Chronic inflammatory demyelinating polyneuropathy

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a symmetrical polyneuropathy or polyradiculoneuropathy, which manifests itself as 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, of whom 3 (23%) had a monophasic course, 4 (30%) had a single episode, and 6 (46%) had multiple exacerbations. In children, the onset of symptoms is rarely preceded by infections, the onset is often gradual, and the debut manifestation is often changes in gait.

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Pathogenesis

As in Guillain-Barré syndrome, the inflammation and demyelination of the roots and proximal nerves suggest that the course of the disease and the pathological changes are best explained by a series of immune processes. In this regard, T and B lymphocytes, specific antibodies to neural antigens, activated macrophages, cytokines (such as TNF-a), and complement components may be important. In chronic inflammatory demyelinating polyneuropathy, however, the immunological cascade is even less well understood than in Guillain-Barré syndrome. It is particularly unclear what specific immunological mechanisms are responsible for the longer course and lower incidence of spontaneous remissions in CIDP than in Guillain-Barré syndrome. The search for an answer to this question may lead to the discovery that Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy are acute and chronic variants of the same process, differing in some specific immune mechanisms.

Experimental allergic neuritis (EAN) provides evidence of the importance of immune mechanisms in the pathogenesis of chronic inflammatory demyelinating polyneuropathy and a possible relationship between acute and chronic inflammatory demyelinating polyradiculoneuropathies. Rabbits immunized with a single large dose of peripheral myelin develop experimental allergic neuritis with a chronic progressive or relapsing course. The clinical, electrophysiological, and pathomorphological characteristics of this condition are similar to CIDP in humans. Although antimyelin antibodies have been identified, specific T-cell responses directed against them have not been identified. Administration of myelin or myelin proteins P2 and P0 to Lewis rats induces a more acute variant of EAN, which can be transferred to syngeneic animals using antigen (P2 and P0)-specific T cells. Humoral mechanisms may also be of some importance if antibodies are able to penetrate the blood-neural barrier. The blood-neural barrier can be disrupted experimentally by the administration of ovalbumin-specific activated T lymphocytes followed by intraneural injection of ovalbumin. This is followed by endoneural perivenous inflammatory infiltration by T lymphocytes and macrophages with the development of conduction block and mild demyelination, which can be significantly enhanced by the simultaneous administration of antimyelin immunoglobulins. Thus, in this experimental model, T lymphocytes accumulate in the peripheral nerves, alter the permeability of the blood-neural barrier, and, together with antimyelin antibodies, cause primary demyelination, with their action being dose-dependent.

The elements of the immune attack that lead to the development of chronic inflammatory demyelinating polyneuropathy in humans are not as well known as in Guillain-Barré syndrome or in experimental models. In sural nerve biopsy from patients with CIDP, CD3 ⁺ T-lymphocyte infiltration was found in 10 of 13 cases, and T cells were found in the epineurium in 11 of 13 cases. In addition, endoneurial perivascular accumulations of CD68 ⁺ macrophages are often found. In contrast to Guillain-Barré syndrome, in chronic inflammatory demyelinating polyneuropathy, the cerebrospinal fluid cytokine level and serum TNF-α levels are not elevated.

The presence and role of the dominant group of circulating antibodies in chronic inflammatory demyelinating polyneuropathy have been studied less well than in Guillain-Barré syndrome. Antibodies to GM1 ganglioside, which belong to IgM, are detected in only 15% of patients with CIDP, and IgG antibodies to GM1 were not detected in any patient. Moreover, only 10% of patients with CIDP have serologic evidence of C. jejuni infection. IgG and IgM antibodies to other gangliosides, chondroitin sulfate, sulfatides, or myelin proteins were detected in less than 10% of cases. IgM monoclonal antibodies that bound to human brain tubulin were detected in several patients with a slowly progressive course and electrophysiologic evidence of demyelination. However, in a larger series of patients with CIDP, antibodies to beta-tubulin were detected by immunoblotting in only 10.5% of cases. Thus, in contrast to Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy is not associated with any specific infections or elevated titers of antibodies to myelin autoantigens or glucoconjugates. Additional studies are needed to identify the factors that provoke 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 chronic inflammatory demyelinating polyneuropathy.

Typically, the symptoms increase over at least 2 months, with steadily progressing, stepwise progressing, or relapsing variants of the course possible. In some patients, the symptoms may increase until death, while others have a fluctuating course with multiple exacerbations and remissions over a long period of time. Weakness may be observed in both proximal and distal muscles. Tendon reflexes are weakened or disappear. Involvement of the cranial nerves, such as the oculomotor, trochlear, and abducens, is uncommon, but possible.

In one study, which included 67 patients who met the clinical and electrophysiological criteria for chronic inflammatory demyelinating polyneuropathy, 51% of them had some deviations from the classical picture of chronic inflammatory demyelinating polyneuropathy, including 10% with purely motor disorders, 12% with sensory ataxia syndrome, 9% with a picture of multiple mononeuritis, 4% with paraplegia syndrome, and 16% with a relapsing course with repeated episodes that resembled Guillain-Barré syndrome. In this same series, 42% of patients had pain syndrome, which is more common than in previous observations. Patients with diabetes mellitus may develop a progressive, moderate, predominantly motor polyneuropathy involving the lower extremities that meets both electrophysiological and clinical criteria for chronic inflammatory demyelinating polyneuropathy.

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Diagnostics chronic inflammatory demyelinating polyneuropathy.

In chronic inflammatory demyelinating polyneuropathy, as in Guillain-Barré syndrome, EMG, nerve conduction velocity measurements, and cerebrospinal fluid examination are of great diagnostic value. Biochemical blood tests help to exclude metabolic polyneuropathies, which may have similar manifestations (for example, polyneuropathies in diabetes mellitus, uremia, liver damage, and hypothyroidism). It is also important to exclude polyneuropathies associated with HIV infection and Lyme disease. Protein electrophoresis helps to exclude monoclonal gammopathy, which may occur in myeloma or monoclonal gammopathy of unknown genesis. Detection of monoclonal gammopathy is an indication for searching for osteosclerotic myeloma or isolated plasmacytoma using bone radiography. In addition, in this case it is also necessary to test urine for monoclonal protein, and sometimes conduct a bone marrow examination.

EMG reveals changes in motor unit potentials characteristic of denervation and varying degrees of fibrillation, depending on the duration and severity of the lesion. Conduction velocity in motor and sensory fibers in the upper and lower extremities is usually slowed by more than 20% (if the demyelinating process is not limited to the spinal nerve roots and proximal nerves). Conduction blocks of varying degrees and temporal dispersion of the total muscle action potential or nerve fiber action potentials may be detected. Distal latencies are usually prolonged in this disease. Conduction velocity in proximal nerve segments is slowed to a greater extent than in distal segments. The electrophysiological criterion of partial conduction block in chronic inflammatory demyelinating polyneuropathy is a more than 20% decrease in the amplitude of the total muscle action potential during proximal nerve stimulation compared to distal stimulation (e.g., in the elbow and hand). Multifocal motor neuropathy is considered a separate disease not associated with CIDP. However, the presence of partial conduction blocks in motor fibers in chronic inflammatory demyelinating polyneuropathy indicates a certain overlap of clinical and electrophysiological data in multifocal motor neuropathy and chronic inflammatory demyelinating polyneuropathy.

When examining the cerebrospinal fluid, the protein level usually exceeds 0.6 g/l, and cytosis remains normal (no more than 5 cells). Local IgG synthesis may be increased. An increase in the Q-albumin level is also possible, which indicates damage to the hematoneural or hematoencephalic barriers.

A biopsy of the sural nerve may have some diagnostic value, revealing signs of inflammation and demyelination, and sometimes marked swelling of the myelin sheath. Nerve fiber examination may reveal signs of segmental demyelination, but in some cases axonal degeneration predominates.

In recent years, there have been a number of reports on the ability of MRI to detect signs of an ongoing inflammatory process in chronic inflammatory demyelinating polyneuropathy. MRI of the brachial plexus reveals a symmetrical increase in signal intensity on T2-weighted images. A sharp thickening of the cauda equina roots can also be detected on MRI of the lumbosacral region. In addition, in CIDP, thickening of the nerve trunks with an increase in signal intensity in the proton density and T2 modes in the demyelination zones established electrophysiologically is possible. It is interesting that with clinical improvement, the lesions stop accumulating contrast after gadolinium administration. This indicates that focal conduction disturbances may correspond to zones of inflammatory lesions with a violation of the hematoneural barrier.

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Treatment chronic inflammatory demyelinating polyneuropathy.

Immunosuppressive therapy remains one of the main methods of treating chronic inflammatory demyelinating polyneuropathy. Until recently, corticosteroids were considered the drugs of choice. Their effectiveness has been proven 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 reduces the dose by 10 mg per month and then switches to taking the drug every other day. An increase in muscle strength usually begins after several months of treatment and continues for 6-8 months, reaching the maximum possible value by this time. When the dose is reduced or corticosteroids are discontinued, relapses are possible, requiring a return to a higher dose of the drug or the use of another method of treatment. The main problem with long-term use of corticosteroids is weight gain, the appearance of Cushingoid features, arterial hypertension, decreased glucose tolerance, agitation or irritability, insomnia, osteoporosis, aseptic necrosis of the femoral neck, cataracts. These side effects can be a very significant clinical problem, especially if the drug has to be taken in high doses. Sometimes they force a switch to another method of treatment.

Plasmapheresis has also been shown to be effective in chronic inflammatory demyelinating polyneuropathy. In an early prospective, double-blind, controlled study, plasmapheresis produced significant improvement in approximately one-third of patients with CIDP. In a recent double-blind study, 18 previously untreated patients were randomly assigned to two groups: one group received 10 plasmapheresis sessions over 4 weeks, while the other group received a sham procedure. The results showed that plasmapheresis produced significant improvement in all assessed parameters in 80% of patients. After completion of the plasmapheresis course, 66% of patients had a relapse, which regressed after resumption of plasmapheresis using the open procedure. However, it was noted that immunosuppressive therapy is necessary to stabilize the effect. Prednisolone was effective in patients who did not respond to plasmapheresis treatment. Thus, the presented data indicate the effectiveness of plasmapheresis in chronic inflammatory demyelinating polyneuropathy. However, this is an expensive treatment method that requires multiple procedures, alone or in combination with immunosuppressive agents, such as prednisolone. Since there are no controlled studies that would allow us to determine the optimal frequency of plasmapheresis sessions when used alone or in combination with prednisolone, various schemes have been developed empirically. Some authors recommend initially conducting 2-3 plasmapheresis sessions per week for 6 weeks, others recommend 2 plasmapheresis sessions per week for 3 weeks, and then 1 session per week for another 3 weeks. After achieving 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 to continue plasmapheresis sessions, but more rarely. If improvement is achieved but frequent plasmapheresis sessions are needed to maintain it, adding 50 mg of prednisolone daily may reduce the need for plasmapheresis. Subsequently, the frequency of plasmapheresis sessions can be reduced and prednisolone can be given every other day. If plasmapheresis is ineffective, alternative immunosuppressive agents should be considered.

Intravenous immunoglobulin in chronic inflammatory demyelinating polyneuropathy has been shown in clinical studies to be as effective as plasmapheresis. In a double-blind, placebo-controlled, prospective, crossover study, 25 patients were sequentially administered immunoglobulin (400 mg/kg) or placebo for 5 consecutive days. All assessed parameters were significantly better with immunoglobulin than with placebo. It was also noted that the effect of immunoglobulin was higher in patients with a disease duration of no more than 1 year. In 10 patients with recurrent chronic inflammatory demyelinating polyneuropathy who responded to immunoglobulin, visual improvement lasted an average of about 6 weeks. In this case, the effect was maintained and stabilized in all 10 patients using pulse therapy with immunoglobulin, which was administered at a dose of 1 g/kg. Thus, the efficacy of immunoglobulin in chronic inflammatory demyelinating polyneuropathy is approximately equal to that of plasmapheresis. As already noted, immunoglobulin is an expensive drug, but its side effects are relatively mild. One study attempted to compare all three treatment methods in 67 patients with CIDP. It showed that plasmapheresis, intravenous immunoglobulin, and corticosteroids produced improvement with approximately the same frequency, but greater functional improvement was noted with plasmapheresis. Of the 26 patients who did not respond to the initial treatment, 9 patients (35%) noted improvement with the alternative treatment method, and of the 11 who required the third treatment method, only 3 patients (27%) improved. Overall, 66% of patients in this series responded positively to one of the three main methods of treating chronic inflammatory demyelinating polyneuropathy. As with Guillain-Barré syndrome, there is a need to evaluate the efficacy of different combinations of the three main treatments in a prospective controlled clinical trial.