Nelson's syndrome

Nelson's syndrome is a rare disorder and occurs in patients who have had both adrenal glands removed owing to Cushing's disease.^[1] During the disorder the patient develops macroadenomas that secrete adrenocoticotropic hormone (ACTH).^[2] The severity of the disease is dependent upon the effect of ACTH release on the skin, pituitary hormone loss, and the effect the tumor has on the surrounding structures within the body.^[2]

The first case of Nelson’s syndrome was reported in 1958 by Nelson et al.^[2] Dr. Don Nelson, an endocrinologist, named the disease. In comparison to the 1980s there have been fewer published cases in the 1990s. Thus, Nelson’s syndrome has become less prevalent. The disease becoming less prevalent is supported by much advancement in the medical field. Within the past ten to twenty years, improvements have been made with identification and care for patients with Cushing’s disease. Improvements have been made with techniques such as pituitary radiation therapy, ACTH assay, transsphenoidal pituitary surgery, higher resolution MRIs, and sampling of the inferior petrosal sinus. The advancements mentioned prior are what have allowed physicians to pursue other routes for Cushing’s disease therapy that don’t involve bilateral adrenalectomy.^[2]

Nelson’s syndrome is also referred to as post adrenalectomy syndrome and is a result of an adrenalectomy performed for Cushing’s disease.^[3] Corticotroph adenomas are detected in more females than males. Therefore, Nelson’s syndrome is observed in more females than males. Corticotroph adenomas are also detected in the younger population compared to the older population.^[2] Earlier, Nelson's syndrome was observed in 20-40% of patients who had a bilateral adrenalectomy with a pituitary adenoma.^[2] Nelson's syndrome is observed in 8-44% of the population who have undergone bilateral adrenalectomy treatment for Cushing's disease.^[2]

Mechanism

After a bilateral adrenalectomy is performed cortisol levels are no longer normal. This increases CRH production because it is not suppressed within the hypothalamus anymore. The increased CRH levels promote the growth of the tumor. Mutations with genes and with the glucocorticoid receptor can affect the tumor as well. Furthermore, differences between Nelson syndrome and Cushing's disease have been studied. Particularly Nelson's syndrome differs from Cushing's disease due to the following: secretions from the tumors, replacement of glucocorticoids, and injury to the hypothalamus due to radiation therapy utilized on the patient.^[2] The pathophysiology of Nelson's syndrome is not understood very well.^[4] Corticotrophinomas are generated from corticotroph cells.^[4] Expression of functional CRH and vasopressin V3 receptors increase in number.^[4] Additionally, there are two isoforms of glucocorticoid receptors. Heterozygosity loss in the glucocorticoid receptor can occur in the tumors present from Nelson's syndrome.^[4] Overall, not all patients that have had a total bilateral adrenalectomy develop Nelson's syndrome, which makes the mechanism harder to understand for such a rare disease.^[5] It is not clear whether the adrenalectomy or reduced cortisol secretion causes aggressive tumor growth.^[6]

Symptoms/Diagnosis

The common symptoms include:

• hyper-pigmentation of the skin
• visual disturbances
• headaches
• abnormal high levels of beta-MSH and ACTH
• abnormal enlargements of the pituitary gland,
• interruption of menstrual cycles in women ^[7]

Common diagnostic techniques include:

• MRIs
• CAT scans
• blood samples.

Blood samples are assessed for the absence or presence of aldosterone and cortisol.^[7] Physical examinations are also useful in patients in order to examine vision, skin pigmentation, how the body replaces steroids, and the cranial nerves.^[8] Recent advancements in high-resolution MRIs allow for adenomas to be detected during the early stages of Nelson syndrome.^[2] Physical examination including height, weight, vital signs, blood pressure, eye examination, thyroid examination, abdominal examination, neurological examination, skin examination and pubertal staging needs to be assessed.^[8] Through blood pressure and pulse readings can indicate hypothyroidism and adrenal insufficiency.^[8] Hyper-pigmentation, hyporeflexia, and loss of vision can also indicate Nelson's syndrome when assessed together.^[8] Specifically for a child who might have Nelson's syndrome, the patient should be questioned about the symptoms of the disease, and well as symptoms of other diseases to narrow down which disease the patient presents with. The patient should be questioned about how often and to what degree headaches, visual disturbances, and symptoms associated with pituitary malfunction occur. Additionally, adrenal steroid replacement should be assessed, especially in children who have prior insufficiency associated with the adrenal gland.^[8]

Cause and Prevention

Common causes include bilateral adrenalectomy for the treatment of Cushing's disease, and hypopituitarism.^[8] The onset of the disease can occur up to 24 years after a bilateral adrenalectomy has been performed, with an average of up to 15 years after.^[4] A preventative measure that can be utilized is prophylactic radiotherapy when a bilateral adrenalectomy is being performed in order to prevent Nelson's syndrome from manifesting.^[9] Screening can also be done with the help or an MRI in order to visualize the pituitary for tumors. If tumors are not present then an MRI should be performed at intervals.^[10] Hyper-pigmentation and fasting ACTH levels within plasma above 154 pmol/l are predictive of Nelson's syndrome after an adrenalectomy.^[10] Risk factors include being younger in age and pregnancy.^[2]

Treatment and Prognosis

Common treatments for Nelson's syndrome include radiation or surgical procedure. Radiation allows for the limitation of the growth of the pituitary gland and the adenomas. If the adenomas start to affect the surrounding structures of the brain, then a micro-surgical technique can be adapted in order to remove the adenomas in a transsphenoidal (bone at base of the skull) process.^[7] Death may result with development of a locally aggressive pituitary tumor. However, does not commonly occur with pituitary diseases.^[6] In the rare case, ACTH-secreting tumors can become malignant. Morbidity from the disease can occur due to pituitary tissue compression or replacement. Compression of the structures that surround the pituitary fossa can also be compressed by the tumor.^[2] The tumor can also compress the optic apparatus, disturb cerebrospinal fluid flow, meningitis, and testicular enlargement in rare cases.^[2]

Recent Research

Through multiple advancements within the medical field, care-givers have been able to stray away from utilizing bilateral adrenalectomy as the treatment for Cushing's disease. This has decreased the risk of patients presenting with Nelson's syndrome. Alternative treatments for Nelson's syndrome have been discovered. The most utilized technique for Nelson's syndrome has been transsphenoidal surgery. In addition, pharmacotherapy, radiotherapy, and radiosurgery have been utilized accompanying a surgical procedure. Pharmalogical drugs can also be given accompanying a transsphenoidal surgery including the following: pasireotide, temozolomide and octreotide.^[9] Within rats/mice, rosiglitazone has been an effective measure, however this has not been discovered in humans yet.^[9]

References