A Role for Selective Serotonin Reuptake Inhibitors in the Management of Residual Cognitive Dysfunction in Pediatric Cushing's Disease

Abstract

To the Editor:

P sychiatric disorders are often identified in Cushing's disease/syndrome. Most of the psychiatric symptoms subside with the normalization of serum cortisol levels. Long-standing hypercortisolism may cause a level of irreversible pathological damage to the brain, manifested by residual psychiatric symptoms. Evidence on management of cognitive dysfunction in Cushing's disease is very limited.

It has been shown that high levels of cortisol in the long term cause cell atrophy in the brain, and stop cell genesis in the hippocampal region and to a lesser extent in other parts of the brain. It has further been suggested that high cortisol levels produce dysfunction of the 5-HT (serotonin) receptor function. We hypothesise that selective serotonin reuptake inhibitors (SSRIs) could help in recovery from cognitive impairment produced by steroids, because SSRIs have been shown both to cause neurogenesis in the hippocampal region (and certain other areas of the brain) and to reverse 5-HT dysfunction. This will be especially relevant for the group of patients who fail to recover completely in their cognitive function and mental state despite normalization of serum cortisol.

We developed our hypothesis when we managed the case of a 14-year-old girl who presented with a variety of physical and psychiatric symptoms in the context of long-standing untreated Cushing's disease. The challenge for child psychiatry was the management of cognitive decline, and this did not reverse itself even after normalization of cortisol. We conducted a literature review for managing neuropsychiatric symptoms in hypercortisolism. Most adult case reports show that psychotic and neuropsychiatric symptoms normalize within a week of cortisol levels returning to the normal range. The length of exposure to high levels of cortisol is a prognostic factor in the recovery of mental state and cognitive function. Concerns were raised about the “watch and wait” approach described in management of psychological symptoms in adult Cushing's disease as being inappropriate for the adolescent developing brain. We treated our patient with fluoxetine (an SSRI) based upon the above hypothesis, and her cognitive function improved.

Introduction

A 14-year-old girl with untreated Cushing's disease was referred to us for management of neuropsychiatric symptoms. Because of the delay in diagnosis and management difficulties, she had long-standing exposure to high levels of cortisol.

History

The patient's early development was described as normal. There was no history of mental illness reported before her current episode. She first started gaining excessive weight in September 2006 (at 11 years of age). At initial visits to her general practitioner (GP) she also reported occasional tiredness and an inability to concentrate. Endocrine pathology was not investigated. She started to exercise and modify her diet in order to try to lose weight. Eventually she developed facial hair; this led to bullying at school. Her physical appearance affected her confidence and self esteem. She was finally diagnosed with Cushing's disease in May 2009 at her third presentation to the GP.

She was referred to the pediatric endocrinology team at her local hospital for a specialist opinion, where she was started on an antisteroid medication: Metyrapone. This was used as an interim measure until she could undergo a surgical procedure to remove part of the pituitary gland, targeting the corticotropin-producing adenoma. She underwent transsphenoidal partial pituitary resection in September 2009, at a tertiary care hospital. The histopathology of the removed gland showed normal cells. Following surgery, the patient was not restarted on antisteroid medication, and symptoms of the Cushing's disease worsened, because despite the surgery, she continued to have a very high blood cortisol level. She became low in mood. The mood symptoms escalated over a period of 3 months into a psychotic episode. At this point, she had developed a delusional belief that there was a tumor in her chest causing all her physical symptoms. She believed that she could remove the tumor herself, which resulted in self-inflicted stab wounds to her chest and neck. During the current admission, she once again received antisteroid medication, underwent transsphenoidal pituitary resection for a second time, and eventually was treated with etomidate, an intravenous anesthetic. Only the latter reduced her cortisol levels, but this was not a long-term treatment option. Consequently, she had to undergo bilateral adrenalectomy. Her cortisol levels eventually stabilized on oral hormone replacement therapy, and most physical parameters normalized. However, her psychological and cognitive functioning did not resume. Her declarative memory was very poor but procedural memory was preserved. Verbal memory was worse than visual. Registration and recall were 0/3. Spatial navigation was markedly poor. Attention was poor and she was unable to do even basic mathematical calculations.

Our challenge was to address the patient's cognitive impairment. During the acute phase we monitored cognitive function and emotional well-being and we addressed her needs accordingly by reorientation, memory aids, and psychological support. In view of the significant cognitive impairment, which did not improve with her physical symptoms during the process of her neurorehabilitation, we explored options of psychopharmacological interventions. Collecting evidence regarding the neurobiological effects of cortisol on the hippocampi and connecting this to evidence regarding the effects of SSRIs on the hippocampi, we decided to prescribe an SSRI (fluoxetine).

Psychiatric Outcome

Outcome was gauged by a psychiatric mental state examination, Mini-Mental State Examination (MMSE), which is a short 30 point questionnaire test that is widely used to screen for cognitive impairment in the medical setting (Folstein 1975). It has been used in the elderly, adults, and children, with numerous studies looking at the norms and applicability (Crum 1993). We also measured daily activity schedule and Children's Orientation and Amnesia Test (COAT). COAT was developed to assess cognition serially during the early stage of recovery from brain injury in children and adolescents. COAT scores are a better predictor of verbal and nonverbal memory performance than the Glasgow Coma Scale score at 6 and 12 months after the injury. COAT has been shown to have adequate reliability and validity as a measure (Ewing-Cobbs 1990). Gradual improvement was noted in memory, orientation, social interaction, activity levels, volition, and attention from the second week or thereabouts on fluoxetine, and it continued for several weeks following, until the patient's premorbid personality emerged. At the time of initiation of fluoxetine, MMSE was 18 and COAT was 7, in 4 weeks MMSE score was 30/30 and COAT score was 14. Improvement was noted in spatial navigation, verbal fluency, and Trail Making Test parts A and B. We were able to discharge her with follow up in the community.

Cushing's Disease/Syndrome

The primary pathology in Cushing's disease is the chronic high levels of blood cortisol/glucocorticoids. Psychiatric symptoms are often identified in Cushing's disease. These include, in order of more common to least: Flat affect, depression, psychosis, mania, and cognitive dysfunction (Sonino and Fava 2001). Most of the psychiatric symptoms in Cushing's disease subside with the normalization of serum cortisol levels (Sonino and Fava 2001); however, long-standing hypercortisolism may cause a level of irreversible pathological damage to the brain, which is manifested by residual psychiatric symptoms (Starkman et al. 1992; Dorn et al. 1997; Forget et al. 2002; Sonino et al. 2006).

Evidence for management of neuropsychiatric symptoms in pediatric Cushing's disease

The literature suggests that reduction and normalization of cortisol/steroids in patients would alleviate psychiatric symptoms, albeit with a lag time of ∼1 week. Suggested effective medication included those drugs that reduce synthesis or action of glucocorticoids. These include metyrapone, etomidate, ketoconazole, aminoglutethimide, and mifepristone; there were also reports that after successful surgical treatment of hypercortisolism, both physical signs and psychiatric symptoms improve substantially (Table 1) (Jeffcoate et al. 1979; Saad et al. 1984; Kramlinger et al. 1985; Gartner et al. 1986; Sonino et al. 1986; Lamberts et al. 1987; Schulte et al. 1990; Van der Lely et al. 1991; Magiakou et al. 1994; Drake et al. 1998; Prince 1997; Hoschl and Hajek 2001; Krakoff et al. 2001; Bilgin 2007; Allolio 1983; Allolio 1988; Greening et al. 2005; Johnson and Canada 2007; Storr et al. 2007; Nieman et al. 2008; Obinata et al. 2008; Savage et al. 2008; Dabbagh et al. 2009; Pereira et al. 2010; Chan et al. 2011). One recent study describes three children on very high doses of steroids for leukemia who were successfully treated with risperidone for steroid-induced mood and behavioral symptoms (Ularntinon et al. 2010).

Table 1.

Studies Describing Pharmacological and Surgical Reduction of Plasma Cortisol Levels

Treatments used in lowering plasma cortisol	Reference
Metyrapone	Jeffcoate et al. 1979; Kramlinger et al. 1985; Sonino 1986; Obinata et al. 2008
Etomidate	Allolio 1983; Allolio 1988; Gartner et al. 1986; Drake et al. 1998; Schulte et al. 1990; Krakoff et al. 2001; Greening et al. 2005; Johnson and Canada 2007; Dabbagh et al. 2009; Chan et al. 2011
Ketoconazole	Prince 1997
Aminogluthetamide	Sonino et al. 1986
Mifepristone	Van der Lely et al. 1991
Comparison of several drugs	Lamberts et al. 1987; Hoschl and Hajek 2001
Surgery	Saad et al. 1984; Bilgin 2007
Guidelines and reviews	Magiakou et al. 1994; Storr et al. 2007; Nieman et al. 2008; Savage et al. 2008; Pereira et al. 2010

Persistent impairment of quality of life and cognitive function has been reported in the literature despite long-term cure of the physical aspects of the illness (Starkman et al. 1992; Dorn et al. 1997; Sonino et al. 2006). Factors that predict the prognosis of psychological features and their persistence are: Genetic predisposition, pre-illness personality traits, presence of life events, the length of untreated hypercortisolism, and, finally, the age of the patient (Sonino et al. 2006, 2010).

What does high cortisol do to the brain?

Prolonged exposure of the brain to high levels of cortisol leads to cortical and subcortical atrophy, especially in the hippocampal region (Brown et al. 2004; deKloet et al. 2005; Patil et al. 2007), possibly because the highest density of glucocorticoid receptors in the central nervous system are in the hippocampal region. The volume loss in the hippocampus has been shown to be correlated to memory dysfunction (Starkman et al. 1992). High levels of corticoids will lead to a reduced synaptic function as well as cell loss and dendritic simplification (Woolley et al. 1990). There are several molecular mechanisms described that explain the effects of cortisol on the neurons; it also decreases the production of neurotrophic factors in the brain (Zhou et al. 2000). Glucocorticoids decrease and prevent neurogenesis in the brain (Gould et al., 2000; McEwen 2005). Glucocorticoids also impact on serotonergic (5-HT) receptor systems in the brain (Beck et al. 1996; Nishi and Azmitia 1996). The effects of high levels of cortisol has been shown to be reversible in some studies, showing that with normalization of blood cortisol, at least partial correction of lost brain volume, and specifically that in hippocampi, was observed (Bourdeau et al. 2002; McEwen 2002). Altered amygdala and hippocampus function has been documented in adolescents with hypercortisolemia using functional magnetic resonance imaging (fMRI) (Maheu et al. 2008). The effect of glucocorticoid excess on children's brains may be different, in that they are more likely to experience cognitive decline despite physical cure and reversal of cerebral atrophy (Merke et al. 2005) and a significantly impaired quality of life a year after cure (Keil et al. 2009).

Role of the hippocampus

We discuss the role of the hippocampus/hippocampal region, as it appears to be an important site of action for the cortisol. There is a rich presence of glucocorticoid receptors in the hippocampal region in comparison to other brain areas (de Kloet 2005). It is also interesting to note that there are large numbers of 5-HT1 receptors in the hippocampal region (Barnes and Sharp 1999).

Some of the many functions attributed to this region are: Declarative memory (Squire 1992; Echinbaum 2000), and spatial memory and navigation (Maguire et al. 1998; Ekstrom 2003; Moser et al. 2008) This region is also important for regulation of mood and emotions. Maguire and colleagues have shown in London taxi drivers (who require and use spatial navigation skills over and above the general population) a larger posterior hippocampal volume (Maguire et al. 2000) than that in controls, as well as an increase in hippocampal volume over time spent in taxi driving (Maguire et al. 2000). This shed light on the role of hippocampi and also evidenced the plastic nature of hippocampi. The increase in volume of hippocampi as a result of practice or repetition of a task could suggest neurogenesis.

SSRIs and the brain

SSRIs are medications used to treat depression and anxiety disorders. There are several hypothesised mechanisms of action for these. In the last decade or thereabouts there has been accumulating evidence that SSRIs cause neuronal genesis (new cell growth) in the hippocampal region of the brain (Santarelli et al. 2003; Wang et al. 2008). SSRIs also reverse 5-HT dysfunction and modulate 5-HT function in the hippocampal region (Gobbi et al. 1997; Kobayashi et al. 2008). Hippocampal evoked potentials manifest enhanced plasticity after administration of fluvoxamine (Ohashi et al. 2002) and fluoxetine (Smith and Lakoski 1998; Stewart et al. 2000). Areas of the brain other than the hippocampal region have been shown to undergo neurogenesis, such as the subventricular zone (SVZ) (Lim and Alvarez-Buylla 1998). Cortisol reduces neurogenesis in SVZ (in animal models) (Lau et al. 2007), and paroxetine, which is one of the SSRI medications, has been shown to increase neurogenesis in SVZ (animal models) (Lau et al. 2007).

Essentially, the two molecular pathologies created by high levels of cortisol (i.e., stopping or reversing neurogenesis and causing 5-HT dysfunction) are reversed by SSRIs. Therefore, we hypothesise that SSRIs can be recruited in clinical scenarios to undo the impact of the cortisol-induced brain damage.

Discussion

Our patient did not regain her psychological and cognitive functioning after weeks of reduced cortisol levels following medical and then surgical intervention. Unlike an adult brain, the adolescent brain is still growing and is more plastic. There is a significant growth and maturation spurt in the brain in adolescence. The clinical view was that important time may be lost in watchful waiting. We were also aware that the patient's brain had already been exposed to high levels of cortisol for a few years before treatment, and we know that the duration of exposure to high cortisol levels is a prognostic factor in neuropsychiatric recovery. There is little research evidence for treatment of cognitive decline in young people with hypercortisolism, but it has been shown that children are more likely to be left with residual neurocognitive symptoms even after reversal of brain atrophy. We based our choice of psychotropic medication on evidence of neurobiological effects of cortisol on the brain, combined with evidence for the effects of SSRIs on the brain. Research findings have demonstrated that the hippocampal region is the area affected most by cortisol, as it has the highest concentration of glucocorticoid receptors, although cortisol can also affect many other parts of the brain. We could not demonstrate specific hippocampal damage through sophisticated tests or histopathological evidence of cell damage, but our clinical findings were in keeping with hippocampal damage. The pattern of memory loss and problems in spatial navigation were indicative of hippocampal pathology. During the patient's admission, because of her critical condition it was not considered a clinical priority or ethical to conduct academic volumetric brain scans (for hippocampal changes), although she did later have standard MRI scans focusing on the pituitary gland. Cerebral dysfunction in such a case is partly caused by brain shrinkage and partly caused by serotonergic dysfunction, as suggested by literature. An SSRI was used to manage cerebral dysfunction and damage, which including the hippocampal region.

It is not possible to say how much of our patient's neuropsychiatric recovery was assisted or hastened by fluoxetine. However, we hypothesize that medication may be especially relevant for the group of patients who fail to recover completely in their cognitive function and mental state despite normalization of serum cortisol. SSRIs may play the role of neuroprotectant in the presence of elevated glucocorticoid levels. There may be a potentially wider role for SSRIs, for example in children who are on chronic steroid therapy for autoimmune diseases or Duchenne muscular dystrophy. In light of the previous discussion, we would argue that more research trials are needed to establish the benefits of the use of an SSRI in such and similar cases. Further research is needed to establish the usefulness of SSRIs in reversing cognitive dysfunction in a developing brain.

Footnotes

Disclosures

Dr. Westphal and Mr. Malik reported no conflicts of interest or financial ties.

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