Current understanding of idiopathic inflammatory polyneuropathies

Currently, about 100 types of polyneuropathies are considered in medical practice. Idiopathic inflammatory polyneuropathies are rare forms of polyneuropathies, so it is very important to know these forms, be able to diagnose them correctly and, most importantly, quickly and adequately treat them, since these diseases in most cases have a progressive course, invariably leading to disability, and in some cases to death.

Idiopathic inflammatory polyneuropathies are a group of heterogeneous diseases of the peripheral nervous system associated with the development of an autoimmune attack against antigens of peripheral nerve fibers, the cause of which remains unclear. According to the course, depending on the specifics of the autoimmune process, they are divided into acute, subacute and chronic. Depending on the type of antigen against which the autoimmune attack occurs, they are demyelinating or axonal, symmetrical or asymmetrical.

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Guillain-Barre syndrome

Guillain-Barré syndrome (GBS) is one of the most prominent examples of idiopathic inflammatory polyneuropathies. The incidence of Guillain-Barré syndrome ranges from 1 to 2 cases per 100,000 population per year, is more common in men, and two peaks of incidence are noted: between the ages of 15 and 35 and between 50 and 75.

Within the framework of Guillain-Barré syndrome, acute inflammatory demyelinating polyneuropathy (AIDP) is distinguished - the frequency of occurrence is more than 85%; acute motor axonal neuropathy (AMAN) - 3%, as its variant - acute motor-sensory axonal neuropathy (AMAN) with the frequency of occurrence less than 1% and Miller-Fisher syndrome, which makes up about 5% of cases.

What causes Guillain-Barré syndrome?

An important role in the etiology of Guillain-Barré syndrome is given to the autoimmune reaction directed against antigens of the peripheral nervous tissue. 1-6 weeks before the appearance of the first symptoms of the disease, more than 60% of patients have signs of a respiratory or gastrointestinal infection. However, by the time the first signs of Guillain-Barré syndrome appear, the symptoms of the preceding infection usually have time to regress. The provoking agents are influenza A and B viruses, parainfluenza, ECHO, Coxsackie, hepatitis B, measles, Campylobacter jejuni. A certain connection has been established between Guillain-Barré syndrome and cytomegaloviruses (15% of cases), Epstein-Barr virus (10% of cases) and Mycoplasma pneumonia (up to 5% of cases). The previous infection, apparently, serves as a provoking factor that launches an autoimmune reaction. Vaccination (against influenza, less frequently against rabies, measles, mumps, rubella), surgical interventions, and blood transfusions may also act as a trigger factor. Cases of Guillain-Barré syndrome have been described in patients with lymphogranulomatosis and other lymphoproliferative diseases, systemic lupus erythematosus, hypothyroidism, and heroin addiction.

Symptoms of Guillain-Barré syndrome

Guillain-Barré syndrome has an acute onset with general weakness and pain in the limbs. Muscle weakness, starting from the distal or proximal parts of the legs, develops in an ascending direction. In a few days (less often weeks), deep flaccid tetraparesis develops, sometimes plegia with fading tendon reflexes, muscle hypotonia. Bilateral prosoplegia, oculomotor nerve damage, and bulbar disorders are possible. In 1/3 of cases, weakness of the respiratory muscles develops. In about a third of patients, superficial sensitivity and joint-muscle feeling decrease. In the late stages of the disease, muscle hypotrophy develops. Severe pain syndrome occurs in 50% of cases of Guillain-Barré syndrome. In 10-20% of cases, sphincter disorders occur in the form of transient urinary retention, which quickly disappear in the first few days from the onset of the disease. Almost all patients have autonomic disorders, which may be one of the possible causes of sudden death of patients.

Guillain-Barré syndrome has a classic monophasic course, consisting of three periods: progression of neurological symptoms (2-4 weeks); stabilization or plateau (2-4 weeks); recovery, lasting from several months to 1-2 years.

Timely use of effective treatment methods helps to shorten the natural course of the disease and reduces the number of fatal outcomes.

How to recognize Guillain-Barré syndrome?

The disease is diagnosed based on the clinical picture and additional research methods. Protein-cell dissociation in the cerebrospinal fluid with high protein levels (up to 3-5, sometimes up to 10 g/l) in both lumbar and occipital punctures is considered pathognomonic for the disease.

Electromyographic (EMG) testing is currently the most sensitive objective diagnostic method for Guillain-Barré syndrome. EMG reveals a decrease in the conduction velocity of sensory and motor nerve fibers or signs of denervation and axonal death that develop in parallel with muscle atrophy and usually portend an unfavorable outcome.

The diagnostic criteria for Guillain-Barré syndrome were first developed by a special group of the American Academy of Neurology back in 1978. They were subsequently revised several times, but did not change fundamentally. The most recent official criteria date back to 1993 and were proposed by the WHO.

Signs necessary for diagnosis of Guillain-Barré syndrome: progressive muscle weakness in two or more limbs, tendon areflexia.

Features that support the diagnosis of Guillain-Barré syndrome: worsening of symptoms over several days or weeks (up to 4 weeks); onset of recovery 2-4 weeks after cessation of progression; relative symmetry of symptoms; mild sensory disturbances; involvement of cranial nerves, often bilateral facial nerves; good recovery in most patients; absence of fever at the onset of the disease, but its appearance does not exclude GBS; autonomic dysfunction; changes in cerebrospinal fluid (CSF): high protein content with normal or slightly increased cytosis (no more than 10 cells per mm ³ )

Signs that cast doubt on the diagnosis: pronounced persistent asymmetry of motor disorders; persistent sphincter dysfunction; absence of sphincter disorders at the onset of the disease; presence of more than 50 mononuclear and polymorphonuclear leukocytes in the CSF; clear level of sensory disorders.

Differential diagnosis of Guillain-Barré syndrome should be made with myasthenia, toxic polyneuropathy, hypokalemia, botulism, diphtheria, hysteria, porphyria, acute cerebrovascular accident in the vertebrobasilar basin, brainstem encephalitis, and AIDS.

How is Guillain-Barré syndrome treated?

Even mild cases of Guillain-Barré syndrome in the acute phase are considered emergency conditions requiring immediate hospitalization. Treatment measures for Guillain-Barré syndrome are divided into specific and non-specific. Specific methods of treating Guillain-Barré syndrome include programmed plasmapheresis and intravenous pulse therapy with immunoglobulins of class G, and these methods are effective not only in the treatment of classical Guillain-Barré syndrome, but also in its variants, including Miller-Fischer syndrome. The course of plasmapheresis operations includes 3-5 sessions with the replacement of approximately 1 volume of plasma (40-50 ml/kg), which are carried out every other day. An alternative method of treating Guillain-Barré syndrome is intravenous pulse therapy with immunoglobulins of class G, the standard course of treatment is based on 0.4 g per 1 kg of the patient's body weight daily for 5 days. It is possible to administer the same course dose according to a faster scheme: 1 g/kg/day in 2 administrations for 2 days. According to the data of randomized blind controlled studies, plasmapheresis and intravenous administration of immunoglobulin were equally effective in improving the symptoms in severe cases of Guillain-Barré syndrome. The combined use of these methods did not bring any additional benefit.

The efficacy of corticosteroids in Guillain-Barré syndrome has been studied in 6 randomized trials, which concluded that the use of these drugs is inappropriate.

Patients who have had Guillain-Barré syndrome should be informed of the need to follow a protective regimen for at least 6-12 months after the end of the disease. Physical overload, hypothermia, excessive insolation, and alcohol consumption are unacceptable. Vaccination should also be avoided during this period.

Acute/subacute idiopathic sensory neuronopathy (ganglionopathy)

Acute/subacute idiopathic sensory neuronopathy (gangliopathy) is a rare disease associated with diffuse inflammatory lesions of the spinal ganglia. The clinical picture of this disease is divided into three forms: ataxic, hyperalgesic and mixed.

The ataxic form is characterized by paresthesia, numbness, impaired coordination of movements, instability, which increases when the eyes are closed, but muscle strength remains intact. During examination, a decrease in vibration, joint-muscle senses, sensory ataxia, impaired stability in the Romberg test, which increases with closed eyes, pseudoathetosis, hypo- and areflexia are revealed.

The hyperalgic form is manifested by dysesthesia, neuropathic pain; examination reveals decreased pain and temperature sensitivity, autonomic dysfunction (impaired sweating, orthostatic hypotension).

The mixed form combines the features of the two forms described above.

The disease most often debuts with an acute onset, neurological symptoms increase over several days, but a slower subacute stage is also observed - symptoms increase over several months. The period of increasing neurological symptoms is followed by a period of disease stabilization, in some cases with further partial regression of symptoms, but in most cases a persistent neurological deficit remains, which continues to gradually increase.

When conducting EMG with the study of sensory fibers, a decrease in amplitude or absence of action potentials is noted. When studying motor fibers, no pathological changes are detected. With needle EMG, no pathological changes are detected either.

Early initiation of treatment is of key importance in the treatment of this pathology. Corticosteroids (prednisolone 1-1.5 mg/kg/day) orally daily for 2-4 weeks with subsequent dose reduction and transition to administration every other day are used as immunotherapy. Or methylprednisolone at a dose of 1 g intravenously by drops for 5 days with subsequent dose reduction using prednisolone orally. It is possible to combine corticosteroids with intravenous immunoglobulin or plasmapheresis. Adequate symptomatic therapy and physical rehabilitation of patients are of great importance.

Subacute inflammatory demyelinating polyneuropathy (SIDP) can be diagnosed in cases of increasing neurological symptoms over 4-8 weeks, but its nosological status has not been finally determined. It is more common in men and is characterized by symmetrical motor-sensory polyneuropathy, less often by isolated motor polyneuropathy. EMG studies reveal signs of demyelination. CSF examination reveals protein-cell dissociation. Early administration of corticosteroids (prednisolone at a dose of 1-1.5 mg/kg/day) gives good results. In severe forms of the disease, combination therapy of corticosteroids with intravenous immunoglobulin, plasmapheresis, and cytostatics is used. The duration of treatment is assessed by regression or stable stabilization of neurological symptoms.

Chronic inflammatory demyelinating polyradiculoneuropathy

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease similar to Guillain-Barré syndrome in pathogenesis and clinical manifestations, but different in its course. It can have a steady or stepwise progressive course, occur in the form of separate exacerbations separated by remissions. Symptoms reach a maximum no earlier than 2 months after the onset of the disease. The incidence rate ranges from 1 to 2 cases per 100,000 population, men are slightly more often affected. The average age of onset of the disease is from 45 to 55 years. Unlike GBS, infection rarely precedes the onset or relapse of the disease, a more important role is given to hereditary immunogenetic factors. In patients with CIDP, the HLA genes are more often detected: DRw3, Dw3, B8, A1, Aw30, Aw31.

The disease begins gradually or subacutely and subsequently acquires a progressive, recurrent or chronic monophasic character. The type of CIDP course (progressive, recurrent, monophasic) does not change in each specific patient during the course of the disease. The severity of symptoms and the severity of the condition may vary in different phases of CIDP.

In most cases, the disease begins with sensorimotor disorders in the distal parts of the limbs. Muscle weakness is the leading symptom. Subsequently, distal or diffuse tetraparesis develops, usually symmetrical. Diffuse muscle hypotonia and the absence of deep reflexes in the limbs are characteristic. With a long course, moderate diffuse muscle atrophy appears, more noticeable in the distal parts of the limbs.

Sensory disturbances (paresthesia, hyperesthesia, hyperpathy, hyperalgesia of the "sock" or "glove" type) also increase during exacerbation of the disease, but never come to the fore in the clinic. Severe pain syndrome is rare.

In rare cases, cranial nerves are affected (most often the facial and bulbar cranial nerves are affected), and this always indicates the activity of CIDP.

Vegetative disorders are observed in most cases of CIDP. A quarter of patients develop postural-kinetic tremor in the hands, which disappears after recovery, and may reappear if the disease recurs.

In almost half of patients with CIDP, magnetic resonance imaging reveals foci of demyelination in the brain, which most often remain asymptomatic.

The main diagnostic criteria, as in GBS, are areflexia: progressive symmetrical muscle weakness and protein-cell dissociation in the CSF, with the protein content being very high. EMG often reveals involvement of axons and one or more conduction blocks, and also reveals varying degrees of denervation in the muscles, depending on the severity and duration of the disease. A comprehensive examination of the patient is mandatory, with determination of clinical, biochemical, virological parameters (or markers), as well as antibodies to ganglioside GM1 and myelin-associated glycoprotein.

Prognosis of CIDP: in 10% of cases patients die, in 25% they remain confined to bed or a wheelchair, but about 60% retain the ability to move and return to work. Relapses are observed in 5-10% of cases.

With adequate immunotherapy, improvement can be achieved in 70-90% of patients with CIDP, but the main problem of treatment is to maintain the achieved positive effect. The main therapeutic measures include the administration of corticosteroids, nonsteroidal immunosuppressants, intravenous immunoglobulin, and plasmapheresis.

Corticosteroids are the first-line drugs for the treatment of CIDP, especially in cases of mild to moderate symptoms. Treatment begins with prednisolone at a dose of 1-1.5 mg/kg/day (usually 80-100 mg/day) once daily in the morning. After a good effect is achieved (usually it takes about 1 month), the dose is gradually reduced, switching to taking the drug every other day at a dose of 1-1.5 mg/kg (for this, the dose is reduced by 10 mg every two weeks). With further improvement or stabilization of the process after 8-10 weeks, a further dose reduction is started. An alternative scheme for managing patients with CIDP is to continue taking prednisolone at the specified dose until muscle strength is normalized (up to 6 months). Then the dose is reduced by 5 mg every 2-3 weeks until it reaches 20 mg every other day, further reduction is carried out by 2.5 mg every 2-4 weeks. To avoid relapse, the maintenance dose (5-10 mg every other day) is maintained for several years. If there is no effect, corticosteroids are discontinued earlier.

Sometimes treatment begins with pulse therapy with methylprednisolone at a dose of 1000 mg intravenously in 200 ml of saline or 5% glucose for 3-5 days, then can be repeated every 4-6 weeks.

The effectiveness of plasmapheresis has been proven in two double-blind, placebo-controlled studies. It achieves temporary clinical improvement. There is currently no experience with long-term use of plasmapheresis. In a comparative study, the effectiveness of intravenous immunoglobulin therapy and plasmapheresis was approximately equal. If a positive effect is achieved, plasmapheresis sessions with the addition of 50 mg of prednisolone per day are necessary to maintain it, which can reduce the need for plasmapheresis.

The efficacy of intravenous immunoglobulin in CIDP has been proven in several open placebo-controlled studies. The initial dose is 0.4 g/kg/day for 5 days. If there is an effect, the patient should be monitored dynamically, and immunoglobulin should not be re-administered. In case of secondary deterioration of the condition, a repeat course of treatment with intravenous immunoglobulin is recommended until the condition stabilizes (depending on the severity of symptoms, the specified daily dose is administered once every 2-4 weeks). In case of frequent relapses, it is advisable to add small doses of prednisolone 0.5 mg/kg/day or cytostatics.

Cytostatics are prescribed for CIDP for a long time and allow to avoid the use of corticosteroids in the presence of contraindications to them. Cytostatics are rarely used as monotherapy, more often they are combined with plasmapheresis and intravenous administration of immunoglobulin.

Active rehabilitation, including therapeutic exercises, massage, and orthopedic devices, contribute to faster functional recovery of patients.

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Multifocal motor neuropathy

Multifocal motor neuropathy (MMN), which is based on selective demyelination of motor fibers, is caused by an autoimmune attack against myelin, primarily in the region of the node of Ranvier. Pathologically, multifocal motor neuropathy reveals signs of demyelination and remyelination with the formation of "onion heads", sometimes axonal degeneration and regeneration.

Multifocal motor neuropathy occurs mainly in men of any age, most often at the age of 40-45 years, clinically characterized by progressive asymmetric weakness in the limbs with no or minimal sensory impairment. In the vast majority of patients, weakness is expressed distally and to a greater extent in the arms than in the legs. Only in 10% of cases is weakness more pronounced in the proximal parts or lower limbs. Muscle atrophy is often detected, but may be absent in the early stages of the disease. Fasciculations and cramps are observed in 75% of cases, myokymia is possible. In most patients, tendon reflexes from paretic muscles are reduced or absent, which often leads to reflex asymmetry. Less often, reflexes remain normal or even accentuated, which gives reason to differentiate multifocal motor neuropathy from amyotrophic lateral sclerosis (ALS). Cranial nerves and nerves innervating the respiratory muscles are affected extremely rarely.

Slow progression of the disease is characteristic, with possible spontaneous remissions.

The electrophysiological marker of this disease is the presence of multifocal partial conduction blocks in motor fibers with normal conduction in sensory fibers. To diagnose multifocal motor neuropathy, it is necessary to identify a conduction block in at least 2 nerves, and outside the areas of frequent nerve compression. Conduction blocks are often determined in the nerves of the hands at the level of the forearm, less often - the shoulder or axillary region. In addition to conduction blocks, other signs of demyelination are often determined. With needle EMG, signs of denervation are detected against the background of secondary axonal degeneration.

When examining the CSF, a slight increase in protein is determined; in 2/3 of patients, the level of creatine phosphokinase in the blood is increased by 2-3 times. In 40-60% of patients, high titers of IgM autoantibodies to ganglion thiosides, primarily to GM1, are determined in the blood; however, this criterion is not reliable for diagnosing multifocal motor neuropathy, since a moderately increased titer of antibodies is determined both in ALS and in CIDP.

The drugs of choice in the treatment of multifocal motor neuropathy are intravenous immunoglobulin and cyclophosphamide. Corticosteroids and plasmapheresis do not have a good therapeutic effect. Immunoglobulin is administered intravenously at a dose of 0.4 g / kg for 5 days, an alternative regimen is 0.4 g / kg once a week for 6 weeks. A positive effect in the form of an increase in muscle strength is noted by 2-4 weeks, then immunoglobulin is administered at 0.4-2 g / kg once every month. Good restoration of muscle strength is noted with early therapy, long-term paresis with muscle atrophy remains stable.

Multifocal acquired demyelinating sensorimotor neuropathy (MADSN) combines features of both multifocal motor neuropathy, involving not only motor but also sensory fibers, and CIDP, differing from it by the multifocal asymmetric nature of the lesion. Mostly men are affected, the process begins with damage to the distal part of the upper limbs, and remains asymmetric for a long time. Involvement of sensory fibers is manifested by the development of pain syndrome and paresthesia in the innervation zone of the affected nerves. Tendon reflexes weaken or disappear completely, but remain intact in unaffected muscles].

The disease progresses rapidly over several months, resulting in significant functional impairment and patient disability.

EMG examination reveals conduction blocks and signs of demyelination, and reveals the absence or reduction of the amplitude of sensory nerve action potentials. In some patients, antibodies to gangliosides are found in the blood.

In treatment, the drugs of choice are corticosteroids and intravenous immunoglobulin in the same dosages as in the treatment of CIDP. If they are ineffective, cyclophosphamide is indicated.

Assoc. Prof. O. L. Pelekhova. Kharkiv Medical Academy of Postgraduate Education // International Medical Journal - No. 4 - 2012

Classification of idiopathic inflammatory polyneuropathies

Symmetrical:

• Acute inflammatory polyradiculoneuropathy (Guillain-Barré syndrome):
  • demyelinating (classical) variant;
  • axonal variants; Miller-Fisher syndrome.
• Acute/subacute sensory neuronopathy (gangliopathy).
• Subacute inflammatory demyelinating polyradiculoneuropathy:
  • chronic inflammatory demyelinating polyradiculoneuropathy;
  • chronic inflammatory axonal polyneuropathy.

Asymmetrical:

1. Multifocal motor neuropathy.
2. Multifocal acquired demyelinating sensorimotor neuropathy.
3. Multifocal acquired axonal sensorimotor neuropathy.

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