RU2188575C1 - Method for diagnostics and prediction of epilepsy development in patients at preclinical stage of the disease - Google Patents

Abstract

FIELD: medicine, psychiatry, neurology. SUBSTANCE: electroencephalographic monitoring is carried out, the study of obtained electroencephalogram is performed due to fractal analysis and fractal dimensionality (D) values. Additionally, it is calculated the values of paroxysmal activity test (PAT) according to the content of autobodies to quisqualate-binding membranous protein in patient's blood. Epileptization index (EI) is evaluated by the following formula: EI = PAT x D. If EI = 132.54 ± 5.32 clinical stage of epilepsy is diagnosed, EI = 45.05 ± 3.31 demonstrates patient's health, its intermediate values indicate pre-clinical stage of epilepsy. EFFECT: higher significance of diagnostics. 4 tbl

Description

 The invention relates to medicine, namely to psychiatry and neurology, and can be used as a method for detecting latent epileptogenesis, which makes it possible to assess the degree of its compensation or mobility, which allows to improve the diagnosis of epilepsy at its preclinical stage.

 In this invention we are talking about three paroxysmal conditions: 1) randomly detected spontaneous paroxysmal activity on the electroencephalogram (EEG); 2) about one seizure without changes on the EEG and 3) about febrile seizures in children.

 These disease states do not have a fully clinically formed symptom complex and therefore the nosological principle of diagnosis cannot be extended to them.

 The matter is complicated by the fact that according to the Helsinki Declaration of Human Rights, which our country has signed, a doctor cannot make a diagnosis without the patient’s consent, which is not clinically substantiated, and especially one that can infringe on his rights and adversely affect the quality of life.

 To date, there are no universally recognized and indisputable definitions of disease, norm and health.

 The most recognized and widespread in the medical literature terms are “pre-painful conditions”, “prenosological”, “subclinical”, “conditionally pathological”, “premorbid”.

 In order to answer questions about what a disease is, to determine its boundaries, to establish a typology of these disorders, it is necessary first to solve general conceptual issues and form a certain position, since pre-illness is not only a concept, but also a concept that can be controversial in many respects.

 A.N. Khlunovsky and A.A. Starchenko, discussing the concept of the disease, give such a definition. A disease is a violation of a normal psychosomatic state and a person’s ability to optimally (within reasonable limits) satisfy the material and spiritual needs of a person. They note that the concepts of “disease” and “health” are complicated by the introduction of gradations such as “pre-illness” [1].

 V.P. Petlenko and G.I. Tsaregorodtsev believe that the disease is a reflection of the attempts of the organism and the personality of an integral person to adapt to the environmental conditions that have individually changed for him [2].

 There are other definitions: biologically, a disease is an objective manifestation of dysfunction [3]; the disease is a “disproportion between irritations and ability to act" [4].

 Along with this, health is defined as a state of complete physical and social well-being.

 The above definitions of the concept of “disease” cannot be extended to the paroxysmal conditions under consideration, since they do little to change the lives of people in whom they are noted. However, in adults with risk specialties in epilepsy (chauffeur, security guard, etc.), one registered seizure with convulsions and loss of consciousness can dramatically change a person’s social and labor status, not to mention the quality of life.

 Sometimes articles appear in the literature in which attempts are made to find out the reason for the presence on the EEG of spontaneous paroxysmal activity in the absence of seizures or other symptoms of epilepsy (personality changes, etc.), but most often no convincing solutions are given or formal answers are given.

 So, at one time, the American scientist R.Hess [5], when asked whether patients with paroxysmal changes on the EEG should be treated, answered that the patient should be treated, not the EEG. Formally, this is correct, but no answer was given to the question of how to evaluate the appearance of paroxysmal changes on the EEG. That this is not the norm is obvious. N.P. Ankylosing spondylitis et al. [1], putting forward the concept of a stable pathological state in brain diseases, he concludes that, in case of brain damage, the adaptation does not occur due to replenishment of the missing links, but as a result of the formation of a new “homeostasis”, a new steady state that provides the best possible condition disease adaptation to the environment [6]. Here, the author associates with the installations of V.P. Petrenko and G.I. Tsaregorodtseva [2]. In her opinion, the stability of a stable pathological condition is associated with the formation of an appropriate matrix in long-term memory. If the pathological process progresses, then in systems that provide a stable pathological state, quantitative changes first occur. Supportive reactions of the body are regarded as compensatory. Further progress of the disease may be associated with qualitative changes and depletion of compensatory-hyperactive systems, i.e. decompensation.

 According to the theory of G.N. Kryzhanovsky [7] on epileptogenesis, one can imagine that under the influence of endogenous or exogenous factors, neuron epileptization occurs that does not reach the stage of formation of the epileptic focus, that is, complete decompensation of the brain defense mechanisms does not occur and epilepsy disease does not develop, but a stable compensated pathological condition forms . Apparently, the pathogenic factor was coming, that is, temporary. Most likely, such a pathogenic effect could take place during childbirth [8].

 The compensated state can remain indefinitely and even progress, although in some cases, under the influence of additional hazards, coming decompensation may occur in the form of a single seizure.

 Apparently, the randomly recorded spontaneous paroxysmal activity on the EEG can be attributed to this stage.

 Attempts to understand and comprehend the prenosological stage of epilepsy have already been made previously. So, V.T. Miridonov believes that the diagnostic criterion for this stage is the period of time that has passed from the beginning of the development of the first cerebral paroxysms to the second unprovoked epileptic seizure, and is, on average, 1-2 years [9]. L.R. Zenkov, combining a number of signs of the risk of developing epilepsy (36 in total) and giving each a certain significance in points, determined the groups of subjects with the maximum and minimum possibility of carrying the epileptic process that is not yet clinically complete [10]. Unfortunately, these researchers were not able to visualize the hidden flow of epileptogenesis, with a routine EEG that does not produce any of the trace elements characteristic of the EEG of a patient with epilepsy.

 A known set of "PA test" (PAT) for the diagnosis of epilepsy [11], which consists in the fact that the content of autoantibodies to the quisqualate-binding membrane protein is determined in the patient’s blood.

 A disadvantage of the known PA-test is the impossibility of reliable prediction of the development of the disease in patients with preclinical stage of epilepsy, such as: 1) accidentally detected spontaneous paroxysmal activity on the EEG; 2) one seizure without changes on the EEG; and 3) febrile seizures in children.

 Closest to the proposed one is a method for diagnosing and predicting epilepsy and its preclinical stage, including electroencephalographic monitoring and subsequent processing of the obtained electroencephalogram by fractal analysis [12].

 The disadvantage of this method is the impossibility of reliable prediction of the development of the disease in patients with a preclinical stage of the disease, especially in three paroxysmal conditions: 1) a spontaneous paroxysmal activity detected on the EEG; 2) one seizure without changes on the EEG; and 3) febrile seizures in children.

 The technical result of the present invention is to increase the reliability and reliability of predicting the development of epilepsy in patients with a preclinical stage of the disease, mainly with the following paroxysmal conditions: 1) randomly detected spontaneous paroxysmal activity on the EEG; 2) one seizure without changes on the EEG; and 3) febrile seizures in children.

This result is achieved by the fact that in a method for diagnosing and predicting the development of epilepsy in patients with a preclinical stage of the disease, including electroencephalographic monitoring and subsequent processing of the obtained electroencephalogram by fractal analysis to obtain fractal dimension values, according to the invention, the content of autoantibodies to quisqualate is additionally determined in the patient’s blood binding protein using a paroxysmal activity test and the epileptic index is calculated nations according to the following formula:
IE = PAT • FR,
where IE is the epileptic index;
PAT - results of a test of paroxysmal activity;
FR - values of fractal dimension (D),
the values of IE = 132.54 ± 5.32 indicate changes in the state of the immune and central nervous system according to the epileptic type, which corresponds to the clinical stage of the disease; IE values of 45.05 ± 3.31 indicate the safety of these systems, which indicates the health of the patient, and intermediate values indicate moderate disorders that are not able to realize the clinical manifestation of epilepsy at this stage.

 In addition, with the following indicators: D> 0.70, PAT> 150 and IE> 105, antiepileptic therapy is started to prevent the disease from transitioning to the clinical stage of epilepsy.

 This study made it possible to theoretically substantiate the concept of the preclinical stage of epilepsy (“pre-illness”) with the development of objective criteria to recognize the epileptic nature of spontaneously arising paroxysmal states that do not reach the clinical symptom complex of epilepsy in their manifestations. This refers to paroxysmal changes in an EEG without seizures, one unprovoked seizure and febrile seizures.

 Research methods: clinical observation method, EEG fractal analysis method (FA EEG), paroxysmal activity test (PAT), EEG, CT, MRI.

 The clinical material of the study is presented in three groups: 1) 33 people (16 men, 17 women); spontaneous paroxysmal (paroxysm-like) disorders on the EEG (PN); 2) an unprovoked epileptic seizure without changes on the EEG (NEP) - 39 people (18 men, 21 women) and 3) febrile convulsions in the early period of life (FS) - 66 people (32 men, 34 women). The observed group includes 138 people (66 men, 72 women) aged 15 to 46 years.

 For the reliability of the analysis, two control groups were introduced: 1) patients with epilepsy, 2) healthy. The analyzed observables should occupy an intermediate position between them according to the concept of "pre-illness" set forth above.

 The control groups consisted of: 1) patients with epilepsy with clinically recorded seizures and a disease duration of up to one year - 68 people (38 men, 30 women) aged 15 to 59 years - the clinical stage of epilepsy (CSE); 2) healthy (volunteers) - 30 people (16 men, 14 women) aged 16 to 40 years old - normal, control (ZD).

 Five-minute digitized EEG recordings (FA EEG method) were performed twice in all examined individuals (with a 3-year interval), and the titer of autoantibodies (autoAT) to glutamate-binding membrane protein (HMB) was determined simultaneously by an improved method of PA test.

 The results of the study were evaluated by conventional units - cu (omitted from the text). Statistical data processing was performed using the paired Wilcoxon test.

 Results. As follows from the table. 1, in control group 3 (ZD), the dependence of spectral density on frequency for fluctuation of the square of the amplitude (power) of the alpha rhythm has a spectral index b of 3.95 ± 0.11 (frequency - 1-4 Hz), which corresponds to a fractal dimension D 0.53 ± 0.06. Although the physiological role of fluctuations of this type is not fully understood, it is known that they are closely related to deep processes in brain tissues and are able to reflect subtle changes in its functional activity [6].

 The fractal structure of fluctuations in the alpha-rhythm power of patients with CSE (see column 2 of Table 1) is significantly different from the norm: the index b for this group of patients is clearly reduced (3.38 ± 0.06), the values of fractal dimension are correspondingly increased compared to the latter in healthy subjects (0.81 ± 0.03) - p <0.05 (column 1, table 1). The revealed difference indicates that the degree of autocorrelation is significantly lower in the control in patients with epilepsy (CSE) than in the control in the examined volunteers (ZD). Fluctuations in the amplitude of alpha waves in a group of patients with clinically recorded seizures (control) demonstrate a low level of predictability, which indicates a mismatch in cerebral mechanisms for controlling alpha activity.

 The fact that neurophysiological and autoimmune disorders are closely related in epileptogenesis shows well the change in the mean groups of autoAT titer to HMB titer in the examined groups. There has been a steady increase of 1.4 times in the preclinical stage of epilepsy and 1.9 in patients with registered seizures. Further observation (column B) preserves this trend.

 It should be noted that a marked change in the immunological and neurophysiological statuses of the human body is not always observed with increasing epileptogenesis. In some cases, optionally, at the highest PAT values, adequately high values of fractal dimension are recorded, and vice versa. It is likely that the autoAT titer to HMB titer and fractal analysis are complementary. Therefore, in order to obtain a single characteristic for assessing the severity of the disease process, we propose an integral indicator of the degree of epileptic disorders - the epileptic index (IE). This indicator is formed by multiplying the values of PAT and fractal dimension: IE = PAT • FR. The obtained high IE values indicate a change in the state of the immune and central nervous system according to the epileptic type - gr. A - (KSE - 132.54 ± 5.32), low - about the safety of these systems (ZD - 45.05 ± 3.31), intermediate - about the reflection of moderate violations in both of the two systems under consideration or some prevalence of them in one of them, but not able to realize the clinical manifestations of epilepsy.

 An important diagnostic factor is the stability of these indicators in the control groups (column B) for a long time, in this case 3 years.

 The growth dynamics of fractal dimension (D) in the subgroups representing the DSE in Table 1 is indicative. 2.

 All three subgroups have D values that exceed the norm, showing an increase in its values from the subgroup 1,3-FS (0.63 ± 0.02) to subgroup 1, 2 - NEP (0.77 ± 0.03) - p < 0.05 - gr. A. After 3 years, these indicators statistically significantly increased (p <0.05), as well as the values of PAT and IE. In general, the DSE group demonstrates intermediate values of b, D, PAT and IE between the same parameters of the control groups (ZD) and patients with clinically diagnosed epilepsy (CSE) at both stages of the study.

 The direction of growth of autoAT titer to HMB titer in the DSE subgroups corresponds, as a rule, to an increase in changes in neurophysiological parameters (102.09 ± 2.18-FS; 118.17 ± 3.02-PN; 138.12 ± 2.09-NEP) .

 It is extremely important to change the studied parameters in those observed with DSE (see table. N 3), having the main, most important risk factors (heredity, weighed down by epilepsy - NOE, and morphological changes in the brain - MI). In the complex of reasons leading to the emergence and, subsequently, the start of epileptogenesis, a significant role belongs to craniocerebral injuries, infections (tonsillitis, rheumatism, malaria, inflammation of the sinuses, acute respiratory viral infections, etc.), as well as developing mixed type of encephalopathy. Presented in the table. 3 results show a greater increase in indicators D, PAT and IE in gr. with RF and it was from this group after 3 years that the subjects had a transition of DSE to CSE.

 An analysis of the dynamics of brain processes in the examined groups (see Table 4), conducted three years later, showed that out of 138 people, 12 (8.7%) with IE values from 80 to 129 had numerous epileptic seizures with the corresponding an increase in IE from 127 to 135. In 34 (24.6%) patients, an increase in IE to 86-124 was noted, but it was not accompanied by the onset of seizures and, therefore, was assigned to DSE with increasing epileptogenesis. Along with this, in 79 (57.3%) significant changes in IE did not occur, and this group can be considered as having a stable compensated state. In 13 (9.4%) people, a regression of paroxysmal conditions was noted and they, apparently, can be excluded from the risk group for epilepsy. Thus, an increase in epileptogenesis or its decompensation (disease) was registered in 46 people (33.3%).

 2 (6.1%) moved from the subgroup with PN to the CSE group; in the subgroup with FS, the development of CSE was noted in 5 (7.6%) and in the NEP subgroup - 5 (12.8%) observed.

 It should be noted that people with NEP have the greatest outcome of the pathological process in SSC. All 12 patients with clinically recorded epilepsy carried risk factors for the development of epilepsy: 1) morphological changes in the brain (MI), 2) heredity, weighed down by epilepsy (NOE). In the subgroup of PN, in addition to paroxysmal EEG disorders, NOE and MI of the brain were detected, in the subgroup of NEP, morphological changes in the brain were revealed in all patients and in 2 - NOE, in the subgroup of FS, all showed MI of the brain, and 2 had NOE .

 As noted above, along with an increase in epileptogenesis in some of the observed (9.4%), on the contrary, its attenuation is recorded, which shows a decrease in IE values to a level close to those in ZD (43-58).

 In this group of 3 people (PN), one risk factor for the development of epilepsy was determined - NOE, in 2 with NEP, MI was detected, and in 1 patient with FS - MI.

 The data obtained, in our opinion, suggest that the period of clinical manifestations of epilepsy is preceded by a relatively long, individually time-varying, latent phase (DSE), during which a progressive accumulation of a whole complex of adverse changes in brain tissue occurs.

 Our integrated diagnostic indicator, IE, is sensitive to the dynamics of brain processes corresponding to different stages of epileptogenesis. Most important is the possibility of using IE to make an early forecast of the onset of a crisis in the development of a disease, i.e. phase change: health (ZD) - the preclinical stage of the disease (DSE) - the clinical stage of the disease (CSE), represented by a complete symptom complex.

 Based on the theory of epileptogenesis, it can be assumed that DSE includes the stage of epileptic neurons, pathological changes of which are not able to be realized in clinical manifestations. That is, of the four successive phases of neurophysiological and neuromorphological changes: epileptic neurons, the formation of an epileptogenic focus, epileptic system, epileptic brain [8], the first one or two are the basis of DSE. This fact is also indicated by some researchers [8], who note that the epileptic focus can last a lifetime, not clinically accompanied by paroxysms. The state of the preclinical stage of epilepsy can last indefinitely and is determined by many endo- and exogenous factors and, above all, the protective compensatory capabilities of the body, that is, this condition can be regarded as stable compensated epileptogenesis. The weakening of these mechanisms leads to the transition to SSC, the preservation or their strengthening - to additional compensation and, often, to regression of the pathological process and a return to the state of health.

 Thus, patients with stable pathological conditions (FS, PN on the EEG, NEP), for which there was previously no single point of view, both in terms of diagnosis and treatment, we, using modern methods (traditional, PAT, FA), depending on the results of the study and the presence of risk factors (heredity, weighed down by epilepsy, morphological changes in the brain) into three groups: 1) people who can expect a regression of registered changes (9.4%) are excluded from the observation group; 2) having these stable pathological conditions without a tendency to an increase in epileptogenesis, not requiring a diagnosis of epilepsy, belonging to the risk group and in need of control observations at least 1 time per year (57.3%); 3) patients with increasing epileptogenesis, accompanied by an increase in the values of D and PAT - the preclinical stage of epilepsy, the state of compensation, apparently, require preventive treatment. With further progression of the pathological process, a transition to the decompensated stage is possible (CSE - 33.3%), i.e. With these observables, one can diagnose epilepsy and begin treatment. For ethical reasons and in connection with the social significance of the diagnosis, its wording should be agreed with the patient. Given the possible etiopathological factors arising from the anamnesis and the results of the examination, a pathogenetic version of the diagnosis can be recommended (“consequences of a traumatic brain injury, neuroinfection”; “encephalopathy of a mixed genesis with a tendency to paroxysmal conditions, etc.).

 Our study suggests that, in the case of registration of compensated epileptogenesis in a subject, only dynamic observation is sufficient. If the conditions detected in patients (FS, PN on EEG, NEP) are complicated by NOE and MI of the brain and contain indicators D (FA EEG)> 0.70, PAT> 150, IE (B-PAT)> 105, 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 AED monotherapy, which should be carried out to the maximum normalization and stabilization of the values of the above indicators.

 In conclusion, it is necessary to emphasize that the proposed method for detecting latent epileptogenesis and making it possible to assess the degree of its compensation or mobility can improve the diagnosis of epilepsy in at least 33.3% of patients, and the appointment of preventive therapy for AEDs prevents the development of the clinical stage of epilepsy.

 Thus, the proposed method for diagnosing and predicting the development of epilepsy in patients with a preclinical stage of the disease allows to increase the reliability and reliability of predicting the development of epilepsy in patients with a preclinical stage of the disease and to begin timely preventive treatment, which should be carried out to the maximum normalization and stabilization of all values.

 A method for diagnosing and predicting the development of epilepsy in patients with a preclinical stage of the disease was developed by the authors and was tested at the Research Psychoneurological Institute. V.M. Ankylosing spondylitis.

List of references
1. Khlunovsky A.N., Starchenko A.A. The concentration of damaged brain disease. St. Petersburg: Publishing House "Doe", 1999-256 p.

 2. Petlenko V. P., Tsaregorodtsev G. I. Philosophy of medicine. - Kiev: "Health", 1979.-230 p.

 3. Sim J. The concept of health // Physiotherapy. - 1990, vol. 76, 7. - p. 423-428.

 4. Hegel T.V. The science of logic // Works of different years: in 2 volumes. T.1. - M., 1970.-608 p.

 5. Hess R. - cit. by P.M. Sarajishvili, T.Sh. Geladze. Epilepsy. - M .: "Medicine", 1977. - 304 p.

 6. Ankylosing spondylitis N. P., Kambarova D.K., Pozdeev V.K. Steady pathological condition in diseases of the brain. - L .: "Medicine", 1978. - 240 p.

 7. Kryzhanovsky G.N. Determinant structures in the pathology of the nervous system: generating mechanisms of neuropathological syndromes. - M., 1980 .-- 360 s.

 8. Gromov S.A., Lobzin V.S. Treatment and rehabilitation of patients with epilepsy. - St. Petersburg: "Education", 1993. - 238 p.

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 11. RU Patent 2112243, cl. A 61 K 39/00, 1995

 12. RU Patent 2156607, cl. A 61 K 5/0476, 1999 a prototype.

Claims (1)

A method for diagnosing the development of epilepsy in patients with a preclinical stage of the disease, including electroencephalographic monitoring, processing of the obtained electroencephalogram by the method of fractal analysis and obtaining values of fractal dimension (FR), characterized in that the values of the paroxysmal activity test (PAT) are additionally calculated by the content of autoantibodies to the patient’s blood a quisqualate-binding membrane protein, the epileptic index (IE) is calculated by the formula
IE = PAT • FR
and with a value of IE = 132.54 ± 5.32, the clinical stage of epilepsy is diagnosed, values of IE = 45.05 ± 3.31 indicate the health of the patient, intermediate values indicate the preclinical stage of epilepsy.

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