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Pediatric Cushing Syndrome: Quality of life and other outcomes

Cushing syndrome (CS) affects children and adolescents in many ways that are different than adults and may be associated with long lasting effects even with successful remission. Early identification and treatment of CS is important, particularly since children have not completed their growth and development. Barriers to optimal care include lack of knowledge about the disease leading to delays in diagnosis and tests used to screen or confirm the diagnosis, lack of access to experienced clinicians (pediatric endocrinologists, surgeon or neurosurgeon), lack of pharmacologic treatments that are effective and well-tolerated, and lack of awareness of long term morbidities associated with CS in childhood.  Also, tests to screen for cortisol excess (24hour urine, salivary cortisol) are often difficult to obtain correctly in children in an outpatient setting. Since cortisol and other hormones are secreted in a circadian pattern, random measurements are not helpful.  As reviewed in the pediatric section on CSRF website, if you suspect your child may have CS, schedule an appointment with a pediatric healthcare provider or pediatric endocrinologist.  Growth records are crucial and pictures are helpful in the evaluation of a child with suspected CS.  Recommendations regarding diagnostic tests and therapeutic strategies for children are available [1-3].

In the hands of an experienced healthcare team there is a high rate of success with treatment of CS. However, residual impairments (physical and psychological) are not uncommon and present challenges for the child, family, and healthcare team. Goals after treatment include: optimize growth and pubertal development, normalize body composition, and promote psychological health and cognitive maturation of the child or adolescent.  Studies of outcome measures after treatment of CS typically include frequency or duration of remission of hypercortisolemia, recovery of the hypothalamic-pituitary-adrenal axis, and clinical measures such as height, weight, waist circumference, body mass index, blood pressure, glucose metabolism, and bone density. When reading the results of a clinical study it is important to understand how the authors define cure or remission of CS in order to interpret the findings. Long-term residual impairments after treatment of CS in childhood are listed in the Table. Some of the long-term effects may be related to the number and type(s) of treatment (transsphenoidal surgery, pituitary irradiation, adrenalectomy, or pharmacologic therapy)[4].

There are a limited number of studies that address the cognitive, behavioral, psychological, and quality of life issues in children after treatment for CS. Quality of life is an important outcome measure to assess the burden of disease as well as the effect of treatment. A recent study of children reported that active CS, particularly in younger children, was associated with low physical and psychosocial scores, and that despite improvement one year after cure, residual impairment remained in physical function (assessment of presence and extent of physical limitations due to health-related problem), role- physical (child is limited in school work or social activity as a result of physical health), global health (subjective assessment of overall health), and emotional impact (measure of  emotional impact on parents) scores. Although most self-reported CS symptoms showed improvement, forgetfulness, unclear thinking, and decreased attention span did not improve after cure[5].  It has been reported in the medical literature, that children with Cushing’s may experience problems with their academic performance during or after treatment for Cushing’s for an indeterminate period of time[6]. These problems may be severe during the first postoperative years; they may gradually disappear but often, children and adolescents experience problems for many years without ever returning to their previous (pre-disease) state. The cause is unclear, but it has also been reported that adult patients with CS have problems with their memory and other mental functions.  Neurocognitive testing has been helpful to identify areas of strength and weaknesses in order to develop an individualized education program targeted to enhance academic performance.  CS may have long-term negative effects on the brain and body; therefore early identification and treatment of CS and associated morbidities are important to improve long-term management. 

Suggestions for Parents

  • Encourage your child to find physical activities they enjoy as part of their daily routine; participate as a family! Walking, dancing, riding a bike, swimming, or individual/ team sports are just a few examples of activities that can become a healthy lifetime habit.
  • Good nutrition starts at home; eliminate ‘empty calories’ such as juice, soda, and sweets and encourage fruits, vegetables, and whole grain products.
  • If your child experiences academic difficulties, arrange a meeting with the teachers and school guidance counselor. It is important to provide the school staff with information about the effect of changes in cortisol levels on the brain that can impact academic performance and behavior.
  • Request formal neurocognitive testing in order to identify areas of strengths and weakness and develop an individualized education plan (IEP).
  • You may ask your child’s healthcare provider to write a letter to support your request for accommodation of your child’s education plan due to a medical condition.
  • Behavioral and mood changes are common before and after treatment of CS and may not normalize for months or years. Reassure your child that it is normal to experience moodiness and fatigue after treatment as the body and brain adjust to normal cortisol levels. If your child is experiencing dramatic mood changes such as episodes of panic, depression, or rage contact your child’s healthcare provider and request consultation with a pediatric psychiatrist or psychologist.
  • It is unknown whether there are specific activities that can facilitate attention and memory in children who experience problems after treatment of CS. Researchers with NICHD and others have shown that cognitive processes are malleable through experience and practice.  So it is a reasonable approach to encourage your child to participate in a variety of activities and games designed to train memory and attention, particularly in a non-classroom setting.  Examples of activities include: Sudoku, crossword puzzles, search and find games, and memory games/apps (e.g. Lumosity).

Table

POTENTIAL TREATMENT RELATED EFFECTS

 

-Transsphenoidal surgery

Partial or complete pituitary hormone deficiency, recurrence of CS, pseudotumor cerebri, neurocognitive decrement

-Pituitary irradiation

Partial or complete pituitary hormone deficiency, cranial neuropathies, tumors, neurocognitive decrement

-Bilateral adrenalectomy

Adrenal insufficiency, Nelson syndrome

-Pharmacological

Recurrence of CS, hepatotoxicity, hypertension, hypokalemia, endometrial hyperplasia

POTENTIAL LONG-TERM CLINICAL EFFECTS

 

-Growth

Compromised final height

-Metabolic

Increased BMI, increased abdominal fat, impaired glucose metabolism, hyperlipidemia

-Cardiovascular

Hypertension, increased arterial rigidity

-Bone

Osteopenia, osteoporosis, vertebral fractures, avascular necrosis

-Other

-Autoimmune disease, kidney stone

-Cognitive and psychological

-Cerebral atrophy, alterations in amygdala or hippocampus function, cognitive decrement, memory or concentration difficulties, personality changes, depression or anxiety, decline in school performance

-Quality of life

Residual deficits in physical (function or ability to perform usual activity) or psychological scores (global health perception, emotional impact on parent).

Table reprinted in modified form with permission of The Endocrine Society, from Quality of Life and Other Outcomes in
Children Treated for Cushing Syndrome, Keil, MF, J Clin Endocrinol Metab. 2013;98:2667-78; permission
conveyed through Copyright Clearance Center, Inc.

References

  1. M. A. Magiakou, G. Mastorakos, E. H. Oldfield, M. T. Gomez, J. L. Doppman, G. B. Cutler, Jr., et al. Cushing’s syndrome in children and adolescents. Presentation, diagnosis, and therapy. N Engl J Med. 1994;331:629-36.
  2. D. L. Batista, J. Riar, M. Keil and C. A. Stratakis. Diagnostic tests for children who are referred for the investigation of Cushing syndrome. Pediatrics. 2007;120:e575-86.
  3. C. A. Stratakis. Cushing syndrome in pediatrics. Endocrinol Metab Clin North Am. 2012;41:793-803.
  4. M. F. Keil. Quality of life and other outcomes in children treated for Cushing syndrome. J Clin Endocrinol Metab. 2013;98:2667-78.
  5. M. F. Keil, D. P. Merke, R. Gandhi, E. A. Wiggs, K. Obunse and C. A. Stratakis. Quality of life in children and adolescents 1-year after cure of Cushing syndrome: a prospective study. Clin Endocrinol (Oxf). 2009;71:326-33.
  6. D. P. Merke, J. N. Giedd, M. F. Keil, S. L. Mehlinger, E. A. Wiggs, S. Holzer, et al. Children experience cognitive decline despite reversal of brain atrophy one year after resolution of Cushing syndrome. J Clin Endocrinol Metab. 2005;90:2531-6.

Authors: Meg F. Keil, PhD, CRNP; Maya Lodish, MD, Constantine A. Stratakis, MD, DMSci, Spring, 2015

Editor’s Note: Drs. Meg Keil, Maya Lodish and Constantine Stratakis work in the area of pediatric endocrinology in NICDH at the National Institute of Health in Bethesda, MD. Dr. Lodish recently presented the information contained in this article at Endo 2015.

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