Sensory Neuropathies

The defeat of the peripheral nervous system, leading to the development of polyneuropathy, determines the disability, disability in this category of patients. When considering clinical symptoms in patients with neuropathy, symmetry, the 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 evaluated.

[1], [2], [3], [4], [5], [6], [7]

Causes of the sensory neuropathies

Important role in the development of a number of neuropathies is played by gangliosides. Gangliosides form a family of acid sialized glycolipids, consisting of carbohydrate and lipid components. They are mainly located in the outer layer of the plasma membrane. The external arrangement of carbohydrate residues suggests that such carbohydrates act as antigen targets in autoimmune neurological disorders. Molecular mimicry between gangliosides and bacterial carbohydrate antigens (especially bacterial lipopolysaccharide) can be a key factor in the development of a number of diseases (Miller-Fisher syndrome, Bickerstaff encephalitis, neuropathy with anti-MAG antibodies).

Antiganglioside antibodies can cross-react with other glycolipids and glycoproteins (HNK1-epitope), including myelin glycoprotein-P0, PMP-22, glycolipids with sulfglucuronyl-paraglobazide and with sulfglucuronyl-lactosaminyl paraglobazide. Recently, an association between cytomegalovirus infection and anti-GM2 antibodies has been described. Antibodies that bind to carbohydrate antigens like anti-ganglioside or anti-MAG (myelin associated glycoprotein) have been found in a variety of peripheral neuropathies. In patients with sensory neuropathies, signs of vegetative and motor fibers can be observed.

[8], [9], [10], [11], [12]

Pathogenesis

From the positions of pathophysiology, nociceptive and neuropathic pain are now isolated. Nociceptive is the pain caused by the action of a damaging factor on pain receptors, with the intactness of other parts of the nervous system. By neuropathic is meant pain arising from organic damage or dysfunction of various parts of the nervous system. 

In the evaluation and diagnosis of neuropathic pain in patients with polyneuropathy, the distribution of neuropathic pain (the zone of innervation of the corresponding nerves, plexuses and roots) is taken into account, the relationship between the history of the disease causing neuropathic pain and localization, and the neuroanatomical distribution of pain and sensory disorders itself, and negative sensory symptoms.

Pathophysiology of pain manifestations in polyneuropathies

In view of the fact that diabetic polyneuropathy is the most frequent and difficult-to-control complication of diabetes mellitus, the pathogenesis of neuropathic pain is best studied with this nosology.

To study the pathophysiology of neuropathic pain, as a rule, experimental models are used. Nerve damage causes the start of pathological changes of affected neurons, but it is still not clear which of the detected disorders determine the initiation and prolonged existence of neuropathic pain. In patients with polyneuropathy in the peripheral nerve, not all neurons are damaged simultaneously. An important role in maintaining the existence of neuropathic pain is played by the pathological interactions of peripheral sensory fibers: spontaneous ectopic neuronal activity, neuronal sensitization against the background of expression of cytokines and neurotrophic factors, are observed in the degeneration of efferent nerve fibers in adjacent intact C fibers. All this may indicate the significance of the damage to thick nerve fibers in the pathogenesis of pain disorders.

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

The increased expression of the channels as Nav1.3, which is normal in adults only to a small extent in the peripheral nervous system, and Nav 1.6 can play an important role in increasing the excitability of neurons and the development of neuropathic pain in damage to the peripheral nerves and spinal cord. The indicated changes are observed for 1-8 weeks. After the beginning of mechanical allodynia. In addition, the weakening of permeability for potassium in myelinated fibers can contribute to an increase in the excitability of the neuron.

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

In the spinal cord of rats, high spontaneous activity, an increase in receptor fields, as well as a lower threshold of neuronal response in response to mechanical stimulation are recorded. Neurogenic inflammation in experimental diabetic polyneuropathy in the case of pain manifestations is more pronounced in comparison with nondiabetic neuropathic pain disorders. It was found that allodynia, which occurs with diabetic polyneuropathy, is a consequence of the death of C-fibers with further central sensitization, damage to Ab-fibers that perceive cold stimuli leads to cold hyperalgesia. Voltages-dependent calcium N-channels located in the posterior horn of the spinal cord participate in the formation of neuropathic pain.

There is evidence of an increase in the release of neurotransmitters in the activation of voltage-dependent calcium channels. It is assumed that the a2D-1 subunit, which is part of all voltage-dependent calcium channels, is the target for the anti-allodynic action of gabapentin. Density of calcium channels with a2D-1 subunit is increased in case of induced diabetes mellitus, but not in vincristine polyneuropathy, which indicates different mechanisms of allodynia with different types of polyneuropathies.

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

It was found in experimental models that the use of tumor necrosis factor TNF-a associated with 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 different features 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 with 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 sensory polyneuropathy of fine fibers (DSPT), sensory neuronopathy (SN).

[13], [14], [15], [16], [17], [18], [19]

Symptoms of the sensory neuropathies

Sensory neuropathy reveals negative symptoms of sensitivity disorder: hypoesthesia / hypalgesia in the form of gloves and socks, lower abdomen. Similar symptoms most often occur with chronic inflammatory demyelinating polyneuropathies, with deficiency of vitamins B12 and E, intoxication with vitamin B6, with paraneoplastic polyneuropathies. Violation of peripheral sensitivity is associated with the death or disruption of at least half of the afferent fibers. These changes can be expressed in varying degrees depending on how rapidly the sensitive fibers attack.

If the process is chronic and occurs slowly, the loss of surface sensitivity during examination is difficult to detect with the functioning of even a small number of sensory neurons. In the case of a rapidly developing nerve fiber lesion, positive symptoms are detected with greater frequency, well recognized by patients, in comparison with clinical neuropathic manifestations that develop as a result of slowly progressive deafferentation. Sensitivity disorders in the preclinical stage, not detectable during examination, can be detected by the study of sensory nerves or somatosensory induced potentials.

Positive sensory symptoms include:

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

The appearance of positive symptoms is associated with the regeneration of axonal processes. With the defeat of fibers that conduct deep sensitivity, develops a sensitive (sensitive) ataxia, characterized by shaky walking, which increases in the dark and with closed eyes. Motor disorders are characterized by peripheral paresis, beginning with the distal parts of the lower extremities. Sometimes the muscles of the trunk, neck, craniobulbar musculature are involved in the process (with porphyria, lead, amyloid, CVD, paraneoplastic polyneuropathy, Guillain-Barre syndrome). The maximum development of hypotrophy is observed at the end of 3-4 months.

In the presence of spontaneous ectopic generation of nerve impulses due to regeneration, neuromyotonia, myochemia, krampi, restless legs syndrome occur. The vegetative symptoms that appear as a result of the defeat of vegetative fibers can be divided into visceral, vegetative-vozomotornye and vegetative-trophic. Visceral symptoms appear due to the development of autonomic polyneuropathy (diabetic, porphyria, amyloid, alcoholic and other toxic polyneuropathies, and Guillain-Barre syndrome).

Forms

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

• Sensory neuropathies with predominant lesion of thick nerve fibers:
  • Diphtheria neuropathy;
  • Diabetic neuropathy;
  • Acute sensory ataxic neuropathy;
  • Disproteinemic neuropathy;
  • Chronic inflammatory demyelinating polyradiculoneuropathy;
  • Neuropathy with biliary cirrhosis;
  • Neuropathy in critical conditions.
• Sensory neuropathies with predominant involvement of thin nerve fibers:
  • Idiopathic neuropathy of fine fibers;
  • Diabetic peripheral neuropathy;
  • MGUS neuropathies;
  • Neuropathy in connective tissue diseases;
  • Neuropathy with vasculitis;
  • Hereditary neuropathies;
  • Paraneoplastic sensory neuropathies;
  • Hereditary amyloid neuropathy;
  • Acquired amyloid neuropathy;
  • Neuropathy with renal insufficiency;
  • Congenital sensory autonomic polyneuropathy;
  • Polineuropathy in sarcoidosis;
  • Polineuropathy for arsenic poisoning;
  • Polyneuropathy with Fabry disease;
  • Polyneuropathy with celiac disease;
  • Polineuropathy in HIV infection.

[20], [21], [22], [23], [24]

Diagnostics of the sensory neuropathies

Methods of clinical diagnosis

It is necessary to test various sensory fibers, since selective involvement of thin and / or thick nerve fibers is possible. It should be borne in mind that sensitivity decreases with age and depends on the individual characteristics of the patient (ability to concentrate and understand the problem). A relatively simple and quick way is to use nylon monofilaments, conventional needles or pins.

[25], [26], [27], [28], [29]

Study of pain sensitivity

Studies begin with the definition of pain sensitivity. The threshold of pain sensitivity (unmyelinated C-fibers) is determined by applying objects with a high and low temperature or by using normal needles or weighted needles (needle). The study of pain sensitivity begins with the study of complaints. Among the most frequent complaints include a complaint of pain, when asking a patient to find out the nature of the pain (acute, blunt, shooting, aching, constricting, stitching, burning, etc.), its prevalence, whether it is permanent or occurs intermittently. Sensations are investigated when certain irritations are applied; it turns out how the patient perceives them. The injections should not be too strong and frequent. First, it is determined whether the patient distinguishes between an injection and a touch. For this, alternately, but without the correct sequence, they touch the skin with a blunt or sharp object, and the patient is offered to define "sharply" or "stupidly". The injections should be short, not causing severe pain. To clarify the boundaries of the zone of altered sensitivity, studies are conducted from both the healthy site and in the opposite direction.

Investigation of temperature sensitivity

Violation of the distinction between warm and cold is the result of the defeat of thin weakly and non-myelinated nerves, responsible for pain sensitivity. To test the temperature sensitivity, tubes with a hot (+40 ° C ... +50 ° C) and cold (not higher than +25 ° C) water are used as stimuli. Studies are carried out separately for thermal (realized by A5-fibers) and cold sensitivity (C-fibers), since they can be broken to varying degrees).

Tactile Sensitivity

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

Investigation of deep sensitivity

The functions of only thick myelinated fibers are evaluated.

Vibration sensitivity: the threshold of vibration sensitivity is usually estimated at the tip of the big toe and on the lateral ankle. Use a calibrated tuning fork, the leg of which is mounted on the head of the first tarsal bone. The patient must first feel the vibration, and then say when it will stop. The researcher at this moment reads one of the values of 1/8 octave applied to the tuning fork. Pathological values are less than 1/4 octave. The test is repeated at least three times. Amplitude of vibration increases gradually. Usually a tuning fork is used, calculated for a frequency of 128 Hz (if the tuning fork is not calibrated, normally the vibration is felt for 9-11 seconds). Violation of vibration sensitivity indicates a violation of deep sensitivity.

The joint-muscular feeling associated with the activation in the capsule of joints and tendon ends of muscle spindles in locomotion is assessed with passive movement in the joints of the limbs. Instrumental methods for the study of sensory neuropathies. Electromyography as a method of 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 (DE) as a functional key link in the neuromuscular system. DE is a complex consisting of a motor cell (motoneuron of the anterior horn of the spinal cord), its axon and a group of muscular fibers innervated by this axon. DE has a functional integrity, and the defeat of one department leads to compensatory or pathological changes in the remaining departments of DE. The main tasks solved during the EMG: assessment of the condition and functioning of the muscle, the nervous system, the detection of changes at the level of neuromuscular transmission.

The following methods of examination are distinguished during EMG:

Needle EMG:

1. Investigation of individual potentials of motor units (PDE) of skeletal muscles;
2. Investigation of an interference curve with Wilson analysis;
3. Total (interference) EMG;

Stimulation EMG:

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

Diagnostic value of the techniques is different and often the final diagnosis is based on the analysis of many indicators.

Needle EMG

Spontaneous activity is also studied with minimal muscle tension, when the potentials of individual DE are generated and analyzed. In the state of rest, several phenomena of spontaneous activity are revealed in pathological changes in muscles.

Positive acute waves (POV) are observed with irreversible degeneration of muscle fibers, are an indicator of irreversible changes in the death of muscle fibers. Enlarged POW, increased amplitude and duration, indicate the death of whole complexes of muscle fibers.

Fibrillation potentials (PF) are the potentials of an individual muscle fiber, resulting from denervation in the traumatic or other lesions of any department of DE. Arise more often on 11-18 day from the moment of denervation. Early onset of PF (3-4 days) is an unfavorable prognostic sign, indicating significant damage to nerve fibers.

Potentials of fasciculations (PFc) spontaneous activity of the whole motor unit. Arise with different variants of lesion DE, PFc are characteristic for the neuronal process. Some phenomena of spontaneous activity are nosologically specific (myotonic discharges in myotonia).

At muscular tension, the potentials of motor units (PDE) are recorded. The main parameters of PDE are the amplitude, duration, degree of polyphasia, which change in the pathology of DE in the form of functional and histological reorganization. This is reflected in the EMG stages of the denervation-re-reinvation process (DRP). The stages differ in the nature of the distribution of the histograms of the duration of the PDE, the change in the mean, minimum and maximum duration of the PDE relative to the norms indicated in the tables. A complex analysis of the electrical activity of the muscle makes it possible to reveal the nature of compensatory changes in the muscle as a result of the pathological process.

The restructuring of the DE structure accurately reflects the level of lesion of the DE departments: muscular, axonal, neuronal.

Investigation of the M-response and the rate of propagation of excitation along the motor nerves.

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

Demyelinating damage is characterized by a decrease in SRVm in 2-3 times (sometimes by an order of magnitude). The magnitude of the amplitude of the distal M-response suffers to a lesser extent. Important in the study of the M-response is the determination of the reflective conductivity of the terminal nerve of residual latency (RL), the increase of which indicates a pathology of terminal branches of axons.

Later neurographic phenomena F-wave and H-reflex

F-wave is the response of the muscle to the impulse sent by motoneuron as a result of excitation by its antidromic wave, which occurs in the course of distal indirect stimulation of the nerve with a current of supramaximal (in relation to the M-response) value. By its nature, the F-wave is not a reflex, while the pulse twice passes through the most proximal nerve segments to the motor roots. Therefore, analyzing the parameters of the time delay (latency) and the propagation velocity of the F wave, we can judge the conductivity in the most proximal areas. Since the secondary response is due to antidromic stimulation of motoneuron, then, by analyzing the degree of variability in the amplitude and latency of the F wave, one can judge the excitability and functional state of motoneurons.

The H-reflex is a monosynaptic reflex. In adults, it is normally caused in the muscles of the tibia by stimulation of the tibial nerve with a submaximal (in relation to the M-response) current. The impulse passes the path along the sensory fibers, then along the back roots, switches to motoneurons. Excitation of motoneurons leads to muscle contraction. Since the pulse travels up the sensory, and down the motor axons, it is possible to evaluate the conductivity along the proximal sections of the sensory and motor tracts. When analyzing the ratio of the amplitude of the H-reflex and the M-response when the stimulus strength increases, the degree of excitability of the reflex arc and the safety 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 accurately determine the defeat of the sensory or motor section of the reflex arc.

Investigation of the potential of nerve action and sensory conduction

The method allows to reveal the damage of sensory fibers, which is especially important for dissociated polyneuropathy.

Somatosensory evoked potentials (SSVP)

Used in the diagnosis of distal neuropathy of fine fibers, somatosensory evoked potentials (SSVP) are a universal method for the diagnosis of afferent sensory systems. However, since the registration of the SSEP occurs with indiscriminate stimulation of nerves, the recorded response reflects the excitation of thick nerve fibers. To evaluate the function of thin A-6 and C-fibers, as well as conductive ways of pain and temperature sensitivity, methods of stimulation of unmyelinated C-fibers by painful temperature influence, weakly myelinated A-6 fibers by thermal stimulation are used. Depending on the type of stimulant, these techniques 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, in spite of the normal density of the epidermal nerves, there is a decrease in the amplitude of the CHEP response, which allows using this method for early diagnosis of distal sensory polyneuropathy of fine fibers.

Limits the application of this method of research to the fluctuation of results against the background of analgesic therapy, undifferentiated stimulation of central or peripheral sensory systems.

Biopsy of nerves, muscles, skin

Biopsies of nerves and muscles are necessary for the differential diagnosis of axonal and demyelinating neuropathies (in the first case, axonal degeneration of neurons, grouping of muscle fibers of types I and II, in the second - "bulbous heads" with biopsy of nerves, muscle biopsy - grouping of muscle fibers I and II types.

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

[30], [31], [32], [33], [34]

Confocal microscopy

Confocal microscopy is a modern non-invasive method that provides information on the density, length, morphology of unmyelinated C-fibers in the cornea. Its use is useful for monitoring the process of damage to fine fibers in Fabry's disease, diabetic neuropathy, in the latter case, there is a correlation of the severity of diabetic polyneuropathy, a decrease in the density of epidermal fibers with the denervation and regeneration processes of the cornea.

For the diagnosis of sensory polyneuropathies, it is necessary to: collect an anamnesis with a careful identification of concomitant somatic nosologies, nutrition characteristics, hereditary anamnesis, neuropathic manifestations of infectious diseases, the work of a patient with toxic substances, the fact of taking medications, a thorough neurological and physical examination with the detection of thickening characteristic of amyloidosis , diseases of Refsum, demyelinating variant of Charcot-Marie-Toot, carrying out ENMG, biopsy of cutaneous nerves (for the claim (clinical and biochemical blood tests), chest X-ray, ultrasound of internal organs.

[35], [36], [37], [38], [39], [40], [41],