Nelson syndrome

Description:

Nelson syndrome - the disease which is characterized by chronic adrenal insufficiency, a hyperpegmentation of integuments, mucous membranes and existence of a tumor of a hypophysis. It arises after removal of adrenal glands at Itsenko-Cushing's disease.

The disease is called by name the scientist Nelson who for the first time in 1958 together with employees described the patient at whom in 3 years after a bilateral adrenalectomy concerning Itsenko-Cushing's disease big chromophobic adenoma of a hypophysis developed.

Reasons of a syndrome of Nelson:

After removal of adrenal glands switching off from a pathogenetic chain of function of bark of adrenal glands creates conditions for deeper disturbances in gipotalamo-pituitary system (a day-night rhythm of secretion of hormones and a feedback mechanism) therefore at Nelson syndrome the AKTG level is always higher, than at patients with Itsenko-Cushing's disease, and has monotonous character within a day, introduction of high doses of dexamethasone does not lead to normalization of the AKTG level.

It is necessary to emphasize that development of a syndrome arises only at a part of the patients subjected to a bilateral total adrenalectomy.

Most of researchers consider that at Itsenko-Cushing's disease and Nelson syndrome there is a uniform pathological process in a hypophysis, but with various stages of disturbance of gipotalamo-pituitary system. After a bilateral total adrenalectomy progressive increase in secretion of AKTG demonstrates hyperplastic process in a hypophysis and formation micro and macrocorticotropin (or kortikomelanotropiny). It is shown that receptors of tumors of a hypophysis lose the specificity, their functions are not autonomous and depend on hypothalamic or central regulation. It is confirmed by the fact that in response to nonspecific stimulators, such as тиролиберин and Metoclopramidum, it is possible to receive at patients with Nelson syndrome AKTG hypersecretion. Specific secretagogues of AKTG, an insulin hypoglycemia and vasopressin at Nelson syndrome considerably increase the AKTG level, and the hypoglycemia reveals considerable reserves of AKTG - above, than at Itsenko-Cushing's disease. It is shown that the receptors which are not functioning in tissue of a normal hypophysis are present in it AKTG-produtsiruyushchikh tumors and thereof the somatostatin which is not influencing secretion of AKTG at the healthy person reduces his secretion at patients with Nelson syndrome.

The pathogeny of a syndrome is directly connected with increase in products of AKTG a hypophysis, its extraadrenal action on melanocytes, metabolism of corticosteroids, etc. For example, at Nelson syndrome of AKTG exerts impact on a xanthopathy and mucous membranes. Action on melanocytes is explained by existence in molecule AKTG of the amino-acid remains which sequence is the general both for molecule AKTG, and for a molecule of alpha MSG. The important role in development of a hyperpegmentation and distribution of influence on melanocytes at Nelson syndrome belongs also beta липотропину and alpha MSG.

Except ability to influence pigmentation, AKTG, as shown in an experiment, has lipolytic activity, hypoglycemic effect owing to increase in secretion of insulin. In experimental works it is also shown that memory, behavior, processes of development of conditioned reflexes and training of experimental animals depend on AKTG or its fragments.

Its influence on peripheral exchange of corticosteroids also belongs to extraadrenal actions of AKTG. Purpose of AKTG to healthy people is followed by increase in speed of metabolism of cortisol, Aldosteronum, cortexone. At patients with Nelson syndrome of AKTG reduces binding of cortisol and its metabolites, accelerates half-life of corticosteroids and participates in redistribution of steroids in an organism. Under the influence of AKTG the speed of formation of connections of metabolites with glucuronic acid decreases and increases with a chamois. Also the speed of transformation of cortisol in 6 - beta oxycortisol increases and time of half-decay of cortisol decreases. Thus, the extraadrenal effect of AKTG causing the accelerated metabolism of glucocorticoid and mineralokortikoidny hormones explains the increased requirement at patients with Nelson syndrome in synthetic analogs of hormones for compensation of adrenal insufficiency.

Formation of testicular, paratesticular and paraovarian tumors is also directly connected with extraadrenal action of AKTG at Nelson syndrome. Development of neoplastic process results from long stimulation of AKTG on steroidosekretiruyushchy cells of gonads. In a paratesticular tumor secretion of cortisol which was controlled by AKTG was found. Decrease in its level tsiprogiptatsiny led to reduction of products of cortisol. The paraovarian tumor caused in the patient a virial syndrome due to synthesizing of androgens, generally testosterone. Level of testosterone depended on extent of secretion of AKTG: at purpose of dexamethasone it decreased and increased at exogenous administration of hormone. Tumors of gonads, testicles and ovaries at Nelson syndrome are similar on clinical shows and synthesis of hormones to tumors of gonads at patients with inborn dysfunction of bark of adrenal glands owing to long hypersecretion of AKTG.

The data on impact of various substances on corticotropic cells which are saved up now say that functional activity of tumors of a hypophysis at patients with Nelson syndrome is caused by hypothalamic and central influences.

Symptoms of a syndrome of Nelson:

Clinical manifestations of a syndrome of Nelson consist of the following symptoms: the progressing hyperpegmentation of integuments, chronic adrenal insufficiency, AKTG-produtsiruyushchey hypophysis tumors - kortikotropinoma, ophthalmologic and neurologic disturbances. The syndrome develops at patients with BIC through different periods after a bilateral total adrenalectomy, from several months to 20 years. As a rule, the syndrome arises at young age within 6 years after operation.

The hyperpegmentation of integuments is a pathognomonic symptom of a syndrome of Nelson. Most often it is the first symptom of a disease, and sometimes it long remains the only display of a disease (at slowly growing hypophysis microadenomas). Distribution of adjournment of a pigment in skin happens as well as at Addison's disease. Integuments are considerably painted in color of suntan on open parts of a body and places of friction: a face, a neck, hands, on a belt, in axillary areas. Coloring of mucous membranes of an oral cavity and anus in the form of spots is characteristic. The expressed pigmentation is noted in postoperative seams. Development of a melanoderma at Nelson syndrome depends on secretion of AKTG and beta липотропина. There is a correlation between degree of a melanoderma and the maintenance of AKTG in plasma. Patients with a black shade have skin and dark-violet coloring of mucous membranes the maintenance of AKTG made more than 1000 ng/ml. The hyperpegmentation expressed only in places of a greniye and postoperative seams is followed by increase in AKTG up to 300 mg/ml. The melanoderma at Nelson syndrome can decrease considerably against the background of adequate replacement therapy by corticosteroids and amplify against the background of a decompensation. Without treatment directed to decrease in secretory activity of a hypophysis and normalization of allocation of AKTG by it the hyperpegmentation is not eliminated.

Adrenal insufficiency at Nelson syndrome is noted by a labile current. Patients need high doses of drugs glyuko-and mineralokortikoidny action. The need for high doses of hormones for compensation of exchange processes is connected with the increased degradation of the entered synthetic hormones under the influence of hypersecretion of AKTG kortikotropinomy. Adrenal insufficiency at Nelson syndrome decompensates without the visible reasons much more often and is followed by development of small and big crises. At small crises at patients weakness, deterioration in appetite, a joint pain, a lowering of arterial pressure are noted. Big crises can suddenly arise: there are nausea, vomiting, a liquid chair, abdominal pains, the expressed adynamia, muscle, joints pains amplify. Arterial pressure decreases, body temperature sometimes increases to 39 C, there is tachycardia.

At crisis of adrenal insufficiency at patients with Nelson syndrome arterial pressure can not decrease, and raise. If during crisis abdominal symptoms prevail, they can be regarded as development of "acute abdomen". It leads to diagnostic mistakes and the wrong tactics of treatment. The increased or normal arterial pressure found during crisis in patients with Nelson syndrome also sometimes leads to a diagnostic mistake and the wrong medical tactics. Parenteral replacement therapy by a hydrocortisone and cortexone quickly eliminates with acetate (DOKSA) symptoms of "acute abdomen", leads to normalization of arterial pressure and helps to avoid unjustified operative measures.

At Nelson syndrome the neuroophthalmologic symptoms characteristic of patients at which the kortikotropinoma has the progressing growth and goes beyond the Turkish saddle are observed. The most characteristic is the hiazmalny syndrome. At the same time the biotemporal hemianopsia and primary atrophy of optic nerves of different degree of manifestation develops. In certain cases the bitemporal hemianopsia arises also at endosellyarny adenomas owing to disturbance of blood supply in a hiazma. Later changes on an eyeground which are expressed as an atrophy of nipples of optic nerves develop. As a result visual acuity decreases, and its total loss is sometimes observed.

The psychoneurological changes characteristic of Nelson syndrome are connected both with a condition of compensation of adrenal insufficiency, and with the size and localization of a tumor of a hypophysis and the increased AKTG level. Results of neurologic inspection of 25 patients with Nelson syndrome in clinic of Institute of experimental endocrinology and chemistry of hormones (ИИЭиХГ) the Russian Academies of Medical Science with the doctor of medical sciences V. M. Prikhozhan allowed to note a number of clinical features. In the psychoneurological status at patients with Nelson syndrome unlike control group of patients after a bilateral total adrenalectomy increase of astenofobichesky and astheno-depressive syndromes, and also emergence of a neurotic syndrome was revealed. Many patients against the background of Nelson syndrome had an expressed emotional instability, decrease in a background of mood, uneasiness, suspiciousness.

At the kortikotropinoma causing Nelson syndrome spontaneous hemorrhages in a tumor are possible. As a result of a heart attack of a tumor decrease or normalization of secretion of AKTG is found. Disturbances from secretion of other tropny hormones at the same time were not found. At hemorrhage in a hypophysis tumor patients had a neurologic symptomatology as an ophthalmoplegia (unilateral paralysis of a third cranial nerve) and a severe form of adrenal insufficiency. Increase in a dose of a hydrocortisone and DOKSA led to normalization of function of a third cranial nerve, disappearance of a ptosis and reduction of a melanoderma.

When the tumor reaches the big sizes, at patients the neurologic symptoms of a disease depending on the direction of growth of a tumor are noted. At antesellyarny distribution disturbances of sense of smell and mental disorders come to light, at parasellyarny there are defeats III, IV, V and VI couples of cranial nerves. With a growth of a tumor up, in a cavity of the III ventricle, all-brain symptoms appear.

Studying of electric activity of a brain at patients with Nelson syndrome was carried out in clinic ИЭЭиХГ of the Russian Academy of Medical Science by the senior research associate G. M. Frenkel. Dynamics of electroencephalograms was observed within 6-10 years at 14 patients with Itsenko-Cushing's disease before emergence of Nelson syndrome at them. The tumor of a hypophysis came to light at 11 patients. Nelson syndrome was diagnosed in 2-9 years after removal of adrenal glands. Before operation and in 0,5-2 later on EEG the expressed alpha activity with weak reaction to light and sound irritants was observed. Tracing of dynamics of electroencephalograms for 9 years found out that most of patients with a postoperative syndrome of Nelson on EEG has lines testimonial of increase in activity of a hypothalamus before the hypophysis tumor radiological comes to light. In record during this period are registered the high-amplitude alpha rhythm irradiating on all assignments, sometimes in the form of categories. At increase in a tumor in sizes there are specific records in the form of categories 6-of waves which were more expressed in front assignments. The obtained data on increase in electroactivity of a brain at patients with Nelson syndrome confirm the fact that the interruption of "feedback" arising during removal of adrenal glands at patients with Itsenko-Cushing's disease leads to uncontrollable increase in activity of gipotalamo-pituitary system. The diagnosis of a syndrome of Nelson is made on the basis of emergence in patients after a bilateral total adrenalectomy of a hyperpegmentation of integuments, the labile course of adrenal insufficiency, change of structure of the Turkish saddle and detection of high content of AKTG in a blood plasma. Dispensary dynamic observation of the patients with Itsenko-Cushing's disease who transferred removal of adrenal glands allows to distinguish Nelson syndrome earlier.

Strengthening of pigmentation on a neck in the form of "necklace" and a symptom of "dirty elbows", adjournment of a pigment in postoperative seams can be a precursory symptom of a melanoderma.

The labile course of adrenal insufficiency is characteristic of most of patients with Nelson syndrome. High doses glyuko-and mineralokortikoid for compensation of exchange processes are required. The recovery period from different intercurrent diseases proceeds is longer and it is heavier, than at patients is after removal of adrenal glands without Nelson syndrome. Existence of difficulties in compensation of adrenal insufficiency, the increased need for mineralokortikoidny hormones also happen signs of development of a syndrome of Nelson in patients after an adrenalectomy concerning Itsenko-Cushing's disease.

Diagnosis:

Important criterion in diagnosis of a syndrome of Nelson is determination of content of AKTG in plasma. Increase in its level in the morning and at night above what on 200 pg/ml is characteristic of development of a kortikotropinoma.

Diagnosis of a tumor of a hypophysis at Nelson syndrome is complicated. Kortikotropinoma are often microadenomas and a long time, being located in the Turkish saddle, do not break its structure. At small adenomas of a hypophysis at Nelson syndrome the Turkish saddle by the sizes is on the upper bound of norm or slightly increases. In these cases on side kraniogramma and roentgenograms with direct increase, and also a tomographic research early symptoms of development of a tumor of a hypophysis allow to distinguish its detailed studying. Diagnosis of the developed and big adenoma of a hypophysis does not represent complexity. The developed hypophysis adenoma usually is characterized by increase in the sizes of the Turkish saddle, straightening, thinning or destruction of walls. Destruction of wedge-shaped shoots, deepening of a bottom of a saddle testify to the growing hypophysis tumor. At a big tumor expansion of an entrance to the Turkish saddle, shortening of wedge-shaped shoots is observed, i.e. the symptoms characteristic for supra-, an anti-, retro and introsellyarny arrangement of a tumor appear. At use of additional methods of a research (the tomography at a pneumoencephalography, flebografiya of a cavernous sine and a computer tomography) can obtain more exact data on a condition of the Turkish saddle and an arrangement of a tumor of a hypophysis beyond its limits.

In diagnosis of a syndrome of Nelson is of great importance ophthalmologic, neurophysiological and neurologic researches of patients. Change of an eyeground, disturbance of side sight, decrease in sharpness up to total loss, a ptosis of an upper eyelid are characteristic of patients with Nelson syndrome. Extent of disturbance of an organ of sight is an important factor for the choice of adequate therapy. Elektroentsefalografichesky researches can help early diagnosis of a syndrome of Nelson in certain cases.

Treatment of a syndrome of Nelson:

Treatment of a syndrome of Nelson is directed to compensation of chronic adrenal insufficiency and impact on gipotalamo-pituitary system. Various methods suppressing secretion of AKTG and preventing growth and development of a kortikotropinoma are applied to treatment of a syndrome. Drug treatment, beam impact on a hypophysis and a surgical oncotomy are used.

From the drugs used at drug treatment, overwhelming effect is had on secretion of AKTG a serotoninovy blocker - ципрогентадин, a stimulator of dopamine secretion - Bromocriptinum, and also Convulexum (sodium Valproatum) suppressing products of AKTG by strengthening of synthesis of piperidic acid (GAMK) in a hypothalamus.

From beam methods of treatment both different types of tele-irradiation, and intersticial are used now. Gamma irradiation, a proton bunch concerns to the first. By an intersticial method reach partial destruction of a hypophysis what apply various radioactive sources to, 90It or 198Au which enter directly into hypophysis tissue.

Medicamentous and radiation therapy is used at treatment of patients with the tumor of a hypophysis which is not going beyond the Turkish saddle and are not applied at more extensive tumors. Besides, the indication to medicamentous and radiation therapy are a recurrence or partial therapeutic effect from a surgical method of treatment. Carrying out radiation by a proton bunch led to decrease in pigmentation and reduction of secretion of AKTG. Introduction 90It or 198ai in a cavity of the Turkish saddle yielded positive takes at all patients of the control group consisting of 8 people.

In clinic ИЭЭиХГ of the Russian Academy of Medical Science to 29 patients with Nelson syndrome gamma irradiation in a dose of 45-50 Gr was carried out. In 4-8 months after that at 23 of them decrease in a hyperpegmentation of integuments is revealed, at the 3rd the melanoderma completely disappeared. Elimination of a heavy labile course of the adrenal insufficiency characteristic of not treated syndrome of Nelson was important reflection of positive effect from radiation. At other three patients in the absence of effect of treatment the further progressing growth of a tumor of a hypophysis was observed.

The operational method of removal is applied by corticotropin both at microadenomas, and at big tumors. Lately the method of microsurgical intervention with transsphenoidal access was widely adopted. This method is applied at the tumors growing down. At the big, invasive, growing up hypophysis tumors at patients with Nelson syndrome use transfrontal access. Results of surgical treatment at small tumors it is better, than at adenomas with widespread growth. In spite of the fact that the microsurgical equipment provides in most cases full removal of pathological fabric, after use of an operational method there is disease recurrence.

Quite often at treatment of a syndrome of Nelson it is necessary to resort to a combination therapy. In the absence of remission of a disease after beam treatment appoint cyproheptadine, Parlodelum, Convulexum. At impossibility to completely remove a tumor in the surgical way apply the radiation of a hypophysis or drugs suppressing secretion of AKTG.

The forecast of a disease depends on dynamics of development of adenoma of a hypophysis and extent of compensation of adrenal insufficiency. At slow development of tumoral process and compensation of adrenal insufficiency a condition of patients the long time can remain satisfactory.

Working capacity almost at all is limited. Dispensary observation of the endocrinologist, neuropathologist and oculist is necessary.

Prevention of a syndrome of Nelson. Most of authors recognize that to prevent development of a syndrome and big tumors it is easier, than to treat Nelson syndrome with widespread processes outside the Turkish saddle. Preliminary radiation therapy on area of a hypophysis of patients with Itsenko-Cushing's disease, according to most of authors, does not prevent development of a syndrome. For prevention irrespective of preliminary radiation of a hypophysis at Itsenko-Cushing's disease after a bilateral total adrenalectomy it is necessary to conduct annually a radiographic research of the Turkish saddle, fields of vision and the maintenance of AKTG in a blood plasma.