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 in Itsenko-Cushing's disease.

The disease is named after the scientist Nelson, who in 1958, together with his colleagues, first described a patient who, 3 years after bilateral adrenalectomy for Itsenko-Cushing's disease, developed a large chromophobe adenoma of the pituitary gland.

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Causes Nelson's syndrome

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

It should be emphasized that the development of the syndrome occurs only in a portion of patients who have undergone bilateral total adrenalectomy.

Most researchers believe that Itsenko-Cushing's disease and Nelson's syndrome involve a single pathological process in the pituitary gland, but with different stages of hypothalamic-pituitary system dysfunction. After bilateral total adrenalectomy, progressive increase in ACTH secretion indicates a hyperplastic process in the pituitary gland and the formation of micro- and macrocorticotropin (or corticomelanotropin). It has been shown that pituitary tumor receptors 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 thyroliberin and metoclopramide, hypersecretion of ACTH can be obtained in patients with Nelson's syndrome. Specific stimulators of ACTH secretion, insulin hypoglycemia and vasopressin in Nelson syndrome significantly increase the level of ACTH, and hypoglycemia reveals significant reserves of ACTH - higher than in Itsenko-Cushing disease. It has been shown that receptors that do not function in the tissue of the normal pituitary gland are present in its ACTH-producing tumors, and as a result, somatostatin, which does not affect the secretion of ACTH in a healthy person, reduces its secretion in patients with Nelson syndrome.

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Pathogenesis

The pathogenesis of the syndrome is directly related to the increased production of ACTH by the pituitary gland, its extra-adrenal effect on melanocytes, corticosteroid metabolism, etc. For example, in Nelson syndrome, ACTH affects 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 to both the ACTH molecule and the alpha-MSH molecule. Beta-lipotropin and alpha-MSH also play an important role in the development of hyperpigmentation and the spread of the effect on melanocytes in Nelson syndrome.

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

The extra-adrenal effects of ACTH also include its effect on the peripheral metabolism of corticosteroids. The administration of ACTH to healthy individuals is accompanied by an increase in the rate of metabolism of cortisol, aldosterone, and deoxycorticosterone. In patients with Nelson syndrome, ACTH reduces 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 metabolite compounds with glucuronic acid decreases and increases with sulfuric acid. The rate of conversion of cortisol to 6-beta-oxycortisol also increases and the half-life of cortisol decreases. Thus, the extra-adrenal effect of ACTH, causing accelerated metabolism of glucocorticoid and mineralocorticoid hormones, explains the increased need in patients with Nelson syndrome for synthetic analogs of hormones to compensate for adrenal insufficiency.

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

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

Pathological anatomy

In Nelson syndrome, 90% of patients have a chromophobe pituitary adenoma, which is almost indistinguishable in structure from tumors found in Itsenko-Cushing disease. The only difference is the absence of Crook's cells in the adenohypophysis, which are characteristic of hypercorticism. Undifferentiated adenomas with mucoid cells have also been described. The use of modern methods - electron microscopy and immunohistochemistry - has shown that both types of tumors consist of corticotropic cells. Light microscopy mainly reveals star-shaped cells; their nuclei are well defined. The cells form cords surrounded by capillaries. Electron microscopy mainly reveals tumor corticotrophs with a pronounced Golgi apparatus, numerous small mitochondria, often of irregular shape. Lysosomes are determined in many cells. In Nelson syndrome, most corticotropinomas are benign; malignant ones are rare.

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Symptoms Nelson's syndrome

Clinical manifestations of Nelson syndrome consist of the following symptoms: progressive hyperpigmentation of the skin, chronic adrenal insufficiency, ACTH-producing pituitary tumor - corticotropinoma, ophthalmological and neurological disorders. The syndrome develops in patients with NIS at different intervals after bilateral total adrenalectomy, from several months to 20 years. As a rule, the syndrome occurs at a young age within 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 pigment deposits in the skin occurs in the same way as in Addison's disease. The skin is significantly colored in the color of tan on exposed parts of the body and in places of friction: face, neck, hands, waist, in the armpits. Staining of the mucous membranes of the oral cavity and anus in the form of spots is characteristic. Expressed pigmentation is noted in 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 ACTH content in the plasma. In patients with a black skin tone and dark purple color of the mucous membranes, the ACTH content was more than 1000 ng / ml. Hyperpigmentation, expressed only in the places of burning and postoperative sutures, is accompanied by an increase in ACTH to 300 mg/ml. Melasma in Nelson syndrome can significantly decrease against the background of adequate replacement therapy with corticosteroids and increase against the background of decompensation. Without treatment aimed at reducing the secretory activity of the pituitary gland and normalizing its secretion of ACTH, hyperpigmentation is not eliminated.

Adrenal insufficiency in Nelson syndrome is characterized by a labile course. Patients require 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 administered synthetic hormones under the influence of ACTH hypersecretion by corticotropinoma. Adrenal insufficiency in Nelson syndrome is much more often decompensated without apparent reasons and is accompanied by the development of minor and major crises. In minor crises, patients experience weakness, loss of appetite, joint pain, and decreased blood pressure. Major crises can occur suddenly: nausea, vomiting, loose stools, abdominal pain, severe adynamia, and increased pain in muscles and joints. Blood pressure decreases, body temperature sometimes rises to 39 C, and tachycardia occurs.

During an adrenal insufficiency crisis in patients with Nelson syndrome, blood pressure may increase rather than decrease. If abdominal symptoms predominate during a crisis, they may be considered 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 syndrome also sometimes leads to a diagnostic error and incorrect medical tactics. Parenteral replacement therapy with hydrocortisone and deoxycorticosterone acetate (DOXA) quickly eliminates the symptoms of an "acute abdomen", leads to normalization of blood pressure and helps to avoid unnecessary surgical interventions.

Nelson syndrome is characterized by neuro-ophthalmological symptoms typical of patients with progressive corticotropinoma growth that extends beyond the sella turcica. The most typical is chiasmal syndrome. In this case, biotemporal hemianopsia and primary atrophy of the optic nerves of varying severity develop. In some cases, bitemporal hemianopsia also occurs with endosellar adenomas due to impaired blood supply in the chiasm. Later, changes in the fundus develop, which are expressed as atrophy of the optic nerve papillae. As a result, visual acuity decreases, and sometimes its complete loss is observed.

Psychoneurological changes characteristic of Nelson syndrome are associated with both the state of compensation of adrenal insufficiency and the size and localization of the pituitary tumor and increased ACTH levels. The results of a neurological examination of 25 patients with Nelson syndrome in the clinic of the Institute of Experimental Endocrinology and Hormone Chemistry (IEHC) of the Russian Academy of Medical Sciences by Doctor of Medical Sciences V. M. Prikhozhan allowed us to note a number of clinical features. In the psychoneurological status of patients with Nelson syndrome, in contrast to the control group of patients after bilateral total adrenalectomy, an increase in asthenophobic and asthenodepressive syndromes, as well as the emergence of a neurotic syndrome, were found. Many patients against the background of Nelson syndrome experienced pronounced emotional instability, decreased mood, anxiety, and suspiciousness.

In corticotropinoma causing Nelson syndrome, spontaneous hemorrhages into the tumor are possible. As a result of tumor infarction, a decrease or normalization of ACTH secretion is detected. No disorders in the secretion of other tropic hormones were detected. In patients with hemorrhage into a pituitary tumor, neurological symptoms such as ophthalmoplegia (unilateral paralysis of the oculomotor nerve) and severe adrenal insufficiency developed. Increasing the dose of hydrocortisone and DOXA led to normalization of the oculomotor nerve function, disappearance of ptosis, and reduction of melasma.

When the tumor reaches large sizes, patients experience neurological symptoms of the disease, depending on the direction of tumor growth. With ante-sellar spread, olfactory disorders and mental disorders are detected, with para-sellar spread, lesions of the III, IV, V and VI pairs of cranial nerves occur. With tumor growth upward, into the cavity of the III ventricle, general cerebral symptoms appear.

The study of the electrical activity of the brain in patients with Nelson syndrome was conducted in the clinic of the Institute of Encephalopathy and Chemotherapy of the Russian Academy of Medical Sciences by senior research fellow G. M. Frenkel. The dynamics of electroencephalograms were observed for 6-10 years in 14 patients with Itsenko-Cushing's disease before and after the development of Nelson syndrome. A pituitary tumor was detected in 11 patients. Nelson syndrome was diagnosed 2-9 years after the removal of the adrenal glands. Before the operation and 0.5-2 years later, pronounced alpha activity with a weak reaction to light and sound stimuli was observed on the EEG. Tracking the dynamics of electroencephalograms for 9 years revealed that in most patients with postoperative Nelson syndrome, features indicating an increase in hypothalamic activity appear on the EEG before a pituitary tumor is radiologically detected. The recording during this period shows a high-amplitude alpha rhythm radiating across all leads, sometimes in the form of discharges. As the tumor increases in size, specific recordings appear in the form of 6-wave discharges, more pronounced in the anterior leads. The data obtained on the increase in the electrical activity of the brain in patients with Nelson's syndrome confirm the fact that the interruption of the "feedback" that occurs when the adrenal glands are removed in patients with Itsenko-Cushing's 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 of hyperpigmentation of the skin in patients after bilateral total adrenalectomy, labile course of adrenal insufficiency, changes in the structure of the sella turcica, and the detection of a high content of ACTH in the blood plasma. Outpatient dynamic observation of patients with Itsenko-Cushing's disease who have undergone adrenal gland removal allows for earlier recognition of Nelson's syndrome.

An early sign of melasma may be increased pigmentation on the neck in the form of a “necklace” and the symptom of “dirty elbows”, the deposition of pigment in postoperative sutures.

Labile course of adrenal insufficiency is typical for most patients with Nelson syndrome. Large doses of gluco- and mineralocorticoids are required to compensate for metabolic processes. The recovery period from various intercurrent diseases is longer and more severe than in patients after removal of the adrenal glands without Nelson syndrome. The presence of difficulties in compensating for adrenal insufficiency, an increased need for mineralocorticoid hormones are also signs of the development of Nelson syndrome in patients after adrenalectomy for Itsenko-Cushing disease.

Diagnostics Nelson's syndrome

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

Diagnosis of pituitary tumor in Nelson syndrome is difficult. Corticotropinomas are often microadenomas and for a long time, located inside the sella turcica, do not disrupt its structure. In case of small pituitary adenomas in Nelson syndrome, the sella turcica is at the upper limit of the norm in size or slightly increases. In these cases, its detailed study on lateral craniograms and radiographs with direct magnification, as well as tomographic examination allow us to recognize the early symptoms of pituitary tumor development. Diagnosis of a developed and large pituitary adenoma is not difficult. A developed pituitary adenoma is usually characterized by an increase in the size of the sella turcica, straightening, thinning or destruction of the walls. Destruction of the wedge-shaped processes, deepening of the sella bottom indicate a growing pituitary tumor. With a large tumor, an expansion of the entrance to the sella turcica, shortening of the wedge-shaped processes is observed, i.e. symptoms characteristic of supra-, ante-, retro- and intrasellar tumor location appear. Using additional research methods (tomography with pneumoencephalography, phlebography of the cavernous sinus and computed tomography ) it is possible to obtain more accurate data on the condition of the sella turcica and the location of the pituitary tumor beyond it.

In the diagnosis of Nelson syndrome, ophthalmological, neurophysiological and neurological examinations of patients are of great importance. Changes in the fundus, disturbances of lateral vision, decreased visual acuity up to complete loss, ptosis of the upper eyelid are characteristic of patients with Nelson syndrome. The degree of visual impairment is an important factor for choosing adequate therapy. Electroencephalographic studies can in some cases help in the early diagnosis of Nelson syndrome.

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Differential diagnosis

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

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

The ACTH content in plasma in ectopic tumors arising in Itsenko-Cushing syndrome is increased to the same limits as in Nelson syndrome.

Treatment Nelson's syndrome

Treatment of Nelson's syndrome is aimed at compensating for chronic adrenal insufficiency and influencing the hypothalamic-pituitary system. Various methods are used to treat the syndrome, suppressing ACTH secretion and preventing the growth and development of corticotropinoma. Medication, radiation to the pituitary gland, and surgical removal of the tumor are used.

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

Among radiation treatment methods, various types of remote irradiation and interstitial ones are currently used. The former include irradiation with gamma rays and a proton beam. The interstitial method achieves partial destruction of the pituitary gland, for which various radioactive sources are used, ⁹⁰ It or ¹⁹⁸ Au, which are introduced directly into the pituitary tissue.

Drug and radiation therapy are used in the treatment of patients with pituitary tumors that do not extend beyond the sella turcica and are not used for more extensive tumors. In addition, indications for drug and radiation therapy are relapses or partial therapeutic effect of surgical treatment. Proton beam irradiation resulted in decreased pigmentation and decreased ACTH secretion. The introduction of ⁹⁰ It or ¹⁹⁸ Au into the sella turcica cavity gave positive results in all patients in the control group, consisting of 8 people.

In the clinic of the Institute of Evolutionary and Chemotherapeutic Genetics of the Russian Academy of Medical Sciences, 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 skin hyperpigmentation, and melasma completely disappeared in 3 patients. An important reflection of the positive effect of irradiation was the elimination of severe labile adrenal insufficiency, characteristic of untreated Nelson's syndrome. In the remaining three patients, with no effect from treatment, further progressive growth of the pituitary tumor was observed.

The surgical method of corticotropin removal is used for both microadenomas and large tumors. Recently, the method of microsurgical intervention with transsphenoidal access has become widespread. This method is used for tumors growing downwards. For large, invasive, upward-growing pituitary tumors in patients with Nelson syndrome, transfrontal access is used. The results of surgical treatment for small tumors are better than for adenomas with widespread growth. Despite the fact that microsurgical technique ensures complete removal of pathological tissue in most cases, relapses of the disease occur after the surgical method is used.

Often, when treating Nelson syndrome, it is necessary to resort to combined therapy. In the absence of remission of the disease after radiation therapy, cyproheptadine, parlodel, convulex are prescribed. If it is impossible to completely remove the tumor surgically, pituitary irradiation or drugs that suppress ACTH secretion are used.

Prevention

Most authors admit that it is easier to prevent the development of the syndrome and large tumors than to treat Nelson's syndrome with widespread processes beyond the sella turcica. Preliminary radiation therapy to the pituitary gland of patients with Itsenko-Cushing's disease, according to most authors, does not prevent the development of the syndrome. For the purpose of prevention, regardless of preliminary irradiation of the pituitary gland in Itsenko-Cushing's disease after bilateral total adrenalectomy, it is necessary to conduct an annual X-ray examination of the sella turcica, visual fields, and ACTH content in the blood plasma.

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Forecast

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

Almost everyone's ability to work is limited. Outpatient observation by an endocrinologist, neurologist and ophthalmologist is necessary.

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