Chronic inflammatory demyelinating polyneuropathy

Description:

The Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is a frequent disease at which hypodiagnosis is quite often observed. It is potentially curable, average prevalence makes about 0,5 cases / 100 000 children and 1–2 cases / 100 000 adults. Clinical similarity to acute inflammatory demyelinating polyneuropathy (a syndrome to Giyena-Barra) and positive effect of immunosuppressors suggests an idea of the immune mediated pathogeny. Since the first description of cases of chronic polyneuropathy with the response to treatment by steroids, the range of clinical symptomatology and diagnostic opportunities considerably extended, same concerns also treatment. Differentiation of the specified state and other widespread motor-touch defeats of the peripheral nerves accompanying diabetes, alcoholism or malnutrition remains the main issue.

Symptoms of chronic inflammatory demyelinating polyneuropathy:

Classical HVDP is characterized by the symmetric weakness of muscles of proximal and distal departments of extremities progressing more than 2 months. It is also associated with sensitive disturbances, easing or disappearance of tendon jerks, increase in protein content in cerebrospinal fluid (SMZh), the changes typical for demyelination at electrophysiologic researches, and demyelination signs by results of a biopsy. Its current can be recurrent or continuously progressing, and the last is more characteristic of young patients.

As diagnosis of the specified disease gradually is improved, it becomes simpler to be distinguished, therefore, various clinical trials also did not avoid this pathology. Definition of above-mentioned type of polyneuropathy was offered several expert groups at once. All of them prove the diagnosis by preferential clinical symptomatology and results of electrophysiologic researches whereas concerning need of the analysis of SMZh or a biopsy to a consensus it was not succeeded to come as degree of clinicodiagnostic accuracy widely varies. Two last methods of a research are necessary for statement of the accurate diagnosis according to criteria of the American academy of neurology, however it will not be coordinated with widely known criteria of Saperstein et al. or recommendations of Group on studying of the reasons and treatment of inflammatory neyropatiya. Classical HVDP is followed, as a rule, by the good response to treatment corticosteroids that helps with differential diagnosis with other forms of the acquired demyelinating polineyropatiya.

The acquired demyelinating distal symmetric polyneuropathy.

It is supposed that this disease is a separate form. Treat the increasing incidence among men and persons its characteristic signs 50 years, touch deficit and easy weakness preferential in distal departments of extremities (unlike more generalizirovanny defeat are more senior at HVDP) and instability of gait. The IgM-paraproteinemia is observed practically at 2/3 patients with a similar state. It, apparently, poorly reacts to immunosuppressive therapy.

Multifocal motive polyneuropathy.

It is very important to distinguish multifocal motive polyneuropathy from motor-neuron diseases. The first is characterized by existence of asymmetric weakness without sensitive defect and begins, as a rule, with muscles of distal departments of extremities. The partial block of a physical activity in various zones is a characteristic electrophysiologic sign, though not at all patients. Same concerns identification of the circulating antigangliozidny antibodies. Protein content and quantity of cells is, as a rule, in norm limits. In spite of the fact that corticosteroids and a plasma exchange at multifocal motor polyneuropathy seldom bring effect, disease improves when using immunoglobulins or cyclophosphamide.

The acquired demyelinating multifocal motor-touch polyneuropathy (Lyuisa-Sumner's syndrome).

The acquired demyelinating multifocal motor-touch polyneuropathy (Lyuisa-Sumner's syndrome) is characterized by a number of the general signs as with HVDP (motor-touch deficit, the increased protein content in SMZh, pathological changes at electrophysiologic researches), and with multifocal motor polyneuropathy (asymmetry of symptoms from the beginning from upper extremities, conductivity blockade). Some persons with this state have antibodies to gangliosides and they rather well react to intravenous administration of immunoglobulins and cyclophosphamide.

Others of polyneuropathy, similar HVDP.

Many other options of the acquired and chronic polineyropatiya similar to HVDP, are divided into the following subgroups. It is axonal, the touch, isolated motor and axonal chronic inflammatory demyelinating polyneuropathy isolated. Each of them is quite seldom mentioned in literature. Generally at patients with demyelination of peripheral nerves at good or at least partial reaction to an immunotherapy the probability of existence of the chronic acquired demyelinating polyneuropathy is maximum. Depending on a clinical picture this diagnosis is possible, probable or unambiguous. Chronic idiopathic axonal polyneuropathy represent heterogeneous group of slowly progressing neyropatiya with a pain syndrome or without that and an easy or moderate invalidism.

Diagnosis:

The diagnosis of the distal acquired demyelinating symmetric polyneuropathy is based preferential on clinical manifestations and results of researches of conductivity of the nerves testimonial of demyelination. Increase in protein content in SMZh without pleocytosis and histologic signs of demyelination and remyelination, often with an inflammation, by results of a biopsy, provide additional information. At the doubtful diagnosis carrying out a biopsy of a nerve is recommended, considering iatrogenic effects and serious side effects of long immunomodulatory and immunosuppressive therapy.

Electrophysiologic diagnostic methods.

Researches of conductivity of nerves allow to reveal the main signs of demyelination. The special committee of the American academy of neurology allocated the obligatory neurophysiological signs typical for the considered pathology: a partial block of conductivity of motor nerves, conductivity reduction of speed, the prolonged latency of distal motor nerves and the prolonged latency of F-waves. For the purpose of specification of criteria of inclusion in clinical trials criteria of demyelination were modified. Thaisetthawatkul et al. allocate dispersion of distal complex action potential in muscle fiber as very sensitive diagnostic character of HVDP. Though research criteria are highly specific, their clinical options have to be even more sensitive for the purpose of identification of patients who will need treatment.

Laboratory researches.

Most of experts recommends the analysis of SMZh for the purpose of identification of typical signs of HVDP: increases in protein content and the normal or slightly raised cytosis. At the same time, according to criteria of INCAP, at such patients the lumbar puncture is not obligatory. Sometimes there is a need for expanded laboratory researches for the purpose of identification of other reasons of demyelinating polyneuropathy and associated diseases.

Biopsy of nerves.

The diagnostic value of a neural biopsy (generally sural nerve) at HVDP is very intensively discussed the last several years. Some experts do not consider it as a diagnostic method in general whereas others consider by a key element of diagnosis and treatment more than at 60% of patients. Bosboom et al. compared signs of demyelination, an axonal degeneration, regeneration and an inflammation in bioptata of patients to HVDP and chronic idiopathic axonal polyneuropathy. Pathomorphologic samples at most of persons of both groups were characterized by similar changes. Besides, for several reasons the biopsy of a nerve has no high diagnostic value at an above-mentioned state. The most expressed changes are observed in proximal segments of motor nerves or spinal roots which are not always anatomically available to this procedure. Besides, the simultaneous or secondary axonal changes appearing at early stages of a disease can mask primary signs of demyelination and an inflammation until carrying out a biopsy.

Despite above-mentioned restrictions, this method in certain cases nevertheless it is useful (fig. 1D-G). According to Haq et al., the biopsy of a sural nerve has higher sensitivity, than electrophysiologic researches. Vallat et al is similar. report that at 8 of 44 patients pathomorphologic changes, characteristic of HVDP, even in the absence of electrophysiologic signs of demyelination were observed. It is important to note that 5 patients positively reacted to treatment.

The biopsy is especially recommended at suspicion on HVDP, at patients at whom neural conductivity does not testify to demyelination, or at a probable vasculitis. At inspection of 100 patients with this neurologic frustration of Bouchard et al. proved that axonal destruction was the most sensitive predictive factor of an adverse course of a disease. At the same time demyelination was observed at 71% of patients, the mixed axonal and demyelinating changes at 21% and only axonal destruction — at only 5%.

Tomography.

MRT is used to show gadolinium strengthening (fig. 1B and 1C) and increase in proximal departments of the nerves or spinal roots reflecting active inflammatory process and demyelination of a horse tail or a brachial plexus. Changes from the last (asymmetric hypostasis and strengthening of signal strength in T2 mode) were observed more than at 50% of patients with HVDP. It is interesting that similar changes were present also at patients with distal demyelinating polyneuropathy at IgM of a monoclonal gammapathy.

Treatment of chronic inflammatory demyelinating polyneuropathy:

In general, treatment of a disease to which this article is devoted is directed to blockade of patoimmunny processes, suppression of an inflammation and demyelination with prevention of a secondary degeneration of axons. At the patients who reacted to it therapy should be continued before achievement of the maximum improvement and stabilization therefore there is a need for the supporting treatment which has to be selected individually for each specific patient for the purpose of prevention, decrease in frequency of aggravations and delay of progressing of a disease. The affirmative therapeutic answer consists in notable improvement of motility and sensitivity, and also ability of the patient to daily activity. It is important to remember that infections and feverish states also influence risk of demyelination and can aggravate HVDP symptomatology. Co-administration of neurotoxic drugs or existence of the general diseases which are followed by polineyropatiya theoretically also influences symptomatology.

The most widespread medical approaches at HVDP are intravenous administration of immunoglobulins, a plasma exchange and reception of corticosteroids (tab. 3). Therapy should be begun at the earliest stages of a disease to prevent the progressing demyelination and secondary destruction of axons, i.e. the processes leading to an invalidism. According to the published data, all three above-mentioned approaches, apparently, are equally effective. The choice of a method depends on cost, availability (for example a plasma exchange) and side reactions (especially if it is about heavy persistent side effects of corticosteroids). Approximately at 60–80% of patients from classical HVDP the state improves when using one of the listed approaches in the monotherapy mode, however the long-term forecast in this case depends on timeliness of an initiation of treatment and extent of axonal defeat. Azathioprinum, cyclophosphamide and cyclosporine were long enough used as cure of the second line for the specified disease, however the exact data on their efficiency based on results of the randomized controlled researches are unavailable. For the unclear reasons of advantage of the specified drugs not so impressive at polyneuropathy with development of antibodies to a myelin - connected to a glycoprotein.
In view of probability of the autoimmune reasons of HVDP, and also pathogenetic similarity of this pathology to multiple sclerosis, researches of the immunomodulators which proved the effect at the second disease were conducted. 20 patients from medicamentous and resistant HVDP were included in a prospective, multicenter, open research of interferon β-1a. The drug was administered intramusculary in a dose of 30 mkg weekly throughout a 6-month course of treatment. At 35% of patients improvement whereas stabilization of a disease managed to be reached in 50% of cases therefore authors considered expedient carrying out large-scale placebo - the controlled research was noted. At the same time, other research in which received treatment of 4 sick HVDP, testified that interferon is effective only in combination with intravenous administration of immunoglobulin. Moreover, small, randomized, double blind, placebo the - the controlled, cross research of 10 patients with pharmakorezistentny option of this disease which appointed interferon β-1a (the 3rd time/week subcutaneously of 3 million ME for 2 weeks and 6 million ME for 10 weeks), did not testify reliable advantages of similar treatment. The α-interferon role at HVDP remains not clear, despite single messages and even results of an open prospective pilot research in favor of efficiency of this means.

There are certain fears as according to several messages the mentioned state arises at use as α-and β-interferon. Besides, the last did not testify effect at patients with IgM with a monoclonal gammapathy and a syndrome to Giyena-Barra. Similar observations raised a loaded question about relationship of cause and effect of interferon and HVDP. Hughes et al. came to a conclusion that now there are no strong evidences in favor of efficiency of the mentioned drugs at this type of polyneuropathy.

Other methods of treatment were studied in open researches on small populations or even certain patients. Positive takes were observed at patients with existence in the anamnesis of pharmakorezistentny HVDP against the background of treatment with combinations of a plasma exchange and intravenous administration of immunoglobulins, the mikofenolata mofetit, cyclosporine, an etanersept, cyclophosphamide and autologichesky transplantation of haematopoietic stem cells. At patients with multifocal motor polyneuropathy or HVDP the combination of immunoglobulins and a mikofenolat of a mofetil allowed to reduce a dose of both the first component of the scheme, and corticosteroids that was confirmed in an open research of 6 patients and in the retrospective analysis of 21 patients. In two last large-scale researches at 30 patients with the IgM-associated demyelinating polyneuropathy improvement of a clinical state at treatment rituksimaby which represents a chimeric human monoclone against CD20 antigen was observed, besides it reduces the level of V-lymphocytes. At the same time, data of the randomized, controlled researches with participation of sufficient number of patients on the basis of which the possibility of development of accurate recommendations about treatment by above-mentioned drugs would appear, no. Proofs of efficiency of a plasma exchange, intravenous administration of immunoglobulins and corticosteroids were received only in short-term researches. Experience of certain doctors demonstrates that purpose of immunosuppressors allows to reduce frequency and even to cancel a plasma exchange and treatment by immunoglobulins with considerable economy of expenses. Need of the controlled researches for assessment of long-term aspects of treatment of HVDP is obvious.