Chronic inflammatory demyelinating polyneuropathy

Chronic inflammatory demyelinating polyneuropathy (CVD) - symmetrical polyneuropathy or polyradiculoneuropathy, manifested by muscle weakness, decreased sensitivity and paresthesia.

Chronic inflammatory demyelinating polyneuropathy is relatively rare in childhood. One study described 13 patients aged 1.5 to 16 years, 3 of whom had a 23% disease monophasic, 4 (30%) had a single episode, 6 (46%) had multiple episodes exacerbations. In children, the onset of symptoms is rarely preceded by infection, the onset is often gradual, with gait changes often being a debut.

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Pathogenesis

As with Guillain-Barre syndrome, inflammation and demyelination of roots and proximal nerves indicate that the features of the course of the disease and pathomorphological changes are best explained by a series of immune processes. In this connection, T- and B-lymphocytes, specific antibodies to neural antigens, activated macrophages, cytokines (such as TNF-a) and complement components can be important. With chronic inflammatory demyelinating polyneuropathy, however, the immunological cascade is even worse than in the Guillain-Barre syndrome. It is especially unclear, by virtue of which specific immunological mechanisms in CVD, a prolonged course is observed and spontaneous remissions occur less frequently than with Guillain-Barre syndrome. Finding the answer to this question can lead to the discovery that Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy are acute and chronic variants of the same process, differing by some specific immune mechanisms.

Experimental allergic neuritis (EAV) serves as evidence of the importance of immune mechanisms in the pathogenesis of chronic inflammatory demyelinating polyneuropathy and the possible relationship between acute and chronic inflammatory demyelinating polyradiculoneuropathies. In rabbits immunized with a single large dose of peripheral myelin, experimental allergic neuritis develops with a chronic progressive or recurrent course. The clinical, electrophysiological and pathomorphological characteristics of this condition and CVD in humans are similar. Although antimielin antibodies have been identified, specific T cell responses have not been identified. The introduction of Lewis rats myelin or myelin proteins P2 and PO induces a more acute variant of EAN, which can be transferred to syngeneic animals with the help of antigen (P2 and PO) - specific T cells. Humoral mechanisms may also have some significance if antibodies are able to penetrate the hematoneural barrier. Disturbance of the hematoneural barrier can be induced experimentally by the administration of ovalbumin-specific activated T-lymphocytes followed by an intranural injection of ovalbumin. This is followed by the development of endonevral perivennous inflammatory infiltration by T-lymphocytes and macrophages with the development of a block of conduction and easy demyelination, which can be significantly enhanced by the simultaneous administration of anti-myelin immunoglobulins. Thus, in this experimental model, T-lymphocytes accumulate in the peripheral nerves, change the permeability of the hematoneural barrier and, together with antimielin antibodies, cause primary demyelination, and their action is dose-dependent.

Elements of the immune attack leading to the development of chronic inflammatory demyelinating polyneuropathy in humans are not known as well as in the case of Guillain-Barre syndrome or experimental models. With biopsy of the gastrocnemius in patients with CVD, CD3 ⁺  T-lymphocytes infiltrate in 10 of 13 cases, T cells were found in epineuria in 11 of 13 cases. In addition, endovenous perivascular clusters of CD68 ⁺  macrophages are often found . In contrast to the Guillain-Barre syndrome, with chronic inflammatory demyelinating polyneuropathy in the cerebro-spinal fluid, the level of cytokines is not increased, and the serum level is the level of the cytokine TNF-a.

The presence and role of the dominant group of circulating antibodies in chronic inflammatory demyelinating polyneuropathy have been studied worse than with Guillain-Barre syndrome. Antibodies to kganglioside GM1, related to IgM, are detected only in 15% of patients with CVD, and no IgG antibodies to GM1 have been detected in any patient. Moreover, only 10% of patients with CVD show serological signs of S. Jejuni infection. IgG and IgM antibodies to other gangliosides, chondroitin sulfate, sulfatides or myelin proteins are found in less than 10% of cases. Several patients with a slowly progressive course and electrophysiological signs of demyelination were diagnosed with IgM monoclonal antibodies that were bound to the human tubulin in the brain. However, in a larger series of patients with CVD, antibodies to beta-tubulin were detected by the immunoblot method only in 10.5% of cases. Thus, unlike the Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy is not associated with any specific infections and elevated titers of antibodies to myelin autoantigens or glucoconjugates. More research is needed to identify factors that trigger the development of chronic inflammatory demyelinating polyneuropathy and to determine the sequence of pathogenetic reactions leading to the development of the disease.

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Symptoms of the chronic inflammatory demyelinating polyneuropathy

Usually, the symptomatology grows for at least 2 months, with a steady progressing, step-like progressing or recurrent flow patterns. In some patients, the symptomatology can grow up to a lethal outcome, others have a long-term fluctuating course with numerous exacerbations and remissions. Weakness can be observed in both proximal and distal muscles. Tendon reflexes are weakened or drop out. It is infrequent, but it is possible to involve cranial nerves - oculomotor, block, draining nerves.

In one study, which included 67 patients who met the clinical and electrophysiological criteria of chronic inflammatory demyelinating polyneuropathy, 51% of them had some deviations from the classic pattern of chronic inflammatory demyelinating polyneuropathy, including 10% - purely motor disorders, 12% had a sensitized ataxia syndrome, 9% had a picture of multiple mononeurosis, 4% had paraplegia, 16% had a recurring course with recurrent episodes that resembled blues drill of Guillain-Barre. In the same series, 42% of patients had pain syndrome - more often than in previous observations. In patients with diabetes mellitus, progressive moderately pronounced predominantly motor polyneuropathy involving lower extremities can develop which satisfies both the electrophysiological and clinical criteria of chronic inflammatory demyelinating polyneuropathy.

[10], [11], [12], [13], [14]

Diagnostics of the chronic inflammatory demyelinating polyneuropathy

In chronic inflammatory demyelinating polyneuropathy, as in Guillain-Barre syndrome, EMG, measurement of nerve conduction velocity, and examination of cerebrospinal fluid are of great diagnostic importance. Biochemical blood tests help to exclude metabolic polyneuropathies, which may have similar manifestations (eg, polyneuropathies in diabetes, uremia, liver damage and hypothyroidism). It is also important to exclude polyneuropathies associated with HIV infection and Lyme disease. Electrophoresis of proteins allows to exclude monoclonal gammopathy, which can occur with myeloma or monoclonal gammopathy of unknown origin. Detection of monoclonal gammopathy is an indication for the search for osteosclerotic myeloma or isolated plasmacytoma by means of radiography of bones. In addition, in this case, it is also necessary to examine urine for monoclonal protein, and sometimes to conduct bone marrow research.

With EMG, changes in the potentials of motor units, characteristic of denervation, and different degrees of fibrillation, are detected, which depends on the duration and severity of the lesion. The speed of the motor and sensory fibers on the upper and lower limbs usually slows down by more than 20% (if the demyelinating process is not limited only to spinal nerve roots and proximal nerves). The blocks of conduction and the temporal variance of the total muscular potential of the action or potentials of the action of nerve fibers can be detected in varying degrees. Distal latencies with this disease are usually elongated. The speed of the passage along the proximal segments of the nerves is slowed down to a greater extent than in the distal segments. The electrophysiological criterion of the partial block of conduction in chronic inflammatory demyelinating polyneuropathy consists in a more than 20% drop in the amplitude of the total muscular potential of the action in proximal stimulation of the nerve compared to the distal (for example, in the elbow and hand). Multifocal motor neuropathy is considered as a separate disease, not associated with CVD. However, the presence of partial blocks of conduction on motor fibers in chronic inflammatory demyelinating polyneuropathy indicates a certain overlap of clinical and electrophysiological data with multifocal motor neuropathy and chronic inflammatory demyelinating polyneuropathy.

In the study of cerebrospinal fluid, the protein level usually exceeds 0.6 g / l, and the cytosis remains normal (no more than 5 cells). Local synthesis of IgG can be increased. It is also possible to increase the level of Q-albumin, which indicates damage to the blood-brain or blood-brain barrier.

Biopsy of the calf nerve can have a certain diagnostic value, revealing signs of inflammation and demyelination, and sometimes pronounced swelling of the myelin sheath. In the study of nerve fibers, signs of segmental demyelination may be detected, but in some cases axonal degeneration predominates.

In recent years, a number of reports have appeared on the ability of MRI to identify signs of the current inflammatory process in chronic inflammatory demyelinating polyneuropathy. With MRI of the brachial plexus, a symmetrical increase in signal intensity on T2-weighted images is detected. A sharp thickening of the roots of the horse tail can also be detected with MRI of the lumbar-sacral region. In addition, with CVD, a thickening of the nerve trunks is possible with an increase in the signal intensity in the regimes of proton density and T2 in the zones of demyelination established electrophysiologically. The fact is interesting that with clinical improvement the lesions cease to accumulate contrast after the introduction of gadolinium. This indicates that the focal disruption of the conduction may correspond to the zones of inflammatory lesion with a violation of the hematoneural barrier.

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Treatment of the chronic inflammatory demyelinating polyneuropathy

Immunosuppressive therapy remains one of the main methods of treatment of chronic inflammatory demyelinating polyneuropathy. Until recently, corticosteroids were considered drugs of choice. Their effectiveness has been demonstrated in randomized controlled trials. Treatment with prednisolone usually begins with a dose of 60-80 mg / day, which the patient takes once in the morning for 8 weeks, then slowly reduce the dose by 10 mg per month and then switch to taking the drug every other day. The increase in muscle strength usually begins after several months of treatment and lasts for 6-8 months, reaching by this time the maximum possible value. When the dose is lowered or corticosteroids are abolished, relapses may occur that require a return to a higher dose of the drug or another treatment. The main problem with prolonged intake of corticosteroids - weight gain, the appearance of Cushingoid features, arterial hypertension, decreased glucose tolerance, agitation or irritability, insomnia, osteoporosis, aseptic neck necrosis, cataracts. These side effects can be a very significant clinical problem, especially if the drug has to be taken in a high dose. Sometimes they force to switch to another method of treatment.

With chronic inflammatory demyelinating polyneuropathy, the efficacy of plasmapheresis has also been demonstrated. In an early prospective, double-blind, controlled study, plasmapheresis caused a significant improvement in about a third of patients with CVD. In a recent double-blind study, 18 previously untreated patients were randomly assigned to two groups: water from the groups for 10 weeks were conducted 10 sessions of plasmapheresis, in another this procedure was simulated. The results showed that plasmapheresis caused a significant improvement in all evaluated parameters in 80% of patients. After completing the course of plasmapheresis, 66% of the patients had a relapse, which regressed after the resumption of plasmapheresis by an open procedure. Nevertheless, it was noted that immunosuppressive therapy is necessary to stabilize the effect. In patients who did not respond to treatment with plasmapheresis, prednisolone was effective. Thus, the data presented indicate the effectiveness of plasmapheresis in chronic inflammatory demyelinating polyneuropathy. However, this is an expensive treatment that requires multiple procedures, alone or in combination with immunosuppressive agents, such as prednisolone. Since no controlled studies have been conducted that would allow the optimal frequency of plasmapheresis sessions to be determined in isolated use or in combination with prednisolone, various schemes have been empirically developed. Some authors recommend conducting 2-3 sessions of plasmapheresis weekly for 6 weeks, others recommend 2 sessions of plasmapheresis per week for 3 weeks, and then 1 session per week for another three weeks. After achieving an improvement in clinical and electrophysiological data, treatment can be discontinued, and the patient should be examined once every 1-2 weeks. Sometimes it is recommended not to stop treatment, but continue to conduct plasmapheresis sessions, but more rarely. If improvement is achieved, but frequent sessions of plasmapheresis are required to maintain it, the addition of 50 mg of prednisone per day can reduce the need for plasmapheresis. In the following, the frequency of plasmapheresis sessions can be reduced and switched to taking prednisolone every other day. If plasmapheresis is ineffective, consider using alternative immunosuppressive agents.

Intravenous immunoglobulin in chronic inflammatory demyelinating polyneuropathy, as shown by clinical studies, is as effective as plasmapheresis. In a double-blind, placebo-controlled, prospective cross-over study, 25 patients consistently received immunoglobulin (400 mg / kg) or placebo for 5 consecutive days. With the use of immunoglobulin, all the parameters evaluated were significantly better than with placebo. It was also noted that the effect of immunoglobulin was higher in patients with duration of the disease not exceeding 1 year. In 10 patients with a recurrent course of chronic inflammatory demyelinating polyneuropathy responding to immunoglobulin, the improvement in vision persisted on average about 6 weeks. In this case, in all 10 patients, the effect was maintained and stabilized by pulse-therapy with immunoglobulin, which was administered at a dose of 1 g / kg. Thus, the effectiveness of immunoglobulin in chronic inflammatory demyelinating polyneuropathy roughly corresponds to the effectiveness of plasmapheresis. As already mentioned, immunoglobulin is an expensive remedy, but its side effects are relatively easy. In one study, an attempt was made to compare all of the three treatment methods in 67 patients with CVD. As a result, it turned out that plasmapheresis, intravenous immunoglobulin and corticosteroids caused an improvement of about the same frequency, but a more significant functional improvement was noted with the use of plasmapheresis. Of the 26 patients who did not respond to initial treatment, 9 patients (35%) reported improvement in the use of an alternative method of treatment, and of the 11 who required the use of the third method of treatment, improvement was noted in only 3 patients (27%). Overall, in this series, 66% of patients responded positively to one of the three main treatments for chronic inflammatory demyelinating polyneuropathy. As with Guillain-Barre syndrome, there is a need to evaluate the effectiveness of various combinations of the three main treatments in a prospective, controlled clinical trial.