Nelson's syndrome

Nelson's syndrome is a disease characterized by chronic adrenal insufficiency, hyperpigmentation of the skin, mucous membranes and the presence of a pituitary tumor. It occurs after removal of the adrenal glands during the Itenko-Cushing disease.

The disease was named after the scientist Nelson, who for the first time in 1958 together with his co-workers described a patient who, 3 years after bilateral adrenalectomy, developed a large chromophobic adenoma of the pituitary gland about the Itenko-Cushing disease.

[1], [2], [3],

Causes of the nelson's syndrome

After removal of the adrenal glands, the exclusion of the function of the adrenal cortex from the pathogenetic chain creates conditions for deeper disturbances in the hypothalamic-pituitary system (the daily rhythm of hormone secretion and the feedback mechanism), which results in the ACTH level always higher in Nelson's syndrome than in patients with Isenko- Cushing's, and is monotonous during the day, the introduction of large doses of dexamethasone does not lead to a normalization of the ACTH level.

It should be emphasized that the development of the syndrome occurs only in a part of patients subjected to bilateral total adrenalectomy.

Most researchers believe that with the Itenko-Cushing disease and Nelson's syndrome, there is a single pathological process in the pituitary gland, but with different stages of the hypothalamic-pituitary system. After bilateral total adrenalectomy, a progressive increase in ACTH secretion indicates a hyperplastic process in the pituitary gland and the formation of micro- and macrocorticotropin (or corticomelanotropin). It is shown that receptors of pituitary tumors lose their specificity, their functions are not autonomous and depend on hypothalamic or central regulation. This is confirmed by the fact that in response to nonspecific stimulants, such as tiroliberin and metoclopramide, hypersecretion of ACTH can be obtained in patients with Nelson's syndrome. Specific stimulants of ACTH secretion, insulin hypoglycemia and vasopressin in Nelson's syndrome significantly increase the level of ACTH, and hypoglycemia reveals significant reserves of ACTH - higher than with Itenko-Cushing's disease. It was shown that receptors that do not function in normal pituitary tissue are present in its ACTH-producing tumors, and consequently somatostatin, which does not affect the secretion of ACTH in a healthy person, reduces its secretion in patients with Nelson's syndrome.

[4], [5], [6], [7], [8]

Pathogenesis

The pathogenesis of the syndrome is directly related to the increase in the production of ACTH by the pituitary gland, its non-adrenal effect on melanocytes, the metabolism of corticosteroids, etc. For example, in Nelson's syndrome, ACTH exerts an effect on the pigmentation of the skin and mucous membranes. The effect on melanocytes is explained by the presence of amino acid residues in the ACTH molecule, the sequence of which is common for both the ACTH molecule and the alpha-MSH molecule. An important role in the development of hyperpigmentation and the spread of influence on melanocytes in Nelson's syndrome also belongs to beta-lipotropin and alpha-MSH.

In addition to the ability to influence pigmentation, ACTH, as shown in the experiment, has lipolytic activity, a hypoglycemic effect due to increased secretion of insulin. In experimental studies, it has also been demonstrated that memory, behavior, conditioned reflexes and training of experimental animals depend on ACTH or its fragments.

The influence of the ACTH on the peripheral exchange of corticosteroids also belongs to the adrenal gland ACTH. Assignment of ACTH to healthy people is accompanied by an increase in the metabolic rate of cortisol, aldosterone, deoxycorticosterone. In patients with Nelson's syndrome, ACTH decreases the binding of cortisol and its metabolites, accelerates the half-life of corticosteroids, and participates in the redistribution of steroids in the body. Under the influence of ACTH, the rate of formation of metabolites with glucuronic acid decreases and increases with sulfuric acid. The rate of conversion of cortisol to 6-beta-oxycortisol is also increased, and the half-life of cortisol is reduced. Thus, the adrenal-mediated effect of ACTH, which causes an accelerated metabolism of glucocorticoid and mineralocorticoid hormones, explains the increased need in patients with Nelson's syndrome in synthetic analogs of hormones to compensate for adrenal insufficiency.

The formation of testicular, paratesticular and parovarial tumors is also directly related to the adrenal-mediated ACTH action in Nelson's syndrome. The development of the neoplastic process occurs as a result of prolonged stimulation of ACTH on the steroid-secreting cells of the sexual glands. In the paratesticular tumor, secretion of cortisol was detected, which was controlled by ACTH. A decrease in its level of ciprohyptacin resulted in a decrease in the production of cortisol. Paraovarial tumor caused virial syndrome in the patient due to the synthesis of androgens, mainly testosterone. The level of testosterone depended on the degree of secretion of ACTH: with the appointment of dexamethasone, it decreased and increased with exogenous administration of the hormone. Tumors of the gonads, testicles and ovaries in Nelson's syndrome are similar in clinical manifestations and the synthesis of hormones with tumors of the gonads in patients with congenital adrenal cortex dysfunction due to prolonged hypersecretion of ACTH.

The accumulated data on the effect of various substances on corticotropic cells suggest that the functional activity of pituitary tumors in patients with Nelson's syndrome is determined by hypothalamic and central influences.

Pathanatomy

With Nelson's syndrome, 90% of patients have a chromophobic adenoma of the pituitary gland, which almost does not differ in structure from tumors that occur in the Itenko-Cushing disease. The only difference is the absence in the adenohypophysis of the Krukov cells, characteristic of hypercorticism. Undifferentiated adenomas with mucoid cells are also described. The use of modern methods - electron microscopy and immunohistochemistry - has shown that both types of tumors consist of corticotropic cells. In light microscopy, mainly star-shaped cells are found; their nuclei are well pronounced. The cells form strands surrounded by capillaries. Electron microscopy reveals mainly tumor corticotrophs with a pronounced Golgi apparatus, numerous small mitochondria, often irregular in shape. Lysosomes are detected in many cells. With Nelson's syndrome, most corticotropin is benign, malignant are rare.

[9], [10], [11]

Symptoms of the nelson's syndrome

Clinical manifestations of Nelson's syndrome consist of the following symptoms: progressive hyperpigmentation of the skin, chronic adrenal insufficiency, ACTH-producing pituitary tumor-corticotropinoma, ophthalmic and neurological disorders. The syndrome develops in patients with BIC at different time intervals after bilateral total adrenalectomy, from several months to 20 years. Typically, the syndrome occurs at a young age for 6 years after surgery.

Hyperpigmentation of the skin is a pathognomonic symptom of Nelson's syndrome. Most often this is the first sign of the disease, and sometimes it remains the only manifestation of the disease for a long time (with slowly growing pituitary microadenomas). The distribution of the pigment in the skin occurs in the same way as in Addison's disease. Significantly colored skin in the color of sunburn on open parts of the body and places of friction: face, neck, hands, on the belt, in the axillary areas. It is characteristic staining of the mucous membranes of the oral cavity and the anus as spots. The marked pigmentation is noted in the postoperative sutures. The development of melasma in Nelson's syndrome depends on the secretion of ACTH and beta-lipotropin. There is a correlation between the degree of melasma and the content of ACTH in the plasma. In patients with black skin tone and dark-violet color of mucous membranes, ACTH content was more than 1000 ng / ml. Hyperpigmentation, expressed only in the places of gritting and postoperative sutures, is accompanied by an increase in ACTH to 300 mg / ml. Melasma in Nelson's syndrome can be significantly reduced against the background of adequate replacement therapy with corticosteroids and intensify against decompensation. Without treatment aimed at reducing the secretory activity of the pituitary gland and normalizing the release of ACTH, hyperpigmentation is not eliminated.

Adrenal insufficiency in Nelson's syndrome is marked by a labile course. Patients need large doses of gluco- and mineralocorticoid drugs. The need for large doses of hormones to compensate for metabolic processes is associated with increased degradation of the introduced synthetic hormones under the influence of hypersecretion of ACTH by corticotrophinoma. Adrenal insufficiency in Nelson's syndrome is much more often decompensated for no apparent reason and is accompanied by the development of small and large crises. At small crises, patients suffer from weakness, worsening of appetite, joint pain, and lowering of blood pressure. Large crises can occur suddenly: nausea, vomiting, loose stools, abdominal pain, pronounced adynamia, pain in the muscles, joints. Arterial pressure decreases, body temperature sometimes rises to 39 C, there is a tachycardia.

With the crisis of adrenal insufficiency in patients with Nelson's syndrome, blood pressure may not decrease, but increase. If abdominal symptoms predominate during a crisis, they can be regarded as the development of an "acute abdomen". This leads to diagnostic errors and incorrect treatment tactics. Elevated or normal blood pressure detected during a crisis in patients with Nelson's syndrome also sometimes leads to a diagnostic error and improper medical tactics. Parenteral replacement therapy with hydrocortisone and deoxycorticosterone acetate (DOXA) quickly eliminates the symptoms of the "acute abdomen", leads to normalization of blood pressure and helps to avoid unnecessary surgical interventions.

In Nelson's syndrome, there are neurological symptoms characteristic of patients with corticotropinoma that has progressive growth and extends beyond the Turkish saddle. The most characteristic is the chiasmatic syndrome. At the same time, biotemporal hemianopsia develops and primary atrophy of optic nerves of different degree of severity. In some cases, bitemporal hemianopsia also occurs in endosyellar adenomas due to impaired blood flow in the chiasm. Later changes develop on the fundus, which are expressed in the form of atrophy of the nipples of the optic nerves. As a result, the visual acuity decreases, and sometimes its complete loss is observed.

The neuropsychiatric changes characteristic of Nelson's syndrome are related both to the state of compensation of adrenal insufficiency, and to the magnitude and localization of the pituitary tumor and elevated levels of ACTH. Results of a neurological examination of 25 patients with Nelson's syndrome in the clinic of the Institute of Experimental Endocrinology and Chemistry of Hormones (IIEiHC) by the RAMS doctor honey. VM Prikhozhan allowed to note a number of clinical features. In the psychoneurological status in patients with Nelson's syndrome, in contrast to the control group of patients after bilateral total adrenalectomy, asthenophobic and asthenodepressive syndromes increased, as well as the appearance of a neurotic syndrome. In many patients on the background of Nelson's syndrome there was a pronounced emotional instability, a decrease in the background of mood, anxiety, suspiciousness.

With corticotropin, which causes Nelson's syndrome, spontaneous hemorrhages to the tumor are possible. As a result of a tumor infarct, a decrease or normalization of ACTH secretion is detected. Violations from the secretion of other tropic hormones were not detected. With a hemorrhage into the pituitary tumor, neurological symptoms, such as ophthalmoplegia (unilateral paralysis of the oculomotor nerve), and a severe form of adrenal insufficiency appeared in patients. An increase in the dose of hydrocortisone and DOXA led to the normalization of oculomotor nerve function, the disappearance of ptosis and the reduction of melasma.

When the tumor reaches a large size, the patients have neurological symptoms of the disease, depending on the direction of tumor growth. During antesellar proliferation, smear and mental disorders are detected, paraselymal lesions of III, IV, V and VI pairs of cranial nerves occur. With the growth of the tumor upward, into the cavity of the third ventricle, there are general cerebral symptoms.

The study of the electrical activity of the brain in patients with Nelson's syndrome was carried out in the IEEiHH Clinic of the Russian Academy of Medical Sciences by senior researcher G. M. Frenkel. The dynamics of the electroencephalogram was observed for 6-10 years in 14 patients with Isenko-Cushing's disease before and after the onset of Nelson's syndrome. Pituitary tumors were detected in 11 patients. Nelson's syndrome was diagnosed 2-9 years after removal of the adrenal glands. Before the operation and 0.5-2 years later, a marked alpha activity was observed on the EEG with a weak response to light and sound stimuli. Tracing the dynamics of electroencephalograms for 9 years found that most patients with Nelson's postoperative syndrome on EEG appear features that indicate an increase in the activity of the hypothalamus, before the pituitary tumor is radioliologically detected. In the recording during this period, a high-amplitude alpha rhythm is recorded, irradiating over all leads, sometimes in the form of discharges. When the tumor increases in size, specific records appear in the form of 6-wave discharges, more pronounced in the anterior leads. The obtained data on the increase of brain electro activity in patients with Nelson's syndrome are confirmed by the fact that the interruption of the "feedback" that occurs when the adrenal gland is removed from patients with Isenko-Cushing disease leads to an uncontrolled increase in the activity of the hypothalamic-pituitary system. The diagnosis of Nelson's syndrome is based on the appearance in patients after bilateral total adrenalectomy of hyperpigmentation of the skin, labile course of adrenal insufficiency, changes in the structure of the Turkish saddle and detection of a high content of ACTH in the blood plasma. Clinical follow-up of patients with Isenko-Cushing's disease who underwent removal of the adrenal glands allows earlier recognition of Nelson's syndrome.

An early sign of melasma is the increased pigmentation on the neck in the form of a "necklace" and a symptom of "dirty elbows", the deposition of the pigment into the postoperative sutures.

The labile course of adrenal insufficiency is characteristic of most patients with Nelson's syndrome. Large doses of gluco- and mineralocorticoids are required to compensate for metabolic processes. The recovery period from different intercurrent diseases is longer and heavier than in patients after removal of the adrenal gland without Nelson's syndrome. The presence of difficulties in compensating adrenal insufficiency, an increased need for mineralocorticoid hormones also are signs of the development of Nelson's syndrome in patients after adrenalectomy for the Itenko-Cushing disease.

Diagnostics of the nelson's syndrome

An important criterion in the diagnosis of Nelson's syndrome is the determination of ACTH in the plasma. An increase in its level in the morning and at night is higher than 200 pg / ml is characteristic for the development of corticotropinoma.

Diagnosis of a pituitary tumor in Nelson's syndrome is difficult. Corticotropinomas are often microadenomas and for a long time, located inside the Turkish saddle, do not disturb its structure. With small adenomas of the pituitary gland in Nelson's syndrome, the Turkish saddle is at the upper limit of the norm or slightly increased. In these cases, a detailed examination of the lateral craniograms and radiographs with direct magnification, as well as tomographic examination, allow one to recognize early symptoms of the development of the pituitary tumor. Diagnosis of the developed and large adenoma of the pituitary gland is not difficult. The developing adenoma of the pituitary gland is usually characterized by an increase in the size of the Turkish saddle, straightening, thinning or destruction of the walls. The destruction of the wedge-shaped processes, the deepening of the bottom of the saddle, indicate a growing tumor of the pituitary gland. With a large tumor, there is an increase in the entrance to the Turkish saddle, shortening of the wedge-shaped processes, i.e. Symptoms appear that are characteristic of supra-, ante-, retro- and introsellar location of the tumor. With the use of additional methods of investigation (tomography in pneumoencephalography, phlebography of cavernous sinus and computed tomography ), it is possible to obtain more accurate data on the state of the Turkish saddle and the location of the pituitary tumor beyond its limits.

In the diagnosis of Nelson's syndrome, ophthalmological, neurophysiological and neurological studies of patients are of great importance. Changes in the fundus, impaired lateral vision, reduced severity until complete loss, ptosis of the upper eyelid are characteristic of patients with Nelson's syndrome. The degree of visual impairment is an important factor in the choice of adequate therapy. Electroencephalographic studies may in some cases help the early diagnosis of Nelson's syndrome.

[12], [13]

Differential diagnosis

In Nelson's syndrome, a diagnosis should be made with the Itenko-Cushing syndrome caused by an ectopic tumor secreting ACTH. These tumors, both the non-endocrine system and the endocrine glands, produce ACTH, which leads to hyperplasia of the adrenal cortex and development of the Itenko-Cushing syndrome. Often, ectopic tumors are small in size, and their location is difficult to diagnose. The Itenko-Cushing syndrome in an ectopic tumor is accompanied by hyperpigmentation of the skin and proceeds with a severe hypercorticism clinic. The condition of patients after removal of the adrenal gland is improving. But the growth of the tumor, ectopic in any organ, progresses, the content of ACTH increases, and the hyperpigmentation increases.

Especially difficult is the differential diagnosis between Nelson's syndrome and the ectopic tumor after bilateral adrenalectomy, if there is insufficient evidence of a pituitary tumor. In these cases, a thorough clinical and computer examination should be undertaken to find the location of the ectopic tumor. Most often these tumors are found in bronchi, mediastinum (thymoma, chemodectomy), pancreas and thyroid gland.

ACTH plasma content in ectopic tumors arising from the Itenko-Cushing syndrome has been increased to the same extent as in Nelson's syndrome.

Treatment of the nelson's syndrome

The treatment of Nelson's syndrome is aimed at compensating chronic adrenal insufficiency and affecting the hypothalamic-pituitary system. To treat the syndrome, various methods are used that suppress the secretion of ACTH and prevent the growth and development of corticotropinoma. Medical treatment, radiation on the pituitary gland and surgical removal of the tumor are used.

Of the drugs used in drug treatment, ACTH has a suppressive effect on serotonin blocker - cyprogentidine, dopamine secretion stimulant - bromocriptine, and also convulex (sodium valproate), which suppresses ACTH production by enhancing the synthesis of gamma-aminobutyric acid (GABA) in the hypothalamus.

Of radiation methods of treatment, various types of remote irradiation, as well as interstitial ones, are currently used. The first includes irradiation with gamma rays, a proton beam. The interstitial method achieves partial destruction of the pituitary gland by using various radioactive sources, ⁹⁰ It or ¹⁹⁸ Au, which are injected directly into the pituitary tissue.

Medication and radiation therapy is used in the treatment of patients with a pituitary tumor that does not extend beyond the Turkish saddle and is not used for larger tumors. In addition, indications for drug and radiation therapy are relapses or a partial therapeutic effect of the surgical method of treatment. The irradiation with a proton beam led to a decrease in pigmentation and a decrease in the secretion of ACTH. The introduction of ⁹⁰ It or ¹⁹⁸ Au into the cavity of the Turkish saddle gave positive results in all patients of the control group consisting of 8 people.

At the IEEiHHII RAMS clinic, 29 patients with Nelson's syndrome were irradiated with gamma rays at a dose of 45-50 Gy. After 4-8 months, 23 of them showed a decrease in hyperpigmentation of the skin, and 3 melanoderma completely disappeared. An important reflection of the positive effect of irradiation was the elimination of the severe labile course of adrenal insufficiency characteristic of untreated Nelson's syndrome. In the remaining three patients, in the absence of the effect of treatment, further progressive growth of the pituitary tumor was observed.

An operative method for the removal of corticotropin is used in both microadenomas and large tumors. Recently, a method of microsurgical intervention with transsphenoidal access has become widespread. This method is used for tumors growing down. With large, invasive, up-growing tumors of the pituitary gland, patients with Nelson's syndrome use transfrontal access. The results of surgical treatment with small tumors are better than with adenomas with common growth. Despite the fact that the microsurgical technique provides in most cases complete removal of pathological tissue, after the application of the operative method, there are relapses of the disease.

Often, in the treatment of Nelson's syndrome, combined therapy is necessary. In the absence of remission of the disease after radiation treatment, it is prescribed cyproheptadine, parlodel, and convullex. If it is not possible to remove the tumor completely surgically, pituitary irradiation or drugs that suppress the secretion of ACTH are used.

Prevention

Most authors admit that it is easier to prevent the development of the syndrome and larger tumors than to treat Nelson's syndrome with common processes outside the Turkish saddle. Preliminary radiation therapy on the pituitary area of patients with Isenko-Cushing's disease, according to the majority of authors, does not prevent the development of the syndrome. In order to prevent, irrespective of the preliminary exposure to the pituitary in the course of the Itenko-Cushing's disease, after a bilateral total adrenalectomy, it is necessary to perform an X-ray examination of the Turkish saddle, the fields of vision and the content of ACTH in the blood plasma.

[14], [15], [16], [17], [18], [19],

Forecast

The prognosis of the disease depends on the dynamics of pituitary adenoma and the degree of compensation of adrenal insufficiency. With the slow development of the tumor process and compensation of adrenal insufficiency, the condition of patients for a long time can remain satisfactory.

Almost everyone has a disability. It is necessary to monitor the endocrinologist, neurologist and ophthalmologist.

[20], [21], [22],