Headache & Pain
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Dec. 02, 2023
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Hypercalcemia is associated with a broad range of neurologic manifestations that have been ascribed to both central nervous system and peripheral nervous system dysfunction. Reported neurologic manifestations can include weakness, fatigue, confusion, posterior reversible leukoencephalopathy syndrome, a Creutzfeldt-Jakob–like syndrome due to hypercalcemic encephalopathy, stupor, and coma. It remains unclear if the weakness associated with hypercalcemia is primarily due to both central nervous system and peripheral nervous system effects of hypercalcemia. In this article, the author reviews the clinical spectrum of neurologic dysfunction associated with hypercalcemia, as well as the evaluation and management of hypercalcemia.
• Depending on the severity and rate of development, hypercalcemia can produce varying degrees of a generalized encephalopathy ranging from mild impairment of attention to coma.
• Primary hyperparathyroidism and malignancy-associated hypercalcemia are the most common causes of hypercalcemia, together accounting for more than 90% of cases.
• Hypercalcemia in the setting of malignancy is a common oncologic emergency and develops in 20% to 30% of patients with cancer.
• For patients with severe hypercalcemia (greater than 13.5 mg/dL) or moderate hypercalcemia and significant clinical manifestations, the initial management entails strategies that directly lower the calcium concentration, independent of the underlying cause.
The parathyroid glands were discovered (but not named) in 1852 by comparative anatomist and paleontologist (later Sir) Richard Owen (1804-1892) in the necropsy of an Indian rhinoceros that died at the London Zoo (211; 61; 43; 122; 95). In his description, Owen referred to the glands as "a small compact yellow glandular body attached to the thyroid at the point where the veins emerged" (211; 61). The significance of this report was only evident in retrospect, and Owen was much more famously recognized for naming the Dinosauria (ie, dinosaurs) in the 1830s and infamously as an antievolutionist opposed to Charles Darwin and his proponent Thomas Huxley after publication of Darwin’s The Origin of Species by Means of Natural Selection (1859) (178; 109; 110; 98; 220). Although Owen was notorious for usurping the work of others and passing it off as his own, in this case Owen was apparently responsible for the observation, although he had no idea of its significance.
Unaware of Owen’s earlier work, published as it was in what was then a relatively obscure society proceeding, the parathyroid glands were identified decades later in humans in 1880 by Ivar Sandstrom (1852-1889), a 25-year-old medical student working as a praelector (lecturer) in anatomy at the University of Uppsala, Sweden (228; 229; 48; 58; 140; 141). In his classic paper, On a New Gland in Man and Fellow Animals (in translation), he described what he called the “glandulae parathyroidae” (parathyroid glands) in dogs, cats, rabbits, oxen, horses, and man (gross and micro). Sandstrom’s principal interest was the organ in man, and he examined 50 individuals and found in most of them two parathyroid glands on each side. Unfortunately, Sandstrom's report was not well received and he later committed suicide at age 37 years.
The clinical importance of the parathyroid glands was not appreciated until 1891, when French physiologist Eugène Émile Gley (1857-1930) observed that tetany and death following experimental thyroidectomy in dogs occurred only if the excised material included the glandulae parathyroidae described by Sandström (103). To this point, tetany in association with thyroidectomy had been misattributed to removal of the thyroid gland. Because of Gley’s discovery, parathyroid glands have sometimes been referred to as "Gley's glands."
From 1903 to 1908, American pathologist William G MacCallum (1874-1944) and Swiss-U.S. pharmacologist (and later the first head of the U.S. National Cancer Institute from 1938-1943) Carl Voegtlin (1879-1960), both working at Johns Hopkins, demonstrated that tetany following parathyroidectomy was the result of the hypocalcemia (177; 176; 138; 181; 86). Not only was there a “marked reduction in the calcium content of the tissues especially of the blood and brain, during tetany” following parathyroidectomy, but the “injection of a solution of a salt of calcium into the circulation of an animal in tetany promptly checks all the symptoms and restores the animal to an apparently normal condition.” MacCallum and Voegtlin also showed that variable production of tetany following parathyroidectomy in animal experiments depended on the presence of residual parathyroid tissue, a result that was not infrequent because of the variable number and location of the parathyroid glands. In 1909, William B Berkeley and S P Beebe, at Cornell University Medical College in New York, described correction of hypocalcemic tetany with parathyroid extract in man (38).
In 1891, German pathologist Friedrich Daniel von Recklinghausen (1833-1910) described osteitis fibrosa cystica, which is characterized by a loss of bone mass, a weakening of the bones as their calcified supporting structures are replaced with fibrous tissue (peritrabecular fibrosis), and the formation of cyst-like brown tumors in and around the bone. This is also known as osteitis fibrosa, osteodystrophia fibrosa, and Recklinghausen disease of bone (which should not be confused with Recklinghausen disease, neurofibromatosis type I). By 1914 Austrian pathologist Jacob Erdheim (1874-1937), working in Vienna, suggested that parathyroid pathology may cause skeletal abnormalities, and this was documented the following year by Z Schlagenhaufer from the observation that in patients with osteitis fibrosa cystica, only one parathyroid gland is typically enlarged (ie, a parathyroid adenoma). If the parathyroid enlargement had been somehow due to or in response to the bony changes, then all of the parathyroid glands routinely should have been similarly enlarged. This ultimately led to the use of parathyroidectomy as a treatment for osteitis fibrosa cystica beginning in 1925.
Parathyroid surgery began before that, though. British surgeon Sir John Bland-Sutton (1855-1936) had described a postmortem specimen of a parathyroid tumor in 1886, had surgically removed a parathyroid cyst in 1909, and had performed a parathyroidectomy for a parathyroid tumor some time before 1917 (79). In 1907, Herbert M Evans, working with American surgeon William Stewart Halsted (1852-1922) at Johns Hopkins in Baltimore, described the vascular supply of the parathyroid glands in man, and in the same paper Halsted discussed preservation of the parathyroid glands with thyroid surgery (115). Evans careful drawing of the parathyroid glands was later used by anatomist Henry Gray in his Anatomy of the Human Body (1918). In 1909, Halsted attempted both iso- and auto- transplantation of parathyroid tissue by transplanting canine parathyroid glands into thyroid tissue and under the skin (114). In 1925, Viennese surgeon Felix Mandl (1892-1957), at the Hochenegg Clinic, performed a successful parathyroidectomy as a means of alleviating the bone disease of hyperparathyroidism; his patient was a 34-year-old tram-car conductor with severe osteitis fibrosa cystica (182).
In 1923 Adolph M Hanson (1880-1959), and two years later Canadian biochemist James B Collip (1892-1965) independently isolated parathyroid hormone from crude glandular extracts (121; 92; 117; 118; 119; 120; 70; 70; 205; 262; 49; 30; 171; 172; 144). The purification of parathyroid hormone greatly accelerated experimental studies to determine the effect of the hormone on bone and kidneys. In addition, American medical physicist Rosalyn Sussman Yalow (1921-2011) successfully developed radioimmunoassays for peptide hormones, including parathyroid hormone (42; 39; 39; 40; 41; 241; 264). Yalow was awarded a Nobel Prize for Physiology or Medicine in 1977.
From the late 1920s until 1956 (when he suffered a career-ending postoperative complication of chemopallidectomy for early-onset Parkinson disease, ie, intracranial hemorrhage with resulting akinetic mutism), American endocrinologist Fuller Albright (1900-1969) and associates at the Massachusetts General Hospital in Boston studied numerous aspects of disordered parathyroid gland function and conducted landmark metabolic balance studies that clearly defined several of the diseases associated with parathyroid dysfunction, as well as related disorders of calcium and phosphorus metabolism (34; 06; 04; 05; 07; 09; 15; 14; 16; 02; 18; 132; 03; 03; 68; 50; 11; 12; 188; 72; 22; 26; 32; 33; 125; 129; 162; 249; 130; 89; 213; 151; 150; 96; 183). In 1929 Albright colleague Read McLane Ellsworth (1899-1970) diagnosed a first case of idiopathic hypoparathyroidism (10). Albright and colleagues noted that most patients treated with parathyroidectomy for primary hyperparathyroidism and osteitis fibrosa cystica also had nephrolithiasis or nephrocalcinosis (06), established the concept of secondary hyperparathyroidism (06), described hyperparathyroidism due to adrenal hyperplasia (06), described vitamin D-resistant rickets and effective treatment with high doses of vitamin D (08), established a primary effect of vitamin D is to increase intestinal absorption of calcium (16), and described postmenopausal osteoporosis (02), hypercalcemia with disuse osteoporosis (02), pseudohypoparathyroidism (18), the milk-alkali syndrome (17), pseudo-pseudohypoparathyroidism (11), and idiopathic hypercalciuria (12).
The subsequent assay, sequencing, and cloning of parathyroid hormone led to the further elaboration of the multiple actions of the hormone and of the abnormalities associated with dysfunction of the parathyroid glands.
In 1957, Walter T St Goar, at the College of Physicians and Surgeons of Columbia University in New York, emphasized the abdominal manifestations of hyperparathyroidism and proposed a mnemonic triad for recognizing the disorder as a “disease of stones, bones and abdominal groans” (244). St Goar had been influenced to pursue studies in this area by Fuller Albright while St Goar and his wife were interns and residents at Massachusetts General Hospital. As St Goar elaborated (244):
Gastrointestinal symptoms appear to represent a clue to the earlier recognition of some cases of hyperparathyroidism…Unexplained episodes of nausea and vomiting, unexplained anorexia and weight loss, peptic ulcers which do not respond in the usual way to therapy, [marked constipation,] and a variety of unexplained abdominal pains should all lead to a consideration of hyperparathyroidism as a possible diagnosis. Hyperparathyroidism, which has been popularly thought of by medical men as a ‘disease of stones and bones,’ might be recognized both earlier and more frequently if it were widely regarded as a ‘disease of stones, bones and abdominal groans.
St Goar recognized that the abdominal manifestations of hyperparathyroidism are nonspecific, but he hoped that greater recognition of their prominence in this disorder might speed clinical recognition and treatment (244):
These gastrointestinal symptoms are meaningless in themselves. An awareness of their occurrence in hyperparathyroidism, however, may prove helpful in recognizing other nonspecific manifestations of a potentially reversible disease and thus lead to its earlier diagnosis.
In 1961, William C Mieher Jr., Yvan Thibaudeau, and Boy Frame, at Henry Ford Hospital in Detroit, emphasized the neuropsychiatric features of hyperparathyroidism, which can include apathy, agitated depression, psychosis with hallucinations or delusions, paranoia, and dementia. They modified St Goar’s mnemonic triad into a mnemonic quadrad by adding “psychic moans” to reflect the neuropsychiatric manifestations: “we wish to add a postscript to St Goar's description and emphasize that hyperparathyroidism is a disease of stones, bones, abdominal groans, and psychic moans” (192).
In 1965 Charles E Boonstra and Charles E Jackson, at the Caylor-Nickel Clinic in Bluffton, Indiana, emphasized the chronic fatigue and nonspecific irritability seen in many patients with hyperparathyroidism (46). Boonstra further modified the existing mnemonic for hyperparathyroidism from a quadrad into a pentad by adding “fatigue overtones” to reflect the fatigue and “nervous irritability” often seen in patients with hyperparathyroidism even when more specific findings are either absent or not clinically manifest (46):
The majority of patients with hyperparathyroidism manifested nonspecific fatigue and nervous irritability that were alleviated by excision of the parathyroid adenoma. The tiredness noted by many patients…was often present in our patients on arising even though it became worse with activity and was partially relieved by resting. St. Goar (1957) proposed that hyperparathyroidism be thought of as a disease of ‘stones, bones and abdominal groans’ to which Mieher, Thibaudeau, and Frame (1961) added ‘and psychic moans.’ Perhaps this statement should be amplified to ‘stones, bones, abdominal groans, and psychic moans with fatigue overtones.
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