Title: Neuropsychological Features in Primary Hyperparathyroidism ...

Introduction
Classical PHPT was a symptomatic disease with commonly recognized neurologic, cognitive and
psychiatric manifestations (1, 2). Many patients with PHPT are now asymptomatic or report only non-
specific symptoms, including weakness, easy fatigability, depression, intellectual weariness, loss of initiative,
anxiety, irritability, and sleep disturbance (3). While these symptoms are concerning, they are difficult to
quantify and there is debate about whether they are directly attributable to the underlying disease. At the
Third International Workshop on Asymptomatic Primary Hyperparathyroidism (4), studies on the
psychological and cognitive features of PHPT were reviewed and not considered to be an indication for
parathyroidectomy (5). The workshop recognized inconsistencies in the abnormalities described, their
association with the underlying disease, and the extent to which these features were reversible after
parathyroidectomy.
A number of studies have attempted to delineate the psychological and cognitive features of PHPT,
and their resolution with surgical cure (6-24). Most have focused on psychological symptoms, such as
depression, anxiety, or quality of life (QOL), rather than cognitive function such as logic, memory,
abstraction, attention/concentration, and mental manipulation. Most have suggested that there are
psychological features of the disease. A number of observational studies, some without control groups, report
improved psychological symptoms or QOL with parathyroidectomy. Findings of the 3 randomized controlled
trials (RCTs) of parathyroidectomy in mild PHPT were inconsistent; two found improved QOL after surgery
(18, 25) while one did not (17).
A smaller number of studies have examined cognitive function in PHPT (6, 9, 12, 14, 15, 26-28).
Explanations for the conflicting results from these studies include: small sample sizes; investigation of only
one or two aspects of cognition, making generalization difficult; lack of control groups or validated measures
in some studies and failure to take into account demographic differences in others. Some studies monitored
subjects shortly after parathyroidectomy, an experimental design which introduces biases due to non-specific
benefits of surgery. Finally, no studies examining cognitive function have assessed the influence of
3