of Health of the Russian Federation No. 1539n and No. 1540n of 12/24/2012), diagnosis of muscular dystonia is required: examination and consultation of a neurologist, if necessary, consultation of related specialists (otolaryngologist, psychiatrist, ophthalmologist, psychiatrist, general practitioner) , dentist, orthopedist); the following laboratory tests: blood level of cerruloplasmin, complete blood count, biochemical blood test, lipid profile; Of the instrumental methods, the main method is needle electromyography; in addition, it is possible to perform MRI of the brain, MRI of the neck, CT of the head and neck, and neck X-ray.

For the treatment of muscular dystonia, it is possible to use the following groups of drugs: non-selective beta-blockers (propranolol); peripheral muscle relaxants (botulinum toxin type A); muscle relaxants centrally acting (lidocaine + tolperisone, tizanidine, baclofen, tolperisone); benzodiazepine derivatives (clonazepam, diazepam); tertiary amines (trihexyphenidyl); dopa and its derivatives (levodopa + [carbidopa]); benzamides (sulpiride, tiaprid); non-selective monoamine reuptake inhibitors (amitriptilline); selective serotonin reuptake inhibitors (fluoxetine, paroxetine, sertraline, fluvoxamine); other antidepressants (trazodone). From non-pharmacological methods of treatment it is possible to use psychotherapy, myoelectrostimulation, exercise therapy, massage.

Thus, based on the standard of care for patients with muscular dystonia, it can be concluded that the treatment of dystonia is only symptomatic and is aimed at reducing the severity of hyperkinesis. The gold standard for the treatment of muscular dystonia is botulinum therapy (Orlova OR, Application of Botox (botulinum toxin type A) in clinical practice: a guide for physicians / OR Orlova, H.N. Yakhno. M .: Catalog, 2000. - 208с Orlova, OR Focal dystonias: modern approaches to the diagnosis and possibilities of botulinotherapy. Nervous diseases 2016; 4; 3-12; Albanese A., Barnes MP, Bhatia KP et al. A systematic review primary (idiopathic) dystonia and dystonia plus syndromes: report of an EFNS / MDS-ES // Eur J Neurol. - 2006. - Vol. 13, N 5. - P. 433-44; Daniel Tarsy., David K. Simon ., Ph.D. Dystonia Neurologi Engl Journal Medizin 2006; 355: 818-829 DOI: 10.1056 / NEJMra055549).

This method has been firmly established in medical practice, replacing systemic drugs, the use of which has often been accompanied by pronounced side effects with low therapeutic efficacy.

However, a significant limitation to the widespread use of botulinum therapy is the need to repeat injections every 3-5 months, in some cases more often. There is an individual variability of the effect of botulinum therapy, which may be insignificant or even negated by the patient and may be pronounced up to the development of remission after the first injections of the toxin, moreover, it may be different for the same patient from injection to injection.

Thus, the treatment of patients with botulinum toxin has only a temporary, often unstable effect; the procedure requires highly qualified personnel who are proficient in this technique. This method does not take into account the individual characteristics and the role of stress in the development of the disease.

The task of the invention is the development of tactics for the treatment of patients with muscular dystonia using a personalized approach.

The technical result is to increase the stability of the effect of treatment, prolonging the period of remission in patients.

The technical result is achieved by the method of electrophoretic mobility of erythrocytes (EPT) being analyzed in the patient's electrophoretic mobility erythrocyte (EPT) analysis 1 (INA) and nuclear index (YI), with values one month after the injection of botulinum toxin EFPA below 1.00 μm × cm / V × s, INA above 0.5 used units. and NI in the range of more than 0.15 and less than 0.35 usled. anxiolytic drugs are prescribed, if at least one of the conditions of INA is lower than 0.45 used units, NI is greater than or equal to 0.35 used units. drugs of metabolic action are prescribed, in the study of EPME, INA and YI 3 months after botulinum toxin injection, if they correspond to or approach the physiological norm compared to baseline values and there is no increase in hyperkinesis decide to transfer the next botulinum toxin injection two months later than previously planned.

The proposed method is as follows. Conduct a comprehensive clinical examination of the patient, including the study of complaints, anamnesis, objective neurological and somatic status, botulinum therapy is prescribed. Before injection, to determine the EFES, INA and YI, 2 ml of venous blood is taken from the patient. One month after the injection of botulinum toxin, EFEP, INA and YI are examined if the obtained values of EFPE are below 1.00 μm × cm / V × s, and the INA is above 0.5 standard units. and NI in the range of more than 0.15 and less than 0.35 usled. anxiolytic drugs are prescribed, and when EFEP is below 1.00 μm × cm / H × s, INA is less than 0.45 used units. or YI is greater than or equal to 0.35 used prescribe drugs of metabolic action. 3 months after the injection, the EFPE, INA and YI are examined, if the EFE, INA and YI correspond to or approach the physiological norm compared to the initial values, in the absence of a hyperkinesis increase, they decide to transfer the next botulinum toxin injection two months later than previously planned.

The method is used in the treatment of 69 patients aged 19 to 75 years with an established diagnosis of muscular dystonia. The average age was 50 ± 13 years. Among them were 29 men and 40 women. 42 people had a disability for this disease (33 people had group III and 9 people group II disability).

The neurological status was studied according to the generally accepted method, which included evaluation of the pyramidal, extrapyramidal, coordinating, sensitive spheres and the function of cranial nerves. Quantitative assessment of the severity of dystonic hyperkinesis was carried out using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) standardized scale for patients with focal and segmental dystonia and the Barry-Albright scale for patients with torsional dystonia. The diagnosis was formulated according to generally accepted criteria and was confirmed by ENMG data. Measurement of EFPE was carried out by microelectrophoresis.

The mean values of EFPE, INA and YI for different forms of dystonias are presented below.

 Focal dystonia is characterized by EFPE 0.99 ± 0.041 μm × cm / H × s at the physiological norm of 1.26 ± 0.01 μm × cm / H × s, which indicates the body’s stress response, INA = 0.54 sr. at a rate of 0.49 ± 0.05 used and YAI 0.22 standard unit at a rate of 0.14 ± 0.02, which indicates the development of a stress reaction and stress of adaptation processes

Segmental dystonia is characterized by EFPE 0.72 ± 0.11 μm × cm / H × s at the physiological norm of 1.26 ± 0.01 μm × cm / H × s, which indicates the body’s stress response is much more pronounced than focal dystonia , INA = 0.59 services unit at a rate of 0.49 ± 0.05 used and NI 0.21 conventional units at a rate of 0.14 ± 0.02, which indicates a voltage of adaptation processes similar to focal dystonia.

Torsion dystonia is characterized by an EFES of 0.99 ± 0.071 μm × cm / V × s at a physiological norm of 1.26 ± 0.01 μm × cm / V × s, indicating a stressful response of the body comparable to focal dystonia, INA = 0.42 unit at a rate of 0.49 ± 0.05 used and YAI 0.35 usd. unit at a rate of 0.14 ± 0.02, which indicates a significant decrease in the specific level of immunity against the background of depletion of adaptation processes.

Clinical example number 1.

Patient A., 53 years old. Diagnosis: “Focal muscular dystonia: cervical dystonia of the second degree of severity with symptoms of dystonic tremor”, the severity of hyperkinesis on the TWSTRS scale was 21 points. The EFEP level before treatment was 0.97 μm × cm / V × s, with the physiological norm 1.26 ± 0.01 μm × cm / V × s, which indicates the body’s stress response, INA = 0.54 standard units at a rate of 0.49 ± 0.05 used and NI = 0,22 srvc.ed. at a rate of 0.14 ± 0.02, which indicates the development of a stress response and stress adaptation processes. The patient received botulinum toxin for the correction of dystonic hyperkinesis. After 1 month, the patient was re-examined and blood was taken. Complaints of difficulty concentrating, forgetfulness, confusion persisted, the patient was not fully satisfied with the effect of botulinum toxin, and there was a pronounced head turn. At the same time, the growth of EFPE was observed up to 0.93 μm × cm / V × s and the indices remained elevated INA = 0.52 used units, UI = 0.17 used units, which indicates that disadaptation persists with pronounced stress reactions of the body. In addition to the treatment with botulinum toxin, an anxiolytic tetramethyltetraazabicyclo octanedio 500 mg three times a day for two months was added. By the 3rd month, an EFES growth of up to 1.059 μm × cm / V × s was obtained, the studied indices were approaching the physiological norm: the INA was equal to 0.50 used units, and the YI was 0.15 used units. Clinically, dystonic hyperkinesis after treatment was weakly 7 points according to the TWSTRS scale, which allowed to delay the next injection of botulinum toxin type A. Thus, botulinum therapy was required for this patient every six months, not once every 4 months, which indicates prolongation of remission.

Clinical example number 2.

Patient V., 34 years old. The diagnosis of segmental muscular dystonia, cervical and brachial dystonia, 3 degrees of severity. The severity of hyperkinesis according to the TWSTRS scale was 35 points. The EFPE level was 0.72 μm × cm / H × s at the physiological norm of 1.26 ± 0.01 μm × cm / H × s, which indicates the body’s stress response, INA = 0.59 standard units. at a rate of 0.49 ± 0.05 used and NI = 0.21 conventional units at a rate of 0.14 ± 0.02, which indicates the stress of adaptation processes. This patient received botulinum toxin therapy. After 1 month, at the repeated intake, the growth of EFES was observed up to 0.74 μm × cm / H × s and the indices remained elevated: INA = 0.51 used units, and NI = 0.24 used units, which indicates that disadaptation persists with pronounced stress reactions of the body. Anxiolytic tetramethyltetraazabicyclo octanedione 500 mg three times a day for two months was added to the treatment. By the 3rd month, the EFES recovered to the norm and amounted to 1.26 μm × cm / V × s, the studied indices approached the physiological norm: INA = 0.49 used units and NI = 0.16 used units. The severity of hyperkinesis according to the TWSTRS scale was 15 points. Repeated injection of botulinum toxin is recommended after 5-6 months, which indicates an increase in the remission interval (previously botulinum therapy was performed once every 3 months).

Clinical example number 3.

Patient A, 20 years old. The established diagnosis of "torsion muscular dystonia", the severity of hyperkinesis was 10 points on the Barry-Albright scale. Dystonic hyperkinesis spread to the muscles of the face, neck, right shoulder and hand, body. More pronounced hyperkinesis was observed in the neck muscles (25 points on the TWSTRS scale). EFPE was 0.99 μm × cm / V × s at a physiological norm of 1.26 ± 0.01 μm × cm / V × s, which indicates the body’s stress response, INA = 0.42 used units. at a rate of 0.49 ± 0.05 used and YAI 0.35 usd. unit at a rate of 0.14 ± 0.02, which indicates a significant decrease in the specific level of immunity against the background of depletion of adaptation processes. This patient received botulinum toxin therapy, and her neck muscles were predominantly injected. At the second dose after 1 month, the EFES was 0.97 μm × cm / V × s; INA = 0.44 st.ed, YAI = 0.30 srv.ed, which indicates the preservation of the stress response. To correct the stress response, a metabolic drug, Meldony, was added to the treatment, 0.5 g 2 times a day for 8 weeks. By 3 months, EFES increased above the norm and amounted to 1.52 μm × cm / V × s, which indicates an increase in stress resistance, the studied indices recovered to the physiological norm: INA = 0.49 standard units, and UI = 0.14 srv. units The severity of hyperkinesis on the Barry-Albright scale was 5 points. The severity of cervical dystonia was 7 points according to the TWSTRS scale, however, the patient began to be more disturbed by the increasing hyperkinesis in her right arm, therefore, despite the fact that the patient notes a significant improvement in her general condition, the muscles of the right shoulder and hand are injected, which does not allow to increase the intervals between botulinum toxin injections .

Clinical example number 4.

Patient K., 52 years old. The diagnosis of segmental muscular dystonia, cervical and oromandibular dystonia, 3 degrees of severity. The severity of hyperkinesis according to the TWSTRS scale was 25 points. The level of EFPA was 0.80 μm × cm / V × s at a physiological norm of 1.26 ± 0.01 μm × cm / V × s, which indicates the body’s stress response, INA = 0.35 used units. at a rate of 0.49 ± 0.05 used and NI = 0.37 srv.uned at a rate of 0.14 ± 0.02, which indicates a significant decrease in the specific level of immunity against the background of exhaustion of adaptation processes. This patient received botulinum toxin therapy. After 1 month, at the repeated intake, the growth of EFES was observed up to 0.92 μm × cm / V × s; INA = 0.40 used units, and NI = 0.35 used units, which indicates the preservation of depletion of adaptation processes. To correct the stress response, a metabolic drug, Meldony, was added to the treatment, 0.5 g 2 times a day for 8 weeks. By the 3rd month, the EFES approached the norm and amounted to 1.23 μm × cm / V × s, the studied indices also approached the physiological norm: INA = 0.49 standard units and NI = 0.18 standard units. The severity of hyperkinesis according to the TWSTRS scale was 7 points. Repeated injection of botulinum toxin is recommended after 6 months, which indicates an increase in the remission interval (previously botulinum therapy was performed every 4 months).

Thus, the use of the method increases the stability of the effect of treatment and contributes to the prolongation of the period of remission in patients.

Claims (1)

A method for selecting tactics for treating patients with muscular dystonia, including clinical examination and prescription of botulinum therapy, characterized in that before starting botulinum therapy, 1 and 3 months after botulinum toxin injection, the red blood cell electrophoretic mobility (EFES) is analyzed in the patient, and the stress adaptation index (INA) is analyzed and nuclear index (YI), with values one month after the injection of botulinum toxin EFPE below 1.00 μm × cm / V × s, INA is above 0.5 used units. and NI in the range of more than 0.15 and less than 0.35 usled. anxiolytic drugs are prescribed, and if at least one of the conditions is fulfilled: INA is less than 0.45 used units, YA is greater than or equal to 0.35 used units, drugs of metabolic action are prescribed, in the study of EPME, INA and YI 3 months after the injection of botulinum toxin, if they correspond or approach the baseline values to the physiological norm and there is no increase in hyperkinesis, they decide to transfer the next injection of botulinum toxin two months later than previously planned.