Salutary effect of parathyroidectomy on neuropsychiatric symptoms in patients with primary hyperparathyroidism: Evaluation using PAS and SF-36v2 scoring systemsP Ramakant, AK Verma, G Chand, A Mishra, G Agarwal, A Agarwal, SK Mishra
Department of Endocrine Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
Correspondence Address: Source of Support: Indian Council of Medical Research, Conflict of Interest: None DOI: 10.4103/0022-3859.81859
Source of Support: Indian Council of Medical Research, Conflict of Interest: None
Background : Indian patients with primary hyperparathyroidism (pHPT) usually present with a triad of advanced disease of bones, stones, and psychic moans. There are hardly any reports from India on the outcome of successful parathyroidectomy on psychiatric symptoms. Aims : To evaluate the outcome of parathyroidectomy on psychiatric symptoms in Indian patients with advanced pHPT. Settings and Design : Prospective study done in a tertiary care super-specialty hospital in northern India. Materials and Methods : Health surveys using parathyroid assessment of symptom score (PAS) and SF-36v2 were carried out, to evaluate the outcome of parathyroidectomy on the psychiatric symptoms of patients. The study included 42 patients of pHPT admitted between November 2007 and December 2009 (two years). Scoring was done preoperatively; and one week, three months, six months, and one year postoperatively. Statistical Analysis Used : SPSS 15 software and nonparametric tests (k Independent Sample test, Kruskal-Wallis H). Results : The mean preoperative PAS score was 430.87 ± 215.61 (range 40 - 880). Statistically significant reduction in scoring was observed postoperatively at one week (293.65 ± 118.31, P < 0.001), three months (109.44 ± 85.09, P < 0.015), six months (70.00 ± 71.65, P 1 < 0.05), and one year (60.10 ± 104.48, P < 0.02). Although the surgery scores for feeling irritability, forgetfulness, difficulty in getting out of chair, headache, and itchy skin did not reduce appreciably at one week, they later showed significant reduction. All other parameters showed significant reduction. The SF-36v2 TM survey also showed significant improvement on all scores except social functioning, while physical functioning improved only after one week. Conclusions : Indian patients with advanced pHPT, after a successful parathyroidectomy, showed significant improvement in their quality of life, as evaluated by the PAS and SF-36v2 systems.
Keywords: Neuropsychiatric symptoms, primary hyperparathyroidism, scoring systems
Indian patients, unlike those in the west, usually present with overtly symptomatic advanced primary hyperparathyroidism (pHPT), with severe skeletal and renal disease, along with neuropsychiatric manifestations. These patients present at a relatively young age, with advanced disease.  Most patients have osteitis fibrosa cystica, fractures, brown tumors, and muscle weakness (parathyroid cripples). Renal manifestations (calculi, nephrocalcinosis) are common. Many have a palpable parathyroid tumor and extremely high s-PTH levels. Severe hypercalcemia is masked due to the coexisting vitamin D deficiency. 
Advanced pHPT in Indian patients leads to a prolonged bed ridden state, and hence, aggravates neuropsychiatric manifestations. Pradeep et al. have studied the long-term improvement in bone and renal disease and other parameters, except the neuropsychiatric manifestations in Indian patients with pHPT.  Hence, a need was felt to conduct a prospective study in Indian patients with advanced pHPT, to objectively document the various neuropsychiatric symptoms with the help of scoring systems designed specifically for such purposes. Greutelaers et al. have assessed the utility of specific tools designed for evaluating the impact of parathyroidectomy on neuropsychiatric symptoms in pHPT patients.  The SF-36v2 TM Health survey is a multipurpose short-form health survey with 36 questions that yield an eight-scale profile of functional health and well-being, as well as two physical and mental health parameters.  It has proved useful in documenting the health benefits provided by a variety of treatment modalities.
In Indian patients there is hardly any data available on the changes in the neuropsychiatric symptoms and quality of life following successful parathyroidectomy. The aim and objectives of our study were to analyze the impact of parathyroidectomy on neuropsychiatric manifestations in Indian patients suffering from advanced pHPT including both short and long term changes post surgery.
From November 2007 to December 2009, a prospective study was conducted on 42 consecutive patients with primary hyperparathyroidism admitted for surgery at a tertiary care hospital in northern India. Pertinent clinical and investigative details, such as, the biochemical, radiological, operative, and histopathological parameters were recorded in a prospective database. All the patients underwent parathyroidectomy either by an open approach or a minimal invasive technique. Patients with concordant imaging with a Tc 99m sestamibi scan and ultrasound of the neck were subjected to minimal invasive parathyroidectomy and those with negative or discordant imaging parameters underwent parathyroidectomy by open bilateral cervical exploration. All the patients with confirmed diagnosis of pHPT, who underwent successful parathyroidectomy, were included in this study. Patients having parathyroid malignancy or frank psychiatric illness preoperatively were excluded.
A single investigator used two scoring systems for all the patients, for assessing neuropsychiatric manifestations before and after surgery. Parathyroid assessment of symptoms score (PAS) designed by Pasieka and the SF-36v2 TM Health surveys were employed for each patient preoperatively and one week, three months, six months, and one year, postoperatively. ,
The PAS scoring system included 13 parameters (pain in bones, feeling tired easily, mood swings, feeling depressed, pain in abdomen, feeling weak, feeling irritable, pain in joints, being forgetful, difficulty in getting up from chair, headache, feeling thirsty, itchy skin, others, quality of life and wellness). The SF-36v2 TM Health survey consisted of 36 questions that evaluated eight discrete areas (physical functioning, social functioning, bodily pain, general health perceptions, vitality, role limitations due to physical health problems, role limitations due to emotional problems, and mental health).
The SF-36v2 TM Health survey (already validated in the local language - Hindi) was used for patients in this study. The PAS scoring system was translated into Hindi by a bilingual expert and verified by a technical expert (from Lucknow University) by retranslating it into English and vice versa.. The translated PAS score was applied in the first five patients and then the Hindi version was slightly modified by the technical expert so that patients understood the exact meaning as desired in the original English version of the scoring system.
The PAS score was calculated as the sum of all 13 answers with a maximum possible score of 1300. The SF-36v2 TM Health survey questionnaire was analyzed using the SF Health outcomes TM Scoring software (Quality Metric Inc., Lincoln, USA), as already described.
The data were analyzed using the SPSS 15 software. The nonparametric test (k Independent Sample test, Kruskal-Wallis H) was used and presented as median values. Non-skewed data were presented as mean ± standard deviation.
Between November 2007 and December 2009, 42 out of 43 consecutive patients with pHPT undergoing surgery were included in the study. One patient who had perioperative mortality was excluded from the study. There were 22 men and 20 women with a mean age of 43.63 years ± 2.37 (Standard error of mean SEM), (range 17 - 73 years). The preoperative mean serum calcium levels were 12.54 mg/dl (± 0.25 SEM, normal range 8.5 - 10.8 mg/dl), mean serum intact PTH (iPTH) levels were 599.74 pg/ml (± 105.28 SEM, normal range, 9 - 55 pg/ml), mean serum Alkaline Phosphatase was 518.5 U/L (± 91.32 SEM, normal range, 35 150 U/L), and mean serum 25 (OH Vitamin D) were 17.98 ng/ml (± 2.37 SEM, normal range, 9 - 47 ng/ml). Mean values for Bone mineral density (BMD) at forearm were - 2.95(±th 0.26, severe osteoporosis), hip - 2.18 (± 0.22, osteopenia), and at spine - 2.51(± 0.24, osteoporosis), respectively.
Minimally invasive parathyroidectomy was carried out in 24 patients, with two conversions, 16 bilateral neck explorations, and two mediastinal explorations. The mean weight of the parathyroid adenoma was 3583.17 mgs (± 594.17 SEM) and mean gland size (maximum diameter) was 2.75 cm (± 0.20). Histopathology showed 37 parathyroid adenomas, two double adenomas, and three with parathyroid hyperplasia. In the follow-up, all except one patient were cured biochemically. One patient subsequently succumbed to severe inflammatory bowel disease and ventilator-induced pneumonia.
By the closing date of the study (31 December, 2009), surveys were done on 42 patients completing a one-week postoperative follow-up, 37 patients completing a three-month month follow-up, 27 patients completing a six-month follow-up, and 21 patients completing a follow-up of one year.
The preoperative PAS score ranged from 40 to 880 of the potential maximum score of 1300. High scores represented severe symptoms, whereas low scores represented mild symptoms. Each PAS parameter (Median ± standard deviation, P value, etc.) has been described in [Table 1]. [Table 2] depicts all the parameters studied for the SF-36v2 TM Health survey along with the median ± standard deviation, P-value, and so on, obtained during the preoperative and postoperative periods, respectively. Scores less than 50% signify severe disease (SF-36v2 TM ). This finding was observed in the following four domains: Physical functioning, role playing, bodily pain, and vitality.
Postoperative status of changes in neuropsychiatric symptoms
Out of 42 patients with pHPT, 42 (100%) patients had completed one week of follow-up and 21 (48 %) patients had completed one full year of follow-up. Compared with the mean preoperative PAS score (430.87 ± 215.61) there was a statistically significant decrease in the PAS score (improvement) at one week (293.65 ± 118.31 standard deviation, P < 0.001), three months (109.44 ± 85.09, P < 0.01), six months (70.00±71.65, P < 0.05), and one year (60.10 ± 104.48, P < 0.01). Even as improvement in symptoms was observed in the follow-up at the first week post operation (which further improved with time), the following five parameters of the PAS score (feeling irritability, forgetfulness, difficulty in getting out of chair, headache, and itchy skin) did not show statistically significant reduction one week post operation, although, later they showed a statistically significant reduction (improvement). Nevertheless, all the parameters (PAS scores) showed a significant reduction (improvement) one week post the operation.
Using the SF-36v2 TM Health survey statistically significant improvement was observed in the following scores - physical role, bodily pain, general health, vitality, emotional role, and mental health, in all postoperative time periods. Physical functioning score improved significantly only after 1 week postoperatively. Scores for social functioning did show improvement with time at all the follow ups after surgery but the improvement was not statistically significant probably due to smaller sample size.
There was no correlation observed (K-independent sample test) between severities of hypercalcemia and vitamin D deficiency when compared with the preoperative PAS scores [Figure 1]. Also no correlation was observed between the types of surgery (minimally invasive or classical open approach), vis-a-vis the preoperative and one-week postoperative PAS scores [Figure 2].
Many studies have shown improvement in neuropsychiatric symptoms post surgery in patients with primary hyperparathyroidism (pHPT). ,, These symptoms range from nonspecific ones such as weakness, fatigue, reduced concentration; sleep disturbances, mild personality change, to severe depression, cognitive impairment, and psychosis. ,
The pathophysiology of neuropsychiatric manifestations in patients with pHPT has been explained by monoamine turnover disturbance, lower 5 - hydroxyindoleacetic acid, lower homovanillic acid, and high concentrations of calcium, uric acid, and albumin, in the cerebrospinal fluid.  Additionally 25-hydroxyvitamin D deficiency has been associated with poor cognition and mood swings.  Studies done using single photon emission computer tomography (SPECT) or functional magnetic resonance imaging (MRI) of the brain have also shown changes in the prefrontal cortex and parietal cortex with shifts in activations seen in patients with pHPT.  Mjaland et al. prospectively studied changes in the regional cerebral blood flow using SPECT, to assess the neuropsychiatric symptoms in patients with pHPT, and showed reduced (pathological) cerebral blood flow preoperatively in 14 patients and improvement in 13 patients after surgery. 
Several studies have shown that parathyroidectomy results in rapid and persistent improvement in the neuropsychiatric symptoms (fatigue, lassitude, mood swings, irritability, anxiety, depression, difficulty in concentrating, memory loss, and increased sleep requirements) and the overall quality of life. ,,,
This prospective study objectively quantifies and compares the various neuropsychiatric manifestations and improvements in the quality of life in Indian patients having advanced pHPT, with vitamin D deficiency, before and after parathyroidectomy. Out of the two scoring systems employed in this study (PAS and SF-36v2 TM Health survey questionnaire) we observed that the PAS scoring system is simple, less time consuming, and easy to fill by the patients, and therefore, more useful, whereas, the SF-36v2 TM Health survey questionnaire is a nonspecific one and is more time consuming and cumbersome.
Goyal et al. studied Indian patients with pHPT using a comprehensive psychopathological rating scale and stated that psychological symptoms are multidimensional (sadness, lassitude, ache, pain, and fatigability) and significantly improve six weeks post surgery.  They did not find any correlation between the serum calcium levels and psychiatric morbidities and also found no cognition impairment. On the contrary our study shows continuous improvement following surgery, which attains the lowest scores (maximum improvement) at one year.
Pasieka et al. have shown that parathyroidectomy results in an improvement in neuropsychiatric symptoms starting seven to ten days post surgery, which improve persistently with time. , In our study we also observed the same and we also observed that the improvement attained statistical significance after the first week of surgery. Pasieka et al. have shown that patients with pHPT have higher preoperative PAS scores compared to euthyroid patients undergoing thyroidectomy. , The comparison (thyroidectomy group) documented no change in the patient's preoperative PAS scores versus postoperative PAS scores, confirming thereby that the PAS scoring system is disease-specific. As we did not employ this kind of control, only the preoperative values were taken as the baseline for comparing changes in the postoperative scores.
Okamoto et al. have shown that even mildly symptomatic or asymptomatic patients with pHPT have neuropsychiatric manifestations.  They have shown that there is no correlation between the severity of hypercalcemia and psychological disturbances. We also observed the same in our study.
Most studies have shown that the improvement in neuropsychiatric disturbances is persistent after surgery. , This fact has also been corroborated in our study for at least up to one year of follow-up.
Pasieka's scoring system is an easier, simpler, and a more reliable method to assess neuropsychiatric manifestations in patients with pHPT, and other studies also have shown this fact, while comparing it with the SF36 health survey. 
Tang et al. have shown that minimally invasive parathyroidectomy is associated with greater improvements in the quality of life and a shorter length of stay, in comparison to the open bilateral approach.  However, this observation was not made in our study.
Parathyroidectomy results in rapid and persistent improvement in neuropsychiatric symptoms in Indian patients with advanced pHPT, with vitamin D deficiency. Pasieka's scoring system is a useful, easy, and reliable tool to assess changes, even for severe neuropsychiatric manifestations, in patients with advanced pHPT.
The authors sincerely thank Dr. Uttam Singh, Associate Professor, Department of Biostatistics, for his assistance in data analysis. The authors are also grateful to the Indian Council of Medical Research for the financial assistance to carry out this project.
[Figure 1], [Figure 2]
[Table 1], [Table 2]