RU2197991C1 - Preparation for treating discirculatory encephalopathy - Google Patents

Abstract

FIELD: medicine, neurology. SUBSTANCE: medicinal preparation contains immunoglobulin G as active substance in efficient quantity. The innovation provides restoration of vascular passability in cerebral microcirculatory route, improves immunological values and decreases cognitive disorders. EFFECT: higher efficiency of therapy. 3 ex, 2 tbl

Description

 The invention relates to medicine, neurology, and in particular to agents for the treatment of discirculatory encephalopathy.

 Discirculatory encephalopathy (DE), including chronic forms of circulatory failure of the brain, is one of the most important neurological problems. This is primarily due to the fact that DE affects young people (up to 50 years old). An important component of DE is the violation of the arteriovenous balance associated with the microvasculature. Over the past decade, a significant step has been taken in the study of the immunological mechanisms of damage to the vascular wall and violations of the reaggregative properties of blood as the causes of prethrombotic changes in microcirculation in the pathogenesis of DE.

 In connection with the detection of various forms of cerebrovascular pathology, including DE, changes in the functional activity of platelets, disaggregants are used in the treatment of DE, especially aspirin (Odinak M.M., Mikhailenko A.A., Ivanov Yu.S., Semin GF Vascular diseases of the brain. St. Petersburg: Hippocrates, 1998, 160 pp.). However, in contrast to the persistent effect of reducing (by about 40%) the risk of myocardial infarction, aspirin does not reduce the risk of ischemic stroke and can complicate its course with intracerebral hemorrhage.

 Attempts to use the latest thrombolytic drugs to treat DE in most countries have been halted due to hemorrhagic complications and fatal outcomes (Bousser M.-G. Antithrombotic strategy in stroke. Thromb Haemost 2001; 86: 1-7).

Known drug for the treatment of DE - INSTEON ^® (Nycomed GmbH Austria, Austria), which is a combined nootropic drug that consists of three active components - hexobendin, ethamivan and etofillin. The drug has a combined metabolic, neurovascular and neurostimulating effect (Instenon. Clinical experience. Edited by A.A. Skoromets. St. Petersburg. OLBIS LLP, 1999, 192 pp.).

 However, all of the listed drugs have a common drawback: none of them is able to sufficiently increase the intensity of reduced cerebral blood flow either in the brain as a whole or in its individual micro-areas.

 The objective of the invention is to increase the intensity of cerebral circulation.

 The problem is solved in that the agent for the treatment of discirculatory encephalopathy containing the active substance according to the invention as an active substance contains immunoglobulin G (IgG) in an effective amount.

 As evidence accumulated, various immunomodulating properties of IgG preparations were identified, which allowed them to be successfully used in numerous immunopathological conditions, secondary immune deficiency, etc. (Totolyan A.A. Immunoglobulin preparations for intravenous administration. - World of Medicine, 2000, p. 5 -6, 16-18). Despite the fact that the manifestation of primary antiphospholipid syndrome (PAFS), which is regarded as autoimmune, and chronic endothelial dysfunction may be caused by increased production of autoantibodies (Kalashnikova L.A., Cerebral circulation disorders and other neurological manifestations of antiphospholipid neurosurgery syndrome, may lie in the pathogenesis of DE). . and psychiatrist., 1997, p. 10, 65-73), we have not found information about the use of IgG in the treatment of DE in the available literature.

 Clinical studies conducted by the authors showed that in the treatment of patients with dyscirculatory encephalopathy of various stages of immunoglobulin G, in addition to improving immunological parameters, vascular patency of the cerebral microvasculature, neurological symptoms, and cognitive impairment are restored.

 For patients with various stages of DE, immunoglobulin G is infused into the cubital vein at a dose of 0.2-0.4 g / kg body weight per course for 3 consecutive days. This dosage is recommended in the treatment of immunodeficiency conditions. Doses of 2 g / kg body weight per course used in immunomodulating therapy were considered by the authors to be inappropriate, as clinical trials did not reveal differences in immunological, clinical and dopplerographic indices in patients receiving these immunoglobulin doses and in patients receiving the drug at a dose of 0 , 2-0.4 g / kg body weight per course.

 The invention is illustrated by the following clinical examples.

 1. Patient V., 26 years old, the disease manifested at the age of 15 with hemicrania, sometimes preceded by a photopic aura. Then low blood pressure was recorded: an average of 90-100 and 60 mm Hg. By the end of high school, monthly (2-3 times) migraine paroxysms, usually stopped by taking citramone, supplemented with diffuse headache, which had a clear dependence on weather and psycho-emotional factors, mental and physical fatigue, anxiety, and disturbances in night sleep. In subsequent years, a relative constancy of subjective disorders was noted. Gradually, along with the permanent symptoms of vegetative-vascular dystonia, episodic panic attacks appeared at first. Subsequently, vegetative crises took on a frequent character. Attacks of fear with a vital shade that arose several times a week, lack of air, sensation of a lump in the throat, palpitations, general hyperhidrosis lasted up to 40-60 minutes, usually ending with polyuria. Repeatedly was forced to contact emergency doctors. Beta blockers were not associated with a significant preventive effect.

 In connection with the suspicion of antiphospholipid syndrome, the patient was examined twice for an antiphospholipid antibody with an interval of 6 weeks. Screening and confirmatory tests for lupus anticoagulant (VA) with diluted Russell viper venom (dRVVT) were positive.

 On admission, the clinical picture was represented by distal hyperhidrosis, altered by dermographism. In a standard neurological examination, weakened convergence and tremors of nystagmus at the extreme leads of the eyeballs, functional insufficiency of the VII, XII pairs of cranial nerves on the left in the central type, oral symptoms of Rossolimo-Venderovich, mild anisoreflexia of deep reflexes on the sides and body axis without pathological signs. Orientation testing of cognitive functions revealed two erroneous answers, which reduced the number of points by 2 units - to 28 points - the absence of cognitive impairment within the Mini Mental State Examination - MMSE (Folstein MF, Folstein SE, McHugh PR 'Mini-Mental State': a practical method for grading cognitive state of patients for clinicians. J Psychiatr Res 1975; 12: 189-198). CG of the brain showed some expansion of the ventricular system. The fundus without pathology.

Morphological and functional assessment of intravascular platelet activation (BAT) showed 20.5-3.1-1.6-0 as the sum of the active forms of platelet hyperactivation. An integrated immunological study revealed: moderate thrombocytopenia 139 • 10 ⁹ / l; signs of activation of antigen expression of recognition and coreceptor molecules; expression of molecules of antigen presentations of class II HCHS within normal limits; a decrease in the concentration of immunoglobulins of classes A and G in the blood serum; blood phagocyte dysfunction.

 Duplex scanning (DS) of the venous part of the brain revealed signs of the 3rd stage of venous stasis.

 Clinical diagnosis: Stage I dyscirculatory encephalopathy associated with lupus anticoagulant circulation.

 The patient received a 3-day course of IgG at a dose of 0.26 g / kg body weight per course.

 Clinical and laboratory examination after 24 days showed a significant improvement: the disappearance of a cerebral defect and panic attacks, a decrease in other asthenovegetative disorders, and adequate mental health up to 30 points on the MMSE scale. When determining the coagulation time with toxic diagnostics (dRVVT test), the ratio of the clotting time in the mixture to the clotting time of normal plasma was below 1.2, which indicated the absence of lupus anticoagulant.

 The control determination of BAT showed the physiological sum of the active forms - 13 (normal to 17.7), as well as the normal distribution of the number of blood plates involved in aggregates and subaggregates: 6.8-3.16-0.13 (the upper limit of the norm is 7, 4-3.51-0.23).

Positive dynamics of immunological parameters was noted: restoration of platelet blood levels to normal, increase in the relative content of CD4 ⁺ cells, incomplete regression of hypoimmunoglobulinemia and partial restoration of blood phagocyte functions.

 Repeated DS showed a latent - 1 stage of difficulties in the intracranial venous outflow, which indicated the restoration of cerebral arteriovenous equilibrium.

 2. Patient V., 20 years old, suffers from a generalized form of convulsive epilepsy from the age of 16, receives depakine, the dose of which has been increased to 1,500 mg per day in the last six months. Along with epilepsy, vegetovascular dystonia and cerebral venous dystonia were previously diagnosed. She was hospitalized in the intensive care unit for epileptic status. The measures included a standard set of tools and methods aimed at stopping daily serial convulsive epiparoxysms, including due to apnea, which repeatedly required emergency mechanical ventilation. Outside of attacks, a constant feeling of heaviness in the back of the head, frequent headaches worry. Last year, due to distraction and professional memory impairment, “it became more difficult to work” in the main specialty.

 Neurological status: mild symptoms of Marinesko-Radovici, proboscis phenomenon, left ventricular dysdiadochokinesis, some brady and oligokinesia, somewhat uncritical. The state of the mental sphere according to the MMSE scale - 27 points - predemental cognitive impairment.

 KG: a small focus of reduced density in the right frontal lobe.

 On the EEG, there is a focus of epiactivity in the oral sections of the trunk.

 Examination for the presence of VA gave a positive result.

 BAT indicators: 34-10.8-4.4-0.2.

An immunological blood test revealed signs of a chronic inflammatory process with autoimmune syndrome: impaired expression of CD3 molecules, a marked increase in the number of cells with cytotoxic activity (CD8 ⁺ and CD16 ⁺ , CD25 ⁺ ), B-lymphocytosis. Blood phagocyte dysfunction. Strengthening RTML in the test with PHA.

 DS - intermittent blood flow along the sphenoparietal sinus and orbital veins (stage 3 venous stasis).

 Clinical diagnosis: Stage II dyscirculatory encephalopathy associated with lupus anticoagulant. Generalized convulsive form of symptomatic epilepsy.

 The patient received a 3-day course of IgG at a dose of 0.2 g / kg body weight per course.

 Paroxysms disappeared completely 1.5 weeks after the completion of the 3-day course. No side effects were observed. Upon repeated examination after a month, laboratory and clinical remission was recorded.

 The amount of active platelet forms and the number of blood platelets involved in aggregates decreased: 23-7.7-3.2.

 On the part of the immune status, correction of the functional activity of blood phagocytes, partial depression of signs of nonspecific inflammation were noted: the expression of the CD18 complex was restored, the sensitization of mononuclear cells was reduced (according to RTML), phagocytosis rates improved; increased expression of HLA-DR molecules and CL-induced blood monocytes remained.

 DS - reduction of venous stasis to stage 2: the discontinuity of blood flow disappeared, which assumed a monophasic high-speed character.

 Follow-up after 6 months: attacks did not resume, disability remains. The dose of depakine is reduced to 600 mg per day.

 3. Patient A., 50 years old, disabled person of group II, complains of a constant headache mainly in the right frontotemporal region with paroxysmal enhancement. At the height of pain, he notes a loss of consciousness (according to the patient). They are also concerned about a significant decrease in memory, noise in the head, sleep disturbances, severe emotional lability. Over the past year, there has been a single generalized convulsive reaction. Criticism to its state is reduced.

 Previously received repeated courses of various neurometabolic therapy. A short-term relative effect occurred after the use of intravenous instenon infusions.

 An examination was performed for the presence of AFA, which revealed the presence of lupus anticoagulant (in the dRVVT and CCT tests) with confirmation of its circulation before the start of the IgG course.

 The patient did not have standard risk factors for early atherothrombosis: arterial hypertension and diabetes mellitus.

 The neuropsychiatric defect included mild dementia (21 points on the MMSE scale), amiostatic disorders, pseudobulbar symptom complex, diffuse pyramidal insufficiency, grasping Yanishevsky phenomena, elements of static and dynamic ataxia.

 CT - multiple foci of gliosis in the hemispheres, moderate atrophy and a decrease in the density of white matter (leukoarayosis).

 Venous plethora on the fundus.

EEG: against the background of a low-amplitude α-rhythm, low-amplitude diffuse Δ-waves with a focus of paroxysmal activity in the left temporal region are recorded. Thrombocytopenia 156 • 10 ⁹ / L.

 BAT indicators: 28-8.5-2-1.2.

 The immune status was characterized by severe lymphocytopenia, combined with a relative increase in the content of cytotoxic T-lymphocytes, a moderate increase in the expression of HLA-DR molecules, hyperimmunoglobulinemia G, and blood phagocyte dysfunction.

 With DS, venous stasis of the 3rd stage was detected.

 Clinical diagnosis: Stage III dyscirculatory encephalopathy. Cortical-subcortical dementia. Autoimmune thrombophilia associated with lupus anticoagulant. PAFS.

The patient was examined a month and six months after treatment with immunoglobulin G at a dose of 0.4 g / kg of body weight per course. At the same time, key studies of the hemostatic system, immunity and DS of the cerebral pool were performed. Thanks to improved cognitive performance (from 21 to 26 points, MMSE) is more adapted, deficiency of voluntary movements has decreased. Immunohematological control showed positive dynamics: normalization of blood levels of HLA-I and HLA-DR ⁺ cells; increased synthesis of immunoglobulins; restoration of the functional activity of phagocytes. Signs of antigenemia and endotoxemia persisted. Remained moderately elevated BAT: 19-14.4-5.4-1. Blood platelet counts returned to normal values.

 At the end of the first month after IgG therapy, stage 2 disorders of the venous outflow from the cranial cavity were recorded. Examination after a month for the presence of AFA did not reveal lupus anticoagulant.

 A search for lupus-type AFA revealed its presence after 6 months in the dRVVT test. The indicated clotting effect was combined with an increase in the DS-signs of intracranial stagnation to the initial 3rd stage.

 Using the proposed tool for the treatment of discirculatory encephalopathy, 40 people (29 women and 11 men) of the main group were treated, the average age was 42 years. The comparison group consisted of 40 people (30 women and 10 men), the average age was 43.2 years, with a close or identical clinic of I-III stages of DE. Patients of the comparison group were treated with instenon monotherapy (10-day course of intravenous infusion).

 Neurological status and cognitive processes on the MMSE scale were assessed in patients of both groups before therapy and 2-3 weeks after therapy, a comprehensive immunological examination was performed, studies to detect VA, as well as extra- and transcranial dopplerography in duplex mode.

 Table 1 presents data on the dynamics of a cognitive defect in patients of the main group and the comparison group.

 As can be seen from table 1, for a group of patients where IgG was the main therapeutic effect, the regression of disorders was significantly higher than in patients treated with instenon.

 Laboratory dynamics after a course of IgG in 40 patients of the main group included the disappearance of the clotting effects of the presence of VA and thrombocytopenia. The correction of the immune status of patients was recorded: the number of blood lymphocytes increased; the expression of signaling molecules of the T-cell receptor (CD3), adhesion molecules (CD18), antigen presentation molecules of class I of the main histocompatibility complex of the system, HCHA (HLA-I), was restored; expression of CD8 coreceptor molecules, which are important in the development of autoimmune, decreased to normal cell damage. A distinct decrease in the chemiluminescence (CL) of blood monocytes was observed as a sign of activity of the chronic inflammatory process. A different picture was observed in 40 patients with DE in the comparison group. In no case was laboratory remission of VA observed. In general, signs of a chronic inflammatory process persisted.

 To determine the functional state of the cerebral microvasculature before and after treatment, the Doppler pattern of intracranial venous stasis was determined using duplex scanning.

 Ultrasonic angioscanning of the vertebral and intracranial veins of the DS of intracranial veins and venous collectors, as well as the main veins of the neck was performed using a universal cardiovascular ultrasound diagnostic system - System Five GE Ultrafound VINGMED SYSTEMS.

 The ocular, external and internal intracranial veins, dural sinuses were located using a vector sensor generating pulsed oscillations with a frequency of 2-2.5 MHz through three standard accesses: transorbital, transtemporal and suboccipital. The jugular veins were located lateral to the common carotid arteries; vertebrates - in a sitting position, with the installation of a pulse sensor below the posterior angle of the mastoid to a depth of 30-50 mm. The stages of venous stasis were recorded on a scale of A.V. Andreev (Andreyev A.V. Ultrasound Dopplerography in Pediatric Neurology. In the book: Ultrasound Doppler Diagnosis of Vascular Diseases. Edited by Nikitin Yu.M., Trukhanova A.I. - M. : Vidar, 1998, pp. 115-127).

 Table 2 presents the dynamics of intracranial venous stasis in patients of the main group and the comparison group.

 From table 2 it can be seen that in patients with DE who received IgG therapy, according to the DS, disappearance or reduction of venous stasis was observed, which indicates the restoration of vascular patency of the cerebral microvasculature. A similar effect was significantly lower in patients with DE who received instenon therapy.

 Using the proposed invention can significantly increase the effectiveness of the treatment of patients with dyscirculatory encephalopathy due to the restoration of vascular patency of the cerebral microvasculature, improvement of immunological parameters, neurological symptoms and reduction of cognitive impairment.

Claims (1)

 An agent for the treatment of discirculatory encephalopathy containing an active substance, characterized in that as an active substance it contains immunoglobulin G in an effective amount.

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