Nelson syndrome is an endocrine disease that develops as a consequence of bilateral adrenalectomy or prolonged mitotan therapy. It is characterized by the formation and / or growth of pituitary adenoma, excessive production of ACTH, chronic insufficiency of the adrenal cortex (CIAC). A specific symptom is pathological pigmentation of the mucous membranes, skin. There is weakness, adynamia, hypotension, nausea, bone pain, loss of vision, loss of sense of smell, memory loss, emotional lability. The diagnosis is established on the basis of anamnesis, the results of ACTH analysis, MRI (CT) of the brain. Complex treatment: surgical, radiation, medication.
ICD 10
E24.1 Nelson syndrome
Meaning
Nelson syndrome got its name from the surname of D. Nelson, a researcher from the USA. In the 1950s, he and his colleagues described a clinical case of a woman who, a few years after bilateral removal of the adrenal glands, developed a pituitary tumor. By 1960, the data had been accumulated and systematized, and the syndrome was isolated as a separate nosological unit. In recent decades, the prevalence of pathology has been decreasing, which is associated with a decrease in the number of adrenalectomies. Among patients with removed adrenal glands, epidemiology is 5-10%. The disease is diagnosed after surgery, the time interval between surgery and the appearance of symptoms ranges from 3-6 months to 20-25 years. The highest risk is observed during the first 6 years.
Causes
Failures in the hypothalamic-pituitary system are caused by the loss of the inhibitory effect of corticoid hormones on the cells of the adenohypophysis synthesizing adrenocorticotropin. Nelson syndrome occurs when there is an absolute loss of function of the adrenal cortex as a result of treatment of Cushing’s disease. The reasons may be:
- Bilateral adrenalectomy. Surgical removal of two adrenal glands is the most common factor in the occurrence of the syndrome. The production of corticosteroids stops, the synthesis of ACTH increases significantly.
- Unilateral adrenalectomy, mitotane therapy. Less often, pathology develops after removal of one adrenal gland, against the background of suppression of the functions of the second by drugs of the group of inhibitors of steroid synthesis. Pathological processes are similar to those in bilateral adrenalectomy, but progress more slowly.
- Long-term treatment with mitotane. The drug belongs to antitumor agents, inhibitors of the production of adrenal hormones. It destroys the tumor and normal tissue of the adrenal cortex. With prolonged use, a complete loss of hormone-secreting function is possible.
Not all patients with adrenal dysfunction suffer from Nelson syndrome. Its formation is facilitated by a number of factors, including high cortisol secretion before therapy, benign pituitary neoplasm, young age of patients at the time of adrenalectomy. The peak incidence occurs at the age of 26, after 40 years the risk approaches zero. The probability of the syndrome is lower in patients who have undergone surgery on the pituitary gland.
Pathogenesis
The key pathogenetic processes of Nelson syndrome are the lack of the inhibitory effect of cortisol on ACTH–producing cells, the resumption of growth and rapid progression of the pituitary tumor formed in Cushing’s disease. After resection of the adrenal glands or with prolonged use of mitotane, the physiological regulation of the functions of the adrenal glands by the hypothalamic-pituitary complex is disrupted. This leads to a significant increase in the amount of ACTH, the formation of pituitary adenoma.
The increased pigmentation is explained by the extrarenal effect of ACTH on melanocytes – skin cells that produce the pigment melatonin of black-brown and yellow-red color. In addition, the hormone stimulates lipolysis and insulin secretion, having a hypoglycemic effect. In individuals with Nelson syndrome, it enhances the metabolism of corticoid hormones, therefore, high doses of their synthetic analogues are required to eliminate signs of adrenal insufficiency.
Symptoms
The clinical picture includes progressive hyperpigmentation of the skin, symptoms of the presence of an ACTH-producing tumor and CIAC, disorders of the central nervous system and visual organs associated with an increase in the size of the adenoma. Hyperpigmentation manifests itself as darkening of exposed areas and areas subject to friction: the face, neck, hands, armpits, places where trousers and collar fit. The oral cavity and the anal area are stained. The brightest pigmentation is characteristic of postoperative sutures. The color varies from light tan to dark brown with a purple tinge, directly correlates with the concentration of ACTH and beta-lipotropin. Melasma becomes less pronounced with adequate hormone replacement therapy, it increases with exacerbation of the disease.
Adrenal insufficiency is prone to decompensation, is realized through small and large crises. With a small crisis, patients feel weakness and joint pain, lose appetite. Often there are attacks of arterial hypotension, dizziness and fainting. With a large crisis, nausea increases sharply, vomiting, diarrhea, abdominal and muscle pain appear. Tachycardia and arterial hypotension are more pronounced, persistent. Body temperature rises to 39° C.
Progressive growth of corticotropinoma is manifested by neuro-ophthalmological symptoms. Chiasmal syndrome is most characteristic: narrowing of the boundaries of the visual field in the upper or lower temporal quadrant, loss of half of the visual fields. Later, the condition of the fundus changes, visual acuity decreases, blindness develops. The psychoneurological status is characterized by an increase in astheno-depressive and astheno-phobic states. Patients become emotionally unstable, anxious, suspicious, often in a depressed mood.
Complications
In the absence of treatment, corticotropinoma increases, the risk of spontaneous intra-tumor hemorrhage, provoking unilateral oculomotor nerve paralysis (ophthalmoplegia), increases. Large adenomas compress the surrounding areas and potentiate a variety of neurological disorders. Antesellar spread of the neoplasm leads to pathology of the sense of smell and mental disorders; parasellar – to the defeat of the III, IV, V and VI pairs of cranial nerves: oculomotor functions are impaired, various types of facial sensitivity suffer. When the tumor grows upwards, general cerebral symptoms occur – confusion, headache, dizziness, vomiting, generalized convulsive seizures.
Diagnostics
The endocrinologist conducts a clinical survey and examination of the patient, collects anamnestic data. The diagnosis of Nelson syndrome is based on the presence of characteristic symptoms, previous Cushing’s disease and total adrenalectomy. Differential diagnosis requires distinguishing this syndrome from Addison’s disease and Cushing’s syndrome, accompanied by an increase in ACTH due to the development of an ectopic tumor. To confirm the diagnosis, it is necessary to confirm the hypersecretion of ACTH, the presence of a tumor in the pituitary gland. The following methods are used:
- Blood test for ACTH. With corticotropinoma and loss of adrenal function, the concentration of ACTH in the blood is 200 pg/ml or more, there is no circadian rhythm of hormone secretion – the analysis indicators are relatively stable day and night. They reflect the activity of neoplasia and directly correlate with the severity of hyperpigmentation. Brown, black and purple coloration is accompanied by an increase in the level of ACTH up to 1000 pg / ml; mild and moderate hyperpigmentation in surgical sutures and areas of frequent friction – up to 200-400 pg/ml.
- MRI of the head. Visualization of microadenomas is difficult because they are often located in the Turkish saddle and do not change its structure. With a small tumor size, the Turkish saddle corresponds to the norm or is slightly enlarged, a close study of the lateral projections allows you to determine the presence of a neoplasm. Large and medium–sized adenomas are more noticeable – the saddle is enlarged, the walls are thinned or destroyed. With large neoplasias, an expanded entrance to the Turkish saddle, shortened wedge-shaped processes are found. Pituitary MRI can be replaced by Turkish saddle radiography, but the data will be less accurate. For more information about the adenoma, a CT scan is performed.
- Neuro-ophthalmological examination. With a progressive increase in the tumor, changes in the fundus, loss of external fields and decreased visual acuity, drooping of the upper eyelid are diagnosed. The EEG shows signs indicating increased activation of the hypothalamus – a high-amplitude alpha rhythm is recorded, spreading through all leads. The rapid growth of the tumor provokes discharges of theta waves, more pronounced in the frontal leads. The general increase in bioelectroactivity of the brain confirms the strengthening of hypothalamic-pituitary processes.
Treatment
Therapy is aimed at removing or suppressing the activity of corticotropinoma, compensation of CIAC. To achieve a positive result and prevent relapses, combined treatment methods are used, including the following procedures in various combinations:
- Taking medications. Medical correction is advisable for a neoplasm that does not go beyond the Turkish saddle, with a relapse of the syndrome. Drugs that reduce the level of ACTH are used: serotonin blockers, dopamine receptor stimulators. Replacement therapy with mineral and glucocorticoids is performed to compensate for CIAC.
- Radiation therapy. The course of procedures is recommended for patients with small adenomas, as well as after resection of the tumor, with relapses of the syndrome. The method of irradiation with gamma rays and proton beams, the introduction of radioactive isotopes of yttrium and silver into the pituitary tissues is used.
- Surgical operation. The method is indicated for adenomas of small, medium and large sizes. Microsurgical equipment allows you to completely remove the formation, but does not exclude the development of relapse, therefore, after surgery, a course of radiation treatment is prescribed.
- Cryotherapy. The low-temperature method of exposure is effective in small tumors. Liquid nitrogen is stereotaxically supplied to the adenoma through the transnasal transsphenoidal access and destroys its tissues.
Prognosis and prevention
The outcome of the disease is favorable with the slow growth of the tumor, its successful removal, and the achievement of CIAC compensation. In such cases, the condition of patients remains stable, the probability of relapse is low. As a preventive measure, patients who have undergone bilateral adrenalectomy are recommended to annually prescribe examinations that allow visualizing the location of the pituitary adenoma, monitoring the content of ACTH. In addition, patients are shown regular ophthalmological examinations.
Literature
- Nelson syndrome/ Pankiv V.I.// International Endocrinological Journal. – 2013.
- Nelson syndrome: questions and answers (clinical case)/ Nijinskaya-Astapenko Z.P., Vlasenko M.V., Gurina N.I.// International Endocrinological Journal. – 2016.
- Treatment of Nelson syndrome by xenotransplantation of tissue cultures of the adrenal glands and liver/ Larin A.S. et al.// Clinical endocrinology and endocrine surgery. – 2010..