Diabetic polyneuropathy: symptoms, classification and directions of treatment. Diabetic neuropathy - pathogenesis, clinical picture, treatment ... Stage of complications of diabetic neuropathy

Diabetes is a disease that affects the entire human metabolic system. Insulin deficiency leads to impaired glucose metabolism, which, in turn, is the cause of a whole cascade of pathological reactions. Therefore, this disease affects many organs and systems, has severe complications, such as diabetic polyneuropathy of the lower extremities. Complications significantly reduce the quality of life of patients. It should be understood that the treatment of diabetic polyneuropathy of the lower extremities depends on the control of the underlying disease - diabetes.

The frequency of this pathology is quite high. Approximately 15% of diabetic patients are diagnosed with polyneuropathy of the lower extremities. Moreover, if the disease lasts more than 15 years, then this complication is detected in 50 or even 70% of patients. Sometimes the attending physician, precisely by the symptoms of neuropathy, may suspect previously hidden diabetes.

The pathogenesis of diabetic polyneuropathy

The appearance of polyneuropathy in diabetes mellitus is a common complication, the main cause of which is multiple metabolic disorders leading to a progressive process of neuronal death and to impaired sensory function and pathological tissue innervation. Due to insulin deficiency in diabetes, blood glucose levels rise to toxic levels. Active glycosylation of blood plasma proteins occurs, which damages the structure of the protein components of cell membranes. Such a change in cells leads to the fact that blood cells cannot fully perform their metabolic and transport functions, tissue trophism decreases.

The most informative indicator in diabetes is the level of glycated hemoglobin. This indicator in medical institutions is used to determine the severity of diabetes. The second group of toxic effects of glucose is associated with its ability to form ketoaldehyde compounds of free radicals, which contributes to the development of oxidative stress and metabolic disorders in diabetes. This refers to the shift in the balance between oxidative and reduction processes towards oxidation, which leads to cell damage in diabetes.

In diabetes, as a result of an increase in glucose and the activation of oxidative processes, vessels, especially small ones, suffer. Multiple damage to their walls, endothelial hypertrophy, wall thickening and changes in its permeability, multiple stasis and microthrombosis develop. Since the nervous tissue is very sensitive to the level of its trophism, it suffers in the first place in diabetes. The developing death of nerve cells, most often, is irreversible due to impaired regeneration processes, which is the result of diabetes.

Violations seen in cells

During histological examination, doctors detect damage to all parts of the nervous system - the number of axons in the nerve trunks decreases, the number of neuronal bodies in the spinal nuclei and horns decreases, foci of demyelination and degeneration of axons are observed. They cause muscle atrophy and degeneration of the muscles they innervate, which is reflected in myography.

When studying the internal structure of nerve cells, a number of specific disorders are observed, such as the accumulation of amyloid, sulfatides, ceramides and galactocerebrosides in them. At the same time, characteristic violations of the walls of blood vessels are revealed - doubling of the basement membrane, proliferation of the endothelium and its hypertrophy, empty capillaries. This proves that polyneuropathy in diabetes mellitus is not accidental.

Risk factors that increase the likelihood of developing neuropathy in diabetes are:

• Long-term presence of diabetes
• Blood sugar
• uncontrolled diabetes
• High levels of glycosylated hemoglobin
• Age of the diabetic
• Inadequate treatment of diabetes

Unfortunately, today there is no single clear classification of this complication, because diabetic polyneuropathy can have a different combination of syndromes. Depending on whether the violation of the neurons of the spinal cord or the autonomic part of the nervous system predominates, two forms of the disease are distinguished:

• Peripheral (spinal cord affected)
  • Touch form
    • symmetrical shape
    • asymmetric
      • Focal (mononeural)
      • Multifocal (polyneuronal)
    • motor form
  • Autonomous (the vegetative part of the central nervous system is affected)
    • Cardiovascular
    • Gastrointestinal
    • Urogenital
    • Diabetic ophthalmopathy

The symmetrical form develops as a result of multiple damage to the axons of the central neurons, and the mononeuronal form is the result of a violation of the blood supply to individual nerves due to occlusion of the vessel of their blood supply.

This condition has several stages of development, and a gradually developing clinical picture. Initially, a subclinical pathology develops, which does not have pronounced symptoms, and manifests itself only as disturbances in electrodiagnostic tests. They show a decrease in the conduction of impulses, a reduced amplitude of neuromuscular potentials.

In the future, a violation of sensitivity is added, which are so small that it only manifests itself during special tests - vibration, tactile and cold. In the case of an autonomous form of polyneuropathy, there are violations of the function of the sinus node of the heart (arrhythmias), sweating, and the reaction of the pupils to light.

In the absence of adequate treatment of diabetes, the pathology progresses and passes into the clinical stage. This happens with a fairly extensive damage to the nervous tissue, and significant violations of its function. The patient already notices the symptoms of diabetic polyneuropathy.

Complaints of a patient with diabetes

The clinical picture is quite diverse, depending on the form of the disease and on the functioning of which nerves is impaired. So, for example, with the central form of the disease, encephalopathy and other intellectual disorders develop. The peripheral form is usually manifested by a decrease in various types of sensitivity - vibration, cold, tactile and even pain. Severe pain symptoms and paresis are also possible, which are associated with acute damage to the corresponding nerves, most often as a result of their ischemia.

The patient may complain of a feeling of numbness, burning, tingling in certain areas of the body, which increase at night.

Disorders of tactile sensitivity are zonal in nature, the syndrome of "socks" or "gloves" is most common.

Normal reflexes are also reduced, pathological ones may occur.

Due to impaired innervation and blood supply, degenerative changes in the skin develop. Due to a decrease in pain sensitivity, multiple microtraumas of the feet develop, which, due to diabetes, almost do not heal, quickly become infected and inflamed. The result can be diabetic foot, one of the most severe complications of diabetes, which is extremely difficult to treat.

In the case of autonomic neuropathy, disorders of the innervation of various organs develop. The rhythm of the heart is disturbed, symptoms of angina pectoris appear. In case of violation of gastric innervation, its atony, biliary dyskinesia is observed. Sometimes these conditions are combined into diabetic enteropathy. To this may be added urination disorders associated with damage to the corresponding nerves.

Differential Diagnosis

Often, at the initial stages of the development of the disease, the doctor may suspect angiopathy, especially if diabetes has not been diagnosed. However, there are a number of important criteria to distinguish between these two pathologies. So, with polyneuropathy, the patient's legs will be warm, bullets can be felt, while if circulation is disturbed, the skin becomes cold, the pulse on the main vessels is weak, it can be difficult to feel. Pain and discomfort in neurological lesions bother a person at rest, and disappear when walking. With angiopathy, symptoms occur during physical exertion, and disappear after rest.

Angiopathy is not characterized by the loss of sensitivity and loss of reflexes that often accompanies neuropathy. It can help in the diagnosis and localization of trophic disorders. In the case of angiopathy, they are located in the distal extremities. With neuropathy, those areas of the skin that are in places of compression, friction and active influence of external factors suffer. An additional diagnostic method is a Doppler rheogram - it shows a decrease in blood flow levels in the case of angiopathy, and normal indicators in polyneuropathy.

Patient management

The treatment of polyneuropathy is very complex. One cannot simply prescribe drugs and forget about the pathology, since the main pathology, diabetes, is still not cured. Therapy should be multifactorial, because it is necessary to treat, first of all, the underlying disease. The patient must modify his standard of living, give up all bad habits, conduct regular examination and foot care. The skin should be washed regularly and antibacterial drugs should be used to treat injuries, and therapeutic massage should be performed.

The most important stage of treatment is the revision of drug therapy for diabetes mellitus and its optimization. A person with polyneuropathy should be prescribed insulin preparations, as this pathology indicates that the previous treatment regimen was not able to control sugar levels. If the patient has taken insulin before, then you need to check the correctness of its use, and re-calculate the dosage.

L.A. Dzyak, O.A. Zozulya, Dnepropetrovsk State Medical Academy

Diabetic polyneuropathy- a disease characterized by progressive death of nerve fibers, which leads to loss of sensation and the development of foot ulcers (WHO). It is one of the most frequent complications of diabetes mellitus, leading to a number of performance-reducing and life-threatening conditions in patients.

Diabetes mellitus is now equated with the "non-communicable epidemic of the XXI century" due to its huge prevalence (more than 190 million people in the world), as well as the earliest of all chronic diseases, disability of patients and high mortality. In terms of lethality, DM ranks third after cardiovascular pathology and oncological diseases, taking more than 300,000 lives annually. In developed European countries, the prevalence of diabetes mellitus is 4-6% in the general population, and among people with risk factors and in the elderly it reaches 30%. By 2025, WHO predicts an increase in the number of patients with diabetes by 41% (up to 72 million people) in developed countries, and in developing countries - by 170%. In Ukraine in 2007 the number of patients with diabetes was 1,048,375 people.

The pathogenesis of diabetes mellitus is based on the toxic effect of hyperglycemia, which develops as a result of a deficiency in insulin secretion or a defect in its action, or a combination of both. This is reflected in the classification of diabetes proposed by the American Diabetes Association (2003), which takes into account the degree of impaired fasting glucose levels. According to this classification, there are 4 clinical types of DM:

Type I - occurs due to the death of pancreatic β-cells and, as a rule, leads to absolute insulin deficiency.

Type II - occurs due to a progressive defect in insulin secretion based on insulin resistance.

Other specific types of DM due to various causes (genetic defects in β-cell function, insulin action, exocrine pancreatic pathology, etc.).

Gestational diabetes (diagnosed during pregnancy).

The aggressive effect of hyperglycemia leads to the development of diabetic angiopathy. It extends both to small vessels (microangiopathy) and to vessels of medium and large caliber (macroangiopathy). Changes in large vessels do not have specific differences from early and widespread atherosclerosis, while diabetic microangiopathy is a specific systemic microvasculitis. In the mechanisms of its formation, the most important are:

hyperglycemia, or direct glucose toxicity, is a trigger that activates the protein kinase C (PC-C) enzyme. The latter normally regulates vascular permeability, contractility, cell proliferation processes, the synthesis of substances by the basement membrane of blood vessels, and the activity of tissue growth factors;

genetic factors.

Hyperactivation of PC-C increases the tone of the vascular wall, aggregation of blood cells, causes the activation of tissue growth factors, thickens the basement membrane of blood vessels. Morphologically, it is manifested by thickening of the basement membrane of capillaries, proliferation and hypertrophy of the endothelium, deposition of glycoprotein PAS-positive substances in the vessel wall, a decrease in the number or complete disappearance of pericytes (mural cells or mesangium cells), which are credited with the ability to regulate vascular tone and the thickness of the basement membrane. This leads to the expansion of the lumen of the capillaries, the stasis of blood cells in them, and the change in the permeability of the vascular membrane.

The toxic effect of high glucose concentrations can also be realized in other ways, in particular, by activating the processes of protein glycosylation (non-enzymatic addition of glucose molecules to the amino groups of proteins). Glycosylation damages the structural protein components of cell membranes, proteins of the circulatory system, which leads to disruption of metabolic, transport and other vital processes in the body.

The most well-known glycosylated protein is HbA1 hemoglobin, the level of which reflects the degree of difficulty in oxygen delivery in the tissue capillary, confirming a decrease in the rate of the HbO2 deoxygenation reaction or the presence of tissue hypoxia. Against the background of diabetic microangiopathy, elevated serum lipids associated with DM can not only change the rate of HbO2 dissociation, but also reduce the permeability of the erythrocyte membrane for O2 due to its enveloping and the formation of the so-called lipid network on it. Hyperlipidemia hinders the diffusion of O2 molecules through plasma due to an increase in the latter of coarse protein-fat macroparticles. Protein-lipid ultrafilm on the inner surface of the capillaries exacerbates the violations of transcapillary diffusion of O2 to the tissues. At the same time, hyperlipidemia increases blood clotting, erythrocyte aggregation, reduces their deformability and permeability to O2. Together, this reduces the delivery of O2 to the tissues. At the same time, an increase in the amount of free fatty acids in the blood, combined with disorders of carbohydrate metabolism, leads to their increased utilization by the myocardium and other tissues, which significantly increases the body's need for O2. Thus, the use of fatty acids and amino acids as an energy substrate increases O2 consumption by 20-25% (J. Ditzel, 1976). Thus, the intensification of glycolysis in muscle, nervous and other tissues leads to the use of lipids and amino acids as an energy source, for the complete catabolism of which more O2 is required - the "hypoxic" circle closes.

The toxic effects of high concentrations of glucose also lie in its ability to form free radical ketoaldehydes in the presence of metals with variable valence, which, at an increased rate of their formation, leads to the development of oxidative or metabolic stress. Oxidative stress is understood as an imbalance in the body between prooxidants and components of the antioxidant defense system. It is accompanied by insulin deficiency and / or insulin resistance of varying severity and can be the result of various mechanisms:

increased formation of reactive oxidants due to the oxidation of carbohydrates, carbohydrate-protein complexes, as well as fatty acids resulting from autoxidation;

reducing the activity of the antioxidant system, represented by glutathione, glutathione peroxidase, catalase, superoxide dismutase, vitamins K, E, C, α-lipoic acid, etc. (taurine, carotene, uric acid and coenzyme Q10);

violations of the enzymes of the polyol metabolism of glucose, mitochondrial oxidation, the exchange of prostaglandins and leukotrienes, a decrease in the activity of glyoxalase;

violations of the concentration or exchange of ions of certain metals.

Insufficient activity of antioxidant enzymes in DM is determined by genetic factors, which is confirmed by the study of gene polymorphism of such enzymes of the body's antioxidant system as catalase (in diabetic retinopathy) and superoxide dismutase (in diabetic polyneuropathy). Tissue ischemia, hypoxia, and pseudohypoxia observed in diabetes mellitus are additional factors that increase the formation of reactive oxidants in various organs and tissues.

Free radical lipid oxidation accompanies many vital processes in the body: from the regulation of the activity of intracellular enzymes to the regulation of the cardiovascular system, external respiration, nervous regulation of the contractile function of the stomach, capillaries, the rate of apoptosis and the expression of various genes responsible for both the synthesis of proteins necessary for normal physiological processes, and those involved in pathological changes in the structures of tissues and organs.

The next way to implement the toxic effect of glucose is the activation of its conversion to sorbitol. The entry of glucose into the brain, vascular endothelium, lens, retina, and glomerular cells of the kidneys is an insulin-independent process. With hyperglycemia, the glucose content in these tissues rises sharply, which contributes to the activation of the intracellular enzyme aldose reductase. The latter catalyzes the conversion of glucose into sorbitol, which is converted into fructose under the influence of sorbitol dehydrogenase. The accumulation in cells of both sorbitol and fructose increases the osmolarity of the cell cytoplasm, which leads to their edema and destruction. Violation of the permeability of the cell membrane in patients with DM exacerbates the violation of the supply of glucose into the cell ("starvation among abundance") and increases energy deficiency ("hypoxia without hypoxemia").

Thus, the formation of micro- and macroangiopathies in DM determines the prognosis for the duration and quality of life of patients, confirming the idea that "diabetes begins as a metabolic disease, and ends as a vascular pathology" . One of the most common complications of DM is diabetic polyneuropathy, which develops as a result of damage to the endoneural vessels. The latter is confirmed by the presence of a relationship between the thickness of the membrane of these vessels and the density of nerve fibers in the peripheral nerve.

Diabetic neuropathy (DN) is the result of widespread damage to neurons and their processes in the central and peripheral nervous system. The progressive death of neurons is often irreversible due to impaired regeneration processes in DM. Thus, histological examination of tissue biopsy specimens reveals signs of damage to all parts of the peripheral nervous system: a decrease in the number of axons in the trunks of peripheral nerves (with a predominance of defects in the distal parts of neurons), a decrease in the number of cells in the spinal ganglia and anterior horns of the spinal cord, the appearance of foci of segmental demyelination and remyelination of the primary and caused by axonal degeneration character, degenerative changes in the cells of the sympathetic ganglia and autonomic nerves. Usually, this results in degeneration of both myelin and axial cylinders, spreading from the distal to the proximal regions. It is important to note that axonal degeneration, like Wallerian degeneration, causes muscle atrophy and denervation changes on myography, in contrast to purely demyelinating lesions. Studies of the ultrastructure of the nerve trunk revealed more or less specific changes in the cytoplasm and axoplasm of Schwann cells - the accumulation of products such as amyloid, sulfatide, galactocerebroside and ceramide. Changes in vessels and connective tissue formations of nerve trunks are characteristic in the form of proliferation and hypertrophy of endothelial cells, thinning and doubling of the basement membrane of capillaries, an increase in the number of empty capillaries (the number of which correlates with the severity of DN), a decrease in the density of the endoneural capillary bed with the presence of many aggregates of blood cells, an increase in interfascicular spaces and collagen deposits.

The DCCT (Diabetes Control and Complications Trial) study includes risk factors for the development of diabetic polyneuropathy: the duration of the disease, the degree of hyperglycemia, the patient's age, male sex, and tall stature. The DCCT and UKPDS (UK Prospective Diabetes Study) studies have shown that there is a clear correlation between hyperglycemia and diabetic complications. The frequency of lesions of the nervous system in DM correlates with the duration and severity of the disease, the age of patients. Most of the known metabolic and vascular mechanisms for the development of pathology in late complications of DM are united by their dependence on the inclusion of superoxide hyperproduction in mitochondria in the pathological process.

The classification of diabetic neuropathy is difficult because there is often a combination of several syndromes. A number of authors classify diabetic neuropathy depending on the predominant involvement in the process of the spinal nerves (peripheral neuropathy) and / or the autonomic nervous system (autonomic neuropathy). Other authors use a syndromic classification, according to which the following are distinguished:

Peripheral (bilateral) neuropathy syndrome: predominant damage to sensory nerves; predominant damage to the motor nerves; combined damage to sensory, motor and autonomic nerves.

Syndrome of proximal (symmetrical or asymmetric) neuropathy of the motor nerves:

• cranial or cranial;

  peripheral.

Syndrome of polyradiculo- and plexopathy.

Autonomic (vegetative) neuropathy syndrome.

Its advantage is that in the presence of modern research methods, changes in the nervous system can be detected even before the appearance of patient complaints and clinical manifestations.

M.I. Balabolkin (1998) proposed a classification of diabetic neuropathy, widely used in Russia, according to which there are:

I. Subclinical stage of neuropathy.

A. Violated electrodiagnostic tests; decrease in the conductivity of the nerve impulse of sensory and motor peripheral nerves, a decrease in the amplitude of neuromuscular induced potentials.

B. Violated sensitive tests: vibration, tactile, thermal and cold tests.

C. Disturbed functional tests of the autonomic nervous system: dysfunction of the sinus node and heart rhythm, changes in sweating and pupillary reflex.

II. Clinical stage of neuropathy.

A. Central: encephalopathy, myelopathy.

B. Peripheral diffuse neuropathy.

Distal symmetrical sensory-motor polyneuropathy.

Primary neuropathy of small nerve fibers.

Primary neuropathy of large nerve trunks (large fibers).

Mixed.

proximal amyotrophy.

B. Diffuse autonomic neuropathy.

Impaired pupillary reflex.

Sweating disorder.

Autonomic neuropathy of the genitourinary system: "nervous bladder" - bladder dysfunction and sexual dysfunction.

Autonomic neuropathy of the gastrointestinal tract: atony of the stomach, atony of the gallbladder, diarrhea.

Autonomic neuropathy of the cardiovascular system.

Asymptomatic hypoglycemia.

G. Local neuropathy.

Mononeuropathy.

Multiple mononeuropathy.

Plexopathy.

Radiculopathy.

D. Neuropathy of the cranial (cranial) nerves:

I pair - olfactory nerve;

II pair - optic nerve;

group of oculomotor nerves: III, IV, VI pairs;

V pair - trigeminal nerve;

VII and VIII pairs - facial nerve;

IX and X pairs - glossopharyngeal and vagus nerves.

In Europe, the P.K. classification is used. Thomas (1997), according to which the following forms of diabetic neuropathy are distinguished:

hyperglycemic neuropathy;

generalized neuropathies:

• sensorimotor;

  acute pain sensory;

  autonomous;

  acute motor;

focal and multifocal neuropathies:

• cranial and limbs;

  thoracolumbar;

  proximal;

combination with CIDP;

hypoglycemic neuropathy.

Classification of diabetic neuropathy (S.V. Kotov et al., 2000)

Peripheral neuropathy

Symmetrical, predominantly sensory and distal polyneuropathy.

Asymmetric, predominantly motor and most often proximal neuropathy.

Radiculopathy.

Mononeuropathy, including multiple.

Autonomic (visceral) neuropathy.

Central neuropathy

Diabetic encephalopathy, encephalomyelopathy.

Acute neuropsychiatric disorders against the background of metabolic decompensation (ketoacidotic, hyperosmolar, lactacidemic, hypoglycemic state).

Acute cerebrovascular accident (transient, stroke).

The lack of a unified classification, the variety of clinical symptoms is reflected in the data of epidemiological studies of diabetic neuropathy. Thus, the most common form, characteristic of both type I and type II diabetes, is distal symmetric sensorimotor polyneuropathy. In a large population-based study conducted in Italy, it was found in 77% of patients with diabetic polyneuropathy. These data are consistent with a study conducted at the Mayo Clinic (USA), where similar results were obtained - 78%. In general, the prevalence of diabetic polyneuropathy varies, according to different authors, from 200 to 371 per 100,000 population.

In a recent survey (US NHANES - the National Health and Nutrition Examination Survey) conducted in the United States, it was found that 10.9% of adults diagnosed with diabetes had symptoms of painful peripheral neuropathy. These symptoms included decreased sensation, pain, and tingling in the legs for at least 3 months. A study conducted in the UK among diabetic patients treated with insulin showed that 10.7% of patients had symptoms of painful sensory polyneuropathy.

Another British study (1990) found that 7.4% of patients seen by a physician diagnosed with diabetes had neuropathic pain (compared to 1.8% in a control population). In a recent study, also from the UK, 16.2% of patients with diabetes had chronic (at least 1 year duration) painful peripheral neuropathy (versus 4.9% of an age- and sex-matched control population). In Japan, in a 20-year study, similar data were obtained: 13% of patients noted intermittent or constant severe pain in the extremities.

Thus, according to cohort studies, up to 70% of patients with diabetes (types I and II) have signs of distal symmetric polyneuropathy, and in approximately 15% it is accompanied by neuropathic pain.

Symmetric, predominantly sensory (or sensorimotor) distal polyneuropathy (DPNP) is the most common form of late neurological complications of DM. Occurs in the vast majority of patients, as a rule, after 5 years from the onset of diabetes, in 30-50% it manifests itself in a clinically pronounced form, the rest have subclinical disorders (according to electromyography (EMG), somatosensory evoked potentials (SSEP)). In typical cases of DPN, the symptoms of impaired sensitivity are combined with moderate weakness in the muscles of the distal extremities and signs of autonomic dysfunction. Patients are concerned about pain, numbness, paresthesia, chilliness, which are localized in the toes, spreading to their plantar, then the back surface, the lower third of the legs, and later to the hands. There is a symmetrical violation of pain, temperature, tactile and deep sensitivity in the zone of "socks" and "gloves", in severe cases, the peripheral nerves of the trunk are affected, which is manifested by hypesthesia of the skin of the chest and abdomen. Achilles reflexes decrease and then fade away, signs of ischemic neuropathy of the terminal branches of the tibial or peroneal nerves are often detected - muscle atrophy, the formation of a "sagging" or "clawed" foot.

A manifestation of autonomous (vegetative) polyneuropathy are trophic disorders (the most severe in the formation of a diabetic foot).

In most patients, the manifestations of DPNP are mild, limited to a feeling of numbness and paresthesia of the feet (feeling of "walking on pebbles", "sand in socks"). In severe cases, paresthesias have the character of burning, non-localized sharp pains that worsen at night. Painful sensations sometimes reach considerable intensity, spread to the region of the lower leg and thigh, are of a hyperpathic hue, when the slightest irritation (touching the skin) causes an aggravation of pain. They can remain untreated for months, and even years. The origin of such pain is determined by the defeat of the sympathetic nervous system. Often, a combination of sympathalgia with neurosis-like, psychopathic and depressive disorders, which, on the one hand, can be regarded as functional, on the other hand, as a manifestation of diabetic encephalopathy.

It should be noted the possibility of paresthesia and pain in the distal lower extremities in the onset of diabetes during treatment with insulin or oral hypoglycemic agents. These sensory disorders are due to the regeneration of peripheral nerves against the background of normalization of metabolism and do not require special treatment. Electromyography and somatosensory evoked potentials are used to confirm the diagnosis of DPN. EMG reveals lengthening of the latent periods of the potential, a decrease in the speed of impulse conduction (SPI) along the motor fibers. It is characteristic that sensory fibers (according to the study of SSEP) suffer to a greater extent than motor ones.

Diagnosis of DPNP is based primarily on clinical data, anamnesis, characteristic complaints, polyneuritic type of sensory-motor disorders.

Diagnostic criteria for diabetic polyneuropathy (P.B. Dyck, P.J. Dyck, 1999) are:

the presence of diabetes;

prolonged chronic hyperglycemia;

the presence of distal symmetrical sensorimotor polyneuropathy;

exclusion of other causes of sensorimotor polyneuropathy;

diabetic retino- or nephropathy is similar in severity to polyneuropathy.

Symptoms of diabetic polyneuropathy are quite typical:

pain, burning, numbness, paresthesia;

neurological deficit (negative neuropathic symptoms);

sensitivity disorders of all modalities;

decrease or absence of Achilles and knee reflexes;

electromyography: amplitude, latency, speed of excitation during stimulation of somatic nerves, VCSP;

electrocardiography: R-R - intervals at rest, with deep breathing, orthostatic test.

Specially designed scales are also used to diagnose diabetic polyneuropathy. According to the TSS (Total Symptom Score) scale, the following symptoms are analyzed: pain, burning, paresthesia, numbness. At the same time, the evaluation of complaints is carried out only within the last 24 hours. The pain should only be acute (shooting, twitching, "like an electric shock", piercing), in addition, a burning sensation, numbness, paresthesia are evaluated. The patient himself decides how to answer the question about the intensity of the sensory symptom. Also, the patient independently evaluates the frequency of sensory sensations. If he cannot do this, the frequency is assessed during the day: 1-3 times - rarely; > 3 times - often; when one episode of sensory sensation occurs, they are guided by its duration: up to 30 minutes - rarely, from 30 minutes to 3 hours - often, more than 3 hours - constantly.

In addition, the NIS-LL scale is used, according to which they evaluate:

muscle strength:

Hip flexion.

Hip extension.

Flexion of the knee.

Knee extension.

Ankle flexion.

Extension of the ankle joint.

Flexion of the toes.

Flexion of the toes.

Reflexes:

Knee.

Sensitivity (thumb: terminal phalanx):

Tactile.

• Vibrating.

  Muscular and joint feeling.

Analyze the sum of points obtained in the study of symptoms from two sides (right side + left side = sum).

Muscle strength is assessed in the position of the patient sitting (in case of doubt in the assessment - lying down) as follows:

0 points - the norm;

1 point - decrease in strength by 25%;

2 points - strength reduction by 50%;

3 points - decrease in strength by 75% (3.25 - movement with the development of effort, 3.5 - movement without the development of effort, 3.75 - muscle contraction without movement);

4 points - paralysis.

Knee reflexes are assessed while sitting (in case of doubt in the assessment - using the Jendrassik technique), Achilles reflexes - in the position of the patient kneeling on a chair (in case of doubt - in the prone position):

0 points - the norm;

1 point - decrease;

2 points - absence.

Sensitivity is examined on 1 phalanx of the big toe with the patient's eyes closed using special tools:

0 points - the norm;

1 point - decreased sensitivity;

2 points - lack of sensitivity.

There are characteristic age-related changes (P.J. Dyck, P.K. Thomas, 1999), which must be taken into account when assessing the patient's condition on the NIS-LL scale:

Patients should be able to walk on their toes and heels until age 75.

The inability to stand up from a squatting position from the age of 60 is not considered a violation.

At the age of 50-69 years, a decrease in the Achilles reflex is considered normal, and its absence is estimated at 1 point. From the age of 70, the absence of a reflex is considered the norm.

Up to 50 years, the norm of vibration sensitivity is 7 points, after - 6 points.

The prevalence of pain forms of diabetic polyneuropathy of the lower extremities ranges from 16.2 to 26.4%.

Of the methods of functional diagnostics, ENMG and the study of SSEP are the most informative.

In the light of the presented features of the development of DM and its complications, in order to achieve compensation, an integrated approach to therapy is required, taking into account all links of pathogenesis. The main areas of treatment are as follows:

Normalization of glucose metabolism.

Normalization of lipid metabolism.

adequate rehydration.

Correction of metabolic acidosis.

Restoration of normal extra- and intracellular electrolyte composition.

Improving hemodynamics in order to compensate for impaired blood circulation and adequate provision of tissues with energy substrates and oxygen, because the first condition for the development of energy deficiency is insufficient oxygenation of neurons.

Protection of neurons from ischemia, preservation of their structure, integrity and functional activity.

Identification and elimination of provoking factors that cause and maintain decompensation of DM.

Currently, despite the emerging epidemiological data and the results of multicenter studies indicating the presence of a pathogenetic relationship between metabolic disorders in DM and its complications, modern clinical guidelines and international recommendations do not pay enough attention to new methods of treating DM that effectively affect metabolic processes.

It should be noted that the variety of clinical symptoms, different duration, intensity, and nature of neuropathic pain in diabetes mellitus, as well as various types of painful neuropathy suggest that different mechanisms of pain syndrome development are involved in different ways. In particular, the role of central mechanisms in the maintenance of pain neuropathic syndrome may increase as the duration of painful polyneuropathy increases. It is also possible that not all fibers of the same type in one nerve are at the same stage of neuropathy, therefore functional disorders predominate in some fibers and then there is a theoretical possibility of their correction, while in others axonal atrophy has occurred, therefore, for these fibers, pathogenetic therapy, including sugar compensation diabetes is ineffective. When it comes to diabetes, it is advisable to choose drugs that combine the effects of activating metabolism, improving hemodynamics and normalizing carbohydrate metabolism. Over the past 15-20 years, clinics in many countries of the world have been actively introducing into clinical practice and studying the effectiveness of Actovegin in conditions of severe ischemia and hypoxia.

Actovegin is a hemoderivat from the blood of young calves, the pharmacological action of which is based on improving the transport of glucose into cells and the absorption of oxygen in tissues. The latter leads to the activation of aerobic oxidation processes, which increases the energy potential of the cell. Under the action of Actovegin in the cell:

the exchange of high-energy phosphates (ATP) increases;

enzymes of oxidative phosphorylation are activated (pyruvate and succinate dehydrogenase, cytochrome C-oxidase);

increased activity of acid phosphatase and lysosomal activity of the cell;

the activity of alkaline phosphatase increases, the synthesis of carbohydrates and proteins is accelerated;

the influx of potassium ions into the cell increases, potassium-dependent enzymes are activated: catalase, sucrose, glucosidases;

accelerates the breakdown of anaerobic glycolysis products - lactate and β-hydroxybutyrate, normalizing intracellular pH.

Actovegin has a pronounced insulin-like effect. At the same time, it was not possible to detect phosphorylation of insulin receptors, which gave reason to assume the presence of a mechanism of action different from that of insulin (Muhlbaker and Haring, 1988). Thanks to inositolphosphate-oligosaccharides contained in Actovegin, glucose transporters in the plasma membrane are activated, which increases its transfer into the cell by more than 5 times. The lack of influence of Actovegin on insulin receptors ensures its effectiveness in patients with type I and type II diabetes mellitus. Thus, the results of the study by S. Jacob et al. (2002) showed that after treatment with Actovegin in diabetic patients for 10 days, glucose uptake increased by 85%, and blood glucose levels decreased without changing insulin levels.

Under the influence of Actovegin, the diffusion and utilization of oxygen by the cells of various organs and tissues is significantly increased. This leads to improved oxygenation in the microcirculatory system. At the same time, anaerobic energy exchange in the vascular endothelium improves, accompanied by the release of endogenous substances with powerful vasodilating properties - prostacyclin and nitric oxide. As a result, organ perfusion improves and total peripheral vascular resistance decreases, which reduces the clinical manifestations of DN.

The positive experience of using Actovegin in diabetic neuropathy has been confirmed by numerous studies, which noted a significant decrease in pain, improved sensitivity in the proximal limbs, revitalization of tendon reflexes, and a tendency towards normalization of electromyography parameters.

Metabolic therapy, in addition to Actovegin, includes thioctic (α-lipoic) acid preparations, B vitamins, high-energy phosphates, antioxidants, nootropics.

Traditionally, the treatment of diabetic polyneuropathy is divided into pathogenetic and symptomatic, i.e. anesthesia. α-lipoic acid belongs to pathogenic drugs that meet the GCP rules. Unfortunately, the possibilities of achieving clinically significant dynamics of peripheral nerve function indicators during pathogenetic therapy turned out to be small. Nevertheless, the effect of α-lipoic acid on the positive, including pain, symptoms of polyneuropathy was more pronounced than that of placebo. There is no experimental or clinical substantiation of the mechanisms of the positive effect of α-lipoic acid on the symptoms of polyneuropathy in the special literature. It is assumed that the improvement in the function of the peripheral nerve should be accompanied by the normalization of sodium channels, a decrease in the synthesis of substances potentially activating neurons, a decrease in the excitability of intact nerve fibers in response to stimuli from neighboring damaged fibers, and, accordingly, a decrease in ectopic impulses. It is also possible that the drug potentially interferes with central pain mechanisms. An analysis of the results of clinical trials of α-lipoic acid suggests that as the sensory deficit worsens, its effect becomes more symptomatic than pathogenetic. According to the results of a meta-analysis by D. Ziegler et al. (2004), in almost 50% of patients with painful forms of polyneuropathy, the effect of α-lipoic acid is insufficient.

M.I. Balabolkin (1997) showed that a 6-week course of treatment with milgamma 100 (100 mg of benfotiamine + 100 mg of pyridoxine hydrochloride) leads to an improvement in the well-being of patients, a decrease or disappearance of sensory disorders. R.A. Sadekov et al. (1998) recommend a longer use of the drug - up to 2-4 months. Positive changes in the condition of patients were noted on the 14th-20th day from the start of treatment and were expressed in a decrease in the severity of pain, cessation or a significant decrease in the degree of manifestation of paresthesia, regression of trophic and sensory disorders. Persistent improvement in function occurred by the end of the 6-8 week course of treatment.

The use of drugs that affect the central and peripheral mechanisms of pain syndrome development is topical. Non-steroidal anti-inflammatory drugs have been shown to be ineffective for the treatment of neuropathic pain, so drugs with a different mechanism of action, such as tricyclic antidepressants, are used. Their main effect is to inhibit the reuptake of serotonin and norepinephrine. In addition, tricyclic antidepressants block α-adrenergic, H1-histamine, M-choline and NMDA receptors. The analgesic effect of drugs is due to the central action. The most common drugs in this group used to treat painful polyneuropathy are amitriptyline and imipramine. The standard effective analgesic dose is at least 75 mg / day. (for amitriptyline), however, in some cases it can reach 100-125 mg. The number needed to treat (NNT) patients in order to be effective in one patient ranges from 2.1 to 2.4. Due to slow titration (increasing the dose once a week), the frequency and severity of side effects can be reduced. At the same time, the number of patients who need to be treated in order to get a side effect from one (number needed to get harm, NNH) averages 2.7. However, orthostatic hypotension, anticholinergic effects, and worsening coronary artery disease are often major obstacles to the widespread use of tricyclic antidepressants. Therefore, treatment with tricyclic antidepressants in people over 65 years of age should be carried out with extreme caution, and with autonomic neuropathy, the appointment of drugs in this group is not indicated.

Noncyclic antidepressants are better tolerated than tricyclic antidepressants. However, their analgesic efficacy was significantly less than that of tricyclic antidepressants and anticonvulsants. Thus, the mean NNT for venlafaxine was 5.5, for duloxetine - 5.2, and the effect of fluoxetine did not exceed placebo. Therefore, drugs in this group can be considered as a reserve in case of ineffectiveness or inability to use tricyclic antidepressants or anticonvulsants.

The first anticonvulsant used to treat neuropathic pain was carbamazepine. The drug blocks sodium channels in the Ad-fibers of peripheral nerves. According to various authors, the NNT index is about 3.3, while the NNH reaches 1.9, which limits the use of carbamazepine, especially in people who lead an active lifestyle. Oxcarbazepine is a chemical analogue of carbamazepine that can be used in the treatment of pain in diabetic neuropathy. The initial dose (150-300 mg twice daily) may be increased (up to 2400 mg/day).

The mechanism of action of gabapentin appears to be related to the interaction of voltage-gated calcium channels with α2δ subunits. This leads to inhibition of the entry of Ca++ ions and, accordingly, reduces the release of glutamate from presynaptic terminals, which is accompanied by a decrease in the excitability of nociceptive neurons in the spinal cord (desensitization). The drug also acts on NMDA receptors and reduces the activity of sodium channels. In addition, the drug increases the synthesis of γ-aminobutyric acid (inhibitory mediator). Clinical trials have shown that gabapentin is quite effective in painful forms of diabetic polyneuropathy (NNT - 3.7) and at the same time is characterized by a relatively low frequency and severity of side effects in the form of sedation, weakness, dizziness (NNH - 2.7) . With a slow dose selection, gabapentin can also be prescribed to patients who lead an active lifestyle. This made it possible to characterize gabapentin as the drug of choice for painful forms of diabetic polyneuropathy. According to the manufacturer's recommendations, the therapeutic dose, if necessary, may exceed the optimal 1800 mg / day, reaching 3600 mg / day. (in three doses). But a satisfactory effect is possible with smaller daily doses. Gabapentin is excreted by the kidneys, therefore, in chronic renal failure, dose adjustment of the drug is necessary, which allows it to be used to treat not only neuropathic pain syndrome, but also uremic pruritus in patients with end-stage diabetic nephropathy.

The action of pregabalin appears to be close to that of gabapentin. Pregabalin is characterized by a lower frequency and severity of side effects, especially sedation. However, its efficiency is somewhat lower - NNT is 4.2. In addition, it is undesirable to combine the drug with thiazolidinediones due to the likely weight gain and the development of edema.

The mechanism of action of preparations based on pepper extracts (capsicam) is associated with stimulation of the release of substance P (peripheral pain neurotransmitter) and, ultimately, with the depletion of this substance, which leads to a decrease in the transmission of pain impulses. Despite moderate efficacy in clinical trials, Kapsikam is rarely used in routine practice due to the need to apply up to 4 times a day, severe burning and skin irritation, and the danger of use in people with chronic venous insufficiency.

The use of opioids for the treatment of pain syndromes is possible only in the absence of the effect of other drugs. Long courses of opioid therapy should be administered with great caution. In the treatment of neuropathic pain, methadone and tramadol have been shown to be most effective. Tramadol acts on both opioid and monoaminergic pain control mechanisms. Addiction to it is less pronounced than to opioids. The drug is quite effective for the treatment of neuropathic pain in high doses - 200-400 mg (NNT - 3.5). At the same time, when using high doses, the frequency of side effects similar to those of narcotic analgesics also increases.

Until now, the selection of analgesic therapy for painful neuropathies is more of an art than a science. As a rule, attempts to introduce into practice structured regimens for the treatment of various types of pain based on their different origins and different mechanisms of action of drugs are successful only in limited groups of patients in the framework of scientific research. In most cases, there is a polymorphism of neuropathic symptoms, so the appointment of several drugs will be accompanied only by the summation of their side effects and an increase in the cost of treatment. In this regard, it seems appropriate to start treatment with monotherapy.

Clinical observations show that the duration of the pain syndrome is less than 6 months and its occurrence after significant disturbances in carbohydrate metabolism have a favorable prognosis. This is most consistent with the experience of treating patients with acute pain form (APF) and, in particular, with "insulin neuritis". It is in this group of patients that the greatest effect of symptomatic therapy should be expected. However, when choosing a drug for patients with OBF, it should be taken into account that the presence of serious autonomic disorders, driving, and an active lifestyle, characteristic of young patients, are completely incompatible with the side effects of tricyclic antidepressants (TCAs). At the same time, the possibilities of prescribing TCAs in elderly people with OBF are limited due to the high prevalence of cardiovascular disease and the increased risk of myocardial infarction, as well as the poor tolerance of therapeutic doses by these patients. Serious side effects and the emergence of new drugs have caused TCAs to lose their status as drugs of choice for painful neuropathies, which they were even assigned to in the standards of care and regulations of the American Diabetes Association. Carbamazepine may also not be the best choice in active patients due to the drowsiness it causes. In addition, in diabetic polyneuropathy, the analgesic effect of the drug is less pronounced than that of amitriptyline. Therefore, gabapentin should be considered the drug of choice for OBF.

In chronic pain form (CBF), the question of prescribing symptomatic treatment arises when the intensity and frequency of pain negatively affect the patient's life. In such cases, the pain score on the visual analogue scale exceeds 4 points, sleep is disturbed, and pain occurs almost daily. As with OBF, in CKD an active lifestyle limits the use of amitriptyline and partially carbamazepine. However, in non-working young patients, the use of these drugs is quite effective. At the same time, it should be taken into account that long-term therapy with amitriptyline reduces heart rate variability, which is accompanied by an unfavorable prognosis in patients with diabetes. We must not forget about the danger of increasing orthostatic hypotension, which can manifest itself when prescribing TCAs. Sometimes, with a small intensity of pain, the use of external preparations is sufficient. In CKD, a significant increase in pain is accompanied by hyperglycemia, so gabapentin therapy is more appropriate. Tramadol should be assigned a supporting role in case of insufficient effect of other drugs. Of great importance for the effective treatment of neuropathic pain are psychological factors, as well as mutual understanding between the patient and the doctor. It is especially important for patients to understand that the effect of any drug does not appear after the first pill and a long-term selection of an adequate dose is necessary.

Without a doubt, the basis for successful treatment of pain neuropathic syndrome in diabetes is the normalization of carbohydrate metabolism. In recent years, taking into account the role of vascular and rheological factors in the pathogenesis of polyneuropathy, great importance is attached to the correction of arterial hypertension and dyslipidemia. In general, the treatment of painful forms of diabetic polyneuropathy is a difficult task, because the choice of the drug is carried out mainly empirically. Unfortunately, situations are not uncommon when the use of any of the above means is not effective enough and there is a need for a combination of drugs, which has no evidence base. The frequency of recurrence of pain after discontinuation of therapy has also not been studied, but clinical experience shows that in CKD recurrence of symptoms occurs in most patients. All this once again emphasizes the importance of achieving stable compensation of diabetes mellitus from the moment of its detection as the most effective measure to prevent the development of polyneuropathy.

Physical treatments for DN include hyperbaric oxygenation (range of "soft" standard modes - 1.2-2.0 atm.), phototherapy, magnetotherapy, electrophoresis, diadynamic currents, electrical stimulation of paretic muscles, acupuncture. A contraindication to their use is the severe condition of the patient, due to somatic pathology, and / or severe metabolic decompensation.

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Diabetic neuropathy (DN) is a lesion of the peripheral nervous system in patients with.

Pathogenesis

The pathogenesis of diabetic neuropathy has not been finally established and is currently based on two main theories: metabolic and vascular.

metabolic theory is based on the main metabolic disorders caused by hyperglycemia:

• activation of the polyol pathway of glucose metabolism with the accumulation of osmotically active substances in nerve cells, oxidative stress with an increase in the formation of free radical compounds;
• increased non-enzymatic glycosylation of proteins in the nerves and endoneural environment;
• deficiency of myonositol, a substrate for the synthesis of membrane phosphatidylinositol, a decrease in the synthesis of neuromodulatory and vasodilating substances - nitric oxide.

Metabolic changes are accompanied by significant vascular- violation of endoneural blood flow and hypoxia, which occur as a result of morphological endoneural changes vasa nervorum, numerous hemorheological and neurohumoral disorders.

All these metabolic and vascular changes, in turn, lead to morphological and functional changes in nerve cells and the occurrence of diabetic neuropathy.

Clinical picture

1. (or diabetic polyneuropathy).

Subclinical sensorimotor polyneuropathy is detected using an electrophysiological research method - electroneuromyography and is characterized by a decrease in the speed of impulse conduction along the peripheral nerves and a decrease in the amplitude of the bioactivity of the distal muscle groups, mainly the lower extremities.

Diabetic peripheral distal sensorimotor neuropathy(clinical) is characterized by a variety of symptoms that reflect sensory, motor and vegetative-trophic disorders. Pain is a common complaint of patients. The pain is dull, pulling, symmetrical, more often in the distal parts of the lower extremities, feet, less often in the upper extremities.

Quite often, patients are concerned about paresthesia: sensation of tingling, "chillness", "crawling", numbness in the lower extremities, "burning" (especially pronounced in the area of ​​​​the sole of the foot). Patients experience cramps in the muscles of the legs, feet, often at rest, at night. Some patients are concerned about the feeling of weakness in the lower extremities.

risk factors the appearance of the first subjective symptoms of diabetic polyneuropathy is decompensation of diabetes, intoxication, hypothermia, infections, injuries, alcohol consumption, smoking, etc.

A common objective symptom of diabetic polyneuropathy is decrease or disappearance of reflexes, first Achilles, then knee. Changes in reflexes on the upper limbs are rare. Sensitive disorders are characterized by hyperesthesia behind the polyneurotic type in the form of "socks" and "gloves", soreness of the muscles and nerve trunks on palpation.

Vibration sensitivity is most often and first disturbed. Pain, tactile and temperature sensitivity also suffer. Musculo-articular sensitivity is rarely disturbed. Motor disorders are characterized by a decrease in muscle strength, hypotrophy of the distal muscle group. In severe cases, paresis and paralysis of the distal lower extremities can be observed.

In some patients, vegetative-trophic disorders are observed: changes in sweating, thinning and flaking of the skin, deterioration in hair growth and trophic nails, trophic ulcers, osteoarthropathy. According to the data of electroneuromyography, there is a decrease in the speed of impulse conduction along the peripheral nerves ( up to the absence of impulse conduction at a pronounced stage of diabetic polyneuropathy) and a decrease in the amplitude of muscle bioactivity ( in its absence with a pronounced stage of diabetic polyneuropathy) upper and lower extremities.

subclinical neuropathy manifested using the method of spectral and statistical analysis of heart rate variability and is characterized by a decrease in the total spectral power, the power of very low frequency (VLF), low frequency (LF) and high frequency (HF) components of the spectrum, a decrease in the coefficient of variation (CV) and a change in other factors of statistical analysis ( SDNN, RMSSD, pNN50, AMo). The course of autonomic neuropathy is characterized by a long asymptomatic period.

1. Autonomic neuropathy (clinical).

Clinical symptoms are few and may relate to one or many functional systems of the body. With cardiovascular autonomic neuropathy, patients complain of constant palpitations, shortness of breath with little physical exertion, temporary visual impairment in the form of “darkening” or “flickering of bright spots” in the eyes. Diabetic neuropathy is characterized by denervated heart syndrome and orthostatic hypotension syndrome.

Syndrome of denervated heart manifested by tachycardia of a permanent nature with a decrease or disappearance of the physiological variability of the heart rate, impaired exercise tolerance, without pain for angina pectoris and myocardial infarction. The syndrome of orthostatic hypotension is characterized by a drop in blood pressure by 30 mm Hg. Art. and more when the patient moves to a vertical position, lability of blood pressure during the day.

Gastrointestinal autonomic neuropathy patients often complain of constipation, sometimes - on periodic or constant debilitating (from 2-3 to 20-30 times a day) painless diarrhea, which is usually observed in the evening and at night. Some patients are concerned about the feeling of heaviness in the stomach, nausea, and sometimes vomiting of the remnants of food that they took more than 2-3 hours ago. Objectively, the phenomena of gastroparesis, cholecystoparesis are detected.

For genitourinary autonomic neuropathy patients are concerned about the feeling of residual urine, rarely - dripping urine drops after urination, impotence. Objectively, they reveal violations of urodynamics - a slowdown in the volumetric flow rate of urine ( especially the first half of the total), an increase in the time of urination, an increase in the threshold of the reflex to urinate, an increase in the capacity of the bladder and an increase in the volume of residual urine after urination.

1. local neuropathy.

It can manifest as mononeuropathy, multiple mononeuropathy, plexo-, radiculo- and neuropathy of the cranial nerves. More common in men with type 1 diabetes regardless of its duration. Most often, there is a lesion of the femoral nerve, the external cutaneous nerve of the thigh, and in the cranial - the oculomotor nerve. Various types of local neuropathy have an acute onset, accompanied by severe pain. The course is favorable - after a few months the process ends with a complete recovery.

1. Diabetic proximal amyotrophy.

It is characterized by atrophy of the muscles of the pelvic girdle, muscle groups of the proximal parts, mainly of the lower extremities. More commonly seen in older men. Often the lesion is asymmetrical. Patients are concerned about pain in the above-mentioned areas of the limbs, intense muscle weakness. Tendon reflexes are reduced, knee reflexes are absent. Sensitivity is rarely disturbed. Fasciculations are observed in areas of the affected muscles.

Classification and examples of the formulation of the diagnosis

Classification of the main types of diabetic neuropathy is.

Class I. Subclinical neuropathy

1. Subclinical sensorimotor neuropathy
2. subclinical neuropathy

Class II c. clinical neuropathy

A. Generalized neuropathy

1. Peripheral distal sensory motor neuropathy
2. Autonomic neuropathy

2.1. Cardiovascular neuropathy

2.2. Gastrointestinal neuropathy

2.3. Genitourinary neuropathy

2.3.1. cystopathy

2.3.2. sexual dysfunction

B. Local neuropathy

1. Mononeuropathy
2. Multiple mononeuropathy
3. Plexopathy
4. radiculopathy
5. Neuropathy of the cranial nerves
6. Diabetic proximal amyotrophy

Peripheral distal sensory motor neuropathy and diabetic neuropathy are divided into the following stages of development:

Stage I - preclinical, or latent;

Stage II - initial;

Stage III - obvious;

IV stages - severe, or pronounced.

Diagnosis examples:

1) peripheral distal sensory-motor neuropathy, II (initial) stage or diabetic polyneuropathy stage III.

2) Diabetic neuropathy, III (severe) stage.

Diagnostics

The volume of examinations for establishing the diagnosis and dynamic monitoring of patients with diabetic symmetric sensorimotor polyneuropathy.

The volume of examinations for establishing the diagnosis and dynamic monitoring of patients with diabetic autonomic neuropathy.

Differential Diagnosis

Differential diagnosis of diabetic symmetric sensory motor polyneuropathy is carried out with disorders of the peripheral nervous system in toxic lesions ( chronic alcoholism, poisoning with salts of heavy metals ), endocrinological and metabolic disorders (hypothyroidism, uremia), infectious and inflammatory diseases ( sarcoidosis, leprosy, periarteritis nodosa ).

Differential diagnosis of diabetic autonomic neuropathy carried out with vegetative lesions that occur during primary ( Bradbery-Egglestone syndrome, Shy-Drager syndrome, familial dysautonomia and other hereditary autonomic neuropathies ) and secondary autonomic failure ( with endocrine diseases - hypothyroidism, adrenal insufficiency, systemic and autoimmune diseases - amyloidosis, scleroderma, Guyen-Barré syndrome, metabolic disorders - alcoholism, porphyria, uremia, infectious diseases - AIDS, herpes, syphilis, leprosy, drug intoxication, toxic lesions with severe salts metals, as well as syringomyelia, tumors of the nervous system, multiple sclerosis ).

Treatment

Treatment of diabetic peripheral sensory-motor polyneuropathy.

Treatment schematically includes:

1. Diet number 9. Drinking alcohol and smoking tobacco are strictly prohibited.
2. with a pronounced stage of diabetic polyneuropathy, insulin therapy is mandatory).
3. Sulfur-containing drugs ( one of them):

a) 30% - 10.0 IV with 10.0 saline 1 time per day, No. 10-20;

b) 5% - 5.0 intramuscularly 1 time per day, No. 10-20;

in) alpha lipoic acid 600 mg (24 ml) IV drip 1 time per day, No. 20;

1. Isodibut 0.5 g 3 times a day for 3-12 months.
2. Physiotherapy:

a) microwave resonance therapy;

b) hydrogen sulfide baths, 4 and 2-chamber baths;

c) massage.

1. vasodilators, angioprotectors: nicotinic acid, xanthinol nicotinate, pentoxifylline, etc.
2. antidepressants lungs (vegetable based on St. John's wort).
3. Care of the skin of the lower extremities with the use of moisturizing, keratolytic and antiseptic creams ( type "Balzamed").
4. Painkillers ( 1 week before the appearance of a decrease in irritative-pain syndrome against the background of the use of sulfur-containing drugs).

Treatment of diabetic autonomic neuropathy.

1. Diet number 9. It is strictly forbidden to drink alcohol and smoke tobacco.
2. Adequate hypoglycemic therapy ( with a pronounced stage of development of diabetic autonomic neuropathy, insulin therapy is indicated using a peak-free analogue of insulin).
3. Sulfur-containing drugs (one of them):

a) 30% - 10.0 IV with 10.0 saline 1 time per day, No. 15-20 ( especially in cardiovascular, gastrointestinal autonomic neuropathy)

b) 5% - 5.0 intramuscularly 1 time per day, No. 15-20 ( especially in cardiovascular, gastrointestinal autonomic neuropathy and diabetic cystopathy)

in) alpha lipoic acid 600 mg (24 ml) IV drip 1 time per day, No. 20 ( especially in cardiovascular and gastrointestinal autonomic neuropathy).

Treatment of local neuropathy.

1. Compliance with diet therapy.
2. Adequate hypoglycemic therapy ( intensive insulin therapy with long-term compensation is indicated).
3. Symptomatic therapy from the list of general neurological practice, taking into account the localization of the process.

Treatment of diabetic proximal amyotrophy.

It is carried out according to the scheme of treatment of local neuropathy.

Efficacy criteria and duration of therapy

The criteria for the effectiveness of therapy are the disappearance or reduction of the irritative-pain syndrome of diabetic polyneuropathy and subjective symptoms of diabetic autonomic neuropathy, an increase in the speed of impulse conduction along the peripheral nerves, an increase in the amplitude of the bioactivity of the muscles of the lower and upper extremities and an improvement in the spectral analysis of heart rate variability, standard cardiovascular reflex tests.

Treatment results in remission of diabetic neuropathy, the duration of which depends on the further state of DM compensation. The duration of therapy is set taking into account the time to achieve compensation or subcompensation for diabetes, the established duration of the course with sulfur-containing drugs.

Prevention

Primary prevention of diabetic neuropathy includes early diagnosis of diabetes, adequate treatment with hypoglycemic drugs with training in self-monitoring of the course of the disease and its subsequent implementation.

Secondary prevention of diabetic neuropathy includes conducting adequate hypoglycemic therapy with maintaining long-term compensation for diabetes, self-monitoring of the course of the disease with careful monitoring of the legs, regular ( once every 1-2 years) carrying out a course of treatment with the above-mentioned drugs.

The manifestations of DP correlate:
with disease duration
with age of patients

This complication ( diabetic polyneuropathy) is heterogeneous in nature, as it affects the proximal and distal peripheral sensory and motor nerves, as well as the autonomic nervous system.

Neurological complications occur with the same frequency in all types of DM.

The most severe manifestations of DP result in:
with somatic DP to the development of ulcerative lesions of the lower extremities
with autonomous DP to high mortality of patients

Epidemiology

Frequency of development of DP:
in patients with type 1 diabetes is 13-54%
in patients with type 2 diabetes is 17-45%

According to a number of epidemiological studies, the incidence of DP in all types of diabetes mellitus varies from 5 before 100% (large data discrepancies are associated with the difficulty of diagnosis and depend on the research methods used).

Classification of polyneuropathies (I.I. Dedov et al., 2002):

1. Lesions of the central nervous system:
encephalopathy
myelopathy
2. Lesions of the peripheral nervous system:
diabetic polyneuropathy:
- sensory form (symmetrical, asymmetrical)
-motor form (symmetrical, asymmetrical)
- sensorimotor form (symmetrical, asymmetrical)
diabetic mononeuropathy(isolated lesion of the pathways of the cranial or spinal nerves)
autonomic (vegetative) neuropathy:
- cardiovascular form
- gastrointestinal form
- urogenital form
- asymptomatic hypoglycemia
- other

According to the classification of Boulton et al., 2005, the following independent types of neuropathies are distinguished:
acute sensory
chronic sensorimotor
thin and thick fibers
vegetative
hyperglycemic
focal mononeuropathies of the extremities
cranial
proximal motor (amyotrophy)
truncal radiculoneuropathy, etc.

Three more clinical varieties of diabetic neuropathy of fine fibers can be distinguished.:
true - characterized by positive neurological symptoms, including burning, tingling, signs of distal desensitization, decreased Achilles reflex
pseudosyringomyelic- characterized by a decrease in pain and temperature sensitivity in combination with neuropathy of autonomic fibers, a skin biopsy reveals a clear lesion of the axons of small fibers and a moderate lesion of large fibers
acute - acute burning pain dominates, allodynia, hypersensitivity to stabbing stimulation, weight loss, insomnia, erectile dysfunction in men, skin biopsy analysis indicates active degeneration of myelinated and unmyelinated fibers

Pathogenesis

According to modern theory pathogenesis, DP is a pathology that develops against the background of metabolic and vascular disorders characteristic of diabetes mellitus.

Absolute or relative deficiency of insulin plays a leading role in the mechanisms of the onset of DP.

DP is a consequence of violations of the structural and functional state and metabolic imbalance in the peripheral nerves.

!!! It should be noted that isolated hyperglycemia cannot underlie the formation of diabetic complications, since it has been noted that intensive control of blood glucose levels significantly reduces the manifestations of nerve and vascular lesions, but cannot completely rid the patient of them.

To date, it is assumed that the cause of the formation of diabetic complications is a complex of metabolic disorders arising from:
hyperglycemia
insulin deficiency

In this regard, the following metabolic disorders deserve the most attention, which are directly related to structural and functional damage to nerve fibers:
protein glycation
polyol metabolic pathway
sorbitol accumulation
oxidative stress
decreased activity of protein kinase C
free radical destruction of cell membranes
metabolic disorders of free fatty acids

!!! To date, it has been proven that under the condition of diabetic peripheral neuropathy, hypoxia of nerve fibers develops simultaneously with a decrease in endoneural blood flow. It is she who is the most important cause of nerve dysfunction in diabetes mellitus.

Non-fleshy nerve fibers take part in the regulation of endoneural blood flow by controlling the formation of arteriovenous anastomoses. Damage to these fibers is observed in the early phase of DP development. The lack of mechanisms to control the formation of arteriovenous anastomoses leads to increased endoneural hypoxia.

!!! One of the essential signs of DP is the stimulation of the formation of arteriovenous shunts, which is manifested by the expansion of the venous vessels of the foot and an increase in the partial pressure of oxygen in them.

A special place in the development of diabetic complications is given oxidative stress. One of its consequences is a decrease in the concentration of nitric oxide (NO), which has antiproliferative and vasodilatory effects. This leads to a deterioration in the blood supply to the nerve fibers and the development of their dysfunction.

The intensity of oxidative stress also increases due to the inhibition of the natural antioxidant system, which is recorded by a decrease in the amount of such tissue components as reduced glutathione, ascorbic acid, vitamin E, as well as a decrease in the activity of antioxidant enzymes. Oxidative stress is accompanied not only by a decrease in the content and disruption of the functioning of natural antioxidants, but also by progressive damage to the function of nerve fibers with the further development of diabetic sensory polyneuropathy.

Nutritional factors, in particular vitamin deficiencies, also play a role in the development of DP.:
impaired absorption of carbohydrates
signs of hypoglycemia are masked (the mechanisms of its counterregulation are suppressed - the glucagon phase of adaptation is inhibited and adrenergic symptoms-precursors are leveled)
altered bioavailability of oral sugar-lowering drugs

Summarizing the data regarding the pathogenesis of DP, it can be concluded that damage to nerve fibers, especially in the early stages of the development of DM, is not irreversible, but can be eliminated by improving blood supply in the neural vessels

Clinical picture of DP

Stage 0: No symptoms or signs.

Stage 1: Subclinical DP
subclinical DP at stage 1 can be diagnosed in specialized neurophysiological departments. Such diagnostic tests are not recommended for routine use.

!!! Clinical differential diagnosis between stages 0 and 1 of DP is not possible.

Stage 2: Clinical DP

1. Chronic pain form:
the presence of symptoms that worsen at night, such as burning, sharp and stabbing pain
tingling (±)
lack or impairment of sensitivity and weakening or absence of reflexes

2. Acute pain form:
poor control of diabetes, weight loss
diffuse pain (torso)
hyperesthesia may occur
may be associated with initiation of antidiabetic therapy
minimal sensory disturbances or normal sensitivity on peripheral neurological examination

3. Amyotrophy:
usually occurs in older people with undiagnosed and poorly controlled type 2 diabetes
manifested by muscle weakness; affects, as a rule, the proximal muscles of the lower extremities; subacute onset
usually accompanied by pain, mostly at night, with minimal sensory disturbances

4. Painless DP combined with complete or partial loss of sensation:
there are no symptoms or numbness of the feet, a violation of temperature and pain sensitivity with a lack of reflexes

Stage 3: Late complications of clinical DP
foot ulcers
neuroosteoarthropathy
non-traumatic amputations

!!! For the stages of DP, see also the article Diabetic neuropathy - solving the problems of objectification in the section "Nurology and Neurosurgery" of the site website

Possible against the background of DP and focal / multifocal neuropathy (mononeuropathy):
cranial nerves
trunk nerves
limb nerves
proximal motor (amitrophy)
concomitant chronic inflammatory demyelinating neuropathies

Clinical manifestations of chronic sensorimotor diabetic polyneuropathy are:
pain (most often burning in nature, worse at night)
paresthesia
hyperesthesia
decreased sensitivity - vibration, temperature, pain, tactile
decrease or loss of reflexes
dry skin
rise or fall in temperature
the presence of callus (callus) in areas of high pressure

At the same time, it should be emphasized that complaints characteristic of neuropathy are noted only in half of the patients, and in the remaining patients, neuropathy is asymptomatic.

According to the utilitarian clinical classification, two main variants of diffuse diabetic polyneuropathy are distinguished:
acute pain (small fiber disease) neuropathy
chronic pain (damage to large and small fibers) neuropathy

Current duration acute painful diabetic neuropathy is 6-12 months, regardless of the therapy. Pathogenetic treatment for acute painful diabetic neuropathy, in particular the administration of alpha-lipoic acid preparations, is not effective.

Chronic pain diabetic neuropathy occurs much more frequently. It is characterized by a gradual onset, an intermittent course, a clear relationship between the severity of the pain syndrome and the level of glycemia, and, accordingly, a decrease in symptoms when compensation for diabetes is achieved.

Risk groups for developing DP:
patients with type 1 diabetes 1 year after the onset of the disease
patients with type 2 diabetes since the diagnosis of the disease

It should also be noted that the relationship between poor glycemic control and the severity of neuropathic manifestations is clearly seen in patients with type 1 diabetes, while it is usually absent in type 2 diabetes.

Diagnosis of DP

The most typical signs of DP:
weakening of the Achilles reflexes
decreased peripheral vibration sensitivity

The difficulty in diagnosing DP is that:
firstly, age-related changes can give a similar clinical picture
secondly, DP can often be asymptomatic and be detected only by electroneuromyography.

There are five risk factors for developing DP (according to the DCCT study):
1. SD duration
2.degree of hyperglycemia
3.age of the patient
4.male
5.higher height

DP is more common in patients with diabetic retinopathy and nephropathy.

A significant length of peripheral nerve fibers determines the high activity of metabolic processes in them, which requires their proper supply of oxygen and energy. In this regard, the lower limbs, especially the feet, are most susceptible to the development of DP.

The defeat of the central nervous system is diagnosed by a neuropathologist using special examination methods.

Methods for diagnosing damage to the peripheral nervous system

Sensory form of neuropathy
violation of vibration sensitivity
mandatory method - calibrated tuning fork (values ​​less than 4/8 of an octave of the scale on the head of the big toe)
additional method (if possible) - biotensiometry
temperature sensitivity disorder
mandatory method - touching with a warm / cold object
pain sensitivity disorder
obligatory method - pricking with a needle
impaired tactile sensation
obligatory method - touching the plantar surface of the foot with a monofilament
impairment of proprioceptive sensitivity
mandatory method - detection of sensitive ataxia (instability in the Rombeog position)
Motor form of neropathy
manifestations: muscle weakness, muscle atrophy
a mandatory method is to identify the weakening or absence of tendon reflexes (Achilles, knee)
additional method (if possible) - electroneuromyography
Autonomous form of neuropathy
cardiovascular form
mandatory method
- the manifestation of orthostatic hypotension (decrease in blood pressure is more than or equal to 30 mm Hg when changing body position from horizontal to vertical)
- lack of acceleration of heart rate on inspiration and slowing down on expiration
- Valsalva maneuver (lack of heart rate acceleration during straining)
additional method (if possible)
- 24-hour blood pressure monitoring (no nighttime blood pressure drop)
- Holter ECG monitoring (the difference between the maximum and minimum heart rate during the day is less than or equal to 14 beats / min)
- ECG recording during the Valsalva maneuver (the ratio of the maximum RR to the minimum is less than or equal to 1.2)
gastrointestinal form (enteropathy)
mandatory method - diagnosed by the clinic of alternating diarrhea and constipation, gastroparesis, biliary dyskinesia
additional method (if possible) - gastroenterological examination
urogenital form
mandatory method - diagnosed by the absence of urge to urinate, the presence of erectile dysfunction, retrograde ejaculation
additional method (if possible) - urological examination
asymptomatic form-diagnosed by the absence of clinical symptoms

Screening for Diabetic Polyneuropathy:
administered to all patients with type 1 diabetes mellitus 5 years after diagnosis and to all patients with type 2 diabetes at diagnosis, then annually
determination of temperature, pain, tactile and vibration sensitivity, tendon reflexes
careful examination of the lower extremities and feet

Treatment of DP

!!! To date, no treatment method has been developed that would become the gold standard for the treatment of DP.

primary goal to prevent DP - achieving normoglycemia

simultaneously in the presence of functional organic changes, it is necessary to prescribe drugs that affect the pathogenesis of DP and the symptoms of DP.

Pathogenic therapy includes:
measures aimed at achieving and maintaining stable compensation for DM
aldose reductase inhibitors - blockers of the polyol pathway of glucose metabolism
B vitamins - benfotiamine and cyanocobalamin - glycolysis inhibitors that block the glucotoxic effect and the formation of glycosylation end products
-lipoic acid - activates mitochondrial enzymes and glucose oxidation, inhibits gluconeogenesis
essential fatty acids - have an antioxidant effect and reduce hyperlipidemia.

Symptomatic therapy includes activities aimed at:
elimination of pain syndrome
elimination of cramps in the limbs
prevention and treatment of foot ulcers
correction of bone mineral density in the development of osteoporosis
treatment of concomitant infections, etc.

Modern approaches in the therapy of DP
Currently, two main approaches are put forward in the implementation of directed neurotropic therapy of DP, as well as in neuropharmacology in general:
the use of combined neurotropic agents containing components that affect various links in the pathogenesis of this syndrome and complement each other in pharmacodynamic and clinical terms
the use of monopreparations of a complex polytopic type of action, which have versatile and important effects from the point of view of pharmacology and clinic

It should be emphasized that such approaches not only do not contradict, but also optimally complement each other, making it possible to fully implement the strategy of complex neurotropic pharmacotherapy in DP.

The main advantages of these combined drugs include:
the possibility of using proven standard effective combinations of biologically active substances within the same dosage form (simplification of the procedure for choosing a therapeutic agent for a practitioner)
reduction of involuntary polypharmacy while maintaining or increasing the effectiveness of treatment
improvement of compliance (convenience of use for the patient and the doctor)
increasing the availability of treatment, depending on the cost of drugs

(1) To date, the most effective means in the treatment of DP are drugs thioctic (-lipoic) acid .

The main mechanisms of action of a-lipoic acid can be summarized as follows:
Impact on energy metabolism, glucose and lipid metabolism: participation in the oxidative decarboxylation of a-keto acids (pyruvate and a-ketoglutarate) with the activation of the Krebs cycle; increased capture and utilization of glucose by the cell, oxygen consumption; increase in basal metabolism; normalization of gluconeogenesis and ketogenesis; inhibition of cholesterol formation.
Cytoprotective action: increased antioxidant activity (direct and indirect through the systems of vitamins C, E and glutathione); stabilization of mitochondrial membranes.
Influence on the reactivity of the body: stimulation of the reticuloendothelial system; immunotropic action (decrease in IL1 and tumor necrosis factor); anti-inflammatory and analgesic activity (associated with antioxidant action).
Neurotropic effects: stimulation of axon growth; positive effect on axonal transport; reducing the harmful effects of free radicals on nerve cells; normalization of abnormal glucose supply to the nerve; prevention and reduction of nerve damage in experimental diabetes.
Hepatoprotective action: accumulation of glycogen in the liver; increased activity of a number of enzymes, optimization of liver function.
Detoxifying action(FOS, lead, arsenic, mercury, sublimate, cyanides, phenothiazides, etc.)

Alpha lipoic acid preparations are available as infusion, as well as in tableted form (thioctacid, berlition, espalipon, thiogamma, etc.).

!!! The standard course of treatment begins with an infusion of the drug at a dose of 600 mg per day intravenously by drop infusion into 150.0 ml of a 0.9% NaCl solution for 3 weeks. (with breaks on weekends) followed by oral administration of the drug for 2-3 months at 600 mg / day. Taking into account the pharmacokinetic features of the absorption of alpha-lipoic acid tablet forms in the intestine, it is recommended to take the tablets at least 30 minutes before a meal.

An alternative scheme has also been proposed. treatment of DP, including initial therapy of 600 mg of alpha-lipoic acid 3 times a day for 3 weeks (1800 mg / day) and maintenance therapy of 600 mg 1 time per day in the morning on an empty stomach for 2-3 months

Currently, a special form has been developed - thioctacid BV, which differs from the standard one by the addition of auxiliary components to the tablet core and a change in the film coating, which ensured the optimization of the pharmacokinetics of the drug, improved bioavailability and a decrease in the coefficient of variability of the level of thioctic acid in blood plasma.

(2) neurotropic vitamins , in particular vitamin B1 (thiamine), are coenzymes in various biochemical processes, improve the energy supply of the nerve cell, and prevent the formation of end products of protein glycation.

(3) Preparations containing benfotiamine.

Benfotiamine is a lipophilic derivative of vitamin B1 that directly affects the metabolism in the nerve cell. If the penetration of conventional (water-soluble) thiamine through cell membranes is largely limited, then the bioavailability of benfotiamine is 100%. It penetrates into the nerve cells in proportion to the dose taken, reaching a high intracellular concentration. Formed from benfotiamine inside cells, biologically active thiamine is metabolized and thus becomes a coenzyme. The ability of benfotiamine to stimulate transketolase is ten times higher than that of water-soluble thiamine compounds, and is 250%.

Benfotiamine blocks four pathways of damage to target cells in diabetes (which is the advantage of benfotiamine compared to other means of pathogenetic therapy for diabetes - aldose reductase inhibitors, protein kinase C inhibitors, blockers of receptors for end products of excess glycation, affecting only one of the pathways of alternative glucose metabolism):
polyol way
glycosamine pathway
activation of protein kinase C
formation of non-enzymatic glycation products

In the painful form of DP, treatment begins with a course of 10-15 daily injections of a combination of neurotropic vitamins containing 100 mg of vitamins B1, B6 and 1000 μg of vitamin B12, and deep intramuscular lidocaine ( Milgamma, Kombilipen).

Milgamma/Combilipen- with severe manifestations, 2 ml daily for 5-7 days, then 2 ml 2-3 times a week for 2 weeks, in mild cases, 2 ml 7-10 days with a frequency of 2-3 times a week. Further switch to oral benfotiamine ( Milgamma, Benfolipen) - tablets are taken after meals, without chewing and with a small amount of liquid, 1 tablet 1-3 times a day. The duration of the course depends on the severity of the clinical manifestations of DN.

In case of severe pain syndrome (neuropathic pain) that accompanies the manifestations of DP, an effective remedy is needed to relieve it.

Until now, most often in patients with persistent severe neuropathic pain tricyclic antidepressants were prescribed for DP. Generally and currently used amitriptyline recommending starting therapy with low doses (25 mg) with a gradual increase in dose up to 150 mg per day.

However, taking these drugs is accompanied by a large number of cholinergic side effects: dry mouth, increased intraocular pressure, urinary retention, constipation, cardiac arrhythmias, etc., which limits the possibility of their use.

(4) In this regard, the emergence of new drugs among analgesics - second generation anticonvulsants(gabapentin, pregabalin) has become a new step in the treatment of neuropathic pain.

(4.1) Gabapentin belongs to the class of anticonvulsants and is structurally similar to α-aminobutyric acid, which performs a neurotransmitter function and is involved in pain modulation. Gabapentin interacts with α-amino acid transport mechanisms and binds with high specificity to the -2 subunit of voltage-gated calcium channels. The antihyperalgic properties of the drug are modulated by the mechanisms of the spinal cord. Symptomatic therapy with gabapentin is accompanied by an increase in the quality of life of patients with DM and DP.

When prescribing gabapentin, treatment should be started at a dose of 300 mg at night with a gradual increase in dose. Most patients need to prescribe the drug at a dose of 1.8 g per day for 3 doses. Monitoring should be carried out in terms of the development of side effects, primarily due to the central mechanism of action of the drug (drowsiness and others).

(4.2) In addition to gabapentin, this group includes a newer drug - pregabalin ( Lyrica), which provides an equivalent analgesic effect (up to 50%) when using significantly lower doses (150-600 mg / day) during the first week of treatment. At the same time, pregabalin improves sleep and is well tolerated. The starting dose of pregabalin - 75 mg 2 times a day - is gradually increased to 600 mg per day. After a 7-day intake and the achievement of an analgesic effect, the dose of the drug is recommended to be reduced.

(5) Anticonvulsants(carbamazepine 100 mg 2 times a day (up to 400 mg 3 times a day), phenytoin (1 tab. 2-3 times a day) also reduce pain in DP.

(6) A new anticonvulsant has been developed for the treatment of diabetic neuropathy- lacosamide, which provides selective slow inactivation of potassium channels, which distinguishes it from other anticonvulsants that can act on various types of receptors and modulate the response of the mediator collapse (CRMP-2). Lacosamide at a dose of 200-600 mg/day reduces pain in DN.

(7) There is evidence of the effectiveness of antiarrhythmic drugs in DP ( lidocaine and mexiletine). The mechanism of action is based on the stabilization of neuronal membranes due to the blockade of sodium channels.

Lidocaine in the form of slow intravenous infusions (30 min) at a dose of 5 mg/kg effectively reduces pain in DN.

The antinociceptive effect of the oral form of mexiletin at a dose of 450-600 mg / day has been proven in a number of double-blind, placebo-controlled studies. On a global pain scale, the improvement was insignificant, but there was a significant decrease in shooting, burning pain, tingling, and a feeling of heat. Side effects in the treatment of antiarrhythmic drugs are less pronounced compared with anticonvulsants.

(8) Some authors recommend the use of local irritants (finalgon, apizatron, viprosal, capsicam, etc.) in the complex therapy of DP, especially in the treatment of burning superficial and stabbing pains. One of the mechanisms of action of these drugs is the depletion of pain mediators and other substances involved in the occurrence and maintenance of pain.

(9) An alternative to achieve an analgesic effect is to use centrally acting non-opioid analgesics, which selectively affect the level of sensitive neurons of the posterior horns of the spinal cord (soanalgesics). The mechanism of action of drugs in this group is based on indirect antagonism to NMDA receptors and agonism towards GABAergic receptors in the absence of effects on serotonin, dopamine, opiate, central muscarinergic and nicotinic receptors, as well as benzodiazepine receptors. As a result, selective activation of neuronal potassium channels occurs and an analgesic effect is provided. At the same time, there is a muscle relaxant effect, which is fundamentally important in painful forms of DN.

This group of drugs is flupirtine (katadolon), which has a proven analgesic effect in pain syndromes of various etiologies (radiculoneuritis, vertebrogenic dorsopathy, postoperative pain syndrome, cancer, diseases of the musculoskeletal system, including osteoporosis, myofascial syndromes, etc.). Assign katadolon should be 100-200 mg 3-4 times a day (daily dose of 600 mg).

(10) Aldose reductase inhibitors

The first clinical studies to evaluate the effectiveness of this group of drugs began to be conducted 25 years ago. However, to date, the only drug from this group, Epalrestat, is approved for clinical use only in Japan. Most clinical trials, for a number of reasons, have not confirmed a significant effect in terms of improving or preventing the development of diabetic neuropathy. Many of the proposed substances had a high hepatotoxicity, which limited their long-term use in clinical practice.

(11) In the structure of metabolic pathogenetic therapy, it is also advisable to use actovegina. It has antihypoxic activity and insulin-like effect, improves microcirculation. Usually actovegin is prescribed 400 mg (10 ml) intravenously by stream or intravenous drip for 10-14 days, then 1 tab. 3 times a day for 3 weeks. Actovegin is a highly active stimulator of oxygen and glucose utilization under conditions of ischemia and hypoxia, which increases the transport and accumulation of glucose in cells, which improves the aerobic synthesis of macroergic compounds and increases the energy resources of neurons, preventing their death.

Its effectiveness in the treatment of diabetic neuropathy has been confirmed in a number of double-blind, placebo-controlled studies.

(12) With concomitant severe diabetic autonomic neuropathy along with the optimization of the level of glycemia and the appointment of drugs of pathogenetic action, symptomatic therapy is also used: for example, with rest tachycardia, selective blockers(metoprolol, bisoprolol, nebivolol), calcium channel blockers(verapamil, diltiazem) or magnesium preparations(kormagnesin, magnerot).

(13) For orthostatic hypotension drinking plenty of fluids, a contrast shower, elastic stockings, refusing to exercise, abolishing antihypertensive drugs, sleeping on a bed with a raised head edge, a slight increase in dietary salt intake are shown. The patient should get up slowly from the bed and chair. If such measures are unsuccessful, the volume of blood plasma can be increased by prescribing salina or fludrocortisone . In the event that orthostatic hypotension develops against the background of hypertension, it is possible to prescribe -blockers, which have intrinsic sympathomimetic activity ( pindolol, oxprenolol). Recently, an agonist has been recommended to relieve symptoms of orthostatic hypotension. -receptor midodrine .

(14) It is possible to use central muscle relaxants, but there is no evidence base regarding their higher effectiveness in DP.

Central muscle relaxants are a heterogeneous group including:
tizanidine (alpha-2-adrenergic agonist)
baclofen (GABAB receptor antagonist)
diazepam (GABAA receptor agonist)
memantine (an inhibitor of NMDA-dependent channels)
tolperisone (Na channel blocker and membrane stabilizer)

From the standpoint of the formation of pain and the preservation of the quality of life in spastic syndrome, it is important to reduce the severity of spasm, improve blood circulation in the muscle, and, finally, the absence of muscle weakness after taking the drug.

The drugs of choice are tinazidine hydrochloride (sirdalud, is prescribed 2-4 mg 3 times a day (no more than 36 mg / day) and tolperisone hydrochloride (mydocalm, tolperisone is prescribed 50 (150) mg 3 times a day or intramuscularly 100 mg 2 times a day).

With muscle cramps in the legs can be prescribed magnesium preparations, including in combination With vitamin B6 (pyridoxine). Magnesium deficiency is accompanied by a violation of muscle relaxation, a decrease in the reserve pool of potassium and relative hypocalcemia, which ultimately leads to the occurrence of muscle cramps in individual muscles or muscle groups.

Magnesium preparations– magne B6, magvit, magnerot- is prescribed for cardiovascular pathology (myocardial infarction, circulatory failure, arrhythmias, vasospasms), and DP often develops in patients with initial cardiac pathology.

(15) Botulinum toxin A recent pilot, double-blind, crossover study demonstrated the efficacy of botulinum toxin type A in the treatment of pain in 18 patients with DP. Pain decreased significantly from the first week after the injection during the 12 weeks of follow-up. In 44% of patients, the reduction in pain on the visual analogue scale (VAS) was more than 3 points. An improvement in sleep was also observed starting at 4 weeks post-injection. The anti-pain effect of botulinum toxin is associated with the ability of the drug to inhibit afferent nociceptive activity in peripheral sensory nerve fibers.

(16) Glyceryl trinitrate Glyceryl trinitrate, traditionally used as a vasodilator for angina pectoris, significantly relieves the pain associated with diabetic neuropathy. It's shown
in a double-blind, placebo-controlled study evaluating the efficacy of glyceryl trinitrate spray in 48 patients with painful diabetic neuropathy. Twenty-four patients in the study group applied topical glyceryl trinitrate spray on their legs during sleep for four weeks, while the other 24 used a spray containing placebo. Glyceryl trinitrate was well tolerated and only one patient was excluded from the study due to adverse side effects. The researchers attribute the positive effect to vasodilation due to nitric oxide, a derivative of glyceryl trinitrate. Good results have been obtained when this spray is used in combination with valproic acid.

(17) Non-pharmacological methods include the use gymnastics for the legs, massage and various physiotherapeutic methods (magnetotherapy, transcutaneous electrical nerve stimulation, acupuncture, etc.).), but their effectiveness has not been proven in multicenter randomized trials.

The effectiveness of physiotherapeutic effects, confirmed in small groups and with a short observation period, allows us to recommend them for inclusion in the complex therapy of DP. At the same time, care must be taken in the choice of physiotherapeutic treatments, since sensory disturbances and autonomic disorders in DP predispose to the formation of burns and ulcers.

Definition of diabetic neuropathy

Presence of signs and/or symptoms indicative of damage to the peripheral nervous system in people with diabetes mellitus (DM), taking into account the exclusion of other causes of neuropathy. The diagnosis of diabetic neuropathy can be made by careful examination of the patient. The absence of symptoms of neuropathy is not a basis for excluding the diagnosis, at the same time, the diagnosis of diabetic neuropathy cannot be established in the presence of a single symptom or sign. According to current recommendations, at least two neurological disorders (symptoms, changes in the speed of propagation of excitation along the nerve fiber, shifts according to quantitative sensory or autonomic tests) are required to make a diagnosis of diabetic neuropathy.

Modern classification of diabetic neuropathy

Generalized symmetrical polyneuropathies

Sensorimotor (chronic)

Sensory (acute)

Autonomic neuropathy

Cranial

Lumbar-thoracic radiculoneuropathy

Focal tunnel neuropathies

Proximal motor neuropathy (amyotrophy)

Chronic inflammatory demyelinating neuropathy (CIDP)

Chronic sensorimotor neuropathy

The most common form of diabetic neuropathy is chronic sensorimotor neuropathy. The manifestations of this form of damage are positive neurological symptoms that occur or intensify at night or at rest. "Negative" symptoms (numbness or loss of stability when walking) are inherent in severe stages of neuropathy. A decrease in proprioceptive sensitivity and sensory innervation of the muscles of the foot, combined with repetitive minor trauma, underlies the formation of neuroosteoarthropathy (Charcot's foot). A manifestation of the severe stage of sensorimotor neuropathy is a characteristic deformity of the foot (pes cavus) and fingers, which is often accompanied by a pronounced limitation of the mobility of the foot joints.

Acute sensory neuropathy

Acute sensory neuropathy is characterized by severe sensory symptoms (hyperesthesia, dysesthesia, allodynia). At the same time, various types of sensitivity and reflexes can remain intact. Pain symptoms are sufficiently pronounced, can be combined with a significant loss of the patient's body weight and the development of depressive disorders. Most often, acute sensory neuropathy develops with a sharp change in glycemic indicators, both in the direction of their deterioration (the state of ketoacidosis), and with a rapid improvement in glycemic control in response to the appointment of hypoglycemic therapy with insulin or oral hypoglycemic drugs (insulin neuritis). The pathogenetic basis in this case is the formation of arteriovenous shunts and the formation of "new" vessels in the system of intraneural blood flow, which causes a state of chronic nerve ischemia.

Hyperglycemic neuropathy

Rapidly reversible neurological disorders, including moderately severe sensory symptoms and disturbances in the rate of propagation of excitation along nerve fibers, occur in individuals with newly diagnosed diabetes, patients with a transient worsening of glycemic control. Normalization of glycemic indices helps to alleviate the severity of neurological symptoms and improve the condition of patients.

Autonomic neuropathy

Manifestations of diabetic autonomic neuropathy are quite common, the most severe of them determine the high level of morbidity and mortality among diabetic patients. The most frequent and characteristic forms of autonomic neuropathy are presented in Table. one.

According to the severity of the manifestations of diabetic neuropathy, several stages are distinguished (Table 2).

Focal and multifocal neuropathies

Tunnel neuropathies occur most often in people with type 2 diabetes in the elderly and advanced age. The most common form is carpal tunnel neuropathy due to compression of the median nerve by the transverse carpal ligament. Neurophysiological signs are detected in 20-30% of patients, while symptoms occur only in 5.8%. Pain in the form of paresthesia and dysesthesia of the fingers can increase as it progresses, radiate to the forearm and shoulder, pain increases at night. In order to avoid progressive demyelination of the nerve fiber, glucocorticoids are injected into the carpal tunnel area, in some cases, surgical decompression is performed by cutting the transverse carpal ligament. This treatment greatly alleviates pain symptoms, but does not always prevent further atrophy of the muscles of the hand and loss of sensitivity. Ulnar tunnel neuropathy develops in 2.1% of patients, accompanied by pain and paresthesia of the IV and V fingers, combined with atrophy of the muscles of the hand in the hypothenar region. Conservative glucocorticoid therapy is preferred. Surgical methods of treatment are rarely used due to their low efficiency.

Cranial neuropathies

Cranial neuropathies are extremely rare (0.05%), mainly in elderly people and patients with a long duration of the disease.

Diabetic amyotrophy

Diabetic amyotrophy occurs in people with type 2 diabetes in the age group of 50-60 years. The determining factor in the clinical picture is severe pain symptoms, which are unilateral or bilateral in nature, accompanied by atrophy of the thigh muscles. Neurophysiological examination reveals changes in the amplitude of the M-response, a decrease in the speed of conduction in n. quadriceps. Recent studies have shown that patients with diabetic amyotrophy have occlusion of epineural blood vessels with the development of necrotizing vasculitis, nerve infiltration with inflammatory cells and hemosiderin. The main treatment for diabetic amyotrophy is immunosuppressive therapy using intravenous infusions of high doses of corticosteroids or immunoglobulin.

Diabetic radiculoneuropathy

Diabetic radiculoneuropathy affects middle-aged and elderly people with diabetes. The pains are girdle in nature, localized at the level of the chest and/or abdominal wall. Clinical examination of the patient reveals the heterogeneity of neurological manifestations from the absence of signs to impaired sensitivity and hyperalgesia. Improvement in glycemic control may contribute to the resolution of clinical symptoms. In some cases, it becomes necessary to prescribe immunosuppressive therapy.

Chronic inflammatory demyelinating polyneuropathy

Suspicion of chronic inflammatory demyelinating polyneuropathy (CIDP) may occur with the rapidly progressive nature of the development of polyneuropathy. To date, there are no clear differential diagnostic criteria to distinguish diabetic polyneuropathy from CIDP. The therapeutic effect consists in long-term immunomodulatory therapy using corticosteroids, azathioprine, plasmapheresis, and intravenous infusions of immunoglobulin. Active tactics of managing this category of patients can reduce the manifestations of neurological deficit and slow down the progressive deterioration of electrophysiological parameters.

Diagnosis of diabetic neuropathy

Signs of neuropathy detected during examination of the patient

Neurological examination of patients includes an assessment of various types of sensitivity (pain, tactile, vibration, pressure, cold, heat, proprioception), as well as Achilles and knee reflexes (Table 3).

It is important to note that, taking into account the high probability of isolated damage to individual nerve fibers responsible for certain types of sensitivity, the examination of the patient should include an assessment of all the listed types of sensitivity.

The symptoms of diabetic neuropathy can be assessed using special questionnaires or scales such as the Neurological Symptoms Scale, the General Symptom Scale, the Michigan Neurological Symptoms Scale, etc. Typical neuropathic symptoms are presented in Table. four.

Many patients have both positive and negative symptoms.

The use of a combined scale of various types of sensitivity and reflexes makes it possible to obtain a quantitative expression of the state of the peripheral nervous system and assess the degree of development of a neurological deficit. The scale of neurological disorders is most widely used (Table 5).

Quantitative assessment of sensitivity allows you to control the intensity of the stimulus and obtain the value of the threshold of pain, temperature and vibration sensitivity in parametric units. Comparison of the obtained values ​​with the normative indicators makes it possible to quantify the state of various types of sensitivity at the subclinical stages of diabetic neuropathy. Despite certain limitations, this technique has become widely used for research purposes for the early diagnosis of diabetic neuropathy.

Neuromyography. The study of the peripheral nervous system using neuromyography is carried out in order to obtain the most objective information about the state of large myelinated nerve fibers. It has been shown that the speed of propagation of excitation (ERV) along the nerve fibers in patients with DM decreases by approximately 0.5 m/s/h. In the DCCT study, over a 5-year follow-up period, the decrease in CRV for the sural nerve was 2.8 m/s, for the peroneal nerve — 2.7 m/s. At the same time, in the intensive observation group, only 16.5% of patients showed a significant deterioration in the CRV parameters, in the traditional treatment group - in 40.2%. Regression analysis showed that a 1% change in the level of glycated hemoglobin is associated with a CVD deviation of 1.3 m/s.

Biopsy of the sural nerve is used to diagnose atypical forms of neuropathy, as well as in a number of clinical studies that evaluate the effectiveness of pathogenetic therapy for neuropathy.

Skin biopsy allows you to get a morphological picture that quantitatively reflects the state of innervation of the skin by small nerve fibers. It has been shown that this technique has a high sensitivity, since changes are detected even in patients with impaired glucose tolerance, in individuals without signs of damage to the nervous system according to neuromyography or quantitative methods for assessing sensitivity.

Magnetic resonance imaging (MRI) used to assess the degree of involvement of the spinal cord in the development of changes in the peripheral nervous system. Studies have shown that patients with subclinical neuropathy show changes in the spinothalamic tract and thalamus.

Treatment and prevention

To date, the main pathogenetically justified and clinically confirmed method of treatment and prevention of diabetic polyneuropathy is the achievement and maintenance of optimal (HbA1c< 6,5%) гликемического контроля (DCCT, SDIS, Oslo Study, Kumamoto Study). В то же время в реальной клинической практике идеальная компенсация углеводного обмена, поддерживаемая в течение длительного периода времени, осуществима лишь у небольшого числа пациентов. Следует также учитывать прогрессирующий характер заболевания, что определяет неуклонный рост числа случаев развития хронических осложнений с увеличением длительности диабета. Следовательно, крайне актуальным является возможность использования лекарственных препаратов, влияющих на различные звенья патогенеза диабетической нейропатии.

Aldose reductase inhibitors

The first clinical studies to evaluate the effectiveness of this group of drugs began to be conducted 25 years ago. However, to date, epalrestat, the only drug from this group, is approved for clinical use only in Japan. Most clinical trials, for a number of reasons, have not confirmed a significant effect in terms of improving or preventing the development of diabetic neuropathy. Many of the proposed substances had a high hepatotoxicity, which limited their long-term use in clinical practice.

Antioxidants

The role of oxidative stress in the pathogenesis of diabetic neuropathy is beyond doubt. Studies to evaluate the effectiveness of the most effective antioxidant - α-lipoic acid (Espa-lipon) have shown the potential of this group of drugs. Preparations of α-lipoic acid are able to reduce glucose levels, reduce insulin resistance. In addition, they have a hepatoprotective effect.

Studies by ALADIN and SYDNEY have shown that the use of intravenous infusions of 600 mg of α-lipoic acid for 3 weeks is accompanied by a significant improvement in neurological symptoms in patients with painful diabetic polyneuropathy. Two large multicenter studies in Europe and North America are currently nearing completion to evaluate the efficacy of α-lipoic acid in the treatment of diabetic neuropathy. α-lipoic acid preparations are available in both infusion and tablet form. It is important to note that the standard course of treatment is the infusion administration of the drug at a dose of 600 mg per day intravenously in drops of 150.0 ml of 0.9% NaCl solution for 3 weeks (with breaks on weekends) followed by oral administration of the drug for 2- 3 months at 600 mg per day. Taking into account the pharmacokinetic features of the absorption of α-lipoic acid tablet forms in the intestine, it is recommended to take the tablets at least 30 minutes before a meal.

Protein kinase C (PKC) inhibitors

Intracellular hyperglycemia increases the level of diacylglycerol, which, in turn, activates the formation of PKC, which leads to impaired expression of endothelial nitric oxide synthase and vascular endothelial growth factor. Data from preliminary studies on the use of an inhibitor of the PKC isoform showed its positive effect on the functional state of the peripheral nervous system. Multicentre studies on the drug will be completed by the end of 2006.

In some cases, in the presence of severe pain symptoms, it becomes necessary to prescribe symptomatic therapy. All symptomatic drugs affect certain pathogenetic mechanisms of chronic pain syndrome formation, have a dose-dependent effect, and are prescribed for a long period of time in order to avoid pain relapses.

Stage of complications of diabetic neuropathy

The most dangerous complication of diabetic distal polyneuropathy is diabetic foot syndrome. The role of neuropathy as an etiopathogenetic factor in the development of foot ulcers and osteoarthropathy (Charcot's foot) has been confirmed by numerous studies. At the same time, it has been shown that the formation of an ulcer in patients with severe neurological deficit does not occur spontaneously, but is the result of the influence of external and/or internal factors on the neuropathic foot. External factors include tight shoes, mechanical and thermal external influences. Internal factors are largely due to increased plantar pressure, the formation of areas of calluses, the formation of deformities of the fingers and the foot as a whole. Special training programs, active monitoring of patients with a high risk of developing ulcers, specialized pediatric care and therapeutic, orthopedic shoes significantly reduce the incidence of ulcers and amputations of the lower extremities in patients with diabetes.

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