Causes and pathogenesis of polyneuropathy

The pathogenesis of polyneuropathic syndromes is a very complex problem. Specific mechanisms of development of polyneuropathic disorders in various forms of pathology have not been fully studied. These difficulties are primarily associated with the diversity of nosological forms capable of causing damage to the peripheral nervous system; from these forms, it is necessary to single out a single one by excluding all the others. The difficulty also consists in the need to determine to what extent this pathology contributes to the development of neuropathy. Based on this, for each disease, one should assume its own mechanisms by which polyneuropathic syndromes are formed.

There are several types of reaction mechanisms of the peripheral nervous system:

1. Wallerian degeneration (reaction to nerve transection);
2. axon atrophy and degeneration;
3. segmental demyelination;
4. primary damage to the bodies of nerve cells. The last three processes are referred to as axonopathy, myelinopathy, and neuronopathy.

Wallerian degeneration is caused by mechanical damage. Paralysis and loss of sensitivity immediately occur in the innervation zone of the trunk. Distal to the site of damage, degeneration of axons and myelin sheaths occurs. The quality of recovery depends on the degree of destruction of lemmocytes (Schwann cells), the nerve sheath, and surrounding soft tissues. Other factors may also play a significant role: focal and multifocal ischemia of the trunk may cause distal degeneration over a large area if blood flow is sharply reduced, which is observed in systemic vasculitis.

Myelinopathy means damage to the myelin sheaths while preserving the axons. The most significant functional manifestation of demyelination is conduction block. Demyelination and remyelination can occur quickly and often end in complete recovery within a few days and weeks. The prognosis for this type is more favorable and recovery is faster.

Axonopathy is based on metabolic disturbances in neurons, leading to distal axonal decay. Clinically, this is manifested by distal symmetrical polyneuropathy. Usually, the development of axonal degeneration of the peripheral nerve is observed in systemic metabolic diseases and the action of exogenous toxins, but the exact sequence of changes in the nervous tissue that result in axonopathy remains unclear.

Neuronopathy means primary destruction of the nerve cell body. If the anterior horn cells are the target, motor neuronopathy occurs. Sensory neuronopathy affects the dorsal root ganglion cells, often causing severe sensory disturbances. Examples include acute sensory neuronopathy, inflammatory diseases of the dorsal root ganglia and cranial ganglia in carcinomatosis, herpes zoster, and toxic conditions. Clinically, neuronopathies are characterized by poor recovery.

In a number of forms of peripheral neuropathies, changes in peripheral vegetative formations are simultaneously detected. The pathological process mainly involves the main vegetative ganglia, unmyelinated visceral fibers, the vagus nerve and smooth muscles. Pathologically altered neurons are found in the sympathetic ganglia, which are significantly larger than normal ones. Lymphocytic infiltrates, macrophages and plasma cells are found along the accumulations of vegetative nerves and ganglia. Sometimes, plexuses of unmyelinated axons are found in lemmocytes in perivascular areas or in abdominal organs. These plexuses closely border on nerve nodes, histologically resembling neuromas, and can reproduce the picture of atypical axonal degeneration. Pronounced demyelination of the vagus nerve can be observed in patients with diabetic and alcoholic neuropathy.

Pathogenesis of polyneuropathy

Regardless of the etiologic factor, two types of pathological processes are identified in polyneuropathies - axon damage and demyelination of the nerve fiber. Both processes are closely interconnected: with an axonal type of damage, secondary demyelination occurs, and with a demyelinating lesion, an axonal component joins secondarily. Most toxic polyneuropathies, the axonal type of Guillain-Barré syndrome, and type II NMSN are primarily axonal. Primary demyelinating polyneuropathies include the classic version of Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, paraproteinemic polyneuropathies, and type I NMSN.

In axonal polyneuropathies, the transport function of the axial cylinder is primarily affected, carried out by the axoplasmic current, which carries a number of biological substances necessary for the normal functioning of nerve and muscle cells in the direction from the motor neuron to the muscle and back. The process primarily involves nerves containing the longest axons. Changes in the trophic function of the axon and axonal transport lead to the appearance of denervation changes in the muscle. Denervation of muscle fibers stimulates the development of terminal and then collateral sprouting, the growth of new terminals and reinnervation of muscle fibers, which leads to changes in the structure of muscles.

In stimulation EMG, the axonal type of changes is characterized by a decrease in the amplitude of the M-response with a relatively preserved excitation conduction velocity. The process of reinnervation leads to muscle enlargement, which indirectly affects the amplitude of F-waves; an increased number of F-waves with an amplitude exceeding 5% of the amplitude of the M-response in this muscle are detected. When studying the MUAP using a needle electrode, signs of muscle fiber denervation (fibrillation potentials), muscle fiber necrosis (positive sharp waves) and reinnervation (increased duration and amplitude of the MUAP) are detected.

Clinically, damage to the motor fiber axon causes muscle weakness in the distal extremities and muscle atrophy.

Demyelination is a disruption of saltatory conduction of nerve impulses, resulting in a decrease in nerve conduction velocity. Normally, the conduction velocity of nerve impulses along the peripheral motor and sensory nerves is 40-70 m/s in the lower extremities and 50-80 m/s in the upper extremities. The most pronounced demyelination is observed in hereditary polyneuropathies, in which the conduction velocity can be 5-20 m/s (Roussy-Levy syndrome, HMSCHIII, IV types); with HMSCHIA type, the conduction velocity in the lower extremities is 25-35 m/s, in the arms - 30-38 m/s. Acquired demyelinating polyneuropathies, as a rule, are characterized by a slight decrease in conduction velocity (30-40 m/s in the lower extremities and 40-50 m/s in the upper extremities).

Demyelinating nerve damage is clinically manifested by the development of muscle weakness (often with a proximal distribution atypical for "classical" polyneuropathy), early loss of tendon reflexes, without the development of muscle atrophy. The presence of atrophy indicates an additional axonal component.

Demyelination of nerves can be caused by autoimmune aggression with the formation of antibodies to various components of the peripheral myelin protein (acquired demyelinating polyneuropathies, paraproteinemic, paraneoplastic polyneuropathies), genetic disorders (type I NMSN), exposure to exotoxins (diphtheritic polyneuropathy). Damage to the nerve axon can be caused by exposure to nerves of exogenous or endogenous toxins (uremic, alcoholic, drug-induced polyneuropathy, polyneuropathy due to poisoning with heavy metals and organic compounds), genetic factors (type II NMSN).

Some important clinical markers of individual etiologic types of polyneuropathy

Cranial polyneuropathy:

OVDP (Miller Fisher variant), diphtheria, trichloroethylene, hereditary amyloidosis, idiopathic cranial polyneuropathy.

Severe tetraplegia with sensory disturbances, bulbar and other brainstem disturbances, respiratory muscle paralysis (Landry type):

Acute inflammatory demyelinating polyneuropathy (AIDP) of Guillain-Barré, post- and parainfectious polyneuropathy, post-vaccination polyneuropathy, diphtheria, hyperthyroidism, porphyria, paraneoplastic polyneuropathy.

Predominantly motor asymmetric forms:

Post- and parainfectious polyneuropathies, lead, gold, penicillin, diabetes, vascular forms.

Polyneuropathy with predominantly proximal accentuation of paralysis:

OVDP, gold, vincrestine, hyperthyroidism, giant cell arteritis, porphyria.

Polyneuropathy with preferential involvement of the upper limbs:

Lead, mercury skin contact, acrylamide, hypoglycemia.

Polyneuropathy with paresis of the eyeball muscles:

Miller Fisher syndrome, alcohol, beriberi, Wernicke encephalopathy, hyperthyroidism, Friedreich disease, Nonne-Mariesche disease, hypertrophic form of neural muscular atrophy of the Dejerine-Sottas type.

Polyneuropathy with pupillary abnormalities:

Pandysautonomia, Miller Fisher syndrome, alcohol, diabetes, hypertrophic form of neural muscular atrophy of the Dejerine-Sottas type.

Polyneuropathy involving the trigeminal nerve: trichloroethylene, diamidine.

Polyneuropathy involving the facial nerve:

AIDP, post- and parainfectious polyneuropathy, diphtheria, amyloidosis, sarcoidosis, Melkersson-Rossenthal disease, Sjogren's syndrome, Guillain-Barré syndrome, Lyme disease, HIV infection, Tangier disease.

Polyneuropathy involving the stato-acusticus nervus:

Dinitrobenzene; streptomycin; gentamicin; Strachan-Scott syndrome described among Liberians, Nigerian "ataxic neuropathy", Jamaican neuropathy, Refsum disease, Waldenstrom disease, sarcoidosis.

Polyneuropathy with loss of pain and temperature sensitivity:

Leprosy, Tangera disease, hereditary sensory polyneuropathy types I-III, amyloidosis, scleroderma.

Polyneuropathy with spontaneous pain:

Thallium, arsenic, gold, carbon disulfide, dinitrophenol, DDT, thalidomide, vincristine, Beriberi, diabetes mellitus, Fabry disease, hereditary sensory polyneuropathy type I-II, porphyria, paraneoplastic sensory neuronopathy, periarteritis nodosa, Guillain-Barré polyneuropathy, amyloidosis, HIV-associated polyneuropathy, alcoholic polyneuropathy

Polyneuropathy with hot feet syndrome:

Isoniazid, thalidomide, alcohol, beriberi, pellagra, Strahn-Scott syndrome, Nigerian "ataxic neuropathy", uremic polyneuropathy, diabetes.

Polyneuropathy with pronounced vegetative-trophic disorders:

Pandysautonomia, arsenic, carbon disulfide, hexacarbon, acrylamide, aryl phosphate, isoniazid, thalidomide, diabetes, Fabry disease, Dejerine-Sottas muscular atrophy, hereditary sensory polyneuropathy type I-II, amyloidosis

Polyneuropathy with ulcerative-mutilation disorders:

Leprosy, arsenic, hereditary sensory polyneuropathy types I and II.

Polyneuropathy with palpable thickening of nerves:

Leprosy, acromegaly, Refsum disease, hypertrophic form of neural muscular atrophy.

Polyneuropathy with a noticeable decrease in the speed of nerve conduction:

AIDP, chronic inflammatory demyelinating polyneuropathy (CIDP), post- and parainfectious polyneuropathy, post-vaccination polyneuropathy, diphtheria, Krabbe globoid cell leukodystrophy, metachromatic leukodystrophy, Refsum disease, hypertrophic forms of neural muscular atrophy, Russy-Levi syndrome, Pellizaeus-Merzbacher disease, lead, hexochlorophene, tellurium, acetylethyltetramethyltetralin (AETT), diabetes, dysproteinemia.

Polyneuropathy with pleocytosis:

Post- or parainfectious polyneuropathy, Garin-Bujadoux-Bannwarth meningo-polyradiculopathy, paraneoplastic polyneuropathy, sarcoidosis.

Polyneuropathy with additional mononeuropathy:

Leprosy, hypothyroidism, acromegaly, amyloidosis, scleroderma, Sicca complex ("dry syndrome").

Polyneuropathy with bladder dysfunction:

AIDP, post- or parainfectious polyneuropathy, postvaccination polyneuropathy, pandysautonomia, acrylamide, aryl phosphate, diabetes, hydroxyquinoline.

Polyneuropathy with concomitant meningeal syndrome:

Parainfectious polyneuropathy, Garin-Bujadoux-strongannwarth meningopolyradiculopathy, paraneoplastic polyneuropathy, leukemic polyneuropathy, sarcoidosis.

Polyneuropathy with associated spasticity:

Mercury, aryl phosphate, pellagra, Jamaican polyneuropathy, folate deficiency syndrome, vitamin B12 deficiency, absorption and nutritional disorders, hypoglycemia, Krabbe globoid cell leukodystrophy, metachromatic leukodystrophy, Bassen-Kornzweig syndrome, Friedreich's disease, Nonne-Miriez disease, OPCA, Roussy-Levy syndrome, porphyria, paraneoplastic polyneuropathy, vascular forms, Behcet's disease.

Polyneuropathy with associated optic nerve atrophy:

Parainfectious polyneuropathy, thallium, mercury, carbon disulfide, acrylamide, isoniazid, streptomycin, Strahn-Scott syndrome, Nigerian "ataxic neuropathy", Jamaican neuropathy, diabetes, Friedreich's disease, Nonne-Maries disease, OPCA, hypertrophic form of neural amyotrophy of Dejerine-Sottas.

Polyneuropathy with papilledema:

AIDP, post- and parainfectious polyneuropathy, post-vaccination polyneuropathy.

Polyneuropathy with concomitant retinopathy:

Chloroquine, diabetes, Refsum disease, Bassen-Kornzweig syndrome.

Polyneuropathy with associated ataxia:

Miller Fisher syndrome, mercury, carbon disulfide, phenytoin, alcohol, pellagra, Nigerian ataxia-neuropathy, Jamaican neuropathy, vitamin deficiency strongi2, malabsorption and nutritional disorders, diabetes, metachromatic leukodystrophy, Refsum disease, Bassen-Kornzweig syndrome, Friedreich disease, Nonne-Mariesch disease, OPCA, Louis-Bar ataxia-telangiectasia, Marinesco-Sjogren syndrome, Roussy-Levy syndrome, paraneoplastic polyneuropathy, Machado-Joseph disease.

Polyneuropathy with associated extrapyramidal symptoms:

Lead, carbon disulfide, disulfuram, pellagra, globoid cell leukodystrophy, Nonne-Mariesch disease, OPCA, Louis-Bar syndrome.

Polyneuropathy with associated myoclonus:

Lead, carbon disulfide, gold, methyl bromide, DDT, globoid cell leukodystrophy.

Polyneuropathy with associated tremor:

Lead, acrylamide, DDT, psychotropic drugs, alcohol, Roussy-Levy syndrome.

Polyneuropathy with associated epileptic seizures:

Lead, thallium, isoniazid, alcohol, pellagra, Friedreich's disease, porphyria, periarteritis nodosa, lupus erythematosus.

Polyneuropathy with concomitant somatically conditioned psychosis:

Chronic intoxication with inorganic and organic poisons, isoniazid, psychotropic drugs, disulfuram, nutritional and absorption disorders, endocrine disorders, globoid cell leukodystrophy, Krabbe metachromatic leukodystrophy, Fabry disease, Friedreich disease, Nonne-Mariesch disease, OPCA, Marinesko-Sjogren syndrome, hereditary sensory neuropathy types III and IV.

Polyneuropathy with associated myopathy:

Chloroquine, emitin, alcohol, hypothyroidism, hyperthyroidism, sarcoidosis, periarteritis nodosa, lupus erythematosus, scleroderma, giant cell arteritis, Sicca-complex.

Polyneuropathy with associated joint involvement:

Periarteritis nodosa, hypersensitivity angiitis, rheumatoid arthritis, lupus erythematosus, Wegener's disease, Sicca complex ("dry syndrome"), Whipple's disease, Behcet's disease.

Polyneuropathy with associated changes in the skin and mucous membranes:

Post- or parainfectious polyneuropathies, Garin-Bujadoux-Bannwarth meningopolyradiculopathy, leprosy, thallium, mercury, arsenic, gold, penicillin, diphenin, disulfuram, Strahn-Scott syndrome, malabsorption and nutrition, Fabry disease, Refsum disease, ataxia-telangiectasia, Riley-Day familial dysautonomia, porphyria, cryoglobulinemia, Merkelson-Rosenthal syndrome, lupus erythematosus, scleroderma, Wegener's granulomatosis, acrodermatitis atrophicans, Behcet's disease.

Polyneuropathies with symptoms of autonomic neuropathy (peripheral autonomic failure):

Acute autonomic neuropathy (paraneoplastic, Guillain-Barré syndrome, porphyric polyneuropathy, toxic (vincristine), autonomic neuropathy in diabetes mellitus, amyloid polyneuropathy, autonomic neuropathy in HIV infection, hereditary sensory and autonomic neuropathy (Riley-Day syndrome).

There are various classifications of polyneuropathy (and neuropathy in general), but there is no generally accepted classification. We would like to supplement the data presented above with one of the general classifications, built primarily on clinical principles.

Classification of polyneuropathy

Currently, there is no generally accepted classification of polyneuropathies. According to the pathogenetic feature, polyneuropathies are divided into axonal, in which the primary damage is to the axial cylinder, and demyelinating, which are based on myelin pathology.

According to the nature of the clinical picture, motor, sensory and vegetative polyneuropathies are distinguished. In their pure form, these forms are rarely observed; more often, a combined lesion of two or all three types of nerve fibers is detected, for example, motor-sensory, sensory-vegetative forms.

According to the etiological factor, polyneuropathies can be divided into hereditary, autoimmune, metabolic, alimentary, toxic and infectious-toxic.

Hereditary polyneuropathies:

• hereditary motor-sensory neuropathy (HMSN) type I (synonyms - Charcot-Marie-Tooth neural amyotrophy, demyelinating type of HMSN);
• Russi-Levy syndrome (phenotypic variant HMSN IA);
• NMSN type II (axonal type NMSN);
• NMSN type III (Dejerine-Sottas syndrome, hypertrophic type of NMSN);
• NMSN type IV (Refsum disease);
• neuropathy with a tendency to pressure paralysis;
• porphyritic polyneuropathy;
• hereditary sensory-vegetative polyneuropathies.

Acquired polyneuropathies:

• Autoimmune polyneuropathies:
  • acute inflammatory demyelinating polyneuropathies (Guillain-Barré syndrome, Miller-Fisher syndrome);
  • acute inflammatory axonal polyneuropathy (axonal type of Guillain-Barré syndrome);
  • chronic inflammatory demyelinating polyneuropathy;
  • paraproteinemic polyneuropathies;
  • paraneoplastic polyneuropathies;
  • multiple mononeuropathies: motor multifocal neuropathy with conduction blocks, sensorimotor multifocal neuropathy with conduction blocks (Sumner-Lewis syndrome);
• Metabolic polyneuropathies:
  • diabetic polyneuropathy;
  • polyneuropathy in other endocrine diseases;
  • uremic polyneuropathy;
  • hepatic polyneuropathy;
  • polyneuropathy in primary systemic amyloidosis;
• Polyneuropathies associated with vitamin deficiency:
  • vitamin B ₁ - deficiency polyneuropathy;
  • vitamin _B6 - deficiency polyneuropathy;
  • vitamin B ₁₂ - deficiency polyneuropathy;
  • vitamin E-deficiency polyneuropathy;
• Toxic polyneuropathies:
  • alcoholic polyneuropathy;
  • drug-induced polyneuropathies;
  • polyneuropathy due to poisoning with heavy metals, organic solvents and other toxic substances;
  • polyneuropathy in systemic diseases (systemic lupus erythematosus, scleroderma, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, vasculitis);
• Infectious toxic polyneuropathies:
  • diphtheritic infectious toxic polyneuropathy;
  • polyneuropathy after influenza, measles, mumps, infectious mononucleosis;
  • post-vaccination polyneuropathy;
  • polyneuropathy in tick-borne borreliosis;
  • polyneuropathy due to HIV infection;
  • polyneuropathy in leprosy.

Multifocal motor and sensorimotor mononeuropathies, strictly speaking, are not polyneuropathies, but are also systemic autoimmune diseases of the peripheral nerves, and therefore are discussed in this section.

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Epidemiology of polyneuropathy

Polyneuropathies are a very common group of diseases. They are detected in approximately 2.4%, and in older age groups - almost 8% of the population. The most common polyneuropathies include diabetic and other metabolic, toxic, and some hereditary polyneuropathies. In clinical practice, the formulation "polyneuropathy of unknown genesis" is very common, which in reality in most cases have an autoimmune or hereditary genesis. 10% of all polyneuropathies of unknown genesis are paraproteinemic, about 25% are toxic polyneuropathies.

The incidence of hereditary polyneuropathies is 10-30 per 100,000 population. The most common are type IA HMSN (60-80% of hereditary neuropathies) and type II HMSN (axonal type) (22%). X-linked HMSN and type IB HMSN are detected quite rarely. Type IA HMSN is detected equally often among men and women; in 75% of cases, the disease begins before the age of 10, in 10% - before the age of 20. Type II HMSN most often begins in the second decade of life, but a later onset (up to 70 years) may also occur.

The prevalence of chronic inflammatory demyelinating polyneuropathy is 1.0-7.7 per 100,000 population, the disease most often begins in the 5th-6th decade of life, although it can debut at any age, including childhood. Men are sick twice as often as women. The incidence of Guillain-Barré syndrome is 1-3 cases per 100,000 population per year, men are sick more often than women. The disease can occur at any age (from 2 to 95 years), the peak is at 15-35 and 50-75 years.

The prevalence of multifocal motor neuropathy is approximately 1 in 100,000 population, with men affected three times more often than women. The average age of onset is 40 years.

Signs of diabetic polyneuropathy are detected in 10-60% of patients with diabetes mellitus (up to 66% with type 1 diabetes mellitus and up to 59% with type 2 diabetes mellitus). When diagnosing diabetes mellitus, signs of polyneuropathy are detected in 7.5%, and 25 years after the onset of the disease - in 50%.

Uremic polyneuropathy is found in 10-83% of patients with chronic renal failure. The likelihood of its development is associated not so much with the patient's age as with the duration and severity of renal failure.

Diphtheritic polyneuropathy develops in 20% of patients who have had diphtheria.

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