S P E C I A L C o n t r o v e r s y
i n
C l i n i c a l
F E A T U R E
E n d o c r i n o l o g y
What Is the Best Way of Assessing Neurocognitive Dysfunction in Patients With Primary Hyperparathyroidism? Paul Grant and Anand Velusamy Diabetes and Endocrine Day Centre (P.G.), St Thomas’ Hospital, London SE1 7EH, United Kingdom; and Department of Diabetes and Endocrinology (A.V.), Royal Sussex County Hospital, Brighton BN2 5BE, United Kingdom
Context: The patient attending with asymptomatic primary hyperparathyroidism (PHPT) is a common occurrence in the outpatient endocrine setting. Indeed, more than 80% of contemporary PHPT patients are considered asymptomatic at diagnosis. A frequent question in clinical practice is at what stage may the patient be offered curative surgery. This may well relate to the duration and the degree of hypercalcemia, evidence of end-organ effects, and whether clear symptoms may or may not be attributable to the underlying condition. Objective: There are well-recognized psychological and cognitive changes that can occur in the context of PHPT. A challenge for the clinician is to discern to what extent these symptoms may be present (often very close questioning is required) and how to measure and categorize them. Interventions: Assessment can be difficult because patients who have PHPT tend to be more elderly, and they often have other overlapping comorbidities that may cloud the diagnosis. A decision then has to made as to whether such symptoms are likely to be a result of prolonged hypercalcemia, to what extent they can be attributed to the underlying disease, and whether they constitute sufficient weight to warrant surgical intervention in an otherwise “asymptomatic” patient. Practice tends to vary, and some clinicians may undertake watchful waiting or conservative management, whereas others may more readily push for surgical parathyroidectomy as a definitive treatment. We reviewed the literature on the subject of neuropsychological testing in the management of PHPT. Positions: A controversy in clinical endocrinology is how to assess the cognitive, quality of life, and psychological effects of hypercalcemia. Multiple tools are being used, and significant changes have often been demonstrated in such parameters after parathyroidectomy. Conclusions: We reviewed the latest studies on this subject and assessed the usefulness and validity of such tools in clinical practice, identifying several scores and measures that have been validated in clinical practice; comparisons are made with similar assessments such as the Adult Growth Hormone Deficiency Assessment questionnaire. (J Clin Endocrinol Metab 99: 49 –55, 2014)
ones, stones, abdominal groans, and psychic moans” used to be the classic description of the patient with persistent hypercalcemia due to primary hyperparathyroidism (PHPT), and it is one of the commonly remembered adages from medical school for many clini-
“B
cians. However, since the 1960s and the introduction of more sensitive, multichannel autoanalyzers, the detection of hypercalcemia consequent to PTH excess is far more frequently uncovered as a coincidental finding. Subsequently, the patient attending with asymptomatic PHPT is
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by The Endocrine Society Received August 12, 2013. Accepted October 29, 2013. First Published Online November 7, 2013
Abbreviations: PAS, Parathyroid Assessment Score; PHPT, primary hyperparathyroidism; RCT, randomized controlled trial; SF-36, Short Form 36-Item Health Survey.
doi: 10.1210/jc.2013-3115
J Clin Endocrinol Metab, January 2014, 99(1):49 –55
jcem.endojournals.org
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 30 September 2014. at 04:57 For personal use only. No other uses without permission. . All rights reserved.
49
50
Grant and Velusamy
Neurocognitive Dysfunction in HPT
Table 1. Questions for Patients With Suspected PHPT (Adapted From Pasieka et al [2]) Easy fatigability Myalgia or bone pains Mood swings Feeling “blue” or depressed Abdominal pains/cramps Feeling weak Headaches Feeling irritable Being forgetful Difficulty getting out of a car or chair
a common occurrence in the outpatient endocrine setting. Indeed, more than 80% of contemporary PHPT patients are considered asymptomatic at diagnosis (1). A frequent question in clinical practice is, therefore, at what stage may the patient be offered curative surgery. This may well relate to the duration and the degree of hypercalcemia, evidence of end-organ effects, and whether clear symptoms may or may not be attributable to the underlying condition (Table 1).
Psychological Disturbance and Neurocognitive Dysfunction Calcium is known to be critical to neurotransmitter function, and elevations in plasma calcium levels have been postulated to affect cerebral function either directly or indirectly (3). There are well-recognized psychological and cognitive changes that can occur in the context of PHPT. The exact mechanisms involved remain unclear. Features include fatigue, depression (ranging from feeling low to full blown depression), anxiety, emotional lability, and sleep disturbance. Cognitive features may be more subtle and run the spectrum of intellectual weariness from feeling “muzzy headed,” to memory impairment and poor concentration, to significant impairment on mental test scores. Examples include: difficulties in direct memory, decreased nonverbal learning processes, impaired verbal fluency, and visual-constructive abilities (4, 5). A challenge for the clinician is to discern to what extent these symptoms may be present (often very close questioning is required) and how to measure and categorize them. Assessment can be difficult because patients who have PHPT tend to be more elderly and they often have other overlapping comorbidities that may cloud the diagnosis. Because PHPT has its highest incidence in the sixth and seventh decades of life, the patient’s problems may be dismissed as part of the normal aging process, menopause, or “chronic fatigue” (6). A decision then has to made as to whether such symptoms are likely to be a result of prolonged hypercalcemia, to what extent they can be attrib-
J Clin Endocrinol Metab, January 2014, 99(1):49 –55
uted to the underlying disease, and whether they constitute sufficient weight to warrant surgical intervention in an otherwise “asymptomatic” patient. Practice tends to vary, and some clinicians may undertake watchful waiting or conservative management, whereas others may more readily push for surgical parathyroidectomy (PTX) as a definitive treatment.
The 2009 Third International Workshop Guidelines on the Management of Asymptomatic Primary Hyperparathyroidism Consensus guidelines produced in 2009 looked at the available evidence and included a discussion of the value of screening for and assessing the neurocognitive changes in the context of asymptomatic PHPT (7). Studies on the cognitive and psychological aspects of PHPT, including functional magnetic resonance imaging studies, were reviewed (8, 9). It is already known that the brains of patients with PHPT are different when looked at using functional imaging. Regional blood flow changes and prefrontal cortical activation are apparent, and these patterns alter after surgical PTX (5). The workshop members recognized that there were inconsistencies in the abnormalities described, data on their precise nature, the degree of association with the underlying condition, and also the extent to which neurocognitive problems were remediable after surgical PTX (6, 10). Ultimately, it was felt at the time that psychological and cognitive aspects of PHPT were not considered to be an indication for surgery (4, 7, 11). We revisit this aspect of PHPT in light of additional research that has subsequently become available.
Specific Research There have been several studies looking at changes in mental health status and cognition in PHPT both before and after surgery. Most research has evaluated psychological symptoms such as anxiety, depression, or quality of life. Observational studies have demonstrated improvements in symptoms and quality of life after PTX (when compared with controls) (12, 13). There have been three good randomized controlled trials (RCTs) to date investigating the influence of PTX on quality of life and psychological factors in the context of “mild” PHPT which, despite relatively small numbers of participants being randomized (range, 50 –191) and limited follow-up (approximately 2 y), have provided some valuable information (Table 2).
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 30 September 2014. at 04:57 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2013-3115
Table 2. Examples of Quality of Life Questions From SF-36 —Mental Components of Health (14) During the past 4 weeks, have you had any of the following problems with your work or other regular activities as a result of any emotional problems (such as feeling depressed or anxious)? A. Cut down the amount of time you spent on work or other activities? (Y/N) B. Accomplished less than you would like? (Y/N) C. Didn’t do work or other activities as carefully as usual? (Y/N) How did you feel and how have things been with you during the past 4 weeks? For each of the questions please give one answer that comes closest to the way that you have been feeling (all of the time/most of the time/a good bit of the time/some of the time/a little of the time/none of the time). A. Did you feel full of pep? B. Have you been a very nervous person? C. Have you felt so down in the dumps that nothing could cheer you up? D. Have you felt calm and peaceful? E. Did you have a lot of energy? F. Have you felt down-hearted and blue? G. Did you feel worn out? H. Have you been a happy person? I. Did you feel tired?
In the Henry Ford PHPT study by Talpos et al (15), 53 patients with PHPT were followed for 2 years, and quality of life, including both physical and psychological wellbeing, was assessed using the Short Form 36-Item (SF36) Health Survey and Symptom Checklist 90 (SCL90R) scale. PTX leads to a significant improvement in social functioning and emotional role function, two parameters of the SF-36, and it is also associated with a reduction in anxiety and phobia compared with the observation group. In the similar-sized study of Ambrogini et al (16) (n ⫽ 50), similar assessments were made, with no differences between controls at baseline. At 6 months and 1 year after PTX, no change was seen in social functioning and emotional role function, but there were improvements in general health, vitality, mental health, and bodily pain in the surgical group, demonstrating a significant difference between the two groups at that stage. In the largest RCT to date, 191 individuals with PHPT not meeting 2002 National Institutes of Health criteria for surgery were randomized to PTX or medical observation in a multicenter Scandinavian study (17). Participants had lower scores in all eight domains of the SF-36, as well as more psychological symptoms on the Comprehensive Psychopathological Rating Scale (CPRS), compared with a demographically matched population. However, there was no clear improvement after PTX at 2 years, although SF-36-reported physical function was reduced in the observation group.
jcem.endojournals.org
51
With regard to cognition, there have been multiple studies looking at changes in patterns of intellectual functioning before and after PTX. A good example is the work of Roman et al (18) who in 2005 undertook a prospective study of patients with PHPT and used a battery of psychometric and neurocognitive instruments to assess whether learning, memory, or concentration improved after PTX (n ⫽ 55). Patients with PHPT improved significantly in terms of both psychological scores but also in cognitive domains such as spatial learning and spatial working memory (5, 19). This was supported by a study undertaken by Babinska et al (4), which was the first to use a battery of neuropsychological tests to evaluate cognitive disturbances in PHPT in relation to calcium levels before and after surgery. All patients were tested before PTX and at the 12- to 18-month stage, and they demonstrated that in the presurgery patient group there were obvious impairments in concentration, decreased nonverbal learning processes, difficulties in using direct memory, verbal fluency, and visual-constructive abilities and memory. Postoperatively, there were significant improvements in visual memory, direct memory, and visual-constructive abilities. The best tests to pick up and highlight these changes were found to be the Memory Verbal Learning Test (DCS), the Benton Visual Retention Test (BVRT), and the Trail Making Test (TMT). Problems with studies in this area are multiple: they may arbitrarily select only a few areas relating to cognitive function, they tend to use only small sample sizes, there is a lack of control groups and no allowance for differences in demographics are made, the studies feature a paucity of validated cognitive measures, there are differences in the timing of assessments relative to PTX, and whereas it is apparent that there is a degree of cognitive impairment relative to matched, normal populations, one confounder that is significant and rarely, if ever, taken into account is that of the recognized impact of psychological symptoms upon cognition, which is very important because anxiety and depression affect cognitive function independently (20, 21). Walker et al (6) designed an interventional study to overcome this issue and demonstrated that at baseline patients with PHPT had much higher scores for depression and anxiety symptoms (measured using the Beck Depression Inventory [BDI] and the State-Trait Anxiety Inventory [STAI-Y]) as well as poorer performance on cognitive tests of verbal memory (Wechsler Memory Scale [WMS] Logical Memory Test, Russell revision; and the Buschke Selective Reminding Test [SRT]) and nonverbal abstraction (Booklet Category Test [BCT]). After PTX, symptoms of depression, scores of nonverbal abstraction, and some aspects of verbal memory improved to the extent that they
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 30 September 2014. at 04:57 For personal use only. No other uses without permission. . All rights reserved.
52
Grant and Velusamy
Neurocognitive Dysfunction in HPT
Figure 1. Wechsler Memory Scale.
became no different from the control group. Importantly, they showed that baseline differences and postoperative changes in measurements of cognition were independent of the anxiety and depression scores and not linearly related with plasma concentrations of corrected calcium or PTH.
J Clin Endocrinol Metab, January 2014, 99(1):49 –55
test is untimed, and the results are professionally scored by form, shape, pattern, and arrangement on the paper (Figure 3). In summary, it is well recognized that asymptomatic PHPT is associated with worse performance in certain cognitive domains such as verbal memory and nonverbal abstraction. This is independent of psychological factors; there is improvement in both elements after PTX, and this is supported by several studies. This may well explain the improved sense of well-being and quality of life that many, but not all, patients experience after surgery (23).
Discussion Examples of Cognitive Test Questions The Wechsler Memory Scale is a neuropsychological test designed to measure different memory functions in a person (22). The patient is presented with a grid containing objects followed by a blank grid. The task is to then recall and reproduce the design and location of the objects from the initial grid (Figure 1). The Buschke Selective Reading Test involves reading the subject a list of 12 unrelated words and then having the subject immediately recall as many of these 12 words as possible (Figure 2). The Benton Visual Retention Test measures visual perception and visual memory. The subject is shown 10 designs, one at a time, and asked to reproduce each one as exactly as possible on plain paper from memory. The
Figure 2. Selective Reading Test (Buschke).
Despite the increasing number of studies looking at selected aspects of improved psychological and cognitive functioning of PHPT patients after PTX and successful correction of hypercalcemia, the systematic assessment of these factors does not appear to be routine in clinical practice. Hypercalcemia is recognized to produce neuropsychiatric symptoms, and this has been supported by functional magnetic resonance imaging studies (8, 25, 26). It may also be the case that the confounding factor of vitamin D deficiency, which is frequently associated with hyperparathyroidism, could explain some of the weakness, impaired cognition, low mood, and fatigue associated with the condition (27). Interestingly, vitamin D insufficiency is highly prevalent in psychiatric inpatients, as demonstrated by a 2013 study by Rylander and Verhulst (28). It is not clear whether this is due to severe mental illness and resultant social isolation or whether vitamin D itself has a regulatory role on upstream genes involved in neural networks that influence affect, cognition, and perception. A recent meta-analysis of memory and executive dysfunctions of hypovitaminosis D has shown that it is associated with global cognitive impairment in adults (29). Specifically, results from 14 observational studies and three interventional studies show that lower serum 25hydroxyvitamin D levels predict cognitive impairment, es-
Figure 3. Benton Visual Retention Test.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 30 September 2014. at 04:57 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2013-3115
pecially in terms of such executive domains as mental shifting, information updating, and processing speed. The association with episodic memory per se remains unclear. Vitamin D repletion resulted in improved executive functions. Vitamin D status in PHPT remains a controversial issue in its own right. Secondary hyperparathyroidism due to vitamin D deficiency needs to be identified and corrected (30), and this may well normalize much of the original deranged biochemical milieu in presumed PHPT. However, it is well recognized that low vitamin D levels are a common occurrence in the context of PHPT, as well as in the general population with no abnormalities of calcium metabolism. Generally, researchers who needed to evaluate psychological indicators in PHPT have been concentrating on quality of life questionnaires such as the SF-36. These tend to focus more on symptom-derived aspects of the disease that included limitations due to physical health and pain, but they did not tackle the more subtle dimensions of neurocognitive impairment that may precede overt symptomatic disease. Management guidelines recommend PTX for patients with asymptomatic PHPT in whom evaluation shows endorgan effects that are likely to be mitigated by intervention (eg, reduced bone mineral density, renal impairment, or recurrent nephrolithiasis) or a higher likelihood of disease progression (eg, young age, high PTH titer). Neurocognitive dysfunction has traditionally not been included as an indication for PTX because of inconsistent data on its precise nature and extent, the association with the underlying disease, and its potential reversibility (7, 31). Problems with studies in this area relate to small sample sizes, their observational rather than RCT-based nature, the inclusion of symptomatic patients, the short duration of comparison before and after surgery, and the absence of decent control groups. PTX, even in asymptomatic disease, is expected to provoke an improvement in the quality of life. This has been shown, as outlined above, by using the SF-36 questionnaire; however, its interpretation can be difficult in routine clinical practice because not all of the components are relevant to PHPT. The introduction of specific tools to assess symptoms relating to surgical outcomes, eg, the 2002 Pasieka Parathyroid Assessment Score (PAS) (2), has been useful. This is a 13-item well-validated questionnaire developed to assess symptoms on a visual analog scale. Mihai and Sadler (32) and Ramakant et al (33) have undertaken prospective studies in populations of patients undergoing PTX surgery (101 and 42 patients, respectively) to evaluate and compare the PAS questionnaire vs the SF-36. They both found strong correlation between the two tests and, because PAS allows faster and easier anal-
jcem.endojournals.org
53
ysis, have advocated that it should be incorporated into the routine assessment of patients with PHPT as a reliable tool to identify symptomatic changes that correlate with improved quality of life. Contrast this with another assessment tool that we are familiar with using in clinical endocrinology (the Adult Growth Hormone Deficiency Assessment [AGHDA] questionnaire, the results of which provide a validated foundation for treatment), and one could argue that an assessment tool that encompasses all the aspects of neurocognitive dysfunction (psychological morbidity, healthrelated quality of life, and cognition impairment) would be very valuable for this gray area of clinical practice. It would appear, therefore, that the most relevant and consistently useful tests to determine the effects of PHPT in asymptomatic patients are the specific elements of the SF-36 (as exemplified by the PAS), BDI, STAI-Y, DCS, BVRT, and the memory test scales (both verbal and visual memory). A composite of these measures needs to be applied to clinical practice and evaluated in relation to both medical and surgical interventions. Such a composite should be validated and refined to allow ease of use in the outpatient setting and ultimately be an aid to decision-making and a supportive guide for the use of PTX or the commencement of calcimimetic medication.
Conclusions To ignore the potential impact of neurocognitive dysfunction in patients with PHPT may be a disservice to our patients. Similar to the way in which the term “mild” diabetes has been dropped because patients were eventually shown to have significant morbidity, perhaps the time has come to stop using the prefix “mild” with regard to PHPT. Alternative terms such as “insidious” could be used, or the use of a precursor could be abandoned altogether (31). PHPT is associated with cognitive deficits, problems with processing, and psychological issues that improve after PTX. Although longer follow-up is necessary, neurocognitive symptoms should arguably be considered as criteria for PTX. An issue that arose from the 2009 guidelines was that it was very difficult on some dimensions to reach a true consensus. There is diversity of opinion and practice globally. A national audit of UK clinical practice is currently under way, using the Third International Workshop as a guide; it will be interesting to see to what extent endocrine centers are undertaking assessments of psychological and cognitive factors as part of their management (34).
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 30 September 2014. at 04:57 For personal use only. No other uses without permission. . All rights reserved.
54
Grant and Velusamy
Neurocognitive Dysfunction in HPT
Medical treatments are now available that could also be used to explore whether they improve the outcomes for patients with “insidious” PHPT. Newer operative techniques have made surgery less invasive, faster, with fewer complications, and with greater relative cost-effectiveness. Indeed, recent studies of the impact of PTX suggest that this is a cost-effective strategy for both day case and inpatient surgery in patients with a life expectancy greater than 5 and 6.5 years, respectively (35, 36). In addition to a practice audit, a large RCT of treatment in “mild” or “insidious” PHPT is urgently required, with both surgical and medical interventions, so that more attention can be paid to the subtle issue of neurocognitive dysfunction (24, 37).
J Clin Endocrinol Metab, January 2014, 99(1):49 –55
10.
11.
12.
13.
14. 15.
Acknowledgments 16.
The authors thank Professor Richard Eastell, Dr Paul Carroll, and Derek Lington. Address all correspondence and requests for reprints to: Paul Steven Grant, MBBS, MSc, MRCP, Consultant Endocrinologist, St Thomas’ Hospital, Department of Endocrinology, Westminster Bridge Road, London SE1 7EH, United Kingdom. E-mail: [email protected]. Disclosure Summary: The authors have nothing to disclose.
17.
18.
19.
References 1. Yu N, Leese GP, Smith D, et al. The natural history of treated and untreated primary hyperparathyroidism: the Parathyroid Epidemiology and Audit Research Study. QJM. 2011;104:513–521. 2. Pasieka JL, Parsons LL, Demeure MJ, et al. Patient-based surgical outcome tool demonstrating alleviation of symptoms following parathyroidectomy in patients with primary hyperparathyroidism. World J Surg. 2002;26:942–949. 3. Imbrici P, Camerino DC, Tricarico D. Major channels involved in neuropsychiatric disorders and therapeutic perspectives. Front Genet. 2013;4:76. 4. Babin´ska D, Barczyn´ski M, Stefaniak T, et al. Evaluation of selected cognitive functions before and after surgery for primary hyperparathyroidism. Langenbecks Arch Surg. 2012;397(5):825– 831. 5. Roman SA, Sosa JA, Pietrzak RH, et al. The effects of serum calcium and parathyroid hormone changes on psychological and cognitive function in patients undergoing parathyroidectomy for primary hyperparathyroidism. Ann Surg. 2011;253(1):131–137. 6. Walker MD, McMahon DJ, Inabnet WB, et al. Neuropsychological features in primary hyperparathyroidism: a prospective study. J Clin Endocrinol Metab. 2009;94(6):1951–1958. 7. Bilezikian JP, Khan AA, Potts JT Jr; Third International Workshop on the Management of Asymptomatic Primary Hyperthyroidism. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. J Clin Endocrinol Metab. 2009;94(2):335–339. 8. Perrier ND, Coker LH, Rorie KD, et al. Preliminary report: functional MRI of the brain may be the ideal tool for evaluating neuropsychologic and sleep complaints of patients with primary hyperparathyroidism. World J Surg. 2006;30(5):686 – 696. 9. Perrier ND, Balachandran D, Wefel JS, et al. Prospective, random-
20.
21.
22.
23. 24.
25. 26.
27.
28. 29.
30.
ized, controlled trial of parathyroidectomy versus observation in patients with “asymptomatic” primary hyperparathyroidism. Surgery. 2009;146(6):1116 –1122. Rubin MR, Bilezikian JP, McMahon DJ, et al. The natural history of primary hyperparathyroidism with or without parathyroid surgery after 15 years. J Clin Endocrinol Metab. 2008;93:3462–3470. Silverberg SJ, Bilezikian JP, Bone HG, Talpos GB, Horwitz MJ, Stewart AF. Therapeutic controversies in primary hyperparathyroidism. J Clin Endocrinol Metab. 1999;84(7):2275–2285. Vestergaard P, Mosekilde L. Cohort study on effects of parathyroid surgery on multiple outcomes in primary hyperparathyroidism. BMJ. 2003;327:530 –534. Weber T, Eberle J, Messelhäuser U, et al. Parathyroidectomy, elevated depression scores, and suicidal ideation in patients with primary hyperparathyroidism: results of a prospective multicenter study. JAMA Surg. 2013;148(2):109 –115. QualityMetric Inc. The Short-Form 36 Health Survey. http:// www.sf-36.org/. Accessed June 10, 2013. Talpos GB, Bone HG 3rd, Kleerekoper 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(6):1013–1020; discussion 1020 –1021. Ambrogini E, Cetani F, Cianferotti L, et al. Surgery or surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial. J Clin Endocrinol Metab. 2007;92(8): 3114 –3121. Bollerslev J, Jansson S, Mollerup CL, et al. Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective, randomized trial. J Clin Endocrinol Metab. 2007;92:1687–1692. Roman SA, Sosa JA, Mayes L, et al. Parathyroidectomy improves neurocognitive deficits in patients with primary hyperparathyroidism. Surgery. 2005;138(6):1121–1128; discussion 1128 –1129. Thomas DC, Roman SA, Sosa JA. Parathyroidectomy in the elderly: analysis of 7313 patients. J Surg Res. 2011;170(2):240 –246. Joborn C, Hetta J, Lind L, Rastad J, Akerström 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(1):72–78. Klasik A, Krysta K, Krzystanek M. Impact of psychotherapy and antidepressive treatment on cognitive functions in patients treated for depression. Psychiatr Danub. 2012;24(suppl 1):S130 –S134. Pearson Education Inc. Wechsler Memory Scale–Fourth Edition (WMS-IV). http://www.pearsonassessments.com/HAIWEB/ Cultures/en-us/Productdetail.htm?Pid⫽015-8895-800. Accessed June 10, 2013. Solomon BL, Schaaf M, Smallridge RC. Psychologic symptoms before and after parathyroid surgery. Am J Med. 1994;96(2):101–106. McKenna SP, Doward LC, Alonso J, Kohlmann T, Niero M, Prieto L, Wíren L. The QoL-AGHDA: an instrument for the assessment of quality of life in adults with growth hormone deficiency. Qual Life Res. 1999;8(4):373–383. Roman S, Sosa JA. Psychiatric and cognitive aspects of primary hyperparathyroidism. Curr Opin Oncol. 2007;19(1):1–5. Mjåland O, Normann E, Halvorsen E, Rynning S, Egeland T. Regional cerebral blood flow in patients with primary hyperparathyroidism before and after successful parathyroidectomy. Br J Surg. 2003;90(6):732–737. Garg MK, Mahalle N. Calcium homeostasis, and clinical or subclinical vitamin D deficiency— can a hypothesis of “intestinal calcistat” explain it all? Med Hypotheses. 2013;81(2):253–258. Rylander M, Verhulst S. Vitamin D insufficiency in psychiatric inpatients. J Psychiatr Pract. 2013;19(4):296 –300. Annweiler C, Montero-Odasso M, Llewellyn DJ, Richard-Devantoy S, Duque G, Beauchet O. Meta-analysis of memory and executive dysfunctions in relation to vitamin D. J Alzheimers Dis. 2013; 37(1):147–171. Grey A, Lucas J, Horne A, Gamble G, Davidson JS, Reid IR. Vitamin
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 30 September 2014. at 04:57 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2013-3115
jcem.endojournals.org
D repletion in patients with primary hyperparathyroidism and coexistent vitamin D insufficiency. J Clin Endocrinol Metab. 2005; 90:2122–2126. 31. Macfarlane DP, Yu N, Donnan PT, Leese GP. Should ’mild primary hyperparathyroidism’ be reclassified as ’insidious’: is it time to reconsider? Clin Endocrinol (Oxf). 2011;75(6):730 –737. 32. Mihai R, Sadler GP. Pasieka’s parathyroid symptoms scores correlate with SF-36 scores in patients undergoing surgery for primary hyperparathyroidism. World J Surg. 2008;32(5):807– 814. 33. Ramakant P, Verma AK, Chand G, et al. Salutary effect of parathyroidectomy on neuropsychiatric symptoms in patients with primary hyperparathyroidism: evaluation using PAS and SF-36v2 scoring systems. J Postgrad Med. 2011;57(2):96 –101.
55
34. Young Diabetologists & Endocrinologists Forum (YDEF). UK National Primary Hyperparathyroidism Audit. http://www.youngdiabetologists. org/pthaudit/ydfhpthaudit. Accessed June 9, 2013. 35. Zanocco K, Heller M, Sturgeon C. Cost-effectiveness of parathyroidectomy for primary hyperparathyroidism. Endocr Pract. 2011; 17(suppl 1):69 –74. 36. Gracie D, Hussain SS. Use of minimally invasive parathyroidectomy techniques in sporadic primary hyperparathyroidism: systematic review. J Laryngol Otol. 2012;126(3):221–227. 37. Doward LC, Meads DM, Thorsen H. Requirements for quality of life instruments in clinical research. Value Health. 2004;7(suppl 1):S13–S16.
All members have access to The Endocrine Legacy – an online journal archive of all articles from 2011 back to Volume 1, Issue 1. www.endocrine.org/legacy
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 30 September 2014. at 04:57 For personal use only. No other uses without permission. . All rights reserved.
i n
C l i n i c a l
F E A T U R E
E n d o c r i n o l o g y
What Is the Best Way of Assessing Neurocognitive Dysfunction in Patients With Primary Hyperparathyroidism? Paul Grant and Anand Velusamy Diabetes and Endocrine Day Centre (P.G.), St Thomas’ Hospital, London SE1 7EH, United Kingdom; and Department of Diabetes and Endocrinology (A.V.), Royal Sussex County Hospital, Brighton BN2 5BE, United Kingdom
Context: The patient attending with asymptomatic primary hyperparathyroidism (PHPT) is a common occurrence in the outpatient endocrine setting. Indeed, more than 80% of contemporary PHPT patients are considered asymptomatic at diagnosis. A frequent question in clinical practice is at what stage may the patient be offered curative surgery. This may well relate to the duration and the degree of hypercalcemia, evidence of end-organ effects, and whether clear symptoms may or may not be attributable to the underlying condition. Objective: There are well-recognized psychological and cognitive changes that can occur in the context of PHPT. A challenge for the clinician is to discern to what extent these symptoms may be present (often very close questioning is required) and how to measure and categorize them. Interventions: Assessment can be difficult because patients who have PHPT tend to be more elderly, and they often have other overlapping comorbidities that may cloud the diagnosis. A decision then has to made as to whether such symptoms are likely to be a result of prolonged hypercalcemia, to what extent they can be attributed to the underlying disease, and whether they constitute sufficient weight to warrant surgical intervention in an otherwise “asymptomatic” patient. Practice tends to vary, and some clinicians may undertake watchful waiting or conservative management, whereas others may more readily push for surgical parathyroidectomy as a definitive treatment. We reviewed the literature on the subject of neuropsychological testing in the management of PHPT. Positions: A controversy in clinical endocrinology is how to assess the cognitive, quality of life, and psychological effects of hypercalcemia. Multiple tools are being used, and significant changes have often been demonstrated in such parameters after parathyroidectomy. Conclusions: We reviewed the latest studies on this subject and assessed the usefulness and validity of such tools in clinical practice, identifying several scores and measures that have been validated in clinical practice; comparisons are made with similar assessments such as the Adult Growth Hormone Deficiency Assessment questionnaire. (J Clin Endocrinol Metab 99: 49 –55, 2014)
ones, stones, abdominal groans, and psychic moans” used to be the classic description of the patient with persistent hypercalcemia due to primary hyperparathyroidism (PHPT), and it is one of the commonly remembered adages from medical school for many clini-
“B
cians. However, since the 1960s and the introduction of more sensitive, multichannel autoanalyzers, the detection of hypercalcemia consequent to PTH excess is far more frequently uncovered as a coincidental finding. Subsequently, the patient attending with asymptomatic PHPT is
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by The Endocrine Society Received August 12, 2013. Accepted October 29, 2013. First Published Online November 7, 2013
Abbreviations: PAS, Parathyroid Assessment Score; PHPT, primary hyperparathyroidism; RCT, randomized controlled trial; SF-36, Short Form 36-Item Health Survey.
doi: 10.1210/jc.2013-3115
J Clin Endocrinol Metab, January 2014, 99(1):49 –55
jcem.endojournals.org
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 30 September 2014. at 04:57 For personal use only. No other uses without permission. . All rights reserved.
49
50
Grant and Velusamy
Neurocognitive Dysfunction in HPT
Table 1. Questions for Patients With Suspected PHPT (Adapted From Pasieka et al [2]) Easy fatigability Myalgia or bone pains Mood swings Feeling “blue” or depressed Abdominal pains/cramps Feeling weak Headaches Feeling irritable Being forgetful Difficulty getting out of a car or chair
a common occurrence in the outpatient endocrine setting. Indeed, more than 80% of contemporary PHPT patients are considered asymptomatic at diagnosis (1). A frequent question in clinical practice is, therefore, at what stage may the patient be offered curative surgery. This may well relate to the duration and the degree of hypercalcemia, evidence of end-organ effects, and whether clear symptoms may or may not be attributable to the underlying condition (Table 1).
Psychological Disturbance and Neurocognitive Dysfunction Calcium is known to be critical to neurotransmitter function, and elevations in plasma calcium levels have been postulated to affect cerebral function either directly or indirectly (3). There are well-recognized psychological and cognitive changes that can occur in the context of PHPT. The exact mechanisms involved remain unclear. Features include fatigue, depression (ranging from feeling low to full blown depression), anxiety, emotional lability, and sleep disturbance. Cognitive features may be more subtle and run the spectrum of intellectual weariness from feeling “muzzy headed,” to memory impairment and poor concentration, to significant impairment on mental test scores. Examples include: difficulties in direct memory, decreased nonverbal learning processes, impaired verbal fluency, and visual-constructive abilities (4, 5). A challenge for the clinician is to discern to what extent these symptoms may be present (often very close questioning is required) and how to measure and categorize them. Assessment can be difficult because patients who have PHPT tend to be more elderly and they often have other overlapping comorbidities that may cloud the diagnosis. Because PHPT has its highest incidence in the sixth and seventh decades of life, the patient’s problems may be dismissed as part of the normal aging process, menopause, or “chronic fatigue” (6). A decision then has to made as to whether such symptoms are likely to be a result of prolonged hypercalcemia, to what extent they can be attrib-
J Clin Endocrinol Metab, January 2014, 99(1):49 –55
uted to the underlying disease, and whether they constitute sufficient weight to warrant surgical intervention in an otherwise “asymptomatic” patient. Practice tends to vary, and some clinicians may undertake watchful waiting or conservative management, whereas others may more readily push for surgical parathyroidectomy (PTX) as a definitive treatment.
The 2009 Third International Workshop Guidelines on the Management of Asymptomatic Primary Hyperparathyroidism Consensus guidelines produced in 2009 looked at the available evidence and included a discussion of the value of screening for and assessing the neurocognitive changes in the context of asymptomatic PHPT (7). Studies on the cognitive and psychological aspects of PHPT, including functional magnetic resonance imaging studies, were reviewed (8, 9). It is already known that the brains of patients with PHPT are different when looked at using functional imaging. Regional blood flow changes and prefrontal cortical activation are apparent, and these patterns alter after surgical PTX (5). The workshop members recognized that there were inconsistencies in the abnormalities described, data on their precise nature, the degree of association with the underlying condition, and also the extent to which neurocognitive problems were remediable after surgical PTX (6, 10). Ultimately, it was felt at the time that psychological and cognitive aspects of PHPT were not considered to be an indication for surgery (4, 7, 11). We revisit this aspect of PHPT in light of additional research that has subsequently become available.
Specific Research There have been several studies looking at changes in mental health status and cognition in PHPT both before and after surgery. Most research has evaluated psychological symptoms such as anxiety, depression, or quality of life. Observational studies have demonstrated improvements in symptoms and quality of life after PTX (when compared with controls) (12, 13). There have been three good randomized controlled trials (RCTs) to date investigating the influence of PTX on quality of life and psychological factors in the context of “mild” PHPT which, despite relatively small numbers of participants being randomized (range, 50 –191) and limited follow-up (approximately 2 y), have provided some valuable information (Table 2).
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 30 September 2014. at 04:57 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2013-3115
Table 2. Examples of Quality of Life Questions From SF-36 —Mental Components of Health (14) During the past 4 weeks, have you had any of the following problems with your work or other regular activities as a result of any emotional problems (such as feeling depressed or anxious)? A. Cut down the amount of time you spent on work or other activities? (Y/N) B. Accomplished less than you would like? (Y/N) C. Didn’t do work or other activities as carefully as usual? (Y/N) How did you feel and how have things been with you during the past 4 weeks? For each of the questions please give one answer that comes closest to the way that you have been feeling (all of the time/most of the time/a good bit of the time/some of the time/a little of the time/none of the time). A. Did you feel full of pep? B. Have you been a very nervous person? C. Have you felt so down in the dumps that nothing could cheer you up? D. Have you felt calm and peaceful? E. Did you have a lot of energy? F. Have you felt down-hearted and blue? G. Did you feel worn out? H. Have you been a happy person? I. Did you feel tired?
In the Henry Ford PHPT study by Talpos et al (15), 53 patients with PHPT were followed for 2 years, and quality of life, including both physical and psychological wellbeing, was assessed using the Short Form 36-Item (SF36) Health Survey and Symptom Checklist 90 (SCL90R) scale. PTX leads to a significant improvement in social functioning and emotional role function, two parameters of the SF-36, and it is also associated with a reduction in anxiety and phobia compared with the observation group. In the similar-sized study of Ambrogini et al (16) (n ⫽ 50), similar assessments were made, with no differences between controls at baseline. At 6 months and 1 year after PTX, no change was seen in social functioning and emotional role function, but there were improvements in general health, vitality, mental health, and bodily pain in the surgical group, demonstrating a significant difference between the two groups at that stage. In the largest RCT to date, 191 individuals with PHPT not meeting 2002 National Institutes of Health criteria for surgery were randomized to PTX or medical observation in a multicenter Scandinavian study (17). Participants had lower scores in all eight domains of the SF-36, as well as more psychological symptoms on the Comprehensive Psychopathological Rating Scale (CPRS), compared with a demographically matched population. However, there was no clear improvement after PTX at 2 years, although SF-36-reported physical function was reduced in the observation group.
jcem.endojournals.org
51
With regard to cognition, there have been multiple studies looking at changes in patterns of intellectual functioning before and after PTX. A good example is the work of Roman et al (18) who in 2005 undertook a prospective study of patients with PHPT and used a battery of psychometric and neurocognitive instruments to assess whether learning, memory, or concentration improved after PTX (n ⫽ 55). Patients with PHPT improved significantly in terms of both psychological scores but also in cognitive domains such as spatial learning and spatial working memory (5, 19). This was supported by a study undertaken by Babinska et al (4), which was the first to use a battery of neuropsychological tests to evaluate cognitive disturbances in PHPT in relation to calcium levels before and after surgery. All patients were tested before PTX and at the 12- to 18-month stage, and they demonstrated that in the presurgery patient group there were obvious impairments in concentration, decreased nonverbal learning processes, difficulties in using direct memory, verbal fluency, and visual-constructive abilities and memory. Postoperatively, there were significant improvements in visual memory, direct memory, and visual-constructive abilities. The best tests to pick up and highlight these changes were found to be the Memory Verbal Learning Test (DCS), the Benton Visual Retention Test (BVRT), and the Trail Making Test (TMT). Problems with studies in this area are multiple: they may arbitrarily select only a few areas relating to cognitive function, they tend to use only small sample sizes, there is a lack of control groups and no allowance for differences in demographics are made, the studies feature a paucity of validated cognitive measures, there are differences in the timing of assessments relative to PTX, and whereas it is apparent that there is a degree of cognitive impairment relative to matched, normal populations, one confounder that is significant and rarely, if ever, taken into account is that of the recognized impact of psychological symptoms upon cognition, which is very important because anxiety and depression affect cognitive function independently (20, 21). Walker et al (6) designed an interventional study to overcome this issue and demonstrated that at baseline patients with PHPT had much higher scores for depression and anxiety symptoms (measured using the Beck Depression Inventory [BDI] and the State-Trait Anxiety Inventory [STAI-Y]) as well as poorer performance on cognitive tests of verbal memory (Wechsler Memory Scale [WMS] Logical Memory Test, Russell revision; and the Buschke Selective Reminding Test [SRT]) and nonverbal abstraction (Booklet Category Test [BCT]). After PTX, symptoms of depression, scores of nonverbal abstraction, and some aspects of verbal memory improved to the extent that they
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 30 September 2014. at 04:57 For personal use only. No other uses without permission. . All rights reserved.
52
Grant and Velusamy
Neurocognitive Dysfunction in HPT
Figure 1. Wechsler Memory Scale.
became no different from the control group. Importantly, they showed that baseline differences and postoperative changes in measurements of cognition were independent of the anxiety and depression scores and not linearly related with plasma concentrations of corrected calcium or PTH.
J Clin Endocrinol Metab, January 2014, 99(1):49 –55
test is untimed, and the results are professionally scored by form, shape, pattern, and arrangement on the paper (Figure 3). In summary, it is well recognized that asymptomatic PHPT is associated with worse performance in certain cognitive domains such as verbal memory and nonverbal abstraction. This is independent of psychological factors; there is improvement in both elements after PTX, and this is supported by several studies. This may well explain the improved sense of well-being and quality of life that many, but not all, patients experience after surgery (23).
Discussion Examples of Cognitive Test Questions The Wechsler Memory Scale is a neuropsychological test designed to measure different memory functions in a person (22). The patient is presented with a grid containing objects followed by a blank grid. The task is to then recall and reproduce the design and location of the objects from the initial grid (Figure 1). The Buschke Selective Reading Test involves reading the subject a list of 12 unrelated words and then having the subject immediately recall as many of these 12 words as possible (Figure 2). The Benton Visual Retention Test measures visual perception and visual memory. The subject is shown 10 designs, one at a time, and asked to reproduce each one as exactly as possible on plain paper from memory. The
Figure 2. Selective Reading Test (Buschke).
Despite the increasing number of studies looking at selected aspects of improved psychological and cognitive functioning of PHPT patients after PTX and successful correction of hypercalcemia, the systematic assessment of these factors does not appear to be routine in clinical practice. Hypercalcemia is recognized to produce neuropsychiatric symptoms, and this has been supported by functional magnetic resonance imaging studies (8, 25, 26). It may also be the case that the confounding factor of vitamin D deficiency, which is frequently associated with hyperparathyroidism, could explain some of the weakness, impaired cognition, low mood, and fatigue associated with the condition (27). Interestingly, vitamin D insufficiency is highly prevalent in psychiatric inpatients, as demonstrated by a 2013 study by Rylander and Verhulst (28). It is not clear whether this is due to severe mental illness and resultant social isolation or whether vitamin D itself has a regulatory role on upstream genes involved in neural networks that influence affect, cognition, and perception. A recent meta-analysis of memory and executive dysfunctions of hypovitaminosis D has shown that it is associated with global cognitive impairment in adults (29). Specifically, results from 14 observational studies and three interventional studies show that lower serum 25hydroxyvitamin D levels predict cognitive impairment, es-
Figure 3. Benton Visual Retention Test.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 30 September 2014. at 04:57 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2013-3115
pecially in terms of such executive domains as mental shifting, information updating, and processing speed. The association with episodic memory per se remains unclear. Vitamin D repletion resulted in improved executive functions. Vitamin D status in PHPT remains a controversial issue in its own right. Secondary hyperparathyroidism due to vitamin D deficiency needs to be identified and corrected (30), and this may well normalize much of the original deranged biochemical milieu in presumed PHPT. However, it is well recognized that low vitamin D levels are a common occurrence in the context of PHPT, as well as in the general population with no abnormalities of calcium metabolism. Generally, researchers who needed to evaluate psychological indicators in PHPT have been concentrating on quality of life questionnaires such as the SF-36. These tend to focus more on symptom-derived aspects of the disease that included limitations due to physical health and pain, but they did not tackle the more subtle dimensions of neurocognitive impairment that may precede overt symptomatic disease. Management guidelines recommend PTX for patients with asymptomatic PHPT in whom evaluation shows endorgan effects that are likely to be mitigated by intervention (eg, reduced bone mineral density, renal impairment, or recurrent nephrolithiasis) or a higher likelihood of disease progression (eg, young age, high PTH titer). Neurocognitive dysfunction has traditionally not been included as an indication for PTX because of inconsistent data on its precise nature and extent, the association with the underlying disease, and its potential reversibility (7, 31). Problems with studies in this area relate to small sample sizes, their observational rather than RCT-based nature, the inclusion of symptomatic patients, the short duration of comparison before and after surgery, and the absence of decent control groups. PTX, even in asymptomatic disease, is expected to provoke an improvement in the quality of life. This has been shown, as outlined above, by using the SF-36 questionnaire; however, its interpretation can be difficult in routine clinical practice because not all of the components are relevant to PHPT. The introduction of specific tools to assess symptoms relating to surgical outcomes, eg, the 2002 Pasieka Parathyroid Assessment Score (PAS) (2), has been useful. This is a 13-item well-validated questionnaire developed to assess symptoms on a visual analog scale. Mihai and Sadler (32) and Ramakant et al (33) have undertaken prospective studies in populations of patients undergoing PTX surgery (101 and 42 patients, respectively) to evaluate and compare the PAS questionnaire vs the SF-36. They both found strong correlation between the two tests and, because PAS allows faster and easier anal-
jcem.endojournals.org
53
ysis, have advocated that it should be incorporated into the routine assessment of patients with PHPT as a reliable tool to identify symptomatic changes that correlate with improved quality of life. Contrast this with another assessment tool that we are familiar with using in clinical endocrinology (the Adult Growth Hormone Deficiency Assessment [AGHDA] questionnaire, the results of which provide a validated foundation for treatment), and one could argue that an assessment tool that encompasses all the aspects of neurocognitive dysfunction (psychological morbidity, healthrelated quality of life, and cognition impairment) would be very valuable for this gray area of clinical practice. It would appear, therefore, that the most relevant and consistently useful tests to determine the effects of PHPT in asymptomatic patients are the specific elements of the SF-36 (as exemplified by the PAS), BDI, STAI-Y, DCS, BVRT, and the memory test scales (both verbal and visual memory). A composite of these measures needs to be applied to clinical practice and evaluated in relation to both medical and surgical interventions. Such a composite should be validated and refined to allow ease of use in the outpatient setting and ultimately be an aid to decision-making and a supportive guide for the use of PTX or the commencement of calcimimetic medication.
Conclusions To ignore the potential impact of neurocognitive dysfunction in patients with PHPT may be a disservice to our patients. Similar to the way in which the term “mild” diabetes has been dropped because patients were eventually shown to have significant morbidity, perhaps the time has come to stop using the prefix “mild” with regard to PHPT. Alternative terms such as “insidious” could be used, or the use of a precursor could be abandoned altogether (31). PHPT is associated with cognitive deficits, problems with processing, and psychological issues that improve after PTX. Although longer follow-up is necessary, neurocognitive symptoms should arguably be considered as criteria for PTX. An issue that arose from the 2009 guidelines was that it was very difficult on some dimensions to reach a true consensus. There is diversity of opinion and practice globally. A national audit of UK clinical practice is currently under way, using the Third International Workshop as a guide; it will be interesting to see to what extent endocrine centers are undertaking assessments of psychological and cognitive factors as part of their management (34).
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 30 September 2014. at 04:57 For personal use only. No other uses without permission. . All rights reserved.
54
Grant and Velusamy
Neurocognitive Dysfunction in HPT
Medical treatments are now available that could also be used to explore whether they improve the outcomes for patients with “insidious” PHPT. Newer operative techniques have made surgery less invasive, faster, with fewer complications, and with greater relative cost-effectiveness. Indeed, recent studies of the impact of PTX suggest that this is a cost-effective strategy for both day case and inpatient surgery in patients with a life expectancy greater than 5 and 6.5 years, respectively (35, 36). In addition to a practice audit, a large RCT of treatment in “mild” or “insidious” PHPT is urgently required, with both surgical and medical interventions, so that more attention can be paid to the subtle issue of neurocognitive dysfunction (24, 37).
J Clin Endocrinol Metab, January 2014, 99(1):49 –55
10.
11.
12.
13.
14. 15.
Acknowledgments 16.
The authors thank Professor Richard Eastell, Dr Paul Carroll, and Derek Lington. Address all correspondence and requests for reprints to: Paul Steven Grant, MBBS, MSc, MRCP, Consultant Endocrinologist, St Thomas’ Hospital, Department of Endocrinology, Westminster Bridge Road, London SE1 7EH, United Kingdom. E-mail: [email protected]. Disclosure Summary: The authors have nothing to disclose.
17.
18.
19.
References 1. Yu N, Leese GP, Smith D, et al. The natural history of treated and untreated primary hyperparathyroidism: the Parathyroid Epidemiology and Audit Research Study. QJM. 2011;104:513–521. 2. Pasieka JL, Parsons LL, Demeure MJ, et al. Patient-based surgical outcome tool demonstrating alleviation of symptoms following parathyroidectomy in patients with primary hyperparathyroidism. World J Surg. 2002;26:942–949. 3. Imbrici P, Camerino DC, Tricarico D. Major channels involved in neuropsychiatric disorders and therapeutic perspectives. Front Genet. 2013;4:76. 4. Babin´ska D, Barczyn´ski M, Stefaniak T, et al. Evaluation of selected cognitive functions before and after surgery for primary hyperparathyroidism. Langenbecks Arch Surg. 2012;397(5):825– 831. 5. Roman SA, Sosa JA, Pietrzak RH, et al. The effects of serum calcium and parathyroid hormone changes on psychological and cognitive function in patients undergoing parathyroidectomy for primary hyperparathyroidism. Ann Surg. 2011;253(1):131–137. 6. Walker MD, McMahon DJ, Inabnet WB, et al. Neuropsychological features in primary hyperparathyroidism: a prospective study. J Clin Endocrinol Metab. 2009;94(6):1951–1958. 7. Bilezikian JP, Khan AA, Potts JT Jr; Third International Workshop on the Management of Asymptomatic Primary Hyperthyroidism. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. J Clin Endocrinol Metab. 2009;94(2):335–339. 8. Perrier ND, Coker LH, Rorie KD, et al. Preliminary report: functional MRI of the brain may be the ideal tool for evaluating neuropsychologic and sleep complaints of patients with primary hyperparathyroidism. World J Surg. 2006;30(5):686 – 696. 9. Perrier ND, Balachandran D, Wefel JS, et al. Prospective, random-
20.
21.
22.
23. 24.
25. 26.
27.
28. 29.
30.
ized, controlled trial of parathyroidectomy versus observation in patients with “asymptomatic” primary hyperparathyroidism. Surgery. 2009;146(6):1116 –1122. Rubin MR, Bilezikian JP, McMahon DJ, et al. The natural history of primary hyperparathyroidism with or without parathyroid surgery after 15 years. J Clin Endocrinol Metab. 2008;93:3462–3470. Silverberg SJ, Bilezikian JP, Bone HG, Talpos GB, Horwitz MJ, Stewart AF. Therapeutic controversies in primary hyperparathyroidism. J Clin Endocrinol Metab. 1999;84(7):2275–2285. Vestergaard P, Mosekilde L. Cohort study on effects of parathyroid surgery on multiple outcomes in primary hyperparathyroidism. BMJ. 2003;327:530 –534. Weber T, Eberle J, Messelhäuser U, et al. Parathyroidectomy, elevated depression scores, and suicidal ideation in patients with primary hyperparathyroidism: results of a prospective multicenter study. JAMA Surg. 2013;148(2):109 –115. QualityMetric Inc. The Short-Form 36 Health Survey. http:// www.sf-36.org/. Accessed June 10, 2013. Talpos GB, Bone HG 3rd, Kleerekoper 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(6):1013–1020; discussion 1020 –1021. Ambrogini E, Cetani F, Cianferotti L, et al. Surgery or surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial. J Clin Endocrinol Metab. 2007;92(8): 3114 –3121. Bollerslev J, Jansson S, Mollerup CL, et al. Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective, randomized trial. J Clin Endocrinol Metab. 2007;92:1687–1692. Roman SA, Sosa JA, Mayes L, et al. Parathyroidectomy improves neurocognitive deficits in patients with primary hyperparathyroidism. Surgery. 2005;138(6):1121–1128; discussion 1128 –1129. Thomas DC, Roman SA, Sosa JA. Parathyroidectomy in the elderly: analysis of 7313 patients. J Surg Res. 2011;170(2):240 –246. Joborn C, Hetta J, Lind L, Rastad J, Akerström 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(1):72–78. Klasik A, Krysta K, Krzystanek M. Impact of psychotherapy and antidepressive treatment on cognitive functions in patients treated for depression. Psychiatr Danub. 2012;24(suppl 1):S130 –S134. Pearson Education Inc. Wechsler Memory Scale–Fourth Edition (WMS-IV). http://www.pearsonassessments.com/HAIWEB/ Cultures/en-us/Productdetail.htm?Pid⫽015-8895-800. Accessed June 10, 2013. Solomon BL, Schaaf M, Smallridge RC. Psychologic symptoms before and after parathyroid surgery. Am J Med. 1994;96(2):101–106. McKenna SP, Doward LC, Alonso J, Kohlmann T, Niero M, Prieto L, Wíren L. The QoL-AGHDA: an instrument for the assessment of quality of life in adults with growth hormone deficiency. Qual Life Res. 1999;8(4):373–383. Roman S, Sosa JA. Psychiatric and cognitive aspects of primary hyperparathyroidism. Curr Opin Oncol. 2007;19(1):1–5. Mjåland O, Normann E, Halvorsen E, Rynning S, Egeland T. Regional cerebral blood flow in patients with primary hyperparathyroidism before and after successful parathyroidectomy. Br J Surg. 2003;90(6):732–737. Garg MK, Mahalle N. Calcium homeostasis, and clinical or subclinical vitamin D deficiency— can a hypothesis of “intestinal calcistat” explain it all? Med Hypotheses. 2013;81(2):253–258. Rylander M, Verhulst S. Vitamin D insufficiency in psychiatric inpatients. J Psychiatr Pract. 2013;19(4):296 –300. Annweiler C, Montero-Odasso M, Llewellyn DJ, Richard-Devantoy S, Duque G, Beauchet O. Meta-analysis of memory and executive dysfunctions in relation to vitamin D. J Alzheimers Dis. 2013; 37(1):147–171. Grey A, Lucas J, Horne A, Gamble G, Davidson JS, Reid IR. Vitamin
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 30 September 2014. at 04:57 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2013-3115
jcem.endojournals.org
D repletion in patients with primary hyperparathyroidism and coexistent vitamin D insufficiency. J Clin Endocrinol Metab. 2005; 90:2122–2126. 31. Macfarlane DP, Yu N, Donnan PT, Leese GP. Should ’mild primary hyperparathyroidism’ be reclassified as ’insidious’: is it time to reconsider? Clin Endocrinol (Oxf). 2011;75(6):730 –737. 32. Mihai R, Sadler GP. Pasieka’s parathyroid symptoms scores correlate with SF-36 scores in patients undergoing surgery for primary hyperparathyroidism. World J Surg. 2008;32(5):807– 814. 33. Ramakant P, Verma AK, Chand G, et al. Salutary effect of parathyroidectomy on neuropsychiatric symptoms in patients with primary hyperparathyroidism: evaluation using PAS and SF-36v2 scoring systems. J Postgrad Med. 2011;57(2):96 –101.
55
34. Young Diabetologists & Endocrinologists Forum (YDEF). UK National Primary Hyperparathyroidism Audit. http://www.youngdiabetologists. org/pthaudit/ydfhpthaudit. Accessed June 9, 2013. 35. Zanocco K, Heller M, Sturgeon C. Cost-effectiveness of parathyroidectomy for primary hyperparathyroidism. Endocr Pract. 2011; 17(suppl 1):69 –74. 36. Gracie D, Hussain SS. Use of minimally invasive parathyroidectomy techniques in sporadic primary hyperparathyroidism: systematic review. J Laryngol Otol. 2012;126(3):221–227. 37. Doward LC, Meads DM, Thorsen H. Requirements for quality of life instruments in clinical research. Value Health. 2004;7(suppl 1):S13–S16.
All members have access to The Endocrine Legacy – an online journal archive of all articles from 2011 back to Volume 1, Issue 1. www.endocrine.org/legacy
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 30 September 2014. at 04:57 For personal use only. No other uses without permission. . All rights reserved.
