Bernardini, Renato

Cantarella, Giuseppina

Li Volti, Giovanni

Pavone, Lorenzo

Pavone, Piero

Praticò, Andrea Domenico

Scuderi, Maria Grazia

English

PubMed

Andrea Praticó

Piero Pavone

Maria Scuderi

Giovanni Volti

Renato Bernardini

Giuseppina Cantarella

Lorenzo Pavone

Springer - Publisher Connector

Case report
Open Access
Symptomatic hypocalcemia in an epileptic child treated with
valproic acid plus lamotrigine: a case report
Andrea Domenico Praticò1*, Piero Pavone1, Maria Grazia Scuderi2,
Giovanni Li Volti3, Renato Bernardini2, Giuseppina Cantarella2
and Lorenzo Pavone1
Addresses: 1Department of Pediatrics, University of Catania, Catania, Italy, 2Department of Experimental and Clinical Pharmacology,
University of Catania, Catania, Italy and 3Department of Biochemistry, University of Catania, Catania, Italy
Email: ADP* - terrenere178@tin.it; PP - ppavone@unict.it; MGS - mrscud@unict.it; GLV - livolti@unict.it; RB - bernardi@unict.it;
GC - gcantare@unict.it; LP - lorenzo_pavone@hotmail.com
*Corresponding author
Received: 21 April 2009 Accepted: 12 June 2009 Published: 17 June 2009
Cases Journal 2009, 2:7394 doi: 10.4076/1757-1626-2-7394
This article is available from: http://casesjournal.com/casesjournal/article/view/7394
© 2009 Praticò et al; licensee Cases Network Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Introduction: An epileptic child had been long treated with valproic acid and lamotrigine. After a
few years of treatment, he manifested severe clinical signs of hypocalcemia. We retain that valproic
acid could have caused such metabolic dysfunction.
Case presentation: We report here the involvement of valproic acid in symptomatic hypocalcemia
in an 11-year-old epileptic white patient in treatment with valproic acid and lamotrigine. During the
treatment the patient developed hypocalcemia associated with high plasma levels of valproic acid,
parathyroid hormone and alkaline phosphatase, indicating increased bone turnover. Plasma levels of
Vitamin D were normal. Plasma calcium values significantly correlated with valproic acid haematic
levels; reduction of valproic acid dose was accompanied by prompt normalization of calcemia.
The specific mechanism through which valproic acid causes hypocalcemia is unknown, although the
relationship between valproic acid dose and haematic levels of calcium appears very likely.
Conclusions: It seems necessary, during long term therapy with valproic acid, to monitor plasma
calcium and alkaline phosphatase plasma levels. Also, these patients should undergo treatment and
perhaps prescribe vitamin D and calcium treatment.
Introduction
Hypocalcemia is defined as low calcium levels in the blood,
usually taken as less than 8.5 mg/dL. A growing body of
evidence suggests a relationship between this condition
and long-term anticonvulsant therapy. Although this
association has been initially confirmed only for those
anti-epileptic drugs (AEDs) inducing the cytochrome P450
enzyme system due to the defective vitamin Dmetabolism
and consequent reduction of intestinal absorption of
calcium (i.e. phenobarbital, phenytoine, carbamazepine,
Page 1 of 3
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primidone), more recent studies highlight the possible
involvement of other anticonvulsant drugs, such as valproic
acid. The mechanism involved in such alteration is still
matter of open debate [1,2].
We herein report the case of an 11-year-old white, epileptic
patient treated with valproic acid and lamotrigine who
developed symptomatic hypocalcemia.
Case presentation
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 malfor-
mations. 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, neuroradio-
logic 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 karyo-
type) 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 numb-
ness, 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 consider-
ably 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).
Discussion
Anticonvulsant drugs have hypocalcemic effects [1-5],
with mechanism that differ depending upon the class of
drugs considered. The inductors of the P450 cytochrome
enzymes diphenylhydantoin, carbamazepine, pyridostig-
mine are known to enhance vitamin D catabolism, with a
consequent reduction of its biological effects. These drugs
can also inhibit the cellular response to parathyroid
hormone, as well as reduce the intestinal absorption of
cations.
Valproic acid is not an enzymatic inducer, nor it interferes
with Vitamin D metabolism. However its metabolites act
as anions, thus, binding plasma calcium ions and for this
reason may cause hypocalcemia [6]. Furthermore, valproic
acid and its metabolites are osmotically active anions that
contribute to the hyperosmolality and acidosis. Its effects
are dose- and time-dependent. Treatment with valproic
acid may produce long-term effects as reduction of the
bone mass, with increased risk of fractures, an effect
associated with high levels of plasma alkaline phospha-
tase. Such risk increases proportionally with the duration
of the therapy [4-7,8], although other studies are
discrepant with this findings [9].
At our knowledge, lamotrigine does not cause hypocalce-
mia, nor it causes increased levels of markers of bone
turnover in the blood, suggesting that this agent exerts no
impact on bone mass even during long lasting treatments
[2,10-12].
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Cases Journal 2009, 2:7394 http://casesjournal.com/casesjournal/article/view/7394
Our patient presented hypocalcemic convulsions after a
6 years treatment with both valproic acid and lamotrigine.
The level of calcium was low (6.2 mg/dL); at the same
time, plasma levels of valproic acid, parathyroid hormone
and alkaline phosphatase were elevated, whereas plasma
phosphate was normal (4.8 mg/dL). Apparently, dietary
calcium intake was appropriate, so to exclude that
hypocalcemia could originate from low calcium diet.
Moreover, the child, although walking only if sustained, is
being mobilized through appropriate physical exercises
and physiotherapy, thus excluding another possible cause
of hypocalcemia, immobilization.
Finally, the long-term therapy with valproic acid, as well as
a diminished catabolic capability for the drug, could well
account for hypocalcemia observed in this patient. In fact,
clinical symptoms became milder and eventually dis-
appeared concomitantly to the reduction of the dose of
valproic acid. As a consequence of such dose reduction,
we also observed normalization of plasma levels of
parathyroid hormone and alkaline phosphatase.
Our assessed experience on epileptic pediatric patients
using long-term treatment with valproic acid suggests that
it is plausible that hypocalcemia could be related with the
use of high doses of valproic acid.
Children long treated with high doses of valproic acid
should be monitored for plasma calcium and alkaline
phosphatase levels on a regular basis, in order that special
care may be given to those patients who display drug
metabolism-related disorders. Moreover, vitamin D and
calcium treatment could be appropriately prescribed
during long term therapy with valproic acid.
Abbreviations
VGB, Vigabatrin; AED, anti-epileptic drugs; VPA, Valproic
acid.
Consent
Written informed consent was obtained from the patient
for publication of this case report and accompanying
images. A copy of the written consent is available for
review from the journal’s Editor-in-Chief.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
ADPwrote themanuscript and assessed the patient. PP and
GV performed the data analysis. MGS, RB, GC performed
the laboratory examinations, suggested the treatment. LP
reviewed the manuscript, interpreted the patient data. The
manuscript was approved by all the authors.
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Symptomatic hypocalcemia in an epileptic child treated with valproic acid plus lamotrigine: a case report

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Symptomatic hypocalcemia in an epileptic child treated with valproic acid plus lamotrigine: a case report

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