Continuing Education Activity

Nelson syndrome or post adrenalectomy syndrome was first reported in 1958 by Dr. Don H. Nelson, an endocrinology fellow at the time. This clinical syndrome was initially called a postadrenalectomy syndrome, but later it was named after Dr. Nelson as "Nelson syndrome." This activity reviews the evaluation and treatment of Nelson syndrome and highlights the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Identify the etiology of Nelson syndrome medical conditions and emergencies.
• Summarize the evaluation of patients with Nelson syndrome.
• Review the management options available for Nelson syndrome.

Introduction

Nelson syndrome or post adrenalectomy syndrome was first reported in 1958 in one patient by Dr. Don H. Nelson, an endocrinology fellow at the time.[1][2][3][4] This clinical syndrome was initially called a postadrenalectomy syndrome, but later it was named after Dr. Nelson as "Nelson syndrome." In 1959, five additional patients were reported by Salassa et al.; thus, it is sometimes called the Nelson-Salassa syndrome.[5] It describes a spectrum of symptoms that have been associated following bilateral adrenal gland resection for the treatment of Cushing disease. It is hypothesized that the loss of feedback inhibition of the hypothalamic-pituitary-adrenal axis leads to the development of an adrenocorticotropic hormone (ACTH) secreting pituitary tumor. Nelson syndrome usually occurs one to five years following bilateral adrenalectomies.[6][7]

Etiology

Nelson syndrome cases are seen as a result of bilateral adrenalectomy for the treatment of Cushing disease.[3] Approximately 7% of the patients with a diagnosis of Cushing disease are treated with bilateral adrenalectomies.[8] Bilateral adrenalectomy rapidly improves symptoms in patients and avoids the long-term complications of elevated cortisol, including hypertension, diabetes mellitus, and muscle weakness. After the adrenal glands are removed, the cortisol production is dramatically reduced which will produce a negative feedback on the hypothalamus creating an enormous release of corticotropin-releasing hormone (CTRH) which will stimulate the pituitary gland to produce large amounts of ACTH (normal plasma ACTH values 1.3 to 16.7 pmol/L or 7.2 to 63 pg/ml). This is thought to stimulate the corticotropic cell to hypertrophy and create a new ACTH secreting pituitary tumor.

Another view is that the corticotropic cells that initially led to the Cushing disease's adenoma are stimulated, which then causes tumor progression.[6][9] Nowadays, bilateral adrenalectomy is rarely used. It is reserved for patients with severe comorbidities or those refractory to other treatment modalities.

Risk factors for developing Nelson syndrome have been studied in an attempt to achieve early detection and treatment. High levels of plasma ACTH one year after bilateral adrenalectomy have the strongest predictive capabilities.[8][10][11][12][13] Fasting ACTH plasma levels above 154-220 pmol/L (700-1000 pg/ml) are predictive of Nelson's syndrome one year after bilateral adrenalectomy.[12][14] Screening is done with the help of a brain magnetic resonance imaging (MRI) to visualize the sellar area for a pituitary tumor. MRI may reveal a small tumor forming. 

If a tumor is not detected, then a brain MRI should be performed at regular intervals. High levels of 24-hour urinary cortisol before the bilateral adrenalectomy is also a predictive factor.[8] Age, sex, and the duration of Cushing disease have not been significantly associated with increased risk; however, younger patients undergoing bilateral adrenalectomy have a higher lifetime risk of developing corticotropic.[6] Graffeo et al. found that prior external beam radiotherapy to treat the original Cushing tumor was associated with the progression to Nelson syndrome; however, this series covers a wide time frame between 1956 and 2015.[15] Different radiation regimens may have been employed throughout the years, which may have influenced the results.

Epidemiology

Nelson syndrome is a rare clinical manifestation after bilateral adrenalectomy and is not prevalent in the general population.[16] The chance of Nelson syndrome development after a patient undergoes bilateral adrenalectomy ranges from 8% through 47% in adults[8][16] and 25% to 66% in children.[17][18] These numbers have been decreasing dramatically as bilateral adrenalectomy is rarely done nowadays for Cushing disease. The onset of the disease can occur up to 24 years after bilateral adrenalectomy has been performed. The prevalence is 38% at three years post bilateral adrenalectomy, which increases to 47% at seven years and then reaches a plateau.[19][20]

According to the University of California Los Angeles group, the incidence is 15% to 25%, occurring approximately one to four years after the bilateral adrenalectomy.[6][15] In a large series in Argentina covering patients seen from 1974 until 2011, the incidence was 46%, with presentation occurring at a mean of 24 months after the procedure.[8] Another large study in Mexico showed a 41.6% incidence.[21]. The most extended series in the literature covering 302 patients between 1956 and 2015 showed an incidence of 53%.[15] A systematic review in 2013, using articles between 1980 and 2012, found an incidence of 21% (range 0 to 47%) presenting at a median of five years after the bilateral adrenalectomy.[22]

Pathophysiology

Patients presenting Nelson syndrome originally suffered from Cushing disease. In Cushing disease, the corticotropic cells in the pituitary adenoma over-express ACTH leading to increased cortisol production. Management of Cushing disease via surgical resection of the pituitary adenoma has a high rate of success, and in many patients, it is the only treatment used. However, refractory cases of Cushing disease may require bilateral adrenalectomies, which provide over 85% success rate for endocrinological control.[11]

Cortisol is produced in the adrenal glands. When patients with Cushing disease are treated with bilateral adrenalectomy, the cortisol production is absent, and the hypothalamus receives the signal to increase the CRH production and the corticotropic cells in the pituitary gland will respond to CRH secreted by the hypothalamus with the secretion of ACTH in large amounts due to the absence of feedback inhibition. This increase in CRH produces an effect on the corticotropic cells, which may hypertrophy and create a new tumor or enlarge the original tumor.[9][11]

The hyperpigmentation results from the elevation of CRH, which increases proopiomelanocortin production in the anterior pituitary's corticotropic cells, which is the precursor of the melanocyte-stimulating hormone and ACTH.[9]

Histopathology

Histopathology in Nelson syndrome is similar to the pituitary adenomas seen in Cushing disease, but with corticotropic cells showing mitosis and pleomorphism.[20] Tumors tend to grow larger and more invasive in Nelson syndrome. They are monoclonal tumors that show basophilic stain and periodic acidic-Schiff positivity.[6] The Ki-67 proliferation index in Nelson syndrome tumors is not elevated, usually below 3%.[7][15]

History and Physical

Hyperpigmentation of the skin is the most common visible manifestation of the syndrome and is unique to this pituitary tumor. Hyperpigmentation in Nelson syndrome is very dark and different from other hyperpigmentation disorders. A prominent linea nigra from the pubis to the umbilicus is noted. Scars, areolae, gingivae, and scrotum may show excessive pigmentation. Other manifestations will include bitemporal hemianopia and progressive visual loss in large tumors. Pituitary dysfunction may occur as the tumor can inhibit the release of other pituitary hormones. Patients may complain of headache, weakness, and fatigue.

A positive history of Cushing disease and bilateral adrenalectomy is confirmed in history.

Evaluation

Fasting plasma ACTH levels are very high. Diagnosis can be confirmed with an ACTH increase greater than 30% of the initial result after bilateral adrenalectomy on three consecutive samples.[8] Pituitary hormonal workup may show decreased levels of anterior pituitary hormones.

Visual fields may show bitemporal hemianopia if the tumor is compressing the chiasm.

The diagnosis of Nelson syndrome is confirmed with a brain MRI showing a new pituitary tumor or the enlargement of a previously known tumor.

Screening of patients with bilateral adrenalectomy is done with fasting plasma ACTH levels and brain MRI performed at regular intervals.

Treatment / Management

The initial recommended treatment for Nelson syndrome is the surgical removal of the tumor.[11][23] Surgery can be performed microsurgical or endoscopically by the transsphenoidal route. Extensive tumors with lateral extensions may require a craniotomy. Endocrinological cure is achieved in approximately 50% of the cases. This is due in part by the infiltration of the cavernous sinus and extra-sellar extension.[7] Sometimes, initial close clinical follow-up is recommended as many of the tumors do not develop clinically meaningful symptoms or have a slow growth pattern of less than 5 mm per year.[15] Surgery can be complicated by postoperative hypopituitarism in 30% of the cases and permanent diabetes insipidus in 20% of the cases.[7]

Radiotherapy in the form of fractionated radiotherapy or stereotactic radiosurgery can be given to the tumor.[14][24][25] Stereotactic radiosurgery with a gamma knife has been studied as an effective means of controlling tumor growth and endocrine disbalances producing 92% radiological tumor control and 62.7% reduction in the ACTH levels.[23][25][26][27] However, some patients may have already received radiation as treatment for the Cushing disease, and a new course may be contraindicated. The effects of radiotherapy usually cause hypopituitarism within 5-10 years; therefore, hormonal replacement may be needed. With radiosurgery for Nelson syndrome, a 21.6% incidence of hypopituitarism had been reported.[26]  Prior radiation for treatment of the Cushing disease will shorten the time of presentation of hypopituitarism. New visual problems is another important complication following the radiotherapy. Radiation is an option for the failure of surgical treatment in Nelson syndrome.[28]

A preventative measure for the development of Nelson syndrome that can be utilized is prophylactic radiotherapy when bilateral adrenalectomy is planned.[19][29][30][31] This is not uniformly accepted, as other authors have not found an advantage in prophylactic radiation.[8][14][32] Nowadays, radiosurgery is used to direct the radiation only to the pituitary gland tissue.[10]

Medical treatment is limited, but some results have been found with somatostatin-analogs (octreotide and pasireotide), dopamine agonists (bromocriptine and cabergoline), sodium valproate, and temozolomide.[32][33][34][35]

Patients need permanent glucocorticoid replacement, as they do not produce cortisol. Hydrocortisone is usually given at a dose of 20 mg in the morning and 10 mg in the afternoon. Mineralocorticoids are also required. Fludrocortisone acetate 0.1 mg is generally used.[36]

Differential Diagnosis

Nelson syndrome is a pituitary adenoma; therefore, any other pituitary adenoma can radiographically present as a Nelson tumor. However, the hyperpigmentation of the skin will be pathognomonic of it. Differentials include:

• Sellar tumors 
• Primary adrenal insufficiency
• Congenital adrenal hyperplasia/hypoplasia
• Hypothalamic tumor secreting CRH
• Addison disease (autoimmune)
• Ectopic secretion of ACTH
• Glucocorticoid therapy

Prognosis

Nelson syndrome can be a deadly disease. If surgically treated, the prognosis is good. In some cases, persistent elevation of ACTH is found secondary to residual tumor predominantly in the cavernous sinus. Radiation will also have good results but are delayed and can cause permanent hypopituitarism. Patients undergoing gamma knife radiosurgery or radiotherapy for Nelson syndrome need to continue on pharmacotherapy until they achieve endocrinological control.

Complications

Complications include:

• Skin hyperpigmentation
• Hypopituitarism
• Visual loss
• Addison crisis

Consultations

Consultations would be required from an endocrinologist, ophthalmologist, neurosurgeon, and radio-oncologist.

Deterrence and Patient Education

Patients and relatives need to know the importance of glucocorticoid and mineralocorticoid replacement. Patients should use a bracelet identifying their need for these medications.

A patient diagnosed with Nelson syndrome requires prompt evaluation as chances of cure are better with earlier management. Surgery is the first line of treatment. Excellent results are obtained in smaller tumors. Those with cavernous sinus extensions may require additional treatment with medication or radiotherapy. The goal is to achieve normal ACTH levels to improve the symptoms.[20]

Enhancing Healthcare Team Outcomes

Early diagnosis and management of Nelson syndrome are crucial for patient safety. Thanks to advanced techniques and diagnostic tools, such as brain MRI, the historical complications associated with Nelson syndrome have significantly reduced. A multidisciplinary approach is crucial in treating conditions such as Cushing disease and Nelson syndrome to improve patient adherence to treatment and positive outcomes. Coordination between the endocrinologist and the neurosurgeon will provide the patient with the best managing strategies to achieve the best outcome. For patients with suprasellar tumors, the neuro-ophthalmologist will be involved in the evaluation and follow up.