Neurology India Medknow Publications on behalf of the Neurological Society of India ISSN: 0028-3886 EISSN: 1998-4022 Vol. 59, Num. 4, 2011, pp. 586-589

Neurology India, Vol. 59, No. 4, July-August, 2011, pp. 586-589

Brief Report

Spectrum of neurological manifestations of idiopathic hypoparathyroidism and pseudohypoparathyroidism

Sanjay Kumar Bhadada¹, Anil Bhansali¹, Vimal Upreti¹, Sridhar Subbiah¹, Niranjan Khandelwal²

¹ Department of Endocrinology, PGIMER, Chandigarh, India
² Department of Radiodiagnosis, PGIMER, Chandigarh, India
Correspondence Address: Sanjay Kumar Bhadada, Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012 India, bhadadask@rediffmail.com

Date of Submission: 28-Feb-2011
Date of Decision: 07-Mar-2011
Date of Acceptance: 05-May-2011

Code Number: ni11175

PMID: 21891938

DOI: 10.4103/0028-3886.84342

Abstract

We describe clinical, biochemical, radiological profile, and treatment outcome in 97 patients with idiopathic hypoparathyroidism seen over a period of 18 years. Of the 97 patients, 78 (80%) had idiopathic hypoparathyroidism and 19 (20%) had pseudohypoparathyroidism. The mean age±standard deviation (SD) at presentation was 28.7±14.1 years. There were 52 males, the mean lag time from first reported symptom to diagnosis was 5.9±5.2 years and the mean (±SD) follow-up was 1.8±0.4 years. The most common presenting manifestation was carpopedal spasm in 68 (70%) patients, followed by paresthesia and seizures in 52 (54%) patients. The mean (±SD) serum calcium and inorganic phosphate concentrations were 6.1±1.5 mg/dl and 6.3±1.5 mg/dl, respectively. The most common imaging abnormality noted was basal ganglia calcification followed by cerebral cortex and cerebellum calcification. More than one-third of patients were on various antiepileptic drugs including phenytoin. In addition to oral calcium and active vitamin D (calcitriol), twenty-six patients (27%) also required hydrochlorothiazide. The important finding in our study was long lag time from the first reported symptom to diagnosis. Phenytoin was the drug in almost one- third of our patients with seizures. Practicing clinicians should have high index of suspicion of diagnosis hypoparathyroidism in the appropriate clinical states to avoid the morbidity associated with hypoparathyroidism. Phenytoin should be avoided in patients with hypoparathyroidism and seizures.

Keywords: Calcification, carpopedal spasm, hypoparathyroidism, idiopathic, pseudohypoparathyroidism, vitamin D

Introduction

Hypoparathyroidism is an uncommon disorder of calcium metabolism characterized by hypocalcemia and hyperphosphatemia due to impaired parathyroid hormone (PTH) secretion or action. ^[1] The etiology of hypoparathyroidism includes post surgical, autoimmune, sporadic idiopathic hypoparathyroidism (IHP) and pseudohypoparathyroidism (PHP). ^[2] In PHP serum intact parathyroid hormone (iPTH) level is elevated or inappropriately normal, ^[2],[3] while it is low in all other causes of hypoparathyroidism. IHP is diagnosed after exclusion of other known causes and usually has a genetic etiology, though sometimes may be due to antibodies against calcium sensing receptor. ^[4] Common clinical manifestation of hypoparathyroidism include tingling and numbness, carpopedal spasm, neurocognitive dysfunction, and seizures. ^[1],[5] The classical radiological finding is basal ganglia calcification. ^[2],[6],[7] Only few case series with small number of cases have been described. ^[5],[8] Here we describe the clinical, biochemical, radiological profile and treatment outcome in 97 patients with hypoparathyroidism seen over a period of 18 years.

Material and Methods

Case records of 97 consecutive patients with sporadic IHP or PHP admitted from January 1990 to September 2008 at our institute and who had at least two follow-up visits over 6 months were analyzed. The study was approved by the institute ethics committee. The diagnosis of IHP and PHP was based on demonstration of hypocalcemia, hyperphosphatemia with low or elevated iPTH, respectively. Patients with postoperative hypoparathyroidism, autoimmune polyendocrine syndrome (APS), history of neck irradiation, and infiltration of the parathyroid gland (hemochromatosis, sarcoidosis) or other secondary causes were excluded. Outcome assessment was done clinically and biochemically.

All patients had detailed demography and clinical features recorded. In all the patients blood samples were collected on three consecutive days after an overnight fast of eight hours to estimate serum calcium (RR: 8.6 -10.2 mg/dl), inorganic phosphorus (RR: 2.8 - 4.5 mg/dl), serum alkaline phosphatase (RR: 3-13 King Armstrong Units/l), albumin, creatinine and estimated by automated analyzer (model: Synchron CX4; make: Beckman). Calcium values were corrected for respective serum albumin level. In all the patients 24-hour urinary samples were collected to assess calciuria. iPTH level was measured by immunochemiluminiscence assay (reference range: 10-69 pg/ml). Serum 25 hydroxyvitamin D levels were estimated by radioimmunoassay (reference range 9-37 ng/ml, Diasorin, Stillwater, Minnesota, U.S.A.). All patients had ultrasound abdomen for nephrolithiasis and nephrocalcinosis. Non-contrast computed tomography of the head was performed in all the patients to look for intracranial calcification. Patients were initially followed up three monthly till serum calcium reached target (low normal) range and subsequently biannually to annually.

All patients were treated with oral calcium, active vitamin D (calcitriol) and hydrochlorothiazide was added if target serum calcium level was not achieved and if patients had hypercalciuria or clinical evidence of hypocalcemia. None of the patients received recombinant iPTH therapy. Phenytoin sodium was substituted by either carbamazepine or sodium valproate as the former is known to cause hypoalcemia while other antiepileptic drugs were continued.

Statistical analysis

Statistical program for the social sciences (Release 10.0.1, PC windows; SPSS Inc. Chicago, IL) was used for data analysis. Data were expressed as mean ± SD (until otherwise specified) in addition to descriptive statistics. Baseline and post treatment data were compared using the paired t test (chi-square test for categorical variables). Linear regression analysis was used to find correlation between independent variables. A probability (P) value of <0.05 was regarded statistically significant and it was calculated two tailed.

Results

Of a total of 97 patients, diagnosis of IHP was made in 78 (80%) and PHP in 19 (20%) patients. There were 52 (54%) were males and the mean age at presentation was 28.7±14.1 years (2 months- 65 years). The mean lag time from first reported symptom to diagnosis was 5.9±5.2 years and mean follow up was 1.8±0.4 years. Clinical and radiological features are given in [Table - 1] and [Table - 2]. [Figure - 1] showing the non-contrast computed tomography (CT) of the brain with extensive basal ganglia and cerebral calcification. Seizures were common in patients younger than 18 years than in other age groups [(n=18); 15 (83%), P=0.02]. Carpopedal spasm was seen more often in those presenting after 18 years of age [(n=79); 43 (54%), P=0.001]. A positive association of seizures was noted with basal ganglia calcification (r=0.56, P=0.001) and serum phosphate levels (r=0.23, P=0.04).

The mean daily doses of drugs prescribed were: Calcium 1883.9±809.3 (range: 500-4000) mg, calcitriol 0.46±0.2 (range: 0.25-1 mg), hydrochlorothiazide 18.3±10.7 (range: 12.5-25) mg (given to 26 patients). The post-treatment biochemical profile is tabulated in [Table - 3]. Fifty-two (54%) patients received antiepileptic drugs (AED) [sodium valproate 21 (42%), phenytoin 19 (35%), carbamazepine 12 (23%)].

Discussion

In our series, the commonest presenting manifestations of hypoparathyroidism were neurological. We suggest that serum calcium profile must be included in the work-up of patients with seizure, numbness and paresthesia. Our study also demonstrates that despite adequate therapy, normocalcemia may not be achieved and patients may develop hypercalciuria requiring addition of hydrochlorothiazide.

The various neurological manifestations observed in our series are similar to those observed in other series. ^[5],[8],[9] The proposed mechanism for carpopedal spasm (Trousseau sign) is increased excitability of the respective nerves caused by hypocalcemia leading to spontaneous muscular contractions. Seizures are thought to occur due to hypocalcemia and intracranial calcification that occurs in vascular and perivascular locations. ^{[2],[8],[10],[11]} PTH exerts its action through the PTH2 receptor in the brain and an endogenous brain specific hypothalamic neuropeptide has been identified as its natural ligand. Diminished activation of PTH2 receptor due to either absolute deficiency or resistance as seen in IHP/PHP is also presumed to result in neuron-psychological abnormalities and low intelligent quotient (IQ) seen in these patient. ^[3],[11] Additionally, hypocalcemia per se can be associated with reversible cognitive impairment. ^[9]

Biochemically, all patients had hypocalcemia and hyperphosphatemia, the hallmark biochemical abnormality in these disorders. Spontaneously occurring hypoparathyroidism may be due to deficient secretion, impaired action of PTH (pseudohypoparathyroidism) or rarely due to secretion of bio-inactive (PTH). Almost one third of our patients had elevated alkaline phosphatase. It is thought to be due to development of osteomalacia secondary to reduced conversion of 25- hydroxyvitamin D to its active form i.e. 1, 25- dihydroxyvitamin D in the absence of PTH action and concurrent vitamin D deficiency. ^[1],[5] The radiological findings of basal ganglia and cerebral calcification seen in this series are well described. ^{[1],[2],[6],[7],[10]}

The response to therapy is often suboptimal due to difficulty in achieving normocalcemia and normophosphatemia and similar trend was also seen in our patients. Calcium and vitamin D therapy can lead to hypercalciuria. Thiazide diuretics reduce renal excretion of calcium and help to maintain normocalcemia. Indeed, one-fourth of our patients required addition of hydrochlorothiazide. Hypercalciuria can lead to nephrolithiasis and nephrocalcinosis as seen in our patients, hence needs to be constantly monitored. Treatment with recombinant PTH has also been described though none of our patients had received it. ^{[12],[13],[14]} Hypocalcemia can occur on stopping the therapy for even short time ^[5] and can be life threatening.

In our series almost 54% of patients had seizures requiring various AEDs. Phenytoin is commonly prescribed AED drug due to its long duration of action and cost effectiveness and almost one third of our patients were on this agent. However, phenytoin can be epileptogenic in presence of hypocalcemia as it increases metabolism of active vitamin D to its inactive form by hepatic enzyme induction resulting in reduced calcium absorption from gut and by causing osteomalacia and reduced calcium mobilization from bones. ^[15],[16] Both these mechanisms lead to worsening of hypocalcemia and seizure control. This possibility must be considered for worsening seizure control in a patient on phenytoin. Hence, phenytoin must be substituted by other agents in patients with hypocalcemia as was done in our patients or supplementation with calcium and vitamin D must be given in case substitution is not feasible.

The major limitation our study is that it is a retrospective analysis, however, it brought out two important points: 1) long mean lag time from first reported symptom to diagnosis and 2) inappropriate AED, phenytoin, selection, which should have been avoided.

References

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