eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Glucocorticoid Therapy and Cushing Syndrome: Follow-up

Author: George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London), Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece
Coauthor(s): Antony Lafferty, MB ChB, FRACP, Senior Lecturer of Pediatric Endocrinology, Monash University Department of Pediatrics, National Institutes of Health, Bethesda, MD, and Princess Margaret Hospital for Children, Perth, Western Australia
Contributor Information and Disclosures

Updated: Mar 11, 2009

Follow-up

Further Outpatient Care

• Regular follow-up care is required for patients with Cushing syndrome (CS) who are receiving adrenal steroid replacement. Obtain a history of the number of illnesses, frequency with which stress doses are administered, and symptoms of adrenal insufficiency at 3-month assessments. Measure height (growth velocity should normalize unless another pathology is present), weight, and blood pressure and look for signs of overtreatment. Encourage patients to adhere to a diet that is rich in calcium (at least 1-1.5 g/d during teenage years) and vitamin D. Patients should also participate in regular exercise to improve muscle tone, to lose weight, and to strengthen bones.
• Perform Cortrosyn stimulation testing at 6-month intervals to determine when HPA axis recovery occurs. Once a 30-minute cortisol exceeds 18 mcg/dL, hydrocortisone can be weaned and stopped.
• Patients who have had bilateral adrenalectomy require similar follow-up care, with the exception of the Cortrosyn testing. Plasma renin activity (PRA) should be measured to ensure adequacy of Florinef (fludrocortisone acetate) replacement. These patients may also require saline tablets in warm humid weather. If Florinef requirements appear excessive, glucocorticoid doses should be reviewed because high requirements may occur with inadequate glucocorticoid replacement.
• Patients with ectopic corticotropin (ACTH) production should be seen every 3 months to ensure that they have no signs of toxicity from their ketoconazole (including checking liver function tests) or other steroid synthesis inhibitor. Patients should undergo reassessment at 6-month intervals to look for the origin of the tumor.

Inpatient & Outpatient Medications

• In patients with endogenous Cushing syndrome, the same medications are used in inpatient and outpatient care, with the exception of etomidate, which is intravenously administered in very sick inpatients.

Transfer

• Age of transfer to adult care varies between institutions, ranging from 16-21 years. Patients who have had adrenalectomy require lifelong care by an endocrinologist. Patients who have achieved full height can switch to a longer-acting steroid, such as dexamethasone, which has the advantage of only 1 daily dose. Fludrocortisone dosing must also be continued.

Deterrence/Prevention

• Prevention of complications related to long-term glucocorticoid treatment requires constant attention to ensure that the drug being used is appropriate for the condition, that systemic absorption of glucocorticoid is minimized, that the duration of treatment is as short as possible, and that the dose is the lowest required to control disease activity.
• When glucocorticoid treatment cannot be stopped, ensuring that intake of vitamin D and calcium is adequate and that a regular exercise routine is maintained is essential. Actively screen for potential complications to ensure that prompt treatment is instituted as needed.

Complications

• Complications of glucocorticoid excess are summarized in Table 2 (for a printable version of Table 2, see Media file 4).
• Complications may arise from the invasive testing that some patients with Cushing syndrome require. Adrenal vein sampling can be associated with hemorrhage into the adrenal gland, which, if it occurs in the unaffected side, may render the patient permanently adrenally insufficient, following excision of their adenoma. Inferior petrosal sinus sampling can rarely cause bleeding or thrombosis of petrosal sinuses with neurologic sequelae. Therefore, reserve these procedures for occasions when findings from prior investigations are either contradictory or inconclusive.
• Surgical management may be associated with the following complications:
  • Pituitary adenoma
    • One of the most common complications is invasion of the walls of the cavernous sinuses or other surgically inaccessible places, which may occur with failure of surgical cure.
    • Complications of transsphenoidal surgery include bleeding due to injury to the carotid arteries, paresis, fracture of the orbit with optic nerve entrapment, or trapping of orbital muscles. Hypopituitarism, infection, and damage to the optic nerves or their blood supply may also occur. Frequency of these complications depends on the extent of the tumor and the skill of the surgeon. Diabetes insipidus (DI) occurs transiently in approximately 25% of cases and is more common with repeat surgery and with tumors near the posterior lobe. In about 25% of cases, DI is permanent. Again, this tends to occur with large tumors and repeat surgeries.
    • Less frequently, transiently excessive secretion of vasopressin may occur (syndrome of inappropriate secretion of antidiuretic hormone [SIADH]), which requires careful management of fluid intake. Nelson syndrome used to occur in 10-30% of patients with incurable pituitary adenoma treated with adrenalectomy. With advances in radiotherapy techniques and surgical techniques, this condition is likely to be avoided.
  • Surgical approach: Morbidity associated with adrenal surgery is reduced considerably if an anterior abdominal approach is avoided, unless carcinoma is suspected and staging of the liver and lymph nodes must be performed. Where possible, employ a laparoscopic approach. Risk of bleeding is always present and may require converting to open procedures in a percentage of cases.

Prognosis

• Hypercortisolism
  • Hypothalamic-pituitary-adrenal (HPA) axis recovery: More than 90-95% of patients have recovery of their HPA axis by 12 months after stopping treatment, with more than 50% of the remainder recovering in the following 6-12 months. Permanent adrenal insufficiency has been described, although it is rare. Early recognition and prompt treatment of the early signs of adrenal insufficiency is essential because this may be life threatening if not managed appropriately.
  • Growth: Growth velocity usually normalizes and weight loss occurs in children once pharmacologic doses of glucocorticoids have been reduced to physiologic levels. However, catch-up growth is frequently disappointing, with a tendency not to achieve predicted final height.
  • Bone density: Patients with significant osteoporosis experience some recovery in bone density, provided they have adequate calcium and vitamin D replacement and regular exercise. Bisphosphonate treatment may be needed in severe cases. Residual deficits in bone density are more likely if treatment was prolonged and occurred at a time of peak bone mass accrual. The role of prophylactic treatment with bisphosphonates is still being studied.
  • Metabolic disorders: Diabetes and insulin resistance resolve with cessation of therapy, although patients who become frankly diabetic when on glucocorticoids are likely to have significant preexisting insulin resistance and are at risk of developing type 2 diabetes in later life. Dyslipidemia should also improve as insulin resistance resolves, although this also depends upon premorbid lipid status.
• Cushing disease: With transsphenoidal pituitary surgery, the cure rate for uncomplicated cases is approximately 95% and the recurrence rate is about 5%. If evidence of cavernous sinus invasion is noted or if repeat surgery is required, the cure rate falls significantly and the complication rate also rises.
• Adrenal neoplasms: For nonmalignant adrenal neoplasms, the cure rate remains excellent. For malignant tumors, surgery offers the best chance of cure or prolongation of survival, with excision of isolated metastases in the lung or lymph nodes being primary treatment. Results of chemotherapy and radiation therapy have been disappointing, and, although disease control has been achieved, cure with these methods is uncommon so they have a more palliative role.

Patient Education

• Educate patients and parents to recognize situations where an increase in glucocorticoid dosage is required. Unfortunately, the medical profession often also needs education on this issue because physicians sometimes do not appreciate the urgency of treatment in the patient who is developing signs of adrenal insufficiency.
• Ensure that parents and patients understand the importance of proper technique for administering their glucocorticoid treatments (eg, the need for a spacer device with asthma, the importance of using potent steroid creams sparingly).
• Children with Cushing syndrome are commonly diligent workers. Warn the family that their school performance and concentration may suffer after successful treatment and that the child may also develop psychiatric symptoms, including anxiety and depression, possibly requiring psychiatric treatment.⁷
• Siblings in the same household should not receive attenuated live-virus vaccines because of the risk of causing infection in the child who is affected by Cushing syndrome.
• All patients receiving glucocorticoid therapy for longer than 1-2 months should be provided a medic-alert bracelet identifying them as dependent on steroids.

Miscellaneous

Medicolegal Pitfalls

• Hypercortisolism
  • Inappropriate use of glucocorticoids because of misdiagnosis of the patient's condition unnecessarily exposes patients to glucocorticoid-associated morbidity. Other potential errors in management include use of excessive doses of glucocorticoid, the inappropriate choice of drug or route for the patient's condition, and inadequate frequency of follow-up visits.
  • The greatest potential for problems relates to the failure to educate the parents and patient about avoiding abrupt cessation of treatment, failure to warn of the signs of acute adrenal crisis, and failure to educate about how adrenal crisis should be treated. Failure of medical professionals to recognize and promptly treat an adrenal crisis is another major area where medicolegal problems may arise.
• Treatment of Cushing syndrome (CS)
  • Cushing syndrome is probably one the most challenging and potentially problematic endocrine disorders to diagnose and manage. Medicolegal problems arise when the workup and communication have been inadequate. Such inadequacies can result in removal of one or both adrenals when the pituitary is the source of the problem, removal of some or all of the pituitary when the corticotropin (ACTH) source is ectopic, or even performance of surgery on a patient who does not have Cushing syndrome.
  • Patients undergoing assessment must do so in centers that treat such patients regularly. Mortality and morbidity for patients with Cushing syndrome is directly related to the duration of disease and the experience of the team treating the patient. Aside from the acute complications associated with hypercortisolism, untreated Cushing syndrome is associated with a cardiovascular mortality risk that is 5-fold higher than that of the non-Cushingoid population.

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