Sensory neuropathies

Damage to the peripheral nervous system, leading to the development of polyneuropathy, causes limited ability to work, disability in this category of patients. When taking into account the clinical symptoms in patients with neuropathy, the symmetry, distribution of neuropathic disorders, heredity, damage to both thin and thick (A-a and A-P) nerve fibers, and the presence of appropriate clinical symptoms are assessed.

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Causes sensory neuropathies

Gangliosides play an important role in the development of a number of neuropathies. Gangliosides form a family of acidic sialylated glycolipids consisting of carbohydrate and lipid components. They are mainly located in the outer layer of the plasma membrane. The external location of carbohydrate residues suggests that such carbohydrates act as antigenic targets in autoimmune neurological disorders. Molecular mimicry between gangliosides and bacterial carbohydrate antigens (especially with bacterial lipopolysaccharide) may be a key factor in the development of a number of diseases (Miller-Fisher syndrome, Bickerstaff encephalitis, neuropathy with anti-MAG antibodies).

Antiganglioside antibodies may cross-react with other glycolipids and glycoproteins (HNK1 epitope), including myelin glycoprotein P0, PMP-22, sulfglucuronyl paraglobazidine glycolipids, and sulfglucuronyl lactosaminyl paraglobazidine glycolipids. An association between cytomegalovirus infection and anti-GM2 antibodies has recently been described. Antibodies that bind to carbohydrate antigens such as anti-ganglioside or anti-MAG (myelin associated glycoprotein) have been found in a variety of peripheral neuropathies. Patients with sensory neuropathies may have evidence of autonomic and motor involvement.

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Pathogenesis

From the standpoint of pathophysiology, nociceptive and neuropathic pain are currently distinguished. Nociceptive pain is pain caused by the action of a damaging factor on pain receptors, with other parts of the nervous system intact. Neuropathic pain is pain that occurs with organic damage or dysfunction of various parts of the nervous system.

When assessing and diagnosing neuropathic pain in patients with polyneuropathy, the distribution of neuropathic pain (the innervation zone of the corresponding nerves, plexuses and roots) is taken into account, the relationship between the history of the disease that caused neuropathic pain and the localization and neuroanatomical distribution of the pain itself and sensory disorders is identified, and the presence of positive and negative sensory symptoms is assessed.

Pathophysiology of pain manifestations in polyneuropathies

Due to the fact that diabetic polyneuropathy is the most common and difficult to treat complication of diabetes mellitus, the pathogenesis of neuropathic pain has been most well studied in this nosology.

Experimental models are usually used to study the pathophysiology of neuropathic pain. Nerve damage triggers pathological changes in the affected neurons, but it is still not entirely clear which of the identified disorders determine the initiation and long-term existence of neuropathic pain. In patients with polyneuropathy, not all neurons in the peripheral nerve are damaged simultaneously. It has been found that pathological interactions of peripheral sensory fibers play an important role in maintaining the existence of neuropathic pain: during degeneration of efferent nerve fibers, spontaneous ectopic neuronal activity, sensitization of neurons against the background of expression of cytokines and neurotrophic factors are observed in the adjacent intact C-fibers. All this may indicate the significance of damage to thick nerve fibers in the pathogenesis of pain disorders.

Serotonin plays an important role in the sensitization of nerve fibers and the occurrence of thermal hyperalgesia in neuropathic pain, the action of which is mediated by 5-hydroxytryptamine 3 receptors. Pain conduction is associated with four main types of sodium channels: Nav1.3, Nav1.7, Nav1.8 and Nav1.9. An increase in the number of Na channels creates conditions for the development of neurogenic inflammation and secondary central sensitization. It has been shown that Nav1.7, Nav1.8, Nav1.9 channels are expressed on thin nociceptive fibers and participate in the conduction of pain afferentation.

Increased expression of both Nav1.3, which is normally only slightly present in the peripheral nervous system in adults, and Nav 1.6 may play an important role in increasing neuronal excitability and the development of neuropathic pain in peripheral nerve and spinal cord injury. These changes are observed 1-8 weeks after the onset of mechanical allodynia. In addition, decreased potassium permeability in myelin fibers may contribute to increased neuronal excitability.

In neuropathic pain, a lower activation threshold of Ap and A5 fibers to mechanical stimulation is revealed. Increased spontaneous activity was found in C fibers. Hyperalgesia to pain stimuli in patients with polyneuropathy may be associated with an increase in the level of cyclooxygenase-2, PG2 in both dorsal ganglion neurons and the posterior horns of the spinal cord, activation of sorbitol and fructose accumulation, which indicates the importance of spinal cord conduction tracts in the formation and conduction of neuropathic pain.

In the spinothalamic tract of rats, high spontaneous activity, an increase in receptor fields, as well as a lower threshold of neuronal response to mechanical stimulation are recorded. Neurogenic inflammation in experimental diabetic polyneuropathy in the case of pain manifestations is expressed to a greater extent in comparison with non-diabetic neuropathic pain disorders. It was found that allodynia occurring in diabetic polyneuropathy is a consequence of the death of C-fibers with subsequent central sensitization, damage to Ab-fibers perceiving cold stimuli leads to cold hyperalgesia. Voltage-dependent calcium N-channels located in the posterior horn of the spinal cord participate in the formation of neuropathic pain.

There is evidence of increased neurotransmitter release upon activation of voltage-dependent calcium channels. It is suggested that the a2D-1 subunit, which is part of all voltage-dependent calcium channels, is the target for the antiallodynic action of gabapentin. The density of calcium channels with the a2D-1 subunit is increased in induced diabetes mellitus, but not in vincristine polyneuropathy, indicating different mechanisms of allodynia in different types of polyneuropathies.

ERK (extracellular signal-regulated protein kinase)-dependent signaling plays an important role in growth factor-induced proliferation reactions, cell differentiation and cytotransformational changes. In experimental models of diabetes mellitus, rapid activation of both MARK kinase (the mitogen-activated protein kinase) and extracellular signal-regulated kinase (ERK 1 and 2), a component of the ERK cascade, is detected, correlating with the onset of streptosycin-induced hyperalgesia.

It was revealed in experimental models that the use of tumor necrosis factor TNF-a associated with the activation of MAPK (p38 mitogen-activated protein kinase) in polyneuropathy leads to an increase in hyperalgesia not only in the affected fibers, but also in intact neurons, which can determine various features of pain syndromes. In hyperalgesia, the activation of kinase A plays an important role in the pathogenesis of pain syndrome. Also, in the pathogenesis of pain in experimental models of diabetic polyneuropathy, the significance of local hyperglycemia in inducing mechanical hyperalgesia was revealed.

The most common clinical variants of sensory polyneuropathies are: distal symmetric polyneuropathy (DSP), distal small fiber sensory polyneuropathy (DSSP), sensory neuronopathy (SN).

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Symptoms sensory neuropathies

Sensory neuropathies reveal negative symptoms of sensitivity impairment: hypoesthesia/hypalgesia in the form of gloves and socks, lower abdomen. Similar symptoms most often occur in chronic inflammatory demyelinating polyneuropathies, in vitamin B12 and E deficiency, vitamin B6 intoxication, and paraneoplastic polyneuropathies. Impaired peripheral sensitivity is associated with the death or cessation of functioning of at least half of the afferent fibers. These changes are expressed to varying degrees depending on how quickly the sensory fibers are damaged.

If the process is chronic and occurs slowly, loss of superficial sensitivity is difficult to detect during examination when even a small number of sensory neurons are functioning. In the case of rapidly developing damage to nerve fibers, positive symptoms are recorded more frequently, which are well recognized by patients, compared with clinical neuropathic manifestations that develop as a result of slowly progressing deafferentation. Disorders of sensitivity at the preclinical stage, not detected during examination, can be detected by studying the conduction along sensory nerves or somatosensory evoked potentials.

Positive sensory symptoms include:

• pain syndrome in diabetic, alcoholic, amyloid, paraneoplastic, toxic polyneuropathies, vasculitis, neuroborreliosis, metronidazole intoxication;
• paresthesia (a feeling of numbness or crawling without causing irritation);
• burning sensation;
• hyperesthesia;
• hyperalgesia;
• dysesthesia;
• hyperpathy;
• allodynia.

The appearance of positive symptoms is associated with the regeneration of axonal processes. When the fibers conducting deep sensitivity are damaged, sensory ataxia develops, characterized by unsteadiness when walking, which intensifies in the dark and with closed eyes. Motor disorders are characterized by peripheral paresis, starting from the distal parts of the lower extremities. Sometimes the muscles of the trunk, neck, craniobulbar muscles are involved in the process (in porphyria, lead, amyloid, CIDP, paraneoplastic polyneuropathy, Guillain-Barré syndrome). The maximum development of hypotrophy is observed by the end of the 3-4th month.

In the presence of spontaneous ectopic generation of nerve impulses, neuromyotonia, myokymia, cramps, and restless legs syndrome occur as a result of regeneration. Vegetative symptoms that appear as a result of damage to vegetative fibers can be divided into visceral, vegetative-vosomotor, and vegetative-trophic. Visceral symptoms appear as a result of the development of autonomic polyneuropathy (diabetic, porphyric, amyloid, alcoholic, and other toxic polyneuropathies, as well as Guillain-Barré syndrome).

Forms

Classification of neuropathies based on the types of affected sensory nerve fibers (Levin S., 2005, Mendell JR, SahenkZ., 2003).

• Sensory neuropathies with predominant damage to thick nerve fibers:
  • Diphtheria neuropathy;
  • Diabetic neuropathy;
  • Acute sensory ataxic neuropathy;
  • Dysproteinemic neuropathy;
  • Chronic inflammatory demyelinating polyradiculoneuropathy;
  • Neuropathy in biliary cirrhosis of the liver;
  • Neuropathy in critical illness.
• Sensory neuropathies with predominant damage to thin nerve fibers:
  • Idiopathic small fiber neuropathy;
  • Diabetic peripheral neuropathy;
  • MGUS neuropathies;
  • Neuropathies in connective tissue diseases;
  • Neuropathies in vasculitis;
  • Hereditary neuropathies;
  • Paraneoplastic sensory neuropathies;
  • Hereditary amyloid neuropathy;
  • Acquired amyloid neuropathy;
  • Neuropathy in renal failure;
  • Congenital sensory autonomic polyneuropathy;
  • Polyneuropathy in sarcoidosis;
  • Polyneuropathy in arsenic poisoning;
  • Polyneuropathy in Fabry disease;
  • Polyneuropathy in celiac disease;
  • Polyneuropathy in HIV infection.

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Diagnostics sensory neuropathies

Methods of clinical diagnostics

It is necessary to test different sensory fibers, since selective involvement of thin and/or thick nerve fibers is possible. It is necessary to take into account that sensitivity decreases with age and depends on the individual characteristics of the patient (ability to concentrate and understand the task). A relatively simple and quick method is to use nylon monofilaments, ordinary needles or pins.

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Pain sensitivity study

The examination begins with determining pain sensitivity. The pain threshold (unmyelinated C-fibers) is determined by applying objects with high and low temperatures or using regular needles or weighted needles (prick testers). The examination of pain sensitivity begins with studying complaints. The most common complaints include pain; when questioning the patient, the nature of the pain is determined (sharp, dull, shooting, aching, squeezing, stabbing, burning, etc.), its prevalence, whether it is constant or occurs periodically. Sensations are examined when certain stimuli are applied; it is determined how the patient perceives them. The pricks should not be too strong and frequent. First, it is determined whether the patient can distinguish a prick or a touch in the area under examination. To do this, the skin is touched alternately, but without the correct sequence, with a blunt or sharp object, and the patient is asked to determine “sharp” or “dull”. The injections should be short and not cause sharp pain. To clarify the boundaries of the zone of altered sensitivity, studies are carried out both from the healthy area and in the opposite direction.

Temperature sensitivity study

Impaired warm/cold discrimination is the result of damage to the thin, weakly and unmyelinated nerves responsible for pain sensitivity. To study temperature sensitivity, test tubes with hot (+40 °C... +50 °C) and cold (not higher than +25 °C) water are used as stimuli. Studies are conducted separately for heat (implemented by A5 fibers) and cold sensitivity (C fibers), since they can be impaired to varying degrees).

Tactile sensitivity

This type of sensitivity is provided by large myelinated A-a and A-p fibers. Frey's apparatus (horse hair of different thickness) and its modern modifications can be used.

Deep Sensitivity Research

Only the functions of thick myelinated fibers are assessed.

Vibration sensitivity: the threshold of vibration sensitivity is usually assessed at the tip of the big toe and at the lateral malleolus. A calibrated tuning fork is used, the stem of which is placed on the head of the first tarsal bone. The patient must first feel the vibration, and then say when it stops. At this point, the researcher reads the values of 1/8 octave on one of the scales applied to the tuning fork. Values less than 1/4 octave are pathological. The test is repeated at least three times. The vibration amplitude increases gradually. A tuning fork designed for a frequency of 128 Hz is usually used (if the tuning fork is not calibrated, vibration is normally felt for 9-11 seconds). Vibration sensitivity impairment indicates impairment of deep sensitivity.

Joint-muscle feeling associated with activation in the joint capsule and tendon endings of muscle spindles during locomotion, is assessed during passive movement in the joints of the extremities. Instrumental methods for studying sensory neuropathies. Electromyography as a method for functional diagnostics of sensory neuropathies.

The key to diagnosing the characteristics of nerve fiber damage is electromyography (EMG), which studies the functional state of nerves and muscles. The object of study is the motor unit (MU) as a functional key link in the neuromuscular system. MU is a complex consisting of a motor cell (motor neuron of the anterior horn of the spinal cord), its axon and a group of muscle fibers innervated by this axon. MU has functional integrity, and damage to one section leads to compensatory or pathological changes in the remaining sections of MU. The main tasks solved during EMG: assessment of the condition and functioning of the muscle, nervous system, detection of changes at the level of neuromuscular transmission.

The following examination methods are used when conducting EMG:

Needle EMG:

1. Study of individual motor unit potentials (IMPs) of skeletal muscles;
2. Interference curve study with Willison analysis;
3. Total (interference) EMG;

Stimulation EMG:

1. Study of the M-response and the velocity of excitation propagation along motor fibers (VEPm);
2. Study of the action potential of the nerve and the velocity of excitation propagation along sensory fibers (SRVs);
3. Study of late neurographic phenomena (F-wave, H-reflex, A-wave);
4. Rhythmic stimulation and determination of the reliability of neuromuscular transmission.

The diagnostic value of the methods varies and often the final diagnosis is made based on the analysis of many indicators.

Needle EMG

Spontaneous activity is also studied under minimal muscle tension, when potentials of individual motor units are generated and analyzed. Several phenomena of spontaneous activity are revealed in the resting state during pathological changes in muscles.

Positive sharp waves (PSW) are observed in irreversible degeneration of muscle fibers and are an indicator of irreversible changes in the death of muscle fibers. Larger PSWs, with increased amplitude and duration, indicate the death of entire complexes of muscle fibers.

Fibrillation potentials (FP) are potentials of a single muscle fiber that arise as a result of denervation during traumatic or other damage to any part of the motor unit. They occur most often on the 11th-18th day from the moment of denervation. Early occurrence of FP (on the 3rd-4th day) is an unfavorable prognostic sign indicating significant damage to nerve fibers.

Fasciculation potentials (FPs) are spontaneous activity of the entire motor unit. They occur in various variants of MU damage, FPs are characteristic of the neuronal process. Some phenomena of spontaneous activity are nosologically specific (myotonic discharges in myotonia).

During muscle tension, motor unit potentials (MUPs) are recorded. The main MU parameters are amplitude, duration, and degree of polyphasy, which change during MU pathology in the form of functional and histological restructuring. This is reflected in the EMG stages of the denervation-reinnervation process (DRP). The stages differ in the nature of the distribution of MU duration histograms, changes in the average, minimum, and maximum MU duration relative to the norms specified in the tables. A comprehensive analysis of the electrical activity of the muscle allows us to identify the nature of compensatory changes in the muscle as a result of the pathological process.

The restructuring of the DE accurately reflects the level of damage to the DE sections: muscular, axonal, neuronal.

Study of the M-response and the speed of excitation propagation along the motor nerves.

Allows to study the functioning of the motor fibers of the peripheral nerve and, indirectly, to judge the condition of the muscle. The method allows to determine the level of damage to the nerve fiber, the nature of the damage (axonal or demyelinating), the degree of damage, the prevalence of the process. With indirect stimulation of the peripheral nerve, an electrical response (M-response) occurs from the muscle innervated by this nerve. The axonal process is characterized by a significant decrease (below normal values) in the amplitude of the M-response obtained with distal stimulation (distal M-response), as well as at other stimulation points, speed indicators suffer to a lesser extent.

Demyelinating lesions are characterized by a decrease in SRVM by 2-3 times (sometimes by an order of magnitude). The magnitude of the amplitude of the distal M-response suffers to a lesser extent. It is important in the study of the M-response to determine the residual latency (RL) reflecting conductivity along the most terminal branches of the nerve, an increase of which indicates pathology of the terminal branches of axons.

Late neurographic phenomena F-wave and H-reflex

The F-wave is a muscle response to an impulse sent by a motor neuron as a result of its excitation by an antidromic wave that occurs during distal indirect stimulation of the nerve by a current of supramaximal magnitude (in relation to the M-response). By its nature, the F-wave is not a reflex, and the impulse passes twice along the most proximal sections of the nerve, the motor roots. Therefore, by analyzing the parameters of the time delay (latency) and the speed of propagation of the F-wave, we can judge the conductivity along the most proximal sections. Since the secondary response is caused by antidromic stimulation of the motor neuron, then by analyzing the degree of variability of the amplitude and latency of the F-wave, we can judge the excitability and functional state of the motor neurons.

The H-reflex is a monosynaptic reflex. In adults, it is normally evoked in the calf muscles by stimulation of the tibial nerve with a current of submaximal (relative to the M-response) magnitude. The impulse passes along the sensory fibers, then along the posterior roots, and switches to motor neurons. Excitation of motor neurons leads to muscle contraction. Since the impulse passes up along the sensory and down along the motor axons, it is possible to assess conductivity along the proximal sections of the sensory and motor pathways. When analyzing the ratio of the amplitude of the H-reflex and the M-response with an increase in the stimulus strength, the degree of excitability of the reflex arc and the integrity of its elements are studied. By calculating the latency of the H-reflex and F-wave, when stimulating from one point, it is possible to determine with sufficient accuracy the lesion of the sensory or motor section of the reflex arc.

Nerve action potential and sensory conduction studies

The method allows to identify damage to sensory fibers, which is especially important in dissociated polyneuropathy.

Somatosensory evoked potentials (SSEPs)

Somatosensory evoked potentials (SSEPs) used in diagnostics of distal small fiber neuropathy are a universal method for diagnostics of afferent sensory systems. However, since SSEPs are recorded with non-selective stimulation of nerves, the recorded response reflects excitation of thick nerve fibers. To assess the function of thin A-6 and C fibers, as well as the pathways of pain and temperature sensitivity, methods of stimulating unmyelinated C fibers with pain and temperature exposure, and weakly myelinated A-6 fibers with thermal stimulation are used. Depending on the type of stimulator, these methods are divided into laser and contact heat-evoked potentials (Contact Heat-Evoked Potential-CH EP). In patients with neuropathic pain in the initial stage of polyneuropathy, despite the normal density of epidermal nerves, a decrease in the amplitude of the CHEP response is noted, which allows using this method for early diagnostics of distal sensory polyneuropathy of thin fibers.

The use of this research method is limited by fluctuations in results against the background of analgesic therapy and undifferentiated stimulation of the central or peripheral sensory systems.

Biopsy of nerves, muscles, skin

Nerve and muscle biopsy is necessary for differential diagnosis of axonal and demyelinating neuropathies (in the first case, axonal degeneration of neurons, groups of muscle fibers of types I and II are determined, in the second - “onion heads” in nerve biopsy, in muscle biopsy - groups of muscle fibers of types I and II.

Skin biopsy is performed in sensory neuropathy with predominant damage to fine fibers (reduced density of unmyelinated and weakly myelinated nerve cells in the skin is revealed).

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Confocal microscopy

Confocal microscopy is a modern non-invasive method that allows obtaining information about the density, length, and morphology of unmyelinated C-fibers in the cornea. Its use is appropriate for monitoring the process of damage to fine fibers in Fabry disease, diabetic neuropathy, in the latter case, a correlation is noted between the severity of diabetic polyneuropathy, a decrease in the density of epidermal fibers with denervation-regeneration processes in the cornea.

To diagnose sensory polyneuropathies, it is necessary to: collect anamnesis with careful identification of concomitant somatic nosologies, nutritional characteristics, family history, infectious diseases preceding neuropathic manifestations, the patient's work with toxic substances, the fact of taking medications, a thorough neurological and physical examination to identify thickenings characteristic of amyloidosis, Refsum disease, demyelinating variant of Charcot-Marie-Tooth, performing ENMG, biopsy of cutaneous nerves (to exclude amyloidosis, sarcoidosis, CIDP), examination of cerebrospinal fluid, blood (clinical and biochemical blood tests), chest X-ray, ultrasound of internal organs.

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