A Curious Case of Hypercalcemia
By Douglas Ian Noboru Motomura MD, and Paul Allan Cameron MD, and Nabha Shetty MD
Hypercalcemia is a clinical entity commonly seen on Internal Medicine inpatient units. Through standard diagnostic algorithms, the etiology of most cases can be elucidated. Brivaracetam is a novel anti-epileptic agent that binds synaptic vesicle protein 2A shown to significantly reduce seizure frequency. We describe the first case of hypercalcemia secondary to brivaracetam.
L'hypercalcémie est une entité clinique couramment observée sur les unités d'hospitalisation en médecine interne. Grâce à des algorithmes de diagnostic standard, l'étiologie de la plupart des cas peut être élucidée. Brivaracetam est un nouvel agent anti-épileptique qui lie la protéine de vésicule synaptique 2A montrée pour réduire significativement la fréquence de saisie. Nous décrivons le premier cas d'hypercalcémie secondaire à Brivaracetam.
A 53-year-old male with medically refractory epilepsy, diabetes mellitus and pancytopenia secondary to anti-epileptic medications who presented to hospital with fatigue and constipation. Investigations revealed creatinine of 390 umol/L (baseline 110 umol/L) and an uncorrected calcium of 3.6 mmol/L. Serum parathyroid hormone level was 1.6, serum protein electrophoresis did not reveal a monoclonal band and urine calcium was elevated. Computed tomography of his chest abdomen and pelvis showed no malignancy or granulomatous lesions. Positron emission tomography was negative. A bone marrow biopsy showed trilineage hematopoiesis and no features of malignancy. Fourteen days after drug cessation, intravenous fluid resuscitation and treatment with pamidronate as well as calcitonin, his calcium normalized. Investigation results are summarized in Table 1.
Excluding all other potential aetiologies of hypercalcemia and clinical as well as biochemical improvement following withdrawal of the drug brivaracetam was felt to be the causative agent. This case demonstrates the ability of brivaracetam to cause symptomatic severe hypercalcemia and emphasizes the need for care providers to monitor calcium while on therapy.
A 53-year-old man, who is originally from Finland but grew up in Halifax, Nova Scotia presented to the emergency department after an elevated creatinine found by a walk-in physician. He has a medical history of a seizure disorder without clear etiology, despite extensive workup. He suffers from 1–2 generalized tonic-clonic seizures per month on average, and they are refractory to medical management. Otherwise, he has type 2 diabetes that is well controlled, and a chronic, mild pancytopenia.
For his seizures, he has tried multiple combinations of anti-epileptics and in August of 2016, started a novel anti-epileptic called Brivlera (brivaracetam), which is a relative of Keppra (levitiracetam). This new anti-epileptic was only recently approved for usage in Canada in March of 2016. It was initially tolerated to good effect, and at the time of presentation had not had any seizure activity since starting the medication. His other medications included lamotrigine, divalproex and metformin.
In mid September 2016, he began to feel generally unwell. He had decreased appetite, worsening weakness, headaches, constipation, and nausea. He was given a requisition for bloodwork which showed a significant kidney injury. Creatinine was 390 umol/L on a baseline near 110 umol/L, and he was asked to come into the emergency department.
Due to the suspicious timing, brivaracetam was held on admission. His other anti-epileptics were continued throughout his stay in hospital. His metformin was held due to his kidney injury as well.
On assessment the patient looked generally deplete. His jugular venous pressure was not visible. His mucous membranes were dry. There was no abdominal pain or costovertebral angle tenderness. Neurologic exam was normal.
Workup for the acute kidney injury began. Urinalysis was completely bland and free of blood, protein, bacteria or leukocytes. Extended electrolytes were ordered and revealed a calcium level of 3.60 mmol/L and corrected with the patient’s albumin of 27g/L, was 3.86 mmol/L. The patient was admitted for treatment of hypercalcemia as well as investigation into the etiology.
Following the diagnosis of hypercalcemia, a thorough history regarding potential etiology was undertaken.
The first blood test ordered was parathyroid hormone (PTH), which was appropriately low at 1.6 pmol/L. To rule out the possibility of familial hypocalcuric hypercalcemia, 24-hour urine calcium was 9.0 mmol/TV, which was appropriately high. Vitamin D levels were normal, suggesting there was no suspicion of exogenous vitamin D supplementation driving his hypercalcemia.
Because of the combination of anemia and pancytopenia along with hypercalcemia, a pan CT was ordered to assess for lymphoma or other malignancies, but no significant abnormalities were detected. A PET scan was done to assess for granulomatous disease. The only uptake seen was in the gluteal muscles,reported to represent calcyphlaxis, a condition most commonly (though not exclusively) associated with longstanding dialysis. . These deposits were not palpable clinically and could not be biopsied (Fig1)
Figure 1. PET CT showing uptake in the gluteal region.
Multiple myeloma was also a diagnostic consideration. SPEP did not show a monoclonal band. Serum free light chains were minimally elevated, but in consultation with hematology, deemed to be not in keeping with multiple myleoma. Regardless, as no other clear etiology emerged, bone marrow biopsy was performed, showing normal trilineage hematopoiesis and no increase in plasma cells.
After discharge from hospital, the PTH-related peptide and 1,25-OH-Vitamin D levels returned from outside labs, both normal, making a neoplastic process or granulomatous process even less likely.
The initial management of his hypercalcemia consistent of aggressive fluid rehydration with normal saline, more than 7 litres over the first 48 hours. Furosemide was started to help maintain euvolemia, as well as for minor amounts of calcium secretion. Pamidronate was administered twice, one week apart, to block calcium resorption from bone.
Calcitonin was started several days following admission and was increased two days later. It was discontinued shortly thereafter for suspected tachyphylaxis. Figure 2 demonstrates the response of the calcium and creatinine to the previously mentioned interventions.
Figure 2. Response of the calcium and creatinine to the previously mentioned interventions.
Finally, the utility of empiric steroids was discussed. At the time of consideration the 1,25-OH-Vitamin D levels were pending, but there was no evidence of any granulomatous disease. The pros and cons of empiric treatment were discussed with the endocrinology, hematology and nephrology consult team, and the consensus decision was to avoid trial of steroid until more substantial evidence was produced.
Upon discharge from hospital, the patient’s creatinine was slowly improving and his calcium had remained stable with only oral rehydration. He was seen in general medicine follow up, and his creatinine had stabilized to 125 umol/L at 6 month’s time from discharge, with a normal ionized calcium at 1.26 mmol/L
He was also reassessed by his neurology team. It was stated that following discharge from the hospital, the patient quickly suffered 3 general tonic clonic seizures, indicating loss of the previously achieved anti-epileptic control. The decision was made to not restart the brivaracetam unless a clear etiology of the hypercalcemia was found. Instead, a trial of topiramate was initiated.
He was seen in follow up by the nephrology service. The consensus from the visit is that his residual kidney injury is most likely secondary to his significant hypercalcemia, instead of a primary kidney process. No nephrology follow-up was indicated.
Brivaracetam is primarily an SV2A (Synaptic vesicle protein 2A) ligand, similar to levetiracetam (keppra).1 Though the exact physiologic mechanism is unknown, robust randomized control trial evidence shows that brivaracetam dosing twice daily significantly reduces the frequency of seizures versus placebo.2 Interestingly, the binding affinity of Brivaracetam is reported to be over 30 times that of Keppra.
Brivaracetam was recently approved for usage in Canada in March of 2016 3 and in the United States as of February 18th 2016.4 Hypercalcemia was not a reported side effect in the clinical trial data (total participants over 1500). Moreover, hypercalemia is not a reported side effect of levetiracetam, whose mechanism is well understood. 5
However, extensive investigations into other possible causes of the patient’s hypercalcemia remained fruitless. This fact, combined with the timing coinciding with the initiation of Brivera, the gradual improvement following the discontinuation of the drug, and the lack of relapse following discharge seem to provide strong evidence of a causative effect from the drug. If so, this would be the first reported case in the literature. It is interesting to note that when the drug manufacturer was directly contacted, they had two other reports of hypercalcemia in the United States. There were no other reports from Canada. Further monitoring will be required as more patients begin to use this novel antiepileptic medication
Consent was obtained from the patient’s substitute decision maker on Jan 19th - 2017
● This case describes a unique side effect from a novel anti-epileptic drug, not previously reported in the literature.
● This case overviews a thorough workup of the various etiologies of hypercalcemia.
● This case provides an overview of the standard treatments for refractory for hypercalcemia, as well as monitoring of the response to treatment.
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 Biton, Victor, et al. Brivaracetam as Adjunctive Treatment for Uncontrolled Partial Epilepsy in Adults: A Phase III Randomized, Double-blind, Placebo-controlled Trial."Epilepsia 55.1 (2013): 57-66. Web.
 "Summary Basis of Decision (SBD) - Brivlera." Health Canada, n.d. Web. 09 Apr. 2017.
 Commissioner, Office Of the. "Press Announcements - FDA Approves Briviact to Treat Partial Onset Seizures." U S Food and Drug Administration Home Page. Office of the Commissioner, n.d. Web. 09 Apr. 2017.
 Aksoy, Duygu et al. "Effects of Oxcarbazepine and Levetiracetam on Calcium, Ionized Calcium, and 25-OH Vitamin-D3 Levels in Patients with Epilepsy." Clinical Psychopharmacology and Neuroscience 14.1 (2016): 74-78. Web.
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