Reversible Dementia From Corticosteroid Therapy

Key words: Corticosteroids, glucocorticoids, reversible dementia, steroid psychoses.
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Corticosteroids are defined as “any of the steroids elaborated by the adrenal cortex (excluding the sex hormones) or any synthetic equivalents.”¹ They are divided into two major groups: glucocorticoids, which physiologically modulate body homeostasis and coordinate adaptive responses to stress, involving almost all organs and tissues (including the brain)²; and mineralocorticoids, which regulate the balance of water and electrolytes in the body.³ Collectively, corticosteroids are involved in a wide range of physiologic systems, including immune and inflammatory responses, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior.⁴ Because of their potent anti-inflammatory and immunosuppressive properties, corticosteroids are often used to treat medical conditions, such as allergies and rheumatologic, respiratory, gastrointestinal, neurologic, and autoimmune diseases. In 1996, it was reported that more than 10 million new corticosteroid prescriptions are filled each year.⁵ While prescribing practices change over time, and very few data exist on oral glucocorticoid use, a 2011 study by French investigators found that approximately 1% of the UK population is on an oral glucocorticoid therapy at any given time.⁶

Glucocorticoids can be taken numerous ways, including by mouth, through an inhaler, via a topical application, or through an injection. Each of these administration methods is associated with various side effects. Oral corticosteroids have been associated with glaucoma, fluid retention, hypertension, weight gain, hyperglycemia, immunosuppression, hypocalcemia, slowed wound healing, cataracts, and hormonal problems. It has also been well established that corticosteroid medications can occasionally cause mental disturbances and impairments in memory performance that are reversible.^7,8 We report one such case in an elderly woman who received a glucocorticoid to treat her giant cell arteritis. Although mineralocorticoids have also been associated with psychiatric disorders, particularly those related to stress,⁹ this article focuses predominantly on glucocorticoids.

Case Report

In February 2008, a 75-year-old woman in good health presented with acute left-sided periocular pain and concomitant scalp tenderness. The patient had a high school education and no history of psychiatric illness. Her erythrocyte sedimentation rate (ESR) was 78 mm/h (normal, 0-20 mm Hg). A temporal artery biopsy confirmed the suspected diagnosis of giant cell arteritis (also known as temporal arteritis or cranial arteritis). Prompt treatment with a corticosteroid medication (prednisone 60 mg/day) relieved her symptoms. Her ESR levels returned to normal. After 7 months of treatment, the patient became forgetful, developed insomnia and impaired memory, and showed anxiety, labile mood, and a decreased motivation to perform activities of daily living, such as driving and bathing. One month later, she demonstrated defective temporal orientation and a clear amnesic syndrome, and she was unable to care for herself.

The results of a neurologic examination performed at her current presentation were normal. Neuropsychologic testing revealed grossly defective temporal orientation and attention as well as deficits in memory retrieval. The patient had a Mini-Mental State Examination (MMSE) score of 22 out of 30. Findings from a standard 16-lead electroencephalogram were normal. Gadolinium-enhanced nuclear magnetic resonance imaging (NMRI) of the brain showed mild temporal atrophy. Single-photon emission computed tomography (SPECT) demonstrated a nondiagnostic pattern of mild, diffuse hypoperfusion. The following laboratory results were within normal limits: thyroid and liver function panels, electrolyte levels, complete blood count, serum vitamin B₁₂ and folate levels, homocysteine levels, megaloblastic anemia profile, ESR levels, rheumatoid factor, antinuclear antibodies, antiendomysial antibodies, antigliadin IgA and IgE antibodies, Lyme antibodies, paraneoplastic antibodies, and anti-HIV antibodies. The results of a venereal disease research laboratory test was also normal. The patient’s serum and urine were negative for mercury, arsenic, and lead. An analysis of her cerebrospinal fluid was inconclusive with regard to her glucose and protein levels, there was an absence of cells, and it was negative for 14.3.3 protein.

The diagnosis of neurodegenerative disease (eg, Alzheimer’s disease, Lewy body disease, or frontotemporal dementia) was improbable because her cognitive deficits were rapidly progressive. In the absence of cancer and of any concurrent inflammatory, infectious, ischemic, toxic, and metabolic cause, the working diagnosis was steroid-induced organic brain syndrome. The patient’s prednisone dosage was lowered over the following 20 days and then discontinued. Her memory and cognitive deficits improved 15 days later. Two months after withdrawal of the corticosteroid therapy, the patient was asymptomatic and exhibited no abnormalities on neurologic examination. Her mood lability and anxiety symptoms were no longer evident, and neuropsychologic tests showed great improvement in almost all cognitive functions. On a repeat MMSE, she scored 28 out of 30, losing one point on temporal orientation and another on recall. A new gadolinium NMRI of the brain obtained 4 months later showed the same findings as those observed on her previous scan. One year after her initial examination, a follow-up SPECT showed no change in findings, but a follow-up neuropsychologic evaluation in August 2009 revealed mild impairment in memory.

Discussion

Our patient was taking prednisone, a glucocorticoid that has been associated with various central nervous system (CNS) effects. Glucocorticoids are comprised of multifunctional domain proteins, which operate as ligand-dependent transcription factors that interact with many other cell signaling systems, including large and small guanine nucleotide-binding proteins (G proteins).¹⁰ G proteins communicate chemical signals from many hormones, neurotransmitters, and other signaling factors, leading to a cascade of changes inside the cell.¹¹ Endogenous and synthetic glucocorticoids cross the blood-brain barrier to access corticosteroid receptors within the CNS.¹² The brain is a major target organ for corticosteroids, which regulate the production and release of the hypothalamic corticotropin-releasing hormone (a reduction in this hormone has been associated with Alzheimer’s disease¹³) and the pituitary adrenocorticotropic hormone (ACTH). In addition, glucocorticoids regulate many functions of the CNS, such as arousal, cognition, mood, and sleep, by modulating neurohippocampal systems and the plasticity and circuitry of many brain regions where, once secreted, they readily enter.¹⁴

There are at least two distinct types of high-affinity receptors in the brain that bind with glucocorticoids: type I receptors (also known as mineralocorticoid receptors), which are found predominantly in the hippocampus; and type II receptors (also known as glucocorticoid receptors), which are found in the hippocampus and are also widely distributed in other regions of the brain.¹⁵ The hippocampal formation is an important target for glucocorticoids in the CNS. This brain region is essential for declarative or explicit memory, which refers to the voluntary recollection of learned information, such as remembering what one had for lunch. Because the hippocampus is one of the essential lability substrates for memory, glucocorticoid-induced adverse effects that alter the hippocampal structure or interfere with its function may impair those memory processes dependent on hippocampal integrity. Abundant evidence shows that both low and high levels of glucocorticoids adversely affect hippocampal physiology. Excessive circulating levels of endogenous or exogenous levels of corticosteroids are frequently associated with decreased memory performance.^16,17 Deficits in declarative memory have been observed even in subjects receiving only 4 or 5 days of dexamethasone or prednisone treatment.^17-19 Whether these memory deficits are common and clinically significant in patients receiving prescription corticosteroids remains unknown. It is important to note, however, that glucocorticoids are not always detrimental to the cognitive process. It has been reported that when type I receptors are saturated and type II receptors are partially occupied, memory is maximized.²⁰ It appears that memory becomes impaired when both type I and type II receptors are not occupied or are saturated.²⁰

Chronic exposure of the limbic regions of the brain to glucocorticoids has been associated with neuropsychiatric changes, neurotransmitter effects, and neuroanatomical changes, including cortical atrophy, ventricular enlargement, and hippocampal degeneration.^21-24 In 1952, Rome and Braceland²⁵ evaluated more than 100 patients who underwent treatment with ACTH, cortisone, or hydro-cortisone for various diseases. They found “thinking disturbances” to be a common symptom of corticosteroid therapy in these patients. Psychiatric adverse relations caused by corticosteroid medications, such as the thinking disturbances noted by Rome and Braceland,²⁵ are often referred to as steroid psychosis. The potential psychiatric adverse effects of corticosteroids span a symptom spectrum ranging from subtle mood changes to full-blown affective syndromes and frank psychosis. The alterations of mood may be transient or persistent.^26,27 Mania and hypomania appear to be more common than depression.^28,29 Other effects of steroids on mental status include anxiety, agitation, irritability, fear, delirium, and frank psychosis typified by hallucinations, delusions, and disorganized thoughts. There is no clear evidence that a patient’s previous psychiatric history increases the risk of psychiatric adverse effects from taking steroids.²⁶ The psychiatric symptoms appear to be dose-dependent and generally occur during the first few weeks of therapy.³⁰

Numerous studies have provided evidence to support the glucocorticoid hypothesis of brain aging, which postulates that long-term exposure to adrenal glucocorticoids (stress hormones) facilitates aging-related functional decline and vulnerability in hippocampal neurons.^31-33 Affected cells show heightened sensitivity to extrinsic injuries and disease, causing hippocampal deterioration and eventual cognitive decline. Lupien and associates³⁴ showed that elevated plasma cortisol levels correlate with reduced hippocampal volume and memory impairment in aging persons. The impact of glucocorticoids on memory retrieval, however, has also been documented in younger populations. A European study examined the in vivo effects of glucocorticoids on the memory retrieval process by using positron emission tomography (PET).³⁵ In the study, young participants (aged 21-27 years) were administered a medium dose of a synthetic glucocorticoid (cortisone 25 mg) 24 hours after learning various declarative memory tasks. Brain activation was measured by PET 1 hour after drug administration. The results showed that the glucocorticoid induced a large decrease in regional cerebral blood flow in the right posterior medial temporal lobe, with participants demonstrating impaired cued recall of word pairs learned 24 hours earlier.³⁵ There have also been case reports of impaired mental concentration in children using inhaled corticosteroids for the treatment of asthma.³⁶ Such acute effects of glucocorticoids on memory retrieval are limited to the time that circulating hormone levels are elevated.

Hall and associates³⁷ noted a 57% incidence of intermittent memory impairment in a group of patients who received corticosteroids. In 1984, Varney and colleagues³⁸ reported six cases in which patients receiving high doses of corticosteroids for a variety of medical illness (which largely did not affect the CNS) developed a mental disorder that was quite distinct from steroid psychosis. These patients appeared to develop a reversible dementia-like decline in mental status. The symptoms, which included significant disturbances in memory retention, decreased attention and concentration, and deficits in mental speed, efficiency, and occupational performance, prompted the investigators to coin the term steroid dementia. These symptoms were reversed after the patients discontinued the glucocorticoid medication.³⁸ More recently, Sacks and Shulman³⁹ documented the case of a man who developed a psychosis followed by dementia as a serious adverse effect of corticosteroid treatment. When the medication was discontinued, the man returned to his previous level of functioning. Similarly, our case patient had a reversible dementia caused by long-term administration of a glucocorticoid. Although the etiology of the patient’s memory deficits at her follow-up neuropsychologic evaluation remains unclear, it is possible that her memory deficits could be attributed to her evolving clinical picture, which may now involve mild cognitive impairment.^40,41

Conclusion

Corticosteroids are given for a variety of common illnesses on both an outpatient and inpatient basis. Therefore, the adverse effects of these medications are of concern to all physicians. Neuropsychiatric adverse effects during systemic corticosteroid therapy occur frequently. Cognitive deficits, particularly declarative and verbal memory deficits, have been documented during both long- and short-term glucocorticoid therapy. The case presented here confirms that long-term use of glucocorticoid medication, administered in the recommended doses, may induce reversible dementia. Future research is needed on steroid-induced cognitive symptoms.

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Disclosures:
The authors report no relevant financial relationships.

Address correspondence to:
Gabriele Cipriani, MD
Neurology Unit
Versilia Hospital
Via Aurelia 55043
Lido di Camaiore, Italy
cprgrl@gmail.com