Toxic and metabolic disorders of the nervous system: clinical guidelines

List of Abbreviations

AAZ – alcohol-associated diseases

AZN – optic nerve atrophy

ALT – alanine aminotransferase

AST – aspartate aminotransferase

ATP – adenosine triphosphate

NCSE – non-convulsive status epilepticus

IV – intravenous

i.m. – intramuscularly

GABA – gamma-aminobutyric acid

HBO – hyperbaric oxygenation

GCS – glucocorticosteroids (ATC H02AB Glucocorticoids)

GHB – gamma-hydroxybutyric acid

DWI – diffusion-weighted imaging

DNA – deoxyribonucleic acid

GI – gastrointestinal tract

CNI – calcineurin inhibitors

NCS – nerve conduction study

TNF-i – Tumor necrosis factor inhibitors

CT – computed tomography

LSD – lysergic acid diethylamide (Ger. Lysergsäurediethylamid)

PT – physical therapy

ICD – International Classification of Diseases

MRI – magnetic resonance imaging

NSAIDs – non-steroidal anti-inflammatory and antirheumatic drugs

CVA – cerebrovascular accident

ASP – acute symptomatic seizure

PSA – psychoactive substances

MUAP – motor unit action potential

SNAP – sensory nerve action potential

PNP – polyneuropathy

PNS – peripheral nervous system

LPO – lipid peroxidation

РКИ – randomized controlled trial

RF – Russian Federation

DM – diabetes mellitus

ADS – alcohol dependence syndrome

ESR – erythrocyte sedimentation rate

CRP – C-reactive protein

USA – United States of America

US – ultrasound examination

OPC – organophosphorus compounds

CAI – chronic alcoholic intoxication

CNS – central nervous system

COX – cyclooxygenase

GCS – Glasgow Coma Scale

ALP – alkaline phosphatase

WE – Wernicke's encephalopathy

ENMG – stimulation electroneuromyography (Single nerve stimulation electroneuromyography)

EMG – needle electromyography (Needle electrode electroneuromyography (single nerve))

EEG – electroencephalography

EEG with FP – electroencephalography with functional tests (Electroencephalography with activation procedures)

CHANTER – Cerebellar Hippocampal and Basal Nuclei Transient Edema with Restricted diffusion

DUDIT – Drug Use Disorders Identification Test

FLAIR – Fluid-attenuated inversion recovery

FOUR – Full Outline of UnResponsiveness

MMSE – Mini-Mental State Examination

MNSI – The Michigan Neuropath Screening Instrument

MoCA – Montreal Cognitive Assessment

NSS – Neuropathy Symptom Score

RCVS – reversible cerebral vasoconstriction syndrome

PRES – posterior reversible encephalopathy syndrome

RUS-AUDIT – Russian Alcohol Use Disorders Identification Test

Terms and Definitions

Withdrawal syndrome (withdrawal state) – a cluster of symptoms of variable grouping and severity arising upon complete cessation of a substance use or reduction of its dose following repeated, usually prolonged and/or high-dose use of that substance. The onset and course of the withdrawal state are limited in time and correspond to the type of substance and the dose immediately preceding abstinence (ICD-10).

Alcoholic polyneuropathy – damage to the peripheral nervous system caused by alcohol consumption, most commonly due to nutritional vitamin deficiency, primarily vitamin B1 deficiency, and manifested by signs of symmetrical damage predominantly to the distal parts of peripheral nerves.

Alcoholic encephalopathy – brain damage caused by alcohol consumption, manifesting as a cerebral symptomatology in the form of mental, neurological, and autonomic disorders of varying severity, sometimes combined with signs of myelopathy and polyneuropathy. Depending on the course features, alcoholic encephalopathy can be acute as a result of severe metabolic disruption, and chronic due to neurodegeneration caused by prolonged systematic alcohol consumption.

Ambivalence – a frequently observed contradictory, dual attitude of the patient when, during a motivational interview with a physician or medical psychologist, they voice arguments both for stopping the use of PSAs and/or changing the frequency and/or amount of PSAs used, and for maintaining their habitual lifestyle (habitual pattern of PSA use, habitual frequency and quantity characteristics of PSAs used).

Diabetic polyneuropathy – a complex of clinical and subclinical syndromes, each characterized by diffuse or focal damage to peripheral and/or autonomic nerve fibers as a result of diabetes mellitus.

Motivational interview – a specific method of non-directive dialogue between a patient and a medical organization specialist aimed at exploring the patient's motivation and increasing their readiness to stop PSA use or reduce the frequency and amount of PSAs used.

Motivational counseling – a clinical conversation with a patient suffering from PSA dependence, aimed at establishing goal-setting regarding sobriety and increasing treatment adherence. The method is based on the idea that people are more inclined to change their beliefs and behavior if they arrive at conclusions themselves rather than being told what needs to be changed. It is a managed dynamic process aimed at identifying, analyzing, and overcoming ambivalence regarding significant changes by engaging the patient's internal motivation to alter problematic behavior.

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

Drug addiction – a disease caused by dependence on a narcotic drug or psychotropic substance (Federal Law No. 3-FZ dated January 8, 1998, "On Narcotic Drugs and Psychotropic Substances").

Narcotic drugs – substances of synthetic or natural origin, preparations included in the List of Narcotic Drugs, Psychotropic Substances, and Their Precursors Subject to Control in the Russian Federation, in accordance with the legislation of the Russian Federation, international treaties of the Russian Federation, including the Single Convention on Narcotic Drugs of 1961 (as amended by Federal Law No. 87-FZ dated May 19, 2010; Federal Law No. 3-FZ dated January 8, 1998, "On Narcotic Drugs and Psychotropic Substances").

New potentially dangerous psychoactive substances – substances of synthetic or natural origin included in the Register of New Potentially Dangerous Psychoactive Substances, the turnover of which is prohibited in the Russian Federation (Federal Law No. 3-FZ dated January 8, 1998, "On Narcotic Drugs and Psychotropic Substances").

Drug-induced polyneuropathies – various variants of toxic and dysmetabolic polyneuropathies arising from prolonged treatment with certain medicinal products.

Polyneuropathy – a term encompassing poisonings by various toxicants characterized by multiple lesions of peripheral nerves.

Precursors of narcotic drugs and psychotropic substances (precursors) – substances frequently used in the production, manufacture, and processing of narcotic drugs and psychotropic substances, included in the List of Narcotic Drugs, Psychotropic Substances, and Their Precursors Subject to Control in the Russian Federation in accordance with the legislation of the Russian Federation.

Preventive counseling – informing the patient about their existing risk factors for chronic non-communicable diseases and providing recommendations on lifestyle modification.

Psychoactive substances – psychotropic substances possessing addictive properties. PSAs are capable of inducing positive emotional experiences upon single use, and physical and psychological dependence upon systematic use.

Psychotropic substances – substances of synthetic or natural origin, preparations, natural materials included in the List of Narcotic Drugs, Psychotropic Substances, and Their Precursors Subject to Control in the Russian Federation, in accordance with the legislation of the Russian Federation, international treaties of the Russian Federation, including the Convention on Psychotropic Substances of 1971 (Federal Law No. 3-FZ dated January 8, 1998, "On Narcotic Drugs and Psychotropic Substances").

Dependence syndrome – a cluster of physiological, behavioral, and cognitive phenomena in which the use of a substance or a class of substances takes on a much higher priority for a given individual than other behaviors that once had greater value. A central descriptive characteristic of the dependence syndrome is the desire (often strong, sometimes overpowering) to take psychoactive substances (which may or may not have been medically prescribed), alcohol, or tobacco. It has characteristic symptoms, specific features of development and course, and definite outcomes (ICD-10).

Alcohol dependence syndrome (alcoholism) – a combination of somatic, behavioral, and cognitive phenomena in which alcohol consumption takes priority in the patient's value system. Alcohol dependence syndrome has characteristic features of development, course, and outcomes determined by persistent somatoneurological disorders, mental degradation, and the presence of social problems (ICD-10).

Screening – individual and mass examination of individuals who do not consider themselves sick, in order to identify those who presumably have a certain disease and/or risk factor for its development.

Resistance – a frequently observed negative reaction of the patient to excessive pressure from a physician or medical psychologist when urging the patient to stop PSA use and/or change the frequency and/or amount of PSAs used. During resistance, the patient may refuse to continue interaction; formally agree with the need to stop PSA use while at the medical organization, but subsequently adhere to habitual behavior.

Substance abuse substances – psychoactive substances not included in the List of Narcotic Drugs, Psychotropic Substances, and Their Precursors Subject to Control in the Russian Federation, approved by the Government of the Russian Federation.

Substance use disorder – dependence on psychoactive substances, excluding alcohol, narcotic drugs, and psychotropic substances.

Toxic myelopathy – spinal cord damage resulting from intoxications, accompanied by spinal disorders.

Toxic polyneuropathy (polyneuritis) – peripheral nervous system damage resulting from intoxications, accompanied by signs of peripheral nerve damage of the polyneuropathic type.

Toxic encephalopathy – brain damage resulting from intoxications, accompanied by cerebral disorders.

Encephalopathy – a general non-infectious brain lesion in which degenerative processes develop due to various causes (hypoxia, dyscirculatory disorders, traumatic brain injury, dysmetabolic processes, exogenous and endogenous intoxications, electrolyte disturbances, etc.).

Symptoms:

Allodynia – pain resulting from a non-painful stimulus, which can be contact (tactile/mechanical or thermal allodynia) or movement-induced (movement-induced or kinesiogenic allodynia).

Anesthesia – complete impairment of single or multiple modalities of sensation (tactile, thermal, proprioceptive, vibratory).

Non-convulsive status epilepticus – a clinical-electroencephalographic syndrome manifested by sudden onset of stupor or coma, confusion, mutism, psychomotor slowing, and automatisms.

Hyperalgesia – increased sensitivity to painful stimuli: intense pain upon mild nociceptive stimulation of the innervation zone of a damaged nerve segment (primary hyperalgesia) or adjacent and even distant zones (secondary hyperalgesia).

Hyperesthesia – increased sensitivity to various stimuli (tactile, warm, cold) that is disproportionate to the stimulus that caused it.

Hyperpathia – an enhanced or altered sensation with an unpleasant emotional component that may persist after the cessation of a painful, tactile, or thermal stimulus. The sensory threshold may be elevated.

Hypoesthesia – partial impairment of single or multiple modalities of sensation (tactile, thermal, proprioceptive, vibratory).

Dysesthesia – a pathological, unpleasant sensation that may occur spontaneously or be provoked.

Acute symptomatic seizure – an epileptic seizure occurring in response to an acute toxic, metabolic, infectious, or structural brain injury.

Paresis – decreased muscle strength.

Paresthesia – a spontaneous sensation or one induced by light tactile, thermal stimulation, or movement, experienced as tingling, crawling, pressure, or tightness in a body part.

Plegia – absence of muscle movement.

Spontaneous pain – pain occurring without any external stimulus.

Diagnostics:

M-wave amplitude – an ENMG (nerve conduction study) parameter that indirectly reflects the number of fascicles in the motor nerve trunk capable of conducting a nerve impulse.

Sensory nerve action potential amplitude – an ENMG (nerve conduction study) parameter that characterizes the functional state of a sensory nerve.

F-wave latency – an ENMG (nerve conduction study) parameter reflecting the nerve conduction velocity in the proximal segments of the peripheral nerves of the upper and lower extremities.

Stimulation electromyography of a single nerve (ENMG) / synonym – nerve conduction study (NCS) – a functional diagnostic method assessing the presence and severity of motor and sensory peripheral nerve impairment.

Electroencephalography – recording of the electrical activity of the brain using electrodes placed on the scalp, unless otherwise specified.

Electroencephalography with activation (functional) procedures – recording and analysis of the EEG during any intervention aimed at altering EEG activity during the EEG recording ¹.

Epileptiform activity (synonym – epileptiform discharge, epileptiform pattern) – electroencephalographic graphoelements or their combinations (patterns) recorded between or during an epileptic seizure².

DUDIT (Drug Use Disorders Identification Test) – a test for identifying disorders related to the use of drugs and psychotropic substances.

RUS-AUDIT (Russian Alcohol Use Disorders Identification Test) – the version of the AUDIT test adapted and validated for the Russian Federation for identifying alcohol use disorders.

Treatment:

Therapeutic physical culture – a group of medical rehabilitation methods characterized by the application of physical exercises to the patient.

Surgical treatment – a method of treating diseases by dividing and joining tissues during a surgical operation.

Level of evidence – the degree of certainty that the found effect of a medical intervention is true.

Grade of recommendation – the degree of certainty regarding the reliability of the intervention's effect and that following the recommendations will yield more benefit than harm in a specific situation.

Working group – two or more people of the same or different professions working together and in coordination to develop clinical guidelines and sharing joint responsibility for the results of this work.

_{¹Such interventions include: eye-closure, hyperventilation, and photic stimulation tests; sensory stimulation (acoustic, somatosensory, or painful); as well as the administration of medicinal products. The choice of the functional procedure is determined by clinical indications. When recording EEG with activation procedures in patients with impaired wakefulness, painful stimulation is most commonly used to assess EEG reactivity, and antiepileptic drugs are administered when non-convulsive status epilepticus is suspected.}

_{²An epileptiform graphoelement must meet at least 4 of 6 criteria: 1) a di- or triphasic sharp wave or spike, 2) a wave duration distinct from background activity (shorter or longer than background waves), 3) wave shape asymmetry: a steeply rising ascending phase and a less steep descending phase, 4) the sharp wave is followed by an associated slow wave, 5) the epileptiform discharge disrupts the structure of background activity, 6) the location of the negative and positive potential phases implies a source in the brain tissue corresponding to a radial, oblique, or tangential dipole.}

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Toxic and metabolic disorders of the nervous system are heterogeneous in etiology, level of involvement, and, consequently, clinical manifestations. CNS and PNS involvement can be conditionally distinguished.

1.1.1. Toxic lesion of the nervous system

1.1.1.1. Toxic lesion of the central nervous system

CNS involvement includes alcoholic and toxic encephalopathies, as well as reversible syndromes – posterior reversible encephalopathy syndrome and reversible cerebral vasoconstriction syndrome.

Alcoholic encephalopathy – brain damage caused by alcohol consumption, manifested by a cerebral symptom complex in the form of mental, neurological, and autonomic disorders of varying severity, sometimes combined with signs of myelopathy and polyneuropathy. It can be acute as a result of acute metabolic disruption and chronic due to neurodegeneration caused by chronic alcohol intoxication [1].

Wernicke's encephalopathy (Gayet-Wernicke syndrome)³ – a life-threatening condition caused by acute or chronic thiamine deficiency, accompanied by brainstem edema with the development of general cerebral and/or focal symptoms of central nervous system damage, requiring immediate treatment to prevent severe disability and death [2].

Toxic encephalopathy – a term combining structural and functional cerebral disorders resulting from exposure to various toxic agents, characterized by a complex of neuropsychiatric and somatovegetative disorders [3]. Depending on the neurotoxicant, several types of toxic encephalopathies are distinguished:

1) drug-induced;

2) induced by narcotic drugs and psychotropic substances;

3) metal-induced;

4) solvent- and industrial toxin-induced.

Posterior reversible encephalopathy syndrome (PRES) – a clinico-radiological syndrome with acute or subacute onset of neurological symptoms (headache, visual disturbance, seizures, altered consciousness) associated with predominant involvement of the white matter of the posterior regions of the brain [4, 5].

Reversible cerebral vasoconstriction syndrome (RCVS) is a collective term used to describe pathological conditions with a similar clinical and radiological presentation characterized by acute thunderclap headache and reversible segmental (multifocal) constriction of cerebral arteries [6].

1.1.1.2. Toxic lesion of the peripheral nervous system

In peripheral nervous system (PNS) lesions, peripheral neuropathies (PNPs) predominate—alcoholic, drug-induced (see 1.5 Classification of the disease or condition), and those caused by other toxic substances. Toxic PNPs are secondary axonal; in terms of symptom onset speed, they can be acute/subacute or chronic⁴ [7].

Polyneuropathy is a term combining poisonings by various toxicants characterized by multiple lesions of the peripheral nerves [7].

1.1.2. Metabolic lesion of the nervous system

1.1.2.1. Metabolic lesion of the central nervous system

Central nervous system (CNS) lesions may occur with the development of electrolyte disturbances (including hypo- and hypernatremia, hypo- and hypercalcemia), endocrine disorders (including hypo- and hyperglycemia, hypo- and hyperthyroidism, hypo- and hypercorticism), internal organ dysfunction (hepatic encephalopathy, uremic encephalopathy, hypercapnic encephalopathy), vitamin deficiencies (including non-alcoholic Wernicke encephalopathy), septic (sepsis, septic shock) and anoxic-ischemic states (cardiac arrest, shock) [8]. Changes may present as reversible syndromes—posterior reversible encephalopathy syndrome and reversible cerebral vasoconstriction syndrome.

1.1.2.2. Metabolic lesion of the peripheral nervous system

In PNS lesions, PNPs predominate—diabetic and those associated with other endocrine diseases and metabolic disorders. Metabolic PNPs are secondary axonal; in terms of symptom development speed—the rate of symptom progression—they can be acute/subacute or chronic⁵ [7].

Diabetic neuropathy is the most common chronic complication of diabetes mellitus, representing a heterogeneous group of conditions affecting various parts of the nervous system and presenting with diverse clinical manifestations [9].

Diabetic polyneuropathy is a complex of clinical and subclinical syndromes, each characterized by diffuse or focal damage to peripheral and/or autonomic nerve fibers as a result of diabetes mellitus [10].

_{³Wernicke encephalopathy can be of alcoholic and non-alcoholic origin.}

_{⁴Classification of PNPs: primary and secondary, axonal and demyelinating, acute/subacute and chronic [7].}

_{⁵Classification of PNPs: primary and secondary, axonal and demyelinating, acute/subacute and chronic [7].}

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

1.2.1. Etiology of toxic lesion of the nervous system

Neurotoxicity is the property of chemical substances or physical agents (neurotoxicants, neurotoxic substances) to damage the structure and/or function of the CNS/PNS. Toxic exposure can be direct—as a result of the direct action of the substance, mediated—via damage to other organs and systems; acute and chronic. The route of entry into the body includes oral, inhalation, transdermal, injection, via a bite, or multiple routes. Substances with direct neurotoxic action can cause functional or organic disorders [3].

1.2.1.1. Toxic lesion of the central nervous system

I. Alcoholic encephalopathy

Alcohol taken on an empty stomach reaches its maximum blood concentration in 40–80 minutes; full resorption takes 45 minutes to 3 hours, and the elimination phase lasts 5–12 hours. The severity of the toxic effect of ethanol depends on the amount and rate of alcohol administration, as well as individual sensitivity. Noticeable clinical manifestations of intoxication occur at a blood pure ethanol level of 1.5 g/L, pronounced ones at 3.5 g/L. The average lethal dose is 4–8 g/L and can reach 12 g/L [11].

Toxic effect of ethyl alcohol is due to its toxic properties as well as metabolic disturbances arising under the influence of ethanol biotransformation products, primarily acetaldehyde. Significant changes during alcohol intoxication occur in catecholamine, serotonin, acetylcholine, and GABA metabolism in brain tissues. Ethanol has an angiotoxic effect. Brain disorders are exacerbated by hypoxia, metabolic acidosis, and electrolyte shifts. A significant role in the development of alcoholic encephalopathy in toxic liver damage of alcoholic etiology is played by free ammonia; patients with liver failure develop pronounced neurological symptoms in the form of cognitive depression, agitation, followed by CNS depression and seizures [12, 13].

In chronic alcohol intoxication (CAI), blood plasma zinc and magnesium ion levels decrease, cortisol concentration increases, and lipid peroxidation processes are sharply activated, which alters neurotransmitter processes in the CNS, leads to changes in intracellular calcium content, imbalance of excitatory and inhibitory mediator systems, an increase in endoperoxides, neuronal apoptosis, demyelination, and cerebral cortex atrophy [13–15]. Nervous system damage in CAI is associated with both the direct toxic effect of ethanol and its metabolites and the emerging cascade of pathological processes resulting from nutrient deficiency, primarily thiamine [16–19].

Wernicke's encephalopathy (Gayet-Wernicke encephalopathy)

The highest prevalence of Wernicke's encephalopathy is recorded among patients with alcohol use disorder (AUD); it occurs against the background of thiamine deficiency, including as a result of malnutrition [20–22].

II. Toxic encephalopathy

Acute toxic encephalopathy develops as a result of microcirculatory disorders, hypoxia, and cerebral edema [3].

Drug-induced toxic encephalopathy

Table 1 presents a group of medicinal products possessing a greater degree of neurotoxicity [23–25].

Table 1. Medicinal products exhibiting neurotoxicity

Toxic encephalopathy caused by narcotic drugs and psychotropic substances.

In the Russian Federation, the List of Narcotic Drugs, Psychotropic Substances and Their Precursors Subject to Control is approved by Decree of the Government of the Russian Federation No. 681 dated June 30, 1998.

The mechanisms of neurotoxicity primarily involve oxidative stress, mitochondrial dysfunction, and cellular apoptosis [26]. Encephalopathy caused by opioid intoxication is toxic-hypoxic (decreased level of alertness, respiratory center depression); that caused by heroin is associated with vacuolar degeneration of the white matter in the cerebellum, occipital lobes, internal capsule, and corpus callosum [27]; and that caused by methadone is associated with necrosis resulting from impaired structure and function of the white matter mitochondria in the cerebral hemispheres and cerebellum, temporo-occipital cortex, hippocampus, and globus pallidus [28–30]. The primary mechanism of action of amphetamine is the release of catecholamines (dopamine, norepinephrine, and serotonin from presynaptic terminals), which leads to a hyperadrenergic state, while the formation of reactive oxygen species leads to toxic metabolites of dopamine and serotonin, and neuronal destruction [31, 32]. Methamphetamine exerts approximately twice the potency of amphetamine. The addition of an extra methyl group to the terminal amine significantly increases its CNS-stimulating effect [33]. Cathinones disrupt the metabolism of norepinephrine, dopamine, and serotonin, leading to an increase in their concentration in the synaptic cleft and exerting psychostimulatory and hallucinogenic effects. Synthetic cathinones (so-called "salts": α-pyrrolidinovalerophenone, mephedrone, flephedrone, etc.) are potent reuptake inhibitors of serotonin, dopamine, and norepinephrine [34]. GHB precursors—1,4-butanediol and γ-butyrolactone—exert a depressing effect on the CNS and possess euphoric and hypnotic properties. The severity of the toxic effect depends on the direct action of GHB (plasma concentration) [34–37] or indirect action (via the conversion of GHB to GABA). GHB also affects other neurotransmitter systems, notably dopamine, serotonin, acetylcholine, and noradrenergic systems [35–37].

Toxic encephalopathy caused by metals

Over 20 metals are considered neurotoxic to varying degrees [38]:

1. Essential (vital) – normally present in the body, but exhibit toxic effects when accumulated (iron, cobalt, manganese, copper, zinc).

2. Conditionally essential – present in the body, their role is undefined (vanadium, lithium, nickel, fluorine).

3. Toxic – absent from the body or present in minimal amounts, leading to toxicity manifestations upon an increase (aluminum, cadmium, methylmercury, arsenic, mercury, lead, thallium, uranium, antimony, barium).

The mechanisms of metal neurotoxicity mainly reduce to oxidative stress and mitochondrial dysfunction, while chronic poisoning involves the deposition of pathological proteins followed by neurodegeneration [39–55].

Toxic encephalopathy caused by solvents and industrial toxins

Organic solvents and alcohols enter the body via inhalation of their volatile vapors or through the skin and mucous membranes. They readily cross the blood-brain barrier (being lipophilic) and, by disrupting the myelin sheath of neurons, lead to diffuse white matter damage of the brain [49, 56] in the periventricular/subcortical areas, and in some cases, mild cerebral cortical atrophy [57, 58]. Prolonged or excessive exposure to organic solvents can lead to the development of encephalopathy [58, 59].

Pesticides, including organophosphorus compounds. The mechanism of pesticide neurotoxicity is associated with mitochondrial dysfunction and oxidative stress [60].

III. Reversible syndromes

Posterior reversible encephalopathy syndrome (PRES) – vasogenic edema of the cerebral white matter, symmetric, most commonly distributed within the white matter of the parietal, occipital, and temporal lobes. It is caused by a breakdown of the blood-brain barrier, arterial hypertension exceeding the limits of cerebral blood flow autoregulation, and reversible cerebral vasoconstriction syndrome [61, 62]. PRES is caused by the intake of medications or drugs (20–60% of cases): immunosuppressants (cyclosporine**, tacrolimus**, methotrexate**, sirolimus, etc.), antineoplastic agents (cytarabine**, cisplatin**, gemcitabine**, oxaliplatin**, bevacizumab**, ipilimumab**, etc.), protein kinase inhibitors (sorafenib**, sunitinib**, etc.), epoetin beta**, indinavir, ivabradine**, high-dose methylprednisolone**, immunoglobulins, contrast agents (for coronary or cerebral angiography); amphetamine, cocaine, synthetic cathinones, mephedrone [61]; and clinical conditions such as arterial hypertension (crisis), preeclampsia, eclampsia, infection / sepsis / shock, autoimmune diseases, post-chemotherapy, and transplantation, including bone marrow or stem cell transplantation [4, 5, 8, 63].

Reversible cerebral vasoconstriction syndrome (RCVS) – pathogenesis is not definitively established; a trigger and bodily predisposition are hypothesized (dysregulation of cerebral arterial tone, sympathetic hyperactivity, excessive oxidative stress, blood-brain barrier disruption, altered trigeminovascular nociception, genetic predisposition, sex hormones, and inflammation [6, 8, 63]; the leading mechanisms are vascular tone impairment and endothelial dysfunction [64]), caused by the intake of medications or drugs (60% of patients) or occurring "spontaneously" (40% of patients) [65]. Medications: glucocorticoids, varenicline, mycophenolate mofetil**, aripiprazole, trazodone, interleukin inhibitors (erenumab, ustekinumab**, and tocilizumab**), leuprorelin**, anastrozole**, as well as drugs belonging to triptans and selective serotonin reuptake inhibitors [66–68]. Drugs: synthetic cathinones, cannabimimetics, cocaine, and nicotine. Clinical conditions: cerebral vascular surgery (including carotid endarterectomy) in genetically predisposed individuals, eclampsia/preeclampsia, migraine, hypercalcemia, porphyria, pheochromocytoma, red blood cell transfusion, etc.

1.2.1.2. Toxic lesion of the peripheral nervous system

I. Alcoholic polyneuropathy

Alcoholic PNP – symmetric sensory PNP; motor PNP develops at later stages of the disease. The underlying mechanism is axonal damage, with the myelin sheath being affected to a lesser degree. Axonal degeneration is caused by the direct effect of toxic alcohol metabolites on the nerve fiber and a deficiency of B vitamins (primarily thiamine). The latter is caused by poor and monotonous nutrition in the patient, as well as impaired absorption of vitamin B₁ due to gastroenteritis. Genetic, autoimmune, age-related, and other factors may also play a role [69–71].

II. Drug-induced polyneuropathy

Drug-induced PNP – damage to the PNS resulting from the action of a chemical substance used for the prophylaxis, treatment, or diagnosis of certain diseases [72]. The underlying mechanisms include axonal degeneration, segmental demyelination, and neuronopathy arising from covalent modification of neuronal DNA, organelle damage, intracellular inflammation, impaired axonal transport, and channelopathies [73]. Drugs exhibiting neurotoxicity are presented in Table 1. Drugs exhibiting neurotoxicity from section 1.2.1.1. Toxic damage to the central nervous system.

III. Polyneuropathy caused by other toxic substances

Polyneuropathy caused by narcotic drugs and psychotropic substances

PNS damage in drug addiction most commonly occurs against the background of intravenous opioid use and is multifactorial in nature [74]. The mechanism of neurotoxicity is delayed demyelination secondary to hypoxia and inflammation.

Polyneuropathy caused by metals

For the mechanism, see section 1.2.1.1. Toxic damage to the central nervous system, Toxic encephalopathy caused by heavy metals

The high neurotropism of arsenic, manganese, mercury, and lead is due to the ability of these metals to accumulate in nervous tissue and disrupt cerebral metabolism. Poisoning with manganese and mercury is accompanied by cholinesterase inhibition, as well as significant shifts in catecholamine and serotonin metabolism. Lead circulates in the blood in the form of phosphate and albuminate colloids, is deposited in the bones, liver, kidneys, and to a lesser extent in the spleen and brain; shifts in porphyrin metabolism (cytotoxic effect) are characteristic. Arsenic compounds actively interact with the sulfhydryl groups of thioctic acid (causing pyruvate metabolism disorders) and penetrate the connective tissue membranes of peripheral nerves [75].

Polyneuropathy caused by solvents and industrial toxins

Organic solvents and alcohols. The development of the toxic reaction is based on disorders of plastic and energy metabolism, as well as the generation, conduction, and transmission of nerve impulses [57].

Pesticides, including organophosphorus compounds. Most organophosphorus compounds act as acetylcholinesterase inhibitors, leading to the accumulation of acetylcholine and erratic transmission of nerve impulses (hyperexcitation, seizures, and subsequently paralysis). There are four hazard classes of pesticides: Class I – potent or extremely hazardous substances, most of which have long been banned from use (DDT); Class II – highly toxic or hazardous substances that have shown high efficacy in pest control, but must be applied in regulated amounts using all safety measures (Decis, Basudin, Bi-58); Class III – moderately toxic or moderately hazardous pesticides (rotenone, diquat, tetramethylthiuram disulfide); Class IV – low-toxicity or low-hazard pesticides, including insecticides (Bordeaux mixture), biological products [76].

Polyneuropathy caused by animal and plant toxins

The venom of certain reptiles, arthropods, and coelenterates possesses neurotoxicity – the mechanism is mainly associated with impaired neuromuscular transmission (spiders, contact with a jellyfish), as well as blood coagulation disorders (scorpion sting). Neurotoxins can enter the human body through the consumption of fish or seafood, poultry, various plants, and canned products. Mushrooms grown in ecologically unfavorable areas are toxic [77].

1.2.2. Etiology of metabolic lesion of the nervous system

Metabolic encephalopathy is the cerebral consequence of organ dysfunction, i.e., a secondary process relative to the metabolic disorder, often multifactorial in etiology [8].

1.2.2.1. Metabolic lesion of the central nervous system

I. Electrolyte disorders

Electrolyte disorders occur as a result of an imbalance between the intake, excretion, and/or regulation of ions [8,63]:

1. Sodium (Na⁺):

   Hyponatremia: syndrome of inappropriate antidiuretic hormone secretion (Schwartz-Bartter syndrome), psychogenic polydipsia, primary (Addison's disease) and secondary adrenal insufficiency, hypothyroidism, vomiting/diarrhea, diuretics.

   Hypernatremia: dehydration, diabetes insipidus (central or nephrogenic), decompensated diabetes mellitus, excess salt.

2. Potassium (K⁺):

   Hypokalemia: diarrhea, abuse of diuretics and laxatives, hyperaldosteronism, hypercortisolism, periodic hypokalemic paralysis.

   Hyperkalemia: renal failure, rhabdomyolysis, primary adrenal insufficiency (Addison's disease), metabolic acidosis, absolute insulin deficiency/decompensation of type 1 diabetes mellitus.

3. Calcium (Ca²⁺):

   Hypocalcemia: hypoparathyroidism, "hungry bone" syndrome following parathyroidectomy, vitamin D deficiency or vitamin D resistance, hypomagnesemia.

   Hypercalcemia: hyperparathyroidism, malignant tumors, granulomatous diseases (sarcoidosis), thiazide diuretics.

4. Magnesium (Mg²⁺):

   Hypomagnesemia: small bowel resection, malabsorption, diarrhea, acute pancreatitis.

   Hypermagnesemia: renal failure, magnesium preparation overdose.

   Electrolyte imbalance leads to complex central nervous system damage via osmotic, membrane, neurotransmitter, and metabolic mechanisms [78–81].

II. Endocrine disorders

Endocrine disorders leading to nervous system damage include hypo- and hyperglycemia, hypo- and hyperthyroidism, and hypo- and hypercortisolism.

Hyperglycemia is an increase in blood glucose concentration above 5.5 mmol/L; depending on etiological factors, the following are distinguished:

1) alimentary (postprandial, physiological);

2) stress-induced;

3) associated with pathological overproduction of counter-regulatory hormones;

4) in diabetes mellitus due to absolute and/or relative insulin deficiency [82].

Type 1 diabetes mellitus (T1D) is a polygenic multifactorial disease based on immune-mediated or idiopathic destruction of pancreatic ß-cells, leading to absolute insulin deficiency [83]. T1D develops in the presence of genetic predisposition, for the realization of which environmental factors acting as a trigger for autoimmune destruction of pancreatic ß-cells are required. Infectious and non-infectious factors can act as triggers [84–86].

Type 2 diabetes mellitus (T2D) is a multifactorial disease based on impaired insulin secretion and insulin resistance [83].

Hypoglycemia [87] is in most cases the result of an overdose of certain glucose-lowering drugs; other causes include insulinoma, endocrine disorders (growth hormone deficiency or adrenal insufficiency), fulminant hepatitis, or end-stage chronic kidney disease (due to impaired gluconeogenesis). In healthy individuals, symptoms of hypoglycemia develop at a glucose concentration of less than 3 mmol/L. The brain depends on glucose as its primary source of ATP, as it is unable to synthesize or store it in significant quantities. CNS damage in hypoglycemia is the result of a cascade of processes: energy collapse, excitotoxicity, oxidative stress, and inflammation. The cerebral cortex, hippocampus, basal ganglia, and brainstem are most sensitive to hypoglycemia [88].

Thyroid dysfunction (hyper- and hypothyroidism) has a significant impact on the CNS through an imbalance of thyroid hormones (T3 and T4).

Hyperthyroidism is characterized by an excess of thyroid hormones (T3 and T4) due to Graves' disease, exerts a complex effect on the CNS by increasing oxygen consumption and the production of reactive oxygen species; an imbalance between their generation and antioxidant defense leads to lipid peroxidation and oxidation of neuronal proteins [89]. Chronic hyperthyroidism is associated with reduced neurogenesis and hippocampal atrophy, which ultimately manifests as cognitive deficit [90]. In congenital hypothyroidism [91], thyroid hormone deficiency during critical periods of development (prenatally or in early childhood) leads to impaired neurogenesis, neuronal migration, synaptogenesis, and myelination, which manifests as delayed mental and motor development.

In hypercortisolism due to pituitary corticotropinomas/Cushing's disease and other ACTH-secreting tumors, as well as adrenal corticotesticomas, CNS involvement includes atrophy of the hippocampus, prefrontal cortex, and amygdala, oxidative stress and mitochondrial dysfunction, excitotoxicity, and neuroinflammation [92].

In hypocortisolism (adrenal insufficiency) due to Addison's disease, CNS damage develops as a result of a complex interplay of metabolic, vascular, inflammatory, and neurochemical mechanisms caused by cortisol deficiency. The loss of the anti-inflammatory action of cortisol enhances the production of pro-inflammatory cytokines (IL-1β, TNF-α) in the brain. Chronic inflammation leads to neuronal and glial cell damage, contributing to neurodegeneration. Cortisol maintains the neuroprotective role of astrocytes and regulates microglial activity. In conditions of cortisol deficiency, there is a loss of metabolic support (astrocytes) and uncontrolled neuroinflammation (microglia) [93].

III. Internal organ dysfunction

The most common pathological conditions are [8, 63]:

hepatic encephalopathy – in acute or chronic liver failure,

uremic encephalopathy – in renal failure,

hypercapnic encephalopathy – in acute respiratory failure (in end-stage chronic obstructive pulmonary disease, diaphragmatic dysfunction).

IV. Vitamin deficiency encephalopathy

A number of deficiency states cause neurological disorders [8, 63]:

thiamine (vitamin B1): Wernicke's encephalopathy;

niacin (vitamin B3 or PP): pellagrous encephalopathy;

pyridoxine (vitamin B6): polyneuropathy, confusion, seizures;

cyanocobalamin (vitamin B12): funicular myelosis;

ascorbic acid (vitamin C): scurvy;

tocopherol (vitamin E): cerebellar disorders, muscular dystrophies.

Among deficiency states, Wernicke's encephalopathy is the most common, and it can occur in non-alcoholic individuals. Risk factors for vitamin B1 deficiency include bariatric surgery, such as Roux-en-Y gastric bypass (which bypasses the duodenum and jejunum, the primary sites of vitamin B1 absorption) [94–98], nutritional deficiency, impaired gastrointestinal absorption of thiamine, intractable vomiting, decreased vitamin B1 storage due to liver disease, as well as chronic hemodialysis and thyroid disorders [99].

V. Septic encephalopathy

Sepsis-associated encephalopathy, meningitis / encephalitis develop in patients with sepsis, septic shock, acute respiratory distress syndrome, acute pancreatitis [8, 63].

VI. Anoxic-ischemic encephalopathy

Hypoxic-ischemic brain injury, delayed postanoxic leukoencephalopathy develop in patients with acute heart failure, following cardiac arrest, and in the development of shock [8, 63].

! Among metabolic encephalopathies, hypoglycemia and Wernicke's encephalopathy should be ruled out on an emergency basis, as these two conditions are life-threatening and require prompt correction to prevent neurological sequelae [8].

1.2.2.2. Metabolic lesion of the peripheral nervous system

I. Diabetic polyneuropathy

Oxidative stress, metabolic disorders, microangiopathy, and other factors associated with hyperglycemia disrupt the normal structure and function of nerve cells, leading to neuronal demyelination and nerve damage, which are the primary drivers of peripheral neuropathy [100, 101].

Previous studies aimed at understanding the pathogenesis of diabetic neuropathy focused on assessing the role of elevated glucose concentrations [102]. In the polyol pathway, aldose reductase converts excess glucose into sorbitol, which subsequently reduces the activity of sodium-potassium (Na-K) adenosine triphosphatase (ATPase), depletes nicotinamide adenine dinucleotide phosphate (NADP) reserves, and promotes the generation of reactive oxygen species. Excess glucose enters the hexosamine pathway, leading to the production of inflammatory byproducts and the activation of protein kinase C, which exacerbates insulin resistance, impairs growth factor activity, and causes alterations in vascular tone.

An important contribution to pathogenesis may come from advanced glycation end-products (AGEs) and their receptors (RAGE), the activation of which leads to inflammation, accumulation of reactive oxygen species, and impaired blood supply to peripheral nerves. The accumulation of AGEs in nerve neurofilaments and microtubules hinders axonal transport, while the formation of AGEs on the myelin sheath leads to local demyelination. Furthermore, the effect of AGEs on arterioles increases their permeability, stimulates the production of pro-inflammatory cytokines, and enhances oxidative stress levels, ultimately leading to nerve ischemia due to altered basement membrane density, pericyte dysfunction, and the formation of arteriovenous shunts [103].

In individuals with type 1 diabetes, insulin level reduction impairs Na⁺/K⁺-ATPase function, leading to neuronal dysfunction, oxidative stress, axonal edema, and apoptosis [103]. Insulin resistance in type 2 diabetes similarly can reduce antioxidant activity, contributing to mitochondrial dysfunction and neuronal apoptosis [104]. Moreover, under conditions of concomitant dyslipidemia, free fatty acids undergo active β-oxidation—the degradation of fatty acids in the mitochondrial matrix via an oxidative cycle of reactions. The transformation of acetyl-coenzyme A leads to a significant increase in acylcarnitines, which are toxic to neurons and Schwann cells [105].

II. Polyneuropathies in other endocrine diseases and metabolic disorders

1. Other disorders of glucose regulation and internal pancreatic secretion [106–108]

Etiology: see the section Hypoglycemia (1.2.2.1. Metabolic lesions of the central nervous system).

Peripheral nervous system involvement in the setting of hypoglycemia is a potential complication, particularly during prolonged or severe hypoglycemia [109]. Key pathogenetic mechanisms include neuronal energy starvation due to glucose deficiency, which disrupts Na⁺/K⁺-ATPase function, resulting in membrane potential and axonal transport dysfunction, free radical accumulation, and oxidative stress; ischemic and vascular disorders; and a direct neurotoxic effect caused by impaired myelin synthesis with subsequent demyelination and axonal degeneration against the background of prolonged severe glucose deprivation.

2. Thyroid diseases [110]

Thyroid hormone deficiency in hypothyroidism leads to impaired metabolism in peripheral nerves, accumulation of mucin in the perineurium, and focal demyelination, causing nerve compression and slowed nerve conduction velocity [111].

In thyrotoxicosis, excess thyroid hormones accelerate metabolic rates, leading to increased oxygen and energy consumption by nerve cells and, consequently, to oxidative stress (accumulation of free radicals that damage neuronal and Schwann cell membranes); ATP deficiency; and hypokalemia associated with the activation of Na⁺/K⁺-ATPase, and consequently impaired neuromuscular transmission [112].

3. Disorders of other endocrine glands

Excess cortisol in hypercortisolism enhances gluconeogenesis and insulin resistance, leading to chronic hyperglycemia, which activates pathological pathways similar to those in diabetic neuropathy (polyol pathway, oxidative stress, etc.). Cortisol enhances protein catabolism, including structural components of nerves, leading to demyelination and axonal degeneration, and also disrupts the synthesis of neurotrophic factors (NGF, BDNF) critical for nerve survival and regeneration [113, 114].

4. Metabolic disorders

The pathogenesis of polyneuropathy in vitamin deficiencies is associated with impaired metabolic processes in peripheral nerves, leading to structural and functional damage of axons, myelin sheaths, and neuronal cell bodies. The primary role is played by B-complex vitamins (B₁, B₆, B₁₂) as well as vitamin D, which participate in energy metabolism, myelin synthesis, and the protection of nerve fibers from toxic effects. For instance, vitamin B₁₂ deficiency leads to the accumulation of toxic metabolites—methylmalonic acid and homocysteine—which cause nerve fiber demyelination and axonal damage [115]. Vitamin B1 deficiency causes the accumulation of lactate and intracellular calcium in neurons, leading to lactic acidosis and neurotoxicity, as well as impaired neurotransmitter synthesis (e.g., acetylcholine), which slows axonal transport [116]. Vitamin B6 deficiency or excess (e.g., from long-term supplementation) can provoke sensory neuropathy due to impaired synthesis of serotonin, GABA, and other neurotransmitters, affecting signal transmission [117]. And vitamin D deficiency is an independent risk factor for diabetic polyneuropathy and may contribute to its development through damage to large myelinated nerve fibers [118].

1.3 Epidemiology of the Disease or Condition

1.3.1 Epidemiology of toxic lesion of the nervous system

1.3.1.1. Toxic lesion of the central nervous system

Globally, more than 400 million people suffer from alcohol use disorders (WHO, 2024). In the Russian Federation in 2024, 1,556,437 people with substance use disorders were under dispensary observation in the state addiction treatment service, including 1,182,678 with alcohol dependence and 362,518 with drug dependence.

Alcoholic encephalopathy is frequently accompanied by cognitive impairment, which is detected in 50–70% of cases; in 10% of cases, cognitive deficits are pronounced, reaching the level of dementia [119]. Cerebellar abnormalities are observed in 10–40% of patients abusing alcohol, and alcoholic cerebellar degeneration is more common in men than in women [120]. The incidence of central pontine myelinolysis can reach up to 3 cases per 1,000 hospitalized patients [121]. Marchiafava-Bignami disease (syndrome) is considered a rare condition, with only 200–300 clinical cases described at the beginning of the 21st century [122]. Korsakoff's syndrome, as a consequence of Wernicke's encephalopathy, is observed in 80% of cases [123].

Wernicke's encephalopathy is more often of alcoholic etiology, developing with prolonged heavy alcohol consumption in individuals with alcohol use disorders, or following severe alcohol withdrawal delirium. In such cases, it is commonly referred to as Gayet-Wernicke encephalopathy. The incidence of Wernicke's encephalopathy in the population can reach up to 3 per 100,000 population per year [124–129].

Toxic encephalopathy most frequently develops in surviving patients after an overdose of narcotic drugs and psychotropic substances. According to Rospotrebnadzor data, 10,126 deaths from overdoses of narcotic drugs and psychotropic substances were registered in the Russian Federation in 2023, the vast majority of which involved opioids; in 2024, 7,896 deaths from acute poisoning by drugs and psychodysleptics (hallucinogens) were registered [130].

Reversible syndromes: data are lacking.

1.3.1.2. Toxic lesion of the peripheral nervous system

Alcoholic polyneuropathy accompanies 13–66% of cases of AUD [7]. The incidence of clinical forms of alcoholic PNP among individuals with alcohol dependence is 10–30%, and subclinical forms reach 70% [131].

Drug-induced polyneuropathy accounts for about 4% of all PNPs [132], and may occur in up to 60% of patients receiving treatment with certain chemotherapy drugs [72].

Polyneuropathy caused by other toxic substances. PNP in substance use disorders is observed in almost 80% of cases, although in the overwhelming majority of cases it is subclinical in character [25, 133].

Occupational polyneuropathies, within the framework of which toxic polyneuropathies are considered [134], occur with a frequency of 1–3% in the general population [135]. With occupational exposure to cadmium, lead, and arsenic, clinical symptoms of PNP are detected in nearly 20% of cases. Upon exposure to mercury, PNP symptoms are observed in the presence of signs of toxic encephalopathy [136]. Manganese parkinsonism is always combined with clinical and electrophysiological manifestations of PNP [137].

1.3.2 Epidemiology of metabolic lesion of the nervous system

1.3.2.1. Metabolic lesion of the central nervous system

Patients with endocrinopathies and electrolyte disturbances may develop central nervous system disorders, the frequency and severity of which vary depending on the type of pathology, the severity of its course, and the timeliness of diagnosis.

In 15% of type 2 diabetes mellitus patients receiving insulin therapy, at least one episode of severe hypoglycemia is observed, which can lead to hypoglycemic encephalopathy [138].

In 50–60% of patients with endogenous hypercorticism, depression and various cognitive impairments occur [139], while in patients with overt and subclinical hypothyroidism, some of the most common psychoemotional disorders are depression (82% of cases), anxiety (78%), and asthenia (70%) [140].

Hepatic encephalopathy develops in 44% of patients with liver cirrhosis over 5 years [141]. In another study involving over 9,000 patients with diagnosed cirrhosis, cirrhosis was decompensated in 1/3 of cases, of whom 51% suffered from hepatic encephalopathy [142]. In the USA in 2018, the prevalence of hepatic encephalopathy was established at 202,000 cases [143]. In China, hepatic encephalopathy was detected in 59.7% of patients hospitalized with liver cirrhosis [144]. Overall, clinically overt hepatic encephalopathy develops in 30–45% of patients with liver cirrhosis, i.e., from 20 to 60% [145]. In patients with liver cirrhosis, hepatic encephalopathy is detected at the time of diagnosis in 20% of cases, and will develop later in 70% [8].

Uremic encephalopathy develops in 60% of patients with chronic kidney disease. Among dialysis patients, cognitive impairment is absent in only 12.7% of cases, while 87.3% exhibit impairments of varying severity, which is associated with uremic encephalopathy [146].

Wernicke's encephalopathy occurs in patients after bariatric surgery in 8% of cases [124].

1.3.2.2. Metabolic lesion of the peripheral nervous system

In patients with diabetes mellitus, the frequency of diabetic PNP ranges from 12 to 95% (an average of about 30%) [7]. The most common is typical sensorimotor or predominantly sensory PNP with a mixed pattern of damage to different types of nerve fibers (more than 90% of all diabetic PNP variants); the painful form is noted in 6–34% of diabetes mellitus patients [147, 148]. The prevalence of autonomic disorders depends on the type of diabetes, amounting to 54% in type 1 diabetes mellitus and 73% in type 2 diabetes mellitus. Cardiac autonomic neuropathy is recognized as the most severe complication of diabetes mellitus with an unfavorable prognosis. Patients with cardiac autonomic neuropathy belong to the high-risk group for sudden cardiac death [149].

In patients with hypothyroidism, PNP is detected in 18–72% of cases [150], carpal tunnel syndrome (due to soft tissue edema) in 30% [151, 152], and myopathy in 5% (and can reach up to 60% in primary hypothyroidism) [153, 154].

1.4 Features of Coding the Disease or Condition

Features of coding toxic and metabolic disorders of the nervous system are presented in Table 2.

Table 2 – Features of coding toxic and metabolic disorders of the nervous system

1.5 Classification of the disease or condition

1.5.1 Toxic lesion of the nervous system

Toxic lesions of the nervous system are heterogeneous in cause of development, level of lesion, and, accordingly, clinical manifestations (Figure 1) [8].

A summary classification of toxic lesions of the nervous system is presented in Figure 1. Toxic lesions of the nervous system can also be classified by neurotoxicant group (Table 3):

Table 3 – Neurotoxic substances

1.5.1.1 Toxic lesion of the central nervous system

The classification of toxic central nervous system lesions is presented in Table 4.

Table 4 – Classification of toxic central nervous system lesions [8, 63]

_{⁶Wernicke's encephalopathy can be classified by etiology into alcoholic and non-alcoholic [99]}

1.5.1.2 Toxic lesion of the peripheral nervous system

See above.

1.5.2 Metabolic lesion of the nervous system

Metabolic disorders of the nervous system are also heterogeneous in terms of etiology, level of involvement, and, accordingly, clinical manifestations (Figure 2) [7, 8].

1.5.2.1. Metabolic lesion of the central nervous system

The classification of metabolic central nervous system disorders is presented in Table 5.

Table 5 – Classification of metabolic disorders of the central nervous system [8, 63]

1.5.2.2 Metabolic lesion of the peripheral nervous system

Classification of diabetic neuropathies [7, 9]:

1. Diabetic neuropathies

1.1. Diffuse neuropathies

1.1.1. Distal symmetric polyneuropathy (DSPN)

• Predominantly small-fiber neuropathy

• Predominantly large-fiber neuropathy

• Mixed small- and large-fiber neuropathy

1.1.2. Autonomic

1.1.2.1. Cardiovascular

• Reduced heart rate variability (HRV)

• Resting tachycardia

• Orthostatic hypotension

• Sudden death (malignant arrhythmias)

1.1.2.2. Gastrointestinal

• Diabetic gastroparesis

• Diabetic enteropathy (diarrhea)

• Reduced colonic motility (constipation)

1.1.2.3. Urogenital

• Diabetic cystopathy (neurogenic bladder)

• Erectile dysfunction

• Female sexual dysfunction

1.1.2.4. Sudomotor dysfunction

• Distal hypohidrosis/anhidrosis

• Auriculotemporal syndrome

• Impaired awareness of hypoglycemia

• Pupillary dysfunction

1.2. Mononeuropathy (mononeuritis multiplex) (atypical forms)

1.2.1. Isolated cranial or peripheral nerve palsy

1.2.2. Mononeuritis multiplex

1.3. Radiculopathy or polyradiculopathy (atypical forms)

1.3.1. Radiculoplexoneuropathy

1.3.2. Thoracic radiculopathy

2. Non-diabetic neuropathies common in diabetes mellitus

2.1. Entrapment neuropathy

2.2. Chronic inflammatory demyelinating polyneuropathy

2.3. Radiculoplexoneuropathy

2.4. Acute painful small-fiber neuropathy (treatment-induced)

1.6 Clinical presentation of the disease or condition

1.6.1. Clinical presentation of toxic lesion of the nervous system

The clinical presentation of poisoning consists of a combination of symptoms resulting from both direct toxic effects on nervous system structures and indirect effects mediated by damage to other organs and body systems. Clinically, exposure to neurotoxicants can cause seizures, motor and sensory disturbances, visual and hearing impairments, cognitive deficits, and productive psychiatric symptoms.

"Specific" clinical symptoms are most prominent in the toxicogenic phase. Certain disorders arising in the toxicogenic stage, such as toxic neuritis of the auditory and optic nerves, may persist into the somatogenic phase of the disease. In certain types of acute poisoning (organophosphates, thallium salts, arsenic, triorthocresyl phosphate, hypnotics), toxic polyneuropathies that were absent in the early period of the disease develop at a later stage. In the somatogenic phase of acute poisoning, new symptoms may also appear, associated with the indirect action of neurotoxicants [3].

1.6.1.1. Toxic lesion of the central nervous system

I. Alcoholic encephalopathy

Alcoholic encephalopathy is a general term for a group of metalcoholic psychoses developing predominantly in the terminal stage of chronic alcoholism due to prolonged continuous alcohol consumption. The clinical presentation is notable for polymorphism of manifestations and is characterized by a combination of neurological and mental disorders. The alcohol withdrawal syndrome is pronounced and prolonged, often accompanied by epileptic seizures. Typically, in 50–65% of cases, patients in this category have a history of delirium of various structures. Marked personality changes and professional decline are constant, often reaching the level of mental and social degradation [155].

It is advisable to subdivide all alcoholic encephalopathies into acute and chronic. A typical acute encephalopathy is Wernicke-Korsakoff syndrome (specifically Wernicke encephalopathy), and chronic is Korsakoff syndrome [155].

Wernicke encephalopathy. It may develop independently or following a severely progressing alcoholic delirium. There is a fulminant form, when coma and death develop after 2-3 days, and a protracted form, lasting up to 2-3 months. The triad of symptoms is always observed: altered consciousness (stupor alternating with amhenia), neurological symptoms (ataxia), and ophthalmoplegia [155].

Korsakoff's (amnestic) syndrome presents as fixation amnesia, often with anterograde and retrograde memory disorders, amnestic disorientation, and paramnesias (confabulations and pseudoreminiscences) [155].

With chronic alcohol abuse over many years, alcoholic cerebellar degeneration with atrophy (of the cerebellar vermis) develops, clinically accompanied by ataxia in the legs, unlike Wernicke encephalopathy, in which truncal ataxia predominates. Abstinence from alcohol in chronic alcohol abuse leads to an increase in blood concentration of antidiuretic hormone, increasing the likelihood of hyponatremia during infusion therapy and diuretic treatment. Inadequately rapid correction of hyponatremia can provoke transient hypernatremia, which in turn can lead to central pontine myelinolysis. The syndrome manifests as central para- or tetraparesis, signs of pseudobulbar palsy, cerebellar symptoms, and impaired consciousness. Progressive demyelination can lead to locked-in syndrome. The clinical manifestations of the gradual development of Marchiafava-Bignami disease (syndrome) include dysarthria, oculomotor disorders, astasia-abasia, muscle tone abnormalities, central paralysis, urinary and fecal incontinence, and profound mental disorders: pseudoparalytic syndrome, severe memory impairment with fixation amnesia and confabulations. In the acute development of the disease, confusion, epileptic seizures, and depressed consciousness are observed. A fatal outcome is possible within several months. There is no reversal of symptoms; surviving patients usually retain abulia and dementia [1, 156, 157].

Non-alcoholic Wernicke encephalopathy

Wernicke encephalopathy develops approximately 4-6 weeks after the onset of vitamin B1 deficiency [158]. Predictors of development are vomiting (in 82% of cases) and significant weight loss [159]. The classic triad of symptoms includes [160]:

Altered consciousness (34-82% of WE patients) [161]. Decreased level of alertness up to coma, qualitative disorders of consciousness: spatial disorientation, confusion, delirium [158, 162].

Oculomotor disorders (75% of patients) [163]. Complete ophthalmoplegia is rarely observed; more common are horizontal nystagmus, diplopia, reduced pupillary light reflex, bilateral abducens nerve palsy, etc. [164].

Ataxia (50% of patients) ranging from unsteadiness of gait to complete inability to stand [164, 165].

In non-alcoholic WE, oculomotor disorders occur more frequently (than in alcoholic WE), while ataxia develops less frequently [99]. According to Sechi G. et al. (2007), the incidence of the complete triad of symptoms in WE associated with prolonged alcohol abuse is only 14% of cases, whereas in non-alcoholic WE it reaches 62% [166].

Rare manifestations of WE include hypo-/less commonly hyperthermia, hearing loss up to deafness in the late stages of the disease, epileptic seizures, arterial hypotension, tachycardia, and syncopal episodes [158, 164].

Lower extremity peripheral neuropathy may occur as the disease progresses and includes paresthesias, weakness, and pain in the distal extremities [158].

The diagnosis of WE is clinical, therefore a high index of suspicion is necessary, especially in patients with a burdened medical history [160]. In 19% of cases, not a single symptom from the classical triad is present at the onset of the disease, but subsequently one or more signs usually appear [166].

Wernicke encephalopathy can lead to irreversible brain damage, severe disability, and, in 10-20% of cases without treatment, death [167].

II. Toxic encephalopathy

Depending on the type and dose of the toxicant, symptoms may resolve, or irreversible changes may develop even after a single exposure. With chronic exposure to low doses of a toxic substance, symptoms develop imperceptibly and remain unrecognized for a long time (mood lability, fatigue, lethargy, cognitive impairment). The patient's condition can be improved, but as a rule, irreversible residual impairments persist [3].

The clinical presentation of poisoning is characterized by neurological deficit symptoms. Depression of the level of alertness is typical for many drugs. However, a wide range of medications can cause irritative symptoms, mainly seizure disorders. Poisonings often clinically manifest as psychiatric and cognitive dysfunctions. The clinical presentation of neurological symptoms has its own characteristics for each drug: the presence of focal neurological deficits and, in many cases, extrapyramidal disorders [23–25].

Toxic encephalopathy caused by narcotic drugs and psychotropic substances

Narcotic drugs and psychotropic substances primarily affect the central nervous system. Most poisonings are characterized by depressed levels of wakefulness, psychiatric and cognitive disorders, seizures, and the appearance of involuntary movements. However, each drug or group of drugs has its own clinical presentation features. For instance, in cocaine poisoning, the probability of seizures can reach 29% [168], while in mephedrone poisoning, psychotic symptoms (including delusions and hallucinations) occur in 40% of patients. Ataxia is observed in 77% of patients with amphetamine poisoning [169]. When involuntary movements develop, their character also varies. Some poisonings are more characterized by tremor (cannabis, methamphetamine, LSD), others by myoclonus (amphetamines, gamma-hydroxybutyrate), and still others by a combination of tremor and dystonia in the form of myoclonus, choreoathetosis, etc. (cocaine, opioids). Amphetamine poisoning may present with non-purposeful repetitive actions, such as head nodding, licking, and lip smacking. Sensory disorders develop mainly in a polyneuritic pattern (opioids, methadone). However, in opioid poisoning, they may be accompanied by hyperalgesia. In methoxyphenidine poisoning, strabismus and horizontal nystagmus were recorded (57%); in mephedrone and MDMA poisoning, bruxism (28.3% and 100%, respectively) [169–171]. Cases of ischemic and hemorrhagic stroke have been reported in patients with cocaine and amphetamine poisoning [25, 168].

Psychiatric disorders develop in all types of poisonings. Methadone poisoning is predominantly characterized by catatonic symptoms (echolalia, rigidity, stupor, mutism); mephedrone by paroxysmal anxiety and manifestations of derealization; amphetamines and opioids by euphoria with psychomotor agitation and hallucinations; cannabis, cocaine, and methoxyphenidine by polymorphic clinical manifestations: euphoria, perceptual distortions, and catatonic symptoms. Many poisonings are characterized by acute paranoid-like manifestations (cannabis, amphetamines, methamphetamine, cocaine, mephedrone). LSD poisoning leads to synesthesia (sounds are "seen", colors "heard"), body scheme disorders, derealization, and depersonalization [25, 169–171]. Cognitive disorders (impaired concentration, memory decline) are also typical for most poisonings.

Acute poisoning symptoms are clearly described for all of the presented narcotic drugs and psychotropic substances, but poisonings with certain substances have specific features associated with chronic use. Long-term cocaine use is accompanied over time by decreased sense of smell, rhinorrhea, chronic cephalgia, dysphagia and dysphonia, amblyopia, cognitive impairment, and the development of subarachnoid hemorrhage and cerebral infarction. Amphetamine use leads to protracted depressive symptoms with suicidal thoughts, and acute paranoid-type psychotic symptoms are possible. Prolonged use of mephedrone leads to PNP [25, 172].

The use of certain narcotic drugs and psychotropic substances (such as cannabis, ecstasy, GHB, amphetamine, methamphetamine) is characterized by a pronounced withdrawal syndrome, manifested by malaise, fatigue, tremor, hyperreflexia, muscle twitching, low mood, depression, dysphoria combined with anxiety and fear; psychotic symptoms are less common [172].

Patients with a long history of cocaine intake exhibit diverse behavioral and higher intellectual-psychiatric function changes due to alterations predominantly in the frontal lobes of the brain, as well as impaired connections with other areas of the cerebral hemispheres. The clinical manifestations of chronic cocaine use are based on changes in the gray and white matter (nerve tracts) of the brain [173].

Chronic methamphetamine intoxication clinically resembles chronic cocaine intoxication. Vascular disorders are typical, frequently combined with movement disorders (tremor, chorea). Chorescent hyperkinesia regresses rather quickly upon drug withdrawal. Polyneuropathy may develop due to nutritional deficiency characteristic of these patients and/or concomitant alcohol abuse [173].

Toxic encephalopathy caused by metals

(copper sulfate, lithium, lead, arsenic, mercury, manganese, nickel, aluminum, zinc, cadmium)

In acute poisoning, headache varies from headache and cognitive impairment to seizures and death.

In chronic poisoning, symptoms such as dementia, parkinsonism, chorea (resembling neurodegenerative disease symptoms), ataxia, and tremor appear, i.e., extrapyramidal and cerebellar disorders. Cognitive and emotional disorders are pronounced, and focal neurological deficits are less common [40, 48, 174–177].

Lead-induced encephalopathy. The clinical manifestations of lead encephalopathy are non-specific. Acute encephalopathy most frequently presents with generalized cerebral symptoms: headache, vomiting, delirium, depressed level of wakefulness, and seizures. Focal symptoms are rare and may include ataxia, motor, and sensory disorders [178]. In patients with chronic lead-induced encephalopathy, the medical history may indicate irritability, memory loss, coordination and sensory disturbances, and movement disorders (including symptoms caused by upper and/or lower limb mononeuropathies). In addition, constipation and abdominal pain are frequent complaints, and there may be records of previously detected anemia with basophilic stippling of erythrocytes, or nephropathy. Examination of patients with chronic lead intoxication reveals the "lead line" (Burton's line)—a bluish pigmentation of the gingival margin, typically around the anterior teeth [55].

Mercury-induced encephalopathy. Manifestations of mercury-induced encephalopathy include cerebellar ataxia, anxiety, delirium, hallucinations, and seizures. Encephalopathy symptoms may be preceded by headache, nausea, anxiety and irritability, decreased visual acuity and constricted visual fields, tremor, paresthesias, sleep disorders, memory impairment, hypersalivation, muscle cramps, and arthralgia [179, 180].

Arsenic-induced encephalopathy. Symptoms of acute encephalopathy: depressed wakefulness, disorientation, delirium, seizures. The development of polyneuropathies running a course similar to Guillain-Barré syndrome is also typical [46]. Extracerebral symptoms include nausea, vomiting, diarrhea, hypersalivation, signs of toxic cardiomyopathy, dermatitis, and hyperpigmentation in chronic intoxication [181].

Toxic encephalopathy caused by solvents and industrial toxins

Organic solvents and alcohols. General symptoms mainly manifest as rapid fatigue, loss of appetite, poorly localized headache, and non-systemic dizziness. Depression of consciousness down to sopor or coma, or qualitative alterations such as hallucinations and delusional disorders, may occur. Ataxia can develop. Impairment of higher cerebral functions manifests as worsening memory and learning ability, and speech alterations. Irritability, anxiety, depression, and sleep disorders have been recorded in patients [58, 182–184].

Pesticides, including organophosphates. Acute poisoning is characterized by anxiety, poor concentration, nausea, headache, dizziness, vision disturbances, speech disturbances, coordination disorders, body aches, seizures, and in severe cases, depression of consciousness to a coma, potentially resulting in death [60], while chronic poisoning is characterized by headache, dizziness, loss of appetite, nausea, vomiting, generalized weakness, increased fatigue, sleep disorders, vision disturbances, muscle cramps, and paresis. Literature describes the association of chronic pesticide poisoning with the development of dementia and parkinsonism, resembling the clinical picture of neurodegenerative diseases [185].

III. Reversible syndromes

Posterior reversible encephalopathy syndrome (PRES). Clinical symptoms: migraine-like headache, visual disturbances (ranging from blurred vision and homonymous hemianopia to cortical blindness), seizures (epileptic status, including non-convulsive, is possible), and altered consciousness (ranging from mild confusion or agitation to coma) [4, 5].

Reversible cerebral vasoconstriction syndrome (RCVS). Clinical symptoms: acute "thunderclap" headache reaching its peak intensity within 1 minute, lasting up to 10 days, most commonly bilateral (can be unilateral), starting in the occipital region and diffusing across the entire head, frequently accompanied by nausea, vomiting, photophobia, and phonophobia; pain recurrences can be triggered by coughing, laughing, defecation, or sexual activity. One in 3 patients may experience seizures and/or focal neurological deficits [6].

1.6.1.2. Toxic lesion of the peripheral nervous system

When the peripheral nervous system (PNS) is affected, motor, sensory, and autonomic symptoms are determined.

Motor disorders in PNS lesions.

Motor disorders in PNS lesions are classified according to the affected structure: neuron, nerve, synapse, or muscle. Each of the four variants features its own distinct clinical presentation, allowing the level of the lesion to be determined clinically. Conditions involving impaired neuromuscular transmission pose the greatest danger.

Sensory disorders in PNS lesions

Sensory disorders of the nervous system in poisoning typically present with a polyneuritic pattern—hypesthesia in a "gloves, socks, and stockings" distribution; painful paresthesias are also characteristic.

Autonomic disorders

In the neurological picture of acute poisoning, somatoautonomic disorders are often the most prominent, such as symmetrical changes in pupil size, and sweating disorders accompanied by altered secretion of the salivary and bronchial glands. Toxicants may cause disorders with predominant damage to either the sympathetic or parasympathetic system, which helps suspect poisoning by a specific substance. Poisoning with substances exhibiting M-cholinomimetic action (organophosphates, barbiturates, alcohol, etc.) is characterized by increased tone of the parasympathetic division of the autonomic nervous system. In such cases, a pronounced "muscarinic-like syndrome" develops, manifesting as miosis, severe sweating, bronchorrhea, and hypothermia. Poisoning with anticholinergic substances (belladonna alkaloids, etc.) is characterized by increased sympathetic nervous system tone and the development of an "atropine-like syndrome." In these cases, the clinical picture shows the opposite phenomena: mydriasis, hyperemia and dryness of the skin, dry mucous membranes, hyperthermia, and psychomotor agitation. At the same time, disturbances in respiratory and cardiovascular function are usually noted [3].

In particular, in poisoning with organophosphates, pachycarpine, methyl bromide, and other substances, an early manifestation is myofibrillation against the background of marked muscle weakness—"toxic myasthenia." In severe poisonings with organophosphates, potassium chloride, arsenic, triorthocresyl phosphate, curariform drugs, and other substances, muscle paresis develops, progressing to paralysis in the limbs. From a diagnostic standpoint, it is important to be aware of the possibility of acute visual impairment up to blindness due to toxic optic neuritis (poisoning with methyl alcohol and quinine), the appearance of "blurred vision" with pronounced miosis (organophosphates) or mydriasis (atropine**, nicotine), and "colored vision" (acetylsalicylic acid**). Hearing impairment in the form of deafness may occur (poisoning with acetylsalicylic acid** and certain systemic antibacterial drugs—streptomycin**, kanamycin**, monomycin, neomycin) in toxic neuritis of the auditory nerve. Sensory disorders in poisoning typically present with a polyneuritic pattern—hypesthesia in a "gloves, socks, and stockings" distribution; painful paresthesias are also characteristic. Toxicants may cause disorders with predominant involvement of the sympathetic (anticholinergic substances) or parasympathetic system (substances with M-cholinomimetic action), i.e., manifesting with symptoms such as symmetrical changes in pupil size, sweating disorders with altered secretion of the salivary and bronchial glands, and others [3].

Toxic lesions of the nervous system may lead to the development of optic neuropathy (or optic atrophy, OA) [186, 187]: impairment of visual functions, up to complete loss of vision and pupillary reactions, irreversible loss of retinal ganglion cell axons, and structural changes in the optic disc. These symptoms occur due to the cessation of axonal transport resulting from damage to both the neuron cell body and its glial elements, when atrophic processes spread toward the synapse [186–188]. Acquired OA is based on secondary damage to the optic nerve fibers, including of toxic origin [189, 190]: chronic exposure to alcohol and nicotine; methyl alcohol poisoning; heavy metals such as lead, arsenic, and thallium; organic solvents including ethylene glycol and toluene; and medications such as ethambutol**, isoniazid**, amiodarone**, lithium preparations, ethambutol** and isoniazid**, linezolid**, ciprofloxacin** and chloramphenicol**, vigabatrin, disulfiram, methotrexate**, cisplatin**, carboplatin**, vincristine**, cyclosporine**, tamoxifen**, sildenafil, etc.)

I. Alcoholic polyneuropathy

Main clinical and pathogenetic forms of polyneuropathy associated with alcohol use disorders [69, 70]:

- toxic (strictly alcoholic) PNP;

- thiamine deficiency-related PNP;

- mixed PNP.

The clinical picture of alcoholic polyneuropathy is dominated by paresthesias in the distal extremities, decreased pain and temperature sensitivity in a polyneuritic pattern, and the development of neuropathic pain syndrome. Autonomic dysfunction is characteristic, manifesting as skin discoloration, limb edema, and distal hyperhidrosis. Trophic changes in the lower extremities are observed (skin hyperpigmentation in the lower leg and foot areas, trophic nail disorders), along with pelvic organ dysfunction, gastrointestinal dysfunctions, and other autonomic manifestations. A slow, progressive course is typical against the background of continued alcohol consumption.

In the thiamine-deficient form of alcoholic polyneuropathy, subacute and acute variants of disease onset are possible. Its development is associated with thiamine deficiency resulting from impaired intestinal absorption, concurrent gastrointestinal diseases, liver damage, and disturbed eating behavior and diet. The clinical picture reveals: peripheral lower (predominantly distal) paraparesis or tetraparesis, superficial and deep sensory impairments in a polyneuritic pattern, and potential development of deep sensory disturbances and sensory ataxia. Cranial nerve involvement is possible, manifesting as mild bulbar and extraocular movement disorders. Autonomic disturbances are usually rare. This form is more frequently accompanied by manifestations of Wernicke's encephalopathy [191–194].

II. Drug-induced polyneuropathy

Symptoms of drug-induced PNP occur after a certain time following the initiation of treatment and are caused by the accumulation of drugs at peak concentrations [132]. The main neurological disorders occur in the upper and lower extremities and are subdivided into motor, sensory, and autonomic types, with a predominance of deficit or irritative symptoms. Both isolated symptoms and combinations thereof may be noted. The clinical picture largely depends on the dose and route of administration [195].

III. Polyneuropathy caused by other toxic substances

Polyneuropathy caused by narcotic drugs and psychotropic substances

PNP in substance use disorders is most frequently characterized by sensory disorders (numbness, paresthesias, pain) in the distal lower extremities in a "gloves and socks" distribution, and less frequently by motor disorders (muscle weakness, decreased tendon reflexes, decreased muscle tone, hypotrophy, fasciculations) with the development of paresis and paralysis. Sensory disorders often include decreased vibratory sensation. A feature of PNP is its subclinical course, meaning that moderately severe PNP is detected using ENMG in the absence of subjective signs of PNS damage. ENMG signs of PNP are observed as early as the early stages of substance abuse. With the use of codeine-containing narcotic drugs (desomorphine), as well as in late stages of psychoactive substance dependence, PNP can be complicated by autonomic-trophic disorders with the formation of long-standing, non-healing trophic ulcers [196].

Polyneuropathy caused by metals

Metal-induced PNS damage in the context of occupational diseases manifests as symptoms of sensory (numbness, paresthesias, pain) and motor (muscle weakness, decreased tendon reflexes, decreased muscle tone, hypotrophy) disorders [135] and most commonly has a subclinical character [197]. In non-occupational poisoning (e.g., of criminal origin), the clinical picture is more vivid. For example, thallium poisoning is characterized by the appearance of muscle pain in various locations, painful paresthesias, and the development of sensory-motor PNP and myopathy [198].

Polyneuropathy caused by solvents and industrial toxins

Organic solvents and alcohols — in addition to general symptoms (see the section Toxic Encephalopathy Caused by Solvents and Industrial Toxins), motor disorders develop, including decreased muscle strength with depressed reflexes, fasciculations, cramps, and tremor, alongside sensory disorders—mainly paresthesias, decreased superficial and deep sensitivity, and pain of various locations. Visual and hearing impairments are possible [58, 182–184].

Pesticides (including organophosphates) — acute poisoning is characterized by anxiety, poor concentration, nausea, headache, dizziness, vision disturbances, speech impairment, coordination disorders, body aches, convulsions, and in severe cases, depressed consciousness up to coma, with a potential fatal outcome [60], while chronic poisoning causes headache, dizziness, loss of appetite, nausea, vomiting, generalized weakness, increased fatigue, sleep disorders, visual disturbances, muscle cramps, and paresis. A relationship between chronic pesticide poisoning and the development of secondary parkinsonism and dementia symptoms has been described [185].

Polyneuropathy caused by animal and plant toxins

The clinical presentation of poisoning by animal venoms is diverse. In some cases, secondary hypoxia and depressed level of consciousness occur due to diaphragmatic weakness and impaired respiratory function.

Spider bites (Funnel-web, Black widow) — generalized muscle weakness and fasciculations, painful cramps, and psychomotor agitation [199–202].

Scorpion stings — muscle weakness (resembling Guillain-Barré syndrome or myelitis), fasciculations (mimicking cramps, hyperkinesia), persistent hypesthesia, psychomotor agitation, activation of the parasympathetic system (nausea, vomiting, diarrhea, sweating, hypersalivation, lacrimation, increased respiratory tract secretions, bradycardia, arterial hypotension), and in severe cases, sympathetic activation (hypertension, arrhythmias, and heart failure); strokes may develop due to coagulation disorders [203, 204].

Jellyfish stings — pronounced autonomic reaction (parasympathetic dysautonomia), peripheral neuropathies, visual impairment, muscle pain and spasms (cramps), aphonia, psychomotor agitation, possible heart failure and hypertension [205].

Ingestion of fish, for example, from the order Tetraodontiformes (including pufferfish [Fugu], tetrodotoxin) or from the order Cypriniformes (cyprinidin) — ranging from perioral numbness and paresthesias to generalized flaccid paralysis, dysphagia, aphonia, and respiratory failure [206].

Other toxins of bacterial and fungal origin can be formed in food. For example, botulinum toxin (produced by spore-forming anaerobic Gram-positive bacteria of the genus *Clostridium* in low-acid canned foods — green beans, mushrooms, fish, meat products) — leads to diplopia, ptosis, dysphagia, descending paralysis, and respiratory failure [207].

Consumption of plants, for example, Conium maculatum (the root is mistakenly eaten instead of horseradish, its leaves instead of parsley) contains coniine and causes symptoms of neuromuscular transmission disorders [208]; plants such as Datura stramonium and Hyoscyamus niger (used in folk medicine) contain atropine, hyoscyamine, and scopolamine, causing decreased salivation, digestive and sweat gland secretion, tachycardia, relaxation of the smooth muscles of the intestines and bronchi, mydriasis, and psychomotor agitation with hallucinations and convulsions [209].

In mushroom poisoning, the toxic substance that caused the poisoning is of primary importance, according to Gummin and colleagues (2020) [210–214]:

Myco-atropine (pantherine) syndrome — mushrooms of the genus *Amanita* (muscimol, ibotenic acid);

Gyromitrin syndrome — mushrooms of the genus *Gyromitra* (gyromitrin);

Muscarine syndrome — mushrooms of the genus *Inocybe*/*Clitocybe* (muscarine and its isomers);

Coprine syndrome — mushrooms of the genus *Coprinus* (coprine);

Psychodysleptic syndrome — *Psilocybe* mushroom (psilocin).

Neurological symptoms of mushroom poisoning include: paresis and convulsions; ataxia; visual disturbances (diplopia, decreased visual acuity, altered color perception); intense and prolonged headache with dizziness and vomiting; psychiatric disorders ranging from mood lability and panic attacks to productive symptoms (hallucinations, delusions); and a depressed level of consciousness [215]. Poisonings with a short incubation period (up to 2–3 hours) are characteristic of mushrooms of the genera *Clitocybe*, *Psilocybe*, certain species of the genus *Amanita* (fly agaric and panther cap), etc., whereas those with a long incubation period (up to 12 hours) are characteristic of mushrooms of the genus *Gyromitra* [216].

1.6.2. Clinical presentation of metabolic lesion of the nervous system

1.6.2.1. Metabolic lesion of the central nervous system

Electrolyte imbalances

Hypernatremia presents with anxiety, irritability, muscle twitching, and convulsions. Hyponatremia presents with headache, nausea, confusion, seizures, and coma (especially with a rapid drop in blood sodium) [78]. Hyperkalemia predominantly affects the heart and peripheral nerves. CNS symptoms are rare and may manifest as paresthesias and flaccid paralysis (at extremely high blood potassium levels). Severe hypokalemia may cause confusion [79]. Hypercalcemia can be accompanied by fatigue, lethargy, and depression; hypocalcemia, by seizures, irritability, tetany, and epileptic seizures [80]. Hypermagnesemia may present with drowsiness, muscle weakness, respiratory depression, and coma, whereas hypomagnesemia presents with tremor, seizures, and delirium [81].

Hyperglycemia.

Patients with type 2 diabetes have a twofold increased risk of developing dementia. Characteristic features include impairments in memory, attention, executive functions, and information processing speed [217–220]. In patients with type 1 diabetes with an HbA1c level greater than 7%, the risk of mild cognitive impairment increases fourfold, with higher HbA1c levels being associated with performance declines in memory, psychomotor skills, and executive functions [221].

Hypoglycemia.

Clinical manifestations are nonspecific. Neurogenic (autonomic) symptoms arise from activation of the autonomic nervous system: sympathetic (palpitations, tremor, agitation, irritability) and parasympathetic (sweating, hunger, paresthesia); neuroglycopenic symptoms are associated with brain damage.

In acute hypoglycemia, neurological disorders are usually transient and completely reversible. Chronic neuroglycopenia can cause sustained neuronal damage in the brain, leading to cognitive impairment, mood disorders, progressive psychiatric conditions, personality changes, and epileptic seizures [87].

Hypothyroidism is frequently accompanied by cognitive impairments (memory impairment, decreased concentration, slowed thinking) and psycho-emotional disorders (apathy, depression, increased fatigue). Cognitive changes in hyperthyroidism include reduced concentration, memory impairment, and spatial disorientation; psycho-emotional changes include increased anxiety and emotional lability [222].

Psychiatric manifestations of hypercortisolism include depression, anxiety, euphoria, emotional lability, psychosis (rarely, but hallucinations, delusions, and thought disorganization ["steroid psychosis"] are possible), irritability, and aggressiveness. Cognitive impairments manifest as memory impairment (especially short-term memory), decreased concentration, and slowed thinking [139].

1.6.2.2. Metabolic lesion of the peripheral nervous system

Diabetic polyneuropathy can be asymptomatic for a long time [223]. Depending on whether thick or thin nerve fibers are predominantly affected, the onset, course, and clinical manifestations may vary. The earliest symptoms are most frequently paresthesia and dysesthesia, felt as pain, burning, or tingling in the feet, which serve as a sign of unmyelinated thin C-fiber degeneration [224, 225]. As neuropathy progresses, large myelinated fiber axons are lost, and patients experience numbness ranging up to loss of sensation in the feet, impaired vibration sense, and proprioception loss, leading to sensory ataxia. Severe nerve damage (loss of protective sensation) can lead to severe complications such as diabetic foot syndrome (neuropathic form).

Manifestations of diabetic autonomic neuropathy include: arrhythmias [226], erectile dysfunction in men, bladder atonia (which can be complicated by urinary retention and ascending urinary tract infection), gastrointestinal disorders (vagus nerve involvement leads to dysphagia, gastroparesis, diarrhea and constipation, and delayed gallbladder emptying) [227], pupillomotor disorders (impaired dark adaptation, dysfunction of the pupillary dilator and sphincter) [228], and sweat gland denervation (impaired sweating, trophic skin changes, and hair loss). The development of optic neuropathy (or anterior ischemic optic neuropathy) is also possible [186, 187]: impaired visual functions up to complete loss of vision, pupillary light reflex abnormalities, irreversible loss of retinal ganglion cell axons, and structural changes in the optic disc [186–190].

Rarely, in long-term uncompensated hypoglycemia (e.g., insulinoma), sensory polyneuropathy may develop, manifesting as pain, burning, and paresthesias. Hypothyroidism is typically characterized by sensorimotor polyneuropathy, marked by symmetrical numbness, leg weakness, and depressed deep tendon reflexes [109]. Hypercortisolism manifests as distal symmetric sensory neuropathy with a predominance of steroid myopathy features—proximal muscle weakness (difficulty rising from a chair, lifting arms) [114].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Generally accepted criteria for establishing a diagnosis/condition for most lesions are absent; diagnosis is based on clinical manifestations, a documented history of toxic/metabolic damage to the nervous system, and, if necessary, laboratory or instrumental confirmation.

Criteria for establishing Wernicke's encephalopathy of alcoholic origin:

1. history of malnutrition associated with alcohol consumption;

2. oculomotor disorders;

3. balance disorders;

4. altered mental status or moderate cognitive impairment [229].

Comments: in 2010, the European Federation of Neurological Societies developed diagnostic criteria for WE of alcoholic origin. To establish a diagnosis of WE, the presence of two out of four specified criteria is required. These criteria are applicable for diagnosing WE of both alcoholic and non-alcoholic origin. The sensitivity of the criteria for diagnosing WE, including in combination with Korsakoff's syndrome, is 85% [229].

2.1 Complaints and Anamnesis

Complaints and medical history are described in the section "Clinical Presentation".

2.2 Physical Examination

Physical examination findings are described in the section "Clinical Presentation".

Comment: in all patients with toxic or metabolic nervous system damage, it is necessary to assess:

1) neurological status (presence of general cerebral symptoms and focal neurological deficit),

2) level of consciousness using the FOUR score (Appendix G1) and the Glasgow Coma Scale (Appendix G2),

3) vital functions (airway patency, respiratory and circulatory functions) [2, 231–234].

Nonspecific but characteristic symptoms of toxic/metabolic encephalopathy include:

1) Delirium⁷,

2) Sleep disturbance,

3) Myoclonus and asterixis,

4) Cranial nerve palsies,

5) Extrapyramidal symptoms and other movement disorders [8].

Cognitive function assessment

Comment: to assess cognitive functions, it is recommended to use the scales:

Mini-Mental State Examination (MMSE) – Appendix G3,

Montreal Cognitive Assessment (MoCA) – Appendix G4 [236, 237].

Comments: to diagnose diabetic neuropathy, diagnostic scales can be used, such as:

1) Neuropathy Symptom Score (NSS) – Appendix G5 [239–241], a score >5 indicates the presence of severe neuropathy;

2) The Michigan Neuropathy Screening Instrument (MNSI) – Appendix G6 [242–244], a score >2 suggests the presence of neuropathy;

3) DN4 questionnaire for diagnosing painful neuropathy – Appendix G7 [245, 246], a score >4 indicates a neuropathic nature of the pain.

Comments: to diagnose diabetic neuropathy, temperature, tactile sensitivity, and vibration sensation are assessed using a 128 Hz calibrated medical tuning fork [9, 82, 238].

Comments: currently, there are no reliable laboratory tests to confirm the presence of diabetic polyneuropathy. It is recommended to verify the loss of protective sensation in peripheral neuropathy:

assessment of tactile sensitivity of the feet is performed using the finger touch test⁸ ;

assessment of vibration sensation is performed using a 128 Hz medical tuning fork.

Once a patient's loss of protective sensation has been determined, testing does not need to be repeated during subsequent screenings.

Comments: VAS scale – Appendix G8.

_{⁷Delirium (according to DSM-5), the following criteria must be met: A. Disturbance in attention and orientation to the environment. B. Develops over a short period of time (hours to days), representing a change from baseline attention and orientation, and tends to fluctuate in severity during the course of a day. C. An additional disturbance in cognition (memory deficit, disorientation). D. The disturbances in criteria A and C are not better explained by another preexisting, established, or evolving neurocognitive disorder and do not occur in the context of a severely reduced level of arousal. E. There is evidence from the history, physical examination, or laboratory findings that the disturbance is a direct physiological consequence of another medical condition, substance intoxication or withdrawal, exposure to a toxin, or caused by multiple etiologies [8].}

_{⁸To assess sensitivity in outpatient practice, it is necessary to use the Ipswich Touch Test, performed by sequentially touching the 1st, 3rd, and 5th toes bilaterally. The absence of sensation in more than 2 touches indicates the presence of diabetic polyneuropathy [560].}

2.3 Laboratory Diagnostics

Laboratory diagnostics aim to determine the etiological factor and identify the acuity of the pathological condition.

Comments: an investigation of total hemoglobin, erythrocyte, platelet, and leukocyte levels in the blood, erythrocyte sedimentation rate (ESR), and differential leukocyte count (leukocyte formula) is performed.

Comments: the differential diagnostic panel includes acute liver failure, chronic liver disease, drug-induced hyperammonemia (valproic acid**, fluorouracil**, asparaginase**), urea cycle defect, and mixed etiologies.

Comments: the most frequently measured vitamins are B1, B9, B12, C, and PP.

Comment: Wernicke's encephalopathy is a life-threatening condition, therefore treatment must be initiated based on clinical data without laboratory confirmation of thiamine deficiency [248, 249]. Up to 90% of vitamin B₁ is located in erythrocytes and leukocytes, and less than 10% in plasma [249, 250]. Assessment of thiamine levels in blood plasma/serum is feasible but has low diagnostic value [250]. Certain diseases can affect thiamine levels. Vitamin B₁ concentration in plasma/serum decreases in sepsis, multiple trauma, coronary artery bypass grafting [251–253], and in patients on renal replacement therapy (presumably due to impaired absorption), which necessitates the inclusion of thiamine** in multivitamin therapy for patients on dialysis [254]. Vitamin B₁ concentration increases in patients with acute liver injury [255].

Comment: 1) free cortisol in saliva is tested at 23:00,

2) free cortisol in urine is tested in a 24-hour urine collection,

3) total cortisol in blood is measured in the morning following the administration of 1 mg of #dexamethasone** at 23:00 on the eve of the test [259].

2.4 Instrumental Diagnostics

The diagnosis of toxic and metabolic nervous system injuries is primarily based on medical history taking and clinical examination. If diagnostic doubts arise, neuroimaging is indicated to rule out other diseases with a similar clinical presentation [8].

Magnetic resonance imaging (MRI) is the primary neuroimaging modality; if it is not available, computed tomography (CT) is used [8, 260]. The main differential diagnoses include acute cerebrovascular accidents, including cerebral venous thrombosis and spinal cord infarction; infectious, demyelinating, and autoimmune disorders; neoplasms; cerebral vasospasm; and posterior reversible encephalopathy syndrome [260].

Toxic and metabolic injuries are characterized by [8, 163, 165, 260–262]:

• in most cases, findings are absent or non-specific [8, 260, 261], but characteristic patterns are identified in certain pathological conditions [8, 260];

• when abnormalities are present, they typically show: symmetry of involvement; selective involvement of specific brain structures; absence or minimal mass effect;

• typical and atypical presentations have been described for many conditions;

• MRI is the method of choice in most cases;

• on CT, affected areas frequently appear hypodense;

• on MRI, primary attention should be paid to FLAIR and DWI combined with apparent diffusion coefficient (ADC) maps. DWI allows the evaluation of cytotoxic edema, which may characterize the acuteness of the process, although these changes resolve over time. The use of T2*-weighted imaging or susceptibility-weighted imaging (SWI, SWAN, FSBB, Ven-BOLD) allows the exclusion of micro- and macrohemorrhages;

• contrast enhancement is frequently absent. Contrast enhancement primarily indicates a breakdown of the blood-brain barrier, which is normally impermeable to it;

• combinations of different patterns are possible (e.g., a combination of Wernicke's encephalopathy and posterior reversible encephalopathy syndrome in pregnant women).

Characteristic patterns for certain types of toxic and metabolic nervous system injuries are presented below.

Cerebral cortex, with characteristic affected areas including:

Opioid-associated amnestic syndrome: bilateral hippocampi, ± cerebellum and basal ganglia. CHANTER syndrome is defined by involvement of the hippocampi, cerebellum, and basal ganglia [263, 264].

Acute hepatic encephalopathy: insular cortex, cingulate gyrus, thalami, posterior limb of the internal capsule, periventricular white matter, dorsal brainstem, and cortex (excepting the occipital and perirolandic regions). Microhemorrhages are occasionally observed [265–268].

Hypoglycemic encephalopathy: cortex (especially the posterior cerebral hemispheres and insular cortex), hippocampi, basal ganglia, white matter (especially the posterior limb of the internal capsule), and occasionally the splenium of the corpus callosum. Thalami and cerebellum are usually spared. Differential diagnosis includes hypoxic-ischemic brain injury [269–271].

Deep grey matter, with characteristic affected areas including:

Wernicke's encephalopathy (alcoholic and non-alcoholic origin): mammillary bodies, dorsomedial thalami, tectum of the midbrain, periaqueductal gray matter, areas along the third ventricle, and occasionally the cerebral cortex and dentate nuclei [163, 262, 267, 272–275].

Methanol poisoning: necrosis of the basal ganglia with preferential involvement of the putamen over the globus pallidus, subcortical white matter, optic nerve, and cerebellum. Contrast enhancement and hemorrhage are occasionally observed [260, 267, 276–278].

Toluene poisoning: thalami, globus pallidus, substantia nigra, dentate nuclei (T2↓); periventricular white matter, deep white matter (FLAIR↑); as well as atrophy of the corpus callosum, cerebrum, and cerebellum. Demylination and reactive gliosis are observed in areas of abnormal signal on FLAIR, T2, and T2*-weighted images [279, 280].

Carbon monoxide poisoning: globus pallidus and cerebral white matter. Hemorrhage and contrast enhancement are occasionally observed [281–285]. May also lead to anoxic brain injury (both acute and delayed).

Metronidazole toxicity**: cerebellum, especially the dentate nuclei, vestibular nuclei (floor of the fourth ventricle), pontine tegmentum, and splenium of the corpus callosum [286, 287].

Uremic encephalopathy: basal ganglia, at the border of the grey matter of the basal ganglia forming the "lentiform fork sign", white matter—posterior limb of the internal capsule, with occasional involvement of the thalami, midbrain, and medial temporal lobes [288, 289].

Acquired hepatocerebral degeneration: globus pallidus (T1WI↑), then subthalamic region and substantia nigra, middle cerebellar peduncles (FLAIR↑) [290, 291].

Diabetic striatopathy (hyperglycemic hemichorea): putamen (T1WI↑, ±FLAIR↑, ±CT↑), caudate nucleus (T1WI↑, ±FLAIR↑, ±CT↑), globus pallidus (T1WI↑, ±FLAIR↑, ±CT↑) [292–294].

White matter, with characteristic lesion sites being:

Marchiafava–Bignami disease: changes begin in the body of the corpus callosum, then the genu. Hemorrhages may be observed. The sandwich sign has been described: involvement of the central layers of the corpus callosum with intact ventral and dorsal layers. Necrosis and demyelination of the corpus callosum are observed in chronic alcohol abuse and malnutrition (B-group vitamin deficiency) [295, 296].

Acute toxic leukoencephalopathy: periventricular white matter presenting as large confluent lesions. Microhemorrhages and contrast enhancement are sometimes noted. The imaging pattern may be associated with a wide variety of conditions: chemotherapy, immunosuppressants, systemic antifungals / anthelmintics / antiprotozoal drugs, opioids, heroin, MDMA, hepatic encephalopathy, uremia, etc. [297–299].

Levamisole**-associated leukoencephalopathy: one or more asymmetric rounded white matter lesions (sometimes resembling pseudotumoral demyelination), frequently involving the centrum semiovale, periventricular white matter, and basal ganglia region, less commonly the spinal cord and cerebellum. Ring-like and incomplete ring-like contrast enhancement is noted (the non-enhancing portion typically facing the cortex), with possible laminar structure and restriction of water molecule diffusion on DWI, resembling the manifestations of acute disseminated encephalomyelitis (ADEM) [260, 300, 301].

Heroin leukoencephalopathy ("chasing the dragon"): cerebellum (white matter and middle cerebellar peduncles in a "butterfly wing" pattern), white matter of the posterior cerebral hemispheres, posterior limb of the internal capsule, pyramidal tracts. Sparing of the gray matter and U-fibers is noted. Caused by inhalation of heroin pyrolysate [302–304].

Osmotic demyelination syndrome (formerly known as central pontine myelinolysis, though extrapontine myelinolysis is also distinguished and can occur without brainstem involvement): central regions of the brainstem, thalami, basal ganglia, body of the corpus callosum. The trident sign is identified: changes in the pons sparing the pyramidal tracts [305–309].

Posterior reversible encephalopathy syndrome (PRES): vasogenic white matter edema of the occipital and parietal lobes, changes in watershed zones, subcortical region ± cortex. Atypical manifestations are occasionally noted, including: unilateral involvement, brainstem and/or basal ganglia involvement, spinal cord involvement. Contrast enhancement is sometimes observed [310–316].

Cytotoxic lesions of the corpus callosum (CLOCCs) or mild encephalopathy with a reversible splenial lesion (MERS): splenium of the corpus callosum along the midline, with occasional extension to the body of the corpus callosum; true restriction of water molecule diffusion on DWI in the acute phase [317, 318].

Diabetic ketoacidotic coma (in patients with newly diagnosed type 1 diabetes): diffuse cerebral edema, decreased gray-white matter differentiation on CT, as well as foci of cerebral infarction, intracerebral hemorrhage, extrapontine myelinolysis, and cerebral venous thrombosis [319–324].

Spinal cord, with characteristic lesion sites being:

Subacute combined degeneration of the spinal cord (vitamin B12 deficiency, nitrous oxide inhalation, copper, folic acid, and vitamin E deficiency): symmetric involvement of the posterior columns of the spinal cord forming an inverted "V" sign, often starting in the upper thoracic spinal cord, with occasional involvement of the lateral corticospinal and lateral spinothalamic tracts [325–332].

The following conditions should be noted separately: reversible cerebral vasoconstriction syndrome, hypoxic-ischemic brain injury, delayed posthypoxic leukoencephalopathy, and hyperglycemic hyperosmolar state. Hypoxic-ischemic brain injury and delayed posthypoxic leukoencephalopathy are not direct manifestations of toxic or metabolic disorders; however, these conditions occupy an important place in differential diagnosis due to their characteristic neuroimaging features, and their radiological manifestations often mimic those of toxic-metabolic encephalopathy.

Reversible cerebral vasoconstriction syndrome (RCVS). The primary diagnostic methods are brain CT and CTA to rule out hemorrhage and assess the state of cerebral arteries, but selective angiography remains the "gold standard." Transcranial Doppler ultrasonography makes it possible to assess the degree of vasospasm in major cerebral arteries and perform dynamic monitoring. High-resolution contrast-enhanced MRI for vessel wall imaging (MR vessel wall imaging) can in some cases assist in the differential diagnosis of focal arterial narrowing associated with vasculitis or intracranial atherosclerosis. It is worth noting that in the RCVS2 criteria [333], involvement of intracranial arteries weighs against the diagnosis of RCVS. Findings may include: convexal subarachnoid hemorrhages, lobar hemorrhages, cerebral infarctions (including in watershed zones), signs of vasogenic edema (sometimes with manifestations similar to posterior reversible encephalopathy syndrome), focal arterial narrowings on angiography (smooth, tapered stenoses affecting large and medium-sized arteries, followed by abnormally dilated segments of second- and third-order branches, the "sausage on a string" sign) [65, 333–339].

Hypoxic-ischemic brain injury. An acute condition developing as a result of cardiac arrest, systemic hypoperfusion, hypoxemia, or asphyxia. Characteristic MRI lesion pattern: cerebral cortex, frequently along with the pericentral cortex, basal ganglia and thalami, isolated basal ganglia, watershed zones, and sometimes the cerebellum. Characterized by true restriction of water molecule diffusion on DWI during the first week. CT sometimes reveals the "white cerebellum" sign and the pseudo-subarachnoid hemorrhage sign [340–347].

Delayed posthypoxic leukoencephalopathy. A specific form of demyelinating CNS lesion that occurs 2–4 weeks after a hypoxic-ischemic episode, often against the background of apparent clinical improvement. Characteristic lesion pattern: deep white matter with true restriction of water molecule diffusion on DWI, while sparing of U-fibers is typical. The condition is associated with carbon monoxide poisoning [348–350].

Hyperglycemic hyperosmolar state (in patients with type 2 diabetes). Has no characteristic neuroradiological signs, but can lead to the appearance of foci of acute cytotoxic edema resembling foci of acute cerebral infarction [351–353]. Some patients also exhibit manifestations of diabetic striatopathy [351].

Electroencephalography (EEG) is the main instrumental method for assessing the functional state of the brain, while characteristic specific changes on the electroencephalogram are observed only in epilepsy and status epilepticus [354]. EEG changes in encephalopathy of any etiology are non-specific and reflect only its severity.

Acute symptomatic seizure (ASS) – a seizure occurring in response to an acute toxic, metabolic, infectious, or structural brain injury [355]. In the case of toxic and metabolic injury, a seizure should be considered an ASS if laboratory indicators show that intoxication persists. Laboratory indicators pointing to metabolic disturbances leading to an ASS are presented in Table 6. A seizure developing against the background of discontinuing prolonged alcohol intake is considered an ASS if it occurs within 48 hours of the last use [355].

Table 6 – Laboratory indicators pointing to metabolic disturbances leading to an acute symptomatic seizure

Non-convulsive status epilepticus (NCSE) is a clinical and electroencephalographic syndrome manifested by suddenly developed stupor or coma, confusion, mutism, mental slowness, and automatisms. NCSE is significantly less common than generalized tonic-clonic status epilepticus, accounting for 5–20% of all cases of status epilepticus. To diagnose NCSE, two essential criteria must be identified:

1) clinically obvious changes in the level of consciousness and behavior that differ from the patient's baseline state;

2) epileptiform activity on the EEG.

The instrumental method for confirming the neural level of the lesion, the extent and symmetry of the process, and determining the type of damage to sensory and/or motor fibers of the peripheral nerves of the limbs (axonal or demyelinating) is stimulational electroneuromyography of a single nerve (ENMG) / synonym – nerve conduction study (NCS) [7].

2.4.1. Instrumental diagnostics of toxic lesion of the nervous system

2.4.1.1. Toxic lesion of the central nervous system

Comments: it is recommended to interpret (describe) neuroimaging results strictly in the context of the clinical picture, medical history, and laboratory findings for the differential diagnosis of toxic, metabolic, and other types of nervous system damage [8, 260].

Comment: Brain MRI has low sensitivity (53%) but high specificity (93%) for the diagnosis of WE [166]. The sensitivity of MRI in detecting WE associated with chronic alcohol consumption is 53% [159]. The highest sensitivity for detecting signs of WE has been established for T2 FLAIR images. On diffusion-weighted images, areas of damage are often characterized by a high signal, and the apparent diffusion coefficient (ADC) may be normal, high, or low depending on the acuity of the process [357]. Typical areas of hyperintense signal on MRI (on FLAIR, DWI, T2-weighted images) in WE include: medial thalami, mammillary bodies, tectal plate, periaqueductal gray area, and the floor of the 4th ventricle [2]. However, changes in these brain areas are detected in only 58% of patients with WE [166, 358]. Atypical locations of high MR signal (on FLAIR, DWI, T2-weighted images): cerebellum, cranial nerve nuclei (VI, VII, VIII, XII pairs), cerebral cortex (pre- and postcentral gyri), basal ganglia (putamen, caudate nucleus). Damage in atypical areas in WE is almost always found in combination with typical locations [163, 164, 359]. The absence of changes on brain MRI does not exclude the diagnosis of WE [160].

Comments: activation procedures, synonyms – functional tests, activating procedures. In patients with toxic encephalopathy and a clinical suspicion of non-convulsive status epilepticus, there is a discrepancy between the laboratory-determined concentration of toxicants and the severity of impaired consciousness. A clear state of consciousness, absence of confusion, aura, motor, and sensory symptoms rule out non-convulsive status epilepticus and the need for an EEG.

EEG and EEG with activation procedures in suspected non-convulsive status epilepticus should be recorded according to the Salzburg criteria algorithm detailed in the clinical guidelines "Epilepsy and Status Epilepticus" [354].

Comments: Single or serial epileptic seizures in the acute period of toxic brain injury (in the first 24 hours) or prior to the elimination of the intoxicant are referred to as acute symptomatic epileptic seizures (ASES). They do not require treatment with antiepileptic drugs and do not indicate a risk of subsequent development of symptomatic epilepsy. Failure to recover consciousness to baseline after the end of the clinical phase of ASES may indicate the transition of convulsive ASES to a non-convulsive form. Only in this case is the recording of an EEG and EEG with activation procedures indicated.

2.4.1.2. Toxic lesion of the peripheral nervous system

Comment: in most cases, a generalized axonal pattern of changes is detected, with predominant involvement of sensory nerve fiber axons and greater involvement of the lower extremities. A demyelinating pattern of axonal damage in sensory and motor fibers is observed in toxic polyneuropathies resulting from the intake of procainamide** (similar to chronic inflammatory demyelinating polyneuropathy).

ENMG is uninformative for diagnosing polyneuropathy with involvement of small sensory fibers observed in drug-induced neuropathies due to the intake of pyridoxine** (B₆), nicotinic acid (B₃), chloramphenicol**, leflunomide**, direct-acting antiviral drugs (didanosine**, stavudine*).

2.4.2. Instrumental diagnostics of metabolic lesion of the nervous system

2.4.2.1. Metabolic lesion of the central nervous system

Comments: it is recommended to interpret (describe) neuroimaging results strictly in the context of the clinical picture, medical history, and laboratory findings for the differential diagnosis of toxic, metabolic, and other types of nervous system damage [8, 260].

Comment: Brain MRI has low sensitivity (53%) but high specificity (93%) for the diagnosis of WE [166]. The sensitivity of MRI in detecting non-alcohol-related WE is higher, reaching 100% [159]. T2 FLAIR images have been established to have the highest sensitivity for detecting signs of WE. On diffusion-weighted images, lesion areas are often characterized by a high signal, while the apparent diffusion coefficient (ADC) may be normal, high, or low depending on the acuteness of the process [357]. Typical areas of high-intensity signals on MRI (on FLAIR, DWI, T2-weighted images) in WE include: medial thalami, mammillary bodies, tectal plate, periaqueductal gray matter, and the floor of the fourth ventricle [2]. However, changes in these brain areas are detected in only 58% of patients with WE [166, 358]. Atypical locations of high MR signal (on FLAIR, DWI, T2-weighted images) include: cerebellum, cranial nerve nuclei (VI, VII, VIII, XII pairs), cerebral cortex (pre- and postcentral gyri), and basal ganglia (putamen, caudate nucleus). Damage in atypical areas in WE is almost always found in combination with typical locations [163, 164, 359]. The absence of changes on brain MRI does not rule out the diagnosis of WE [160].

Comments: activation procedures, synonyms include functional tests, activating tests.

In patients with metabolic encephalopathy and a suspected non-convulsive status epilepticus, an inconsistency between the laboratory-determined concentration of toxicants and the severity of consciousness impairment is observed. Clear consciousness, absence of confusion, aura, motor, and sensory symptoms rule out non-convulsive status epilepticus and the need for EEG.

EEG and EEG with activation procedures in suspected non-convulsive status epilepticus should be performed according to the algorithm of the Salzburg criteria, detailed in the clinical guidelines "Epilepsy and Status Epilepticus" [354].

Comments: Single or serial seizures in the acute period of brain metabolic injury (in the first 24 hours) or prior to toxicant elimination are termed acute symptomatic seizures. They do not require treatment with antiepileptic drugs and do not indicate a risk of subsequent development of symptomatic epilepsy. Failure of consciousness to return to baseline after the clinical phase of an acute symptomatic seizure may indicate the transition of a convulsive seizure into a non-convulsive form. Only in this case is the registration of EEG and EEG with activation procedures indicated.

2.4.2.2. Metabolic lesion of the peripheral nervous system

Comment: the study is recommended due to the high probability of developing dysimmune neuropathies in diabetes mellitus.

Electrophysiological criteria for ENMG diagnosis of diabetic polyneuropathy have not been developed.

A symmetrical, primarily axonal pattern of peripheral nerve involvement is typical, with a predominance of changes in the nerves of the lower extremities and preferential involvement of sensory nerve axons. The described neurophysiological changes are often combined with electrographic signs of carpal tunnel syndrome.

ENMG examination is not informative for the diagnosis of diabetic polyneuropathy affecting small sensory fibers and autonomic diabetic neuropathy.

2.5 Other Procedures

Patients with a clinical picture of toxic or metabolic nervous system damage of undetermined diagnosis may require studies such as chest CT, abdominal and pelvic CT, spinal MRI (one segment), and pure-tone audiometry to detect frequently occurring asymptomatic abnormalities in other organs, the spine, the central nervous system, and the peripheral nervous system [8]. However, the following additional diagnostic examinations are most frequently required:

Comment: especially in cases of altered level of consciousness and fever to rule out meningoencephalitis.

2.5.1. Other diagnostic procedures in toxic lesion of the nervous system

Comment: the initial examination by an ophthalmologist includes standard visual acuity testing (visometry), intraocular pressure measurement (ophthalmotonometry), biomicroscopy of the anterior segment of the eye, and ophthalmoscopy of the fundus. To verify the diagnosis, additional examinations are necessary: optical coherence tomography of the retina and optic nerve, computer perimetry, fluorescein angiography of the eye, eye ultrasound, and color Doppler imaging of ocular vessels.

Patients with toxic optic neuropathy may receive treatment for this condition on an outpatient basis or in a day hospital setting. Depending on the etiology, pathogenesis, and degree of optic nerve damage, the frequency of follow-up consultations is established individually for each patient, but at least once every 6 months during the first 2 years from the time of diagnosis [186, 365, 366].

Comment: Korsakoff's syndrome includes symptoms of anterograde amnesia, retrograde amnesia, confabulations, executive dysfunction, and emotional disturbances [368]. Wernicke's encephalopathy is the acute phase of Wernicke-Korsakoff syndrome, in the chronic stage of which Korsakoff's syndrome develops [2]. Korsakoff's syndrome is caused by damage to the dorsal thalamus and mammillary bodies and most commonly occurs in patients with WE who have not received treatment [158]. According to Manzo G. et al. (2014), Korsakoff's syndrome develops in 85% of surviving patients [164].

Comments: Patients with motor disorders are strictly referred for a consultation with a physical therapy doctor. All patients receive home-based self-rehabilitation.

Other diagnostic procedures in metabolic lesion of the nervous system

Comment: the initial examination by an ophthalmologist includes standard visual acuity testing (visometry), intraocular pressure measurement (ophthalmotonometry), biomicroscopy of the anterior segment of the eye, and ophthalmoscopy of the fundus. To verify the diagnosis, additional examinations are necessary: optical coherence tomography of the retina and optic nerve, computer perimetry, fluorescein angiography of the eye, eye ultrasound, and color Doppler imaging of ocular vessels.

Patients with toxic optic neuropathy can receive treatment for this condition on an outpatient basis or in a day hospital setting. Depending on the etiology, pathogenesis, and degree of optic nerve damage, the frequency of follow-up consultations is established individually for each patient, but at least once every 6 months during the first 2 years from the date of diagnosis.

Exception: patients with proliferative diabetic retinopathy and glaucoma. The standard of follow-up in this case is visiting an ophthalmologist every 3 months on an ongoing basis, provided there is no significant deterioration [186, 365, 366].

Comments: patients with motor disorders are strictly referred for a consultation with a physical therapy doctor. All patients receive home-based self-rehabilitation.

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

3.1. Provision of emergency medical care outside a medical organization for acute toxic and metabolic nervous system disorders

Provision of medical care in the intensive care unit for acute toxic and metabolic nervous system damage

Treatment of a patient with toxic or metabolic nervous system damage in the intensive care unit includes:

symptomatic treatment, etiological treatment [8].

Symptomatic treatment is performed regardless of the etiology [8]:

Monitoring of vital signs (blood pressure, heart rate, respiratory rate, body temperature).

Monitoring of glucose and sodium levels.

Prevention of hypercapnia / severe hypocapnia.

Ensuring a comfortable environment: a quiet setting with low-intensity lighting and lights turned off at night, earplugs and eye masks, presence of a clock in the room.

In case of a decreased level of consciousness – performing mechanical ventilation.

Treatment of seizures (has no specific features, but myoclonus or triphasic waves are often mistaken for epileptiform activity).

Prevention of infectious and venous thromboembolic complications.

Abatement of psychomotor agitation.

Comments: measures aimed at the prevention of venous thromboembolic complications include: early patient mobilization, prevention of water-electrolyte imbalances, prescription of prophylactic doses of heparin sodium** (unfractionated heparin) (5000 units subcutaneously 2 or 3 times a day) or low-molecular-weight heparins (ATC B01AB heparin group), application of intermittent pneumatic compression (A21.12.002 Intermittent pneumatic compression). The choice of method is made individually.

Comments: restraint should be performed as delicately as possible, using soft non-traumatic means (towels, sheets, cloth straps, etc.). Each limb and the shoulder girdle must be securely restrained; compression of nerve trunks and blood vessels must be avoided. The restrained patient must be constantly within the staff's field of vision. Restraint does not imply the removal of supervision, but rather requires round-the-clock observation and continuous monitoring of the patient's condition. The use of patient restraint must be justified and requires a mandatory entry in the medical documentation indicating the time of prescription and cancellation of this measure and a description of changes in the patient's subsequent condition.

Comments: the drug of choice is #diazepam**, which is prescribed as a 5-10 mg bolus (slow IV), followed by a maintenance dose of 0.03 to 0.10 mg/kg every 0.5–6 hours [382]. It must be taken into account that #diazepam** and other anxiolytics are contraindicated in acute intoxication with substances that exert a depressing effect on the central nervous system; therefore, they should not be used for short-term agitation in patients with alcohol intoxication.

Recommended drug doses:

#diazepam** solution, 5-10 mg slowly IV (maintenance dose 0.03 to 0.10 mg/kg every 0.5–6 hours);

#haloperidol** solution 5 mg IM (the dose may be repeated after one hour, maximum daily dose 20 mg/day);

#droperidol** solution 5-10 mg IM for patients with psychoactive substance poisoning presenting with psychomotor agitation.

Comment: in acute intoxication with stimulating psychoactive substances and psychotic states with agitation, it is crucial to rapidly relieve agitation using hypnotics and sedatives whenever possible, since CNS oxygen and energy substrate demands increase sharply in these states. The delivery capacity in addiction patients is generally reduced, which can lead to oxygen deprivation, CNS dysfunction, and cerebral edema. Therapy with hypnotics and sedatives should be administered with caution, avoiding excessive sedation. The drug of choice is #haloperidol**, which is prescribed as a 0.5% solution in a single dose of no more than 10 mg.

Comment: a specific therapeutic strategy involving a short, structured dialogue conducted with the patient by a medical organization specialist (physician, medical psychologist).

Etiological treatment (treatment of the underlying disease / poisoning) is carried out in accordance with current disease-specific clinical guidelines [8].

Treatment of patients with toxic lesion of the nervous system

Toxic lesion of the central nervous system

I. Alcoholic encephalopathy

Comment: chronic alcohol consumption leads to a deficiency of B vitamins, particularly thiamine. Thiamine hypovitaminosis leads to impaired nerve conduction in the central and peripheral nervous systems, subsequently resulting in Wernicke's encephalopathy and polyneuropathy.

Comment: the drug is prescribed at a dose of 500 mg 2 times a day for 2 weeks..

Comment: the drug is administered intravenously as an infusion at a dose of 10 ml diluted in 200 ml of 0.9% sodium chloride** solution for 10 days, followed by oral administration of 2 tablets 2 times a day for 25 days.

Comment: the drug is prescribed at a dose of 10 mg per day intramuscularly for 10 days.

Comment: with parenteral administration, the daily dosage is determined by specific parameters and ranges from 3–4 g (in alcohol withdrawal syndrome) to 10–15 g (in comatose states). In the management of delirium tremens, #piracetam** is administered parenterally at a dose of up to 4 g. The drug is prescribed as a 20% solution intravenously [404].

Comment: the drug is prescribed at a dose of 100 mg 2-3 times a day for 30 days.

Comment: the drug is prescribed at a dose of 0.5 g 3 times a day.

Comment: the drug is prescribed at a dose of 5 ml intravenously.

II. Wernicke's Encephalopathy

Comment: the cornerstone of treatment for Wernicke's encephalopathy is the immediate administration of #thiamine** when this condition is suspected, since with early initiation of therapy, the clinical and radiological symptoms of Wernicke's encephalopathy are reversible, up to complete recovery: regression of ocular motility symptoms occurs within several hours or days, ataxia within 8-14 days, and restoration of the level of consciousness within several days or weeks [2, 408]. Thiamine overdose is unlikely because B vitamins are water-soluble. According to the European Federation of Neurological Societies guidelines, #thiamine** is preferably administered intravenously rather than intramuscularly [229].

Due to the fact that intravenous administration at a dose of 1000 mg/day [234] is not provided for by the official prescribing information for #thiamine** (approved routes of administration are oral and intramuscular), administering the drug in accordance with this recommendation must be carried out based on a decision of the medical commission.

III. Toxic Encephalopathy

Comment: the drug is prescribed at a dose of 4 ml of a 5% solution once a day as an intravenous infusion for 5–10 days for encephalopathy / at a dose of 500 mg (10 ml) per day as an intravenous infusion for 4 days for psychodysleptic poisoning / parenterally at 100–400 mg 2 times a day (200–800 mg/day) for 15 days for psychoactive substance intoxication and psychoactive substance withdrawal syndrome.

Comment: in toxic encephalopathy, the drug is administered in a volume of 10 ml per injection 2 times a day at 8-12 hour intervals for 5 days. In a comatose state—in a volume of 20 ml per injection diluted in 200 ml of dextrose solution. In post-anesthetic depression of consciousness—as a single dose in the same amounts.

It is possible to prescribe the drug at a dose of 20 ml per 400 ml of 5% dextrose** 2 times a day as a 7-day course [412], or at a dose of 0.57 ml/kg of body weight per day daily for 9 days [413], or at a dose of 20 ml once a day daily [410, 414].

Comment: the drug is prescribed at a dose of 30 mg every 8-12 hours orally for 30 days. In a study by Cho S. et al. (2019), the duration of the clinical course of reversible cerebral vasoconstriction syndrome was compared among patients in three groups categorized according to the time elapsed from disease onset to the initiation of #nimodipine** therapy. Early initiation of treatment (less than 6 days) was characterized by the shortest duration of clinical manifestations of this syndrome [415].

3.1.2. Toxic lesion of the peripheral nervous system

I. Alcoholic Polyneuropathy

Comment: the drug is prescribed at a dose of 2–3 ml of a 5% solution intramuscularly, followed by a transition to oral administration [416].

Comment: the drug is prescribed at a dose of 2 ml intramuscularly for 10 days, followed by 1 tablet 3 times a day for 2-3 months.

Comment: the drug is prescribed at a dose of 600 mg orally once a day in the morning 30 minutes before meals for 1.5-2 months; in severe cases, treatment is initiated with parenteral administration of the drug for 2-4 weeks, after which the patient is switched to the tablet form.

Comment: the drug is prescribed at a dose of 200 mg once daily – 5 ml of the drug in 100 ml of 0.9% sodium chloride solution** intravenously as an infusion, the course of treatment is 3 weeks.

Comment: the drug is prescribed at an initial dose of 300 mg once daily, with a further increase in the dose up to 1800 mg per day (divided into 3 doses). The duration of treatment is 6 weeks, followed by a slow withdrawal of the drug.

Comment: the drug is prescribed at an initial dose of 75 mg once daily in the evening for a week, then the dose is gradually increased to 300 mg per day.

Comment: the drug is prescribed at an initial dose of 100–200 mg 1–2 times daily; as a rule, a gradual increase in the dose to 400 mg 2–3 times daily is sufficient.

Comment: the drug is prescribed at a dose of 50–150 mg once daily at bedtime or the dose is divided into 2–3 intakes.

II. Drug-induced polyneuropathy

Comment: the attending physician and the patient may make different decisions regarding the advisability of continuing therapy when the patient develops severe manifestations of polyneuropathy. In such situations, the attending physician can determine whether it is reasonable to use alternative treatment regimens that do not cause neurotoxicity.

GCR CLoE 3Grade of Recommendation C (Level of Evidence – 3)

Comment: the drug is prescribed at a dose ranging from a preventive 10 mg once daily to 100 mg daily.

Comment: the drug is prescribed at a dose of 600 mg once daily intravenously as an infusion daily for 3 weeks, then 600 mg orally once daily for 1 month [424][426, 427]. A positive effect of treatment was observed with the combined administration of #thioctic acid** and ipidacrine [425].

Comment: the drug is prescribed subcutaneously or intramuscularly at a dose of 5–15 mg 1–2 times daily, with a course of 10–15 days (in severe cases, up to 30 days); further treatment is continued with the tablet form of the drug: 20–60 mg per day orally for 20 days or 20–60 mg per day orally for 30 days [425, 427].

Comment: pain symptoms can also be alleviated by topical application of 1–3 g of 1% menthol cream to the affected area 2–3 times daily for 3–4 weeks [429].

Comment: the 5% #lidocaine patch is prescribed up to 3 patches per day, with a course of up to 4 weeks.

Comment: the drug is prescribed at an initial dose of 900 mg/day in three equal doses; if necessary, depending on the effect, the dose is gradually increased to the maximum of 3600 mg/day. It should be taken into account that when gabapentin is used at a dose of more than 1800 mg/day, no additional efficacy is observed. Treatment can be started immediately at a dose of 900 mg/day (300 mg 3 times daily) or the dose can be increased gradually to 900 mg per day during the first 3 days according to the following schedule: Day 1: 300 mg of the drug once daily; Day 2: 300 mg twice daily; Day 3: 300 mg 3 times daily.

Comment: the drug is prescribed at an initial dose of 150 mg per day, divided into two or three doses. Based on individual patient response and tolerability, the dose may be increased to 300 mg per day after an interval of 3–7 days, and if necessary, to a maximum dose of 600 mg per day after an additional interval of 7 days. Compared to gabapentin, pregabalin** is absorbed faster and has a higher bioavailability.

Comment: the drug is prescribed at a dose of 30 mg per day orally [436] for 1 week, then the dose is increased to 60 mg per day (further titration up to 120 mg per day is possible) [432].

Comment: the drug is prescribed at a dose of 75–150 mg per day [432].

Comment: the drug is prescribed at a dose of 25–50 mg per day for 6 months or more; in case of persistent pain syndrome, the daily dose may be increased to 150 mg [438]. Therapy should be started with low doses (e.g., 6.25–12.5 mg at bedtime) with a gradual increase in dosage until an effect is achieved or side effects occur. #Amitriptyline** has anticholinergic, antihistamine, and sedative effects, which helps improve sleep quality in patients with chronic pain, especially when pain worsens at night [437, 439].

Comment: tramadol** is prescribed at a dose of 50–400 mg per day as needed, #tapentadol** 50–500 mg per day as needed, fentanyl** transdermal patch 25–100 mcg per hour as needed. When prescribing analgesic therapy, it is not necessary to sequentially move from one step of therapy to another: a patient with severe pain syndrome may immediately require strong opioid analgesics. The transition from one therapy step to the next is determined by increased pain, an insufficient response to the applied analgesic therapy, and adverse drug reactions in a particular patient [433, 441].

All patients taking opioids are at risk of developing constipation [441]. The incidence of constipation reaches 90%. Opioids inhibit longitudinal intestinal peristalsis while simultaneously spastically increasing smooth muscle contractions. Relief of bowel evacuation can be achieved by prescribing osmotic laxatives that increase water adsorption in the intestine (lactulose**, macrogol**, etc.), agents that stimulate the function of the large intestine (senna glycosides A and B** (ATX code A06AB, Contact laxatives), bisacodyl**, sodium picosulfate) and small intestine (castor oil, liquid paraffin). Laxatives should be taken throughout the entire period of opioid therapy, since tolerance to this side effect of opioids does not develop [442].

III. Polyneuropathy caused by other toxic substances

Comments: the drug is prescribed at a dose of 600 mg once daily.

Comment: the drug is prescribed at a dose of 200 mg once daily – 5 ml of the drug in 100 ml of normal saline IV drip, treatment course – 3 weeks.

Table 7 – Drugs for the treatment of neuropathic pain.

Comments: the drug is prescribed at an initial dose of 300 mg once daily, with a gradual increase of 300 mg every 3 days up to 1800 mg per day in two divided doses.

Table 8. Antidepressants for the treatment of neuropathic pain

Comments: special considerations for antidepressant use:

1. Before initiating antidepressant therapy, it is important to explain the treatment goals, expected effects, and timeline to the patient;

2. Patients should be warned about temporary adverse effects during the first weeks of administration. Informing the patient about their transient nature will increase treatment adherence;

3. It is also worthwhile to dispel the patient's main fears associated with taking antidepressants, inquire about all arguments 'against', and provide a reasoned response.

Table 9. Levels of recommendation grades and levels of evidence for opioid analgesics in the treatment of neuropathic pain.

Comments: Special considerations for opioid analgesic use:

1. Drugs of this group are classified as third-line therapy due to the risk of drug dependence and adverse events with long-term use;

2. When choosing a drug, one should consider the history of opioid analgesic use and any history of drug dependence;

3. The drug dosage is selected individually based on the product labeling, tolerability, efficacy, and the presence of concomitant cancer pain in the patient.

Comments: the dosing regimens of drugs used in Russian medical practice are presented in Table 10 [463].

Table 10. Nonsteroidal anti-inflammatory and antirheumatic drugs used in Russian medical practice

3.2. Treatment of patients with metabolic lesion of the nervous system

Patients with metabolic nervous system disorders should primarily receive treatment for the underlying condition (poisoning) in accordance with current relevant clinical guidelines.

3.2.1. Metabolic lesion of the central nervous system

Comment: the drug is prescribed at a dose of 600 mg once daily in 200 ml of 0.9% sodium chloride solution** as an intravenous infusion over three weeks, followed by oral administration of 300 mg (2 tablets) once daily in the morning for three weeks.

Comment: the drug is prescribed at a dose of 1000 mg daily for 8 weeks.

Comment: the drug is prescribed at a dose of 10 ml diluted in 200 ml of 0.9% sodium chloride** for 10 days, followed by oral administration of 2 tablets twice daily for 25 days.

Comment: the drug is prescribed at a dose of 400 mg 3 times daily for three months.

Comment: the drug is prescribed at a dose of 10 mg (1 ml) once daily intramuscularly for 10 days.

Comment: Glycine** is prescribed at a dose of 0.1 g sublingually 3 times a day, and #Citric acid + Succinic acid is prescribed at a dose of 0.25 g sublingually 3 times a day; the treatment course is 3 months.

3.2.2. Metabolic lesion of the peripheral nervous system

Comments: optimization of glycemic control helps prevent or delay the development of diabetic PNP in patients with DM. Medical therapy is recommended for DM patients with painful diabetic PNP to relieve its symptoms [9, 223, 474].

Comment: the drug is prescribed at a dose of 1 tablet 2-3 times daily after meals for 3-4 weeks.

Comment: the drug is prescribed at a dose of 600 mg in 200 ml of 0.9% sodium chloride solution** intravenously as an infusion once daily for 14-15 days. Afterwards, switch to the oral form at 600 mg once daily for 2-3 (1-2*) months [480, 481].

Comment: the drug is prescribed at a dose of 15 mg/ml 1–2 times a day intramuscularly or subcutaneously for 10 days, followed by a switch to the tablet form at 1 tablet (20 mg) 3 times daily for a total course of up to 2 months.

Comment: the drug is prescribed at a dose of 20 ml diluted in 200 ml of 0.9% sodium chloride** for 10 days, followed by oral administration of 2 tablets twice daily for 75 days [483].

Comment: the drug is prescribed at a dose of 2000 mg/day as daily intravenous infusions for 20 days, then orally at a dose of 1800 mg (3 tablets 3 times a day), with a duration of administration up to 4-5 months.

The following drugs are used to treat the painful form of distal polyneuropathy (Table 10) [486]:

Table 10 – Medications used for the treatment of painful diabetic neuropathy

Comment: the drug is prescribed at an initial dose of 300 mg once daily, on the 2nd day – 300 mg twice daily, on the 3rd day – 300 mg 3 times daily. Subsequently, the dose is gradually increased until an effect is achieved, possibly up to 1800–3600 mg per day. The minimum duration of test therapy is 3 to 8 weeks of dose titration, plus at least 2 weeks at the maximum tolerated dose. The minimum course of treatment is 3–6 months.

Comment: the drug is prescribed at an initial dose of 150 mg per day, divided into two or three doses. Based on the patient's individual response and tolerability, the dose can be increased to 300 mg per day after an interval of 3–7 days, and if necessary – to a maximum dose of 600 mg per day after an additional interval of 7 days. Compared to gabapentin, pregabalin** is absorbed faster and has higher bioavailability. Minimum duration of test therapy: 2–4 weeks at the maximum tolerated dose.

Comment: the drug is prescribed at a dose of 200 mg – 100 mg twice daily; dose escalation by 100 mg every 3 days, bringing it up to 800 mg per day in 4 doses [422, 488, 489].

Comment: the drug is prescribed at an initial dose of 300 mg twice daily, the therapeutic dose for analgesia is 1800–2400 mg per day. The minimum duration of therapy is 2–3 weeks at the maximum tolerated dose.

Comment: the drug is prescribed at an initial dose of 60 mg once daily; effective analgesic doses are 60 and 90 mg daily, and 120 mg daily in 2 divided doses. The minimum duration of test therapy is at least 4 weeks at the maximum tolerated dose.

Comment: the drug is titrated for 1 week at 37.5 mg daily, for the 2nd week at 75 mg daily, then at 150 mg daily, up to a maximum of 225 mg daily [480, 491].

Comment: the drug is prescribed at a dose of 5–10 mg daily in 2 divided doses. If well tolerated, after 3–4 days the dose is increased to 10–25 mg in 2 divided doses; further increases are made once every 10–14 days until a therapeutic dose of 50–150 mg daily in 2–3 divided doses is reached. The duration of therapy should be at least 3 weeks at the maximum tolerated dose.

Comment: the drug is prescribed at a dose of 50 mg 1–2 times daily, with a gradual increase if necessary up to 100 mg 2–4 times daily. In patients over 75 years of age, the maximum daily dose should not exceed 300 mg due to the risk of impaired consciousness (confusion).

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Medical rehabilitation of patients with toxic/metabolic disorders of the nervous system includes a set of measures consisting of:

1) discussions with the patient about the disease, its clinical course variants, potential complications, and prevention measures;

2) training in self-monitoring skills regarding the development or worsening of complications;

3) rehabilitation using external physical factors;

4) discussions with the patient about the importance of adhering to self-rehabilitation and limiting factors that may worsen the course of the disease;

5) informing the patient about methods to promote health and well-being [369, 492–494].

The patient is provided with information about the disease and its treatment methods (Appendix B1-BN).

Patients with alcohol use disorder or other psychoactive substance use disorders need medical rehabilitation, which includes a combination of medical, psychological, and social measures aimed at the maximum possible compensation or restoration of impaired/lost body functions and social adaptation of the patient.

The goal of medical rehabilitation is the restoration (formation) and qualitative modification of the mental, physical, social, and spiritual health of patients with alcohol dependence or dependence on other psychoactive substances based on unlocking and developing their creative, intellectual, moral, and emotional potential, changing relationships with the external world, and gaining spiritual experience as a condition for their successful social integration under conditions of complete abstinence from alcohol and other psychoactive substances [496, 497]. The duration of medical rehabilitation is determined strictly individually for each patient, taking into account the clinical features of the addiction disorder, the level of rehabilitation potential, the state of cognitive, emotional, and behavioral disorders, the depth and features of anosognosia in the patient and family members [497], codependent individuals, and the patient's degree of readiness to change their behavior under conditions of complete abstinence from alcohol or other psychoactive substances [498].

The strategic goals of medical rehabilitation in patients with alcohol dependence or dependence on other psychoactive substances are presented in the relevant clinical guidelines.

4.1 Toxic lesion of the nervous system

Comments: acupuncture is used only as an additional method of physical rehabilitation in patients with toxic nervous system damage receiving standard treatment.

Comment: hyperbaric oxygenation achieves various clinical effects—correction of neurological disorders [504], including reduction of chronic pain syndrome, such as neuropathic pain [505–507], improvement of cognitive functions [508], neuroprotection [509], neuroregeneration [510], and neuromodulation [511]. Studies have been conducted to evaluate the efficacy of hyperbaric oxygenation in toxic encephalopathy associated with carbon monoxide exposure [513, 514], chemotherapy drugs [514], and others.

4.2 Metabolic lesion of the nervous system

Order of the Ministry of Health of the Russian Federation No. 404 dated December 10, 1996, "On measures to implement the federal target program 'Diabetes Mellitus' and to unify the scientific and methodological approach to educating patients with diabetes mellitus" [492].

Stratification of risk groups for diabetic foot syndrome is based on the presence and combination of risk factors for diabetic foot syndrome. A patient with severe diabetic polyneuropathy and loss of protective sensation is included in the "high risk" group for wound development and requires more frequent examinations in the diabetic foot clinic.

Structured foot care education should include information on [520]:

√ diabetic foot syndrome and its potential consequences;

√ behaviors aimed at preventive foot care measures (the need for proper hygiene, etc.) (see the "Patient Information" section);

√ the need to wear "protective" footwear appropriate for the diabetic foot syndrome risk group (see the "Patient Information" section);

√ the importance and necessity of regular foot status assessments by a qualified specialist;

√ timely seeking of professional help upon identifying a foot problem.

Comprehensive therapeutic and preventive measures in the presence of a high-risk group for diabetic foot syndrome

The complex of therapeutic and preventive measures consists of treatment aimed at eliminating risk factors for diabetic foot syndrome, as well as professional foot care. Professional foot care should be provided by an appropriately trained medical professional and consist of treating risk factors and pre-ulcerative lesions, structured foot care education, and providing appropriate footwear (see the "Patient Information" section) [521–523].

Comment: physical exercise can improve the course of diabetic polyneuropathy (reliable evidence level – B, evidence grade – 2) [472].

Comments: acupuncture is used only as an additional physical rehabilitation method in patients with metabolic nervous system lesions alongside standard treatment [525]. The effect of acupuncture persists for up to 2 months after treatment compared to the control group [526]. Most studies focus on diabetic polyneuropathy and neuropathic pain, ranging from older publications (1998) [527] to recent ones (2025) [528]. Both comparisons between 2 types of acupuncture [529] and comparisons of true acupuncture with "sham" acupuncture [530] have been studied. Separate studies are dedicated to evaluating the efficacy of acupuncture in treating patients with hypoxic-ischemic encephalopathy (following COVID-19) [531], hepatic encephalopathy [532], etc. However, there remains an issue of low methodological quality of studies to date [533].

Comment: hyperbaric oxygen therapy achieves various clinical effects: correction of neurological disorders [504], including reduction of chronic pain syndrome, such as neuropathic pain [505–507], improvement of cognitive functions [508], neuroprotection [509], neuroregeneration [510], and neuromodulation [511]. Studies have been conducted to evaluate the efficacy of hyperbaric oxygen therapy in hypoxic-ischemic encephalopathy [536], etc.

Comment: numerous studies prove the positive effect of treating diabetic foot using hyperbaric oxygen therapy [538–549].

Comment: the goal of cognitive behavioral therapy in patients with chronic neuropathic pain is to reduce anxiety, depression, and pain catastrophizing, as well as to improve quality of life and functional activity [518].

5. Prevention and Dispensary Observation

6. Organization of Medical Care

Indications for emergency hospitalization to a medical organization:

1) Toxic or metabolic nervous system lesion accompanied by altered level of consciousness;

2) Toxic or metabolic nervous system lesion accompanied by fever, cerebral, and meningeal symptoms;

3) Toxic or metabolic nervous system lesion with progressive neurological symptoms.

Indications for planned hospitalization in a medical organization:

1) Comprehensive examination of the patient with a toxic or metabolic nervous system lesion to establish a diagnosis;

2) Restriction of patient mobility.

Indications for patient discharge from a medical organization:

1) Establishment of diagnosis;

2) Stabilization of the patient's condition (no life-threatening condition or risk of complications requiring emergency treatment);

3) The patient needs to be transferred to another medical organization or social welfare institution.

Upon discharge, a patient with a history of harmful use or alcohol/substance dependence syndrome must consult a psychiatrist-narcologist at their place of residence; a patient who was not previously diagnosed with harmful use or dependence syndrome but is newly diagnosed with acute intoxication / poisoning must be referred for an initial appointment (examination, consultation) with a psychiatrist-narcologist.

For patients with a lack of protective sensation (tactile sensation on the foot): referral to the diabetic foot clinic.

7. Additional Information

Data not available.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Anna M. Antonova, Candidate of Medical Sciences, researcher at the Department of Clinical Toxicology, Saint Petersburg I.I. Dzhanelidze Research Institute of Emergency Medicine; radiologist at the S.N. Golikov Scientific and Clinical Center of Toxicology of the Federal Medical-Biological Agency.

Ekaterina V. Artemova, Candidate of Medical Sciences, endocrinologist, researcher at the Diabetic Foot Department, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Andrey A. Belkin, Doctor of Medical Sciences, Professor at the Departments of Anesthesiology and Intensive Care, Physical Rehabilitation Medicine and Nervous Diseases, Ural State Medical University; Director of the Brain Institute Clinic; Chief freelance specialist of the Russian Ministry of Health for rehabilitation in the Ural Federal District.

Alla B. Gekht, Doctor of Medical Sciences, Professor, Corresponding Member of the Russian Academy of Sciences, Director of the Z.P. Solovyov Scientific and Practical Psychoneurological Center of the Moscow Healthcare Department; Professor at the Department of Neurology, Neurosurgery and Medical Genetics, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation; Member of the Presidium of the National Stroke Association; Scientific Secretary of the All-Russian Society of Neurologists.

Ilya L. Gubsky, Candidate of Medical Sciences, researcher at the Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation.

Evgeny I. Gusev, Doctor of Medical Sciences, Academician of the Russian Academy of Sciences, Professor at the Department of Neurology, Neurosurgery and Medical Genetics, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation; President of the National Stroke Association; Chairman of the All-Russian Society of Neurologists.

Ivan I. Dedov, President of the National Medical Research Center for Endocrinology of the Russian Ministry of Health, Hero of Labour of the Russian Federation, Member of the Presidium of the Russian Academy of Sciences, Academician, Doctor of Medical Sciences, Professor, President of the Russian Association of Endocrinologists, Chief freelance endocrinologist of the Russian Ministry of Health.

Lesya B. Zavaliy, Candidate of Medical Sciences, Senior Researcher at the Research Department of Emergency Neurology and Restorative Treatment, neurologist at the N.V. Sklifosovsky Research Institute of Emergency Medicine of the Moscow Healthcare Department.

Galina E. Ivanova, Doctor of Medical Sciences, Professor, Head of the Medical Rehabilitation Research Center, Federal Center of Brain Research and Neurotechnologies of the Federal Medical-Biological Agency; Head of the Department of Medical and Social Stroke Rehabilitation, Research Institute of Cerebrovascular Pathology and Stroke; Head of the Department of Medical Rehabilitation, Faculty of Additional Professional Education, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation; Chairman of the Dissertation Council at Pirogov Russian National Research Medical University; Chief freelance specialist in medical rehabilitation of the Russian Ministry of Health; Chairman of the Presidium of the All-Russian Public Organization for the Promotion of Medical Rehabilitology Development “Union of Rehabilitologists of Russia”; Secretary General of the Russian Association for Sports Medicine and Rehabilitation of Patients and Persons with Disabilities.

Yana Yu. Iotova, neurologist at the Center for Radiosurgery, N.V. Sklifosovsky Research Institute of Emergency Medicine of the Moscow Healthcare Department.

Marina V. Kalantarova, medical psychologist at the N.V. Sklifosovsky Research Institute of Emergency Medicine of the Moscow Healthcare Department, senior lecturer at the Moscow State University of Psychology and Education.

Tatyana V. Klimenko, Doctor of Medical Sciences, Professor, Director of the National Scientific Centre on Addictology – a branch of the V.P. Serbsky National Medical Research Centre for Psychiatry and Narcology of the Russian Ministry of Health, member of the Russian Society of Psychiatrists.

Ella A. Kovaleva, Candidate of Medical Sciences, Senior Researcher at the research department of emergency neurology and restorative treatment, neurologist at the N.V. Sklifosovsky Research Institute of Emergency Medicine of the Moscow Healthcare Department, associate professor at the Department of General Psychology, Russian State University for the Humanities.

Ksenia I. Kovalenko, lecturer at the educational and clinical department, neurologist at the neurological department for acute cerebrovascular accident patients, N.V. Sklifosovsky Research Institute of Emergency Medicine of the Moscow Healthcare Department.

Khedi V. Korigova, neurologist at the neurological department for acute cerebrovascular accident patients, junior researcher at the research department of emergency neurology and restorative treatment, N.V. Sklifosovsky Research Institute of Emergency Medicine of the Moscow Healthcare Department.

Natalya Yu. Kutrovskaya, Candidate of Medical Sciences, ophthalmologist, associate professor at the Department of Ophthalmology, Russian University of Medicine of the Russian Ministry of Health.

Olga A. Levina, Candidate of Medical Sciences, leading researcher at the Department of Emergency Neurosurgery, physician at the Hyperbaric Oxygenation Department, N.V. Sklifosovsky Research Institute of Emergency Medicine of the Moscow Healthcare Department.

Igor V. Litvinenko, Doctor of Medical Sciences, Professor, Head of the Department and Clinic of Nervous Diseases, S.M. Kirov Military Medical Academy of the Ministry of Defense of the Russian Federation, Chief Neurologist of the Ministry of Defense of the Russian Federation, Vice-President of the National Society for the Study of Parkinson's Disease and Movement Disorders.

Bogdan S. Litvintsev, Doctor of Medical Sciences, Chief Physician of the S.N. Golikov Scientific and Clinical Center of Toxicology of the Federal Medical-Biological Agency, associate professor at the Department of Neurology and Neurosurgery, Medical Institute, Saint Petersburg State University.

Alexey N. Lodyagin, Doctor of Medical Sciences, Professor at the Department of Anesthesiology and Intensive Care, North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health; Chief freelance toxicologist of the Russian Ministry of Health.

Lobacheva Anna Stanislavovna, PhD in Medicine, Leading Research Scientist, Department of Clinical Addictology, National Scientific Centre on Addictions – Branch of the V.P. Serbsky National Medical Research Centre for Psychiatry and Narcology of the Russian Ministry of Health, Member of the Russian Society of Psychiatrists.

Mazhlumova Naida Garibovna, Neurologist, Neurological Department for Patients with Acute Cerebrovascular Accidents, Sklifosovsky Research Institute for Emergency Care of the Moscow Healthcare Department.

Marskaya Natalia Andreevna, Research Scientist, Department of Vascular Diseases of the Nervous System, Federal Center of Brain Research and Neurotechnologies of the Federal Medical-Biological Agency.

Martynov Mikhail Yuryevich, MD, Professor, Corresponding Member of the Russian Academy of Sciences, First Deputy General Director of the Federal Center of Brain Research and Neurotechnologies of the Federal Medical-Biological Agency, Acting Head of the Department of Neurology, Neurosurgery, and Medical Genetics, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation, Scientific Secretary of the All-Russian Society of Neurologists, Board Member of the National Stroke Association.

Mokrysheva Natalia Georgievna, Director of the Endocrinology Research Centre of the Russian Ministry of Health, Corresponding Member of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, Physician of the Highest Qualification Category, Honoured Doctor of the Russian Federation, Head of the Department of Personalized and Translational Medicine.

Nikolaeva Anna Yuryevna, Neurologist, City Polyclinic No. 134 of the Moscow Healthcare Department.

Petrikov Sergey Sergeevich, Doctor of Medical Sciences, Corresponding Member of the Russian Academy of Sciences, Director of the Sklifosovsky Research Institute for Emergency Care of the Moscow Healthcare Department.

Potskhveriya Mikhail Mikhaylovich, Doctor of Medical Sciences, Head of the Scientific Department of Acute Poisoning and Somatopsychiatric Disorders, Sklifosovsky Research Institute for Emergency Care of the Moscow Healthcare Department; Professor, Department of Clinical Toxicology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health.

Ramazanov Ganipa Ramazanovich, PhD in Medicine, Deputy Director – Head of the Regional Vascular Center, Head of the Scientific Department of Emergency Neurology and Restorative Treatment, Sklifosovsky Research Institute for Emergency Care of the Moscow Healthcare Department.

Rakhmanina Anastasia Alekseevna, Research Scientist, Senior Medical Psychologist, Department of Medical Psychology, Sklifosovsky Research Institute for Emergency Care of the Moscow Healthcare Department.

Rogal Ekaterina Yuryevna, PhD in Medicine, Endocrinologist, Research Scientist, Department of Neuroendocrinology, National Medical Research Centre for Endocrinology of the Russian Ministry of Health.

Rychkova Olga Valentinovna, Doctor of Psychological Sciences, Professor, Department of Clinical Psychology and Psychotherapy, Moscow State University of Psychology and Education.

Samartsev Igor Nikolaevich, Doctor of Medical Sciences, Neurologist, Associate Professor, Department of Nervous Diseases, Kirov Military Medical Academy of the Ministry of Defense of the Russian Federation.

Sakharov Anatoly Vasilyevich, Doctor of Medical Sciences, Deputy Director for Research and Methodological Work, National Scientific Centre on Addictions – Branch of the V.P. Serbsky National Medical Research Centre for Psychiatry and Narcology of the Russian Ministry of Health, Chief Freelance Pediatric Specialist Psychiatrist of the Russian Ministry of Health in the Far Eastern Federal District, Member of the Russian Society of Psychiatrists.

Simonova Anastasia Yuryevna, PhD in Medicine, Toxicologist, Leading Research Scientist, Sklifosovsky Research Institute for Emergency Care of the Moscow Healthcare Department, Chief Freelance Specialist Toxicologist of the Moscow Healthcare Department, Acting Head of the Department of Clinical Toxicology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health.

Sinkin Mikhail Vladimirovich, Doctor of Medical Sciences, Leading Research Scientist, Neurologist, Functional Diagnostics Physician, Sklifosovsky Research Institute for Emergency Care of the Moscow Healthcare Department, Professor, Acting Head of the Department of Medical Neurotechnologies, Institute of Neuroscience and Neurotechnologies, Pirogov Russian National Research Medical University of the Russian Ministry of Health.

Seliverstova Ekaterina Gennadievna, PhD in Medicine, Senior Research Scientist, Department of Emergency Neurosurgery, Functional Diagnostics Physician, Sklifosovsky Research Institute for Emergency Care of the Moscow Healthcare Department.

Sukhodolova Galina Nikolaevna, Professor, Doctor of Medical Sciences, Leading Research Scientist, Sklifosovsky Research Institute for Emergency Care of the Moscow Healthcare Department, Professor, Department of Pediatric Anesthesiology and Intensive Care, Pirogov Russian National Research Medical University of the Russian Ministry of Health.

Trofimova Tatiana Nikolaevna, Professor, Doctor of Medical Sciences, Corresponding Member of the Russian Academy of Sciences, Chief Research Scientist, Institute of the Human Brain of the Russian Academy of Sciences, Head of the Department of Diagnostic Radiology, Saint Petersburg State University, Professor, Department of Radiology, Academician I.P. Pavlov First Saint Petersburg State Medical University.

Fadeeva Evgenia Vladimirovna, PhD in Psychology, Head of the Department of Preventive Care Organization in Addiction Medicine, National Scientific Centre on Addictions – Branch of the V.P. Serbsky National Medical Research Centre for Psychiatry and Narcology of the Russian Ministry of Health.

Kholmogorova Alla Borisovna, Doctor of Psychological Sciences, Professor, Dean of the Faculty of Counseling and Clinical Psychology, Moscow State University of Psychology and Education, Leading Research Scientist, Sklifosovsky Research Institute for Emergency Care of the Moscow Healthcare Department.

Tsukarzi Eduard Eduardovich, PhD in Medicine, Head of the Department of Intensive Care and Non-Drug Treatments, Moscow Research Institute of Psychiatry – Branch of the V.P. Serbsky National Medical Research Centre for Psychiatry and Narcology of the Russian Ministry of Health, Member of the Russian Society of Psychiatrists.

Tsygan Nikolay Vasilyevich, Doctor of Medical Sciences, Professor, Deputy Head of the Department and Clinic of Nervous Diseases, Acting Chief Neurologist, Kirov Military Medical Academy of the Ministry of Defense of the Russian Federation.

Shamalov Nikolay Anatolyevich, MD, Chief Freelance Neurologist of the Ministry of Health of the Russian Federation, Chief Freelance Neurologist of the Moscow Healthcare Department, Director of the Institute of Cerebrovascular Pathology and Stroke, Federal Center of Brain Research and Neurotechnologies of the Federal Medical-Biological Agency, Executive Secretary of the National Stroke Association.

Shevchenko Evgeny Vladimirovich, PhD in Medicine, Head of the Neurological Department for Patients with Acute Cerebrovascular Accidents – Neurologist, Senior Research Scientist, Scientific Department of Emergency Neurology and Restorative Treatment, Sklifosovsky Research Institute for Emergency Care of the Moscow Healthcare Department.

Shport Svetlana Vyacheslavovna, Doctor of Medical Sciences, Chief Freelance Psychiatrist of the Russian Ministry of Health, Chief Freelance Psychiatrist-Narcologist of the Russian Ministry of Health, General Director of the V.P. Serbsky National Medical Research Centre for Psychiatry and Narcology of the Russian Ministry of Health, Member of the Russian Society of Psychiatrists.

Conflict of interest: none.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. neurologist;

2. toxicologist;

3. endocrinologist;

4. functional diagnostics physician;

5. radiologist;

6. ophthalmologist;

7. physical and rehabilitation medicine physician;

8. emergency physician;

9. anesthesiologist-reanimatologist;

10. general practitioner (family physician);

11. internist;

12. district general practitioner;

13. emergency department physician;

14. psychiatrist;

15. psychiatrist-narcologist;

16. medical psychologist;

17. clinical pharmacologist.

Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Rating scale for levels of evidence (LE) for preventive, therapeutic, and rehabilitation methods (interventions)

Table 3. Rating scale for grades of recommendation (GR) for preventive, diagnostic, therapeutic, and rehabilitation methods (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 specific diseases, or in 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. Federal Law No. 323-FZ of November 21, 2011 (as amended on July 2, 2021) "On the Fundamentals of Health Protection in the Russian Federation" (Collected Legislation of the Russian Federation, 2011, No. 48, Art. 6724) (with rev. and add., effective October 1, 2021); (https://roszdravnadzor.gov.ru/documents/100).

2. Order of the Ministry of Health of the Russian Federation No. 203n dated April 14, 2025, "On Approval of Criteria for Assessing the Quality of Medical Care"; (Registered with the Ministry of Justice of Russia on May 28, 2025, No. 82382); (http://publication.pravo.gov.ru/document/0001202505290045); effective September 1, 2025.

3. Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, "On Approval of the Procedure and Deadlines 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."

4. International Statistical Classification of Diseases and Related Health Problems (ICD-10) (https://mkb-10.com/).

5. State Register of Medicines (http://www.grls.rosminzdrav.ru/grls.aspx).

6. Order of the Ministry of Health of Russia No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services", registered with the Ministry of Justice on November 7, 2017, registration No. 48808 (as amended on March 24, 2020).

Appendix B. Physician Action Algorithms

Appendix B1. Neurological examination algorithm for a comatose patient in the intensive care unit

Appendix B2 Diagnostic algorithm of physician actions in suspected toxic-metabolic encephalopathy [8]

Appendix B3. Algorithm for providing medical care to a patient with Wernicke's encephalopathy [2]:

1. Assessment of the patient's condition and decision-making regarding the need for admission to the intensive care unit.

2. Tracheal intubation, initiation of mechanical ventilation in case of decreased level of consciousness and/or respiratory failure.

3. Intravenous administration of #thiamine** at a dose of 1000 mg/day.

4. Prevention of deep vein thrombosis and pulmonary embolism.

Appendix B4 Algorithm for motivating a patient (or patients) with signs of addictive disorders to seek specialized (addiction treatment) medical care [552, 553]:

For patients with signs of addictive disorders, a necessary recommendation is to refer the patient to a psychiatrist-addictologist. Due to objective and subjective reasons, the patient and/or their relatives may not fully realize the need to seek specialized (addiction treatment) care. Therefore, it is necessary to additionally motivate the patient and/or their relatives to seek preventive, consultative, or diagnostic care from a psychiatrist-addictologist.

The procedure for providing medical care in the field of "psychiatry-addiction treatment" is regulated by Order of the Russian Ministry of Health No. 1034n dated December 30, 2015. According to this order, medical care includes prevention, diagnosis, treatment, and medical rehabilitation measures for individuals with addictive disorders.

At the same time, despite the identified physical and mental health problems associated with psychoactive substance use, all individuals with addictive disorders have a low level of motivation to seek specialized addiction treatment. Motivational interventions increase the likelihood that individuals with addictive disorders will seek specialized addiction treatment.

The following methods and techniques are used for motivational therapy: screening, preventive counseling, and motivational interviewing (Figure 1).

During a motivational interview, patients may exhibit a number of psychological defense mechanisms and psychopathological phenomena (ambivalence, resistance, anosognosia).

Extended motivational counseling is part of the job duties of specialists providing specialized medical care in the fields of "psychiatry" and "psychiatry-addiction treatment".

Figure 1. Algorithm for identifying individuals with risk factors for addictive disorders (using alcohol abuse as an example) and motivating them to seek specialized (addiction treatment) care.

Below are recommendations for the actions of a physician (or medical psychologist) when working with patients at risk for addictive disorders:

(1) When acute or chronic intoxication with alcohol or other psychoactive substances is detected, the physician (or medical psychologist) is recommended to conduct screening diagnostics to identify risk factors for addictive disorders.

(2) To identify individuals with risk factors for addictive disorders associated with alcohol use, it is recommended to use the RUS-AUDIT test (Appendix G8).

(3) To identify individuals with risk factors for addictive disorders associated with the use of narcotic drugs and psychotropic substances, it is recommended to use the DUDIT test (Appendix G9).

Depending on the identified risk level, various interventions may be recommended to the patient (Figure 1).

Mastering motivational interviewing skills by a physician increases the likelihood that patients with risk factors for addictive disorders will seek specialized addiction treatment.

Appendix C. Patient Information

Appendix B1. Information for patients with alcoholic encephalopathy and/or alcoholic polyneuropathy

How does alcohol dependence manifest? What signs do you have?

Alcohol dependence (AD) is characterized by an impaired ability of a person to stop or control alcohol consumption, despite the associated negative consequences affecting health, social life, and professional activities.

Psychiatrist-addictologists have clear criteria on which they base the diagnosis of AD. AD has different stages, and its manifestations can vary in severity. Self-diagnosing is not recommended, but you are invited to independently identify symptoms that may indicate the presence of AD in your case. The aggravation of the consequences of AD is reflected in an increasing number of positive responses to the statements presented in the list below.

Find free time and a quiet place, and while sober, carefully analyze your situation and answer whether you have observed the following manifestations over the past year:

1. There were times when you drank significantly more and/or longer than you intended before starting to drink.

2. You repeatedly wanted to reduce the amount or frequency of alcohol intake, or tried to stop drinking altogether, but failed.

3. After drinking alcohol, you felt unwell, spent effort trying to improve your condition as quickly as possible, and took special actions for this (called a doctor at home or independently took any medications).

4. Sometimes you wanted to drink so much that you could not think about anything else, abandoned any other activities for the sake of drinking, or had to give up or reduce the time allocated to activities that you considered important, interesting, or pleasant in order to drink, or because of alcohol consumption it became difficult for you to work (or study, if you are studying instead of working).

5. Alcohol consumption or feeling unwell caused by alcohol consumption often prevented you from taking care of your home and keeping it in order.

6. Over the past year, you found yourself in situations where, while intoxicated, you put yourself or others at increased risk (for example: driving a car / swimming in open water / walking in dangerous areas / engaging in unsafe sexual contact).

7. You spent a lot of time drinking (regardless of whether you were in company or alone) and continued to drink even though it created problems in relationships with loved ones or close friends (your family members are not satisfied with your participation in their lives).

8. You continued to consume alcohol even if you felt it negatively affected your mood: provoked anxiety, lowness, or depression.

9. You experienced memory blackouts against the background of intoxication.

10. You continued alcohol consumption despite the fact that doctors saw this as the cause of the deterioration of your physical health and strongly recommended that you remain sober.

11. When comparing your current alcohol consumption with your alcohol consumption a few years ago, it is obvious that you now need to drink much more than before to achieve the desired state of intoxication, or the amount of alcoholic beverages usual for you no longer gives the same effect as before.

12. You discovered that during the period when the effect of alcohol taken the day before wears off, your condition noticeably worsens, sleep problems appear, body tremors, anxiety, nausea, sweating, palpitations, a sharp drop in mood with irritability, dissatisfaction, general malaise, or bouts of pain.

If, upon a conscientious and honest assessment, you acknowledge the presence of any of the statements listed above, your alcohol consumption is considered problematic and requires seeking medical care. If the number of affirmative answers is six or more, then with a high degree of probability you have a severe form of AD.

Self-identifying certain symptoms is a signal for lifestyle changes and a reason to consult a specialist. The treatment of alcohol dependence is carried out by a psychiatrist-addictologist. The more symptoms you find in yourself, the more urgent this consultation is for you. Only a psychiatrist-addictologist can accurately and objectively assess the presence of AD and the severity of its manifestations, and together with you develop the best course of action.

Appendix B2. Patient guide for Wernicke encephalopathy, relatives, and caregivers

Wernicke encephalopathy is a severe, life-threatening condition caused by vitamin B1 deficiency.

The most common cause of Wernicke encephalopathy is chronic alcohol abuse. In addition to alcohol dependence syndrome, causes of vitamin B1 deficiency and, consequently, Wernicke encephalopathy may include malignant neoplasms of the gastrointestinal tract, bariatric surgery, liver and pancreatic diseases, intractable vomiting, nutritional deficiency, thyroid diseases, chronic hemodialysis, immunodeficiency syndromes, etc.

A favorable outcome of Wernicke encephalopathy depends on early diagnosis and timely initiation of therapy. If left untreated, Wernicke encephalopathy can lead to severe cognitive impairment, severe disability, and death.

Appendix B3. Guide for patients with diabetes mellitus and diabetic polyneuropathy: foot care

1. It is necessary to inspect your feet carefully every day, especially the plantar surface, heels, and interdigital spaces. Elderly and overweight patients may find this quite difficult. They can be advised to use a mirror placed on the floor during inspection or ask relatives to do it. The help of relatives is especially important for individuals with visual impairment. Daily inspection allows for the timely detection of wounds, cracks, and abrasions.

2. Feet must be washed daily. After washing, dry the skin with gentle blotting motions, especially in the interdigital spaces. High humidity in these areas promotes the development of diaper rash and fungal infections. For the same reason, when using a moisturizing cream for excessive dry skin, it should not be applied between the toes.

3. Nails should be treated regularly (once every 2 weeks) using a pedicure file. This will not only avoid trauma but also help form a correct horizontal nail edge, leaving its corners untouched.

4. The most suitable tool for removing corns and areas of excessive keratinization (thickening and dryness) of the skin is pumice. It is best to buy a special foot care pumice at the pharmacy. It should be used before washing the feet (treating dry, unsteamed skin) and you should not try to fix all problem areas in one sitting. You just need to do this regularly.

5. If your feet are cold, they should be warmed with warm socks of the appropriate size and without tight elastic bands. Make sure that the socks do not bunch up inside the shoes.

6. Make it a rule to check the inside of your shoes with your hand before putting them on to ensure there are no foreign objects inside, the insole is not folded over, and sharp nails are not protruding. We remind you once again that this is necessary because foot sensitivity may be reduced.

7. Your feet are securely protected if you wear properly fitted shoes. Advice on choosing the right shoes for each specific patient can be obtained at the Diabetic Foot clinic.

8. After foot hygiene, wipe the skin thoroughly dry, especially in the interdigital spaces. Use creams with a high urea content. Do not apply cream to the interdigital spaces.

9. If abrasions or wound defects appear, use aqueous antiseptics. Contact the Diabetic Foot clinic or your local surgeon.

DO NOT DO THIS!

1. Do not use any sharp objects for foot care: scissors, corn knives, razor blades. The use of such objects is one of the most common causes of injuries, especially in conditions of reduced sensitivity and poor vision! In the absence of these "risk factors", using scissors is acceptable, but you should not cut the nails too short or trim the corners too deep. This can lead to the formation of a so-called ingrown toenail, which causes pain, inflammatory processes, and prolonged treatment, up to and including surgery. Wearing narrow shoes contributes to nail ingrowth.

2. If your feet are cold, do not warm them with heating pads (including electric ones), central heating radiators, or electric heaters. Temperature sensitivity in diabetes is often reduced, so it is easy to get a burn and not notice it in time.

3. For the same reason, do not take hot foot baths. The water temperature should not exceed 37 °C (it is best to measure it with a water thermometer, like for bathing babies). Foot baths should not be prolonged—this makes the skin loose and more prone to trauma.

4. Walking barefoot (even at home) is not recommended, as there is a high risk of injury with simultaneous infection entering the damaged area. Swimming shoes should be worn at the beach and when swimming. Feet should also be protected from sunburn. Wearing shoes on bare feet is unacceptable due to the high likelihood of abrasions.

5. You must avoid uncomfortable (narrow, rubbing, tight) shoes and refrain from wearing high heels (more than 5 cm). High heels contribute to the formation of high-pressure zones on the plantar surface. Caution is needed with new shoes: wear them for no more than an hour the first time, and under no circumstances use any stretching methods, such as wearing them with a wet sock. Shoes that are open and therefore do not protect the toes and heel create an additional risk. Sandals or flip-flops with a strap passing between the toes can injure the delicate skin in this area.

6. If there are corns on your feet, do not try to get rid of them with corn liquids, ointments, or plasters, as they all contain substances that corrode the skin. Corns usually form as a result of wearing poorly fitted or low-quality shoes that put pressure on the foot in certain areas.

7. Pay attention to the elastic bands of your socks. If they are too tight and leave indentations on the skin of the lower legs, this impairs blood circulation.

Appendix B4. Patient Guide for Diabetes Mellitus and Diabetic Polyneuropathy: Footwear Recommendations

orthopedic shoes must be worn constantly; it is advisable to have several pairs for indoor and outdoor use;

orthopedic insoles from orthopedic shoes must not be transferred into regular footwear (sneakers, slippers);

it is important to replace the insoles in your shoes several times a year (usually 1-2 times);

shoes must be intact, without significant outsole wear; you should inspect them for folded insoles, trapped foreign objects, etc.

Recommendations for physical activity dosing after healing of a diabetic foot ulcer, foot reconstruction, or partial foot amputation.

Schedule for breaking in new orthopedic shoes

Day 1 – 30 min

Day 2 – 1 hour

Day 3 – 1.5 hours

Day 4 – 2 hours

Day 5 – 3 hours

• After each attempt to wear new shoes, immediately remove your shoes and socks and inspect your foot. Check your toes, the top and bottom of your foot, and look for any redness or abrasions.

• If there is no redness or abrasion, increase the wearing time the next day.

• If there is redness, but it disappears within 15 minutes or less, increase the wearing time the next day.

• If redness lasts longer than 15 minutes, do not increase the wearing time and consult an orthopedic traumatologist (orthotist), as adjustment of the shoe design and/or insoles may be required.

• Any changes to the skin of the feet during this period require monitoring. Discuss the frequency of follow-up examinations with your orthotist (orthopedic specialist) to regularly assess wear, offloading effectiveness, and the absence of injuries associated with returning to shoe wear.

Scheduling the return to your usual physical activity level should not begin until the wearing time of new orthopedic shoes reaches up to eight hours a day.

Week 1 – 1,000 steps/day

Week 2 – 2,000 steps/day

Week 3 – 3,000 steps/day

Week 4 – 4,000 steps/day

Week 5 – 5,000 steps/day

• Use a fitness tracker or smartphone to track your daily step count.

• If you consistently use the same tracking device, the data will be more accurate.

• If at any time during your daily foot inspection you observe prolonged skin redness (more than 15 minutes), stay at the same daily step count (or slightly decrease it) until the redness disappears. In such cases, a visit to an orthopedic traumatologist (orthotist) may be necessary to modify your insoles and/or shoes.

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

Appendix G1. Full Outline of UnResponsiveness (FOUR) Score

Russian title: Full Outline of UnResponsiveness Score for assessing the level of consciousness in intensive care unit patients

Original title: Full Outline of UnResponsiveness Score (FOUR)

Source: [232,554]

Type (underline): rating scale

Purpose: for assessing the level of consciousness in intensive care unit patients

Content:

Eye Response (E) subscale

Motor Response (M) subscale

Brainstem Reflexes (B) subscale

Respiration (R) subscale

Key (interpretation) and notes:

Eye response (E). Assess the best response after performing at least three attempts to achieve the highest level of arousal. A score of E4 indicates at least three voluntary movements. If the patient's eyes are closed, open them and assess tracking of a finger or other object. In the presence of eyelid edema or facial trauma, observing tracking upon opening one eye is sufficient. If horizontal tracking is absent, vertical tracking must be checked. Alternatively, recording blinking twice on command is sufficient. This helps establish the presence of locked-in syndrome, in which patients are conscious. A score of E3 indicates the absence of voluntary tracking. A score of E2 indicates the patient's ability to open the eye to a loud voice. A score of E1 indicates eye opening in response to a painful stimulus. A score of E0 indicates that the patient's eyes remain closed despite a painful stimulus.

Motor response (M). Score the best response of the upper extremities. A score of M4 indicates that the patient can perform at least one of three movements with either hand (thumbs up, make a fist, or show a V sign - the "peace sign"). A score of M3 indicates that the patient touches the physician's hand in response to a painful stimulus in the temporomandibular joint area or supraorbital notch (pain localization). A score of M2 indicates the presence of any flexion movement of the arms in response to pain. A score of M1 indicates an extensor response to pain. A score of M0 indicates no response to pain or generalized myoclonic status epilepticus.

Brainstem reflexes (B). Score the best response. Check the pupillary and corneal reflexes. The corneal reflex is preferably checked by applying 2–3 drops of sterile normal saline** to the cornea from a distance of 10–15 mm (this minimizes corneal trauma during repeated testing). Sterile cotton swabs can also be used. The cough reflex is assessed during tracheal suctioning. It should only be checked if both of the above reflexes are absent. A score of B4 indicates preservation of pupillary and corneal reflexes. A score of B3 indicates that one pupil is dilated and unreactive to light. A score of B2 indicates the absence of either the pupillary or corneal reflex. A score of B1 indicates the absence of both reflexes. A score of B0 indicates the absence of pupillary, corneal, and cough reflexes (the latter is checked using tracheal suctioning).

Respiration (R). Assess the spontaneous breathing pattern in a non-intubated patient. A score of R4 indicates regular breathing. A score of R3 indicates Cheyne–Stokes breathing. A score of R2 indicates irregular breathing. In mechanically ventilated patients, evaluate the airway pressure waveform during spontaneous breaths or ventilator triggering in response to an inspiratory effort (score R1). To determine spontaneous breathing movements in a ventilated patient, assess the breathing pattern displayed on the ventilator monitor. Do not change ventilator settings during the assessment, though evaluation is recommended at a normal PaCO₂ level. A score of R0 indicates that the patient's respiratory rate matches the set ventilator rate, and a standard apnea test may be required.

Appendix G2. Glasgow Coma Scale

Russian title: Glasgow Coma Scale for assessing the level of consciousness in intensive care unit patients

Original title: The Glasgow Coma Scale (GCS)

Source: https://www.glasgowcomascale.org

Type: rating scale

Purpose: Designed to assess the degree of impaired consciousness and coma. The scale consists of three tests evaluating eye opening (E), verbal (V), and motor (M) responses

Content:

Eye Opening (E) subscale

Verbal Response (V) subscale.

Motor Response (M) subscale.

Key (interpretation):

15 points – clear consciousness

10–14 points – moderate and deep obtundation

8–10 points – stupor

6–7 points – moderate coma

4–5 points – terminal coma

3 points – brain death

Notes:

The assessment results are recorded as an alphanumeric code (e.g., E2V3M4). Presenting Glasgow Coma Scale results with a breakdown of each individual category has been recognized as the most appropriate method. Interpreting the total GCS score as a specific level of impaired consciousness is invalid and not recommended.

Principles of patient assessment using the GCS:

1. Check. Assess whether there are factors hindering communication, ability to respond, or other injuries.

2. Observation. Observe eye opening, speech content, and movements of the right and left limbs.

3. Stimulation. Auditory stimulus: response to a normal or loud voice. Pain stimulus: pressure on the nail bed, trapezius muscle, or supraorbital notch.

4. Assessment. Score the best response.

Appendix G3. Mini-Mental State Examination (MMSE)

Russian title: Mini-Mental State Examination

Original title: Mini-Mental State Examination, MMSE

Type: rating scale

Purpose: This tool is designed to assess orientation and cognitive functions: attention, memory, speech, writing, reading, executive functions, visuospatial skills, and calculation

Source: [555]

Content:

1. Orientation in time (0–5 points):

Name the date: day of the month, month, year, day of the week, season;

2. Orientation in place (0–5 points):

Where are we: country, region, city, clinic, floor;

3. Registration (0–3 points):

Repeat three words: pencil, house, coin;

4. Attention and calculation (0–5 points):

Serial subtraction ("subtract 7 from 100") — five times, or:

Spell the word "world" backwards;

5. Recall (0–3 points):

Recall the 3 words;

6. Language (0–2 points):

Naming objects (show a pen and a watch);

Repetition of a phrase: "No ifs, ands, or buts";

7. Following a 3-stage command (0–3 points):

"Take the paper in your right hand, fold it in half, and put it on the table"

8. Reading: "Read and obey" (0–2 points):

1. "Close your eyes"

2. "Write a sentence"

9. Copy the drawing (*see below) 0–1

Key (Interpretation): Points are awarded for correct answers. The maximum possible score is 30.

28–30 points — no cognitive impairment;

25–27 points — pre-dementia cognitive impairment;

20–24 points — mild dementia;

10–19 points — moderate dementia;

0–9 points — severe dementia.

Notes:

1. Orientation in time. The maximum score (5) is awarded for an independent and correct answer to each sub-item. In case of an error or no answer, the score is reduced by one point (the number of points deducted equals the number of errors).

2. Orientation in place. The maximum score (5) is awarded for an independent and correct answer to each sub-item. In case of an error or no answer, the score is reduced by one point (the number of points deducted equals the number of errors).

3. Registration. Words must be pronounced clearly and distinctly at a rate of one word per second. Correct repetition of each word in the list is awarded one point (the number of points deducted equals the number of errors). The number of trials should be sufficient for the subject to repeat them correctly. Only the first repetition is scored.

4. Attention and calculation. The subject is asked to sequentially subtract 7 from 100 (down to 65). The maximum score (5) is awarded for an independent and correct answer to each subtraction. In case of an error or no answer, the score is reduced by one point (the number of points deducted equals the number of errors). Alternative: spelling the word "world" backwards. For example, if spelled "dlrow" correctly, 5 points; if "dlorw" — 4 points, etc.

5. Recall. Recall of words learned earlier in item 3. Correct recall of each word in the list is awarded one point (the number of points deducted equals the number of errors).

6. Language. a) Naming presented objects. Each correct answer is awarded one point. b) Repetition of a sentence. Correct repetition is awarded one point (no points are awarded if an error is made).

7. Following a three-stage instruction. Correct execution of each given action is awarded one point (the number of points deducted equals the number of errors).

8. Reading. The instruction is presented in writing. The text of the instruction in large print on a blank sheet of paper. Correct execution of the second command involves independently writing a complete sentence (no points are awarded if an error is made).

9. Copying the Benton visual retention design (two intersecting pentagons with equal angles). The pentagons must be closed, approximately equal in area, and their intersection must form a four-sided figure (no points are awarded if an error is made).

Appendix G4. Montreal Cognitive Assessment (MoCA)

Russian title: Montreal Cognitive Assessment

Original title: Montreal Cognitive Assessment, MoCA

Type: rating scale

Purpose: Designed for screening assessment of orientation and cognitive functions: attention, executive functions, memory, speech, visuospatial skills, abstract thinking, and calculation

Source: https://mocacognition.com/

Content:

Key (Interpretation): Points are awarded for correct answers. Normal result is a total score of 26–30. A score of 25 and below indicates cognitive decline.

1. Trail Making Test. Instruction: "Please draw a line going from a number to a letter in ascending order. Start here [point to (1)] and draw a line from 1, then to A, then to 2, and so on. End here [point to (E)]". Scoring: One point is awarded if the subject successfully draws the line as follows: 1-A-2-B-3-C-4-D-5-E, without intersecting lines (no points are awarded if an error is made).

2. Cube copying. Performance is scored as correct if the drawing is three-dimensional, the given proportions of the figure are observed, the figure is closed, and there are no extraneous additions (no points are awarded if an error is made).

3. Visuospatial functions (clock). Instruction: "Draw a clock. Put in all the numbers and set the time to 11 past 11". Scoring: One point is awarded for each of the following criteria — a) contour (closed figure); b) numbers (Roman or Arabic numerals from 1 to 12 in the correct order and corresponding quadrants on the clock face; numbers may be placed outside the clock face contour); c) hands (there must be two hands jointly showing the correct time; the hour hand must be noticeably shorter than the minute hand; the hands must be placed in the center of the clock face, with their junction close to the center). No points are awarded if an error is made.

4. Naming. Instruction: "Name this animal". Scoring: One point is awarded for correctly naming each animal.

5. Memory: Instruction: "I am going to read a list of words that you will need to remember. Listen carefully. When I finish, tell me all the words you can remember. Order is not important." Second presentation instruction: "I am going to read the same words a second time. Try to remember and repeat as many words as you can, including the ones you repeated the first time." Learning set: "I will ask you to repeat these words again at the end of the test." Scoring: No points are awarded during the learning phase.

6. Attention. Instruction: "I will read a few numbers, and when I am finished, repeat them exactly as I said them." Read five numbers sequentially at a rate of one number per second. Backward repetition: "I am going to read a few numbers, and you need to repeat them in reverse order." Scoring: Award one point for each correctly repeated sequence.

7. Vigilance. Instruction: "I will read you a sequence of letters. Every time I read the letter A, you need to clap your hands (snap your fingers)." Scoring: Awarded if no more than 1 error is made.

8. Serial 7s subtraction. Instruction: "Now I will ask you to subtract 7 from 100, and then keep subtracting 7 from your answer until I tell you to stop." Scoring: If no more than 1 error is made — 3 points, no more than 3 errors — 2 points, 4 errors — 1 point. Each subtraction is scored independently; thus, if the participant gives an incorrect answer but then continues to accurately subtract 7 from it, give a point for each accurate subtraction. For example, the participant might answer "92-85-78-71-64", where "92" is incorrect, but all subsequent values are subtracted correctly. This is one error, and 3 points are awarded for this item.

9. Sentence repetition. Instruction: "I will read you a sentence. Repeat it exactly as I say it." Scoring: 1 point is awarded for each error-free repetition.

10. Verbal fluency. Instruction: "You need to name as many words as possible starting with the letter "_" in 1 minute. You can name any words except proper nouns. Avoid cognates." Scoring: One point is awarded if the number of words is greater than or equal to 11.

11. Abstraction. Instruction: "An orange and an apple are fruits, and a train and a bicycle? A ruler and a watch." Scoring: Generalization at the categorical level is considered correct, 1 point is awarded for each correct generalization.

12. Delayed recall: Instructions: "Earlier you memorized a list of words. Try to recall them. The order does not matter." Scoring: Exactly reproduced words are considered correct answers. 1 point is awarded for each correct answer. Answers obtained via prompting are not scored.

13. Orientation. Instructions: "State today's full date and the place where we are located." Scoring: One point is awarded for each correctly named item.

If the patient has 12 or fewer years of education, 1 additional point is added.

Appendix G5. Neurological Symptoms Score (NSS)

Russian title: Neurological Symptoms Score

Original title: Neurological Symptoms Score, NSS

Type: rating scale

Purpose: The method is designed to assess the presence and severity of peripheral neuropathy symptoms, but is not a diagnostic tool for polyneuropathy.

Source: [239–241].

Content:

Key (interpretation):

• 3–4 points – mild manifestations, monitoring and symptomatic therapy are indicated;

• 5–6 points – moderate painful polyneuropathy;

• 7–9 points – severe painful polyneuropathy.

Appendix G6. The Michigan Neuropath Screening Instrument (MNSI)

Russian title: Michigan Neuropathy Screening Instrument

Original title: The Michigan Neuropath Screening Instrument, MNSI

Type: rating scale

Purpose: The method is designed for neuropathy screening. The questions in the first part are aimed at identifying subjective patient sensations, while the second part assesses vibration perception and the Achilles reflex.

Source: [242–244]

Content:

A. History

Answer the following questions by checking "yes" or "no" based on your usual sensations.

B. Physical examination

Key (interpretation):

With a total question score of 7 or more on Part A (history), the probability of polyneuropathy is high, and a physical examination is recommended. For more precise diagnostics, a lower cutoff point can be used: 4 or more points for the questionnaire and more than 2 points for the examination [556].

With a score of more than 2.5 on Part B (physical examination), the presence of a neuropathic component is confirmed.

Comment:

The question of the threshold score—7 or 4—remains controversial to this day. The Michigan Neuropathy Screening Instrument (MNSI) was first proposed in 1994. The questionnaire consists of two parts. The questions in the first part are aimed at identifying subjective sensations of patients, while the second part assesses vibratory sensation and the Achilles reflex. The number of points indicating a high risk of developing diabetic neuropathy (the first part of the questionnaire) remains a matter of debate. Initially, it was believed that seven points or more corresponded to a high risk of neuropathic pain, but it was later proven that four points or more correspond to this risk. Thus, in the DCCT/EDIC studies involving patients with type 1 diabetes, it was established that at seven points or more, the sensitivity and specificity of the method in detecting diabetic neuropathy are 13% and 99%, respectively, and the positive and negative predictive values are 84% and 73%, respectively. When four points or more were chosen as the threshold value, the sensitivity of the method increased to 40%, and the specificity to 92%. The probability of establishing a correct diagnosis increases when assessing the condition using the second part of the MNSI questionnaire. At 2.5 points or more, the diagnosis of diabetic neuropathy is considered most likely. The Neuropathic Pain Questionnaire (NPQ) (12 questions) is also used to detect diabetic neuropathy [557].

Appendix G7. DN4 questionnaire for the diagnosis of neuropathic pain

Russian name: DN4 Douleur Neuropathique 4 Questions

Original name: Douleur Neuropathique en 4 Questions

Type: rating scale

Purpose: The method is intended for the verification of painful neuropathy

Source: [245, 246]

Content:

Key (interpretation):

The tool consists of 10 items. The items of the first block (7 items) of the questionnaire describe the quality of pain and allow the assessment of positive sensory symptoms. This block is filled out based on the patient interview.

The items of the second block (3 items) reflect the presence or absence of decreased sensation and allodynia in the pain area based on a brief clinical examination assessing pain and tactile sensitivity.

To calculate the score, 1 is assigned to each positive item and 0 to each negative item (total score range from 0 to 10). If the total is 4 or more points, this indicates that the patient's pain is neuropathic or that there is a neuropathic component of pain (in mixed, nociceptive-neuropathic pain syndromes).

Appendix G8. VAS scale with reference

Russian name: Visual Analogue Scale for pain (VAS)

Original name: Visual Analogue Scale – VAS

Type: rating scale

Purpose: assessment of pain intensity

Source: [558]

Content:

Basically, a ruler made of paper, cardboard, or plastic with a length of 10 cm is used. Centimeter divisions are marked on the back of the ruler to record the obtained value [247].

Key (Interpretation):

0 points – no pain;

1–3 points – mild pain (mild impairment);

4–6 points – moderate pain (moderate impairment);

7–8 points – severe pain (severe impairment);

9–10 points – excruciating pain (absolute impairment).

Notes: a higher score indicates greater pain intensity.

Appendix G9. RUS-AUDIT test for the detection of alcohol use disorders (Russian Alcohol Use Disorders Identification Test)

Russian title: RUS-AUDIT test for the detection of alcohol use disorders

Original title: Russian Alcohol Use Disorders Identification Test (RUS-AUDIT)

Source: [559]

Type (underline): screening test

Content:

Brief instructions for administering the RUS-AUDIT test:

1. The healthcare professional reads the question and response options aloud. The patient selects the appropriate response.

2. The healthcare professional marks the score corresponding to the selected response in a separate box on the questionnaire form.

3. Upon completion of the test, the healthcare professional tallies the scores and records them on the questionnaire form.

4. Depending on the total score, the healthcare professional provides the appropriate level of care.

1. How often do you consume alcoholic beverages?
□ Never (0)	□ Once a month or less (1)		□ 2-4 times a month (2)		□ 2-3 times a week (3)		□ 4 times a week or more (4)
2. How many alcoholic drinks (standard units) do you consume on a typical day when you drink? A standard drink (SD) contains 10 grams of ethanol. Examples of one SD are provided in the table. If you consume several different alcoholic beverages on a typical day, sum the number of SDs.
Small glass of wine or champagne, 100 ml ABV 12-13%		Half a mug of beer, 250 ml ABV 4.5-5%		Glass of fortified wine, 60 ml ABV 16-22%		A small shot of spirits, 30 ml ABV 40%

Interpretation of RUS-AUDIT test results for men and women

Note: The indicated scores are preliminary; a consultation with an addiction psychiatrist is required to diagnose harmful use or alcohol dependence.

Appendix G10. DUDIT – Drug Use Disorders Identification Test

Russian title: DUDIT test for identifying disorders related to the use of drugs or psychotropic substances

Original title: Drug Use Disorders Identification Test (DUDIT)

Source: [553]

Type (underline): screening test

Content:

Interpretation of DUDIT results

Note: The indicated scores are preliminary; a consultation with an addiction psychiatrist is required to diagnose harmful use or dependence.