ABSTRACT: Hypoparathyroidism refers to a group of disorders in which extracellular calcium levels cannot be maintained within the normal range due to relative or absolute deficiency of parathyroid hormone. Clinically, hypoparathyroidism manifests predominantly as neuromuscular dysfunction caused by hypocalcemia. Basal ganglia calcification in particular is associated with hypoparathyroidism. Two different presentations of basal ganglia calcification associated with idiopathic hypoparathyroidism illustrate common features and clinical findings of this condition.
Two case reports show how hypocalcemia due to a deficiency of parathyroid hormone can cause neuromuscular dysfunction.
Case 1 data
In January 2007, a 62-year-old male was involved in a motor vehicle collision secondary to a sudden loss of consciousness following a witnessed generalized tonic-clonic seizure. Investigations found low levels of serum parathyroid hormone levels at 1.4 pmol/L (reference range 1.2 to 8.4 pmol/L), low serum total calcium (Ca) at 1.48 mmol/L (2.10 to 2.55 mmol/L), low ionized calcium (iCa) at 0.91 mmol/L (1.17 to 1.29 mmol/L), and low albumin at 26 g/L (35 to 51g/L). Levels were within the reference range for phosphate at 0.91 mmol/L (0.81 to 1.45 mmol/L), magnesium at 0.78 mmol/L (0.70 to 1.00 mmol/L), and creatinine at 101µmol/L (71 to 133 µmol/L). A CT scan of the head showed prominent basal ganglia calcification (BGC), especially in the lentiform nuclei bilaterally (Figure). Findings from an EEG were normal, and full neurological and cardiac assessment found no apparent cause for the loss of consciousness. The seizure was presumed to be secondary to hypocalcemia due to primary hypoparathyroidism. The patient was started on vitamin D (50000 units daily) and calcium carbonate (3000 mg daily). On discharge, the patient’s serum calcium level had increased to 2.15 mmol/L, and his serum phosphate had increased to 1.37 mmol/L. In retrospect, he described a history of cramping of the thumbs bilaterally, sweeping across the hands and fingers, but no other symptoms of hypocalcemia. His medical history was unremarkable otherwise, and he was not taking any medications prior to the motor vehicle collision.
Case 2 data
In 2008, a 27-year-old female pres-ented with a 14-year history of headaches and a 1-year history of hand cramps. Investigations found low levels of both total serum calcium at 1.28 mmol/L and ionized calcium at 0.6 mmol/L, and a very low level of PTH. The patient’s serum creatinine level was normal and her medical history was unremarkable. After a CT scan of the head found calcification of the basal ganglia she was diagnosed with primary hypoparathyroidism and started on alfacalcidol and calcium supplementation. Follow-up investigations in 2011 revealed low serum calcium at 1.64 mmol/L, elevated phosphate at 1.7 mmol/L, and low 24-hour urinary calcium excretion at 0.4 mmol (reference range 1.0 to 7.0 mmol). The patient’s dose of alfacalcidol was increased from 0.5 µg daily to 0.75 µg daily and she was continued on calcium carbonate at 3000 mg daily.
Basal ganglia calcification is a nonspecific finding in 1% of all CT head scans. It is divided into two broad categories: physiological and patho-logi-cal. Physiological BGC is an incidental asymptomatic finding on CT, most com-monly seen in elderly patients. Conversely, pathological BGC presents with clinical manifestations and should be suspected in patients under age 30. The most common causes of pathological BGC are hypoparathyroidism and pseudo-hypoparathyroidism. Other causes include hypoxia at birth, exposure to toxins (lead, carbon monoxide, chemo-therapeutic agents), radiation therapy, infections (TORCH infections, HIV, tuberculosis), infil-trative diseases (malignancy, sarcoidosis), and inherited neurodegenerative disorders. Familial idiopathic BGC, known as Fahr disease, is a rare dis-order that can be sporadic or inherited in an autosomal dominant pattern. It is diagnosed when infectious, toxic, and traumatic causes have been ruled out.
BGC was first described in assoc-iation with chronic hypoparathyroidism by Eaton in 1939. Pathogenesis is unknown, but its occurrence with hypocalcemia suggests that increased calcium-phosphorus complex formation plays a role. Radiological studies have found that calcification surrounding cerebral blood vessels most frequently occurs in the lentiform (putamen and globus pallidus) and the caudate nuclei of the basal ganglia; however, the factors that predispose individuals to basal ganglia calcification have not been identified.
Other areas affected by BCG include the thalamus, dentate nuclei, cerebral cortex, gray-white junctions, and the cerebellum.[4,6] Such intracranial calcification occurs in 0.3% to 1.5% of patients with hypoparathyroidism, and is often detected incidentally.[7,8]
As a result of calcification and hypocalcemia, various neurological symptoms may arise. Most commonly, seizures and tetany occur. Extra-pyramidal symptoms such as parkinsonism and cerebellar dysfunction are also seen. Other complications are known to result from hypocalcemia, including increased risk of fractures, but generally the lack of large long-term prospective studies means the natural history of idiopathic hypo-parathyroidism and related complications are not well understood.
There are various causes of hypoparathyroidism. These include postsurgical effects from thyroid, parathyroid, or radical neck surgery for head and neck cancer, and autoimmune, radiation-induced, infiltrative, and infectious destruction of the parathyroid glands. Abnormal development of the parathyroid gland, abnormal production of PTH, or abnormal function of the calcium-sensing receptors regulating PTH can also occur, secondary to genetic mutations. Some patients have idiopathic hypoparathyroidism, and in these cases, it may be useful to investigate for an attenuated form of DiGeorge syndrome with a 22q11.2 deletion on chromosome 22.
Basal ganglia calcification in idiopathic hypoparathyroidism is a progressive disorder and has been observed to worsen despite maintenance of normal calcium levels. A recent prospective study found that increased risk of BGC progression–defined as new sites of calcification or increased volume of calcification detected on CT–is significantly associated with a low calcium to phosphorus ratio (119% vs 151%; P < 0.001), hyperphosphatemia (2.1 mmol/L vs 1.7 mmol/L; P < 0.01), and a history of seizure (71.4% vs 28.6%; P = 0.01). Interestingly, 25(OH)D (calcifediol) or 1,25(OH)2D (calcitriol) levels were not significantly associated with progression. Furthermore, the researchers found that for every 1% increase in the calcium to phosphorus ratio, progression of basal ganglia calcification decreased by 5%. These findings suggest that early diagnosis and strict control of phosphorus is another crucial component in treating and preventing progression of BGC.
In a prospective study, Aggarwal and colleagues found there was a significant association between cognitive dysfunction and the duration of hypocalcemia, serum calcium levels, and calcium-phosphorus complex formation, but no association with serum 25(OH)D levels, serum PTH levels, or the volume or site of basal ganglia calcification.
Despite some uncertainty about the exact pathogenesis of BGC, treatment is known to prevent progression. Thus, clinicians are advised to:
1. Investigate for hypoparathyroidism in the presence of basal ganglia calcification.
2. Identify any manifestations of basal ganglia calcification and hypoparathyroidism, including cognitive dysfunction, neuromuscular dysfunction, and seizure.
3. Treat hypoparathyroidism with cal-cium and vitamin D.
4. Treat to obtain a target serum calcium level in the low normal range (~ 2.00 to 2.13 mmol/L).
5. Monitor for a target 24-hour urinary calcium excretion rate of 2.5 to 3.75 mmol daily.
Clinicians should remain aware that treatment with calcium supplements and vitamin D analogs increases the risk of hypercalciuria, which in turn can lead to nephrolithiasis, nephrocalcinosis, and decreased renal function.
Recombinant parathyroid hormone replacement has been studied but not yet approved for hypoparathyroidism. Although some studies have shown that subcutaneous administration of parathyroid homone can decrease hypercalciuria and decrease skeletal complications when compared with administration of calcitriol, the long-term safety of this therapy has not been established.[13-16]
The two cases described here show that idiopathic hypoparathyroidism associated with basal ganglia calcification can present in different ways. Various neuromuscular manifestations secondary to basal ganglia calcification, hypoparathyroidism, and hypocalcemia commonly occur. Presently, treatment consists of calcium supplementation and the use of vitamin D analogs, but PTH replacement is under investigation. Treatment is important to prevent progression of BGC.
1. Rumboldt Z, Castillo M, Huang B, et al. (eds). Brain imaging with MRI and CT: An image pattern approach. New York: Cambridge University Press; 2012. p. 387-388.
2. Radaideh AM, Jaradat DM, Haddad FH. Prevalence of incidental basal ganglia calcification on routine brain computed tomo-graphy. Rawal Med J 2012;37:1-8.
3. Donaldson I, Marsden CD, Schneider SA, et al. (eds). Marsden’s book of movement disorders. New York: Oxford University Press; 2012. p. 585-596.
4. Rastogi R, Beauchamp NJ, Ladenson PW. Calcification of the basal ganglia in chronic hypoparathyroidism. J Clin Endocrinol Metab 2003;8:1476-1477.
5. Goswami R, Sharma R, Sreenivas V, et al. Prevalence and progression of basal ganglia calcification and its pathogenic mechanism in patients with idiopathic hypoparathyroidism. Clin Endocrinol Oxf 2012;77:200-206.
6. Rizvi I, Ansari NA, Beg M. Widespread intracranial calcification, seizures, and extrapyramidal manifestations in a case of hypoparathyroidism. N Am J Med Sci 2012;4:369-372.
7. Verulashvili IV, Glonti LS, Miminoshvili DK, et al. Basal ganglia calcification: Clinical manifestations and diagnostic evaluation. Georgian Med News 2006;140:39-43.
8. Basak R. A case report of basal ganglia calcification: A rare finding of hypoparathyroidism. Oman Med J 2009;24:220-222.
9. Abe S, Tojo K, Ichida K, et al. A rare case of idiopathic hypoparathyroidism with varied neurological manifestations. Intern Med 1996;35:129-134.
10. Mitchell DM, Regan S, Cooley MR, et al. Long-term follow-up of patients with hypoparathyroidism. J Clin Endocrinol Metab 2012;97:4507-4514.
11. Cao Z, Yu R, Dun K. 22q11.2 deletion presenting with severe hypocalcaemia, seizure and basal ganglia calcification in an adult man. Intern Med J 2011;41:63-66.
12. Aggarwal S, Kailash S, Sagar R. Neuro-psychological dysfunction in idiopathic hypoparathyroidism and its relationship with intracranial calcification and serum total calcium. Eur J Endocrinol 2013;168:895-903.
13. Winer KK, Yanovski JA, Cutler GB Jr. Synthetic human parathyroid hormone 1-34 vs calcitriol and calcium in the treatment of hypoparathyroidism. JAMA 1996;276:631.
14. Winer KK, Ko CW, Reynolds JC, et al. Long-term treatment of hypoparathyroidism: A randomized controlled study comparing parathyroid hormone-(1-34) versus calcitriol and calcium. J Clin Endocrinol Metab 2003;88:4214-4220.
15. Winer KK, Yanovski JA, Sarani B, et al. A randomized, cross-over trial of once-daily versus twice-daily parathyroid hormone 1-34 in treatment of hypoparathyroidism. J Clin Endocrinol Metab 1998;83:3480-3486.
16. Rubin MR, Dempster DW, Sliney J Jr, et al. PTH(1-84) administration reverses abnormal bone-remodeling dynamics and structure in hypoparathyroidism. J Bone Miner Res 2011;26:2727-2736.
Dr Wong is an internal medicine resident at the University of British Columbia. Dr Dahl is a clinical professor in the Division of Endocrinology at UBC.
Above is the information needed to cite this article in your paper or presentation. The International Committee
of Medical Journal Editors (ICMJE) recommends the following citation style, which is the now nearly universally
accepted citation style for scientific papers:
Halpern SD, Ubel PA, Caplan AL, Marion DW, Palmer AM, Schiding JK, et al. Solid-organ transplantation in HIV-infected patients. N Engl J Med. 2002;347:284-7.
About the ICMJE and citation styles
The ICMJE is small group of editors of general medical journals who first met informally in Vancouver, British Columbia, in 1978 to establish guidelines for the format of manuscripts submitted to their journals. The group became known as the Vancouver Group. Its requirements for manuscripts, including formats for bibliographic references developed by the U.S. National Library of Medicine (NLM), were first published in 1979. The Vancouver Group expanded and evolved into the International Committee of Medical Journal Editors (ICMJE), which meets annually. The ICMJE created the Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals to help authors and editors create and distribute accurate, clear, easily accessible reports of biomedical studies.
An alternate version of ICMJE style is to additionally list the month an issue number, but since most journals use continuous pagination, the shorter form provides sufficient information to locate the reference. The NLM now lists all authors.
BCMJ standard citation style is a slight modification of the ICMJE/NLM style, as follows:
- Only the first three authors are listed, followed by "et al."
- There is no period after the journal name.
- Page numbers are not abbreviated.
For more information on the ICMJE Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals, visit www.icmje.org