Psychosomatics 43:413-417, October 2002
© 2002 The Academy of Psychosomatic Medicine
New Onset of Neuropsychiatric Symptoms in the Elderly: Possible Primary Hyperparathyroidism
Lea C. Watson, M.D., and
Christine E. Marx, M.A., M.D.
Received Nov. 6, 2001; revision received March 8, 2002; accepted April 2, 2002. From the Department of Psychiatry, University of North Carolina at Chapel Hill. Address reprint requests to Dr. Watson, Robert Wood Johnson Clinical Scholars Program, UNC Department of Psychiatry, 5034 Old Clinic Building, Chapel Hill, NC 27599-7105; lea_watson{at}unc.edu (e-mail).
ABSTRACT
Primary hyperparathyroidism is a disorder of calcium homeostasis that occurs most commonly in older adults. Resultant hypercalcemia may be accompanied by neuropsychiatric symptoms, ranging from mild depression and cognitive changes to extreme agitation and psychosis. Surgical intervention almost invariably reverses these symptoms. The authors reviewed the importance of considering this diagnosis in the setting of neuropsychiatric symptoms in the elderly and reported on a 63-year-old man with mild hypercalcemia and a new onset of psychosis.
Primary hyperparathyroidism is characterized by hypercalcemia, hypophosphatemia, and high levels of parathyroid hormone. In approximately 80% of cases, the etiology of the disorder is a solitary parathyroid adenoma (typically benign), resulting in overproduction of parathyroid hormone, increases in serum calcium, and decreases in serum phosphorus.1 The incidence of primary hyperparathyroidism is believed to be between 0.01% and 0.10%, but in persons over 60 years of age, the incidence may be as high as 0.2%, with a prevalence of 1.0% or greater in this elderly population.1–4 Despite evidence to suggest a possibly greater prevalence of secondary hyperparathyroidism among African Americans due to vitamin D insufficiency, there are no reported differences among races for the prevalence of primary hyperparathyroidism.5 A high level of serum calcium, in combination with elevated levels of parathyroid hormone, is strong evidence for the diagnosis, which is strengthened by a 99mTc-sestamibi scan suggesting an adenoma, and confirmed by surgical neck exploration. Patients may remain asymptomatic for years; historically, patients were diagnosed with primary hyperparathyroidism quite late in the illness course, after renal and skeletal damage had already occurred.3,6,7 Improvements in biochemical screening in the 1970s permitted the detection of calcium levels on a routine basis and greatly enhanced diagnostic sensitivity for the disorder. As a result, the reported incidence of primary hyperparathyroidism increased, and more subtle presentations of the illness were characterized.2,3,6,7 The neuropsychiatric manifestations of primary hyperparathyroidism are incompletely characterized but appear to be relatively common, possibly occurring in more than half of all cases.8–10 The precise mechanisms responsible for the production of these neuropsychiatric symptoms remain unknown, although it has been speculated that high calcium levels are integral to mediating this pathology.
Neuropsychiatric symptoms associated with primary hyperparathyroidism span a range of affective, anxiety, cognitive, and psychotic presentations. The most common neuropsychiatric manifestations of the disorder appear to be depressive symptoms with general apathy and mild cognitive disturbance.10,11 The degree of elevation of calcium levels may be correlated with the level of psychopathology, but this is not always the case,10 and prospective studies are lacking. Paranoid psychosis, delirium, and stupor have also been associated with the hypercalcemia of primary hyperparathyroidism.10,12,13 Surgical removal of the adenoma almost always reverses neuropsychiatric symptoms, making this disease a potentially reversible nonpsychiatric etiology for these complaints, particularly in elderly populations at higher risk for the disorder.1–4,10 The ease of detection of the illness, the striking response to surgical intervention, and the higher incidence in older individuals argue for a vigilant search for this diagnosis in the exclusion of nonpsychiatric etiologies for mental status changes in the elderly. This particular case highlights a new onset of severe psychopathology in a 63-year-old man in the setting of mild hypercalcemia and a high level of parathyroid hormone, with complete reversal of symptoms after surgical intervention.
Case Report
Mr. A, a 63-year-old African American man with no prior psychiatric history, came to the University of North Carolina Hospitals under a commitment initiated by an outlying hospital. His wife of over 40 years had noticed that Mr. A "had not been himself" for 6–8 weeks, had been "getting lost" while driving, and had been "talking strange." Interviews with several family members revealed that Mr. A was uniformly known as a warm, gentle man who rarely angered and enjoyed staying home to care for his grandchildren. His four adult children, who all lived nearby and saw him regularly, also noticed that he was acting quite differently. Four weeks before his admission, Mr. A refused to eat his wife's cooking on several occasions, voicing the paranoid delusion that she was poisoning him. He also accused his young grandchild of "being against him," acting upon this belief by insisting that she get out of the car on a routine trip to the grocery store. As his paranoia worsened, Mr. A's wife arranged for an appointment with his primary care physician. Mr. A fled from this appointment, claiming "everyone was trying to kill me." He hurried home from the physician's office, removed a shotgun from its storage place, and climbed to the roof to defend himself against "people moving in on me." His wife arrived to find Mr. A on the roof, shouting that he would kill her if she came any closer. She and several of her children who were present fled to a neighbor's house and called the police. After the police arrived, Mr. A was subdued without further incident. His shotgun was found to be full of ammunition.
Mr. A was taken to a local community hospital, where a computerized tomography of the brain was found to be normal, as were a CBC, a chemistry panel of seven electrolytes (not including calcium), and urine toxicology tests. Mr. A was transferred to an inpatient psychotic disorders unit for further evaluation. His family accompanied him and provided additional history. Mr. A had never suffered from any psychiatric problems, nor had any of his first-degree family members. He did not use alcohol, illegal drugs, or moonshine. He smoked a half-pack of cigarettes each day and had no history of occupational exposures. Mr. A had worked as a chauffeur and groundskeeper for over 30 years at the same facility before retiring in recent years to assist his wife in taking care of his grandchildren during the day. No relative could identify any recent stressors for the patient, and family members were clearly distraught at his pronounced change. His past medical history was significant for hypertension and gout (infrequent episodes). Mr. A was taking two medications at the time of admission to treat his hypertension—doxazosin mesylate and amlodipine besylate. He had been receiving both of these medicines for several years. Neither Mr. A nor any family members had a history of endocrine abnormalities.
Upon physical examination, Mr. A was a robust man who was alert and oriented, cooperative but rather guarded. His affect was unusual, notably for inappropriate smiling and indifference toward his family members. According to the relatives present, this was very different from his usual demeanor. Mr. A denied the events leading to his admission and provided little additional history. His thoughts appeared mildly confused but generally goal directed and contained paranoid content about people being against him. He reported no suicidal or homicidal ideation and contracted for safety. Despite a degree of disorganization noted during the interview, his Mini-Mental State Examination (MMSE) score on admission was 29 of 30. The patient's blood pressure was high, 190/90; his other vital signs were within normal limits.
Given this presentation of a new onset of psychotic symptoms in an elderly gentleman with no prior psychiatric history, a rigorous search was undertaken to exclude nonpsychiatric etiologies for his symptoms. Results for the following tests were normal at admission: ECG, thyroid-stimulating hormone level, B12 level, urine toxicology screen, erythrocyte sedimentation rate, CBC, and electrolyte levels. His creatinine level was high at 1.8 (0.8–1.4), his calcium level was mildly elevated at 10.8 mg/dl (8.5–10.2), his magnesium level was mildly elevated at 2.4 (1.6–2.2), and his phosphorus level was mildly low at 2.3 (2.4–4.5). A brain magnetic resonance imaging (MRI) study revealed mild cortical atrophy. On the second day of admission, Mr. A's serum calcium level remained mildly high at 10.8, and a parathyroid hormone measurement was ordered. The patient's parathyroid hormone level was determined to be high at 127, consistent with a diagnosis of primary hyperparathyroidism (based on a laboratory nomogram). A single positron emission computerized tomography scan with sestamibi revealed a homogeneous mass in the right midpole of the parathyroid gland, consistent with an adenoma, and a surgical evaluation was requested. Through the course of this investigation, testing also excluded syphilis, HIV, Wilson's disease, pheochromocytoma, heavy metal exposure, multiple myeloma, lung mass, and prostate cancer.
Mr. A did not exhibit dangerous behaviors as an inpatient but remained quite paranoid in his early hospital course. He was given oral risperidone, 0.5 mg b.i.d., to target his psychotic symptoms, and he tolerated a gradual increase in risperidone to a total of 2.0 mg/day during his 7-day hospitalization. Mr. A was evaluated by the endocrine consultation team, who recommended intravenous fluids and diuretics to treat the hypercalcemia. This treatment resulted in the return of the patient's serum calcium to a normal level by the third day of hospitalization. Mr. A was also evaluated for medical management of hypertension (his maximum blood pressure during hospitalization was 200/90), and blood pressure control was optimized with the addition of atenolol and clonidine to his antihypertensive regimen. Since Mr. A had an elevated creatinine level, a renal ultrasound was performed to rule out structural kidney abnormalities; results of this study were negative. Given a B12 level within normal limits but in the low–normal range, the patient was also supplemented with this vitamin. The surgery team was consulted, and nonemergent parathyroid surgery was scheduled for the outpatient setting.
During his 7-day hospital course, Mr. A had a significant reduction in his psychotic symptoms, which appeared to coincide with normalization of his serum calcium level. He contracted for safety throughout his hospitalization. The decision was made to discharge him on the eighth day of hospitalization to live with his family, who promised to provide 24-hour care. Risperidone, 2.0 mg/day, and furosemide, 50 mg/day, were continued, and outpatient parathyroid surgery was scheduled for 2 weeks after discharge. The patient and his family were agreeable to this plan, and relatives removed all firearms from the patient's home.
Six days after his hospital discharge, Mr. A was readmitted after his wife petitioned for his commitment. Mr. A had become progressively more paranoid and was threatening homicide and suicide. He had not been taking his medications. A repeat physical examination revealed a presentation similar to that at his first admission, although he now appeared more disorganized and scored only a 16 of 30 on the MMSE. He became combative and required seclusion shortly after his arrival on the unit. Of note, the patient's calcium level was 11.1 (8.5–10.2) at readmission, his highest recorded serum calcium level to date. Intravenous fluids and furosemide therapy were reinstituted, and his serum calcium normalized to 10.3 by the second day of hospitalization, accompanied by mild improvement in his psychotic symptoms. Risperidone, 2.0 mg/day, had also been restarted at the time of readmission. The patient's blood pressure during this hospitalization was in the 160–190/70–100 range. Surgery was scheduled for 1 week after admission, and Mr. A remained hospitalized on the inpatient psychotic disorders unit until that date. His serum calcium level remained within normal limits with hydration and diuretic treatment. Slow improvement in cognition, affect, and psychotic symptoms continued. His MMSE before surgery was 28 of 30, and at this time Mr. A was beginning to demonstrate insight into the recent course of events. A minimally invasive partial parathyroidectomy was performed without complications. Mr. A was discharged the next day with a normal calcium level and was scheduled to follow up in the psychiatry and surgery outpatient clinics. He continued taking risperidone, but the dose was decreased to 1.0 mg/day, to be continued until his first psychiatric follow-up appointment 12 days later.
At his outpatient psychiatric appointment, the patient's wife described him as "completely back to normal" and said that his return to baseline had occurred within 24 hours after parathyroid surgery. The patient's children were also in agreement with this assessment. In the 12 days after surgery and before his outpatient psychiatry appointment, no unusual behaviors were noted by family members. Mr. A reported no psychotic symptoms at this follow-up visit. His affect was cheerful and open, with no evidence of suspiciousness or paranoia, and his serum calcium level was within normal limits. Mr. A voiced that he was very grateful to "feel myself again," elaborating that although he did not remember the specific violent events leading to his hospitalizations, he recalled being confused and afraid of his family. He was remorseful that he had caused concern and stated that he knew he had not been "thinking straight." In the continuing absence of psychotic symptoms, risperidone was discontinued at his next psychiatric outpatient visit approximately 1 month later. Mr. A was seen for his third outpatient psychiatric follow-up appointment 3 months after his parathyroid surgery, again with a normal serum calcium level. There was no evidence of psychotic symptoms, despite risperidone cessation, and his wife and family continued to concur that the patient had returned to his prior high level of functioning. Mr. A was evaluated psychiatrically at 9 months and again at 1 year after parathyroid surgery. He remained well and completely asymptomatic.
Discussion
We have presented a case of a mildly elevated serum calcium level leading to the diagnosis of primary hyperparathyroidism and successful surgical resection in a 63-year-old man with a new onset of neuropsychiatric symptoms and no prior psychiatric history. Several other options initially emerged in the differential diagnosis. Given evidence of mild atrophy on MRI, a diagnosis of early Alzheimer's dementia with psychotic symptoms was considered. This possibility was believed to be unlikely, however, since the patient continued to function at a very high level, with complete remission of symptoms and no evidence of cognitive decline at the 1-year follow-up. The possibility that hypertensive encephalopathy and borderline B12 deficiency may have played a role in the initial presentation was also considered, but the evolution of symptoms and normalization of blood pressure and B12 level were not correlated. In contrast, serum calcium level was well correlated with the severity of psychiatric symptoms in this patient, and surgical resection resulted in complete remission, strongly suggesting primary hyperparathyroidism as the etiology for the patient's complaints.
Several points emerge from a review of the literature. First, given the curative potential of surgery and the higher incidence of primary hyperparathyroidism in older patients, the routine exclusion of this disorder as an etiology for acute or subacute mental status changes in the elderly may be warranted. Primary hyperparathyroidism may be underdiagnosed in this population, since common manifestations of the disorder, such as apathy, depression, and mild cognitive impairment, may be subtle and potentially attributable to other causes, such as a primary psychiatric disorder or consequences of a vascular event. In addition, it is possible that psychotic symptoms in elderly patients may be ascribed to comorbid vascular or Alzheimer's dementia, potentially excluding other etiologies for psychotic symptoms prematurely. Since patients with dementia are more vulnerable to mild metabolic derangements, this population may be particularly susceptible to neuropsychiatric symptoms related to primary hyperparathyroidism. It may therefore be reasonable to employ a high index of suspicion in the setting of new-onset or worsening affective or psychotic symptoms in this population. Supporting this hypothesis, a reversal of neuropsychiatric symptoms has been demonstrated in elderly patients with dementia and primary hyperparathyroidism, and in some cases a regression of the perceived baseline dementia has been noted.2,14
Second, although the degree of psychopathology appeared to correlate with serum calcium level in this particular patient, it is important to recall that this calcium elevation was relatively modest in scope and not immediately suggestive of metabolic alterations potentially responsible for severe psychopathology. In other words, it appears that even mild hypercalcemia may accompany significant psychiatric morbidity in the setting of primary hyperparathyroidism,9,14,15 suggesting a low threshold for further testing to exclude the disorder in clinical practice. Furthermore, some patients with primary hyperparathyroidism demonstrate elevated ionized serum calcium levels but normal total serum calcium concentrations.3 Ionized serum calcium levels may therefore represent a helpful screening tool for the disorder, followed by parathyroid hormone testing if elevations are detected. It has also been reported that calcium elevations in this disorder may be intermittent, underscoring another potential challenge to expedient diagnosis.3
Finally, there have been reports of paranoid delusions associated with primary hyperparathyroidism very similar to those in this case, leading to completed acts of violence;16–18 therefore, prompt diagnosis may be an urgent matter. Although psychotic symptoms due to primary hyperparathyroidism appear to be less common than affective or cognitive symptoms, they may occur as the sole manifestation of the disorder and lead to dangerous behaviors. This particular case underlines this point, since Mr. A demonstrated severe psychotic pathology as his most prominent psychiatric symptom at initial presentation, threatening his wife and children with a firearm in response to his delusional system.
In conclusion, geriatric practitioners encounter complaints of apathy, depression, cognitive disturbance, and psychosis with great frequency. Since these symptoms commonly accompany primary hyperparathyroidism, it is suggested that routine serum calcium testing at regular intervals, followed by parathyroid hormone determination if indicated, may have clinical use. It is important to consider primary hyperparathyroidism in the differential diagnosis of the elderly patient presenting with neuropsychiatric symptoms, given the higher incidence of hyperparathyroidism in older individuals, the ease of screening for the disorder, and the potential reversibility of symptoms.
ACKNOWLEDGMENTS
Supported by an NIMH grant (MH-65080) (to Dr. Marx) and a grant from the Robert Wood Johnson Clinical Scholars Program (to Dr. Watson).
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W. J. G. Hoogendijk, P. Lips, M. G. Dik, D. J. H. Deeg, A. T. F. Beekman, and B. W. J. H. Penninx
Depression Is Associated With Decreased 25-Hydroxyvitamin D and Increased Parathyroid Hormone Levels in Older Adults
Arch Gen Psychiatry,
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508 - 512.
[Abstract]
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