RU2537886C1 - Method for prediction of developing symptomatic epilepsy accompanying neuroinfections in children - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: recent comatose condition is detected; magnetic resonance imaging shows centres of cerebral structural changes; electroencephalography shows epileptiform activity, diffuse sharp waves, spikes, reduced complexes, high-amplitude low activity paroxysmal events, frequent paroxysmal events of 'peak-slow wave' and 'spike-slow wave' complexes. The EEG also shows irritant activity, local transient high-frequency beta-activity, advanced transient low-amplitude and advance continuous long-term high-amplitude activity. The presence of an aetiological agent of the disease caused by tick-borne encephalitis or the presence of encephalitis of other and uncertain aetiology is stated. The derived data are scored depending on the presence, absence and manifestations thereof. The derived data are used to calculate linear classification functions and to detect the favourable (LCF1) outcome of encephalitis without symptomatic epilepsy (SE) progression and the unfavourable (LCF2) outcome of encephalitis with SE progression. If LCF1>LCF2, the encephalitis outcome without SE progression is predicted, while LCF2>LCF1 shows the unfavourable outcome with SE progression.

EFFECT: method provides more reliable assessment of the SE progression in encephalitis that is ensured by taking into account additional EEG data and calculating the linear classification functions.

2 ex

Description

The invention relates to medicine, namely to predicting the development of symptomatic epilepsy (SE) in children with neuroinfections and can be used in the clinical practice of infectious disease specialists and neurologists to predict the development of SE after suffering meningitis and encephalitis.

The term neuroinfection refers to a group of infectious diseases with invasion of the pathogen into the central nervous system and clinical signs of damage to any of its departments: meningitis - with damage to the soft and hard meninges, encephalitis - with damage to the substance of the brain.

The relevance of acute neuroinfections is determined by the known severity of their course, involvement of children of younger age groups (up to 50%) in the epidemiological process, the frequent development of life-threatening cerebral and extracerebral complications and persistent residual consequences, as well as the persistent high mortality rate, reaching various age groups with a number of nosological forms from 15% to 70%.

Encephalitis is one of the most serious diseases in children and accounts for 10 cases per 100,000 children (Koskiniemi M, Korppi M, Mustonen K, et al. Epidemiology of encephalitis in children: a prospective multicentre study \\ Eur J Pediatr. - 1997. - Vol. 156, No. 7. - P.541-545). The consequences of encephalitis in the form of impaired motor, sensory higher brain functions range from 30% to 60% (Åsa Fowler et al., 2010). The recovery period after encephalitis in children is 6-12 months (Åsa Fowler et al., 2010). In the recovery period, the affected functions are restored, pathological syndromes regress. However, complete recovery is rare, a number of pathological syndromes remain, although they are weakening in their severity. During this period, as a consequence of the disease, SE can also form (Åsa Fowler et al., 2010). Symptomatic epilepsy is a fairly frequent and severe complication of encephalitis in children. SE, formed in the long-term period of transferred encephalitis, is represented by various forms of manifestations and severity: (1) focal manifestations with frequent and constant muscle twitches during tick-borne encephalitis, as well as, as a rule, (2) secondary generalized convulsive seizures reaching frequencies several times per day, leading to a delay in brain development, a violation of personality traits. SE can be resistant to therapy and have an aggressive course. This significantly reduces the vital activity of patients after encephalitis (EL). The risk of developing SE is determined by a number of factors in the development and manifestation of the disease in the acute period. Knowledge of risk factors for the development of symptomatic epilepsy allows you to adjust treatment tactics and reduce or prevent the development of this syndrome in children.

It is believed that the risk of developing SE increases in children who have epileptic seizures in the acute period of the disease, as well as the severity of the condition treated in the intensive care unit (ICU) (Fowler A, Stödberg T, Eriksson M. Wickström R. Long-term outcomes of acute encephalitis in childhood \\ Pediatrics. - 2010. - Vol.26, No. 4. - P.828-835.). In 30% -60% of cases in the acute period of EL, epileptic seizures develop (U.K. Misra et al. Seizures in viral encephalitis // Epilepsia. - 2008. - Vol. 49 (Suppl. 6). - P.13-18). But in much more cases (up to 90%) in the acute period of EL, there are changes in the EEG in the form of focal or generalized slow activity with the presence or absence of epileptiform discharges (Lahat E, Barr J, Barkai G, Paret G, Brand N, Barzilai A. Long term neurological outcome of herpes encephalitis \\ Arch Dis Child. - 1999. - Vol.80, No. 1. - P.69-71). Therefore, the use of only EEG data in predicting the development of SE in outcomes of EL seems to be insufficiently substantiated.

A known method for predicting the course of encephalitis by recording and evaluating data on age, level of C-reactive blood protein, cytosis of cerebrospinal fluid, the presence of coma (A. Schmidt, R. BÜhler, K. MÜhlemann, CW Hess, MG Täuber. Long-term outcome of acute encephalitis of unknown aetiology in adults // Clinical Microbiology and Infection. - 2011. - Vol.17, No. 4. - P.621-626). However, when using this method, MRI and EEG data are not taken into account. The assessment of the prognosis is intended for adults and does not take into account the development of SE as the most severe and, in some cases, small-curable effects of encephalitis.

A known method for predicting the course of acute neuroinfections in children by recording and evaluating MRI data and evoked potentials of the brain. In accordance with this forecasting method, the outcome of the disease is determined (Skripchenko N.V., Savina M.V., Ivanova G.P., Grigoryev S.G. Method for predicting the outcome of viral encephalitis in children. Patent No. 2372839). However, when using this method, approaches to assessing the possibility of developing SE are not proposed.

A known method for predicting the development of SE in acute neuroinfections in children by taking into account clinical indicators (Åsa Fowler et al., 2010). In this method, only two clinical parameters are recorded: the presence of seizures in the acute period of the disease, as well as the severity of the disease, the characteristic of which is the patient in the intensive care unit.

With this method, the volume of brain damage using various methods of neuroimaging is not taken into account, the etiological factor of the disease and EEG data are not taken into account.

Closest to the proposed one is a method for predicting SE in children who have had encephalitis, based on clinical and encephalographic and virological data (Chen YJ, Fang PC, Chow JC. Clinical characteristics and prognostic factors of postencephalitic epilepsy in children \\ J Child Neurol. - 2006 . - Vol.21, No. 12. - P.1047-51.). The authors propose to predict the development of SE by taking into account the development of an epileptic status in the acute period, the presence of slow-wave activity and mulfocal spikes on the EEG and the development of encephalitis by the herpes simplex virus. The disadvantage of the described method is that the authors take into account only neurophysiological, virological data and the presence of status epilepticus, while the severity of clinical manifestations in the form of the length of stay in the intensive care unit or the duration of the coma, as well as the degree of structural brain disorders, are not taken into account. This can lead to an underestimation of the severity of functional disorders of the central nervous system during the study in the acute period of the disease. In addition, the use of only functional indicators for encephalitis without assessing the severity of clinical disorders and neuroimaging data does not provide sufficient accuracy for the development of symptomatic epilepsy.

The technical result achieved by the invention is to increase the accuracy of predicting the development of SE in children by assessing coma and structural brain damage according to MRI.

This result is achieved by the fact that in the known method, which includes determining the presence of an etiological agent-causative agent of the disease, foci of the brain on MRI, the presence of a coma, an additional assessment of the epileptiform activity on the encephalogram, EEG registration is carried out in the first 5 days after the child leaves the coma or the first 10 days of the disease in cases without the development of a coma, they evaluate the irritative activity on the encephalogram and use the data obtained to construct linear classification functions, ifichnye for favorable (LKF1) encephalitis outcome of FE and without adverse (LCF 2) developmental outcome encephalitis FE by the formulas:

LKF1 = -12.1-0.1 ∗ X1 + 10.1 ∗ X2-1.9 ∗ X3 + 5.3 ∗ X4 + 8.4 ∗ X5

LKF2 = -20.1-0.5 ∗ X1 + 4.0 ∗ X2 + 2.1 ∗ X3 + 8.2 ∗ X4 + 10.9 ∗ X5

Where

X1 - the presence of a coma in days, 0 - the absence of a coma;

X2 - foci of the brain on MRI: the absence of foci is estimated at 0 points; the presence of foci - 1 point;

X3 - epileptiform activity on the EEG: absence - 1 point; diffuse sharp waves - 2 points; sharp waves, commissures, reduced complexes, high-amplitude paroxysms of slow activity - 3 points; frequent paroxysms of the complexes "peak-slow wave", "spike-slow wave") - 4;

X4 - irritative activity on the EEG: absence - 1 point; local inconsistent high-frequency beta activity - 2 points; widespread unstable low-amplitude high-frequency activity - 3 points; common long-term high-amplitude high-frequency activity - 4 points;

X5 - etiological agent-causative agent of the disease: encephalitis caused by tick-borne encephalitis virus - 1 point; encephalitis of another and unexplained etiology - 0 points;

and with LKF1> LKF2 predict the outcome of encephalitis without the development of SE, and with LKF2> LKF1 - an unfavorable outcome of encephalitis with the development of SE.

As a result of many years of experience in the treatment of acute forms of neuroinfectious diseases, such as encephalitis, meningitis, we often noted the occurrence of severe consequences in the form of neurological complications. We found that symptomatic epilepsy is a fairly frequent and severe complication of encephalitis in children, even death. After analyzing the features of the course of SE and the results of treatment in the recovery period after encephalitis in children, the authors became aware of the need for an early prognosis for choosing the right treatment tactics. In the process of analyzing numerous clinical, instrumental and laboratory data, the most informative indicators were found that are significant for predicting the outcomes of encephalitis, ensuring the accuracy of the prognosis in the early stages of the disease, which formed the basis of the invention. We showed that in children with severe neuroinfection, the presence of EEG indicators of not only epileptiform, but also irritative activity in the first 5 days after leaving the coma or in the first 10 days of the disease in cases without the development of a coma was the most unfavorable in predicting the development of SE. Earlier registration of the EEG of children in a coma did not allow us to judge the real bioelectric activity, as the patients underwent sufficient sedative and muscle relaxant therapy.

We found that taking into account the duration of a coma, and not the usual duration of children in the intensive care unit, characterized the true severity of the condition in the acute period. The length of stay in the intensive care unit in some cases was associated with somatic complications and did not have a sufficient correlation with the severity of the patients.

The authors first established that if tick-borne encephalitis virus is a neuroinfection, it increases the risk of SE, which is associated with the possibility of the formation of a chronic course of tick-borne encephalitis. A lesser role in the risk of SE development in our observation was played by herpes simplex viruses and type 6 herpes viruses, which, apparently, is associated with a fairly quick and adequate antiherpetic therapy that we are conducting.

The authors first established that it is a comprehensive analysis taking into account the severity of clinical and neurological disorders, the prevalence of CNS structural changes according to MRI, the severity of functional disorders according to EEG results in an increase in the accuracy of the forecast for the development of SE, which was 88.9% and exceeds the accuracy of other known methods .

Fundamentally new is that as a result of a step-by-step discriminant analysis, the authors obtained statistically reliable (p <0.001) and informative formulas of linear classification functions, which included the most significant indicators for predicting encephalitis outcomes, namely, the presence of a coma, the prevalence of foci on MRI, the presence of epileptiform activity on the EEG, the presence of irritative activity on the EEG, the etiological agent-causative agent of the disease

The highest sensitivity of the method was revealed in predicting favorable outcomes of encephalitis without SE 93%, less sensitivity - in predicting adverse outcomes of encephalitis with the development of SE - 81.8%. The sufficiently high informative ability of the method in predicting adverse outcomes of encephalitis (81.8%) allows timely neurometabolic therapy aimed at the duration and volume to reduce the risk of developing SE.

The method is as follows: after hospitalization of a patient with suspected encephalitis, a clinical and neurological examination is carried out to determine the severity of the condition, duration of stay in a coma (in days), clarification of the etiological factor of the disease. To clarify the prevalence, the nature of focal changes, an MRI of the brain is performed.

In parallel with clinical and MRI studies, in the first 5 days after the child leaves the coma or in the first 10 days of the disease, in cases without the development of a coma, EEG studies are carried out in standard leads in the first days of the disease.

After a clinical screening, MRI and neurophysiological examination, coding of the signs used in the formula is performed. Carry out the calculation on the calculator. The amounts obtained by the formulas LKF1 and LKF2 are compared among themselves and the outcome is determined by the prevailing absolute value of one of the LKF, i.e. when LKF1> LKF2 a favorable outcome of encephalitis without the development of SE is predicted, with LKFK <LKF2 - unfavorable with the development of SE.

The effectiveness of this forecasting method can be confirmed by the following examples.

Example 1. Child M., 1 year. Diagnosis: cytomegalovirus encephalitis, severe course. Symptomatic epilepsy. The child fell ill against a background of low-grade fever, the appearance of liquefied stool up to 3 times a day, vomiting after eating 1-2 times a day. On the 3rd day of illness, the condition worsens in the form of a rise in temperature to 38.2 ° C, against the background of which generalized tonic-clonic seizures developed within 2 minutes, stopped on their own. The child was urgently hospitalized in Children's Hospital No 5 with a diagnosis of acute gastroenteritis, febrile seizures. From the anamnesis of life, it is known that a child from 1 pregnancy amid toxicosis of the 1st trimester, ureaplasmosis (the mother received treatment during pregnancy), childbirth is 1 urgent, the baby cries immediately, birth weight is 4840, length 56 cm, Apgar 8/9 points. Breastfeeding up to 3 months. In the first year of life, he suffered an acute respiratory viral infection 6 times, not examined. Vaccinated according to an individual schedule. Heredity is not burdened. On the first day of hospitalization, a deterioration in the condition of the child was noted in connection with the development of epistatus against a background of low-grade body temperature. In neurological status: level of consciousness - stunning (X1 = 0), smoothness of the nasolabial folds on the right, half-ankle, tongue in the oral cavity along the midline, muscle tone S> D, deep reflexes in the limbs are caused with the expansion of reflexogenic zones S> D. Meningeal symptoms are negative. According to the results of a CT scan of the brain on the 3rd day of illness, no data were obtained for volumetric brain formation; there are signs of cerebral edema (X2 = 0). On the EEG on the 3rd day of the disease - severe violations of BEA with the presence of slow-wave, epileptiform and irritative activity. To stabilize the patient's condition, a lumbar puncture was performed: cytosis 6/3 lymphocytic. protein 0.06 g / l. No data were received for meningitis. Cytomegalovirus DNA (X5 = 0) was isolated from CSF by polymerase chain reaction (PCR). In order to stop the epistatus, the child was transferred to mechanical ventilation with drug sedation. the use of muscle relaxants. Against the background of the appointment of depakine in a dose of 15 mg / kg / day. convulsions did not recur, the child was extubated, but after 12 hours again a series of secondary-generalized convulsions with a focal component, which required repeated ventilation, the appointment of 2 anticonvulsants. From the first days of hospitalization, the child received Zovirax 10 mg / kg / time, after establishing the etiological factor - a cytotect of 2 mg / kg / one-time No. 3, dexazone 1 mg / kg / day. 5 days, depakine syrup from 3 days of illness at a dose of 15 mg / kg / day. with further titration of the dose up to 40 mg / kg / day., from the 11th day of illness - finlepsin 5 mg / kg / day., diacarb, asparkum, iv 10 Actovegin course, cytoflavin, pantogam at a dose of 50 mg / kg / day ., Elcar orally at a dose of 100 mg / kg / day. The restoration of neurological status was gradual: the epistatus was stopped by the 10th day of the disease, the hemisyndrome persisted for 10 days with a gradual regression. On MRI on the 20th day of the disease, pathological volume formations and foci of changes in brain tissue were not detected. Mixed hydrocephalus of the substitution type (X2 = 0). A repeated EEG study on the 10th day of the disease revealed moderate disturbances in the form of slow-wave activity without irrigation (X4 = 1), focal paroxysms and epicomplexes (X3 = 1). To predict the possibility of development of SE, a calculation was carried out according to the formulas.

LKF1 = -12.1-0.1 ∗ 0 + 10.1 ∗ 0-1.9 ∗ 1 + 5.3 ∗ 1 + 8.4 ∗ 0 = -8.7

LKF2 = -20.1-0.5 ∗ 0 + 4.0 ∗ 0 + 2.1 ∗ 1 + 8.2 ∗ 1 + 10.9 ∗ 0 = -9.8

In this case, it was found that LKF1> LKF2, therefore, a favorable outcome was predicted. In follow-up observation of the child, there was no seizure 1.5 years after discharge from the hospital, anticonvulsant therapy was canceled under the control of routine EEG, convulsions were not repeated.

The above example shows that, despite the severity of the course of the disease in the acute period, a calculation based on the proposed formula predicted a favorable outcome of the disease, which was further confirmed by clinical and instrumental data.

Example 2. Patient A., 3 months. Diagnosis. Herpetic meningoencephalitis. Symptomatic epilepsy. He became acutely ill with a rise in temperature to 38.5, the appearance of loose stools, frequent spitting up, and repeated vomiting. Upon admission to the hospital the condition of a child of moderate severity. The neurological status of meningeal and focal symptoms was not detected. On the 2nd day of stay, the condition worsened, the development of secondary generalized convulsive attacks with the development of a coma was noted. In neurological status: level of consciousness - coma, large fontanel 2 × 2 cm in size swells, does not pulsate, smoothness of the nasolabial fold on the right, pupils are narrow, photoreaction is absent, muscle tone is diffusely reduced, tendon reflexes from the extremities are low S> D, Babinsky symptom from 2 sides are positive. According to the severity of the condition, the child was in ICU for 10 days, exit from the coma by day 6 (X1 = 5), mechanical ventilation - 7 days. To stabilize the condition, a lumbar puncture was performed: cytosis 256/3 (182 - lymphocytes, 74 - neutrophils), protein - 1.2 g / l, herpes simplex virus type 1-2 DNA was isolated from CSF by PCR (X5 = 0). When conducting a CT scan of the brain in the acute period of the disease, edema was detected, a decrease in the density of the brain substance in the temporal sections on both sides (X2 = 1). When conducting an EEG on the 2nd day after leaving the coma, gross diffuse changes in the BEA of the brain were detected with the presence of focal slow-wave, paroxysmal activity and pronounced irration of brain structures (X3 = 3, X4 = 3). From the first days of being in the hospital, the child received zovirax iv in a dose of 10 mg / kg / day. within 21 days, anticonvulsant therapy - depakine 30 mg / kg / day., dexazone 1 mg / kg / day. 7 days, dehydration therapy, neurometabolic therapy: actovegin No. 15, pantogam 50 mg / kg / day. - 1.5 months, elkar 100 mg / kg / day. - 1 month. When conducting repeated EEG studies, moderate BEA disorders persisted with the presence of focal slow-wave activity and mild manifestations of irritation of the brain structures. On a series of MRI in the period of convalescence, an MRI of the brain was performed: MP-picture of the effects of herpetic meningoencephalitis. Cystic-gliotic changes in the temporal lobes on both sides.

To predict the possibility of SE development, a calculation was performed according to the formulas:

LKF1 = -12.1-0.1 ∗ 5 + 10.1 ∗ 1-1.9 ∗ 3 + 5.3 ∗ 3 + 8.4 ∗ 0 = 7.8

LKF2 = -20.1-0.5 ∗ 5 + 4.0 ∗ 1 + 2.1 ∗ 3 + 8.2 ∗ 3 + 10.9 ∗ 0 = 12.4

Given that LKF1 <LKF2, an adverse disease outcome is predicted. When a child is discharged from a hospital in a neurological status, hemiparesis is noted on the left, despite the ongoing anticonvulsant therapy, focal convulsions of the facial muscles are preserved without impairment of respiratory and cardiovascular activity. During follow-up observation of the child, a gross delay in psychomotor, speech development is noted, hemiparesis is left, the child continues to receive combined anticonvulsant therapy, and focal seizures are noted against the background of intercurrent diseases.

Thanks to the application of the proposed method, the accuracy of predicting the development of symptomatic epilepsy with neuroinfections in children will increase. The high informative ability of the method in predicting the development of SE contributes to an increase in the prognosis of the development of precisely adverse outcomes of SE, which allows timely neurometabolic therapy directed to the duration and volume to reduce the risk of developing SE, and accordingly reduce the length of stay in patients' hospitals. This method can be widely used in clinical practice, in infectious hospitals, neurological, intensive care units.

Claims (1)

A method for predicting the outcome of neuroinfection in children with encephalitis, including determining the presence of an etiological agent that causes the disease, foci of structural changes in the brain on MRI, the presence of a coma, assessing epileptiform activity on an encephalogram, characterized in that the EEG is additionally recorded in the first 5 days after release a child from a coma or in the first 10 days of the disease in cases without the development of a coma, evaluate the irritative activity on the encephalogram and obtained th data build linear classification functions specific to a favorable (LKF1) encephalitis outcome without the development of symptomatic epilepsy (SE) and unfavorable (LKF2) the outcome of encephalitis with the development of solar cells according to the formulas:
LKF1 = -12.1-0.1 * X1 + 10.1 * X2-1.9 * X3 + 5.3 * X4 + 8.4 * X5
LKF2 = -20.1-0.5 * X1 + 4.0 * X2 + 2.1 * X3 + 8.2 * X4 + 10.9 * X5
Where
X1 - the presence of coma in days, 0 - absence;
X2 - foci of structural changes in the brain on MRI: absence of 0 points, presence of 1 point;
X3 - epileptiform activity: absence - 1 point; diffuse sharp waves - 2 points; sharp waves, commissures, reduced complexes, high-amplitude paroxysms of slow activity - 3 points; frequent paroxysms of the “peak-slow wave”, “spike-slow wave” complexes - 4 points;
X4 - irritative activity on the EEG: absence - 1 point; local inconsistent high-frequency beta activity - 2 points; widespread unstable low-amplitude high-frequency activity - 3 points; common long-term high-amplitude high-frequency activity - 4 points;
X5 - etiological agent-causative agent of the disease: encephalitis caused by tick-borne encephalitis virus - 1 point; encephalitis of another and unexplained etiology - 0 points;
and with LKF1> LKF2 predict the outcome of encephalitis without the development of SE, and with LKF2> LKF1 - an adverse outcome of encephalitis with the development of SE.