We report here a case of an 11-year-old male white patient. The patient was first observed at the age of 6 months, with a 1-month history of infantile spasms and multiple malformations. Treatment with vigabatrin (VGB) was initiated and maintained for two years, when felbamate was associated for persisting Lennox-Gastaut-type seizures. Felbamate was withdrawn a few weeks later due to severe irritability.
At the age of 3 years, a number of metabolic, neuroradiologic and other investigations (arylsulfatase A, sialic acid, long chain fatty acids, urinary organic acid, Bratton-Marshall test, oligosaccharides, amino acids, hand X-ray, electromyography, nerve conduction velocity and karyotype) were performed and all tests were shown to be within normal ranges. The child was discharged with a diagnosis of Multiple Congenital Anomalies/Mental Retardation.
At the age of six years, due to the risk of adverse ocular effects of VGB, this drug was gradually replaced with valproic Acid (VPA). Several long-lasting seizure crises were observed during the early period of this regimen, followed by further crises of shorter duration in the following months. Therapy was therefore changed to a combination of Slow-release valproic acid (Depakin Chrono®) 825 mg/day and lamotrigine (Lamictal®) 25 mg twice daily, with complete control of seizure crises.
In 2006, at the age of 11 years, due to clinical signs of hypocalcemia (positive Trusseau sign, tetany, focal numbness, muscle spasms, laryngospasm and prolonged QT-c) the patient was hospitalized in the Pediatric Department of the University of Catania, Catania, Italy. Physical examination revealed macrocephaly, high-grade mental retardation, dyschromic and large teeth, a few café-au-lait spots on the right shoulder and leg, and right hemiparesis. The patient pronounced only some syllables, walked only if supported, and the patellar reflex was significantly augmented. Motor stereotypes of the hand and head were present, with absence of sphincter control. His dietary history did not reveal any abnormalities. Molecular investigations for Angelman Syndrome, ATRX syndrome, and FG syndrome were negative.
At this time, hypocalcemia (calcium 6.6 mg/dl, n.v. 8.5-10.5) and high levels of valproic acid (110 μg/ml, n.v. 40-100) were found in the blood, the remainder of the laboratory investigations were normal. Treatment with calcium and vitamin D was started and serum calcium was rapidly normalized.
In January 2007, the child was readmitted to the Department because, after a whithdraw of the calcium and vitamin D treatment, a new reduction of calcemia was noticed, albeit without clinical manifestations. Laboratory tests showed hypocalcemia (6.2 mg/dl), associated with high levels of VPA (106.00 µg/ml) and of PTH (289.00 pg/ml, n.v. 5-72) with normal levels of vitamin D (23.8 ng/ml n.v. 10-120), albumin (4.0 g/l), and phosphate (4.8 mg/dl). The high levels of alkaline phosphatase indicated an increased bone turnover and a state of decreased bone mineral density. The dose of valproic acid was considerably reduced, whereas the dose of lamotrigine was not varied, leading to reduction of plasma valproic acid levels and paralleled by normalization of plasma PTH, calcium and ALP values. The patient was followed up for 8 months, and the levels of calcium, vitamin D, and VPA in the blood have been maintained in the normal range. According to the Naranjo ADR probability scale, valproate subsequent hypocalcemia was classified as highly probable (score = 9).