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Mexidol: use of the drug
in chronic cerebral ischemia

What is chronic cerebral ischemia (CCI)?

Chronic cerebral ischemia is a slowly progressive structural and functional
change in the brain that occurs as a result of diffuse and/or focal
damage to brain tissue in the context of long-term cerebral
blood flow insufficiency [1]. CCI is not an independent disease; it is a cerebrovascular
complication of various pathological cardiovascular processes.



Sequential therapy with Mexidol® and Mexidol® FORTE 250 demonstrated
a high degree
of efficacy and safety in an international multicenter,
randomized, double-blind
, placebo-controlled study evaluating
the efficacy and safety of sequential therapy
in patients with chronic
cerebral ischemia.

Read the study

Terminology and classification

In foreign neurological practice, chronic cerebral ischemia is not considered as an independent nosological entity, but vascular cognitive impairments are distinguished, which are considered the main clinical manifestation of chronic cerebrovascular disease [2]. In the latest classification of syndromes and diseases of mental disorders (DSM-5), among vascular cognitive impairments, moderate vascular neurocognitive disorder and major vascular neurocognitive impairment (vascular dementia) are distinguished [3]. In Russia, several schools of neurology have historically developed, and in each of them this brain dysfunction is designated differently. The terms "chronic cerebral ischemia", "cerebrovascular insufficiency", "chronic cerebrovascular disease (CCVD)", "chronic cerebral circulatory failure", "ischemic brain disease", "vascular encephalopathy", "atherosclerotic encephalopathy" are used [1]. In ICD-10, chronic forms of cerebrovascular diseases are described in the chapter “Pathology of the circulatory system” in the section (I67.0 – I67.9) “Other cerebrovascular diseases”, which looks like this [ICD 10 – Other cerebrovascular diseases (I67) (mkb-10.com)] : 

  • I67.2: cerebral atherosclerosis (as independent nosology is not used); 
  • I67.3: progressive vascular leulyopalopalopathy (in the absence of dementia; otherwise it is classified as Binswanger's disease); 

  • I67.4: hypertension encephalopathy (used only for acute conditions, for example, with hypertensive crisis);
  • I67.8: Other specified disorders of cerebral vascular disease - cerebral ischemia (chronic).

The consequences of cerebrovascular diseases (I69.0 - I69.8). The symbol “i67.3: progressive vascular leukoencephalopathy, as a rule, is encoded by Binswanger's disease - a chronic progressive brain disease associated with damage to the white substance of the cerebral hemispheres, which develops against the background of a vascular risk factor (usually with hypertension) or signs of a systemic disease) vascular disease. The symptoms of the disease have a steady-proceeding with possible periods of prolonged stabilization. To make a diagnosis, it is necessary to have cognitive disorders that reach the degree of dementia in the later stages, as well as mandatory confirmation by the methods of neuroimaging [4].

Currently, in clinical practice, it is customary to use the classification of chronic brain ischemia according to the stages depending on the severity of the clinical picture [5]. This classification will be considered in the "Clinical Picture" section.

Epidemiology

Today, chronic brain ischemia is one of the most common diagnoses in Russia in both neurological and general -in -Russian practice and the most common diagnosis among a group of cerebrovascular diseases [6]. The high prevalence of a group of cerebrovascular diseases and, therefore, chronic brain ischemia confirm the data of Rosstat [7].

Thus, in 2022, there were 6.65 million people in Russia suffering from
cerebrovascular diseases. The number of people with newly diagnosed
cerebrovascular diseases this year amounted to more than 1.1 million.

Mortality from Cerebrovascular diseases (I60 - I69) in 2022 amounted to almost 250 thousand people. In the period from 2010 to 2022, a picture of a sustainable decrease in mortality from cerebrovascular diseases was observed, which is probably largely associated with the active development and implementation of the vascular program in the Russian Federation, as well as the introduction of new medical diagnostic methods and algorithms into the clinical practice.

Nevertheless, this problem remains one of the most relevant. The high frequency of comorbid conditions and diseases that predispose to the development of chronic brain ischemia, the association with the risk of stroke and dementia increase the disability of patients [8]. 

Etiology and pathogenesis

Currently, an idea of ​​the multifactorial mechanism for the development of Khim has been formed.

etiological factors in the development of chronic cerebral ischemia
are: arterial hypertension, atherosclerosis and
their combination, as well as venous outflow disorders and diabetes mellitus [9].

As a rule, one patient has a combination of several risk factors, and it is difficult to evaluate a separate contribution of each of them. Moreover, no risk factor can fully explain the severity of neurological disorders or the nature of the course of the disease, which confirms the complexity of the mechanisms of its occurrence and progression.

It is noted that any somatic pathology can aggravate the course of the disease. Social factors, emotional status (the presence of depression or anxiety), the standard of living [10] are also of great importance. The main risk factors are presented in table 1 [5, 6]. 

Unorrogative risk factors


Elderly age

Male Paul

Genetic factors

Previously suffered stroke or myocardial infarction

Modifiable
risk factors


Arterial hypertension

Atherosclerosis

Diabetes

Dyslipidemia

Violation of the rheological properties of blood

Factors associated with the way of life: 

  • smoking;
  • excessive drinking;
  • excess body weight;
  • low physical activity;
  • irrational nutrition

Table 1. Risk factors of chronic brain ischemia

The brain is most sensitive to the pathological changes that occur with
hypertension. Almost half of patients with hypertension
have "small vessel disease" or "silent" brain damage.

Long -existing, incorrectly treated arterial hypertension leads to an increase in the tone of arterioles and general peripheral resistance in the vessels of the microcirculatory channel. In addition, patients develop morphological changes in the vascular wall: the thickening of the wall (lipohyalinosis), the formation of microanevrism, apologia and excess of arteries, endothelial dysfunction, and the reactivity of the vessels changes [5]. With a combination of arterial hypertension with type 2 diabetes mellitus, the processes of deformation of the vascular channel are significantly exacerbated, which accelerates the development of atherosclerosis due to the activation of fibrosis and impaired myogenic auto-regulation of the lumen of the vessel [11]. Thus, the basis of chronic brain ischemia is a pathology of a small caliber vessels, which is a classic microangopathy. The most vulnerable are long perforant cerebral vessels. Therefore, the first morphological and radiological signs of chronic brain ischemia are usually detected in the region of subcortical gray nodes and the deep parts of the white substance of the brain [12]. 

The main pathogenetic mechanisms of the chronic progressive vascular lesion of the brain are repeated brain heart attacks without a stroke clinic (“dumb heart attacks”), micro -power and diffuse changes in white matter (leukeoireosis). Mute heart attacks are detected in 5–40 % of people over 40. Their cause is most often arterial hypertension [13]. Micro -power is the result of the diampower impregnation of the plasma and uniform elements of the blood through the vascular wall. The presence of micro -power states indicates the special nature of inflammatory changes in the vascular wall, accompanied by increased permeability of the hematoencephalic barrier [14]. The diffuse changes in the periventricular white substance of the brain (leulyoiresis, vascular leulyoencephalopathy) are determined in people over 55 in 28–94 % of cases, and subcortical white matter is found in 48–97 % of patients [15]. According to general confession, arterial hypertension and other vascular diseases are proved by risk factors of leulyaureosis. However, his pathogenesis continues to be clarified [12]. 


The brain is a complex multi -level system that operates, depending on the level of the energy metabolism that is flowing in it, determined primarily by the flow of oxygen and glucose blood flow. The need for the brain for oxygen and glucose is determined by the intensity of its functional activity [16]. The development of morphofunctional changes in chronic brain ischemia is due to insufficiency of cerebral circulation (hypoperfusion). It can be in a relatively stable form or in the form of repeated short -term episodes of discication, which can be asymptomatic or manifested by clinically [10]. In conditions of chronic brain hypoperfusion, compensation mechanisms are depleted, the energy support of the brain becomes insufficient, as a result of which functional disorders, and then irreversible diffuse morphological changes in the brain, first develop. The degree of structural changes in the brain during discirculation can fluctuate from changes in individual neurons, gliocytes and white fibers to heart attacks of various sizes and localization, which is eventually manifested by focal changes in the brain, diffuse changes in white matter and cerebral atrophy [17].

The deficiency of blood supply in chronic brain ischemia is currently associated with structural-functional changes in the so-called neurovascular units. They are functionally closely interconnected neurons, astrocytes and vascular cells (endotheliocytes, smooth muscle cells, pericitis). The close interaction of cerebral vessels with neurons is mediated by glial cells, primarily astrocytes. Thanks to the conjugation of the activity of the components of neurovascular units, the phenomenon of functional hyperemia is realized - an increase in perfusion of the currently working area of ​​the brain at the moment [18]. Chronic brain ischemia is characterized by a violation of the functioning of neurovascular units as a single whole associated with the functional separation of their main elements [19]. Violation of the activities of neurovascular units is already noted at the early stage of chronic brain ischemia. Moreover, one of the most important factors leading to a violation of neurovascular mechanisms can be endothelial dysfunction at the level of small vessels. It is it that causes a decrease in the reactivity of the vessels and, accordingly, the deficiency of perfusion of activated areas of the brain [20]. 

Clinical picture

Khim is characterized by a progressive course with a gradual increase in neuropsychiatric disorders with a combination of various complaints of the patient and objectively identified cognitive disorders, neurological symptoms and syndromes (vestibular-auto, pyramidal, amyostatic, pseudobulbaric) and emotional affective disorders, the nature and severity of which largely reflect the stage development of the pathological process.

The core clinical picture of chronic cerebral ischemia and its distinctive
feature are cognitive impairments, which are detected already in stage I and progressively
develop concurrently
motor and emotional disorders

Chronic brain ischemia has a progredient course and is divided by the severity of symptoms in three stages (Table 2) [5, 6]. It is characteristic that with the progression of chemicals against the background of an increase in objective symptoms, the number of complaints, especially reflecting cognitive abilities (memory impairment, attention) decreases.

The main features

Complaints

Cognitive disorders

Motor disorders

Disability

Household dependence

Stage I

+/++

Lungs

Light and moderate

The patient is able to work

Independent

Stage II

+/++

Moderate

Mild, moderate
or severe

Partially able -handed / disabled

Can be partially dependent on others

Stage III

+

Significantly expressed
(dementia)

Moderate or
severe

Inappropriate

Depending on others

The main features

Complaints

Cognitive disorders

Motor disorders

Disability

Household dependence

Stage I

+/++

Lungs

Light and moderate

The patient is able to work

Independent

Stage II

+/++

Moderate

Mild, moderate
or severe

Partially able -handed / disabled

Can be partially dependent on others

Stage III

+

Significantly expressed
(dementia)

Moderate or
severe

Inappropriate

Depending on others

Table 2. Stage of chronic brain ischemia

Stage I
(early, mild)

It is characterized by the predominance of polymorphic subjective disorders in the form of headaches and the feeling of heaviness in the head, dizziness, general weakness, increased fatigue, emotional lability, sleep disturbances and other complaints. When examining the cognitive status at this stage, disorders of control functions, attention, and light disorders of the mnestic sphere may be determined. Focal neurological symptoms during this period are manifested by reflexes of oral automatism, weak convergence of eyeballs, sometimes anisoreflexion, decrease in postural stability, reducing the length of the step, and slowness of walking. At this stage, as a rule, there is no formation of distinct neurological syndromes, an important component of the clinical picture is asthenic syndrome. The vital activity of patients under normal conditions is not disturbed. Difficulties can occur only with increased emotional, intellectual and physical activity. 

Stage II
(moderate)

It differs from the first appearance of clear neurological symptoms. It includes reflexes of oral automatism, the central paresis of the VII and XII nerves, oculomotor and coordinator disorders, mild pyramidal failure or extrapyramidal symptoms - hypomymia, oligobradicinesia and others. 1-2 moderate leading neurological syndromes are gradually formed: dysmnestic, discoordinative, extrapyramidal, and so on. Complaints become less pronounced and not so significant for the patient. A more distinct decrease in cognitive functions (attention, thinking, the ability to plan and control their actions), as well as an increase in asthenic and emotional disorders, is characteristic. Light pelvic disorders in the form of rapid urination at night and other manifestations of the hyperactive bladder may take place. The patient has a decrease in professional and social adaptation, but at the same time the ability to self -service is preserved. 

Stage III
(pronounced)

It is characterized by a decrease in the volume of complaints (due to a decrease in criticism of patients to their condition), the presence of clinical signs of three or more neurological syndromes (pyramidal, discoordinator, pseudobulbar, amyostatic, psycho -organic), more pronounced than at the II stage of the disease, as well as paroxysmal states ( falls, fainting, less often epileptic seizures), and a frequent violation of control over the function of the pelvic organs. Cognitive disorders become clinically significant, which usually reach the degree of dementia and are accompanied by a gross emotionally personal defect: a sharp decrease in criticism, apathy-abedic syndrome, disorder, explosiveness. Such patients are usually disabled, their social and household adaptation is significantly violated, often they need extraneous care. 

Diagnostics

The diagnosis of chronic brain ischemia is based on the identification of a causal relationship between a violation of cerebral blood supply and clinical, anamnestic or determined by instrumental techniques with signs of brain damage in the progression of the disease [21]. The causal relationship between the clinical picture and the vascular damage to the brain is confirmed by the features of the clinical picture (for example, the subcortical-red type of cognitive defect or a combination of a cognitive defect with early manifesting walking or pseudobulbar symptoms); compliance of the changes in the brain of vascular genesis (taking into account their localization or prevalence) with clinical manifestations that are detected during CT/MRT; features of the course of the disease, which indicate its vascular nature (step -like progression with alternating episodes of rapid deterioration, partial regression and stabilization); the exception of other diseases that can explain the existing clinical picture.

Diagnostic minimum during the examination of patients with chronic brain ischemia, in addition to the general somatic and traditional clinical and neurological study, should include neuropsychological testing, CT/MRI of the brain, ultrasound dopplerography of blood vessels (arterium) of the head and neck with duplex scanning of Extra and intracranial vessels [ 19]. To study the cognitive status of patients and the establishment of the severity of cognitive disorders, neuropsychological testing is necessary. In outpatient practice and hospital, it is recommended to use brief questionnaires, rating scales, allowing to determine the presence, type of cognitive disorders and assess the degree of their severity.


For screening of vascular cognitive impairment, it is currently recommended to use the Montreal Cognitive Assessment (MoCA), which has high sensitivity for mild (pre-dementia) cognitive impairment of the subcortical type [12]. The following scales and tests have also become widely used [19, 22, 23]:


CT or MRI of the brain in patients with chronic brain ischemia allow you to exclude an extra- and intracerebral tumor, hydrocephalus, other diseases, as well as to obtain evidence of disorders of vascular genesis, which include [24]: 

01

Diffuse white matter lesion
(leukoaraiosis) in
the periventricular zone,
optic radiation, and
semiovale center; 

02

Multiple lacunar foci
(3–15 mm in size) in the basal ganglia,
thalamus, pons, cerebellum, internal
capsule, and white matter of the frontal lobes,
reflecting pathology of small arteries;

03

Larger cortical
and subcortical infarcts
reflecting pathology
of large vessels; 

04

Secondary brain atrophy,
manifested
by the expansion of the ventricular
system and cortical sulci.

Treatment

The purpose of the treatment of chronic brain ischemia is the rupture of the pathogenetic mechanisms of the formation and progression of cerebrovascular failure, which will contribute to stabilization and, if possible, the regression of the clinical manifestations of the disease [25]. The main directions in the complex treatment of patients with chronic brain ischemia are [6, 21]: 

  • prevention of stroke and prevention of progression of brain vessels and substances of the brain (elimination of corrigered risk factors - arterial hypertension, dyslipidemia, hypergomocystinemia, diabetes, etc.); 
  • mobilization of hemodynamic and cognitive reserves (improvement of brain perfusion and rheological characteristics of blood); 
  • protection of nerve cells from damage in conditions of hypoxia - neuroprotection; 
  • adequate correction of concomitant somatic pathology, especially cardiac (arrhythmias, chronic heart failure, etc.); 
  • Symptomatic treatment, i.e., correction of individual syndromes and symptoms of the disease.

Among non -operational methods, the refusal of smoking or a decrease in the number of smoked cigarettes, the cessation of alcohol, regular physical activity, and effective treatment of arterial hypertension and diabetes mellitus are of leading importance. Long -term education, mental work create a cerebral reserve that allows you to slow down the clinical manifestations of organic brain damage and, thereby, slow down the progression of cognitive impairment and reduce the risk of dementia [26]. Proper nutrition plays an important role in the prevention of many diseases associated with age. The introduction of a large number of fruits and vegetables, vegetable oils, sea products and limiting the consumption of products rich in cholesterol reduces the risk of stroke and associate with a decrease in the progression of cognitive impairment [27]. Complex therapy of chronic brain ischemia in Russia includes antioxidants, drugs that optimize brain metabolism, vasoactive agents. To stop depressive and anxious disorders, antidepressants and anxiolytics are used. With clinically pronounced asthenia, antiasthenic agents are possible [28]. 

An important component of the treatment of chronic cerebral ischemia is
the administration of drugs with multimodal action, as well as
antioxidant, antihypoxic and neuroprotective activity.

The justification for multimodal pharmacotherapy is multifactorial etiology and pathogenesis of chronic brain ischemia, requiring the treatment of somatic pathology, as well as the risk of polypragmasis to develop drugs with a similar action mechanism [29]. A bright representative of drugs with a multimodal action mechanism is Mexidol® (original ethylmethylhydroxypyridine succinate) [22]. Treatment of brain ischemia with Mexidol® allows you to stabilize the patient's condition and reduce the clinical manifestations of the disease. Mexidol® is a unique development of the domestic pharmaceutical industry and has a 25-year clinical experience in successful use in various fields of medicine [30]. The mechanism of action of the drug Mexidol® is due to a combination of pharmacological effects: antioxidant, antihyplance and membrane -stabilizing. Penetrating through the hematoencephalic barrier, Mexidol®, with brain ischemia, enters the nerve cells and concentrates in mitochondria, which ensures its high pharmacological activity. Due to the multifactorial mechanism of action and a wide range of pharmacological effects, the drug is given by nootropic, anti -amnestic, anti -aircraft and other clinical effects, and also positively affects the blood supply to the brain, improving the rheological and hemocoagulation properties of the blood [29].

The proven effectiveness of the drug Mexidol® and its high security profile are confirmed in numerous studies, including double blind multicenter placebo-controlled (RCTs "Epica", 2017; MEMO RKI, 2021, RCT "Mega", 2022 g. .) that have high levels of reliability of evidence and persuasiveness of recommendations [31, 32, 33]. Consistent therapy with Mexidol® and Mexidol® Forte 250 showed a high degree of efficiency and safety in the international multicenteric randomized double blind placbo-controlled study of the effectiveness and safety of sequential therapy of patients with chronic brain ischemia-memo. Mexidol® for brain ischemia was used intravenously (500 mg) once a day for 14 days, followed by the oral administration of the drug Mexidol® Fort 250 in a dose of 250 mg (1 tablet) 3 times a day for 60 days [32]. 

Go to the study of memes

The purpose of the study was to study the effectiveness and safety of consistent therapy with Mexidol® Parentiteralno and Mexidol® Fort 250 oral in patients with chronic brain ischemia. The study of 318 patients aged 60.4 ± 9.45 years with chronic brain ischemia of 15 clinical centers of various regions of Russia and Uzbekistan took part in the study. The results of the study convincingly indicate the high clinical efficiency of prolonged sequential therapy with Mexidol® and Mexidol® Forter 250 in patients with chronic brain ischemia, which was expressed in the regression of the severity of such important manifestations of chronic brain ischemia as cognitive, emotional, vegetative and motorized impairment , and about safety comparable to placebo. The simultaneous significant regression of all the main clinical manifestations of chronic brain ischemia is an important argument in favor of the fact that Mexidol®, with brain ischemia, affects the pathogenetic foundations of chronic vascular brain damage, not limited to symptomatic improvement. Mexidol® for memory and attention also has a favorable effect.

It is recommended that the drug is recommended for chronic brain ischemia according to the following scheme that confirmed a high degree of efficiency and safety in numerous studies [29, 32, 34, 35]: Mexidol® intravenously (500 mg) once a day for 14 days (saturation phase of saturation of saturation Therapeutic effect) Further Mexidol® Fort 250 in a dose of 250 mg (1 tablet) 3 times a day for 60 days (maximization phase of the therapeutic effect).


Application scheme

In order to strengthen and retain the clinical effect, courses are recommended according to the above scheme 2-3 times a year.

How to take Mexidol® for cerebral ischemia?

Block of articles on this topic

The results of an international multicenter randomized double-blind-controlled study of evaluating the effectiveness of the effectiveness and safety of consistent therapy of patients with chronic brain ischemia with Mexidol and Mexidol Forte 250 (study of Memo)

Registered on ClinicalTrials 

A.I. FEDIN1, V.V. ZAKHAROV2, M.M. TANASHYAN3, E.I. CHUKANOVA1, E.N. MAJIDOVA4, L.A. SCHEPANKEVICH5.6, O.D. OSTROUMOVA7

1Pirogov Russian National Research Medical University, Moscow, Russia;
2I.M. Sechenov First Moscow Medical University,
3Neurology Research Center,
4, Russia;
5Novosibirsk State Medical University, Novosibirsk
6Federal Research Center for Fundamental and Translational Medicine, Novosibirsk, Russia;
7Russian Medical Academy of Continuous Professional Education, Moscow, Russia

 

Place of publication:
S.S. KORSAKOV JOURNAL OF NEUROLOGY AND PSYCHIATRY, 2021, Vol. 121, No. 11

Read more
The results of clinical studies of the effectiveness and safety of the use of ethylmethylhydroxypyridine of succinate in patients with chronic brain ischemia

Authors:
M.V. ZHURAVLEVA1,2, P.R. KAMCHATNOV3, N.S. VASYUKOVA4, V.V. ARKHIPOV1, E.V. KUZNETSOVA5, T.R. KAMENEVA6, S.Yu. SEREBROVA1,2

Read more
The effectiveness of Mexidol in patients of different age groups with chronic brain ischemia with cognitive disorders (the results of subanalysis of the international multicenter randomized double blind placebo-controlled study of memes)

Authors:
V.V. ZAKHAROV1, O.N. TKACHEV2,3, E.A. MKHITARYAN2,3, A.I. FEDIN2

Read more
Approaches to pharmacotherapy of vascular moderate cognitive disorders in patients of various age groups

Authors:
V.V. ZAKHAROV1, A.I. FEDIN2, E.A. MKHITARYAN2,3

Read more
Features of pharmacotherapy of vascular cognitive impairment in elderly people

Author:
A.N. BOGOLEPOVA1,2

1N.I. Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation, Moscow, Russia;
2Federal Center for Brain and Neurotechnology of the Federal Medical and Biological Agency of Russia, Moscow, Russia

Read more
The possibilities of multimodal neuroprotection in patients with chronic brain ischemia against the background of arterial hypertension and atherosclerosis

Authors:
I.A. GRIBACHEV, T.F. POPOVA, E.V. PETROVA, A.V. ZVONKOVA

FSBEI in Novosibirsk State Medical University of the Ministry of Health of Russia

Read more
Increasing the efficiency of pharmacotherapy in comorbide patients with chronic brain ischemia on an outpatient basis

Authors:
T.L. VISILO1, E.G. AREFIEV2

Read more
The effectiveness and safety of therapy of drugs Mexidol and Mexidol Forte 250 in patients with chronic brain ischemia

Author:
L.A. SCHEPANKEVICH1,2, Yu.A. NIKOLAEV1, E.V. TANEEVA3, M.A. PERVUNINSKAYA1, M.S. SCHEPANKEVICH1,2

Read more
Hypoxia and oxidant stress with cerebrovascular failure and effective ways to correct them

Authors:
E.I. CHUKANOVA, A.S. CHUKANOVA, D.M. RODIONOVA

FGAOU in Russian National Research Medical University named after N.I. Pirogov »Ministry of Health of Russia, Moscow, Russia

Read more
Original and reproduced drugs: what do the clinician need to know?

Author:
A.V. SHCHULKIN, A.A. FILIMONOVA
Federal State Budgetary Educational Institution of Higher Education “Ryazan State Medical University” of the Ministry of Health of the Russian Federation, Ryazan, Russia

Read more

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