Magnesium therapy in a hypocalcemic African grey parrot (Psittacus erithacus).
Article Type: Report
Subject: Hypocalcemia (Diagnosis)
Hypocalcemia (Care and treatment)
Parrots (Diseases)
Parrots (Care and treatment)
Magnesium in the body (Health aspects)
Calcium, Dietary (Health aspects)
Authors: Kirchgessner, Megan S.
Tully, Thomas N. Jr
Nevarez, Javier
Guzman, David Sanchez-Migallon
Acierno, Mark J.
Pub Date: 03/01/2012
Publication: Name: Journal of Avian Medicine and Surgery Publisher: Association of Avian Veterinarians Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2012 Association of Avian Veterinarians ISSN: 1082-6742
Issue: Date: March, 2012 Source Volume: 26 Source Issue: 1
Product: Product Code: 2834791 Calcium Supplements; 2819821 Calcium NAICS Code: 325412 Pharmaceutical Preparation Manufacturing; 325188 All Other Basic Inorganic Chemical Manufacturing SIC Code: 2834 Pharmaceutical preparations
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 288978073
Full Text: Abstract: Hypocalcemic-induced seizure activity is a clinical entity that is commonly diagnosed in neurologic African grey parrots (Psillacus erithacus). Plasma calcium levels are typically less than 6.0 mg/dL at the time of seizure activity, and although the underlying cause of the hypocalcemia has not yet been determined, many theories have been proposed. An African grey parrot that had been fed a seed diet for 8 years was presented with hypocalcemia and seizures and exhibited precipitously declining plasma calcium levels, despite aggressive calcium and vitamin A, D, and E supplementation for 4 days. Baseline magnesium levels in this parrot were determined to be 1.9 mg/dL; therefore, magnesium sulfate was administered at a dose of 20 mg/kg IM once. Twenty-four hours after supplementation, the plasma magnesium level was 3.3 mg/dL, and no further seizure activity was observed. We believe that a primary dietary magnesium deficiency may have been present in this African grey parrot, similar to a syndrome in leghorn chicks, which is frequently characterized by progressive hypocalcemia that is unable to be corrected by calcium supplementation alone.

Key words: hypocalcemia, hypomagnesemia, seizures, calcitriol, calcium, magnesium, avian, African grey parrot, Psittacus erithacus

Clinical Report

An approximately 10-year-old Congo African grey parrot (Psittacus erithacus erithacus) of unknown sex was presented to the referring veterinarian for the chief complaint of abnormal neurologic behavior of 24-hour duration. The abnormal behavior exhibited by the African grey parrot included the inability to right itself, frantic vocalization, and the inability to perch. The bird had been fed a commercial seed diet supplemented with occasional fruits and vegetables since acquisition 8 years earlier. After obtaining a history and performing a physical examination on the bird, the veterinarian referred the parrot to the School of Veterinary Medicine at the Louisiana State University for further diagnostic testing and hospitalization.

On physical examination (day 1), the bird was observed to be mentally depressed, yet still responsive. Although no overt seizure activity was observed during the examination, the bird was sternal, unable to right itself, and hypertonic. Its ventrum lacked feathers (chronic feather picking had been observed by the owner), and the choanal papilla were blunted. Initial emergency stabilization treatment included the administration of diazepam (0.5 mg/kg IM); calcium glubionate (100 mg/kg PO); calcium gluconate (100 mg/kg IM); supplemental fluids (45 mL/kg SC; Normosol-R, Hospira, Inc, Lake Forest, IL, USA); doxycycline (60 mg/kg IM; Vibravenos formulation, Pfizer Laboratories, London, Ontario, Canada); vitamins A, D, and E (3300 IU/kg IM; Northwest Pharmacy and Compounding Center, Houston, TX, USA); and edetate calcium disodium (35 mg/kg IM; calcium disodium versenate, 3M Pharmaceuticals, Northridge, CA, USA).

The bird was then placed in an incubator at 26.7[degrees]C (80[degrees]F) and 65% humidity. Approximately 4 hours later, 0.3 mL of blood was drawn from the right jugular vein, and a plasma biochemical analysis was performed with a point-of-care chemistry analyzer (VetScan Classic, Abaxis Inc, Union City, CA, USA). The results showed the following abnormalities: aspartate aminotransferase (AST; 559 IU/L; reference range, 100-350 IU/ L), creatine kinase (6270 IU/L; reference range, 123-875 IU/L), uric acid (22 mg/dL; reference range, 4-10 mg/dL), and calcium (5.5 mg/dL; reference range, 8-13 mg/dL). (1)

On day 2, the bird was noted to be brighter and more alert. The bird was able to stand on its own on a flat surface but was unable to walk or properly perch. The bird was placed under general anesthesia with isoflurane and oxygen, and another phlebotomy was performed from the right jugular vein. The collected blood sample was submitted for a complete blood count (CBC) and heavy metal panel (lead, zinc, copper). Ventrodorsal and lateral radiographs were also obtained while the bird was under general anesthesia. The CBC results and radiographs were within reference range. The heavy metal results were as follows: lead (<0.02 ppm; reference range, <0.02 ppm), zinc (0.6 ppm; reference range, 1.25-2.29 ppm), and copper (0.5 ppm; reference range, 0.074). 19 ppm). (2) These heavy metal reference ranges refer specifically to Amazon parrots, and the elevated copper level may be due to species variation as well as dietary influence. Diazepam (0.5 mg/kg IM q12h), calcium glubionate (100 mg/kg PO q12h), and Normosol-R (45 mL/kg SC q12h) treatments were continued.

On day 3, another plasma biochemical analysis was performed and the following abnormalities were identified: AST, 1831 IU/L; bile acids, 184 [micro]mol/L (reference range, 13-90 [micro]mol/L); (3) creatine kinase, >14000 IU/L; and calcium, 4.5 mg/dL. The calcium glubionate dose was consequently doubled (200 mg]kg PO q12h). On day 5, the bird exhibited seizure-like activity and was administered diazepam (0.5 mg/kg IM) to treat the clinical condition, after which it was placed in an oxygen cage. A blood sample was again submitted for a plasma biochemical analysis on day 5 postpresentation, and the following abnormalities were noted: AST, 1979 IU/L; bile acids, 53 [micro]mol/L; calcium, <4 mg/dL; and phosphorus, 1.8 mg/dL (reference range, 3.2-5.4 mg/dL). (1) An ionized calcium level was determined to be 0.54 mmol/L (reference range, 0.96-1.22 mmol/L). (4)

Despite the administration of calcium glubionate at 100 mg/kg PO q12h for the first 2 days of treatment, an increased dose of calcium glubionate (200 mg/kg PO q12h) administered for another 2 days, and a single dose of vitamins A, D, and E, the bird's plasma calcium levels continued to drop precipitously. On the day of presentation, the bird's plasma calcium level was 5.5 mg/dL, but, by treatment day 5, the plasma calcium level had fallen to less than 4.0 mg/dL. Because of the declining plasma calcium level in the face of aggressive calcium supplementation, a blood sample was submitted for magnesium, amylase, and lipase levels on day 5 after presentation. Although the amylase and lipase levels were determined to be within published reference ranges, the magnesium level was found to be low at 1.9 mg/dL (reference range, 2.1-3.4 mg/dL). (5) Magnesium sulfate (20 mg/kg IM once; Magnesium Sulfate Injection, USP 50%, Abraxis Pharmaceutical Products, Schaumberg, IL, USA) was administered. (6) Calcium glubionate administration was discontinued, and treatment with calcium gluconate (50 mg/kg IM once, then 10 mg/kg IM q12h) was initiated. A second injection of vitamins A, D, and E (3300 IU/kg IM once) was also administered.

A blood sample was submitted for a repeat biochemical analysis on day 9 (24 hours after the administration of the magnesium) and the following abnormalities were identified: AST, 851 IU/L; creatine kinase, >14 000 IU/L; and calcium, 7.7 mg/dL. The bird was gradually weaned off Normosol-R, diazepam, and calcium gluconate, and a final plasma biochemical analysis was run on day 12 after presentation (4 days after the administration of the magnesium). The following abnormalities were identified: creatine kinase, >14 000 IU/L; and calcium, 8.3 mg/dL. The plasma magnesium level was determined to be 3.3 mg/dL at that time. The bird was released from the hospital with the recommendations to provide calcium supplementation in the water, gradually change to a balanced commercial pelleted diet, and continue with cuttlebone and/ or mineral block access in the cage. The referring veterinarian performed follow-up examinations, and the bird's owner reports that no more seizure activity had occurred since discharge from the hospital.

Discussion

Hypocalcemic-induced seizure activity is a well-recognized syndrome of African grey parrots. (1,7-9) Clinical signs are reported to occur in birds between 2 and 15 years old. (8,10) The clinical manifestation of the syndrome varies greatly, depending on the individual bird and its absolute calcium status. Incoordination, such as stumbling or falling off a perch, may be the first observed signs. Patients exhibiting mild neurologic abnormalities often demonstrate calcium levels within the published laboratory reference range (8-13 mg/dL). (1,9) The episodes gradually increase in frequency and are often exacerbated with excitement or stress. Eventually, overt seizure activity is observed, and plasma calcium levels measured at this time are usually less than 6.0 mg/dL. (8) Occasionally, clinically affected birds exhibit low plasma ionized calcium levels and concurrent total plasma calcium concentrations within the reference range. (4)

Many theories that have been proposed to explain the hypocalcemic syndrome of African grey parrots, but the underlying pathophysiologic etiology of the condition remains elusive. One hypothesis postulates that African grey parrots, secondary to viral damage to the parathyroid gland, lack the ability to mobilize skeletal calcium in response to hypocalcemia. (8) Another theory proposes that a loss of calcium through the kidney is responsible for the hypocalcemia, although a mechanism for this has yet to be described. (7) A third supposition suggests that simple dietary insufficiency of calcium and vitamin D, along with excess fat intake, leads to eventual hypocalcemia in African grey parrots. High dietary fatty acids, commonly associated with seed-based diets, can form insoluble salts with calcium and thereby prevent intestinal absorption of calcium. (11)

The physiologic roles of calcium, magnesium, and 1,25-dihydroxycholecalciferol (the active metabolite of vitamin [D.sub.3]), are intimately associated. The primary functions of calcium in the body include its role as a regulatory ion and the promotion of structural bone integrity, with approximately 99% of calcium being stored in the inorganic matrix of bones. (12) Magnesium is an essential dietary element that functions as an activator or cofactor for more than 300 enzymes in the body, including 1-[alpha]-hydroxylase; (12) 1-[alpha]-hydroxylase is an enzyme involved in vitamin [D.sub.3] metabolism. (13) Magnesium also complexes with parathyroid hormone (PTH) receptors, and decreased levels of magnesium result in an impaired response to PTH. (14) The PTH is secreted by the parathyroid gland in response to reduced plasma calcium concentrations. The major functions of PTH are stimulation of renal calcium reabsorption in the distal convoluted tubules, increased osteoclastic bone resorption, and increased intestinal absorption of calcium. (15)

The principle active form of vitamin [D.sub.3] is 1,25-dihydroxycholecalciferol (calcitriol). It is produced by the conversion of cholecalciferol to the circulating form of vitamin [D.sub.3], 25-hydroxycholecalciferol. The precursor 25-hydroxycholecalciferol then travels to the kidney, where it is hydroxylated by 1-[alpha]-hydroxylase to form calcitriol. Calcitriol acts to facilitate intestinal absorption of calcium by increasing the production of calcium-binding proteins and by reducing the renal excretion of calcium via the augmentation of tubular resorption. This occurs synergistically with PTH. (11,16) Calcitriol also increases osteoclast activity, which induces bone resorption and increases the total calcium level. (11,16) A large amount of research regarding the relationship between calcium, PTH, calcitriol, and magnesium has been performed in growing leghorn chicks. Most significantly, primary magnesium depletion in leghorn chicks has been found to be characterized by progressive hypocalcemia and insufficient production of calcitriol. (15,17)

Research in leghorn chicks has revealed that a normocalcemic, magnesium-deficient diet induces low plasma magnesium and calcium levels. (15,17) Notably, the secondary hypocalcemia cannot be corrected via calcium supplementation alone; the hypomagnesemia must be rectified before the calcium levels normalize. Additionally, the calcium- and magnesium-deficient chicks fail to demonstrate the expected compensatory increase in plasma calcitriol levels, but chicks fed a calcium-deficient, normomagnesemic diet exhibit a threefold increase in calcitriol and attain higher calcium levels. (17) The lack of calcitriol production in chicks fed the magnesium-deficient diet is not associated with inadequate circulating 25-hydroxycholecalciferol (ie, the precursor to calcitriol). Additionally, 1-[alpha]-hydroxylase activity in the renal tubules is not elevated, as would be expected in calcium-deficient individuals. (17) This suggests that, even in the face of exogenous cholecalciferol supplementation, increased production of calcitriol does not ensue in magnesium-deficient chicks. It is probable that this phenomenon occurs because magnesium is a cofactor for 1-[alpha]-hydroxylase. (13) This same trend of reduced calcitriol production, in the face of adequate cholecalciferol concentrations, may occur in affected African grey parrots that continue to exhibit decreasing plasma calcium levels despite cholecalciferol administration in the form of vitamin A, D, and E injections.

Further research has demonstrated that chicks fed a magnesium-deficient diet exhibit significant parathyroid gland hyperactivity in the absence of bone resorption. (18) This finding is consistent with affected African grey parrots, which typically demonstrate enlarged parathyroid glands with severe, destructive, parathyroid degeneration. Despite apparent active secretion of PTH, cortical bones from affected African grey parrots usually exhibit normal thickness, indicating an absence of bone resorption and calcium mobilization. (8) The decrease in calcium mobilization from cortical bones in the magnesium-deficient chicks is correlated with significant bone magnesium depletion and an ensuing elevation in bone calcium content. (18) This suggests that, in the face of primary hypomagnesemia, supplemental calcium administered before the correction of the low magnesium may be sequestered in the bone rather than leading to an elevated plasma calcium level. Evidence suggests that this phenomenon occurs in magnesium-deficient leghorn chicks because of bone resistance to the action of PTH secondary to the hypomagnesemia, (18) and this same mechanism of action may be occurring in affected African grey parrots.

The African grey parrot presented in this case report exhibited a continued precipitous drop in its plasma calcium levels in spite of aggressive oral calcium and injectable vitamin A, D, and E supplementation. Although we propose that a primary magnesium deficiency was the reason for the lack of response to calcium and cholecalciferol supplementation, other treatments that were administered, such as edetate calcium disodium (Ca[Na.sub.2] EDTA) and injectable doxycycline, may have interfered with the bird's calcium balance. In domestic cows, it has been proposed that intravenous infusion of edetate disodium ([Na.sub.2] EDTA) disrupts calcium homeostatic mechanisms. (19) Additionally, although there are no reported human cases of Ca[Na.sub.2]-EDTA--induced hypocalcemia, there are at least 2 reports of pediatric deaths attributed to [Na.sub.2]-EDTA administration and associated hypocalcemia. (20) No research pertaining to the affects of either [Na.sub.2]-EDTA or Ca[Na.sub.2]-EDTA on calcium homeostatic mechanisms in birds has been published, to our knowledge. The bird in this case study received only 4 doses of intramuscular Ca[Na.sub.2]-EDTA over 48 hours, and its serum calcium levels continued to drop for 3 days after discontinuing the drug. The parrot also received a dose of injectable doxycycline on presentation. Although the detrimental effects of calcium on the activity of orally administered tetracycline-class drugs has been frequently reported, (21) doxycycline is reported to exhibit a low affinity for calcium binding. (22) The administration of this drug should, therefore, not have affected the bird's total plasma calcium levels.

Hypocalcemic-induced seizure activity is a clinical entity that is commonly diagnosed in neurologic African grey parrots. Although several theories have been proposed to explain this clinical entity, none have fully accounted for the hematologic, histologic, and clinical findings. We propose that the continual precipitous decline in plasma calcium levels, in spite of aggressive calcium and vitamin A, D, and E supplementation, exhibited by the African grey parrot in this case report was the result of a primary hypomagnesemia caused by a prolonged nutritionally poor diet. After administration of magnesium sulfate (20 mg/kg IM once) and subsequent attainment of a normocalcemic state, this bird was gradually transitioned to a nutritionally complete diet. The patient's neurologic abnormalities have not returned.

Because of their popularity as pets and their potential for long life, additional information regarding optimal dietary magnesium and calcium levels in the African grey parrot is needed. Until such information is available, it is recommended that these birds be fed an appropriately formulated avian diet that is balanced in both magnesium and calcium.

Acknowledgments. We thank Dr James Rumore for referring this case to the Louisiana State University Veterinary Teaching Hospital's Small Animal Clinic and Drs Sara Schultz and Brook Fahrig Grasperge for their exemplary work with this patient.

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Megan S. Kirchgessner, DVM, Thomas N. Tully Jr, DVM, MS, Dipl ABVP (Avian), Dipl ECAMS, Javier Nevarez, DVM, PhD, David Sanchez-Migallon Guzman, Lic en Vet, MS, Dipl ECZM (Avian), Dipl ACZM, and Mark J. Acierno, MBA, DVM, Dipl ACVIM

From the Virginia Department of Game and Inland Fisheries, 4010 W Broad St, Richmond, VA 23230, USA (Kirchgessner); the Department of Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Skip Bertman Dr, Baton Rouge, LA 70803, USA (Tully, Nevarez, Acierno); and the Companion Exotic Animal Medicine & Surgery Service, University of California Davis School of Veterinary Medicine, 1 Shields Ave, Davis, CA 95616, USA (Guzman).
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