RU2329762C2 - Method of neuroimmune disorder diagnostics - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine and can be used for neuroimmune disorder diagnostics associated with epilepsy. Electroencephalographic (EEG) monitoring is performed. Thus EEG is registered on head surface and if slow waves are found in rest state with amplitude 1.5-2.0 times exceeding background values, and alpha activity index is lowered in posterior diversions, as well as alpha index is lowered after functional tests in all hemisphere diversions while it is increased in anterior cerebrum area, neuroimmune disorders are diagnosed for epilepsy patient. Method provides widen range of means for neuroimmune disorders diagnostics associated with epilepsy.

EFFECT: development of new effective method of neuroimmune disorders diagnostics associated with epilepsy.

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Description

The invention relates to medicine and can be used to diagnose neuroimmune disorders.

The neuroendocrine and immune systems (NEIS) in the human body are a single integrative functional system with many connections. The interdependence and interdependence of the nervous and immune systems is based on the mediator and antigenic communities, the ability to form memory, network relationships, self-regulation and the leading role in the process of providing functional dynamic homeostasis and adaptation, providing a known reliability of intersystem relations. At the same time, the functioning of a complex NEIS is fraught with the possibility of the development of disregulatory disturbances in the event of failure of the compensatory mechanisms and pathology of its constituent systems.

Neuroimmunopathology is characteristic of almost any nosological form of brain disease. Neuroimmunological disorders are not only an important part of pathogenesis, in addition, these disorders can be a risk factor for the development of chronic process, its atypical course and the formation of resistance to pharmacotherapy. The pathology of the nervous regulation of the immune system can manifest itself in two main types of functional disorders: immunological deficiency, up to severe IDS, or excessive activation of immune reactions, including autoimmune processes.

The pathogenesis of neurodysregulatory pathology is associated with the formation of pathological integration in the damaged nervous system (Abramov V.V. Integration of the immune and nervous systems. - Novosibirsk: "Science". - 1991. - 168 p.) / 1 / in connection with the violation of inhibitory control. The initial link in this process is the formation of an aggregate of hyperactive neurons, which produces an amplified uncontrolled flow of pulses, i.e. generator pathologically enhanced excitation. The generator overactivates the structure of the central nervous system in which it originated or with which it is functionally connected, as a result of which this structure significantly changes the functional state of other central nervous system structures and together with them forms a complex pathological integration - pathological system (PS). Moreover, in the early stages of formation, such a hyperactive structure also determines the behavior of PS and ensures its stabilization. It plays the role of a pathological determinant. The pathological chain of PS formation after damage to the central nervous system represents the following stage mechanisms: generator formation - the occurrence of pathological determinants - the formation of a pathological system. If PS has exits to the periphery, its effector link is altered somatic structures, which are the final link of PS.

Paroxysmal changes in the electroencephalogram (EEG) are associated with high sensitization to NAH. A connection was established between the concentration of NSF and the severity of the clinical picture in patients with central nervous system diseases. The standard response of a neuron to NAG is a significant depolarization of the cell membrane, a decrease in the threshold of action potentials, an increase in the amplitude of the depolarization spike and EPSP, which occurs in hippocampal neurons in response to electrical stimulation of the Stefer collaterals. Thus, the immunological induction of a pathologically enhanced excitation generator is associated with a typical mechanism of neuronal hyperactivation - membrane depolarization, the basis of which is the activation of sodium and especially calcium channels.

The occurrence of paroxysmal depolarization shifts is a characteristic sign of the epilepticization of neurons, which ultimately leads to the formation of a pathologically enhanced excitation generator from these neurons. NeuroATs can induce a generator or maintain and enhance its power. Thus, antibodies to synaptic brain vesicles cause an increase in the frequency of discharges of pacemaker neurons and initiate the activity of previously silent neurons.

When analyzing the effect of neuroAT, it is emphasized that their main electrographic option is epileptiform activity, and it is believed that the main target of neuroAT is synaptic structures (Stark M.V. Iosgospecific proteins (antigens) and neuron function. - M .: Medicine, 1985. - 310 p.) / 2 /. In this regard, it should be noted that antibodies to synaptic structures, which induce a powerful generator of pathologically enhanced excitation, have the maximum effect.

The EEG method, being a non-invasive method of intravital topical diagnosis with visualization of the lesion in the brain, becomes a valuable source of information about the functional state of the brain and the neuroimmune system controlled by it. The possibility of obtaining a timely qualitative assessment of these changes for the doctor is valuable in terms of determining the clinical situation as a whole. Quantitative changes in a number of EEG parameters can detect a tendency to move to critical values and, therefore, have prognostic value, which serves as a guide for the doctor of appropriate preventive therapy. There is experimental evidence of the dependence of the nature of the electrical activity of brain structures on the level of immunodeficiency (Kryzhanovsky GN, Magaeva SV, Makarov SV Neuroimmunopathology. - M., 1987. - S.146-153) / 3 /.

The closest in technical essence and the achieved result is a method for the diagnosis of neuroimmune disorders, including electroencephalographic monitoring (Korneva E.A., Grigoryev V.A., Klimenko V.M., Stolyarov N.D. Electrophysiological phenomena of the brain in immune reactions .-- L .: "Science", 1989. - S. 52-59) / 4 /.

The authors prove the correlation between the nature of electrical processes in the nervous system and the level of immunity. The interaction of the nervous and immune systems based on the analysis of the impulse activity of a number of brain structures is shown. Although the authors managed to prove the relationship between the electrical parameters of the nervous system and the level of immunity, the invasive technique used cannot have wide clinical distribution.

The method for diagnosing neuroimmune disorders that we developed differs from the method of the authors of the book in its non-invasiveness, which allows using the method in wide clinical practice as an additional clinical output for recording EEG.

The technical result, the achievement of which the present invention is directed, is to increase the efficiency and effectiveness of the method for the diagnosis of neuroimmune disorders by determining the need for expensive studies for the presence of IDS, which avoids unnecessary expensive laboratory tests.

It should also be noted that immunological testing methods of the "second level" are carried out in specialized laboratories and they are quite laborious and expensive.

The specified technical result is achieved by the fact that in the method for the diagnosis of neuroimmune disorders, including electroencephalographic monitoring, characterized in that when the values of slow waves (especially delta), in amplitude exceeding more than 1.5-2 times the background values, it is recommended to conduct additional studies immunodeficiency state (IDS).

Indications and contraindications for the use of the method.

Indications:

1. Chronic progressive diseases of the central nervous system in the stage of decompensation (encephalopathy of various origins, epilepsy, etc.).

2. Atypical course of neuropsychiatric syndromes.

3. Complicated forms of central nervous system diseases, their combination with VIN syndromes.

4. The presence of drug-resistant forms of neuropsychiatric disorders.

5. Assessment of the dynamics of the course of the central nervous system disease and determination of the prognosis.

6. Indication of the likelihood of immunodeficiency.

There are no contraindications.

The studies were carried out on a digital teleencephalograph "Telepath" (St. Petersburg) with 8 symmetrical points on the surface of the head at rest and under the behavior of standard load EEG samples. Equal sections of the electroencephalogram are processed statistically (calculation of the power spectrum of the main rhythms).

Comparison of the EEG picture was carried out in patients with epilepsy, divided into groups depending on the level and severity of changes in immunological parameters: group I - with deep T-dependent immunodeficiency, a sharp decrease in phagocytosis and serum Ig content, the presence of lymphocyte sensitization to NAG (protein S- 100, memeAG, OBM and Gal-c I); Group II - with a moderate decrease in the phagocytic immunity.

An analysis of the results of statistical processing of the values of various sections of the EEG at rest (before the presentation of functional samples) showed that patients of group I determine higher values of the values of slow (especially, delta) waves, which are approximately 2 times higher than those of patients of group II. At the same time, the alpha index in patients of this group is lower (in the posterior leads, the power-rhythm spectrum is reduced to 6% at 11% in patients of group II). The magnitude of these indicators was high in both hemispheres with relative right-hand predominance. The local accent of EEG changes is unstable and its formation is apparently due to the localization of the foci of destruction (more often in the occipital and posterior temporal leads). After carrying out functional tests, a clear decrease in this indicator is determined for all leads of the left hemisphere (3.4-0.3%) with a significant increase (up to 13%) in the anterior (especially frontal) areas.

In most patients of group II, the predominance of alpha activity in the occipital leads is clearly determined, both in severity and in amplitude, which reflects the preservation of regional differences (the power spectrum for the posterior regions is 2-3 times higher than in the anterior and temporal leads ) In them, hemisphere prevalence of slow EEG components is significantly more often determined with significant values of the power spectra of slow waves. However, after conducting samples with rhythmic photostimulation and hyperventilation, a tendency was found to increase the severity and generalization of alpha and slow waves in the anterior and anterior temporal regions.

A comparison of the EEG data of two groups of patients revealed a correlation between violations of the immunological status and changes in the bioelectric activity of the brain. In particular, in patients of group II, functional differentiation of the cortex is more pronounced without signs of a decrease in cortical function in general. An increase in the severity and generalization of the alpha rhythm allows us to talk about the relative predominance of functional EEG changes in these patients. The EEG picture in patients of group I most likely reflects the presence of destructive processes in the hemispheres of the brain with increased reactions of deep brain structures.

The change in EEG parameters during the functional load - hyperventilation for various durations of epilepsy is shown in Table 3. For different conditions of preclinical epileptogenesis (DSE) and in patients with the clinical stage of epilepsy, there was a clear difference in immunological parameters (Table 4). A comparison of the above tables reveals a tendency for changes in EEG parameters depending on immunological parameters.

When studying the indicators of EEG power fluctuations at different stages of epileptogenesis, data were obtained that also confirm the tendency to a change in the studied parameters in the classical EEG analysis depending on the stage of epileptogenesis, comparable with changes in immune changes.

When conducting dynamic examinations of patients with DSE according to the results of a fractal analysis, the following groups of patients are revealed: 1) persons who regress registered changes (9%); 2) that do not have a tendency to increase epileptogenesis and do not require a diagnosis of epilepsy, but are at risk and need to be monitored at least 1 time per year (57%); 3) patients with increasing epileptogenesis, requiring prophylactic treatment (34%). With further progression of the pathological process, a transition to the decompensated stage (SSC) is likely, i.e. With these observables, one can diagnose epilepsy and begin treatment.

In the case of registration with the subject, compensated epileptogenesis is sufficient only for dynamic observation. If the conditions detected in patients such as febrile seizures, paroxysmal EEG disorders that are not accompanied by seizures, or a single unprovoked seizure are complicated by heredity, aggravated by epilepsy, morphological changes in the brain, and are also accompanied by fractal indicators indicating the progression of epileptogenesis, then you should think about the transition of compensation to decompensation, i.e. into epilepsy. In this case, it is necessary to carry out preventive treatment with the mandatory use of antiepileptic therapy, which should be carried out to the maximum normalization and stabilization of the values of the above indicators.

A method for the diagnosis of neuroimmune disorders is illustrated by examples of the specific implementation of the method.

Example No. 1. Patient D., born in 1980, the duration of the disease is 15 years. Clinical diagnosis: Residual-organic brain disease of mixed genesis with hypertension syndrome.

The clinical picture is represented by focal neurological microsymptomatics, cephalgic, infectious-allergic and cerebrosthenic syndromes.

The immune status of patient D-va (see Table 1) is characterized by deep T-dependent immunodeficiency (low values of the main subpopulations of T-lymphocytes: CD3 +, CD4 +, CD8 +, immunoregulatory index, suppression of phagocytosis) and a decrease in serum IgG and IgM, the presence of sensitization to several neuroantigens.

Table 1 The immune status of the patient Immune indicators The number of identified NAGs CD3 + CD4 + CD8 + IRI HCT test of bases. HCT test Steam. RK HCT test A patient 3 33 22 eleven 2.0 twenty 28 1.4 Norm Absent 52-76 31-46 23-40 1-1.7 6-10 40-80 > 6.5 Immune indicators CD20 + IgA IgG IgM A patient fifteen 0.7 3.8 1,0 Norm 6-18 0.9-4.5 8-18 0.6-2.5

An analysis of the results of statistical processing of the values of different EEG sections of this patient at rest (before presentation of functional samples) showed that high values of slow (especially delta) waves are determined, while the alpha index is reduced (in the rear leads, the α-rhythm power spectrum is reduced until 6%). The magnitude of these indicators is high in both hemispheres with relative right-hand predominance. The existing local accents of changes in the EEG are apparently due to the localization of the foci of destruction (occipital-posterior temporal leads). After carrying out functional tests, a clear decrease in these indicators is determined for all leads of the left hemisphere (3.4-0.3%) with a significant increase (up to 13%) in the anterior (especially frontal) areas. EEG of this patient reflects the presence of destructive processes in the hemispheres of the brain with increased reactions of deep brain structures.

Example No. 2. Patient A., the duration of the disease is 9 years. Clinical diagnosis: Post-traumatic encephalopathy.

The clinical picture is presented by cephalgic and astheno-vegetative syndromes.

The patient's immune status (see Table 2) is characterized by the presence of sensitization to a single neuroantigen with a moderate decrease in the phagocytic immunity.

table 2 The immune status of the patient A-va Immune Indicators The number of identified NAGs CD3 + CD4 + CD8 + IRI HCT test of bases. HCT test Steam. RK HCT test A patient one 73 51 22 2,31 32 52 1,63 Norm Absent 52-76 31-46 23-40 1-1.7 6-10 40-80 > 6.5 Immune Indicators CD20 + IgA IgG IgM A patient twenty 1.8 8.8 1.4 Norm 6-18 0.9-4.5 8-18 0.6-2.5

The background EEG of this patient is characterized by a clear predominance of alpha activity in the occipital leads both in severity and in amplitude, which reflects the preservation of regional differences (the power spectrum for the posterior regions is 2-3 times higher than in the anterior and temporal leads), the alpha index in this patient is reduced to 11% (the power spectrum of the alpha rhythm in the rear leads), not so high values of slow, especially delta waves). In addition, the interhemispheric predominance of the slow EEG components is determined with significant values of the power spectra of slow waves. However, after conducting samples with rhythmic photostimulation and hyperventilation, a tendency was found to increase the severity and generalization of alpha and slow waves in the anterior and anterior temporal regions. On the patient’s EEG, functional differentiation of the cortex is clear without signs of a decrease in cortical function in general. An increase in the severity and generalization of the alpha rhythm indicates the relative predominance of EEG changes of a functional nature.

The proposed method for the diagnosis of neuroimmune disorders allows you to quickly recognize the general nature of neuroimmune disorders by the method of routine EEG, to carry out, according to indications, a more in-depth immunological study, therapeutic correction of the identified syndromes, and rehabilitation measures. The opportunity was given to give a clinical assessment of individual pathophysiological phenomena. Using the proposed method allows to improve the diagnosis of central nervous system diseases with a protracted or relapsing course, to prevent further progression of the disease, thereby preventing the chronicity of the disease, worsening the quality of life of patients.

A method for the diagnosis of neuroimmune disorders allows you to determine the need for a study for the presence of IDS, which avoids unnecessary laboratory tests.

It should also be noted the economic advantage of the EEG method, since immunological testing methods of the “second level” are carried out in specialized laboratories, which are rather laborious and expensive.

Table 3 EEG of persons with NEP during the 5-year follow-up during hyperventilation The nature of the EEG changes Study time The number of observations with this attribute (n = 72) Abs. number % 1. The increase in the severity of alpha rhythm index Initial data eighteen 25 1 year 16 22.2 3 years 13 18.1 5 years 10 13.9 2. The increase in the amplitude of the alpha rhythm above 90 μV. Initial data fourteen 19,4 1 year 16 22.2 3 years eighteen 25 5 years 22 30.6 3. The increase in the severity of slow activity in the index up to 50% Initial data 19 26,4 1 year twenty 27.8 3 years 22 30.6 5 years 24 33.3 4. Deformed complexes acute wave - slow wave across all leads Initial data 22 30.6 1 year 23 31.9 3 years 24 33.3 5 years 34 47.2 5. The appearance of sharp waves with an amplitude of up to 70 μV Initial data 16 22.2 1 year eighteen 25 3 years 21 29.2 5 years 28 38.9 6. Hypersynchronous bursts of alpha, beta, theta rhythms, exceeding the background values in amplitude of 1.5-1.9 times Initial data 32 44,4 1 year 35 48.6 3 years 42 58.3 5 years 46 63.9

Table 4 Immunological parameters in patients with different conditions of preclinical epileptogenesis and in patients with the clinical stage of epilepsy Indicators: relative (O),% and absolute Healthy faces (volunteers), n = 30 Preclinical Epileptogenesis Condition SSC (n = 10) All subjects Regressed (n = 14) Compensated Rising (n = 15) Decompensated content (A) × 10 ⁹ / l (n = 62) (n = 16) (n = 17) CD3 + -O 78.1 ± 2.2 67.7 ± 2.1 74.7 ± 3.1 69.2 ± 2.5 65.3 ± 1.4 61.4 ± 1.5 60.2 ± 1.04 -BUT 1.21 ± 0.03 1.05 ± 0.01 1.15 ± 0.02 1.07 ± 0.03 1.02 ± 0.01 0.95 ± 0.02 0.93 ± 0.03 CD4 + -O 47.8 ± 2.3 37.9 ± 1.9 44.1 ± 1.9 40.3 ± 2.1 34.6 ± 1.8 32.4 ± 1.7 30.9 ± 1.2 -BUT 0.4 ± 0.01 0.31 ± 0.02 0.37 ± 0.02 0.33 ± 0.03 0.29 ± 0.02 0.27 ± 03 0.25 ± 0.02 CD8 + -O 27.2 ± 1.1 36.3 ± 1.4 30.3 ± 1.4 34.9 ± 2.1 38.1 ± 1.7 41.8 ± 1.5 44.5 ± 2.2 -BUT 0.23 ± 0.03 0.28 ± 0.02 0.24 ± 0.02 0.27 ± 0.03 0.3 ± 0.02 0.33 ± 0.03 0.35 ± 0.02 CD4 + / 1.76 ± 0.06 1.04 ± 0.07 1.45 ± 0.09 1.15 ± 0.07 0.91 ± 0.05 0.78 ± 0.03 0.69 ± 0.02 CD8 + CD20 + -O 14.1 ± 2.5 17.7 ± 2.2 15.1 ± 1.8 17.3 ± 2.1 18.7 ± 2.1 19.6 ± 3.4 21.1 ± 2.5 -BUT 0.32 ± 0.05 0.42 ± 0.04 0.36 ± 0.03 0.4 ± 0.04 0.44 ± 0.05 0.49 ± 0.06 0.51 ± 0.03 CD22 + -O 20.6 ± 0.5 15.3 ± 0.04 19.1 ± 0.6 17.4 ± 0.3 13.3 ± 0.05 11.2 ± 0.02 9.4 ± 0.2 -BUT 0.36 ± 0.04 0.26 ± 0.02 0.33 ± 0.02 0.3 ± 0.01 0.23 ± 0.04 0.19 ± 0.03 0.16 ± 0.05 CD25 + -O 12.4 ± 2.3 14.9 ± 1.4 13.1 ± 2.2 14.2 ± 1.1 15.7 ± 2.1 16.4 ± 1.9 18.5 ± 1.3 -BUT 0.27 ± 0.05 0.32 ± 0.04 0.28 ± 0.03 0.31 ± 0.02 0.34 ± 0.01 0.35 ± 0.03 0.4 ± 0.02 IgE (mg / L) 175.16 ± 5.82 220.18 ± 4.79 197.54 ± 7.12 212.48 ± 4.49 229.15 ± 3.76 241.75 ± 5.87 268.35 ± 6.17 CEC (unit opt. Pl.) 0.074 ± 0.002 0.082 ± 0.003 0.077 ± 0.002 0.081 ± 0.003 0.084 ± 0.004 0.086 ± 0.005 0.089 ± 0.004

Claims (1)

A method for the diagnosis of neuroimmune disorders in patients with epilepsy, including electroencephalographic (EEG) monitoring, characterized in that the EEG is recorded from the surface of the head and when slow waves are detected at rest, whose amplitude exceeds 1.5-2.0 times the background values and the index decreases alpha activity in the posterior leads, as well as a decrease in the alpha index after functional tests in all leads of the left hemisphere and an increase in the anterior regions of the brain, diagnose neuroimmune disorders in patients with epi lepsy.