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Parathyroidectomy improves concentration and retentiveness in patients with primary hyperparathyroidism
Parathyroidectomy improves concentration and retentiveness in patients with primary hyperparathyroidism Gerhard Prager, MD, Andreas Kalaschek, PhD, Klaus Kaczirek, MD, Christian Passler, MD, Christian Scheuba, MD, Gernot Sonneck, MD, and Bruno Niederle, MD, Vienna, Austria
Background. Many patients with primary hyperparathyroidism (PHPT) show symptoms of hypercalcemia syndrome, including psychologic and psychiatric disorders. The aim of this study was to find out whether parathyroidectomy improves cognitive performance with regard to concentration and retentiveness in patients with PHPT. Methods. Twenty patients with PHPT underwent psychologic testing preoperatively as well as 6 and 12 weeks postoperatively. Concentration under stress (timing) was proved by the d2-Test of Attention. To evaluate retentiveness, parts of the Wilde Intelligence Test were used. Patients were tested under identical circumstances with regard to time, location, and tester to minimize exterior influences. Results. The patients’ concentration enhanced significantly postoperatively ( P < .001). The same applied to the total number of items processed ( P < .01). Improvement of patients’ ability to memorize numbers reached statistical significance when comparing the preoperative with the postoperative result ( P = .0396); furthermore, there was a tendency to perform the tests more carefully and accurately ( P = .069). Conclusions. Parathyroidectomy not only betters physical symptoms of PHPT but can also positively influence the patients’ cognitive performance. These findings reflect the clinical observation of the patients’ improved mental capacity after parathyroidectomy. (Surgery 2002;132:930-6.) From the Section of Endocrine Surgery, Division of General Surgery, Department of Surgery, and the Institute for Medical Psychology, University of Vienna, Medical School, Vienna, Austria
PRIMARY HYPERPARATHYROIDISM (PHPT) is the most common cause of hypercalcemia in nonhospitalized patients, affecting approximately 1% of the adult population, with probably an even higher prevalence in the older age groups.1-3 With the widespread use of the multichannel autoanalyzer and the determination of serum calcium during routine medical evaluation a shift in the clinical appearance of PHPT occurred. The presentation of patients with PHPT changed from the classic clinical picture with renal, osseous, and gastrointestinal manifestations (“painful bones, Presented at the 23rd Annual Meeting of the American Association of Endocrine Surgeons, Banff, Alberta, Canada, April 7-9, 2002. Reprint requests: Bruno Niederle, MD, Professor of Surgery, Section of Endocrine Surgery, Division of General Surgery, Department of Surgery, University of Vienna, Medical School, AKH – Vienna, Leitstelle 21A, Waehringer Guertel 18-20, A1090 Vienna, Austria. © 2002, Mosby, Inc. All rights reserved. 0039-6060/2002/$35.00 + 0 11/6/128606 doi:10.1067/msy.2002.128606
930 SURGERY
renal stones, abdominal groans and psychic moans,”4,5 symptomatic patients) toward a more vague symptomatology. This latter group (minimally symptomatic) represents nowadays the majority of patients and has psychologic and psychiatric disorders (depression, myopathy, loss of memory, confusion, insomnia, headaches, apathy, psychosis, organic brain syndromes, paranoid conditions), a general feeling of illness along with general manifestations like polyuria, polydipsia, weight loss, vomiting, and epigastric discomfort without any apparent organic cause.6,7 These symptoms are summarized under the term hypercalcemia syndrome.8 A third group of patients only presents with biochemical characteristics of PHPT (elevated serum calcium and parathyroid hormone levels) without any evidence of clinical symptoms (asymptomatic patients). Today, the majority of patients with PHPT are elderly women, presenting with nonspecific, vague psychiatric or neuromuscular symptoms or even appearing to be asymptomatic.6,7 Several studies showed an improvement of these symptoms after
Prager et al 931
Surgery Volume 132, Number 6 Table I. Patient characteristics and laboratory findings Age (y) Preoperative calcium (mmol/L) Preoperative PTH (pg/mL) Postoperative calcium (mmol/L) Postoperative PTH (pg/mL)
Mean ± 12 SD
Range
Normal range
60.9 ± 12.8 2.9 ± 0.2 133.4 ± 62.6 2.4 ± 0.2 35 ± 12
30-78 2.7-3.5 54-295 2.1-2.6 13-58
2.1-2.6 10-60 2.1-2.6 10-60
SD, Standard deviation.
Table II. Descriptive statistics of raw scores investigated CP1 CP2 CP3 TN1 TN2 TN3 E%1 E%2 E%3 FR1 FR2 FR3 NM1 NM2 NM3
N
Minimum
Maximum
Mean
Standard deviation
20 20 20 20 20 20 20 20 20 20 20 20 20 20 20
64.0 55.0 99.0 200.0 240.0 235.0 0.9 0.0 0.2 5.0 6.0 8.0 9.0 13.0 13.0
181.0 207.0 218.0 465.0 545.0 527.0 26.0 30.5 16.2 25.0 44.0 23.0 39.0 51.0 43.0
115.6 132.5 144.7 329.1 381.3 384.2 7.0 7.3 4.5 11.3 13.8 12.9 23.5 25.0 26.0
33.1 39.8 33.4 85.2 89.4 83.2 5.4 6.7 3.7 5.1 8.4 3.9 7.4 8.7 7.0
1, Preoperative testing; 2, 6 weeks postoperative testing; 3, 12 weeks postoperative testing.
successful parathyroidectomy backed up by psychiatric scores and questionnaires.6,7,9-18 The aim of this study was to find out whether parathyroidectomy improves cognitive performance with regard to concentration and retentiveness in patients with PHPT by applying standardized psychologic tests. PATIENTS AND METHODS Twenty consecutive patients (14 women, 6 men) with sporadic PHPT and admitted for surgery were studied. Diagnosis of PHPT was confirmed by repeated measurements of elevated serum calcium and parathyroid hormone levels. In none of these patients was hyperparathyroidism suspected on account of apparent psychologic abnormalities. All but 2 patients with double adenoma had single gland disease. Only enlarged parathyroid glands were removed, without routine biopsy of normal appearing glands. Surgical findings were confirmed by pathologic examinations. Permanent normocalcemia was documented in all patients during postoperative follow-up (range, 21 to 24 months; mean, 23 months), indicating cure. According to the classification mentioned above, 2 patients were considered to be asympto-
matic, 11 patients minimally symptomatic, and 7 patients symptomatic. Informed consent for participation in this study was obtained from all patients. Their characteristics and preoperative and postoperative laboratory findings are listed in Table I. Psychologic testing was performed in all patients preoperatively as well as 6 and 12 weeks postoperatively. Special attention was paid to ensure identical testing conditions with regard to time (9 to 12 AM), location (same room, same lighting conditions), and tester to minimize exterior influences. Psychologic testing. Two tests were combined to investigate concentration and attentiveness under stress (d2-Test of Attention)19 and retentiveness (Numbers Memorizing, part of the Wilde Intelligence Test).20 All tests were administered according to standardized instructions as given in the test manual. d2-Test of Attention. The d2-Test of Attention consists of 14 rows with 47 figures each. The test taker has to identify relevant figures and cross them out. The actual test is preceded by a practice part to prove whether the test taker has understood the instructions. Twenty seconds are available for each
932 Prager et al
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Table III. Student t test for paired samples Paired differences 95% Confidence interval of difference Mean CP1-CP2 CP1-CP3 CP2-CP3 TN1-TN2 TN1-TN3 TN2-TN3 E%1-E%2 E%1-E%3 E%2-E%3 FR1-FR2 FR1-FR3 FR2-FR3 NM1-NM2 NM1-NM3 NM2-NM3
–16.9 –29.2 –12.3 –52.1 –55.1 –2.9 –0.4 2.4 2.8 –2.5 –1.5 1.0 –1.5 –2.4 –0.9
Standard deviation
Standard error (mean)
15.9 11.8 13.8 59.3 49.6 30.3 7.2 5.8 3.7 10.0 5.4 8.0 6.5 5.0 5.6
3.6 2.6 3.1 13.3 11.1 6.8 1.6 1.3 0.8 2.2 1.2 1.8 1.5 1.1 1.3
Lower –24.3 –34.7 –18.7 –79.9 –78.3 –17.1 –3.8 –0.3 1.0 –7.2 –4.1 –2.8 –4.6 –4.8 –3.6
Upper –9.5 –23.6 –5.8 –24.4 –31.9 11.2 3.0 5.2 4.5 2.1 1.0 4.8 1.6 –0.1 1.7
t test –4.8 –11.1 –4.0 –3.9 –5.0 –0.4 0.2 1.9 3.3 –1.1 –1.3 0.6 –1.0 –2.2 –0.8
P value (2-sided) .0001 .0000 .0008 .0009 .0001 .6679 .8183 .0786 .0286 .2662 .2174 .5845 .3180 .0396 .4578
1, Preoperative testing; 2, 6 weeks postoperative testing; 3, 12 weeks postoperative testing.
row; processing of items is performed without interruption. The end of each row and the beginning of the next row are clearly announced by the tester. The d2-Test of Attention measures processing speed, rule compliance, and quality of performance, allowing for a neuropsychologic assessment of individual attention and concentration performance. It is applicable within 10 to 15 minutes, either individually or in a group format. Concentration-Performance. Concentration-Performance (CP) is similar to the number of “hits” and is in accordance with a standard psychologic method, evaluating achievement, being quite resistant to falsification. Neither omitting parts of the test as a result of superficial, unconcentrated behavior nor crossing out characters on a random basis will raise this level. CP is normal-distributed and highly reliable; it is the most important parameter of the d2-Test in this setting. Total Number of Items Processed. Total number of items processed (TN) describes the quantitative performance; it is a highly reliable measure of processing speed and the amount of work completed. Percentage of Errors. Percentage of errors (E%) is a qualitative variable that describes the amount of errors within the part of the test being handled. This variable represents the meticulousness, precision, and circumspection in performing the test (low values, high accuracy). Fluctuation Rate. Fluctuation rate (FR) is the difference between the maximum and minimum of
items processed involving individual test parts. It describes the stability or inconstancy of processing speed. This parameter is neither normal-distributed, nor is it a highly reliable variable. The test manual describes in detail the high testretest stability (stability coefficient, 0.9), documented in a large number of healthy adults, given for time intervals from 5 minutes to 40 months.19 A standard collective consisting of standardized spot checks of more than 6000 persons has been established for this test. Numbers-Memorizing subtest of the Wilde Intelligence Test. This part of the Wilde Intelligence Test measures retentiveness, the immediate memorizing. In identical intervals, series of 5 to 11 digits are recited by the tester. Those series of numbers must be written down immediately after their verbal presentation. Approximately 15 minutes are necessary to run this test. The raw score Number Memorizing (NM) represents the total number of hits. Statistical methods. For comparison of 2 different samples, the Student paired t test and the nonparametric Wilcoxon signed rank test were applied. For comparing 3 different samples (preoperative, 1; 6 weeks postoperative, 2; 12 weeks postoperative, 3) the Dunnett t test, unifactorial variance analysis with repeated measurements, and the Friedman test were used. For correlating data Pearson correlation coefficient was applied. Linear regression analysis for CP, preoperative parathyroid hormone (PTH) level, and serum calcium level as well as age and gender was calculated. All calcula-
Surgery Volume 132, Number 6
tions were performed with SPSS for Windows 10.0 (SPSS, Inc, Chicago, Ill). RESULTS Descriptive statistics of different raw scores are summarized in Table II. CP improved significantly within the first 6 and 12 postoperative weeks (Table III). The greatest improvement was seen within the first 6 postoperative weeks. Dunnett t test for the difference among all 3 groups (CP1, CP2, CP3) reached statistical significance (P = .0407), illustrating the improved concentration and attentiveness. TN enhanced significantly within the first 6 weeks (TN1 to TN2, P < .001) but did not show any further development in the following 6 weeks (TN2 to TN3, P = .668). Because of the similarity of TN2 and TN3 Dunnett t test, the difference among all 3 samples (TN1-TN2-TN3) did not reach statistical significance (P = .08). E% was widespread among the different samples (Table II). Neither Wilcoxon test (E%1-E%2-E%3, P = .2) nor Student t test showed statistical significance (Table III). FR proved to be stable; only 5 patients showed a variation of more than 6% among the 3 samples. Neither Wilcoxon test (FR1-FR2-FR3, P = .4) nor Student t test indicated a statistical change of this parameter (Table III). NM showed a slight increase with time (NM1NM2-NM3), which reached significance comparing the preoperative (NM1) with the later postoperative (NM3) result (Table III). Dunnett t test for the difference among NM1, NM2, and NM3 was P = .5. Bivariate correlation (Pearson) analysis showed significant correlation for serum calcium and PTH levels (P = .004). In calculating the regression analysis, no significant correlation for the changes of CP (preoperative to 6 weeks postoperatively and preoperative to 12 weeks postoperatively), preoperative serum calcium and PTH levels, age, and gender were found. The same was documented for postoperative PTH levels and the magnitude of the change in serum calcium or PTH levels. Furthermore, no difference in the degree of improvement among the different groups of patients (asymptomatic, minimally symptomatic, symptomatic) could be shown. DISCUSSION Successful parathyroidectomy improved CP and TN significantly within 6 weeks. E% showed no significant positive change within the first 6 weeks; nevertheless, there was a tendency to perform the
Prager et al 933
tests more accurately and meticulously within 12 weeks. There was absolutely no significant change of the FR. NM showed no significant improvement within the first 6 postoperative weeks but reached significance level 12 weeks postoperatively. This is the first report using objective assessment tools to evaluate the influence of restoring normocalcemia on mental performance. To investigate cognitive functions, 2 tests were applied; the d2-Test has become the mainstay of attentional assessment in Europe. The reliability (internal/test-retest) has proved to be very high, and the criterion, construct, and predictive validity of the technique has been documented by a number of research studies.19 Because of the small sample size (n = 20) and the large interindividual differences, no comparison with an established, standardized population, as described in the test manual, was done. The d2-Test has been used extensively in the area of clinical (neuro) psychology, clinical psychiatry, and several other fields. The NM subtest of the Wilde Intelligence Test was used to measure retentiveness and memorizing. The Wilde Intelligence Test has been used widely in the German-speaking areas of Europe. Its reliability was confirmed by thousands of tested persons. The subpart NM is liable to be influenced by different situations and external interferences that must be taken into consideration when planning the test. This was taken into account by identical testing conditions with regard to time (9 to 12 AM), location (same room, same lighting conditions), and tester to minimize exterior influences. In reviewing the literature, the improvement of cognitive functions as found in this study is only demonstrated in a few case reports21-27 or in very small series.28-30 In the majority of articles, observation31-33 and questionnaires/interviews6,7,9-18 were used, reflecting the patients’ subjective mood and condition to describe the general improvement of psychologic and psychiatric symptoms. Studying central nervous system manifestations before and after parathyroidectomy in only 4 patients with PHPT, Cogan et al30 showed no significant changes in any of the psychologic parameters tested. Numann et al28 found dysfunction of memory, learning, and cognition even in patients without neurologic manifestations of PHPT. A significant turn to the better was found in 10 patients at an average of 4.38 months postoperatively. Herrmann et al34 applied 3 different psychologic tests in 19 patients with PHPT. They showed a significant decrease of psychic complaints within 1
934 Prager et al
week after surgery as did Pasieka et al16 by using questionnaires. Petersen33 found a correlation between the elevation of the preoperative serum calcium level and the degree of mental disturbance/degree of mental changes after normalization of serum calcium levels. No correlation between the improvement of concentration/retentiveness and the serum calcium/PTH level, age, and gender was found in this study. Moreover, several other studies13,17,34,35 did not show a correlation between the preoperative serum calcium level and any psychologic dimension score. Nevertheless, Brown et al36 and Cogan et al30 found a relationship between preoperatively elevated serum calcium levels and neurobehavioral impairment. Pasieka et al16 and Herrmann et al34 describe a significant improvement of investigated symptoms only 1 week after parathyroidectomy. Burney et al35 discovered a significant change to the better within 2 months after operation. In this study some raw scores (CP, TN) improved significantly within the first 6 weeks, whereas others (NM, E%) took longer to demonstrate a significant turn to the better. The pathophysiologic mechanism responsible for psychiatric disorders and reduced cognitive functions in hypercalcemic patients remains unclear. Joborn et al12 showed elevated calcium/ PTH concentrations and decreased levels of monoamine metabolites in the cerebrospinal fluid of patients with PHPT. Furthermore, one third of the patients with PHPT had signs of a certain degree of damage to the blood-brain barrier. Although investigated only in a small group of patients, significant improvement of cognitive functions (concentration, retentiveness) was demonstrated in patients with PHPT after successful parathyroidectomy, irrespective of the preoperative clinical manifestations. Symptomatic, minimally symptomatic, as well as asymptomatic patients seemed to improve likewise, underlining the importance of parathyroidectomy.
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REFERENCES 1. Christensson T. Menopausal age of females with hypercalcaemia: a study including cases with primary hyperparathyroidism, detected in a health screening. Acta Med Scand 1976;200:361-5. 2. Christensson T, Hellstrom K, Wengle B. Clinical and laboratory findings in subjects with hypercalcaemia: a study including cases with primary hyperparathyroidism detected in a health screening. Acta Med Scand 1976;200:355-60. 3. Akerstrom G, Rudberg C, Grimelius L, Bergstrom R, Johansson H, Ljunghall S, et al. Histologic parathyroid
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abnormalities in an autopsy series. Hum Pathol 1986; 17:520-7. Albright F, Reifenstein C. The parathyroids and metabolic bone disease. Baltimore: Williams & Wilkins; 1948. St Goar W. Gastrointestinal symptoms as a clue to the diagnosis of primary hyperparathyroidism: a review of 45 cases. Ann Intern Med 1957;46:102. Chan AK, Duh QY, Katz MH, Siperstein AE, Clark OH. Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy: a case-control study. Ann Surg 1995;222:402-14. Joborn C, Hetta J, Johansson H, Rastad J, Agren H, Akerstrom G, et al. Psychiatric morbidity in primary hyperparathyroidism. World J Surg 1988;12:476-81. Niederle B, Roka R, Woloszczuk W, Klaushofer K, Kovarik J, Schernthaner G. Successful parathyroidectomy in primary hyperparathyroidism: a clinical follow-up study of 212 consecutive patients. Surgery 1987;102:903-9. Burney RE, Jones KR, Coon JW, Blewitt DK, Herm AM. Assessment of patient outcomes after operation for primary hyperparathyroidism. Surgery 1996;120:1013-9. Burney RE, Jones KR, Peterson M, Christy B, Thompson NW. Surgical correction of primary hyperparathyroidism improves quality of life. Surgery 1998;124:987-92. Joborn C, Hetta J, Rastad J, Agren H, Akerstrom G, Ljunghall S. Psychiatric symptoms and cerebrospinal fluid monoamine metabolites in primary hyperparathyroidism. Biol Psychiatry 1988;23:149-58. Joborn C, Hetta J, Niklasson F, Rastad J, Wide L, Agren H, et al. Cerebrospinal fluid calcium, parathyroid hormone, and monoamine and purine metabolites and the bloodbrain barrier function in primary hyperparathyroidism. Psychoneuroendocrinology 1991;16:311-22. Joborn C, Hetta J, Lind L, Rastad J, Akerstrom G, Ljunghall S. Self-rated psychiatric symptoms in patients operated on because of primary hyperparathyroidism and in patients with long-standing mild hypercalcemia. Surgery 1989; 105:72-8. Lundgren E, Ljunghall S, Akerstrom G, Hetta J, Mallmin H, Rastad J. Case-control study on symptoms and signs of “asymptomatic” primary hyperparathyroidism. Surgery 1998;124:980-6. Pasieka JL, Parsons LL. Prospective surgical outcome study of relief of symptoms following surgery in patients with primary hyperparathyroidism. World J Surg 1998;22:513-9. Pasieka JL, Parsons LL. A prospective surgical outcome study assessing the impact of parathyroidectomy on symptoms in patients with secondary and tertiary hyperparathyroidism. Surgery 2000;128:531-9. Solomon BL, Schaaf M, Smallridge RC. Psychologic symptoms before and after parathyroid surgery. Am J Med 1994;96:101-6. Talpos GB, Bone HG III, Kleerekoper M, Phillips ER, Alam M, Honasoge M, et al. Randomized trial of parathyroidectomy in mild asymptomatic primary hyperparathyroidism: patient description and effects on the SF-36 health survey. Surgery 2000;128:1013-21. Brickenkamp R. Test d2 - Aufmerksamkeits-Belastungs-Test. 8th revised ed. Goettingen: Hogrefe-Verlag GmbH & CoKG; 1994. Jaeger A, Althoff K. Der WILDE-Intelligenz-Test (WIT). 2nd revised ed. Goettingen: Hogrefe-Verlag GmbH & CoKG; 1994. Emmelot-Vonk MH, Samson MM, Raymakers JA. [Cognitive deterioration in elderly due to primary hyperparathyroidism: resolved by parathyroidectomy]. Ned Tijdschr Geneeskd 2001;145:1961-4.
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22. Logullo F, Babbini MT, Di Bella P, Provinciali L. Reversible combined cognitive impairment and severe polyneuropathy resulting from primary hyperparathyroidism. Ital J Neurol Sci 1998;19:86-9. 23. Pfitzenmeyer P, Besancenot JF, Verges B, Cougard P, Lorcerie B, Cercueil JP, et al. Primary hyperparathyroidism in very old patients. Eur J Med 1993;2:453-6. 24. Spivak B, Radvan M, Ohring R, Weizman A. Primary hyperparathyroidism, psychiatric manifestations, diagnosis and management. Psychother Psychosom 1989;51:38-44. 25. Thurling ML. Primary hyperparathyroidism in a schizophrenic woman. Can J Psychiatry 1987;32:785-7. 26. Kleinfeld M, Peter S, Gilbert GM. Delirium as the predominant manifestation of hyperparathyroidism: reversal after parathyroidectomy. J Am Geriatr Soc 1984;32:689-90. 27. Ebel H, Schlegel U, Klosterkotter J. [Chronic schizophreniform psychosis in primary hyperparathyroidism]. Nervenarzt 1992;63:180-3. 28. Numann PJ, Torppa AJ, Blumetti AE. Neuropsychologic deficits associated with primary hyperparathyroidism. Surgery 1984;96:1119-23. 29. Gatewood JW, Organ CH Jr, Mead BT. Mental changes associated with hyperparathyroidism. Am J Psychiatry 1975; 132:129-32. 30. Cogan MG, Covey CM, Arieff AI, Wisniewski A, Clark OH, Lazarowitz V, et al. Central nervous system manifestations of hyperparathyroidism. Am J Med 1978;65:963-70. 31. Karpati G, Frame B. Neuropsychiatric disorders in primary hyperparathyroidism. Arch Neurol 1964;10:387-97. 32. Joborn C, Hetta J, Frisk P, Palmer M, Akerstrom G, Ljunghall S. Primary hyperparathyroidism in patients with organic brain syndrome. Acta Med Scand 1986;219:91-8. 33. Petersen P. Psychiatric disorders in primary hyperparathyroidism. J Clin Endocrinol Metab 1968;28:1491-5. 34. Herrmann JM, Schonecke OW, Raue F, Ziegler R. [Primary hyperparathyroidism: psychological factors before and after parathyroidectomy]. MMW Munch Med Wochenschr 1983;125:369-71. 35. Burney RE, Jones KR, Christy B, Thompson NW. Health status improvement after surgical correction of primary hyperparathyroidism in patients with high and low preoperative calcium levels. Surgery 1999;125:608-14. 36. Brown GG, Preisman RC, Kleerekoper M. Neurobehavioral symptoms in mild primary hyperparathyroidism: related to hypercalcemia but not improved by parathyroidectomy. Henry Ford Hosp Med J 1987;35:211-5.
DISCUSSION Dr Patricia J. Numann (Syracuse, New York). Ours was the paper from 1984 you referenced. We didn’t report the calcium because we didn’t have enough patients to really make any comments about it, but it was our impression at that time that their serum calcium didn’t make any difference. I would like to ask you a question about the age. I have been impressed through the years that even though the young people had the same improvement in retention and improvement in cognitive function, it is less disabling to the younger person to have hyperparathyroidism memory deficits than to the older person. I would wonder if you have looked at the type of quality of life indices in the older person and how that correlates to their retention of detail. I have found in the older peo-
Prager et al 935
ple that when they suffer the retention of memory loss, they can’t function. Many of them end up in different environments of care, whereas, when you do your parathyroidectomy, then they can come back to a very comfortable lifestyle even with the other aging factors. Dr Prager. We did not look for their health status; we just looked for cognitive performance with regard to concentration and retentiveness. But I agree with you; I also had the impression that older people start from a lower level of cognitive performance. So it is more apparent to these people than to younger patients. But I think our group of patients is too small to offer definite conclusions for this question. Dr Sally E. Carty (Pittsburgh, Pennsylvania). Based on the literature, we currently counsel patients not to look for the full positive effects of the surgery until 6 months in terms of mood and energy levels, so it is particularly wonderful that you got a P value at 3 months. Clinically, however, when we follow patients for longer than 6 months, there is a rebound, and a year after the surgery their energy level and/or their mood may not be as good as it was at 3 or 6 months postoperatively. I encourage you to look for a rebound effect at 6 or 12 months with this research tool. Dr Prager. We have not done that. But Janice Pasieka found the most significant improvement 10 days after parathyroid surgery without any later rebound effect; people stayed at an improved level for a long time. Dr Janice L. Pasieka (Calgary, Alberta, Canada). You are absolutely right, Gerhard. Dr Carty, we didn’t find a rebound effect. In our study, we followed these people for 1 year, and the improvement in their symptoms was maintained at 1 year. Dr Thomas J. Fahey III (New York, New York). I was wondering if you happened to correlate the objective results with the patients’ subjective feelings. We likely won’t be doing these tests. We wonder how many of our postoperative patients who say they don’t have any improvement actually might have objective improvement on a comprehensive test. Dr Prager. Those numbers I presented document the objective improvement. For this reason we applied standardized psychologic tests and did not make any questionnaires or patient interviews, how they, themselves, felt about their improvement. Dr Bradford Mitchell (Morgantown, Virginia). Given the fact that there is no correlation with the calcium level and that patients with renal failure with normal calcium levels have similar types of symptoms, do you think it is appropriate to refer to this as a hypercalcemic syndrome? Do you think it is appropriate to refer to this as a hypercalcemic syndrome in light of the fact that you can see similar symptoms and symptom resolution in patients with renal failure? Dr Prager. I can’t answer this question properly. Janice Pasieka presented a paper on this question with patients with renal hyperparathyroidism. In this study we just stick to primary hyperparathyroidism. Dr Pasieka.We also found there was no correlation between the calcium, the phosphate, PTH, and alkaline
936 Prager et al
phosphatase. So what do you think is affecting the cognitive function of these patients? Have you postulated what you think the underlying problem is? Dr Prager. I cannot give a definite answer to your question, but in a former paper, Joborn studied the cerebrospinal fluid of patients with primary hyperparathyroidism before and after surgery. She found preoperatively elevated calcium and PTH levels and
Surgery December 2002 decreased monoamine metabolite levels in the cerebrospinal fluid of patients with primary hyperparathyroidism when compared to a control group. After operation the calcium level in the cerebrospinal fluid decreased, whereas the monoamine metabolites increased. Probably the improvement of cognitive functions is due to a change in the pattern of neurotransmitters. I agree that this is a possible answer to the question.
Background. Many patients with primary hyperparathyroidism (PHPT) show symptoms of hypercalcemia syndrome, including psychologic and psychiatric disorders. The aim of this study was to find out whether parathyroidectomy improves cognitive performance with regard to concentration and retentiveness in patients with PHPT. Methods. Twenty patients with PHPT underwent psychologic testing preoperatively as well as 6 and 12 weeks postoperatively. Concentration under stress (timing) was proved by the d2-Test of Attention. To evaluate retentiveness, parts of the Wilde Intelligence Test were used. Patients were tested under identical circumstances with regard to time, location, and tester to minimize exterior influences. Results. The patients’ concentration enhanced significantly postoperatively ( P < .001). The same applied to the total number of items processed ( P < .01). Improvement of patients’ ability to memorize numbers reached statistical significance when comparing the preoperative with the postoperative result ( P = .0396); furthermore, there was a tendency to perform the tests more carefully and accurately ( P = .069). Conclusions. Parathyroidectomy not only betters physical symptoms of PHPT but can also positively influence the patients’ cognitive performance. These findings reflect the clinical observation of the patients’ improved mental capacity after parathyroidectomy. (Surgery 2002;132:930-6.) From the Section of Endocrine Surgery, Division of General Surgery, Department of Surgery, and the Institute for Medical Psychology, University of Vienna, Medical School, Vienna, Austria
PRIMARY HYPERPARATHYROIDISM (PHPT) is the most common cause of hypercalcemia in nonhospitalized patients, affecting approximately 1% of the adult population, with probably an even higher prevalence in the older age groups.1-3 With the widespread use of the multichannel autoanalyzer and the determination of serum calcium during routine medical evaluation a shift in the clinical appearance of PHPT occurred. The presentation of patients with PHPT changed from the classic clinical picture with renal, osseous, and gastrointestinal manifestations (“painful bones, Presented at the 23rd Annual Meeting of the American Association of Endocrine Surgeons, Banff, Alberta, Canada, April 7-9, 2002. Reprint requests: Bruno Niederle, MD, Professor of Surgery, Section of Endocrine Surgery, Division of General Surgery, Department of Surgery, University of Vienna, Medical School, AKH – Vienna, Leitstelle 21A, Waehringer Guertel 18-20, A1090 Vienna, Austria. © 2002, Mosby, Inc. All rights reserved. 0039-6060/2002/$35.00 + 0 11/6/128606 doi:10.1067/msy.2002.128606
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renal stones, abdominal groans and psychic moans,”4,5 symptomatic patients) toward a more vague symptomatology. This latter group (minimally symptomatic) represents nowadays the majority of patients and has psychologic and psychiatric disorders (depression, myopathy, loss of memory, confusion, insomnia, headaches, apathy, psychosis, organic brain syndromes, paranoid conditions), a general feeling of illness along with general manifestations like polyuria, polydipsia, weight loss, vomiting, and epigastric discomfort without any apparent organic cause.6,7 These symptoms are summarized under the term hypercalcemia syndrome.8 A third group of patients only presents with biochemical characteristics of PHPT (elevated serum calcium and parathyroid hormone levels) without any evidence of clinical symptoms (asymptomatic patients). Today, the majority of patients with PHPT are elderly women, presenting with nonspecific, vague psychiatric or neuromuscular symptoms or even appearing to be asymptomatic.6,7 Several studies showed an improvement of these symptoms after
Prager et al 931
Surgery Volume 132, Number 6 Table I. Patient characteristics and laboratory findings Age (y) Preoperative calcium (mmol/L) Preoperative PTH (pg/mL) Postoperative calcium (mmol/L) Postoperative PTH (pg/mL)
Mean ± 12 SD
Range
Normal range
60.9 ± 12.8 2.9 ± 0.2 133.4 ± 62.6 2.4 ± 0.2 35 ± 12
30-78 2.7-3.5 54-295 2.1-2.6 13-58
2.1-2.6 10-60 2.1-2.6 10-60
SD, Standard deviation.
Table II. Descriptive statistics of raw scores investigated CP1 CP2 CP3 TN1 TN2 TN3 E%1 E%2 E%3 FR1 FR2 FR3 NM1 NM2 NM3
N
Minimum
Maximum
Mean
Standard deviation
20 20 20 20 20 20 20 20 20 20 20 20 20 20 20
64.0 55.0 99.0 200.0 240.0 235.0 0.9 0.0 0.2 5.0 6.0 8.0 9.0 13.0 13.0
181.0 207.0 218.0 465.0 545.0 527.0 26.0 30.5 16.2 25.0 44.0 23.0 39.0 51.0 43.0
115.6 132.5 144.7 329.1 381.3 384.2 7.0 7.3 4.5 11.3 13.8 12.9 23.5 25.0 26.0
33.1 39.8 33.4 85.2 89.4 83.2 5.4 6.7 3.7 5.1 8.4 3.9 7.4 8.7 7.0
1, Preoperative testing; 2, 6 weeks postoperative testing; 3, 12 weeks postoperative testing.
successful parathyroidectomy backed up by psychiatric scores and questionnaires.6,7,9-18 The aim of this study was to find out whether parathyroidectomy improves cognitive performance with regard to concentration and retentiveness in patients with PHPT by applying standardized psychologic tests. PATIENTS AND METHODS Twenty consecutive patients (14 women, 6 men) with sporadic PHPT and admitted for surgery were studied. Diagnosis of PHPT was confirmed by repeated measurements of elevated serum calcium and parathyroid hormone levels. In none of these patients was hyperparathyroidism suspected on account of apparent psychologic abnormalities. All but 2 patients with double adenoma had single gland disease. Only enlarged parathyroid glands were removed, without routine biopsy of normal appearing glands. Surgical findings were confirmed by pathologic examinations. Permanent normocalcemia was documented in all patients during postoperative follow-up (range, 21 to 24 months; mean, 23 months), indicating cure. According to the classification mentioned above, 2 patients were considered to be asympto-
matic, 11 patients minimally symptomatic, and 7 patients symptomatic. Informed consent for participation in this study was obtained from all patients. Their characteristics and preoperative and postoperative laboratory findings are listed in Table I. Psychologic testing was performed in all patients preoperatively as well as 6 and 12 weeks postoperatively. Special attention was paid to ensure identical testing conditions with regard to time (9 to 12 AM), location (same room, same lighting conditions), and tester to minimize exterior influences. Psychologic testing. Two tests were combined to investigate concentration and attentiveness under stress (d2-Test of Attention)19 and retentiveness (Numbers Memorizing, part of the Wilde Intelligence Test).20 All tests were administered according to standardized instructions as given in the test manual. d2-Test of Attention. The d2-Test of Attention consists of 14 rows with 47 figures each. The test taker has to identify relevant figures and cross them out. The actual test is preceded by a practice part to prove whether the test taker has understood the instructions. Twenty seconds are available for each
932 Prager et al
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Table III. Student t test for paired samples Paired differences 95% Confidence interval of difference Mean CP1-CP2 CP1-CP3 CP2-CP3 TN1-TN2 TN1-TN3 TN2-TN3 E%1-E%2 E%1-E%3 E%2-E%3 FR1-FR2 FR1-FR3 FR2-FR3 NM1-NM2 NM1-NM3 NM2-NM3
–16.9 –29.2 –12.3 –52.1 –55.1 –2.9 –0.4 2.4 2.8 –2.5 –1.5 1.0 –1.5 –2.4 –0.9
Standard deviation
Standard error (mean)
15.9 11.8 13.8 59.3 49.6 30.3 7.2 5.8 3.7 10.0 5.4 8.0 6.5 5.0 5.6
3.6 2.6 3.1 13.3 11.1 6.8 1.6 1.3 0.8 2.2 1.2 1.8 1.5 1.1 1.3
Lower –24.3 –34.7 –18.7 –79.9 –78.3 –17.1 –3.8 –0.3 1.0 –7.2 –4.1 –2.8 –4.6 –4.8 –3.6
Upper –9.5 –23.6 –5.8 –24.4 –31.9 11.2 3.0 5.2 4.5 2.1 1.0 4.8 1.6 –0.1 1.7
t test –4.8 –11.1 –4.0 –3.9 –5.0 –0.4 0.2 1.9 3.3 –1.1 –1.3 0.6 –1.0 –2.2 –0.8
P value (2-sided) .0001 .0000 .0008 .0009 .0001 .6679 .8183 .0786 .0286 .2662 .2174 .5845 .3180 .0396 .4578
1, Preoperative testing; 2, 6 weeks postoperative testing; 3, 12 weeks postoperative testing.
row; processing of items is performed without interruption. The end of each row and the beginning of the next row are clearly announced by the tester. The d2-Test of Attention measures processing speed, rule compliance, and quality of performance, allowing for a neuropsychologic assessment of individual attention and concentration performance. It is applicable within 10 to 15 minutes, either individually or in a group format. Concentration-Performance. Concentration-Performance (CP) is similar to the number of “hits” and is in accordance with a standard psychologic method, evaluating achievement, being quite resistant to falsification. Neither omitting parts of the test as a result of superficial, unconcentrated behavior nor crossing out characters on a random basis will raise this level. CP is normal-distributed and highly reliable; it is the most important parameter of the d2-Test in this setting. Total Number of Items Processed. Total number of items processed (TN) describes the quantitative performance; it is a highly reliable measure of processing speed and the amount of work completed. Percentage of Errors. Percentage of errors (E%) is a qualitative variable that describes the amount of errors within the part of the test being handled. This variable represents the meticulousness, precision, and circumspection in performing the test (low values, high accuracy). Fluctuation Rate. Fluctuation rate (FR) is the difference between the maximum and minimum of
items processed involving individual test parts. It describes the stability or inconstancy of processing speed. This parameter is neither normal-distributed, nor is it a highly reliable variable. The test manual describes in detail the high testretest stability (stability coefficient, 0.9), documented in a large number of healthy adults, given for time intervals from 5 minutes to 40 months.19 A standard collective consisting of standardized spot checks of more than 6000 persons has been established for this test. Numbers-Memorizing subtest of the Wilde Intelligence Test. This part of the Wilde Intelligence Test measures retentiveness, the immediate memorizing. In identical intervals, series of 5 to 11 digits are recited by the tester. Those series of numbers must be written down immediately after their verbal presentation. Approximately 15 minutes are necessary to run this test. The raw score Number Memorizing (NM) represents the total number of hits. Statistical methods. For comparison of 2 different samples, the Student paired t test and the nonparametric Wilcoxon signed rank test were applied. For comparing 3 different samples (preoperative, 1; 6 weeks postoperative, 2; 12 weeks postoperative, 3) the Dunnett t test, unifactorial variance analysis with repeated measurements, and the Friedman test were used. For correlating data Pearson correlation coefficient was applied. Linear regression analysis for CP, preoperative parathyroid hormone (PTH) level, and serum calcium level as well as age and gender was calculated. All calcula-
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tions were performed with SPSS for Windows 10.0 (SPSS, Inc, Chicago, Ill). RESULTS Descriptive statistics of different raw scores are summarized in Table II. CP improved significantly within the first 6 and 12 postoperative weeks (Table III). The greatest improvement was seen within the first 6 postoperative weeks. Dunnett t test for the difference among all 3 groups (CP1, CP2, CP3) reached statistical significance (P = .0407), illustrating the improved concentration and attentiveness. TN enhanced significantly within the first 6 weeks (TN1 to TN2, P < .001) but did not show any further development in the following 6 weeks (TN2 to TN3, P = .668). Because of the similarity of TN2 and TN3 Dunnett t test, the difference among all 3 samples (TN1-TN2-TN3) did not reach statistical significance (P = .08). E% was widespread among the different samples (Table II). Neither Wilcoxon test (E%1-E%2-E%3, P = .2) nor Student t test showed statistical significance (Table III). FR proved to be stable; only 5 patients showed a variation of more than 6% among the 3 samples. Neither Wilcoxon test (FR1-FR2-FR3, P = .4) nor Student t test indicated a statistical change of this parameter (Table III). NM showed a slight increase with time (NM1NM2-NM3), which reached significance comparing the preoperative (NM1) with the later postoperative (NM3) result (Table III). Dunnett t test for the difference among NM1, NM2, and NM3 was P = .5. Bivariate correlation (Pearson) analysis showed significant correlation for serum calcium and PTH levels (P = .004). In calculating the regression analysis, no significant correlation for the changes of CP (preoperative to 6 weeks postoperatively and preoperative to 12 weeks postoperatively), preoperative serum calcium and PTH levels, age, and gender were found. The same was documented for postoperative PTH levels and the magnitude of the change in serum calcium or PTH levels. Furthermore, no difference in the degree of improvement among the different groups of patients (asymptomatic, minimally symptomatic, symptomatic) could be shown. DISCUSSION Successful parathyroidectomy improved CP and TN significantly within 6 weeks. E% showed no significant positive change within the first 6 weeks; nevertheless, there was a tendency to perform the
Prager et al 933
tests more accurately and meticulously within 12 weeks. There was absolutely no significant change of the FR. NM showed no significant improvement within the first 6 postoperative weeks but reached significance level 12 weeks postoperatively. This is the first report using objective assessment tools to evaluate the influence of restoring normocalcemia on mental performance. To investigate cognitive functions, 2 tests were applied; the d2-Test has become the mainstay of attentional assessment in Europe. The reliability (internal/test-retest) has proved to be very high, and the criterion, construct, and predictive validity of the technique has been documented by a number of research studies.19 Because of the small sample size (n = 20) and the large interindividual differences, no comparison with an established, standardized population, as described in the test manual, was done. The d2-Test has been used extensively in the area of clinical (neuro) psychology, clinical psychiatry, and several other fields. The NM subtest of the Wilde Intelligence Test was used to measure retentiveness and memorizing. The Wilde Intelligence Test has been used widely in the German-speaking areas of Europe. Its reliability was confirmed by thousands of tested persons. The subpart NM is liable to be influenced by different situations and external interferences that must be taken into consideration when planning the test. This was taken into account by identical testing conditions with regard to time (9 to 12 AM), location (same room, same lighting conditions), and tester to minimize exterior influences. In reviewing the literature, the improvement of cognitive functions as found in this study is only demonstrated in a few case reports21-27 or in very small series.28-30 In the majority of articles, observation31-33 and questionnaires/interviews6,7,9-18 were used, reflecting the patients’ subjective mood and condition to describe the general improvement of psychologic and psychiatric symptoms. Studying central nervous system manifestations before and after parathyroidectomy in only 4 patients with PHPT, Cogan et al30 showed no significant changes in any of the psychologic parameters tested. Numann et al28 found dysfunction of memory, learning, and cognition even in patients without neurologic manifestations of PHPT. A significant turn to the better was found in 10 patients at an average of 4.38 months postoperatively. Herrmann et al34 applied 3 different psychologic tests in 19 patients with PHPT. They showed a significant decrease of psychic complaints within 1
934 Prager et al
week after surgery as did Pasieka et al16 by using questionnaires. Petersen33 found a correlation between the elevation of the preoperative serum calcium level and the degree of mental disturbance/degree of mental changes after normalization of serum calcium levels. No correlation between the improvement of concentration/retentiveness and the serum calcium/PTH level, age, and gender was found in this study. Moreover, several other studies13,17,34,35 did not show a correlation between the preoperative serum calcium level and any psychologic dimension score. Nevertheless, Brown et al36 and Cogan et al30 found a relationship between preoperatively elevated serum calcium levels and neurobehavioral impairment. Pasieka et al16 and Herrmann et al34 describe a significant improvement of investigated symptoms only 1 week after parathyroidectomy. Burney et al35 discovered a significant change to the better within 2 months after operation. In this study some raw scores (CP, TN) improved significantly within the first 6 weeks, whereas others (NM, E%) took longer to demonstrate a significant turn to the better. The pathophysiologic mechanism responsible for psychiatric disorders and reduced cognitive functions in hypercalcemic patients remains unclear. Joborn et al12 showed elevated calcium/ PTH concentrations and decreased levels of monoamine metabolites in the cerebrospinal fluid of patients with PHPT. Furthermore, one third of the patients with PHPT had signs of a certain degree of damage to the blood-brain barrier. Although investigated only in a small group of patients, significant improvement of cognitive functions (concentration, retentiveness) was demonstrated in patients with PHPT after successful parathyroidectomy, irrespective of the preoperative clinical manifestations. Symptomatic, minimally symptomatic, as well as asymptomatic patients seemed to improve likewise, underlining the importance of parathyroidectomy.
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REFERENCES 1. Christensson T. Menopausal age of females with hypercalcaemia: a study including cases with primary hyperparathyroidism, detected in a health screening. Acta Med Scand 1976;200:361-5. 2. Christensson T, Hellstrom K, Wengle B. Clinical and laboratory findings in subjects with hypercalcaemia: a study including cases with primary hyperparathyroidism detected in a health screening. Acta Med Scand 1976;200:355-60. 3. Akerstrom G, Rudberg C, Grimelius L, Bergstrom R, Johansson H, Ljunghall S, et al. Histologic parathyroid
19. 20.
21.
abnormalities in an autopsy series. Hum Pathol 1986; 17:520-7. Albright F, Reifenstein C. The parathyroids and metabolic bone disease. Baltimore: Williams & Wilkins; 1948. St Goar W. Gastrointestinal symptoms as a clue to the diagnosis of primary hyperparathyroidism: a review of 45 cases. Ann Intern Med 1957;46:102. Chan AK, Duh QY, Katz MH, Siperstein AE, Clark OH. Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy: a case-control study. Ann Surg 1995;222:402-14. Joborn C, Hetta J, Johansson H, Rastad J, Agren H, Akerstrom G, et al. Psychiatric morbidity in primary hyperparathyroidism. World J Surg 1988;12:476-81. Niederle B, Roka R, Woloszczuk W, Klaushofer K, Kovarik J, Schernthaner G. Successful parathyroidectomy in primary hyperparathyroidism: a clinical follow-up study of 212 consecutive patients. Surgery 1987;102:903-9. Burney RE, Jones KR, Coon JW, Blewitt DK, Herm AM. Assessment of patient outcomes after operation for primary hyperparathyroidism. Surgery 1996;120:1013-9. Burney RE, Jones KR, Peterson M, Christy B, Thompson NW. Surgical correction of primary hyperparathyroidism improves quality of life. Surgery 1998;124:987-92. Joborn C, Hetta J, Rastad J, Agren H, Akerstrom G, Ljunghall S. Psychiatric symptoms and cerebrospinal fluid monoamine metabolites in primary hyperparathyroidism. Biol Psychiatry 1988;23:149-58. Joborn C, Hetta J, Niklasson F, Rastad J, Wide L, Agren H, et al. Cerebrospinal fluid calcium, parathyroid hormone, and monoamine and purine metabolites and the bloodbrain barrier function in primary hyperparathyroidism. Psychoneuroendocrinology 1991;16:311-22. Joborn C, Hetta J, Lind L, Rastad J, Akerstrom G, Ljunghall S. Self-rated psychiatric symptoms in patients operated on because of primary hyperparathyroidism and in patients with long-standing mild hypercalcemia. Surgery 1989; 105:72-8. Lundgren E, Ljunghall S, Akerstrom G, Hetta J, Mallmin H, Rastad J. Case-control study on symptoms and signs of “asymptomatic” primary hyperparathyroidism. Surgery 1998;124:980-6. Pasieka JL, Parsons LL. Prospective surgical outcome study of relief of symptoms following surgery in patients with primary hyperparathyroidism. World J Surg 1998;22:513-9. Pasieka JL, Parsons LL. A prospective surgical outcome study assessing the impact of parathyroidectomy on symptoms in patients with secondary and tertiary hyperparathyroidism. Surgery 2000;128:531-9. Solomon BL, Schaaf M, Smallridge RC. Psychologic symptoms before and after parathyroid surgery. Am J Med 1994;96:101-6. Talpos GB, Bone HG III, Kleerekoper M, Phillips ER, Alam M, Honasoge M, et al. Randomized trial of parathyroidectomy in mild asymptomatic primary hyperparathyroidism: patient description and effects on the SF-36 health survey. Surgery 2000;128:1013-21. Brickenkamp R. Test d2 - Aufmerksamkeits-Belastungs-Test. 8th revised ed. Goettingen: Hogrefe-Verlag GmbH & CoKG; 1994. Jaeger A, Althoff K. Der WILDE-Intelligenz-Test (WIT). 2nd revised ed. Goettingen: Hogrefe-Verlag GmbH & CoKG; 1994. Emmelot-Vonk MH, Samson MM, Raymakers JA. [Cognitive deterioration in elderly due to primary hyperparathyroidism: resolved by parathyroidectomy]. Ned Tijdschr Geneeskd 2001;145:1961-4.
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22. Logullo F, Babbini MT, Di Bella P, Provinciali L. Reversible combined cognitive impairment and severe polyneuropathy resulting from primary hyperparathyroidism. Ital J Neurol Sci 1998;19:86-9. 23. Pfitzenmeyer P, Besancenot JF, Verges B, Cougard P, Lorcerie B, Cercueil JP, et al. Primary hyperparathyroidism in very old patients. Eur J Med 1993;2:453-6. 24. Spivak B, Radvan M, Ohring R, Weizman A. Primary hyperparathyroidism, psychiatric manifestations, diagnosis and management. Psychother Psychosom 1989;51:38-44. 25. Thurling ML. Primary hyperparathyroidism in a schizophrenic woman. Can J Psychiatry 1987;32:785-7. 26. Kleinfeld M, Peter S, Gilbert GM. Delirium as the predominant manifestation of hyperparathyroidism: reversal after parathyroidectomy. J Am Geriatr Soc 1984;32:689-90. 27. Ebel H, Schlegel U, Klosterkotter J. [Chronic schizophreniform psychosis in primary hyperparathyroidism]. Nervenarzt 1992;63:180-3. 28. Numann PJ, Torppa AJ, Blumetti AE. Neuropsychologic deficits associated with primary hyperparathyroidism. Surgery 1984;96:1119-23. 29. Gatewood JW, Organ CH Jr, Mead BT. Mental changes associated with hyperparathyroidism. Am J Psychiatry 1975; 132:129-32. 30. Cogan MG, Covey CM, Arieff AI, Wisniewski A, Clark OH, Lazarowitz V, et al. Central nervous system manifestations of hyperparathyroidism. Am J Med 1978;65:963-70. 31. Karpati G, Frame B. Neuropsychiatric disorders in primary hyperparathyroidism. Arch Neurol 1964;10:387-97. 32. Joborn C, Hetta J, Frisk P, Palmer M, Akerstrom G, Ljunghall S. Primary hyperparathyroidism in patients with organic brain syndrome. Acta Med Scand 1986;219:91-8. 33. Petersen P. Psychiatric disorders in primary hyperparathyroidism. J Clin Endocrinol Metab 1968;28:1491-5. 34. Herrmann JM, Schonecke OW, Raue F, Ziegler R. [Primary hyperparathyroidism: psychological factors before and after parathyroidectomy]. MMW Munch Med Wochenschr 1983;125:369-71. 35. Burney RE, Jones KR, Christy B, Thompson NW. Health status improvement after surgical correction of primary hyperparathyroidism in patients with high and low preoperative calcium levels. Surgery 1999;125:608-14. 36. Brown GG, Preisman RC, Kleerekoper M. Neurobehavioral symptoms in mild primary hyperparathyroidism: related to hypercalcemia but not improved by parathyroidectomy. Henry Ford Hosp Med J 1987;35:211-5.
DISCUSSION Dr Patricia J. Numann (Syracuse, New York). Ours was the paper from 1984 you referenced. We didn’t report the calcium because we didn’t have enough patients to really make any comments about it, but it was our impression at that time that their serum calcium didn’t make any difference. I would like to ask you a question about the age. I have been impressed through the years that even though the young people had the same improvement in retention and improvement in cognitive function, it is less disabling to the younger person to have hyperparathyroidism memory deficits than to the older person. I would wonder if you have looked at the type of quality of life indices in the older person and how that correlates to their retention of detail. I have found in the older peo-
Prager et al 935
ple that when they suffer the retention of memory loss, they can’t function. Many of them end up in different environments of care, whereas, when you do your parathyroidectomy, then they can come back to a very comfortable lifestyle even with the other aging factors. Dr Prager. We did not look for their health status; we just looked for cognitive performance with regard to concentration and retentiveness. But I agree with you; I also had the impression that older people start from a lower level of cognitive performance. So it is more apparent to these people than to younger patients. But I think our group of patients is too small to offer definite conclusions for this question. Dr Sally E. Carty (Pittsburgh, Pennsylvania). Based on the literature, we currently counsel patients not to look for the full positive effects of the surgery until 6 months in terms of mood and energy levels, so it is particularly wonderful that you got a P value at 3 months. Clinically, however, when we follow patients for longer than 6 months, there is a rebound, and a year after the surgery their energy level and/or their mood may not be as good as it was at 3 or 6 months postoperatively. I encourage you to look for a rebound effect at 6 or 12 months with this research tool. Dr Prager. We have not done that. But Janice Pasieka found the most significant improvement 10 days after parathyroid surgery without any later rebound effect; people stayed at an improved level for a long time. Dr Janice L. Pasieka (Calgary, Alberta, Canada). You are absolutely right, Gerhard. Dr Carty, we didn’t find a rebound effect. In our study, we followed these people for 1 year, and the improvement in their symptoms was maintained at 1 year. Dr Thomas J. Fahey III (New York, New York). I was wondering if you happened to correlate the objective results with the patients’ subjective feelings. We likely won’t be doing these tests. We wonder how many of our postoperative patients who say they don’t have any improvement actually might have objective improvement on a comprehensive test. Dr Prager. Those numbers I presented document the objective improvement. For this reason we applied standardized psychologic tests and did not make any questionnaires or patient interviews, how they, themselves, felt about their improvement. Dr Bradford Mitchell (Morgantown, Virginia). Given the fact that there is no correlation with the calcium level and that patients with renal failure with normal calcium levels have similar types of symptoms, do you think it is appropriate to refer to this as a hypercalcemic syndrome? Do you think it is appropriate to refer to this as a hypercalcemic syndrome in light of the fact that you can see similar symptoms and symptom resolution in patients with renal failure? Dr Prager. I can’t answer this question properly. Janice Pasieka presented a paper on this question with patients with renal hyperparathyroidism. In this study we just stick to primary hyperparathyroidism. Dr Pasieka.We also found there was no correlation between the calcium, the phosphate, PTH, and alkaline
936 Prager et al
phosphatase. So what do you think is affecting the cognitive function of these patients? Have you postulated what you think the underlying problem is? Dr Prager. I cannot give a definite answer to your question, but in a former paper, Joborn studied the cerebrospinal fluid of patients with primary hyperparathyroidism before and after surgery. She found preoperatively elevated calcium and PTH levels and
Surgery December 2002 decreased monoamine metabolite levels in the cerebrospinal fluid of patients with primary hyperparathyroidism when compared to a control group. After operation the calcium level in the cerebrospinal fluid decreased, whereas the monoamine metabolites increased. Probably the improvement of cognitive functions is due to a change in the pattern of neurotransmitters. I agree that this is a possible answer to the question.