Pathophysiology of Neurologic and Psychiatric Manifestations in Cushing Syndrome
The neurologic and psychiatric symptoms of Cushing syndrome result primarily from excess endogenous glucocorticoids causing structural brain damage, particularly cerebral atrophy with selective vulnerability of the hippocampus and frontal/temporal lobes, leading to cognitive impairment and depression. 1
Primary Pathophysiologic Mechanism
Excess circulating glucocorticoids directly damage brain tissue through multiple mechanisms:
- Brain atrophy develops in both adults and children with active Cushing syndrome, with considerable cerebral atrophy documented at diagnosis 1
- Grey matter volume loss occurs diffusely but shows selective persistence in frontal and temporal lobes even after remission, regions strongly associated with cognition and memory 1
- Hippocampal damage is particularly prominent, with decreased glucose utilization leading to neurogenesis impairment, inhibition of long-term potentiation, and decreased neurotrophic factors 2
Specific Neurobiological Mechanisms
At the cellular level, glucocorticoid excess causes:
- Hippocampal structural changes including alterations in neurogenesis, neuronal morphology, signaling pathways, and gene expression 2
- Glutamate accumulation in hippocampal tissue, contributing to excitotoxic damage 2
- Impaired glucose metabolism in brain tissue, which may explain the mechanisms of glucocorticoid-induced brain atrophy 2
- Damage to basal ganglia in addition to hippocampal injury 2
Clinical Manifestations by System
Psychiatric Symptoms
Depression is the most common psychiatric manifestation:
- Major depression occurs most frequently, along with emotional instability, anxiety disorders, and impulsivity 2, 3, 4
- Mania and psychosis are less common but well-documented complications 5, 4
- These symptoms are directly associated with excess endogenous circulating glucocorticoids 1
Cognitive Impairments
Multiple cognitive domains are affected:
- Episodic and working memory deficits are prominent features 5
- Executive function and attention are impaired at diagnosis 5
- Paradoxical cognitive decline can occur even after successful surgical cure, despite reversal of brain atrophy 1
Reversibility and Long-Term Consequences
Critical distinction between reversible and irreversible changes:
- Almost complete reversal of cerebral atrophy occurs within 1 year after transsphenoidal surgery cure 1
- Grey matter volume loss reverses within 3 months after remission, except in frontal and temporal lobes which remain affected 1
- Long-term cognitive and memory problems persist in approximately 25% of patients despite successful treatment 1
- Severe psychiatric and behavioral symptoms show notable improvement after cure, but complete recovery is not universal 1
Important Clinical Pitfalls
The paradoxical post-treatment decline requires awareness:
- Despite near-complete reversal of structural brain atrophy at 1 year post-surgery, a paradoxical decline in cognitive function can occur 1
- This dissociation between structural recovery and functional improvement underscores that irreversible effects of previous glucocorticoid excess on the central nervous system may persist 2
- Long-standing hypercortisolism may cause irreversible pathological damage and induce highly individualized affective responses 4
Monitoring Implications
Given these pathophysiologic mechanisms, the 2024 Nature Reviews Endocrinology consensus guideline recommends: