Calcimimetic Agent Resolves Cognitive Deficits and Psychotic Symptoms in an Older Patient with Primary Hyperparathyroidism
A 72-year-old female in previously good health was admitted electively to an inpatient geriatric psychiatry unit for evaluation and treatment of a one-year history of anxiety, paranoid delusions, hallucinations, confusion, and memory loss. She had no history of prior psychiatric problems or psychiatric treatment of any kind. According to her children, the first change in her behavior was the onset of hoarding. Shortly after she began hoarding, family members observed that she was becoming withdrawn, displaying odd behaviors, and verbalizing paranoid thoughts, including beliefs of “people hiding under the car,” and “terrorists targeting me.” She had started ignoring necessary household upkeep, including paying bills, and had become generally more confused and forgetful. She had worked for over 20 years in the local post office as a letter sorter, but her psychiatric symptoms interfered with her work to the extent that she was forced into retirement after an employer-mandated psychiatric evaluation determined that she had a psychiatric illness incompatible with ongoing employment. The day prior to admission, she had spent most of the day in bed crying, although she denied depressed mood when questioned.
Evaluations by her primary care physician and a neurologist included a normal metabolic panel, normal hematology panel, normal thyroid function tests, and normal urinalysis. A magnetic resonance imaging scan of the brain and a positron emission tomography scan were performed, and neither revealed any significant abnormal findings. Her past medical history included ablation for Wolff-Parkinson-White syndrome, a prior Bell’s palsy with some residual left-sided facial droop, hypertension, osteoporosis, and a thyroid disorder of unclear nature. The patient did not smoke, drink alcohol, or use recreational drugs. Her medications included lisinopril and alendronate. She had not been prescribed psychotropic medications for her current symptoms.
As part of the standard admission evaluation for patients admitted to the unit, a geriatric internal medicine consultation was obtained. The patient appeared well-hydrated with stable vital signs, and the remainder of her physical examination was notable for a residual left facial droop and a systolic ejection murmur at the base of the heart, consistent with a flow murmur.
The patient’s mental status examination at admission revealed a disheveled appearance, the wearing of large, darkly tinted sunglasses in a dimly lit room, inappropriate laughter in response to what appeared to be internal stimuli, and the verbalization of a belief that there were strange men following her. The patient scored 25 out of 30 on the Folstein Mini-Mental State Examination (MMSE),1 missing three on delayed recall and two on orientation. Neuropsychological testing was attempted shortly after admission but was limited by the patient’s thought disorder and other behavioral symptoms. A Mattis Dementia Rating Scale2 was successfully administered, however, and the patient scored 129 out of a maximum possible score of 144 points, which was consistent with moderate cognitive impairment.
Repeat diagnostic studies revealed a normal hematological panel, normal urinalysis, normal thyroid function tests, normal liver function tests, and a normal metabolic panel, with the exception of a slightly elevated calcium level of 11.0 mg/dL (normal range, 8.8-10.3 mg/dL) with an albumin of 3.7 g/dL (normal range, 3.3-5.0 g/dL). Review of the outpatient medical evaluation showed a calcium level of 10.4 mg/dL (normal range, 8.5-10.6 mg/dL). A repeat calcium level was 10.5 mg/dL, and an ionized calcium level was elevated at 5.73 mg/dL (1.43 mol/L normal range, 4.53-5.29 mg/dL [1.13-1.32 mol/L]).
Further work-up of her hypercalcemia revealed a parathyroid hormone level of 99 pg/mL (normal range, 10-66 pg/mL). Evaluations for other etiologies of hypercalcemia were nondiagnostic, including a normal parathyroid hormone-related protein level, a normal vitamin D 1,25 level, and normal thyroid function. In addition, recent prior cancer screening identified no malignancies. The patient’s hypercalcemia was attributed to primary hyperparathyroidism, and a technetium parathyroid scan showing increased tracer activity within the lower pole of the right thyroid was consistent with a parathyroid adenoma. The physicians caring for her concluded that the patient’s psychiatric symptoms were most likely caused by her mild hypercalcemia and hyperparathyroidism.
The prevalence of primary hyperparathyroidism in people older than age 65 years in the United States is estimated to be as high as 1.5%, and symptoms can include nephrolithiasis, renal failure, and osteoporosis.3,4 Psychiatric symptoms and cognitive changes also have long been reported as a manifestation of primary hyperparathyroidism and span a wide gamut that includes depression, anxiety, psychosis, and cognitive symptoms.5-8 While the true incidence of neuropsychiatric symptoms in patients with primary hyperparathyroidism is unknown, it is estimated that over half of such patients may have cognitive complaints.9 Prior reports suggest that the level of psychiatric symptoms may not correlate to the degree of calcium elevation.6,9
It is unclear how primary hyperparathyroidism leads to neuropsychiatric disturbances. One study evaluated the cerebrospinal fluid of 22 patients with primary hyperparathyroidism and found elevated levels of calcium and parathyroid hormone, along with decreased levels of monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA).10 After the patients underwent parathyroidectomy, a repeat lumbar puncture was performed, which showed a normalization of calcium, parathyroid hormone, 5-HIAA, and HVA. These findings suggest that changes in neurotransmitter signaling may be responsible for the neurocognitive symptoms associated with primary hyperparathyroidism. Receptors for parathyroid hormone have been previously shown in brain tissue, thus providing another possible mechanism by which parathyroid hormone could influence neuronal metabolism and physiology, perhaps via alterations in local cerebral calcium regulation.11
Parathyroidectomy remains the definitive therapy for treatment of primary hyperparathyroidism. Past studies utilizing various psychiatric and cognitive assessment methods have shown some improvement in depression, anxiety, concentration, and memory,4,12-15 while others have failed to show benefit in these areas following parathyroidectomy.16-18 Due to the lack of specificity of neuropsychiatric symptoms and the reports of inconsistent therapeutic benefit from parathyroidectomy, it remains unclear whether patients who have laboratory evidence of primary hyperparathyroidism that temporally correlates with the appearance of neuropsychiatric symptoms should be diagnosed with “symptomatic” primary hyperparathyroidism or “asymptomatic” primary hyperparathyroidism. The prevailing view is that patients with laboratory evidence of primary hyperparathyroidism and neuropsychiatric symptoms should be diagnosed with “asymptomatic” primary hyperparathyroidism. Current guidelines for asymptomatic primary hyperparathyroidism do not list neuropsychiatric symptoms as a sole indication for parathyroidectomy (Table).19,20 While bisphosphonates, calcimimetic agents, and hormonal therapies appear to have an effect on calcium levels and nonneuropsychiatric symptoms, currently there are no Food and Drug Administration (FDA)–approved pharmacologic agents for treatment of primary hyperparathyroidism.21
Outcome of the Case Patient
While initiating her diagnostic work-up, the patient was continued on lisinopril and alendronate. She was also prescribed olanzapine at 2.5 mg daily and, in spite of titration to 10 mg daily, she showed little improvement in her psychotic symptoms and behaviors. Head and neck surgery and endocrinology consultations were obtained, and an outpatient surgical parathyroidectomy was recommended on the basis of her osteoporosis. Furthermore, it was recommended that her psychiatric symptoms be stabilized prior to any surgical intervention. As the patient appeared well-hydrated on examination with a calcium level only slightly higher than normal, she did not require intravenous hydration nor diuretic therapy.
After 2 weeks of treatment with olanzapine, the patient continued to have impaired cognition and bizarre thinking. The endocrinology consultation team recommended the addition of cinacalcet, a calcimimetic agent approved for treatment of secondary hyperparathyroidism due to renal failure and hyperparathyroid cancer, and which is currently being investigated for primary hyperparathyroidism.22,23 Cinacalcet works by allosterically activating the calcium-sensing receptor, and thereby down-regulates parathyroid hormone and calcium.24,25 In one multicenter, randomized, double-blinded, placebo-controlled trial of 78 patients with primary hyperparathyroidism, serum calcium and parathyroid hormone levels were decreased in 73% of cinacalcet-treated patients for 12 months as compared to 5% in the placebo group.26 Changes in neuropsychiatric symptoms were not assessed. Cinacalcet has also been used in tertiary hyperparathyroidism. In one case report, a patient with tertiary hyperparathyroidism became overtly hypercalcemic following administration of the vitamin D analogue paricalcitol, and developed acute delirium.27 Subsequent treatment of the hypercalcemia by removal of the offending agent and initiation of treatment with the bisphosphonate pamidronate and cinacalcet proved effective in returning her calcium levels and cognition to baseline.
Within days of starting cinacalcet, the case patient’s calcium level decreased to 9.8 mg/dL, and she experienced a dramatic improvement in her neuropsychiatric symptoms. The family decided to move the patient to an assisted living facility while awaiting outpatient parathyroidectomy. She was discharged on cinacalcet and olanzapine in addition to her regular outpatient medication regimen.
At the time of a 2-week, post-discharge follow-up visit, the patient had complete resolution of her previous neuropsychiatric symptoms, with a MMSE score of 30 out of 30 and no recall of her prior psychotic symptoms. Her affect was appropriate, and she was eager to return to independent living. Repeat laboratory testing showed a normal calcium level of 9.0 mg/dL, with a decreased parathyroid hormone level of 79 pg/mL. The patient underwent successful outpatient parathyroidectomy within a few weeks of the follow-up visit without complication. The cinacalcet and olanzapine were tapered off following her surgery without any re-emergence of psychiatric symptoms. When seen 1 month following surgery, her physical and mental status examinations, including cognition, were normal. Shortly afterwards, she returned to independent living.
Calcium levels are often part of the routine evaluation of delirium and confusional states. Primary hyperparathyroidism is a relatively common disorder among older adults and often, but not invariably, causes significantly elevated serum calcium levels. It is unknown whether cognitive disturbances are directly related to the level of hypercalcemia or some other factor.
Surgical parathyroidectomy remains the definitive treatment for symptomatic hyperparathyroidism. Improvements in neuropsychiatric symptoms related to primary hyperparathyroidism have not been clearly demonstrated with surgical parathyroidectomy. As a result, the current surgical criteria for asymptomatic hyperparathyroidism do not include neuropsychiatric symptoms. To date, there are no FDA-approved medical treatments for primary hyperparathyroidism. The lack of an effective alternative medical treatment in patients who do not meet the current surgical criteria creates a treatment dilemma.
We present the case of an older woman with primary hyperparathyroidism, who presented with atypical mood and anxiety symptoms, confusion, and psychosis. She had an elevated parathyroid hormone level, but only slight elevations in serum calcium and ionized calcium. She was on bisphosponate therapy and did not require intravenous hydration or loop diuretic therapy. An antipsychotic medication provided little benefit for her psychiatric symptoms. It was not until the addition of cinacalcet that improvement in her clinical course was observed. To our knowledge, improvement in neuropsychiatric symptoms in patients with primary hyperparathyroidism treated with calcimimetic agents has not previously been reported. Finally, a parathyroidectomy provided final resolution of her neuropsychiatric symptoms, even in the eventual absence of treatment with a calcimimetic agent or psychotropic medication.
This work was presented at the Annual Scientific Meeting of the American Geriatrics Society, Washington, DC, April 30-May 4, 2008, where it received the “Presidential Poster Award” in the Case Studies Category. The work was supported, in part, by grants from the National Institute of Mental Health, Department of Veterans Affairs, and the John A. Hartford Foundation. Dr. Sewell reports that he has received speaker honoraria from and is Chair of the Education Committee for the American Association for Geriatric Psychiatry, is a paid advisory board member for the Healthcare Group, Inc., and is the President of Traveling Educational Presentations, Inc. The other authors report no relevant financial relationships. Drs. Tam and Daly are from the Division of Geriatric Internal Medicine, Department of Internal Medicine, University of California, San Diego, and Dr. Tam is also from the Neurology Service, VA San Diego Health Care System; and Drs. Meeks, Rice, and Sewell are from the Division of Geriatric Psychiatry, Department of Psychiatry, University of California, San Diego.
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