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Study protocol 070927: Version 1.4 Oskar Ragnarsson Quality of life and cognitive function at long term follow-up in patients with Cushing’s syndrome. 1. Background In the beginning of the 19th century Harvey Cushing an American neurosurgeon, described twelve patients that shared a similar clinical picture of central obesity, abdominal striae, muscle and skin atrophy, arterial hypertension and diabetes mellitus (Cushing 1932). Ever since has this syndrome been known as Cushing’s syndrome (CS) and is caused by an increased endogenous production of glucocorticoids (GC). GC are steroids, predominantly produced in the cortex of the adrenal glands. The main GC in humans is cortisol. The production and secretion of cortisol is regulated by a complex system that includes the hypothalamus, pituitary gland and the adrenal cortex i.e. hypothalamic-pituitary-adrenal (HPA) axis. By producing corticotrophinreleasing hormone (CRH), the hypothalamus stimulates the pituitary gland to produce adrenocorticotropic hormone (ACTH), which in turn affects the adrenal cortex that responds by increasing production and secretion of cortisol. The HPA axis is activated by several physical and psychological stressors. Under stress conditions such as physical activity, fever, surgery or mental stress, the serum cortisol concentration is increased through enhanced activity of the HPA-axis. Similarly, under physiological condition the axis is under a negative feedback control of cortisol itself, i.e. in the presence of cortisol excess the activity of axis decreases. The most common causes of CS are ACTH producing pituitary adenoma (Cushing’s disease), cortisol producing adrenal adenoma and other ACTH producing tumours such as lung cancer, medullary thyroid cancer and carcinoid tumours (Boscaro 2001). All these conditions share the same final common pathway of cortisol excess and similar clinical picture as described above. Other biochemical features of CS are loss of the normal feedback of the HPA-axis and disturbance of the normal circadian rhythm of cortisol secretion. CS is considered an uncommon syndrome with an incidence of approximately 2 cases per million. However, the recently discovered milder form of CS (subclinical or preclinical CS) suggests that the true prevalence has been strongly underestimated, especially among patients with obesity, diabetes and hypertension (Catargi 2003). Untreated patients with CS have a grave prognosis with an estimated 5 year survival of only 50% (Plotz 1952). With modern treatment majority these patients can however be cured from their hypercortisolemia. Despite this so-called biochemical cure, a Study protocol 070927: Version 1.4 Oskar Ragnarsson substantial number of patients still suffer from disabling neuropsychiatric symptoms such as fatigue, impaired memory and concentration difficulties, often leading to significantly reduced quality of life (QoL) and working capacity (Lindsey 2006). The studies, that have used standardized questionnaires to evaluate QoL, have confirmed markedly impaired scores when compared to normal population or patient groups with nonfunctional pituitary adenoma. Fatigue is one of the most common and distressing symptoms in patients with CS and has been reported by 41-85% of patients at long term follow-up after treatment (Lindsey 2006). Cognitive function is also negatively affected in patients with CS. In an early study of 35 patients with CS, a diffuse bilateral cerebral dysfunction was found in two-thirds of patients (Whelan 1980). In another study of 23 patients with CS 66% had difficulty in concentration and 83% had memory difficulties (Starkman 1986). A significant correlation has been found between the degree of hypercortisolism, the extent of cognitive impairment and reduction in hippocampal volume based on magnetic resonance imagine (MRI) (Starkman 1992). Improvement in cognitive function (Dorn 2000, Forget 2002) as well as morphological brain changes (Starkman 1999, Boudreau 2002) following treatment has been reported. Post treatment studies evaluating these aspects are however few, the number of patients is limited and the follow-up time is short. Larger studies with longer follow-up are therefore needed. The aetiology of the neuropsychiatric symptoms and the morphological changes in cured CS is not clearly understood. Depression which has been noticed in up to 24% of patients one year after curative treatment (Dorn 1997) is however one possible factor. Another explanation might be the hormone deficiency that is commonly seen postoperatively. In one study 89% of patients needed replacement with one or more hormones after treatment of CS (Fekete 2002). Growth hormone (GH) secretion is for example commonly affected, and because GH deficiency (GHD) is a well known cause of impaired QoL this might be part of the explanation (Rosen 1994). A study where these factors are taken into account is therefore important. There is also growing evidence that inflammation in the brain (neuroinflammation) might play the primary role in the pathogenesis of a number of neurodegenerative diseases like Alzheimer's disease (AD) and Parkisons disease (PD) (Minghetti 2005). Activation of immune cells in the central nervous system leads to the release of proinflammatory factors such as IL-1, IL2, IL-6 and TNF- which in turn have cytotoxic effects (neurotoxicity). It has also been speculated that neuroinflammation with disturbed glutamate metabolism is the cause of the fatigue that characterizes diseases like CS (Rönnback 2004). So far this is only a hypothesis. 2. Aims Study protocol 070927: Version 1.4 Oskar Ragnarsson The overall aim of this project is to study the prevalence and etiology of the neuropsychiatric consequences of CS. 2.1 Primary aim To study the prevalence of chronic fatigue (CF), cognitive dysfunction (CognD) and Astheno-Emotional Disorder (AED) at a long term follow-up among patients previously treated for CS. 2.2. Secondary aims a) To study preoperative baseline characteristics that may predict the development of CF, CognD and AED at long term follow-up. Special attention will be focused on preoperative serum and urine cortisol concentrations and the source of the hypercortisolism. b) To corrugate for the possible role of depression and other affective disorders when evaluating CF, CognD and AED. c) To study the influence of other various hormone deficiencies (i.e. growth hormone deficiency) when evaluating affected patients. d) To relate neuroendocrine regulation of the HPA-axis with neuropsychiatric outcome. e) To study the possible role of chronic neuroinflammation as an independent etiological factor in affected patients. f) To study if morphological changes in the brain (by MRI) are present at long term follow-up and if these changes are related to cognitive impairment. 3. Subjects Inclusion criteria Patients previously treated for CS caused by ACTH-producing pituitary adenoma or cortisol-producing adrenal adenoma will be asked to participate in the study. The estimated number of patients will be around 50 patients with ACTH-producing pituitary adenoma and 20 with adrenal adenoma. Healthy control subjects will be recruited from the general population of the same background area as the patients using random lists received from the population registry. They will be matched fore age, sex, education level and body mass index. Exclusion criteria Any known major psychiatric disorder Active malignancy Heart failure Respiratory insufficiency Study protocol 070927: Version 1.4 Oskar Ragnarsson Severely impaired renal function Pregnancy or breast feeding Any other illness that significantly affects the patients’ Quality of life and cognitive function according to the investigators opinion. 4. Design This is a cross-sectional case-controlled study conducted at the Department of Endocrinology, Sahlgrenska University Hospital, Sweden. 5. Methods a) Patients with CS, treated at Sahlgrenska University Hospital, will be identified by using the hospital’s registrations system. Patients will be searched by ICD-10 diagnostic numbers of CS (E24.0, E24.8 and E24.9). To minimize the number of possibly lost patients the search will be completed by manually searching through a register of patients at the Department of Endocrinology. With similar strategy patients will be identified at three other hospitals in western Sweden (Norra Älvsoborg, Södra Älvsborg, Skaraborg). b) Preoperative characteristics and other information will be sampled in a retrospective manner from medical files. c) All patients suitable for the study will be contacted and asked to participate. d) Participants will be examined as out-patients. e) Questionnaires. i. The fatigue impact scale (FIS) will be used to evaluate fatigue. FIS is an effective tool for assessing the impact of fatigue on patient’s lives and has been recommended for research purposes and in clinical practice. (Fisk 1994). The scale is a ‘self-report’ instrument made of 40 questions. The subjects are asked to rate the extent to which fatigue has caused problems for them during the last month, in relation to exemplar statements on a five level scale. Zero indicates no problem and 4 extreme problem, yielding a maximum score of 160. The FIS is well validated and has been used in number of diseases such as MS, stroke, brain injury and certain liver diseases (Dittner 2004; Bjornsson 2004). ii. Depressive disorder will be diagnosed by using the Mini-International Neuropsychiatric Interview (M.I.N.I.) (Sheehan 1998) iii. Quality of life will be assessed by 36-item short-form health survey (SF36) Study protocol 070927: Version 1.4 Oskar Ragnarsson f) Prevalence of organic psychiatric disorders (OPD) such as the Astheno-Emotional Disorder (AED) will be evaluated by neuropsychiatric examination as described in the diagnostic system constructed by Lindqvist and Malmgren (LM system). The LM system has been used for studying OPD in patients with various central nervous system disorders (Rodholm 2002). It has been shown that AED can be reliably assessed and has a predictive validity (Rodholm 2001). g) Cognitive dysfunction will be assessed by standardized cognitive tests h) Blood analysis. Blood-, electrolyte- and liver-status, glucose and creatinin. TSH, freeT4, IgF-1, prolactin, FSH, LH, testosterone, estrogen, androstenedion, SHBG. i) j) Tests of HPA-axis performance: i. Dexamethasone suppression test overnight (1 mg) ii. 24h urinary free cortisol iii. CRF test with measurements of ACTH, kortisol and DHEA-sulphate Body composition and bone mineral density will be evaluated by dual-energy xray absorptiometry (DEXA) k) Cerebrovascular fluid analysis: Il-1, Il-2, Il-6, TNFα and various markers of brain damage. l) MRI. Morphological changes will be studied be conventional MRI and the areas involved in cognitive dysfunction by functional MRI technique. 6. Current status The study has been approved by the ethical comity in Göteborg. Patients have been indentified at Sahlgrenska University Hospital. In a pilot study with 22 patients with Cushings disease the patients have been evaluated by three questionairs (FIS, Montgomery Asberg Depression Rating Scale (Svanborg 1994) and AED). The study showed that fatigue and AE disorder without the presence of depression is common among cured CD patients at long term follow-up. This data was presented at the Annual Endocrine Society meeting in Boston in June 2006. 7. Importance This project will give important information on chronic fatigue and cognitive dysfunction in patients treated for CS. The number of studies on this subject is limited and the aetiology mainly unknown. Similarly have previous studies not routinely taken into account the possible effect of other common causes to chronic fatigue and cognitive dysfunction, namely depression and various post-treatment hormone deficiencies such as GHD. Study protocol 070927: Version 1.4 Oskar Ragnarsson The possible role of neuroinflammation will be studied for the first time by measuring different inflammatory markers in spinal fluid. The morphological changes that have been noted in patients with active CS and 6-12 months after treatment, will studied for the first time at long term follow-up (up to 20 years following treatment). The study might find important predictor for poor neuropsychiatric outcome that can be used in the future to early detect such patients. Moreover, the neuropsychiatric profile might help to find a therapeutically approached to this debilitating condition “PostCushing AE-syndrome” lacking specific treatment options at present. 8. References Bjornsson E, Simren M, Olsson R, Chapman RW. Fatigue in patients with primary sclerosing cholangitis. Scand J Gastroenterol. 2004;39:961-8. Boscaro M, Barzon L, Fallo F, Sonino N 2001 Cushing’s syndrome. Lancet 357:783–791. Bourdeau I, Bard C, Noel B, Leclerc I, Cordeau MP, Belair M, Lesage J, Lafontaine L, Lacroix A. Loss of brain volume in endogenous Cushing's syndrome and its reversibility after correction of hypercortisolism. J Clin Endocrinol Metab. 2002;87:1949-54. Catargi B, Rigalleau V, Poussin A, Ronci-Chaix N, Bex V, Vergnot V, Gin H, Roger P. Tabarin A. Occult Cushing's syndrome in type-2 diabetes. J Clin Endocrinol Metab. 2003;88:5808-13. Cushing HW. The basophil adenomas of the pituitary body and their clinical manifestation (pituitary basophilism). Bull Johns Hopkins Hosp (1932);50:137-95. Dittner AJ, Wessely SC, Brown RG. The assessment of fatigue: a practical guide for clinicians and researchers. J Psychosom Res. 2004;56:157-70. 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. Study protocol 070927: Version 1.4 Oskar Ragnarsson Dorn LD, Cerrone P. Cognitive function in patients with Cushing syndrome: a longitudinal perspective. Clin Nurs Res. 2000;9:420-40. Fekete Z, Landin-Wilhelmsen K, Jakobsson KE, Petruson B. Follow-up of Cushing’s syndrome in western Sweden. Läkartidningen 2002;99:4635-9. Fisk JD, Ritvo PG, Ross L, Haase DA, Marrie TJ, Schlech WF. Measuring the functional impact of fatigue: initial validation of the fatigue impact scale. Clin Infect Dis. 1994;18:S79-83. Forget H, Lacroix A, Cohen H. Persistent cognitive impairment following surgical treatment of Cushing's syndrome. Psychoneuroendocrinology. 2002;27:367-83. Lindsay JR, Nansel T, Baid S, Gumowski J, Nieman LK. Long-term impaired quality of life in Cushing's syndrome despite initial improvement after surgical remission. J Clin Endocrinol Metab. 2006;91:447-53. Minghetti L. Role of inflammation in neurodegenerative diseases. Curr Opin Neurol. 2005;18:315-21. Plotz CM, Knowlton AI, Ragan C. The natural history of Cushing's syndrome. Am J Med 1952;13(5):597-614 Rodholm M, Starmark JE, Svensson E, Von Essen C. Astheno-emotional disorder after aneurysmal SAH: reliability, symptomatology and relation to outcome. Acta Neurol Scand. 2001;103:379-85. Rodholm M, Starmark JE, Ekholm S, von Essen C. Organic psychiatric disorders after aneurysmal SAH: outcome and associations with age, bleeding severity, and arterial hypertension. Acta Neurol Scand. 2002;106:8-18. Ronnbeck L, Hansson E. On the potential role of glutamate transport in mental fatigue. J Neuroinflammation 2004;1:22 Rosen T, Wiren L, Wilhelmsen L, Wiklund I, Bengtsson BA. Decreased psychological wellbeing in adult patients with growth hormone deficiency. Clin Endocrinol (Oxf). 1994;40:111-6. Study protocol 070927: Version 1.4 Oskar Ragnarsson Schteingart DE, Tsao HS, Taylor CI, McKenzie A, Vicotria A, Therrian BA. Sustained remission of Cushing’s Disease with mitotane and pituitary irradiation. Ann Intern Med 1980;92:613–20. 144 J.K. Sheehan, DV.;Lecrubier, Y.;Sheehan, KH.;Amorim, P.;Janavs, J.;Weiller, E.;Hergueta, T.;Baker, R.; Dunbar, GC. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSMIV and ICD-10. J Clin Psychiat. 1998;59 Suppl 20:22–33 Starkman MN, Schteingart DE, Schork MA. Cushing’s syndrome after treatment: changes in cortisol and ACTH levels, and amelioration of the depressive syndrome. Psychiatry Res 1986;19:177–88. 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. 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. Svanborg P, Asberg M. A new self-rating scale for depression and anxiety states based on the Comprehensive Psychopathological Rating Scale. Acta Psychiatr Scand. 1994;89:218. Whelan TB, Schteingart DE, Starkman MN, Smith A. Neuropsychological deficits in Cushing’s syndrome. J Nerv Ment Dis 1980;168:753–7.