RU2790195C1 - Method for neuroimaging prediction of the outcome of viral encephalitis in children in the acute period of the disease - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to medical neuroimaging, and can be used for neuroimaging prediction of the outcome of viral encephalitis in children in the acute period of the disease. In children in the age group from 3 months to 12 years in the acute period of the disease, a multiparametric MRI of the brain with diffusion-weighted sequences (DWI) is performed and the indicator of the measured diffusion coefficient (CDI) in the inflammation focus is determined. With a focus size of more than 10 mm, with an ACD value in the center of the focus less than 0.54×10^-3 mm²/s and less than 0.6×10^-3 mm²/s along the periphery, an unfavorable course of encephalitis is predicted.

EFFECT: method provides a prediction of the outcome of viral encephalitis in children by quantifying diffusion in the focus of inflammation.

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Description

The invention relates to the field of modern medical neuroimaging and can be widely used in clinical practice, in infectious diseases hospitals, neurological departments as a prediction of the outcome of focal brain damage and ischemic changes in the brain with encephalitis in children.

Viral encephalitis is a widespread form of infectious lesion of the central nervous system in children, which is of great clinical importance. Viral encephalitis is characterized by a severe course and is a common cause of death and disability in patients, including children. Currently, magnetic resonance imaging (MRI) is the method of choice for differential diagnosis and follow-up of acute CNS infections in children.

In addition to direct viral damage to the substance of the brain, ischemic changes are observed in the focus of inflammation. When carrying out the DWI technique, it is possible to detect vasogenic and/or cytotoxic edema in the foci of inflammation, which occurs in response to a violation of aerobic processes and characterizes the degree of damage to the brain tissue.

At the same time, according to the literature, there are no clear criteria for MRI indicators to predict the outcome of viral encephalitis.

Viral encephalitis is characterized by a severe course and is a common cause of death and disability in patients, including children, so it is important to timely identify changes in the substance of the brain in the acute period, which can lead to an unfavorable outcome and adjust and intensify therapy in time to minimize the risk of complications. further.

Currently, a study is known with an analysis of the prognosis of the outcome of cases with Japanese encephalitis in adults (T.N. Wang, J.Chen, G.X. Wang et al. Prognosis analysis of 112 cases with Japanese encephalitis in adults // Chinese medical journal. 2020. - V 100 (7) - P. 541-545 doi: 10.3760/cma.j.issn.0376-2491.2020.07.013). The authors carried out a thorough collection of clinical and anamnestic data; MRI was used as an imaging technique. The neurological status was assessed 6 months and 1 year after the onset of the disease. Neurological functional recovery was assessed using a modified rating scale (mRS). However, in patients at the outcome of the disease, only neurological status was assessed and division into groups with good and poor prognosis based on primary clinical manifestations, laboratory data and MRI of the brain with the determination of two predictors of poor prognosis, such as cerebrospinal fluid pressure > 250 mm H( 2)O and the presence of a midbrain lesion on MRI.

Another analogue is the study of MP-characteristics of inflammatory foci in the brain (Feng Chen, Jianjun Li, Tao Liu et al. MRI characteristics of brainstem encephalitis in hand-foot-mouth disease induced by enterovirus type 71-Will different MRI manifestations be helpful for prognosis ? // European Journal of Pediatric Neurology. 2013. - V. 17 (5) - P. 486-491. doi.org/10.1016/j.ejpn.2013.03.004), in which foci of stem encephalitis in the acute period of the disease in children were classified into 2 types of severity depending on the intensity of the MP signal on T1-WI, T2-WI, and the clarity of the contours of the foci. In the first group, which included patients with a serious condition, the patients had neurological complications in the outcome of the disease, and several of them died in the acute period of the disease. In the second group, with less pronounced changes on MRI, the outcome of the disease was a complete recovery and several cases of mild neurological deficit. However, assessment of lesions based on structural MRI sequences alone is not objective and depends largely on the experience of the radiologist, making it difficult to determine the extent of brain damage. This method does not provide prediction accuracy.

Closest to the proposed method is the study of diffusion-weighted images in encephalitis caused by the herpes simplex virus (Sener RN Herpes simplex encephalitis: diffusion MR imaging findings // Computerized Medical Imaging and Graphics. 2001. V. 25 (5). - P. 391 -397). The study evaluated 5 MRIs of patients with herpes simplex encephalitis, obtaining DWI data and a numerical index of ACD at the lesions. In lesions with acute ischemia, values of 0.18-0.56 (0.37±0.18)×10 ^-3 mm ² /s were obtained, indicating cytotoxic edema; and values of 1.18-2.22 (1.58±0.27)×10 ^-3 mm ² /s, indicating vasogenic edema. With regard to the prognosis of herpes encephalitis in patients with cytotoxic edema in the foci of inflammation, the prognosis was unfavorable compared to patients in whom vasogenic edema was detected in the foci of inflammation. However, this method does not allow us to talk about statistically significant results, and a large range of age indicators among the presented patients does not allow us to trace the course and outcome of encephalitis in children, which is difficult to use in pediatric practice. Thus, the method does not provide accuracy in predicting the outcome of viral encephalitis in children.

In order to eliminate the above disadvantages, the authors propose a fundamentally new method for neuroimaging prediction of the outcome of viral encephalitis in children in the acute period of the disease. carrying out diffusion-tensor research.

As a result of many years of experience in the field of treatment in children with organic lesions of the central nervous system and analysis of the results of treatment, diagnosis of focal lesions of the brain, with encephalitis in children, the authors found that the development of a method for predicting viral encephalitis in children makes it possible to timely optimize the tactics of managing such patients, which is of social importance due to the high incidence of morbidity in comparison with adult patients, pronounced neurological consequences and the cause of a high mortality rate. A significant role in the pathogenesis of these diseases is played by a comprehensive assessment of research data. To develop this method, we were prompted by many years of experience in the field of differential diagnosis of viral encephalitis in children.

We have shown that the use of DWI with the determination of ACD is the most informative MRI technique, which makes it possible to reliably assess cerebral ischemia in any etiology of hypoxia, including infectious inflammation.

Based on the results obtained in acute focal brain lesions caused by viral encephalitis, the authors for the first time reliably proved that there is a correlation between the ACD index and the severity of the existing focal neurological symptoms in children with viral encephalitis in comparison with the control group.

The authors reliably proved that the diffusion-weighted study (DWI) is an MRI technique that allows quantifying the degree of involvement of the brain substance, including the conduction system, in the pathological process during the infectious process of the CNS, allows you to control the dynamics of the identified changes during the treatment of the disease with the possibility evaluation of the effectiveness of treatment, which is of paramount importance when choosing the tactics of managing a patient and the frequency of clinical, laboratory and neuroimaging monitoring of his condition.

The authors for the first time made a correlation between the severity of ischemia of the brain substance in the focus of inflammation in the acute period of the disease and the degree of neurological deficit in children of different ages in the outcome of encephalitis and determined the ACI value, less than which the prognosis is characterized as unfavorable.

The advantage of using the DWI technique is its universal availability, ease of measurement during post-processing, and high sensitivity to cerebral ischemia. With a comprehensive assessment of clinical, neurophysiological, biochemical, virological parameters, MRI of the brain provides a clear diagnosis of encephalitis in the acute period of the disease and makes it possible to predict the outcome of the process, and therefore therapy can be intensified to reduce negative effects. We have not found a similar method in the available literature.

Children in the age group from 3 months to 12 years old with a complex diagnosis of encephalitis undergo an MRI of the brain.

The standardized multiparametric brain MRI protocol includes T2-WI, FLAIR, SWI, DWI, 3D T1-WI programs before and after intravenous contrast enhancement, as well as DTI, MRS, T2*-perfusion. The total study time averages 35 minutes.

If necessary, and in order to exclude motor artifacts, intravenous anesthesia is used by an anesthesiologist with monitoring of vital functions (pulse rate, respiration, ECG, SpO ₂ ) throughout the study. For intravenous contrast, a paramagnetic contrast agent based on the active substance dimeglumine gadopentetate is used, which has a good safety profile and is approved for use in children of all ages. The contrast agent is administered intravenously at a dosage of 0.1 mmol/kg of the patient's body weight.

If focal changes in the brain substance are detected in a patient with a laboratory-confirmed viral infection during post-processing data processing of an MP study, the ACD value in the lesion is measured. CDI is a quantitative characteristic of diffusion (movement of water molecules) in tissue and is calculated from diffusion-weighted images (DWI), this value is estimated by changing the gradient of the curve, which is built by comparing different values of the b-factor. If an ACD value is detected in a focus larger than 10 mm, less than 0.54×10 ^-3 mm ² /s in the center and less than 0.6×10 ^-3 mm ² /s along the periphery, an unfavorable course of encephalitis is diagnosed.

According to the ROC analysis, the ACD value in the center of the focus is ≤0.54×10 ^-3 mm ² /s and along the periphery ≤0.6×10 ^-3 mm ² /s (with a focus size of more than 10 mm) in the acute period of encephalitis turned out to be a very good predictive model for the development of an unfavorable outcome of encephalitis (sensitivity 77.8%, specificity 94.4%, AUROC>0.8, p<0.01) (Figure 1).

The grading for adverse and favorable outcome of encephalitis is based on the GMFCS scale, which assesses spontaneous movements with an emphasis on the ability to sit, move and move around; presence/absence of epilepsy, socialization of patients. Also, patients in the period of late convalescence underwent a control MRI of the brain with an assessment of structural changes.

An unfavorable outcome is determined at level 5, characterized by physical limitation of movement, motor functions, the need to use a wheelchair and assistive adaptive devices to hold the body.

Also, patients in the period of late convalescence underwent MRI of the brain, EEG.

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

Example 1

Patient E., 5 years old.

Diagnosis - G04.8 - Herpetic meningoencephalitis. OGM. Symptomatic epileptic convulsions.

Anamnesis of the disease: on August 30, 2019, febrile fever, repeated vomiting, NSAIDs were taken to stop the fever. In the evening of the same day, repeated vomiting, after which the patient was hospitalized in the infectious diseases department with suspected AII. On 09/01/2019, the appearance of generalized tonic-clonic convulsions against the background of normothermia was stopped by IV Relanium. The next day, a repeated episode of convulsions against the background of an increase in body temperature. On 09/04/2019, a lumbar puncture was performed, the results of which determined pleocytosis 22/3 of a neutrophilic nature, protein 0.033, sugar 3.2. In the cerebrospinal fluid, PCR detected DNA of the herpes virus types 1.2. Blood ELISA: IgM to herpes simplex virus type 1. Started antiviral, anticonvulsant, symptomatic therapy.

An MRI of the brain dated September 6, 2019 (day 7 from the onset of the disease) visualized an extensive area of cytotoxic edema in the left temporal lobe with a decrease in the ACD value to 0.35 × 10 ^-3 mm ² /s with involvement of the medial part of the left occipital lobe with decrease in ICD to 0.37×10 ^-3 mm ² /s, parietal lobe to 0.4×10 ^-3 mm ² /s (Fig. 2). The obtained ADC values characterize the cytotoxic cerebral edema in response to ischemia in the focus of inflammation. The authors predicted an unfavorable outcome of encephalitis on the basis of the obtained MRI data due to the low values of the ACD index (less than 0.54-0.6×10 ^-3 mm ² /s), since such values in the outcome of the process lead to the destruction of the brain substance.

After 1 year, the patient underwent an EEG, the results of which determined regional epileptiform activity in the form of COMV locally in the central parietal, and central and posterior temporal regions.

Example 2

Child T., 2 years, 6 months.

Diagnosis - G93.8, Generalized herpesvirus infection with lesions of the central nervous system (encephalitis), heart, liver, severe form (PCR - HSV type 1/6). Anamnesis of the disease: She has been ill since July 26, 2019, when subfebrile temperature appeared, which was stopped by medication. The next day there was a febrile temperature, hand tremor, cyanosis of the lips, vomiting 1 time and loose stools. On July 28, 2019, the body temperature increased to 38.7C, lethargy increased, there was a lack of response to examination and pain stimuli. Due to the severity of the condition, the patient was transferred to the ICU on a ventilator. During laboratory examination: during the etiological examination of blood and cerebrospinal fluid, PCR was detected in the blood for type 6 hepatitis B and IgM for herpes simplex virus type 2.

MRI of the brain on the 5th day of the disease visualized asymmetric zones of structural changes in the visual tubercles (D>S), in both hemispheres of the cerebellum, in the periventricular white matter of the cerebral hemispheres, in the pons Varolii in the form of an inhomogeneous increase in the MP signal on FLAIR. When performing DWI, the ICD value was reduced to 0.3×10 ^-3 mm ² /s in the periventricular white matter of both hemispheres, to 0.5×10 ^-3 mm ² /s in the left cerebellar hemisphere, to 0.46×10 ^-3 mm ² /s in the brainstem (Fig. 3). The obtained ADC values characterize the cytotoxic cerebral edema in response to ischemia in the focus of inflammation. In this example, the authors also predicted an unfavorable outcome of the course of encephalitis on the basis of the obtained digital indicators of the ICD, less than 0.54-0.6×10 ^-3 mm ² /s.

In dynamics, after 1 year, a control MP-study was carried out, according to the results of which cystic-glial residual changes were detected in the foci of inflammation in the outcome of the disease (Fig. 4). In the neurological status of the patient, mixed tetraparesis, gross delay in psychomotor and speech development, epilepsy, and partial atrophy of the optic nerves were noted.

This example demonstrates that, according to the results of the primary MRI, a pronounced decrease in the ACD in the foci of inflammation ultimately led to the destruction of the brain substance and the neurological deficit associated with this.

The use of the method proposed by the authors will make it possible to predict the outcome of focal brain changes in viral encephalitis in children, due to the ability to assess the severity of ischemia in inflammatory foci, will allow monitoring changes in the brain substance during treatment, which will make it possible to correct therapy in a timely manner and, thereby, will help to minimize neurological deficit and the development of disabling complications of the disease.

This method of prediction does not require additional equipment, technical capabilities, which will allow the use of the technique in routine clinical practice of radiology departments equipped with MRI with a magnetic field strength of 1.5 T and higher.

The method is a sensitive, specific and reproducible method of multiparametric MRI in the assessment of cerebral ischemia in the complex diagnosis of encephalitis in children and allows to predict the outcome of the disease.

Claims (1)

A method for neuroimaging prediction of the outcome of viral encephalitis in children in the acute period of the disease, including clinical and neurological examination, multiparametric MRI of the brain, characterized in that in children in the age group from 3 months to 12 years in the acute period of the disease, a multiparametric MRI of the brain is performed with diffusion-weighted images, determine the indicator of the measured diffusion coefficient in the focus of inflammation and with a focus size of more than 10 mm, with an ACD value in the center of the focus less than 0.54×10 ^-3 mm ² /s and along the periphery less than 0.6×10 ^-3 mm ² /s, corresponding to ischemia in the foci of inflammation, predict an unfavorable outcome of encephalitis.

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