Mental and behavioral disorders due to use of alcohol. Amnestic syndrome due to use of alcohol: clinical guidelines

List of Abbreviations

BP – blood pressure

ALT – alanine aminotransferase

AST – aspartate aminotransferase

AS – amnestic syndrome

ATC – anatomical therapeutic chemical

GABA – gamma-aminobutyric acid

Gamma-GT – gamma-glutamyl transferase

Brain – brain

CT – cognitive training

CT – computed tomography

Med – medication

Russian Ministry of Health – Ministry of Health of the Russian Federation

ICD-10 – International Statistical Classification of Diseases and Related Health Problems, Tenth Revision

MRI – magnetic resonance imaging

ADR – adverse drug reaction

AE – adverse events

psychoactive substance – psychoactive substance

AC – alcohol craving (pathological craving for alcohol)

PNS – peripheral nervous system

РКИ – randomized controlled trial

ADS – alcohol dependence syndrome

LCE – level of confidence of evidence

GRS – grade of recommendation strength

CNS – central nervous system

RR – respiratory rate

HR – heart rate

CGI – Clinical Global Impression scale

MoCA – Montreal Cognitive Assessment

Terms and Definitions

Amnesia — a memory disorder characterized by the loss of the ability to retain and recall previously acquired knowledge.

Anterograde amnesia — the loss of memory for events that occurred after the onset of the disease.

Retrograde amnesia — the loss of memory for events immediately preceding the disease.

Anteroretrograde amnesia — a combination of anterograde and retrograde amnesia.

Progressive amnesia — a gradual weakening, and eventually complete and irreversible depletion, of all memory stores and acquired knowledge.

Fixation amnesia — the loss of the ability to memorize and record current events while memory for knowledge acquired in the past remains relatively intact.

Amnestic disorientation — the inability to orient oneself in time and surroundings due to the inability to remember one's location and the current date.

Dementia — a profound impoverishment of all mental activity, primarily intellect, the emotional-volitional sphere, and individual personality traits, accompanied by a simultaneous deterioration (up to complete loss) of the ability to acquire new knowledge, use it practically, and adapt to the environment.

Hypomnesia (dysmnesia) — a pathological weakening (but not complete loss) of memory or its individual components (memorization, retention, recall; episodic and semantic memory).

Cognitive functions — higher mental functions: memory, attention, psychomotor coordination, speech, gnosis, praxis, calculation, thinking, orientation, planning, and control of higher mental activity.

Cognitive impairment — a decline in memory, mental performance, and other cognitive functions compared to the baseline level (individual norm).

Confabulations — pathological fictions that have taken the form of memories ("memory hallucinations").

Adverse drug reaction (Eng. – adverse reaction) — any untoward and harmful reaction in a human body occurring with the use of a medicinal product in recommended doses for prophylaxis, treatment, or diagnosis, or for the modification of a physiological function, for which a causal relationship with the medicinal product is established.

Paramnesias — a group of qualitative memory disorders in which false or distorted memories occur, along with a confusion of the present and past, real and imaginary. They include: pseudoreminiscences, confabulations, and cryptomnesias.

Polyneuropathy — multiple lesions of peripheral nerves manifested by flaccid paralysis, sensory disturbances, trophic and autonomic-vascular disorders, predominantly in the distal extremities.

Pseudoreminiscences — erroneous memories of actual past events shifted in time ("memory illusions").

Alcohol dependence syndrome (Eng. – alcohol dependence syndrome) — a combination of physiological, behavioral, and cognitive phenomena in which alcohol use takes a leading place in the patient's value system. The main characteristic of the dependence syndrome is the desire (often strong, sometimes irresistible) to drink alcohol. It is a chronic, progressive disease caused by the action of alcohol as a narcotic substance. It has its characteristic symptoms, developmental and clinical course features, and specific outcomes.

Pathological craving syndrome (psychological dependence) (Eng. – alcohol craving) — a nosologically specific psychopathological disorder characteristic of addictive diseases, clinically manifested by ideational (thought), behavioral, affective (emotional), autonomic, and sensory disturbances. Diagnostic criteria for alcohol craving include: a strong desire or necessity to consume alcohol, loss of quantitative and situational control, and continued alcohol use despite clear harmful consequences while being aware of the connection between use and consequences.

Tolerance (Lat. – tolerantia, "endurance, ability to endure") — the progressive attenuation of the desired psychotropic effect of a psychoactive substance (euphoria, sedation, relaxation, etc.), which forces the patient to increase doses and frequency of use. It is based on the physiological mechanism of the body's adaptation to the toxic effect of the substance.

Tremor (Lat. – tremor, "shivering") — rhythmic, rapid, involuntary contractions of the muscles of the torso or extremities.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Alcohol-induced amnestic syndrome (hereinafter referred to as AS) is a disorder manifested by persistent, often irreversible impairment of short-term and/or long-term memory, which is manifested predominantly by the loss of the ability to memorize new information (fixation amnesia and anterograde amnesia) and to a lesser extent by a decline in memory for events preceding the disease (retrograde amnesia) [1].

This definition corresponds to the term "Korsakoff syndrome".

Definition of AS according to ICD-10 [2]: A syndrome associated with a chronic, marked impairment of recent memory: remote memory is sometimes impaired, while immediate recall may be preserved. There is typically a disturbance of the sense of time and order of events, leading in severe cases to amnestic disorientation, as well as an inability to acquire new material. Confabulations may be present, but are not obligatory. Other cognitive functions are usually intact, and memory defects are disproportionately severe relative to other impairments.

The term "Korsakoff's psychosis" ("polyneuritic psychosis" according to S.S. Korsakoff [3]) is included in this diagnostic category, but in addition to the described mental disorders, it implies the presence of neurological disturbances as well. In foreign literature, this condition is more often designated by the term "Wernicke-Korsakoff syndrome", reflecting the simultaneous presence of psychiatric (Korsakoff syndrome) and neurological (Wernicke's encephalopathy) pathology [4]. Wernicke's encephalopathy is always an acute condition that develops most frequently after severe alcohol psychoses, and the classic clinical tetrad is represented by gaze palsy (ophthalmoplegia) associated with cranial nerve IV damage, nystagmus, cerebellar ataxia, and clouding of consciousness (amentia) [5]. Studies indicate that the classic tetrad may not be fully represented or may be supplemented by other symptoms, but the presence of impaired consciousness strictly contradicts the diagnostic criteria of AS [5].

It should be understood that non-specific cognitive impairments can be observed with the use of virtually any psychoactive substance (hereinafter referred to as PAS), but for some of them, the predominance of memory impairment is more characteristic. These include: benzodiazepine tranquilizers, other hypnotic and sedative agents, inhalants, and certain psychostimulants [6].

Strictly speaking, AS is characteristic only of alcohol, since its pathogenesis is known and a clear clinical picture has been described. When using other PAS, it is more correct to speak of cognitive disorders of varying severity, since the pathogenesis of their development differs from alcoholic AS, and the clinical picture typically includes diverse disturbances of memory, attention, intellect, emotional sphere, and behavior. Differential diagnosis in such cases is quite difficult, and a consensus on this issue has not yet been reached. Mentions of AS caused by other PAS are found in the literature, but these descriptions are limited to case reports [7–11] and do not allow for a sufficiently accurate understanding of the clinical features, etiology, and treatment of such conditions.

Synonyms: Korsakoff syndrome.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Alcoholic AS is caused by a deficiency of thiamine (vitamin B₁) in the central nervous system (hereinafter referred to as the CNS), resulting from nutritional disorders, decreased intestinal absorption of thiamine, impaired phosphorylation, and impaired thiamine transport across the blood-brain barrier [4]. The development of alcoholic AS is most frequently preceded by Wernicke's encephalopathy; therefore, Wernicke's encephalopathy is often regarded as the "acute phase" of Wernicke-Korsakoff syndrome, and AS (Korsakoff's syndrome) as the "chronic phase" [4]. Wernicke's encephalopathy occurs approximately 4–6 weeks after the onset of thiamine deficiency and, in the absence of adequate treatment, progresses to Korsakoff's syndrome or psychosis [5]. Alcoholic AS is characterized by a chronic course, and even with adequate therapy, only moderate improvement is possible [12–14].

1.3 Epidemiology of the Disease or Condition

It is traditionally believed that alcoholic AS develops after severe alcohol-induced psychoses; however, researchers point out that Wernicke's encephalopathy is frequently misdiagnosed as delirium tremens, meaning patients do not receive the necessary treatment, which leads to the development of AS [4, 5, 15]. According to the European Federation of Neurological Societies, the diagnosis of Wernicke-Korsakoff syndrome is not established during life in 70% of cases, although corresponding changes are found at autopsy [15]. A population-based study in Finland found that from 1998 to 2015, the prevalence of alcohol-induced AS was 3.7 (3.4 – 3.9) per 100,000 population among men and 1.2 (1.1 – 1.3) among women. The age-standardized mortality rate was 5.67 (5.25 – 6.13), the 10-year survival rate was 48.3% (44.6 – 51.8) among men and 62.9% (56.7 – 68.3) among women, and 32.6% of deaths were due to alcohol-related causes [16]. In Switzerland, during the period from 2012 to 2020, a similar prevalence of alcohol-related Wernicke's encephalopathy was identified, equal to 5.43 per 100,000 population; in-hospital mortality among these patients was 3.2%, and Korsakoff's syndrome developed in 16.9% of cases [17].

Data on the prevalence of AS in the Russian population have not been published. The total incidence of alcohol dependence syndrome in 2022 was 1,167,401 individuals, which equals 802.0 cases per 100,000 population, of which alcohol-induced psychoses occurred in 35,490 patients, amounting to 24.4 cases per 100,000 population [18]. Since AS frequently develops following severe alcohol-induced psychoses, their prevalence can serve as an indirect indicator of the prevalence of AS.

1.4 Features of Coding the Disease or Condition

F1X.6 – Amnestic syndrome (AS) is coded according to the psychoactive substance that caused its development:

F10.6 – AS due to use of alcohol

Includes:

- Korsakoff's syndrome (synonym for AS).

- Korsakoff's psychosis (a form of chronic alcoholic encephalopathy; in addition to AS manifestations, it includes alcoholic peripheral polyneuropathy).

Excludes: non-alcoholic Korsakoff's psychosis or syndrome.

1.5 Classification of the disease or condition

AS occurs in many psychiatric disorders and conditions. Possible causes of AS, besides alcohol use, include: eating disorders, hypoglycemia, cerebrovascular disorders, metabolic disorders, temporal lobe epilepsy, traumatic brain injuries, oncological diseases, chemotherapy, surgical interventions, hypoxia (including attempted hanging or carbon monoxide poisoning), multiple sclerosis, infections, and genetic abnormalities leading to defective forms of transketolase [1, 4].

In such cases (i.e., of non-alcoholic etiology), AS is categorized by severity into [1]:

Mild amnestic syndrome – relatively mild memory impairment, imprecise orientation in place and time.

Moderate amnestic syndrome – clear impairment of memory for past and present events, disorientation in place and time, phenomena of retro- and anterograde amnesia.

Severe amnestic syndrome – profound impairment of memory and orientation, pronounced retro- and anterograde amnesia, confabulations may occur.

Considering that the diagnostic criteria for AS of alcoholic and non-alcoholic etiology are identical, this gradation can be used for practical purposes (e.g., to choose the organizational form of treatment); however, it should be understood that such a division is subjective.

In DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) [6], AS is regarded as a variant of major neurocognitive disorder and, when making a diagnosis, is considered comorbid with dependence syndrome. In turn, major neurocognitive disorder due to alcohol use is divided into two types: amnesic-confabulatory and nonamnesic-confabulatory. The amnesic-confabulatory type corresponds to Korsakoff's syndrome, whereas the nonamnesic-confabulatory type manifests with greater impairment of other cognitive functions, i.e., essentially pertaining to dementia.

1.6 Clinical presentation of the disease or condition

The clinical picture of AS is characterized by impaired learning of new information and difficulties in recalling past experience. AS typically manifests as a chronic impairment of new learning and memory for recent events. Patients' consciousness is clear, delusions and hallucinations are absent, behavior is generally appropriate to the environment, and mood is most often indifferent with a tendency toward fatigability and irritability [19, 20]. The inability to learn can reach the level of amnestic disorientation in the most severe cases; however, in most cases, patients retain the ability to orient themselves in a familiar environment and perform activities mastered before the development of AS. Impairment in recalling past experience may be accompanied by the emergence of false memories (confabulations and/or pseudoreminiscences), which are easily formed by giving the patient appropriate "hints" about false events. Confabulations are possible, but not mandatory. In AS, other cognitive functions are not significantly impaired apart from memory, which distinguishes AS from dementia [19]. It should be emphasized that other cognitive functions are usually either preserved, or memory deficits are disproportionately large relative to other impairments.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Clinical diagnosis is of primary importance in diagnosing AS, consisting of collecting complaints, assessing mental status, taking a history, and analyzing the obtained data. Other diagnostic methods play a secondary role [4, 13, 19].

Criteria for establishing the diagnosis of the disease/condition.

Alcohol-induced AS must meet the general criteria for organic AS [2]:

a) presence of memory impairment for recent events (reduced ability to acquire new material); anterograde and retrograde amnesia, reduced ability to recall past events in reverse chronological order;

b) (criterion "b" is not relevant for alcohol-induced AS) history or objective evidence indicating the presence of stroke or brain disease (especially involving the bilateral diencephalic and mid-temporal structures);

c) absence of deficit in immediate recall, attention, and consciousness, and in global intellectual state.

Personality changes may also be present, often with the onset of apathy and loss of initiative (tendency to neglect self-care), but they should not be considered mandatory for diagnosis.

Confabulations, lack of insight, and emotional changes (apathy, lack of initiative) are additional, but not invariably mandatory, factors for establishing the diagnosis.

The diagnosis of "Alcohol-induced AS" can be established in the presence of [2]:

A) memory impairment manifested by two features:

1) impaired learning and memory deficit for recent events (impaired acquisition of new material) to a degree sufficient to cause difficulties in daily life, up to amnestic disorientation;

2) reduced ability to recall past experience;

B) with the absence (or relative absence) of the following features:

1) clouding or depression of consciousness, attention deficit, perceptual disturbances, thought disorders, psychomotor behavioral disturbances, emotional disturbances, and sleep-wake cycle disturbances (such a condition is coded according to the criteria for F05.X Delirium not induced by alcohol or other psychoactive substances);

2) profound intellectual decline (dementia).

C) Absence of objective evidence (physical and neurological examination, laboratory tests) and/or anamnestic data of brain disease, other than alcoholic encephalopathy, that could reasonably be considered the cause of the clinical manifestations in the form of memory impairments described above.

AS is generally understood to be a condition of longer duration than intoxication or alcohol withdrawal syndrome (hereinafter referred to as AWS) due to the chronic course of AS. The diagnosis of AS caused by alcohol use implies a causal relationship between alcohol consumption and the development of AS [2]. AS predominantly occurs in the final stage of alcohol dependence, as an outcome of acute encephalopathies and/or severe alcohol delirium [7, 19]. The symptoms of AS may decrease with alcohol abstinence.

2.1 Complaints and Anamnesis

Complaints regarding both mental and somatic disorders in patients with AS may be absent due to the presence of fixation amnesia [21]. Anamnesis collection in patients with memory disorders may also be difficult, which is why it is necessary to refer to all available sources of information.

Comments: when collecting anamnesis in patients with memory impairments, all available anamnestic data sources should be used due to the likelihood that the patient has no memories or has distorted or completely false memories [21]. Efforts should be made to obtain comprehensive anamnestic data on the patient's past and chronic diseases to assess concomitant somatic pathology. It is necessary to identify the presence or absence of other potential causes for the development of AS [2, 19].

2.2 Physical Examination

Physical examination findings are non-specific in AS; they provide guidelines for determining the severity of the patient's condition. Physical examination of patients with alcohol-induced AS may reveal symptoms of neurological disorders, concomitant somatic diseases, and weight loss [15, 22–25].

Comments: somatic and neurological examinations are performed before starting therapy and during the course of treatment. Differential diagnosis between AS and acute encephalopathy should be performed in the first place.

The presence of two or more of the following criteria (Caine criteria) indicates the presence of Wernicke's encephalopathy (i.e., thiamine deficiency) [4, 5, 15, 22]: ocular motor abnormalities (ophthalmoplegia, nystagmus, or gaze palsy), cerebellar signs (ataxia, gait abnormalities, or other signs of cerebellar dysfunction), nutritional status (body mass index <18.5 kg/m^2, clinical findings such as hypoalbuminemia and/or evidence of severe dietary deficiency), and mental status changes (confusion or delirious clouding of consciousness) and/or memory impairment. In addition, patients with AS often suffer from concomitant somatic pathology, which requires the physician's attention to prevent complications.

2.3 Laboratory Diagnostics

Comments: laboratory diagnostics in addition to the classical clinical examination make it possible to objectively assess the patient's current condition, rule out acute conditions requiring specialized medical care, and detect hidden organ pathology [19]. Routine laboratory tests in most cases allow indirect confirmation of chronic high-dose alcohol consumption: the levels of indirect biomarkers—AST, ALT, and gamma-GT—increase in response to higher frequency and dose of alcohol consumption. Indirect biomarkers have a fairly wide range of sensitivity/specificity values. For instance, AST has a sensitivity/specificity of 20–80%/50–95%; ALT of 18–58%/50–57%; and gamma-GT of 40–60%/80–90% [31–33]. Therefore, to confirm the specifically alcoholic nature of organ damage, they are more often used in combination [33, 34].

Chronic alcohol consumption does not have a clear definition in either legislative acts or medical reference books. Various patterns of systematic alcohol intake fall under this definition: from risky drinking to established alcohol dependence [19].

2.4 Instrumental Diagnostics

Instrumental diagnostics for alcohol-induced AS are of an auxiliary nature, as the clinical picture serves as the basis for diagnosis. In complex cases and when differential diagnosis of the cause of AS development is required, neuroimaging methods (magnetic resonance imaging (hereinafter – MRI), computed tomography (hereinafter – CT)) can be informative.

Comments: neuroimaging methods allow differential diagnosis between alcohol-induced AS and memory impairments arising from other causes [2, 19]. Determining the etiology of AS is necessary for accurate diagnosis and selection of treatment tactics.

Prolonged alcohol consumption is characterized by cerebral atrophy, predominantly in the anterior parts of the brain; hyperintense signal foci in the globus pallidus, substantia nigra, and cerebellar dentate nucleus (MRI, T1-weighted); and diffuse hyperintense signals of the cerebral hemispheric white matter (MRI, T2-weighted) [41].

Neurodegeneration of the Alzheimer's type is characterized by MRI signs of cerebral atrophy in the form of ventricular system and subarachnoid space widening. The severity of general cortical atrophy has limited diagnostic value, whereas the predominance of atrophic changes in the medial temporal lobe (especially the hippocampus) is more specific. In younger patients (with presenile AD), atrophy may be more pronounced in the parietal lobes of the brain [41–44].

Structural neuroimaging methods play a key role in the evaluation of patients with suspected mixed dementia, as they make it possible to assess the severity of both focal ("vascular") changes (classic radiological markers of which are lacunar infarctions in the subcortical white and gray matter and hyperintense signal from the white matter of periventricular and subcortical areas ["leukoaraiosis"], considered clinically significant when involving at least 25% of the white matter [45]) and atrophic changes characteristic of neurodegenerative processes.

If multiple sclerosis or brain neoplasms are suspected, contrast-enhanced brain magnetic resonance imaging should be performed; therefore, a preliminary consultation with a neurologist is carried out to determine the indications [41].

Comments: due to the high frequency of neurological pathology among patients with alcohol-related dementia and the need to rule out other causes of alcohol-related dementia, consultation with a neurologist is the most effective screening method [19].

2.5 Other Procedures

Comments: the Montreal Cognitive Assessment (MoCA) (Appendix G1) was developed as a rapid screening tool for mild cognitive impairment [45]. It assesses various domains: attention and concentration, executive functions, memory, language, visuospatial skills, abstract thinking, calculation, and orientation. The MoCA takes approximately 10 minutes to administer. The maximum possible score is 30; a score of 26 and above is considered normal and indicates the absence of impairment, while 25 and below indicate the presence of impairment [45]. Inability to complete tasks in the categories of attention, concentration, executive functions, visuospatial skills, abstract thinking, and calculation contradicts the diagnostic criteria for alcohol-related dementia [2]. The Russian-language version of the MoCa test is validated for assessing cognitive functions in the elderly [44]. When evaluating the diagnostic properties of MoCa for a population of patients with cognitive disorders caused by alcohol use, it was found that a score ranging from 24 to 20 indicates the presence of cognitive impairment, and a score of 20 and below on the MoCa scale indicates alcohol-related dementia. At the same time, the only parameter that statistically significantly differed in the alcohol-related dementia group from the cognitive impairment group was memory [47]. The MoCa scale was also compared in terms of sensitivity and specificity with another well-known cognitive scale, the MMSE (Mini-Mental State Examination), in a sample of 30 patients with alcohol-related dementia and 30 healthy volunteers, where it was established that MoCa more accurately detects the presence of alcohol-related dementia [48]. Existing systematic reviews note that the results of MoCa validity studies for assessing cognitive disorders caused by psychoactive substance use are consistent and demonstrate sufficient accuracy. It is also noted that MoCa allows for the differentiated assessment of various cognitive domains, which is a prerequisite for diagnosing alcohol-related dementia [42,43,49].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Treatment of alcohol-related dementia is a comprehensive, individualized, and long-term process that can be carried out on an outpatient and/or inpatient basis. Inpatient treatment may be required if it is necessary to clarify the diagnosis, in case of an acute worsening of cognitive impairment, clouded consciousness, or the emergence of previously absent neurological or somatic disorders.

For patients with moderate and severe alcohol-related dementia, round-the-clock medical monitoring must be provided [26].

Treatment goal:

- correction of mnemonic disorders, stabilization of the emotional sphere and somatoneurological status, fostering commitment to alcohol abstinence, long-term treatment, and rehabilitation [26]. In patients with mild mnemonic impairment and prolonged abstinence from alcohol, partial restoration of working capacity is possible [26].

3.1. Drug therapy

Randomized clinical trials (hereinafter referred to as RCTs) on the treatment of alcohol-related dementia caused by alcohol use are few in number [50,51]. A treatment protocol for alcohol-related dementia associated with alcohol use is currently lacking. In the literature, there are a number of studies on the efficacy of acetylcholinesterase inhibitors (N06DA – Anticholinesterase drugs), antidepressants (N06AB – Selective serotonin reuptake inhibitors), certain stimulants (N06BX - Other psychostimulants and nootropic drugs), and clonidine** (C02AC – Imidazoline receptor agonists); the quality of the studies is predominantly low, and the results demonstrate a lack of positive effect from the use of the listed drug groups, making their use inappropriate [50,51].

It should be understood that the most important part of alcohol-related dementia therapy is abstinence from alcohol and other psychoactive substances [19].

Comments: the use of #memantine**, which belongs to the ATC group "N06DX - Other anti-dementia drugs", is indicated at an initial dosage of 5 mg with a weekly increase of 5 mg until a dosage of 20 mg per day is reached over 12 weeks, with evaluation of the clinical effect. In a study of a sample of 16 patients with Wernicke-Korsakoff syndrome, without specification of etiology, who were treated with #memantine** at a dosage of 20 mg per day for 28 weeks, a sequential improvement in condition according to the CGI (Clinical Global Impression) scale was revealed; data on other scales are not provided in the article [52]. In another open-label, non-randomized study, #memantine** was evaluated in a sample of 19 patients with alcoholic dementia with a sobriety duration of more than 2 months: #memantine** was titrated weekly by 5 mg, and starting from week 4, patients received 20 mg until week 12; as a result, a statistically significant improvement on the MMSE scale and improved word recall were established [53]. Other data on the use of #memantine** are lacking. It is important to note that discontinuation of memantine after long-term use, according to some reports, can lead to a sharp deterioration in patients' condition, and therefore medication intake must be strictly monitored [54].

Comments: #Thiamine** belongs to the ATC group "A11DA – Vitamin B1". Despite the existing consensus [4,9,19] regarding the role of thiamine in the pathogenesis of alcohol-related dementia developing as part of Wernicke-Korsakoff syndrome, high-quality data on the efficacy of thiamine for the treatment of cognitive impairment are lacking [44–46]. The regimen for #thiamine** administration depends on the severity of its deficiency [51,54–57]:

1) all patients with alcohol use disorders, as they are in a risk group, are prescribed #thiamine** at a dosage of 100 mg per day orally, including as part of vitamin complexes;

2) patients with underweight or evidence of malnutrition over the past month, or a blood #thiamine** concentration of less than 170 nmol/L, are prescribed 250 mg of #thiamine** intravenously or intramuscularly once daily for 3–5 days;

3) patients with severe somato-neurological disorders (ataxia, nystagmus or ophthalmoplegia, confusion or depression of consciousness, unexplained hypotension and hypothermia – such a condition does not meet the diagnostic criteria for AS) and patients with a history of delirium tremens are prescribed #thiamine** at a dosage of 500 mg three times a day intravenously until neurological symptoms resolve.

Comments: drugs from the group "N06BX — Other psychostimulants and nootropic drugs" are capable of exerting psychostimulant, anti-asthenic, sedative, antidepressant, antiepileptic, proper nootropic, mnemotropic, adaptogenic, vasovegetative, antiparkinsonian, antidyskinetic action, and they also increase the level of wakefulness and clarity of consciousness [7]. It is possible to use #aminophenylbutyric acid at a dosage of 750–1500 mg/day orally, #vinpocetine** 5–10 mg 3 times a day orally, hopantenic acid  1500–3000 mg/day, #nicotinoyl gamma-aminobutyric acid in a single dose of 20–50 mg orally, average daily dose of 40–300 mg, #piracetam** in a single dose of 400–1200 mg orally, average daily dose of 2400–3200 mg, #cerebrolysin (TN) only parenterally: i.m. – 1–5 ml, i.v. – 10–60 ml. Course – daily for 4 weeks [1,7,27,58,59].

Comments: therapy should be carried out with heightened attention to the possibility of undesirable and adverse events, taking into account the pharmacokinetics and pharmacodynamics of the drugs. Patients with AS often experience affective and behavioral disorders, which can lead to poor compliance, dangerous behavior, difficulties in patient care, deterioration of somatic status, etc., which in turn increases the risk of death in such patients [20,21,24,61,62].

It is rational to start therapy with atypical antipsychotics at the minimum effective doses: #risperidone** up to 2-4 mg per day orally or #quetiapine** orally 200 mg per day [1,26]. RCTs to evaluate the efficacy and safety of treating behavioral disorders in patients with alcohol-induced AS have not been conducted. According to an epidemiological study including the Finnish population from 1998 to 2015, aged over 40 years with diagnosed Wernicke-Korsakoff syndrome or alcohol dementia, it was shown that mortality from poisonings, accidents, assaults, suicides, and alcohol-related causes among patients receiving antipsychotics was statistically significantly lower than among those who did not receive them [60].

In Alzheimer's type dementia, vascular and mixed dementias, it has been shown that antipsychotics have moderate efficacy in reducing agitation, but significantly increase the risk of adverse events, including the risk of fatal outcome, and therefore should be prescribed with caution and with the consent of the patient or their legal representative [63]. It has also been shown that psychotic disorders and agitation in dementia are temporary in nature, and therefore the use of antipsychotics as continuous therapy is not justified [63,64].

3.2. Psychotherapy

Psychotherapeutic techniques in alcohol-induced AS can be used in cases of mild severity, as they require a relatively preserved ability to memorize. In this case, psychotherapy should be aimed at building motivation to maintain sobriety and teaching skills to cope with alcohol cravings. A fundamental task for psychotherapeutic interventions is maintaining sobriety.

3.3. Assessment of treatment efficacy and safety

Comments: the effectiveness of complex treatment is assessed based on the dynamics of psychopathological, somatovegetative, and neurological disorders in patients diagnosed with alcohol-induced AS [19].

Criterion for the effectiveness of drug treatment: stabilization of the patient's psychophysical state [19].

Comments: the safety and tolerability of therapy are assessed throughout its duration by the frequency of occurrence and development of adverse events (hereinafter referred to as AEs) (Appendix A3).

AEs are recorded according to:

– spontaneous patient reports;

– physical examination and clinically significant changes in vital signs (BP, HR, RR, body temperature) from baseline;

– clinically significant deviations of laboratory test results and instrumental diagnostic methods from baseline values.

The causal relationship between AEs and medicinal products is assessed using the Naranjo algorithm (Appendix G2). When an AE occurs, the physician must record their actions in the primary documentation, for example, prescribing additional drugs (which ones, at what dose, for what period), etc., and also fill out the appropriate form (Appendix A3).

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Rehabilitation measures for alcohol-induced AS are aimed at improving cognitive functions, increasing daily efficiency and patient independence. One of the most effective rehabilitation methods is cognitive training (hereinafter referred to as CT), which represents special programs and techniques for training memory, attention, and other cognitive functions, as well as teaching compensation strategies or restoring lost functions [66]. CT can be implemented using specialized computer programs or in the format of individual or group sessions with a specialist.

Comments: computerized methods have demonstrated good efficacy in improving working memory in patients with cognitive impairment caused by alcohol use, whereas comprehensive programs that include problem-solving (skill-oriented) training and working memory training are effective for daily functioning [51,57,67]. In a randomized study involving 31 combat veterans with alcohol dependence syndrome and cognitive impairment—where the experimental group (15 patients) engaged in a computer program and listened to audio exercises for 5 hours per week for 13 weeks, along with occupational therapy for 15 hours per week, while the control group participated only in occupational therapy—it was found that verbal memory scores in the experimental patients were significantly higher after 3 months [68]. One of the most effective problem-solving training methods is "errorless" learning, which relies on the following principles: step-by-step presentation of a daily task, and if the patient fails to perform a step within 2 seconds, the specialist gives a direct instruction in the format of "we take this basket", "open the box", "close the door". An important distinction from conventional learning is the immediate instruction and the avoidance of any commentary regarding incorrect actions.

The results of studying "errorless learning", proposed at the Korsakoff Center in the Netherlands, demonstrated that patients with AS who underwent "errorless" learning had a significantly better level of daily functioning (training was conducted using a washing machine as an example) compared to training that allowed for the possibility of errors [69]. In this study, patients underwent training for 4 weeks and were tested 6 "control" times 4 weeks after the end of training; there were 8 patients in each of the experimental and control groups. A similar method was used for memorizing routes in a study with 10 patients [70]. Subsequently, this method was tested in a study involving 83 patients with AS, 52 of whom underwent "errorless learning" and 31 did not. As a result, improvements in daily functioning and the subjective perception of quality of life were identified in the experimental group, alongside a reduction in confabulations and affective disorders [71,72]. This method also showed efficacy in a study on a Japanese population [73]. As with other psychotherapeutic methods, the main difficulty in assessing interventions is the impossibility of blinding, which makes the interpretation of results challenging. In an early study involving comprehensive cognitive training for 5 patients with AS and group therapy sessions including games, walks, news discussions, and social activities for another 5 patients with AS, no differences were found between the groups, and cognitive improvement was achieved in both groups [74].

Currently, there are collections of methodological recommendations with detailed descriptions of tasks: "Cognitive Training for Patients with Mild Cognitive Impairment" [75] and "Cognitive Training: Intelligence and Speech Exercises in Old Age" [76].

5. Prevention and Dispensary Observation

Dispanser observation (clinical follow-up) is carried out in accordance with the Procedure for Dispensary Observation of Individuals with Mental Disorders and (or) Behavioral Disorders Associated with Psychoactive Substance Use (Appendix A3) [19].

Comments: dispensary observation is carried out: during the first year of remission—at least once a month; for those in remission from 1 to 2 years—at least once every six weeks; for those in remission over 2 years—at least once every three months. The grounds for terminating dispensary observation in patients diagnosed with "dependence syndrome" include the presence of: confirmed sustained remission for at least three years; confirmed sustained remission for at least two years provided that the patient independently sought medical care in the specialty "psychiatry-narcology" and has no court-mandated obligation to undergo diagnostics, preventive measures, treatment, and/or medical and/or social rehabilitation in connection with the use of narcotic drugs or psychotropic substances without a doctor's prescription or new potentially dangerous psychoactive substances.

Comments: the frequency of visits to the psychiatrist-narcologist after the establishment of sustained remission is determined individually by the attending psychiatrist-narcologist and averages once every 3–6 months.

GCR CLEL 5Grade of Recommendations C (Level of Evidence 5)

6. Organization of Medical Care

Treatment for AS can be carried out in inpatient settings (including day hospitals) and outpatient settings. The duration of treatment is determined by the dynamics of the patient's condition; in the absence of positive dynamics and the persistent nature of severe disorders, continuous monitoring of the patient may be required [19,21,62]. Treatment for moderate AS (memory impairment for past and present events, disorientation in place and time, signs of retrograde and anterograde amnesia) and severe AS (helplessness and life-threatening conditions associated with amnesic disorientation, inability to care for oneself; false memories) is carried out in conditions that provide round-the-clock medical supervision. Inpatient treatment duration is up to 90 days [19]. Patients with moderate and severe AS whose cognitive disorders persist for over 90 days should be provided with a medical commission involving a neurologist and a psychiatrist to address the following issues:

- differential diagnosis and/or the presence of comorbid pathology;

- transfer to a medical organization providing psychiatric care in inpatient settings;

- the need for medical and social expertise (disability evaluation);

- the necessity of filing a petition in court to declare an individual legally incapacitated [19].

Comments: the provisional diagnosis of alcohol-induced AS is established within the first 24 hours based on clinical examination data. The final diagnosis is established within 3–7 days based on clinical examination data, instrumental and laboratory findings, and dynamic observation [26].

6.1. Indications for hospitalization:

Upon hospitalization of a patient presenting with AS who requires involuntary hospitalization, the medical documentation must provide a detailed description of the patient's mental state, clearly indicating that it meets one of the three criteria for involuntary hospitalization: the patient's direct danger to themselves or others, their helplessness (i.e., inability to independently satisfy basic life needs), or significant harm to their health due to deterioration of their mental state if the person is left without psychiatric care.

Presence of neurological disorders accompanying alcohol-induced AS.

Lack of clinical response to ongoing outpatient therapy.

6.2. Indications for outpatient treatment:

Presence of AS of any severity.

6.3. Indications for discharge:

Discharge of a patient diagnosed with alcohol-induced AS may be performed in the event of clinical improvement of the patient's condition, taking into account the ability to provide care and/or self-care.

7. Additional Information

No additional information available.

Criteria for Evaluating the Quality of Medical Care

Quality of care criteria for specialized medical care in AS (ICD-10 code: F10.6)

References

Appendix A1. Working Group Composition

Co-Chairs:

Klimenko Tatiana Valentinovna, MD, Prof.

Krupitsky Evgeny Mikhailovich, MD, Prof.

Masyakin Anton Valerievich, MD, Assoc. Prof.

Secretary:

Gubanov Georgy Alexandrovich.

Working Group Members:

Agibalova Tatiana Vasilievna, MD

Arkus Maxim Leonidovich, PhD

Buzik Oleg Zhanovich, MD

Korchagina Galina Alexandrovna, MD, Prof.

Lobacheva Anna Stanislavovna, PhD

Mikhailov Mikhail Albertovich, MD

Nadezhdin Alexey Valentinovich, PhD

Nenastyeva Anna Yuryevna, PhD

Poplevchenkov Konstantin Nikolaevich, PhD

Rybakova Ksenia Valerievna, MD

Tetenova Elena Yuryevna, PhD

Utkin Sergey Ionovich, PhD

Authors:

• Vinnikova Maria Alekseevna, Doctor of Medical Sciences, Professor. Russian Society of Psychiatrists.

• Severtsev Vsevolod Vladislavovich, Candidate of Medical Sciences. Russian Society of Psychiatrists.

Conflict of interest: none

All members of the working group have confirmed the absence of financial support / conflicts of interest that need to be disclosed.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. Psychiatrist-addictologist

2. District psychiatrist-narcologist

3. Adolescent psychiatrist

4. Psychiatrist

5. District psychiatrist

6. Psychotherapist

7. Medical psychologist

The following information resources were used in the development of these clinical guidelines:

• Order of the Russian Ministry of Health No. 103n dated February 28, 2019 (as amended on June 23, 2020) "On Approval of the Procedure and Timeframes for the Development of Clinical Guidelines, Their Revision, the Standard Form of Clinical Guidelines and Requirements for Their Structure, Composition, and Scientific Validity of Information Included in Clinical Guidelines" (with amendments and additions that entered into force on August 4, 2020).

• Analysis of scientific literature sources and other data, as well as internet resources over the past 10 years:

  - domestic: medical guidelines, scientific publications in periodicals, e-library scientific electronic library, State Register of Medicines, Register of Medicines, Federal State Statistics Service of the Russian Federation;

  - foreign: Cochrane Library, Medline, MedScape, PubMed, National Institute on Alcohol Abuse and Alcoholism (NIAAA), Substance Abuse and Mental Health Services Administration (SAMHSA), European Monitoring Centre for Drugs and Drug Addiction (EMCDDA)

  - regulatory documents of the Government of the Russian Federation and the Ministry of Health of the Russian Federation.

Rating schemes for assessing the levels of evidence certainty (1, 2, 3, 4, 5) and the levels of recommendation consensus (A, B, C) were used in the development of these clinical guidelines.

Appendix A2.1 – Level of Evidence Certainty (LEC) Rating Scale for Diagnostic Methods (Diagnostic Interventions)

Appendix A2.2 - Level of Evidence Certainty (LEC) Rating Scale for Prevention, Treatment, and Rehabilitation Methods (Preventive, Therapeutic, Rehabilitative Interventions)

Appendix A2.3 - Level of Recommendation Consensus (LRC) Rating Scale for Prevention, Diagnostic, Treatment, and Rehabilitation Methods (Preventive, Diagnostic, Therapeutic, Rehabilitative Interventions)

Appendix A2.4 - Rating Scheme for Evaluating the Level of Recommendation Consensus (LRC) for Therapeutic, Rehabilitative, and Preventive Interventions

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of AS, or upon the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Order of the Russian Ministry of Health No. 1034n dated December 30, 2015 "On Approval of the Procedure for Providing Medical Care in the Field of 'Psychiatry-Addictology' and the Procedure for Dispensary Observation of Individuals with Mental and (or) Behavioural Disorders Associated with Psychoactive Substance Use" (with amendments and additions).

2. Order of the Russian Ministry of Health No. 103n dated February 28, 2019 (as amended on June 23, 2020) "On Approval of the Procedure and Timeframes for the Development of Clinical Guidelines, Their Revision, the Standard Form of Clinical Guidelines and Requirements for Their Structure, Composition, and Scientific Validity of Information Included in Clinical Guidelines" (with amendments and additions that entered into force on August 4, 2020).

3. Article 29 of the Law of the Russian Federation No. 3185-1 dated July 2, 1992 (as amended on August 4, 2023) "On Psychiatric Care and Guarantees of Citizens' Rights in Its Provision".

4. Order of Roszdravnadzor No. 3518 dated June 17, 2024 "On Approval of the Pharmacovigilance Procedure for Medicinal Products for Medical Use."

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Amnestic syndrome is a mental disorder that occurs in individuals who regularly and chronically consume alcohol.

What factors provoke the development of amnestic syndrome?

– Prolonged and/or systematic alcohol consumption.

– Liver disease.

– History of psychosis (delirium tremens) resulting from alcohol use.

– Inadequate intake of minerals and vitamins (especially vitamin B1) resulting from poor, inadequate nutrition, vomiting, or diarrhea.

What are the symptoms of amnestic syndrome?

As a rule, amnestic syndrome develops after severe delirium, but it can also occur without severe preceding disturbances of consciousness. A person suffering from amnestic syndrome is characterized by confusion in the chronological sequence of events, difficulties in memorizing new information, and depressed mood. They recount events from the distant past of their everyday life or professional activities as if they had just occurred (for example, a patient who has not left the clinic for several weeks says that yesterday they went to the country house, dug the soil, planted seedlings, etc.). Sometimes fantastic, adventurous statements are observed. A decrease in pain, temperature, and tactile sensitivity in the arms and legs, instability, and an unsteady gait may be observed. The degree of damage to the nerves of the legs can vary from mild gait disturbances to a complete inability to move independently. Recovery, if it occurs, is extremely rare and happens within a year from the onset of psychosis, i.e., the disease inevitably becomes chronic. Most often, a pronounced lifelong memory impairment develops.

Who can make a diagnosis?

Amnestic syndrome is diagnosed and treated by psychiatrists and addiction psychiatrists (psychiatrists-narcologists). Diagnosis is based on identifying characteristic signs of the disease. You should seek medical help, because to confirm the diagnosis, it is necessary to exclude the presence of other serious diseases that can cause similar symptoms.

Treatment and prognosis.

The objectives of therapeutic measures are: correction of memory disorders; improvement of the somatic and neurological state, as well as the emotional sphere; development of a commitment to alcohol abstinence, long-term therapy for alcohol dependence, and rehabilitation.

Modern treatment strategies include medication, as well as active methods of cognitive restoration. It is important that medications have limited effectiveness in such situations and cannot restore a person's condition to the previous, pre-morbid level, and non-pharmacological methods play a huge role precisely because they allow patients to regain lost or impaired abilities.

Unfortunately, treatment for amnestic syndrome is not always effective. Patients with amnestic syndrome often require constant support and assistance even in daily activities. In severe cases, the patient cannot fully take care of themselves and needs round-the-clock care, as well as the establishment of legal incapacity.

How can I help myself and my loved one?

1. Refraining from alcohol consumption in any amounts and forms, including pharmacy tinctures.

2. Involvement in an active and healthy lifestyle: maintaining a sleep-wake schedule, ensuring proper nutrition, and maintaining physical activity—all of this plays a major role in restoring and preserving mental abilities.

3. Sources of B vitamins include: The main source of vitamin B1 is plant-based foods: grains, cereals, bran, sprouted grains, nuts, seeds, and legumes. At the same time, it should be remembered that bran contains almost twice as much thiamine as ready-to-eat cereals. Meat, dairy products (fresh and fermented), fish, herbs, and vegetables on average contain up to 10% of the daily allowance of B1. Vitamin B6 is found in nuts (pistachios, peanuts, hazelnuts), seeds (sunflower, sesame), wheat bran, garlic, beans, soybeans, marine fish (tuna, salmon, mackerel, pink salmon), and sweet peppers. Dairy products contain from 2 to 20% of the daily requirement of pyridoxine. Vitamin B12 is found only in animal products: liver, heart, poultry meat, marine fish and seafood, and eggs.

4. Strictly follow the prescriptions of the doctor and other specialists, whether taking medications or taking daily walks.

5. If you have chronic diseases of the heart, liver, stomach, pancreas, etc., periodically visit a doctor to carry out necessary measures to prevent possible exacerbations.

6. If you have any complaints about your well-being, even those that quickly disappeared, you should consult doctors: if you have tremor, gait instability, dizziness – a neurologist; if you have shortness of breath, sweating, fatigue, edema – a general practitioner (therapist); if you have insomnia, mood swings, aggressiveness – a psychiatrist and addiction psychiatrist (psychiatrist-narcologist).

7. Use exercises to improve cognitive functions independently in any accessible format (computer programs, audio or video recordings, books, etc.).

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. MoCA Scale

Russian title: Montreal Cognitive Assessment

Original title: The Montreal Cognitive Assessment (MoCA-test)

Source (official developer website, validation publication): www.mocatest.org

Freud T. et al. Validation of the Russian Version of the MoCA Test as a Cognitive Screening Instrument in Cognitively Asymptomatic Older Individuals and Those With Mild Cognitive Impairment // Front Med (Lausanne). 2020. Vol. 7. P. 447.

Type (underline): rating scale; index; questionnaire; other (specify):_____________

Purpose: detection (screening) and assessment of the severity of cognitive impairment

Content (template):

Option No. 1

Alternative versions of the MoCA test (used when examining a patient dynamically, assessment is carried out similarly to the method described above for Option No. 1)

Option No. 2

Option No. 3

Key (interpretation):

The Montreal Cognitive Assessment (MoCA test) was developed as a quick assessment tool for mild cognitive impairment (MCI). It assesses various cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, abstract thinking, calculation, and orientation. The time to administer the MoCA test is approximately 10 minutes. The maximum possible score is 30; 26 points and above is considered normal. 25 and below indicate the presence of cognitive impairment.

1. Alternating Trail Making: The investigator instructs the subject: "Please draw a line, going from a number to a letter in ascending order. Begin here [point to (1)] and draw a line from 1, then to A, then to 2 and so on. End here [point to (D)]."

Scoring: One point is awarded if the subject successfully draws a line in the following order: 1-A-2-B-3-C-4-D-5-E, without intersecting lines. Any error that is not immediately self-corrected by the subject earns 0 points.

2. Visuoconstructional Skills (Cube):

Administration: The investigator gives the following instructions, pointing to the cube: "Copy this drawing as accurately as you can in the space below the drawing."

Scoring: One point is allocated for a correctly executed drawing:

- Drawing must be three-dimensional;

- All lines are drawn;

- No extra lines are added;

- Lines are relatively parallel and their length is similar (a rectangular prism is acceptable).

A point is not awarded if any of the above-mentioned criteria are not met.

3. Visuoconstructional Skills (Clock):

Administration: Point to the right third of the space on the sheet and give the following instructions: "Draw a clock. Put in all the numbers and set the time to 11 past 11 (ten past eleven)."

Scoring: One point is awarded for each of the following three criteria:

- Contour (1 point): The clock face must be a circle with only minor distortion (e.g., slight imperfection in closing the circle);

- Numbers (1 point): All clock numbers must be present, with no extra numbers; numbers must be in the correct order and placed in the appropriate quadrants on the clock face; Roman numerals are acceptable; numbers can be placed outside the clock face contour;

- Hands (1 point): There must be two hands jointly indicating the correct time; the hour hand must clearly be shorter than the minute hand; the hands must be centered with their junction close to the center.

No point is allocated for this item if any of the above-mentioned criteria are not met.

4. Naming:

Administration: Beginning on the left, point to each figure and say: "Name this animal."

Scoring: One point is awarded for each of the following responses: (1) camel or dromedary, (2) lion, (3) rhinoceros.

5. Memory:

Administration: The investigator reads a list of 5 words at a rate of one word per second, giving the following instructions: "This is a memory test. I am going to read a list of words that you will have to remember. Listen carefully. When I am through, tell me as many words as you can remember. It doesn't matter in what order you say them." Mark a check in the designated space for each word the subject names on the first trial. When the subject indicates that they have finished (named all words), or can recall no more words, read the list a second time with the following instructions: "I am going to read the same list for a second time. Try to remember and tell me as many words as you can, including the words you said on the first trial." Mark a check in the designated space for each word the subject repeats on the second trial. At the end of the second trial, inform the subject that they will be asked to recall these words again: "I will ask you to recall those words again at the end of the test."

Scoring: No points are given for either the first or the second trials.

6. Attention:

Forward Digit Span:

Administration: Give the following instructions: "I am going to say some numbers and when I am through, repeat them to me exactly as I said them." Read the five numbers sequentially at a rate of one per second.

Backward Digit Span:

Administration: Give the following instructions: "I am going to say some numbers, but when I am through, you must repeat them in the reverse order." Read the three numbers sequentially at a rate of one per second.

Scoring: Give 1 point for each successfully repeated sequence (N.B.: the correct response for the backward span is 2-4-7).

Vigilance:

Administration: The examiner reads a list of letters at a rate of one per second, following these instructions: "I am going to read a sequence of letters. Every time I say the letter A, tap your hand once. Do not tap your hand if I say a different letter."

Scoring: Give 1 point if there is either zero or only one error (an error is a tap on a wrong letter or a failure to tap on letter A).

Serial 7s:

Administration: The examiner gives the following instructions: "Now I will ask you to subtract 7 from 100, and then keep subtracting 7 from your answer until I tell you to stop." Repeat the instructions if necessary.

Scoring: This item is scored out of 3 points. Give 0 points for no correct subtractions, 1 point for one correct subtraction, 2 points for two to three correct subtractions, and 3 points if the subject performs four or five correct subtractions. Count each correct subtraction of 7 starting from 100. Each subtraction is scored independently; thus, if a participant gives an incorrect answer but then continues to accurately subtract 7 from it, give a point for each accurate subtraction. For example, a participant might answer "92-85-78-71-64", where "92" is incorrect, but all subsequent values are subtracted correctly. This is one error, and this item receives 3 points.

7. Sentence repetition:

Administration: The examiner gives the following instructions: "I am going to read you a sentence.

Repeat it exactly as I say it (pause): I know that John is the only one who can help today." Following the response, say: "Now I am going to read you another sentence. Repeat it exactly as I say it (pause): The cat always hid under the couch when the dogs were in the room."

Scoring: Allocate 1 point for each correctly repeated sentence. Repetition must be exact. Listen closely for errors due to word omissions (e.g., omitting "only", "always") and substitutions/additions (e.g., "John is the only one who helped today"; replacing "hid" with "was hiding", using plural forms, etc.).

8. Verbal fluency:

Administration: The examiner gives the following instructions: "Tell me as many words as you can think of that start with a particular letter of the alphabet that I will tell you. You can name any type of word, except for proper nouns (such as Peter or Moscow), numbers, or words that begin with the same sound but have different suffixes, such as love, lover, loving. I will stop you after one minute. Are you ready? (Pause) Now, tell me as many words as you can think of that start with the letter F. (Time: 60 sec). Stop."

Scoring: Allocate 1 point if the subject names 11 words or more in 60 seconds. Record the responses at the bottom or on the side of the page.

9. Abstraction:

Administration: The examiner asks the subject to explain what each pair of words has in common, starting with an example: "Tell me what an orange and an apple have in common." If the patient answers in a concrete manner, say only once more: "Tell me another way they are alike." If the subject does not give the correct answer (fruit), say, "Yes, and they are also both fruits." Do not give any other instructions or explanations.

After the trial attempt, say: "Now, tell me what a train and a bicycle have in common." After the response, give the second task by asking: "Now, tell me what a ruler and a watch have in common." Do not give any other instructions or prompts.

Scoring: Only the last two pairs of words are scored. 1 point is given for each correct answer.

The following answers are considered correct:

Train-bicycle = modes of transport, means of travel, you can ride on both;

Ruler-watch = measuring instruments, used for measuring.

The following answers are not considered correct:

Train-bicycle = they have wheels;

Ruler-watch = they have numbers on them.

10. Delayed recall:

Administration: The examiner gives the following instructions: "I previously read a list of words to you and asked you to remember them. Tell me as many words as you can remember." Make a mark for each word correctly recalled without a cue in the designated space.

Scoring: Allocate 1 point for each word recalled without any cues.

Optional: Following the delayed free recall trial, provide the subject with a semantic category cue for each uncued word. Make a mark in the designated space if the subject recalled the word using a category cue or a multiple-choice cue. Prompt all words that the subject did not recall in this manner. If the subject fails to recall a word after the category cue, give him/her a multiple-choice cue using the following instructions: "Which of the following words do you think it was: NOSE, FACE, or HAND?" Use the following category cues and/or multiple-choice cues for each word:

FACE category cue: body part; multiple choice: nose, face, hand

VELVET category cue: type of fabric; multiple choice: denim, cotton, velvet

CHURCH category cue: type of building; multiple choice: church, school, hospital

DAISY category cue: type of flower; multiple choice: rose, tulip, daisy

RED category cue: color; multiple choice: red, blue, green

Scoring: No points are awarded for cued word recall. Cues are used for informational clinical purposes only and may provide the test interpreter with additional information regarding the type of memory impairment. In memory impairment due to retrieval deficits, performance improves with cueing. In memory impairment due to encoding deficits, test performance does not improve after cueing.

11. Orientation:

Administration: The examiner gives the following instructions: "Tell me today's date." If the subject does not give a complete answer, provide the appropriate prompt: "Tell me (the year, month, exact date, and day of the week)." Then say: "Now, tell me this place and the city it is located in."

Scoring: Allocate 1 point for each correctly named item. The subject must name the exact date and exact place (name of the hospital, clinic, outpatient clinic). No point is awarded if the patient makes an error in the day of the week or the date.

Total score: Sum all scores in the right column. Add one point if the patient has 12 years of education or fewer, up to a maximum possible score of 30 points.

Notes: none

Appendix G2. Naranjo Algorithm

Russian title: Naranjo algorithm for assessing the causal relationship "adverse drug reactions (hereinafter – ADR) – drug"

Original title: Naranjo algorithm

Source (official developer website, validation publication): Naranjo C.A., Busto U., Sellers E.M., et al. A method for estimating the probability of adverse drug reactions. Clinical Pharmacology and Therapeutics. 1981; 30(2):239-245. DOI: 10.1038/clpt.1981.154

Type (underline): rating scale; index; questionnaire; other (specify):_____________

Purpose: The Naranjo algorithm is used to assess the probability of a relationship between a drug and an adverse drug reaction. When determining the degree of certainty of the "drug–ADR" relationship, this questionnaire is focused on obtaining specific answers scored in points. A certain number of points corresponds to a specific degree of probability.

Content (template):

Key (interpretation):

Categories of probability for the "ADR–drug" relationship based on the Naranjo scale from the 10-question responses are defined as:

Notes: none