Download Chronic fatigue, cognitive dysfunction and the Asteno

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.