Nelson Syndrome Treatment & Management

Updated: Mar 25, 2021
  • Author: Thomas A Wilson, MD; Chief Editor: Robert P Hoffman, MD  more...
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Treatment

Approach Considerations

Nelson syndrome can be treated by observation (for stable small tumors), [2] tumor resection, radiation, and/or pharmacotherapy. However, resection of pituitary adenoma is typically the treatment of choice. If surgery is ineffective or not possible, radiotherapy or radiosurgery can be performed. [14]

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Medical Care

Although Nelson syndrome was previously thought to be primarily due to a pituitary macroadenoma, and medical treatment alone was thought to be rarely curative, recent high-resolution magnetic resonance imaging (MRI) that allows detection of microadenomas and the use of a newer class of drugs have shown promising results for medical treatment alone to be possible in some cases.

Case reports have demonstrated successful remission of Nelson syndrome with cabergoline (dopamine receptor agonist), with decline and normalization of adrenocorticotropic hormone (ACTH) levels and resolution of the pituitary macroadenoma or microadenoma. [15, 16, 17]

Various other drugs that have been used in an attempt to medically control tumor growth, with variable success, include octreotide (a parenterally administered somatostatin analog), cyproheptadine with and without bromocriptine, and sodium valproate. Octreotide or other analogue of somatostatin may be helpful to control ACTH levels, although it is only useful as a means of controlling levels until definitive treatment is undertaken because it does not result in appreciable tumor shrinkage. Because it suppresses other hormones, including insulin, it may result in other problems, such as carbohydrate intolerance. In addition, it may cause sludging within the gall bladder.

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Radiation Therapy

Radiotherapy is important in the treatment of patients with Nelson syndrome. [18] Historically, the irradiated field needed to be large, which led to increased risk of damage to the surrounding brain. The most serious long-term problems have included learning and memory difficulties, radiation-induced visual damage, and, most importantly, the risk of secondary tumors. With the advent of newer means of reducing radiation scatter (eg, linear accelerator [LINAC], gamma radiosurgery [19, 20, 21] ), radiotherapy-associated morbidity has significantly decreased and may be helpful in tumors that are not amenable to surgery.

When radiation therapy is given after Nelson syndrome has developed, it is considered therapeutic; given before or immediately after bilateral adrenalectomy, it is considered prophylactic. [22] The first line of treatment is transsphenoidal resection. [11]

Stereotactic radiosurgery, called gamma knife surgery (GKS), has been successfully performed in secretory pituitary tumors (including Nelson syndrome tumors) that are refractory to other surgical interventions. [19, 20, 21, 23, 24, 25]

Losa et al conducted a retrospective analysis of 28 patients with a growing adrenocorticotropin (ACTH)–secreting pituitary adenoma treated with gamma knife radiosurgery between 1995 and 2019. Progression-free survival at 10 years was 91.7%; two patients (7.1%) had recurrence during follow-up. No patient had visual or oculomotor adverse effects. The investigators concluded that, with proper planning of the distribution of radiation to critical structures, gamma knife radiosurgery is an effective treatment for Nelson syndrome. [26]

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Surgical Care

Surgery remains one of the best hopes of cure for patients with Nelson syndrome and is the treatment of choice for large tumors that are producing acute compression of the optic apparatus and other vital structures, with success rates ranging from 10 to 70%. [2] The goal of surgery is to remove all macroscopic tumor tissue without compromising vital structures. In cases of incomplete removal or where invasion is present, adjunctive irradiation reduces that rate of recurrence and improves the prognosis.

Transsphenoidal surgery (TSS) is optimal because it offers the lowest risk of hypothalamic injury. [11] Determinants of success include the degree of tumor invasion of brain parenchyma, optic apparatus, cavernous sinuses, dura, and bone and the skill of the surgeon. Overall mortality after surgical management of corticotroph tumor progression is around 5%, but the prevalence of hypopituitarism is high with a 69% occurrence rate. Other morbidity rates include cranial nerve palsy in 5%, CSF leak in 15%, and meningitis in 8% of patients. [2]

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Consultations

For children and adolescents who undergo bilateral adrenalectomy for Cushing disease, consultation with the following specialists may be needed:

  • Pediatric endocrinologist

  • Pediatric ophthalmologist

  • Pediatric neurosurgeon (with expertise in transsphenoidal and/or gamma knife surgery)

  • Radiation oncologist (stereotactic radiosurgical center)

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Prevention

Nelson syndrome has become increasingly uncommon because of the significant improvements in all aspects of biochemical and radiological diagnosis and surgical and medical management of Cushing syndrome.

Hyperpigmentation with adrenocorticotropic hormone (ACTH) levels above 154 pg/mL have been shown to have a high positive predictive value of Nelson syndrome but other predictors are not understood. [27] Thus, long-term follow-up is important and should include clinical examinations for hyperpigmentation, ACTH measurements, and MRI scans. These should be performed annually with a decrease in frequency based on previous findings. [8]

Temozolomide may prevent or postpone the need for bilateral adrenalectomy in patients with recurrent or metastatic ACTH–secreting tumors who are poor surgical candidates. [28]

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Long-Term Monitoring

Monitor patients at 3-month to 4-month intervals with measurement of growth parameters, blood pressure, and assessment of thyroid function and pubertal development. Loss of pituitary function after pituitary radiotherapy is inevitable, although the time taken for this to occur varies and depends on the dose and number of fractions of radiation that are administered. Growth failure may precede biochemical evidence of growth hormone deficiency with pharmacologic testing. Overnight growth hormone sampling is thought to be more sensitive than pharmacologic testing because the hypothalamus is more radiosensitive than the pituitary and neurosecretory dysfunction may precede actual growth hormone (GH) deficiency. For this reason, patients who have received pituitary radiation need ongoing follow-up of their growth and thyroid function at 3-month and 6-month intervals by an endocrinologist, and patients may require pubertal induction or treatment of hypogonadism in addition to their ongoing replacement with hydrocortisone and fludrocortisone.

Thyroid function should be measured at least every 6 months or more frequently if growth velocity is declining and deficiency is evolving. Thyroxin supplementation is necessary when the free T4 levels are below the reference range. Thyroid-stimulating hormone (TSH) is not helpful in determining adequacy of thyroxin replacement in patients with central hypothyroidism.

Patients with central diabetes insipidus require treatment with desmopressin acetate (DDAVP). The dosage required varies among individuals and can range from 50-400 mcg/d administered as a single or twice daily dose orally. It may also be administered as a nasal spray, in which case the dose is 5-40 mcg/d usually in 2 divided doses. The evening dose is usually larger to reduce problems with nocturia.

Children who receive DDAVP need to have regular sodium measurements, with the frequency determined by the stability of the child. More frequent measurements are needed if the child develops increased fluid losses due to intercurrent illness, hot ambient temperatures, or GI losses.

Patients with a normal sense of thirst should be allowed to drink ad libitum because by doing so they regulate their own osmolality. Fluid management is difficult in patients with diabetes insipidus who lack normal thirst sensation. Regular weighing on accurate scales is important, and prescribed fluid intake must be administered based upon the size of the child and the environmental conditions. Greater vigilance and more frequent measurements of sodium are needed in these children.

Some physicians believe that children receiving DDAVP should be allowed to "break through" and become polyuric periodically to avoid the risk of hyponatremia. Mixed opinion exists about the frequency with which breakthrough is required.

Patients with Nelson syndrome who have undergone radiotherapy and have multiple pituitary hormone deficiencies require lifelong endocrine follow-up. Transition is ideally achieved in the late adolescent years in a clinic that has both adult and pediatric endocrinologists.

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