Correction of cognitive impairment in patients with cerebral vascular disorders

The principles of correction of cognitive impairment in patients with cerebrovascular disorders are considered. The effectiveness of memantine hydrochloride on cognitive functions, daily activity, emotional and somatic state has been proven, its administration to patients with this pathology is recommended.

Key words: cerebral disorders, memantine hydrochloride.

Cognitive impairment (CI) is observed in 20-50% of patients who have suffered a stroke and has a negative impact on social activity and quality of life of patients. A close correlation between quality of life and prognosis of the degree of disability of patients has been proven.

According to epidemiological data, 4-6% of patients who have suffered a stroke develop dementia in the following six months. After 5 years, this figure increases to 20-25%. Moderate cognitive impairment or mild dementia are even more common.

Post-stroke cognitive impairment (PSCI) should be understood as any cognitive impairment that has a temporal relationship with stroke, i.e. is detected in the first 3 months after stroke (early PSCI) or at a later time, but usually no later than a year after stroke (late PSCI). The three-month interval was introduced in the NINDS-AIREN criteria for vascular dementia as one of the pieces of evidence for a causal relationship between cerebrovascular disease and dementia.

In 1993, V. Hachinski proposed the term "vascular cognitive disorders" (VCD) to denote cognitive impairments arising as a result of cerebrovascular disease. The VCD structure proposed to consider vascular dementia proper, cognitive impairment due to a combination of vascular and neurodegenerative pathology of the brain (mixed dementia with a vascular component), and vascular cognitive impairments that do not reach the level of dementia.

Based on the degree and prevalence of cognitive deficit, three types of cognitive impairment that occur after a stroke can be distinguished:

• focal (monofunctional) cognitive impairments, usually associated with focal brain damage and affecting only one cognitive function (aphasia, amnesia, apraxia, agnosia); in such cases, over time, some degree of compensation for cognitive deficit is possible due to brain plasticity and preserved cognitive functions;
• multiple cognitive impairments that do not reach the level of dementia (post-stroke mild cognitive impairment);
• multiple cognitive impairments that cause a disruption of social adaptation (regardless of the existing motor or other focal neurological deficit) and, accordingly, allow the diagnosis of dementia (post-stroke dementia).

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Symptoms of vascular cognitive impairment

The clinical picture of vascular cognitive disorders, reflecting dysfunction of the frontal lobes of the brain due to the formation of a syndrome of disconnection of the cortex of the frontal lobes and subcortical ganglia, often includes slowness of thinking, difficulty concentrating, impaired voluntary attention and switching from one task to another, increased distractibility, perseveration and increased impulsivity, decreased speech activity, analytical abilities, planning, organization and control of activities.

Primary memory impairments (impaired memorization of new material, difficulty recalling previously learned information) are not typical for vascular cognitive disorders, but working memory impairments may be observed: patients find it difficult to retain a large amount of information, to switch from perceiving one piece of information to another. This complicates learning and acquiring new skills, but does not extend to memorization and reproduction of life events. Patients with arterial hypertension (AH) show lower results in all neuropsychological tests (reaction time, spatial, auditory and visual memory, immediate and delayed reproduction of memorized words, speed of choice reaction, information analysis, problem solving, identifying similarities and differences, generalization, activity, motivation, program construction, inference, voluntary attention).

The morphological basis for the development of cognitive impairments may be:

• stroke in strategic areas of the brain that provide memory and other important mental functions; when they are damaged, a significant cognitive defect occurs;
• multiple vascular lesions (lacunae), when extensive brain damage leads to a breakdown of connections between the frontal cortex and other important centers, which causes cognitive deficits;
• leukoaraiosis - rarefaction of white matter, which is the cause of cognitive disorders in patients with hypertension, during the formation of cerebrovascular insufficiency.

Vascular damage to the brain is accompanied by a disruption in the functioning of neurotransmitter systems involved in the regulation of cognitive functions. Among the latter, the glutamatergic system is of particular importance.

It is known that glutamate receptors play a major role in the development of the central nervous system, modulating the processes of neuronal migration, ensuring their survival and the formation of neuronal networks. These receptors are divided into ionotropic, associated with ion channels, and metabolotropic, inducing changes in metabolic processes. A characteristic feature of ionotropic receptors of the NMDA class is their inherent function of regulating the conductivity of ion channels for CA2+. Due to this, NMDA receptors play an important role in regulating the duration of the excitatory potential, thereby participating in the implementation of cognitive functions, mediating such processes in the brain as learning, coordination, memory.

Treatment of vascular cognitive impairment

The spectrum of therapeutic interventions aimed at treating and preventing progressive cognitive disorders is quite wide and includes the following types of therapy: antiplatelet, antihypertensive, as well as aimed at stimulating neuroplasticity processes and correcting neurotransmitter disorders. The latter areas include cholinergic therapy, the use of neurotrophic drugs, and correction of glutamatergic neurotransmission disorders. One of the drugs that corrects the state of the glutamatergic system is memantine hydrochloride.

Memantine hydrochloride is a potential-dependent, non-competitive NMDA receptor antagonist with medium affinity. It blocks calcium currents, enhances glucose utilization in the brain and dopamine release, has neuroprotective properties, increases mitochondrial resistance to hypoxia and slows down neurodegeneration processes. By blocking the activity of ion channels at low glutamate concentrations and interacting with the receptor when it is in the "open" state, memantine hydrochloride does not disrupt the physiological activation of the NMDA receptor, which is necessary for the effect of long-term potentiation and memory consolidation. The clinical efficacy of the drug has been noted in many patients with varying degrees of cognitive impairment.

Thus, memantine hydrochloride, possessing neuroprotective properties, entered clinical practice as a drug capable of improving the condition of patients with cognitive impairment.

The aim of the work is to study the effectiveness of the drug memantine hydrochloride in patients with cognitive impairment that developed after acute cerebrovascular accident (2-3 months after stroke) and after ischemic or hemorrhagic stroke (1-2 years after stroke).

The tolerability, efficacy and safety of a course of therapy with memantine hydrochloride (Mema, Actavis) were studied according to the following regimen: 5 mg only in the morning for 5 days, then 5 mg 2 times a day for 3 months in patients with acute cerebrovascular accident and in patients with a history of ischemic or hemorrhagic stroke with cognitive impairment.

The study included 60 people aged 47 to 78 years who had any acute cerebral event, against the background of which they had various cognitive disorders. Patients were divided into 2 groups: the main group (n = 30) received memantine hydrochloride according to the scheme against the background of basic therapy; the control group (n = 30) received basic therapy (metabolic, anti-edematous).

Neuropsychological testing was aimed at identifying cognitive impairments such as memory, attention, concentration, mental performance, and psychomotor function impairments. Objective assessment of cognitive impairments was performed using a set of neuropsychological tests. Mental state was determined using the MMSE (mini mental state examination), the 10-word test, the Isaac test, and the 3A33O-ZCT test at the beginning of therapy, after 1 month, and after 3 months. Side effects of the drug were recorded throughout the entire observation period.

MRI of the brain was performed on patients in hospital to confirm the presence of a history of ischemic or hemorrhagic stroke.

In patients of both groups, vascular events developed against the background of hypertension, cardiac arrhythmias, diabetes mellitus, and atherosclerosis. No statistically significant differences were found between the groups for the above indicators.

In the main group, cognitive impairment was observed against the background of hemorrhagic stroke in 4.5% of cases, ischemic stroke - in 22.7% of cases, lacunar conditions - in 18.2% of cases, in the presence of consequences of hemorrhagic stroke - in 9.1% of cases, consequences of ischemic stroke - in 31.8% of cases, against the background of chronic cerebrovascular accident of the 2nd-3rd degree - in 13.6% of cases.

Upon admission, patients complained of weakness in the limbs with impaired motor functions in them, speech impairment (slurred, unclear pronunciation of some sound combinations), dizziness, headaches of various nature and localization, increasing with psycho-emotional and physical stress, memory loss, impaired attention, mood, inability to concentrate, rapid fatigue, psycho-emotional instability with a predominantly depressive background. Some patients noted a disturbance in the rhythm of sleep, which became superficial, with frequent awakenings.

Focal symptoms were represented by motor disorders: mono- and hemiparesis of varying severity, sensory disorders (hypesthesia of pain sensitivity by mono- or hemitype), speech disorders (elements of motor aphasia, dysarthria), oculomotor disorders, decreased pharyngeal reflex; symptoms of cerebellar disorders (diffuse muscle hypotonia, static-locomotor ataxia), oral automatism were observed.

The dynamics of cognitive functions in patients with vascular events during treatment with memantine hydrochloride was assessed using MMSE. During treatment, reliable changes in the severity of cognitive impairment were noted.

The long-term memory, fatigue, and attention activity were assessed using the 10-word test. A large number of "extra" words indicates disinhibition or disorders of consciousness. When examining adults, by the third repetition, a subject with normal memory usually correctly reproduces up to 9 or 10 words. The memorization curve may indicate a weakening of attention, severe fatigue. Increased fatigue is recorded if the subject immediately reproduced 8-9 words, and then less and less each time. In addition, if the subject reproduces fewer and fewer words, this may indicate forgetfulness and absent-mindedness. In the main group of patients who received memantine hydrochloride before the start of treatment, the results improved significantly.

In the control group, the improvement was not as pronounced.

The Isaac speech activity test set was used to assess the ability to reproduce word lists in 4 semantic categories, the maximum result was 40 points. Patients in the main group showed a decrease in speech activity before treatment, after 3 months it reached the norm. All patients repeated the same words, used words from other semantic categories.

In the Zazzo proofreading test, the speed of task completion before the start of treatment indicated a decrease in concentration and overall performance; it increased by the 3rd month of treatment.

The obtained results indicate the effectiveness of memantine hydrochloride in the complex therapy of cognitive impairment in patients with acute (2-3 months after stroke) cerebral vascular events, their consequences (1-2 years after stroke). The use of memantine hydrochloride is safe and is not accompanied by pronounced side effects. It affects the central mediator processes, promotes regression of existing cognitive impairment, reduces concomitant emotional-affective and behavioral disorders and improves the quality of life of patients.

After the treatment, there were changes in the cognitive status of the patients. According to the MMSE scale, the indices improved by an average of 4.5 points (up to 29.45±0.19 points) in the main group and by 1.8 points (up to 27.44±0.27 points) in the control group. No dynamics of the symptoms of organic brain damage were observed. Some patients noted an increase in general motor activity. In the Isaac test, repetitions of the same words ceased, the speed of test performance increased significantly in patients receiving memantine hydrochloride. Also, in the patients of this group, in the Zazzo proofreading test, in all cases, a significant increase in the speed of task performance and a decrease in errors was registered, which indicates an increase in concentration and an improvement in performance in general compared to the control group. The obtained results indicate high efficiency, good tolerability and a sufficiently long-term therapeutic effect of memantine hydrochloride.

Thus, the use of NMDA receptor antagonists is a justified and effective method of complex therapy of cognitive impairment. Given the complex nature of the effect of memantine hydrochloride on cognitive functions, daily activity, emotional and somatic state, its administration to patients with cerebral vascular events can be recommended for wide use.

Prof. V. A. Yavorskaya, O. B. Bondar, T. Kh. Mikhaelyan, Yu. V. Pershina, Ph.D. B. E. Bondar // International Medical Journal - No. 4 - 2012