A variety of Psychiatric and Neurocognitive symptoms have been described in patients with Cushing's syndrome (CS). The initial description of these symptoms finds mention in the article by Harvey Cushing. The most commonly observed psychiatric disorders in patients with CS are depression and anxiety. In fact, 5% of the observed deaths in patients with CS are due to suicides. The initial studies on cognitive function in patients with CS described memory impairments and concentration difficulties as the common manifestations in patients with active hypercortisolism. The decline in memory is found to be associated with a reduction in brain volume and more specifically with reduced hippocampal volume. The functional improvement in memory encoding has also been documented after effective control of hypercortisolism with the reversal of hippocampal atrophy. Thus, both structural and functional outcomes of hypercortisolism on the brain have been well documented in CS.
STRUCTURAL ANOMALIES AND IMAGING
Brain structural abnormalities related to CS include smaller hippocampal volumes, enlarged ventricles, and cerebral atrophy. Specific correlations between hippocampal volume and verbal learning, recall, and memory function scores have been seen. Hypercortisolism affects the entire brain with white matter tracts demyelination. White matter hyperintensities (WMH) seen in patients with CS may be related to the increased cardiovascular risk factors leading to cerebrovascular injury. Studies with various neuroimaging techniques including magnetic resonance imaging (MRI), functional MRI (fMRI), diffusion tensor imaging (DTI), and proton magnetic resonance spectroscopy (MRS) have identified the involvement of widespread damage and certain specific areas of the brain such as hippocampus, amygdala, uncinate fasciculus, and prefrontal cortex.
Both improvements in psychiatric and cognitive manifestations as well as residual effects have been reported on long-term follow-up in cohorts of CS in remission. These have been associated with a structural increase in brain volume although the correlation to specific areas is still not well delineated.
Depression is the most common psychiatric manifestation seen in CS patients ranging from 50-81%. The current study in this issue found depression in 80% of CS patients. They also found a positive correlation of depression severity with 0800 hour cortisol and ACTH. In the study by Sonino et al., 54% patients with active Cushing's syndrome (CS) had major depression and this was associated with a higher urinary cortisol levels and the severity of the syndrome. There have been studies where general anxiety was the most common affective disorder in 79%, followed by depression in 68% and panic disorder in 53%.
After curative surgery maximal improvement was seen in patients who had severe depression particularly suicidal tendencies were improved significantly in the current study. This is similar to previous reports where depressive disorder reduced from 67% to 24% at the end of one year after remission of CS. The mean duration of follow-up of 7 months is relatively short in the current study as compared to previous such studies.
Improvement in the cognitive functions after curative surgery in patients of CS was seen in this study as assessed by several tests. Results on neurocognitive improvement post-surgery in CS patients have previously been published by the same group. Improvements in executive function and attention have been seen 3 years after treatment in a study by Forget H, et al. In a recent meta-analysis, most cognitive domains (apart from concept forming and reasoning) were significantly affected in CS patients and these responded favorably to the surgery along with improvement in quality of life (QOL) parameters.
The meta-analysis, however, did not detect any strong evidence of reduced Hippocampal volume (HV) in patients with CS, nor an increase of HV after surgery. This is in contrast to the current study results which suggest increase in brain volume derived from a reduction in the third ventricular and bicaudate nucleus diameter from baseline after curative surgery. Few previous studies have shown a reduced HV in CS patients and that HV increases but does not normalize following remission. A recent study did show that patients with CS had significantly more cortical and subcortical atrophy and a higher prevalence of white matter hyperintensity (WMH) and the brain atrophy and WMH was partially reversible after correction of hypercortisolism.
To conclude, there is a high prevalence of neuropsychiatric and neurocognitive dysfunction seen in CS patients as a result of persistently elevated cortisol levels. The current study does highlight this aspect of a relatively uncommon endocrine condition. Structural brain changes may be visualized by various MRI techniques. Functional imaging is increasingly playing an important role. Remission leads to reversal of a significant component of this neurological dysfunction leading to improved QOL, although complete reversal is not seen despite eucortisolemia in these patients. A better understanding of the pathophysiologic aspects of neuropsychiatric dysfunction in CS will help in directing treatment of the residual symptoms in this disease in future.
1. Cushing H. The basophil adenomas of the pituitary body and their clinical manifestations (Pituitary Basophilism) Bull Hohns Hopkins Hosp. 1932;50:137–95
2. Ragnarsson O, Olsson DS, Papakokkinou E, Chantzichristos D, Dahlqvist P, Segerstedt E, et al Overall and disease-specific mortality in patients with cushing disease: A Swedish nationwide study J Clin Endocrinol Metab. 2019;104:2375–84
3. Whelan TB, Schteingart DE, Starkman MN, Smith A. Neuropsychological deficits in Cushing's syndrome J Nerv Ment Dis. 1980;168:753–7
4. Starkman MN, Gebarski SS, Berent S, Schteingart DE. Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing's syndrome Biol Psychiatry. 1992;32:756–65
5. Starkman MN, Giordani B, Gebarski SS, Berent S, Schork MA, Schteingart DE. Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing's disease Biol Psychiatry. 1999;46:1595–602
6. Starkman MN, Giordani B, Gebarski SS, Schteingart DE. Improvement in learning associated with increase in hippocampal formation volume Biol Psychiatry. 2003;53:233–8
7. Andela CD, van Haalen FM, Ragnarsson O, Papakokkinou E, Johannsson G, Santos A, et al MECHANISMS IN ENDOCRINOLOGY: Cushing's syndrome causes irreversible effects on the human brain: A systematic review of structural and functional magnetic resonance imaging studies Eur J Endocrinol. 2015;173:R1–14
8. Pires P, Santos A, Vives-Gilabert Y, Webb SM, Sainz-Ruiz A, Resmini E, et al White matter alterations in the brains of patients with active, remitted, and cured cushing syndrome: A DTI study Am J Neuroradiol. 2015;36:1043–8
9. van der Werff SJA, Andela CD, Nienke Pannekoek J, Meijer OC, van Buchem MA, Rombouts SARB, et al Widespread reductions of white matter integrity in patients with long-term remission of Cushing's disease NeuroImage Clin. 2014;4:659–67
10. Williamson W, Lewandowski AJ, Forkert ND, Griffanti L, Okell TW, Betts J, et al Association of cardiovascular risk factors with MRI indices of cerebrovascular structure and function and white matter hyperintensities in young adults JAMA. 2018;320:665–73
11. Maheu FS, Mazzone L, Merke DP, Keil MF, Stratakis CA, Pine DS, et al Altered amygdala and hippocampus function in adolescents with hypercortisolemia: A functional magnetic resonance imaging study of Cushing syndrome Dev Psychopathol. 2008;20:1177–89
12. Crespo I, Santos A, Gómez-Ansón B, López-Mourelo O, Pires P, Vives-Gilabert Y, et al Brain metabolite abnormalities in ventromedial prefrontal cortex are related to duration of hypercortisolism and anxiety in patients with Cushing's syndrome Endocrine. 2016;53:848–56
13. Pivonello R, Simeoli C, De Martino MC, Cozzolino A, De Leo M, Iacuaniello D, et al Neuropsychiatric disorders in Cushing's syndrome Front Neurosci. 2015;9:129
14. Sonino N, Fava GA, Raffi AR, Boscaro M, Fallo F. Clinical correlates of major depression in Cushing's disease Psychopathology. 1998;31:302–6
15. Loosen PT, Chambliss B, DeBold CR, Shelton R, Orth DN. Psychiatric pphenomenology in Cushing's disease Pharmacopsychiatry. 1992;25:192–8
16. Dorn LD, Burgess ES, Friedman TC, Dubbert B, Gold PW, Chrousos GP. The longitudinal course of psychopathology in Cushing's syndrome after correction of hypercortisolism J Clin Endocrinol Metab. 1997;82:912–9
17. Nehra R, Grover S, Bhansali A, Khehra N. Effect of corrective surgery on neurocognitive functions in endogenous cushing syndrome Endocrinologist. 2009;19:205–7
18. Forget H, Lacroix A, Bourdeau I, Cohen H. Long-term cognitive effects of glucocorticoid excess in Cushing's syndrome Psychoneuroendocrinology. 2016;65:26–33
19. Frimodt-Møller KE, Møllegaard Jepsen JR, Feldt-Rasmussen U, Krogh J. Hippocampal volume, cognitive functions, depression, anxiety, and quality of life in patients with cushing syndrome J Clin Endocrinol Metab. 2019;104:4563–77
20. Chen Y, Zhang J, Tan H, Li J, Yu Y. Detrimental effects of hypercortisolism on brain structure and related risk factors Sci Rep. 2020;10:12708