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00019616-200909000-00002MiscellaneousThe EndocrinologistThe Endocrinologist© 2009 Lippincott Williams & Wilkins, Inc.19September 2009 p 205-207Effect of Corrective Surgery on Neurocognitive Functions in Endogenous Cushing SyndromePreliminary StudyNehra, Ritu PhD*; Grover, Sandeep MD*; Bhansali, Anil DM†; Khehra, Nitasha PhD*From the Departments of *Psychiatry and †Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.Reprints: Sandeep Grover, MD, Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India. E-mail: [email protected] aim of this study was to evaluate the neurocognitive functioning in subjects with endogenous Cushing syndrome before and after surgical cure of the hypercortisolemic state. Thirteen cases of endogenous Cushing syndrome were assessed on neuropsychological battery prior to the corrective surgery and after achieving eucortisolemia. Prior to surgery, the mean Intelligence Quotient of the subjects was 90 (range, 66–108) and they had borderline to mild impairment in perceptuomotor skills. The assessment done after achieving eucortisolemia showed improvement in all the subtests, with statistically significant improvement in immediate recall, overall memory, performance quotient, and Intelligence Quotient. Correlation analysis showed that deficits in attention and concentration were greater in subjects with higher preoperative cortisol levels. From this study it can be concluded that subjects with Cushing syndrome suffer from neurocognitive deficits which improve with correction of cortisol levels.Cushing syndrome (CS) results from the chronic exposure to supraphysiological levels of glucocorticoids and other steroids. Although glucocorticoids serve a variety of important functions throughout the body, persistently elevated levels of glucocorticoids in CS cause neural dysfunction and loss. Due to wide distribution of glucocorticoid receptors throughout the cerebral cortex, several cognitive functions are affected by the dysregulation of glucocorticoids.1,2 However, hippocampus is thought to be affected most because of being richest in glucocorticoids receptors.1,2 In addition to the neuropsychological dysfunction elevated levels of glucocorticoids is also associated with emotional problems.3,4In terms of type of cognitive dysfunction, earlier studies showed that impairments more specifically involves learning, memory, and nonlanguage functions.5–7Recent studies have shown that subjects with CS have more frequent and more severe impairments in nonverbal visual–ideational and visual memory functions,5 involvement of verbal learning and verbal functions more than nonverbal functions.8 Forget et al4,9 showed that patients with CS have significant dysfunction in the areas of visual and spatial information, memory, reasoning and concept formation, language and verbal functions, and attention.However, relatively few studies have examined the effect of eucortisolemia in CS on the cognitive functions. Mauri et al7 reported significant improvement on tests of immediate and delayed recall of verbally presented short stories, as well as on a test sensitive to disruptions of brief attention (ie, digit span forward) after 6 months of successful treatment. Forget et al9 reported that CS patients improved significantly only on a task of visual organization and a test of phonemic fluency, but not on tests of attention, memory, reasoning, language, or visual spatial processing. A recent study by Hook et al10 reported recovery in verbal fluency and recall but not in brief attention. The authors also reported that age of participants was a significant factor as to when recovery of function occurred; younger patients regained and sustained their improvement in cognitive functioning more quickly than older participants.In view of the lack of consensus on the type of cognitive functions which improve after treatment of CS, the present study aimed to evaluate the neurocognitive functioning in subjects with endogenous CS before and after surgical cure of the hypercortisolemic state.METHODOLOGYThe study was carried out at the Postgraduate Institute of Medical Education and Research, Chandigarh, a multispecialty teaching tertiary-care referral hospital providing services to a major area of north India. All the subjects were recruited on the basis of a written informed consent assuring confidentiality and freedom of choice of participation. The study was approved by the institute ethic committee. The patients were recruited between August 2002 and September 2003 on the basis of purposive sampling.The sample consisted of 13 cases of Cushing syndrome diagnosed as per the following inclusion criteria: High baseline cortisol levels with loss of circadian rhythm, nonsuppressible low-dose dexamethasone and high-dose dexamethasone, computerized tomography and/or Magnetic Resonance Imaging of the pituitary gland during the etiological investigation of CS. Therefore, biochemically and surgically proven ACTH-secreting pituitary corticotroph adenoma for Cushing disease and cortisol secreting adenoma for adrenal adenomas was the basis of inclusion in the study.InstrumentsNeuropsychological BatteryThe patients were administered PGI Battery of Brain Dysfunction comprising of Intelligence tests, Memory tests, and Perceptuomotor tests.IntelligenceBhatia Battery of Performance Tests of Intelligence (Short Scale).11Only 2 sub tests, namely, Kohs block design and pass along tests were used in this study for assessment of the Performance Quotient (PQ) and Intelligence Quotient (IQ). Extrapolation and interpolation was used to derive the IQ score. Age and education appropriate standardized Indian norms are available for the test.Verbal Adult Intelligence Scale.12Verbal Intelligence was assessed by using the Hindi version of Wechsler's Adult Intelligence Scale-R. It is a verbal test for subjects' aged more than 14 years with 4 subtests ie, information, arithmetic, digit span, and comprehension. It is a standardized test available with age and education appropriate norms for the Indian population.MemoryPGI Memory Scale.13This scale was developed in Department of Psychiatry, PGIMER, Chandigarh. It is an Indian adaptation of the Wechsler Memory Scale (Wechsler, 1979). It consists of 10 subtests of memory, which are for remote memory, recent memory, mental balance, attention and concentration, delayed recall, immediate recall, verbal retention for similar pairs, verbal retention for dissimilar pairs, visual retention, recognition, and overall memory. It is a standardized test available with age and education appropriate norms for the Indian population.Perceptuomotor SkillsBender Visual Motor Gestalt Test.14This test assesses visual-perceptual and visual-motor functioning, yielding possible signs of brain dysfunction. It consists of 9 figure cards and the subject is presented with a card one by one. The subject has to copy the figures and the Heinz's method was employed for scoring the errors namely perseveration, rotation, concretism, added angles, separation of lines, overlap, distortion, embellishments, partial rotation, omission, abbreviation, separation, absence of erasure, closure, and point of contact. Each sign is scored only once and finally the total score is calculated. The total error scores range from 0 to 34. It is a standardized test and used widely in clinical population.ProcedureAll the eligible subjects were approached and explained about the purpose of the study. The sociodemographic and clinical data of the consenting subjects was recorded by the consultant endocrinologist (A.B.) and then the subjects were assessed on the neuropsychological tests prior to surgery by the consultant psychologist (R.N.). Prior to neuropsychological assessment, psychiatry morbidity was ruled out by a qualified psychiatrist. The follow-up assessment was done at least 6 months after the curative surgery. The time of reaching eucortisolism was defined as the date when postoperative hydrocortisone replacement was 30mg or less per day along with normal circulating cortisol levels.Statistical AnalysisDescriptive analysis was computed for categorical variables in terms of frequency and percentage. Mean and standard deviation was used to represent continuous variables like age, number of educational years, IQ, cortisol levels, etc. Paired “t test” was used to compare the various continuous variables before and after the surgery. Pearson correlation coefficient was calculated to evaluate the correlation between the cognitive function and clinical profile.RESULTSSociodemographic ProfileMajority of the subjects who participated in the study were male (N = 9; 68.2%). The mean age of the study group was 28.0 ± 8.28 years (range, 14–38 years) and the mean duration of education was 12.61 ± 3.25 years (range, 9–19 years) at the time of first assessment. Majority of the subjects were either farmers, shopkeepers, or on clerical jobs (53.8%) at the time of assessment.Clinical ProfileOf the 13 subjects, 4 had Cushing disease, 5 had ectopic Cushing, and 4 had adrenal neoplasias. The mean cortisol (am) level was 946.15 ± 235 nmol/L, mean cortisol (p.m.) was 829.61 ± 270.09 nmol/L, and the mean ACTH level was 76.69 (SD = 62.05) pg/L, prior to surgery.Neuropsychological ProfileThe preoperative evaluation on the neuropsychological test of the patients with CS showed that the mean IQ of the subjects was 90 (range, 66–108) and a BVMG score of 3, suggesting borderline to mild impairment in the perceptuomotor skills. Significant impairments were not seen in other domains at the baseline compared with norms.The second assessment was done after a mean period of 7.76 ± 3.08 months following eucortisolism (range, 6–15 months). As evident from Table 1, subjects showed improvement in all the subtests after achieving eucortisolism, however, improvement was statistically significant for immediate recall, overall memory, PQ, and IQ.JOURNAL/endst/04.03/00019616-200909000-00002/table1-2/v/2021-02-17T201925Z/r/image-tiff Comparison of Neuropsychological Functioning Before and After Surgery (n = 13)DISCUSSIONThis study examined the effects of excess of endogenous glucocorticoids in 13 patients with either pituitary/adrenal/ectopic etiologies on the neuropsychological functioning. Using objective and standardized neuropsychological batteries, our data shows that neurocognitive deficits are present in patients of CS irrespective of etiologies. Our findings suggests that all the neuropsychological parameters are affected in presence of high glucocorticoid levels, higher impact is seen in the domain of immediate recall, overall memory, PQ, and IQ. However we did not find significant improvement in perceptomotor functioning.Our findings provide credence to the findings of Mauri et al,7 who reported significant improvement on tests of immediate and delayed recall after 6 months of successful treatment. Our findings also emphasize the improvement in recall but not in tests of attention, as reported by Hook et al.10 However, our findings are in contradiction to Forget et al,9 who reported that CS patients do not improve significantly on tests of memory.Our study was limited by small sample size. Future studies should evaluate the neurocognitive functioning in larger sample with more specific area related neuropsychological tests to provide more insight into the issue.Correlation analysis showed that deficits in attention and concentration were more in subjects with higher preoperative cortisol levels.REFERENCES1. Starkman MN, Gebarski SS, Berant S, et al. Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing's syndrome. Biol Psychiatry. 1992;32:756–765.[Context Link][CrossRef][Medline Link]2. Grillon C, Smith K, Haynos A, et al. Deficits in hippocampus mediated pavlovian conditioning in endogenous hypercortisolism. Biol Psychiatry. 2004;56:837–843.[Context Link][CrossRef][Medline Link]3. DeKloet ER, Vreungdenhill E, Oitzl MS, et al. Brain corticosteroids receptor balance in health and disease. Endocr Rev. 1998;19:269–301.[Context Link][Medline Link]4. Forget H, Lacroix A, Somma M, et al. 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