Vol 14, No 1 (2020)

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Full Issue

Original articles

Chronic disorders of consciousness: terminology and diagnostic criteria. The results of the first meeting of the Russian Working Group for Chronic Disorders of Consciousness

Piradov M.A., Suponeva N.A., Voznyuk I.A., Kondratyev A.N., Shchegolev A.V., Belkin A.A., Zaitsev O.S., Pryanikov I.V., Petrova M.V., Ivanova N.E., Gnedovskaya E.V., Ryabinkina Y.V., Sergeev D.V., Yazeva E.G., Legostaeva L.A., Fufaeva E.V., Petrikov S.S.


Introduction. To date, patients with chronic disorders of consciousness (CDC) represent a serious problem from the medical, social, and economic points of view. Because of the relatively small incidence of this condition, accumulation of the sufficient experience in its diagnosis and treatment remains a complex task, while the lack of a unified approach among Russian specialists to classification of the CDC makes it even harder to solve. At the same time, there are widely used terms overseas that are accepted by the medical community and used in current recommendations.

Aim. Specialists of the Federal State Funded Research Institution, Research Centre of Neurology, have put forward an initiative to create a Russian Working Group for Chronic Disorders of Consciousness, to discuss and approve unified Russian terminology for CDC and criteria for classifying CDC, and to then develop clinical recommendations for the diagnosis and treatment of patients with CDC.

Results. The first roundtable meeting on the issues related to CDC took place at the ХI Russian Congress of Neurologists in June 2019. The attendees included staff members from the FSFRI Research Centre of Neurology, FSFRI Federal Research and Clinical Centre of Intensive Care Medicine and Rehabilitation Medicine, the Polenov Neurosurgical Institute - Branch of the FSFI Almazov National Medical Research Centre, FSFEI HE Ural State Medical University, SFI Saint Petersburg I.I. Dzhanelidze Research Institute of Emergency Medicine, FSAEI HE Pirogov Russian National Research Medical University, SFHI Research Institute of Emergency Paediatric Surgery and Traumatology of the Moscow Department of Health, and the SFHI N.I. Sklifosovsky Research Institute of Emergency Medicine of the Moscow Department of Health. Based on the results of the meeting and voting, a list of terms was composed to describe CDC and the corresponding diagnostic criteria were approved. The roundtable discussion also included the working group’s future plans, and the development of a plan for Russian recommendations for the diagnosis and treatment of the CDC.

Conclusion. The terms and criteria mentioned in the article are recommended for use in clinical practice and research in Russia, for patients with CDC.

Annals of Clinical and Experimental Neurology. 2020;14(1):5-16
pages 5-16 views

Cerebrovascular disorders and glucolipotoxicity

Tanashyan M.M., Antonova K.V., Raskurazhev A.A., Lagoda O.V., Shabalina A.A., Romantsova T.I.


Introduction. Rapid progression of atherosclerosis and, consequently, an increase in the risk of stroke and myocardial infarction are associated with the presence of diabetes mellitus (DM). There is a search for new biomarkers of these pathological conditions, including their preclinical forms, primarily associated with insulin resistance (IR), which underlies these metabolic disorders. Development of the glucose and lipid toxicity is considered as one of the decisive factors in the development of IR and atherosclerotic cardiovascular disease in the presence of disturbances in carbohydrate and lipid metabolism. The negative consequences of isolated glucose- and/or lipid toxicity are less than the presence of both conditions simultaneously, known as glucolipotoxicity. The triglyceride glucose (TyG) index, initially developed to assess such combined changes, is of great interest to researchers as a marker or predictor of diseases associated with IR.

Aim: to investigate the effect of glucolipotoxicity in patients with ischaemic stroke and to determine the diagnostic value of the TyG index.

Materials and methods. The study included 251 people: group 1 (n = 145) — patients with acute ischaemic stroke, and group 2 (n = 120) — patients with carotid atherosclerosis and chronic cardiovascular disease but without stroke or acute coronary disease in the medical history. The control group (n = 86) consisted of people without atherosclerosis or cardiovascular disease. All patients underwent comprehensive clinical, laboratory and imaging tests, including biochemical tests measuring the TyG index.

Results. Insulin resistance was found in all patient subgroups after acute stroke (irrespective of the ischaemic stroke subtype), and it was greater in patients with Type 2 DM (T2DM). The median TyG index value in patients with stroke and T2DM was 5 [4.8; 5.2], compared with 4.7 [4.6; 4.9] in patients with stroke but without T2DM. The TyG index was elevated in all patients with carotid atherosclerosis (median 4.9 [4.7; 5.2]), TyG index was statistically lower in people without atherosclerosis (median 4.6 [4.45; 4.7], p = 0.000).

When the TyG index values were evaluated using ROC curves as a predictor of significant carotid artery stenosis (lumen narrowing of 60% or greater), the area under the curve was 0.821 and the TyG threshold value was 5.3 for patients with T2DM, while these values were 0.9153 and 4.71 for people without T2DM, respectively.

Conclusion. The new method of glucolipotoxicity evaluation by calculating the TyG index has an important diagnostic and predictive role in identifying carotid atherosclerosis, IR, and metabolic syndrome in patients with cerebrovascular disease. This may allow us to stratify the patient categories that require vascular wall investigations, as well as to monitor treatment adequacy.

Annals of Clinical and Experimental Neurology. 2020;14(1):17-24
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Atherothrombotic stroke in women: blood thrombogenicity and the vascular wall

Maksimova M.Y., Chechetkin А.O., Moskvicheva A.S., Shabalina A.A.


Introduction. Haemostasis and functional changes of the vascular wall are the strategic and actively developing aspects in the study of ischaemic stroke pathogenesis.

The aim of current work was to examine the relationship between hormonal status, thrombogenic blood factors, and the structural and functional changes in the vascular wall in women after atherothrombotic stroke in the internal carotid territory.

Materials and methods. Twenty-nine women (mean age 55 years) in the first 3 months after atherothrombotic stroke, diagnosed using the international TOAST criteria, were included in the study. The severity of neurological impairment was evaluated using the NIH Stroke Scale. The follicular stimulating hormone (FSH) and homocysteine levels, along with haemostasis parameters and rheological properties of red blood cells were examined. Ultrasound of the major arteries of the head, assessment of the elastic properties and mural shear stress in the common carotid artery, as well as evaluation of the vasomotor function of the brachial artery endothelium were conducted.

Results. Clinical differences in the atherosclerotic stroke were found in women depending on their FSH levels: moderate and severe neurological impairments were noted when the FSG level was ³30 mIU/mL, while mild impairments were present when the FSG level was <30 mIU/mL. It was found that a high FSH level in women is associated with significant arterial hypertension, obesity and type 2 diabetes mellitus. The group of women with high FSH levels had elevated fibrinogen, homocysteine, von Willebrand factor, erythrocyte aggregation amplitude, along with the accelerated formation of 3D aggregates and increased erythrocyte aggregate strength. In women with insufficient estrogen production in the ovaries (FSH ³30 mIU/mL), the stiffness index of the common carotid artery wall was significantly higher, while the mural shear stress and endothelial vasomotor function were lower than in the group of women with preserved ovarian function.

Conclusions. A link between menopause, increased blood thrombogenicity, and structural and functional changes in the vascular wall (increased stiffness, reduced mural shear stress and endothelial vasomotor function) was found in women after atherothrombotic stroke.

Annals of Clinical and Experimental Neurology. 2020;14(1):25-32
pages 25-32 views

The assessment of cerebral white matter microstructure in cerebral small vessel disease based on the diffusion-weighted magnetic resonance imaging

Kremneva E.I., Maximov I.I., Dobrynina L.A., Krotenkova M.V.


Introduction. Multidimensional or biophysical modelling approaches are actively used to examine the complex microstructure of brain matter in diffusion-weighted MRI, where tissue structures are schematically simplified and divided into separate regions to calculate the diffusion values. This approach demonstrates greater specificity when compared with the widely used diffusion tensor MRI (DT-MRI) and its metrics.

The aim of the study was to compare DT-MRI and the biophysical diffusion models, and to evaluate their possible use in a more precise studying of the affected white matter in cerebral small vessel disease (CSVD).

Materials and methods. We examined 96 patients (including 65 women; mean age 61.0±6.6 years) with CSVD and 23 healthy volunteers, comparable in age and gender (including 15 women; mean age 58±6 years). The patients were divided into 3 groups according to the severity of white matter disease as measured using the Fazekas scale. All study subjects underwent a brain MRI (3 T) with diffusion-weighted MRI (b = 0, 1000 and 2500 sec/mm2, 64 gradient directions) followed by the data processing; we obtained DT-MRI metric maps, as well as white matter tract integrity model and model using the spherical mean technique.

Results. Significant differences were found between the study groups (except groups F0 and F1) in all metrics when the overall value of the white matter skeleton was examined (p £ 0.05): there was a decrease in tissue anisotropy and axonal density in the white matter, as well as increased intra- and extra-axonal coefficients with more severe white matter disease. Analysis of individual white matter regions showed that the radial diffusion values had greater intergroup differences than the axial diffusion values in the corpus callosum (particularly, in the body and splenium).

Conclusion. Biophysical models allow us to evaluate white matter disease in patients with CSVD using structural tissue features and indirect measures of intra- and extracellular diffusion. To clarify and increase the statistical significance of the obtained results, it is necessary to analyse the diffusion metrics using data from a larger patient sample.

Annals of Clinical and Experimental Neurology. 2020;14(1):33-43
pages 33-43 views

Clinical, molecular, and genetic characteristics of the hereditary spastic paraplegia type 3

Rudenskaya G.E., Kadnikova V.A., Beetz C., Proskokova T.N., Sermyagina I.G., Stepanova A.A., Fedotov V.P., Dadaly E.L., Guseva D.M., Markova Т.V., Ryzhkova O.P.


Introduction. The autosomal dominant hereditary spastic paraplegia type 3 (SPG3), associated with the ATL1 gene, is a common form of the hereditary spastic paraplegia (HSP). The molecular genetic and clinical features of the SPG3 have not been sufficiently studied.

Study aim: to conduct the first clinical, molecular, and genetic study of HSP in Russia, using a high-throughput exome sequencing technology — massively parallel sequencing (MPS).

Materials and methods. Study subject: 14 identified families with SPG3. Clinical and molecular genetic methods used: Sanger sequencing, MPS panel for spastic paraplegia, multiplex ligation-dependent probe amplification.

Results. SPG3 made up 7.2% of the 195 examined families, 13.6% of 103 molecularly identified cases, and 16.9% of the dominant forms, coming in second place after SPG4 (>50%). We found 9 missense mutations in 14 families (7 in ‘hot exons’), with 4 new ones and the known p.Arg415Trp mutation identified in 4 families. One case was caused by a de novo mutation, the others were familial; incomplete penetrance was found in 5 families (subclinical cases). Gender distribution of the probands was equal, but there were more males among the affected relatives. Most of the 25 examined patients, as well as the relatives with clinical data, had early-onset (in the first decade of life, often at the age of 1 to 3 years), uncomplicated HSP with slow progression; many of those subjects were initially diagnosed with a cerebral palsy. Subclinical axonal polyneuropathy was found in 3 out of 6 cases using EMG. Atypical severe paraparesis was combined with skeletal pathology (likely independent of the major condition) in one female patient. Intellectual disability in males of another family was also considered to be an independent condition.

Conclusion. SPG3 has a significant prevalence among HSP in Russian patients. The clinical features in most cases are similar and relatively non-severe; clinical diagnosis may be challenging, especially in non-familial and non-apparent familial (incomplete penetrance) cases, as well as when combined with other conditions. An incorrect diagnosis of cerebral palsy is often made. A verified diagnosis is necessary for genetic counselling and is important for patient management. MPS methods are the most informative in the molecular genetic diagnosis of HSP.

Annals of Clinical and Experimental Neurology. 2020;14(1):44-54
pages 44-54 views

The impact of DRD3, HS1-BP3, and LINGO1 gene mutations on the development and clinical heterogeneity of essential tremor in the Sakha Republic (Yakutia)

Govorova T.G., Popova T.E., Tappakhov A.A., Golikova P.I., Danilova A.L., Antipina U.D., Samorseva V.N., Petrova A.Y., Andreev M.E., Lyasheeva N.N.


Introduction. The ETM1, ETM2 and ETM3 loci are linked with the development of essential tremor (ET). It has been established that a mutation in the LINGO1 gene is a significant risk factor for ET development.

The aim of the study was to investigate the role of Ser9Gly polymorphism in the DRD3 gene, the Ala265Gly mutation in the HS1-BP3 gene and rs9652490 polymorphism in the LINGO1 gene in the development and clinical heterogeneity of ET in the Sakha Republic population (Yakutia).

Materials and methods. Thirty-nine patients with a confirmed diagnosis of ET and 48 patients with Parkinson disease were examined. The control group consisted of 87 healthy individuals. Polymorphism carrier status and gene mutations were identified using real-time polymerase chain reaction.

Results. The Ser/Gly genotype with Ser9Gly polymorphism in the DRD3 gene and the A/A genotype with rs9652490 polymorphism in the LINGO1 gene increases the risk of developing ET by 2.35 (p = 0.02) and 2.42 (p = 0.04) times, respectively. Moreover, the A/A genotype of the rs9652490 in the LINGO1 gene increases the risk for ET-plus syndrome by 2.17 times (p = 0.02). Our data didn’t confirm the role of the Ala265Gly mutation in the HS1-BP3 gene in development of the ET.

Annals of Clinical and Experimental Neurology. 2020;14(1):55-61
pages 55-61 views

The use of a pharmabiotic based on the Lactobacillus fermentum U-21 strain to modulate the neurodegenerative process in an experimental model of Parkinson disease

Danilenko V.N., Stavrovskaya A.V., Voronkov D.N., Gushchina A.S., Marsova M.V., Yamshchikova N.G., Ol'shansky А.S., Ivanov M.V., Illarioshkin S.N.


Introduction. Experimental and clinical studies have repeatedly shown the interplay between the intestinal microbiota properties and the nervous system, with a clear link established between changes in microbiota and the development of a neurodegenerative process. It is thought that inflammation and microbiota disturbances provoke the spread of pathological forms of a-synuclein in the nervous system, which is recognized as the main cause of neurodegeneration in Parkinson disease (PD).

Aim of the study: to identify the effect of a pharmabiotic based on a Lactobacillus fermentum U-21 strain in Wistar rats with paraquat-induced parkinsonism.

Materials and methods. Two groups of animals received intra-abdominal paraquat injections (8 doses of 10 mg/kg, every second day for 15 days) and then received orally either a 0.9% NaCl solution, or the U-21 preparation daily for 15 days. The control groups received 0.9% NaCl injections and either a U-21 preparation, or a 0.9% NaCl solution orally under the same regimen. Motor activity was tested in the open field and narrowing beam walking tests. Changes in tyrosine hydroxylase positive enteric plexus fibers and the in quantity of intestinal villi goblet cells were measured morphologically.

Results. Paraquat administration led to a gradual animal death, however, administration of the U-21 increased their survival rate and preserved their motor activity at the level of the control rats. Oral administration of the pharmabiotic only did not alter the animals’ motor activity. Paraquat reduced density of the tyrosine hydroxylase positive fibers and increased the number of goblet cells, while the study drug partially diminished the changes induced by paraquat.

Conclusion. The U-21 preparation demonstrated high biological activity in the neurotoxin-induced model of PD, which justifies further, extended studies of its effects.

Annals of Clinical and Experimental Neurology. 2020;14(1):62-69
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The role of long noncoding RNAs in ischaemic stroke

Novikova L.B., Gareev I.F., Raskurazhev A.A., Beylerli O.A., Minibaeva G.M.


Ischaemic stroke (IS) is one of the leading causes of death and disability in the world. The consequences of IS manifest as severe and persistent neurological symptoms. The currently used methods for the management of IS are insufficient, partly because of incomplete understanding of the molecular mechanisms that occur in IS. Long noncoding RNA (lncRNAs) are noncoding RNAs that are longer than 200 nucleotides. It has been shown that lncRNAs control many processes: transcription, translation, regulation of gene expression, cell cycle regulation, apoptosis, cell proliferation, and differentiation. There is plenty of evidence that lncRNAs play a direct role in the pathogenesis of many human diseases, including IS. LncRNAs are found in the human bodily fluids, such as blood, urine, cerebrospinal fluid, and saliva. The expression profile of these circulating lncRNAs consists of a certain part of the cells, where they are modified and secreted in accordance with the physiological and pathological status of those cells. Due to their various ways of transport from cells into bodily fluids within exosomes or liposomes, lncRNAs are protected from the effect of RNases and remain in a stable form. Because of this, circulating lncRNAs are considered as novel biomarkers, which are of interest in many diseases, including IS. It likely appears that lncRNAs have the potential to be used in the diagnosis, management, and prevention of IS.

Annals of Clinical and Experimental Neurology. 2020;14(1):70-77
pages 70-77 views


Validation of the modified Ashworth scale in Russia

Suponeva N.A., Yusupova D.G., Ilyina K.A., Melchenko D.A., Butkovskaya A.A., Zhirova E.S., Taratukhina A.S., Zimin A.A., Zaitsev A.B., Klochkov A.S., Lyukmanov R.K., Kotov-Smolensky A.M., Khizhnikova A.E., Gatina G.A., Kutlubaev M.A., Piradov M.A.


Spasticity after stroke is a factor that causes disability and restricts activities of daily living, and represents a problem for both doctors and patients’ relatives. At the present time, the modified Ashworth scale (MAS) is a useful method of assessing increased muscle tone in patients after a cerebrovascular incident.

The aim of the work is the linguistic and cultural adaptation of the MAS, with subsequent evaluation of its psychometric properties.

Materials and methods. The study included 50 patients. The validation procedure consisted of linguistic and cultural adaptation and evaluation of the psychometric properties of the Russian language version of the MAS. Test-retest was used to examine reliability (calculating Spearman’s rank correlation coefficient) and Cohen’s kappa coefficient was used to evaluate inter-rater agreement. Criterion validity was assessed by comparing the MAS results with the Spasticity Scale score of the Research Centre of Neurology. Sensitivity was measured using Wilcoxon nonparametric test, which reflects the statistical significance of intertest differences before and after rehabilitation measures.

Results. Test-retest analysis showed a significant correlation (0.87) between reassessment results. Inter-rater reliability was average (0.56), which confirms the scale’s subjectivity and proves that patient assessment over time should be performed by the same investigator whenever possible. The correlation coefficient between the MAS and the Spasticity Scale of the Research Centre of Neurology was 0.79. Statistically significant differences were found when patients were reassessed after rehabilitation treatment (p<0.0001).

Conclusion. The Russian version of the MAS is a valid, reliable, and sensitive instrument, which can be recommended for use in clinical practice, both for the initial assessment of spasticity and for monitoring the effect of treatment.

Annals of Clinical and Experimental Neurology. 2020;14(1):89-96
pages 89-96 views

Interventional therapies for the chronic pain in degenerative spine conditions

Gushcha A.O., Gerasimova E.V., Vershinin A.V.


Back pain due to degenerative spine conditions is one of the most common causes for seeking medical care. Standard pharmaceutical and physiotherapy interventions are offered to manage the pain. However, those approaches can be insufficient, and interventional therapies may be used in addition to standard treatment. The main principle of the interventional therapy is administering the medication directly to the affected part of the spinal segment. The article reviews the main interventional techniques, their indications, and differences between them.

Annals of Clinical and Experimental Neurology. 2020;14(1):78-88
pages 78-88 views

Clinical analysis

Nonconvulsive status epilepticus with triphasic wave EEG pattern: a case report

Baranova E.A., Danilova T.V., Khalitov I.R., Sinkin M.V.


Introduction. Triphasic waves in an electroencephalogram (EEG) in patients with decreased alertness traditionally is associated with hepatic encephalopathy. The development of digital technologies and the introduction of systems that allow long-term EEG monitoring of the neurocritical care patients has led to accumulation of significant experience in recording triphasic waves in various metabolic, toxic, and structural brain disorders, as well as in nonconvulsive status epilepticus.

Materials and methods. We present a case of diagnosis and successful treatment of a nonconvulsive status epilepticus, that developed in a female patient after CABG, and that presented electrographically as a triphasic wave pattern.

Results. Description of the patient’s EEG according to the classification of rhythmic and periodic patterns of the American Clinical Neurophysiology Society and the use of clinical and EEG criteria of nonconvulsive status epilepticus of the International League Against Epilepsy enabled us to correctly diagnose the cause of her decreased alertness and other neurological symptoms. Proper selection of the antiepileptic drugs along with monitoring of daily EEG recordings led to a recovery of consciousness in the patient and to normalization of the EEG pattern, which confirmed the clinical hypothesis of a nonconvulsive status epilepticus.

Conclusions. Utilization of the modern clinical and electrographic classifications enables the diagnosis of a nonconvulsive epileptic seizure and status epilepticus when the EEG pattern is ambiguous and traditionally associated with other conditions. EEG monitoring must be performed in patients with a sudden deterioration of consciousness that cannot be explained by brain imaging studies.

Annals of Clinical and Experimental Neurology. 2020;14(1):97-103
pages 97-103 views

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