Indian Epilepsy Society

Valproic Acid:
Indian Consensus Document

Editor-in-Chief
Man Mohan Mehndiratta

ELSEVIER
 Indian Epilepsy Society:
Valproic Acid: Indian Consensus Document

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ii
 Core Committee and Contributors

Man Mohan Mehndiratta – Convener Sanjeev V. Thomas – Convener

Director; Professor & Head, Professor of Neurology and
Department of Neurology, Head of R. Madhavan Nayar Centre for
Janakpuri Super Speciality Hospital, Comprehensive Epilepsy Care,
New Delhi Department of Neurology, Sree Chitra Tirunal
Institute for Medical Sciences and Technology,
Thiruvananthapuram

Neeraj N. Baheti Jayantee Kalita

Consultant Neurologist and Epileptologist, Professor, Department of Neurology
Central India Institute of Medical Sciences, Sanjay Gandhi Post Graduate medical Sciences,
Nagpur 440010, Maharashtra Lucknow

Atma Ram Bansal Parampreet S. Kharbanda

Neurologist and Epileptologist, Additional Professor Neurology & In-charge
Medanta—The Medicity Gurgaon, Comprehensive Epilepsy Program,
Haryana Department of Neurology,
Postgraduate Institute of Medical Education &
Sanjeev Bhoi
Research (PGIMER), Chandigarh
Assistant Professor, Department of Neurology
Sanjay Gandhi Post Graduate medical Sciences, Chanda Kulkarni
Lucknow Advisor – Department of Clinical Pharmacology,
SAKRA World Hospital; Bangalore, India
Deepanshu Dubey
Senior Resident, Department of Neurology Bindu Menon
Sanjay Gandhi Post Graduate medical Sciences, Senior Consultant Neurologist,
Lucknow Apollo Speciality Hospitals, Nellore
Usha Kant Misra
Sheffali Gulati
Professor & Head, Department of Neurology,
Professor of Pediatrics,
Sanjay Gandhi Post Graduate Institute of
Chief of Child Neurology Division,
Medical Sciences,
Department of Pediatrics,
Raebareli Road, Lucknow
All India Institute of Medical Sciences,
New Delhi P. Satishchandra
Director/Vice Chancellor and Senior Professor of
Satish Jain Neurology, National Institute of Mental Health &
Director, Indian Epilepsy Centre, New Delhi Neuro Sciences (NIMHANS),
Bengaluru, Karnataka
Sita Jayalakshmi
Senior Consultant Neurologist, Vinod S. Saxena
Krishna Institute of Medical Sciences, Life Trustee Indian Epilepsy Association –
Secunderabad, Telangana 18th International Epilepsy Congress Trust, Delhi

iii
 Suvasini Sharma Sudhindra Vooturi
Assistant Professor, Department of Neurology, Krishna Institute of
Department of Pediatrics, Medical Sciences, Minister Road,
Lady Hardinge Medical College and Secunderabad - 03, Telangana,
Associated Kalawati Saran Children’s Hospital, India
New Delhi
Nandan Yardi
Gagandeep Singh Consultant Epileptologist & Pediatric Neurologist
Professor & Head, Associate Professor,Pediatrics ,
Department of Neurology, BJ MEDICAL COLLEGE(MUHS)
Dayanand Medical College, Ludhiana Yardi Epilepsy & sleep clinic, Kothrud, Pune
KEM hospital, Jehangir Hospital, Deenanath
Sanjib Sinha Mangeshkar Hospital Pune
Professor of Neurology, Member, Task force on pediatric
NIMHANS, Banglore Epilepsy Surgery (2004-)
Manjari Tripathi Member, ILAE Treatment Strategies Commission
Professor, Department of Neurology, (2004-2009)
Neurosciences Centre,
All India Institute of Medical Sciences, New Delhi

iv
 ELSEVIER INDIA
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Dr. Nitendra Sesodia Mr. Ganesh Venkatesan

EDITORIAL OFFICE
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v
 Contents

Statement of Need and Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Historical Aspect of Valproic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Clinical Pharmacology of Valproic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Valproic Acid – Role in Idiopathic Generalized Epilepsy (IGEs) . . . . . . . . . . . . . . . . . . . . . . . 15

Valproic Acid in Focal Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Valproic Acid in Epileptic Syndromes with Special Reference to Juvenile Myoclonic Epilepsy . . . . . . 23

Valproic Acid in Status Epilepticus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Efficacy of Valproic Acid – Comparison with Other Anti-Epileptic Drugs . . . . . . . . . . . . . . . . . 30

Valproic Acid – Adverse Effects and Tolerability Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

Pharmacoeconomics of Valproic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

Valproic Acid – A Paediatric Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

Valproic Acid Use in Girls and Women with Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

Valproic Acid in Epilepsy with Various Comorbidites and Systemic Disorders . . . . . . . . . . . . . . . 59

vi
Statement of Need and Introduction
Man Mohan Mehndiratta

Neurology, as a branch of medicine, is a society, the practitioners need to update themselves

superspecialty that requires knowledge of a wide on the current approaches and the wide variety of
range of clinical presentations. Because of the choices now available. India has a distinct need
diversity of clinical conditions encountered and for comprehensive programs about the drugs and
the modification of the presentation of these at disease conditions that fit into the Indian context
various stages of growth and development, it takes of the situation. It has to be a continuous process
longer to acquire the pattern recognition and to be that aims at updating the clinicians on the current
able to recognize presentations of the common and scenario and clear the apprehensions based on
rare conditions. Epilepsy is a common neurological scientific evidence and approaches the problem on
disorder with 65 million People with Epilepsy (PWE) the basis of the experience of the specialists in India
worldwide and approximately more than 12 million who are among the stalwarts in this field.
in India. Two-third of PWE live in resource-limited This document provides a useful basis from which
countries. to view new and existing perspectives in usage and
In this age, where at times there seems to be an position of Valproic Acid in the management of
overabundance of information, it is important for epilepsy, coupled with the more traditional protocols.
the practicing clinician to have an authoritative It will be a valuable update tool and reference point
source of quality advice and genuine practice for the many professionals engaged in the field of
wisdom. Keeping in mind the requirements of the Neurology.

1
2
Historical Aspect of Valproic Acid
Vinod Saxena

Introduction Bromides came next. The Royal Medical and

Chirurgical Society of London met under the
The description of epilepsy dates back to antiquity. chairmanship of Sir Charles Locock then the
Written texts have been found in Akkadian language obstetrician for Queen Victoria. He must have been
in Mesopotamia in 2000 BC, in Sanskrit in Charaka very busy having delivered her nine children yet he
Samhita in 600 BC, in the Greek classic On the presided over scientific meetings of consequence.
Sacred Disease and in the Hippocratic collection of In one such meeting on 11th May 1857, Dr. Edward
medical writings in 400 BC.1 Shrouded as it has been Seiveking5 reported positive outcome with potassium
in superstition, dogmatism, mysticism, or even star bromide in 52 women. Locock endorsed the idea for
constellations, the treatments remained similarly treating more cases as he cited the observations of
obscurantist. Alchemy was some relief till modern another German physician who had seen similar
chemistry brought in a series of specific anti-epileptic benefit with valerian.
drugs (AEDs).
As a group of chemicals with medicinal use
In such a scenario, one compound, valproic acid
barbiturates had existed for four decades before,
(VPA) stands out as singularly unique.
phenobarbitone was recommended in 19126 to sedate
It came into therapy in 1960’s, through an
agitated patients suffering from epilepsy. Three
illustratively piquant expression: serendipity. By now,
decades later in 1938, phenytoin became the first
it occupies an exalted position in the Pantheon of
AED supported with specific experimental proof.
AEDs. It remains the subject of perpetual research
There were demonstrable EEG changes and positive
into its ever expanding clinical horizons. VPA is
results on a cat experimental model,7 leading to an
now a part of more than 130 national health care
established clinical use of phenytoin ever since.
programmes. Since 1988, it has regularly featured as
an anticovulsant in the WHO Model List of Essential Then stepped in VPA to fulfil its greatest promise
Medicines.2 as an AED.
VPA is even considered for a ‘marooned island The discovery of VPA came out of ‘serendipity’ a
drug list’. It will protect against seizures, could word attributed to Horace Walpole for its coinage.
be useful for analgesia, preventing migraine and Walpole was referring to a collection of short stories
stabilizing the mood particularly if one becomes which were published in 1557 titled The Three
mentally unbalanced on the island. It might even Princes of Serendip8 (set in an island Serendip or
help to prevent the development of cancer. A simple Swarandeep in Sanskrit and present day Sri Lanka).
chemical yet, it has so much to offer.3 The original Persian fairy tales were put together as
Hasht-Bihisht by Amir Khusrau’s
Treatment Before Valproic Acid (Sixteenth (1253-1325, born in Etah, UP), who
to Early Twentieth Century) is more famous as a musicologist
and who wrote his songs in a
Valerian (Valeriana officinalis) root was used in language combining Persian, Hindi
1592 by Fabio Colonna to cure his own epilepsy. and Awadhi.
It remained the best treatment for the next three Walpole called these stories as
centuries. Valerian yields isovaleric acid, which “silly fairy tales” where the three Fig. 1:
is analogous to valproic acid and hence could be princes by “accidents and sagacity” Horace Walpole
considered as the first (AED).4 discern the nature and make (1717-1797)

3
continuous discoveries in their travels. The example indeed proved correct as dose levels of 250 and 420
of serendipity: “they discovered that the mule that mg/kg proved to be anticonvulsant in all animals
had recently covered the same road was blind in the while lower doses were only partially effective.
right eye because the grass was more worn out on These positive results were first presented
the left side.” at the French Society of Therapeutics and
Pharmacodynamics on December 19, 1962 and later
Valproic Acid as a Chemical Entity published in 1963.11
VPA as an analogue of valeric acid was first
Towards a Drug Candidate in Europe
synthesised in 1881 in by an American chemist
(1963-1973)
Beverly S. Burton.9 It is a simple branched –
chain carboxylic acid di-n-propylacetic acid or Mention of VPA includes valproic acid and its
2-propylpentanoic acid or 2-propylvaleric acid. sodium, magnesium and calcium salts in various
The molecular formula is C8H16O2 and the formulations.
molecular weight is 144.21 g/mol. It is water- Chemically VPA is one of the simplest drugs
insoluble (1.27 mg/mL), weakly acidic (pKa = 4.8) currently available in our therapeutic arsenal with
but the sodium salt is freely water soluble and very eight carbons and no nitrogen atom or cyclic ring. It
hygroscopic. was been found that increase in carbon atoms from
CH2CH2CH2 8 to 9 enhanced the sedative activity. Straight chain
CHCOOH acids had mild to no activity. Amide compound
CH2CH2CH2 valpromide had greater liposolubility and helped
The year 1881 saw another co-incidence of cross the blood-brain barrier compound. It was also
paramount consequence as Sir William Gower10 fully twice as potent in anticonvulsant activity.
described epilepsy in the same year. Screening with PTZ led to tests on other models
e.g. seizure induced by maximal electroshock (MES)
The First Evidence of VPA as an
and seizures induced by strychnine, bicuculline and
Anticonvulsant (1962-1963) picrotoxin in mice and audiogenic seizures in rats.
Khelline has been a valuable herbal source All these test models also gave positive results.
for diverse therapeutic areas (e.g. amiodarone The group of researchers was getting wider as
and chromolyn). One, Mr. Pierre Eymard, a Georg Carraz then contacted Sergio Berselli and
doctoral student in the University of Lyon, France Pierre Lambert in the Hôpital Psychiatrie, Bassens,
had synthesised a number of compounds from France. Carraz got help from the School of Medicine
khelline. While wanting to test these further, he and Pharmacy and from Berthier Laboratories
found these to be water-insoluble. He sought both at Grenoble. The joint publication12 aroused
advice from Laboratoire Berthier in Grenoble who pharmaceutical interest. Later, Laboratoire Azidique
recommended valproic acid as a lipophilic vehicle. (Azide Laboratory) took over the research and
To Eymard’s surprise all the compounds synthesised renamed itself Labaz having decided to develop VPA
showed activity in the anticonvulsant screen. Two as an AED in Europe.
pharmacologists who worked along, H. Meunier and Consequently, more extensive work on
Y Meunier suspected the solvent vehicle to be active. pharmacology, pharmacokinetics, monitor of
They checked VPA on the standard anticonvulsant interactions with other drugs, biochemical and its
models. Pentylenetetrazole seizure (PTZ) test was possible adverse effects began along with chronic
applied to experimental groups of four rabbits each toxicity studies. The regulatory environment was
who were given the recommended anticonvulsant becoming tighter in most countries following ban
protective dose of PTZ 30 mg/kg intravenously. on thalidomide marketing in early to mid-1960
Forty minutes later, varying doses of VPA were with increased controls on introduction of new
administered intraperitoneally. Their contention was drugs.13 The developing company was required to

4
produce extensive basic scientific and clinical data first launched in France in 1967 followed by Holland
with particular emphasis on safety. To commit to and Belgium in 1971, Switzerland, Finland, Denmark
additional scientific, toxicity and clinical evidence in and Italy in 1972 and in Germany in 1973, for use in
the renewed regulatory environment with possible refractory cases or as add-on therapy.
legal responsibilities entailed huge financial risks.
Labaz seemed willing to take up this challenge Towards Drug Approval in the
with a remarkable foresight. The first few clinical United Kingdom (1973-1977)
trials to establish VPA and its role in various types of
epilepsies, with valpromide then with a combination Labaz prepared itself for wider introduction of
of VPA with phenobarbitone. Encouraged with VPA after achieving good success in Europe. A joint
positive clinical indicators they tested VPA alone. venture called Reckitt-Labaz was found in the UK in
There was indeed reduction in the number of seizures 1973 with Reckitt & Colman UK as the latter operated
with VPA and “…the patients felt themselves more; in at least 60 Anglophone countries where Labaz did
not have a direct reach. The new company Reckitt-
the mental stickiness, viscosity that had sometimes
Labaz was then headed by a physician Dr. Richard
been the standard with the older agents, was less. We
Smith (latterly Chief Editor British Medical Journal).
saw the disappearance of the tendency to depression,
He sponsored Dr. V.S. Saxena in 1973 to work with
sometimes even a mild euphoria”.14
Prof. Paul Turner, St Bartholomew Hospital, London
So far the pharmacological work was mostly limited
for pharmacokinetics of VPA and another CNS-
to rodent models using PTZ, MES etc. These were
active drug. Afterwards Dr. Saxena worked under
not adequate to elicit range of activities where VPA
Dr. Alan Richens, Cardiff and Dr. Harry Meinardi
could be used e.g. in absence attacks where clinical
from the Instituut voor Epilepsiebestrijding, Meer-
evidence was very encouraging. So primates, which
en-Bosch, Heemstede, Holland. Dr. Meinardi had the
replicate human response more accurately, were used
longest experience since 1965 with VPA in Europe in
despite their high cost. Rhesus monkey was a good
its kinetics, blood level estimation,18 EEG correlation
model for eliciting focal fits by alumina gel implant
and clinical work and he invited Dr. Saxena for work
but it required animals to be maintained over several
on the kinetics of VPA.
months and negative outcome wasted time and
In the UK, Dunlop Committee was replaced by
resource. Ciba-Geigy Research Centre, Bombay (Dr.
the Committee on Safety of Medicines (CSM) as an
RS Grewal and Dr. Joy David) despite their earlier
independent advisory entity to the UK Licensing
success on rhesus monkey model for focal seizures
Authority on the quality, efficacy and safety of drugs.
and interictal EEG abnormalities15; they had novel
On their first review on VPA of data submitted
primate models including one for absence attacks in
by Reckitt-Labaz they insisted on further animal
rhesus monkey but those remained unpublished.
teratogenicity data. This was then carried out in
Meldrum16 found baboon (Papio papio) to be a
comparison with phenobarbitone, phenytoin and
very useful photosensitivity model as seizures could
carbamazepine in the Toxicology Laboratories of
be produced ‘on order’. This model was even more
Reckitt and Colman, Hull.19
expensive and the susceptible species was exclusive
to certain part of Senegal. The prospect of faster Clinical Trials
response encouraged Labaz to explore this model
further in this erstwhile French colony. This model Prof. Peter Jeavons Aston University, Birmingham
closely resembled the human photoconvulsive since 1964 was working on photoconvulsive model
seizure model and for instant response on EEG. in children with or without absence attacks (then
Herein once again VPA was proved very effective. mostly called petit mal) collaborating with an
So far most clinical trials with VPA were carried ophthalmologist Prof. Graham Harding20 at the
out as add-on to existing therapy using refractory same University. They were impressed with the very
cases The first placebo controlled double blind trials positive clinical response they got with VPA. Prof
was published by Meinardi in 1971.17 The drug was Jeavons then agreed to conduct the first clinical trial

5
 Fig. 2: Leading early investigators (1973-75) for valproate who associated with Dr. V.S. Saxena

1 2 3

(1) Prof. Paul Turner, Head Clinical Pharmacology Dept., St. Bartholomew’s Hospital, London. (2) Prof. Harry Meinardi,
Instituut voor Epilepsiebestrijding, Heemstede, Holland with Dr. V.S. Saxena on his right. (3) Dr. F.E. Dreifuss,
Comprehensive Epilepsy Centre, Univ. of Virginia, USA. (4) Dr. P. Jeavons on the right with Dr. V.S. Saxena in the middle
at Aston Univ., Birmingham. (5) Dr. M.C. Maheshwari, Dudley Road Hospital, Birmingham. (6) Dr. A. Covanis, Aston
Univ., Birmingham. (7) Dr. D. Chadwick, Liverpool, UK.

4 5 6 7

with VPA at the Dudley Road (now City) Hospital, representation or infrastructure to file new drug
Birmingham, where he was assisted by Dr. M.C. application with FDA, USA. Meanwhile, Reckitt-
Maheshwari for adult patients and Dr. A Covanis Labaz was taken over by Sanofi who in 1975 sold
for children.21 Other clinical trials were initiated their rights to Abbott for development of VPA in the
since 1973 with Dr. Edward Reynolds (London), Dr. American markets.
Robert Elwes (London) and Dr. David Chadwick There was urgent requirement to carry out more
(Liverpool). trials to introduce the drug. National Institutes of
The data generated on pharmacodynamics, Health (NIH), USA had designed new parameters
pharmacokinetics, toxicology and clinical trials for controlled clinical trials with AEDs. The
carried out in the UK became part of the dossier awareness of beneficial effects of VPA was coming
submitted to the CSM. Based on this Reckitt-Labaz into the US through press and television shows.
received Product License to market VPA as Epilim in Some patients started getting VPA from Mexico or
the UK and Ireland in 1975. travelling to Ireland, UK or Europe for treament.
Many neurologists tried to reason and persuade
Roll out in Other Markets (1975-1978) for its early introduction. Prof. FE Dreyfuss had
just then established a Comprehensive Epilepsy
Reckitt-Labaz did not have an adequate Centre in Charlottesville, Virginia with the aid of

6
NIH. He established radiotelemetry for the first Indonesia approved VPA for the local market.
time and he obtained excellent results in absence The political environment during 1970’s to 1980’s
seizures with VPA. He tried impressing upon FDA, in India and Bangladesh favoured local industries
for its introduction. One complicating information rather than multinational companies (MNCs).
came out in early 1978 as four out of five fatalities Foreign companies faced stringent conditions on
resulting from hepatitis with VPA.22 Prof. Dreiffuss manufacture, marketing, pricing, profits etc. Imports
as President of the American Epilepsy Society in were virtually impossible except by individual
1978, and as Chairman of the Professional Advisor patients who needed foreign exchange to pay more
Board of the Epilepsy Foundation of America at the than 120% import duty.
same time put up the correct scientific perspective By then the drug laws were amended in India as
of mitochondrial disorders in those cases. VPA it was decided that the first sponsoring company
was finally approved in the USA in mid-1978 and must conduct local clinical trials. The trials with
marketed by Abbott as Depakene. VPA were then started in 1978 in six major centres.
These were completed by 1980 and published.23 The
South Asia, South East Asia and Pacific Rim new drug laws also required obtaining industrial
countries (1977-1985) licensing for local manufacture as import was not
permitted. These functions were outside Dr. Saxena’s
When Reckitt-Labaz was taken over by Sanofi, area of responsibility. Yet pressure was faced from
Dr. Saxena was assigned to the associate company, the neurologists and needy patients. The advantages
Reckitt & Colman India in 1977, to review the of continued treatment were obvious just as denial
regulatory situation and progress to introduction of had increased seizures in some patients. Knocking
VPA in South Asia and Southeast Asian countries, on many official doors and sharing actual patient
Japan, Australia and New Zealand. master charts seemed to melt bureaucratic hearts.
Japan curiously got stuck on rat spermatogenesis Finally, in November 1981, VPA/Epilex was approved
data which they wanted to be repeated locally. for marketing and manufacture in India. VPA/Epilex
Australia and New Zealand needed local clinical was launched in India in February 1982.
trials. All these requirements were complied with
based on the data submitted in the UK and some Conclusion
additional local trial data which led to marketing of
VPA by1978/79. On the basis of usage VPA perhaps remains the
In Singapore, Thailand, Malaysia, Hong Kong and Number One AED the world over. Yet the molecule
Philippines the regulatory authorities were willing to could be modified to a more effective, neuroprotective
work on the basis of the dossiers submitted to the and site-specific targeted drug. Patients are still
CSM in the UK as long as the product was sourced looking for better tolerance and safety during
from the manufacturers in the UK. These countries pregnancy. The continuous development of VPA
needed minor labelling changes and use of local may hold encouragement for future and it will be
language in addition in Thailand. South Korea and a while before the last word is written about the
Taiwan registered the drug in 1979 for import with history of valproic acid.
data with labelling in local languages and English.
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París: Masson. 1966; 1034-1039. Practitioner.1982; 35.6:271-283

8
Clinical Pharmacology of Valproic Acid
Chanda Kulkarni

Introduction anticonvulsant for the last 40 years and subsequently

approved by FDA and EMA for the treatment of
Valproic acid [VPA] is regarded as a first generation migraine and bipolar disorder. VPA is a simple
anti-epileptic drug with its derivatives as second isooctanoic acid. Many of the derivatives have been
generation or follow up compounds [valrocemide synthesized as CNS active follow up compounds
and valnoctamide]. The reasons for design and which are currently under investigation for non-
development of this new group is a] to enhance brain neurological disorders and appear to have a huge
penetration b] to eliminate toxic metabolites c] to therapeutic potential.2,3
avoid teratogenicity seen with parent compound.1,2

Chemistry References
1. Meir Bialer. Chemical properties of antiepileptic drugs (AEDS). Advanced
Valproic acid (VPA) is chemically an achiral, unique, Drug Delivery Reviews.2012; 64: 887 – 895.
simplest branched short chain fatty acid molecule 2. Bialer M, Yagen B. Valproic acid – second generation. Neurotherapeutics
2007; 4:130–137.
derived from naturally occurring valeric acid and 3. Nalivaeva NN, Belyaev NCD, Turner AJ. Sodium valproate: An old drug
is devoid of a nitrogen atom or a cyclic ring. A with new roles. THIPS2009; 30:509–514.
4. Comelli NC, Duchowicz PR, Lobayan RM et al. QSPR study of valproic
weak acid insoluble in water but its sodium salt is acid and its functionalized derivatives. Molecular Informatics 2012; 31:
freely water soluble. VPA is well established as an 181–188.

Fig. 1: Valproic acid structure (2 propyl-

pentanoic acid), a unique simple small
monocarboxylic acid (fatty acid), was
discovered accidentally when being used as a
solvent in previous antiepileptic drug (AED)
testing. It is postulated that the main functional
group responsible for the antiepileptic activity
is the C = O (circled). This region provides
the initial electrostatic interaction between
VPA and the target protein causing reversible
inhibition (Comelli et al., 2012)4.

9
 Clinical Pharmacology
Clinically Relevant Drug-Drug Interactions of VPA
Table 1: Influence of Co-administered Drugs on VPA

Drug Group Interaction Comments

1. Influence of co-administered antiepileptic drugs on VPA
Phenobarbital /Primidone Double the VPA clearance Monitor the levels of VPA and
concomitantly used drugs whenever
Phenytoin
enzyme inducing drugs are
introduced or withdrawn
Carbamazepine May decrease plasma VPA levels. Close monitoring of VPA
Discontinuation of carbamazepine concentration whenever
may increase levels of VPA carbamazepine is initiated or
discontinued
Clonazepam May precipitate absence status in Use the combination with caution
patients with a history of absence
type seizures.
Felbamate May increase mean peak plasma Decrease in dosage of VPA
levels of VPA
2. Influence of chemotherapeutic agents on VPA
Carbapenems - May reduce concentration of VPA Avoid concomitant use, or monitor
ertapenem, imipenem, leading to loss of seizure control VPA levels, or consider alternative
meropenem anti-infective
Acyclovir May decrease levels of VPA, an Use concomitantly with caution
increase in seizure frequency and
worsening in EEG
3. Influence of other drugs on VPA
Aspirin VPA free fraction increased by Caution to be observed during
four-fold due to decreased protein concomitant use
binding and inhibition of its
metabolism
Rifampin May increase VPA clearance VPA dosage adjustment
Alcohol Additive effects with VPA Caution when used concomitantly
Chlorpromazine May increase trough levels of VPA Avoid concomitant use
Extracted from – Reference
[Link] ›Professionals › FDA PI Valproate – FDA prescribing information, side effects and uses Drug
Interactions

10
Table 2: Influence of VPA on Co-administered Drugs
Drug Group Interaction Comments
1. Influence of VPA on antiepileptic drugs
Phenytoin VPA increases plasma free phenytoin Monitor plasma phenytoin
concentration, displaces phenytoin concentrations when VPA is added or
from binding sites with increase in withdrawn
seizure frequency and phenytoin
intoxication
Clonazepam Possible but not common Precipitates absence status in patients
with absence seizures. Caution to avoid
administration
Diazepam, VPA increases free fraction of Excessive somnolence/ depressant
Phenobarbital/ diazepam by displacing from binding effect. Monitor patients closely for
Primidone or CNS sites and inhibits metabolism of neurotoxicity
depressants phenobarbital
Lamotrigine VPA inhibits metabolism of lamotrigine Possibility of increased risk of rash,
and increases elimination half-life. [SJS, TEN]. Reduce dose of lamotrigine
and use slower lamotrigine titration
rate
Topiramate Concurrent administration VPA leads Measure blood ammonia, discontinue
to hyperammonemia with/without VPA if symptoms appear
encephalopathy
2. Influence of VPA on psychotropic agents
Amitriptyline/ VPA reduces clearance and increased Consider close monitoring and dosage
Nortriptyline levels of amitriptyline/nortriptyline reduction of amitriptyline
Monoamine oxidase Potentiation of effects of MAO Consider dosage reduction of MAO
[MAO] inhibitors inhibitors inhibitors
3. Influence of VPA on chemotherapeutic agents
Zidovudine VPA inhibits metabolism of zidovudine Altered efficacy and toxicity of
and its clearance, hence increases its zidovudine. Close monitoring is
bioavailability recommended
4. Influence of VPA on other drugs
Oral anti-coagulant VPA may increase unbound fraction of Monitor coagulation tests when used
[warfarin] warfarin concomitantly
Extracted from – Reference
[Link] › FDA PI Valproate – FDA prescribing information, side effects and uses Drug
Interactions

11
 Mechanisms of Actions of VPA Glutamate antagonistic action

The identification of appropriate therapeutic VPA induces its anticonvulsant effects both by direct
strategies often depends on mechanisms underlying and indirect mechanisms such as:
epileptogenesis. Evaluation of these is not only a. Attenuation of NMDA receptor mediated
important for treatment of epilepsies, but also to excitation
help in developing new targets for treating seizures1. b. Inhibition of sodium and calcium channel function
A variety of experimental animal models of seizure which reduces glutamatergic transmission with
have demonstrated VPA as a broad spectrum increased brain levels of GABA.
anti-epileptic drug2. Extensive literature supports c. Most recently, animal experiments have provided
involvement of multiple mechanisms which explains robust evidence that supports involvement of PIP3
its wide spectrum of anti-epileptic activity. The depletion with seizure activity that is attenuated
following paragraphs summarize neurochemical by VPA producing reversal of these effects, thus
and neurophysiological mechanisms implicated providing a novel mechanism of action for VPA
primarily in anticonvulsant activity of VPA in in epilepsy treatment.1
animals as well as in humans. Lastly, a note on the d. Other possible undefined mechanisms include
basis for possible diverse therapeutic effects of VPA reduction in excitatory neurotransmission,
in other neurological and non-neurological disorders modulation of monoamines namely dopaminergic
is included. and serotonergic transmission.6
Effects on ion channels3
Mechanisms of Anti-epileptic Actions of VPA a. VPA produces weak inhibition of voltage-gated
sodium channels, leading to prolongation of
Neurochemical effects on the γ-aminobutyric acid
refractory period of high frequency neuronal
[GABA] system3
firing thus limiting the frequency of neuronal
Enhancement of GABAergic transmission by depolarization.7
VPA, an inhibitory neurotransmitter as a primary b. The blockade of T-type calcium channels is also
mechanism was postulated as early as 1968 and is said to contribute to its anticonvulsant effects.
supported and explained through its –
Neurophysiological effects on neuronal membranes8
a. Inhibitory effect on GABA degradation
b. Enhancement of GABA synthesis and its VPA at lower concentrations is shown to diminish
release through stimulation of glutamic acid high frequency repetitive firing of action potentials
decarboxylase, the enzyme instrumental in GABA of central neurons critically involved in its activity in
synthesis generalized tonic-clonic seizures.
c. An indirect effect on presynaptic GABA levels by Neurochemical and neurophysiological effects of
potentiation of postsynaptic GABAergic function active metabolites8
leading to feedback inhibition of GABA turnover
Several pharmacologically active metabolites of VPA
leading to increases in nerve terminal GABA
have been identified and explored for anticonvulsant
d. Increase in GABA concentrations within the brain activity following its rapid metabolism in vivo. One
is also said to be via multiple enzyme systems of the most active, potent and major metabolites
such as – GABA transaminase, α-ketoglutarate identified is the trans isomer of 2-en-valproate [E-2-
dehydrogenase and succinic semialdehyde en-valproate]
dehyrdrogenase, thus reducing excessive
neuronal firing4 and increase release of GABA, Putative mechanisms involved in early and late
possibly through stimulation of glutamic acid anticonvulsant effects8
dehydrogenase, the enzyme primarily involved in Carrier mediated active transport of VPA is
GABA synthesis.5 proposed to be involved in both extracellular [e.g.

12
ion channel] and intracellular [e.g. GABA synthesis] The conditions like – asthma due to hyperactivity
sites of action. The quick accesses to extracellular of central nervous system and to induce delay in
sites following acute administration of VPA and slow aging related to degenerative changes are under
access to intracellular sites is reported to explain investigation.22
its immediate and late anti-convulsant actions
respectively in pre-clinical and clinical studies. Conclusions
The above literature appears to support VPA with
Summary of Newer Novel Mechanisms of multiple mechanisms of actions to have a huge
Actions and Possible Indications for VPA in potential for its utility in wide variety of therapeutic
Other Neurological and Non-neurological indications.
Conditions
References
Non-epileptic and Neurological conditions 1. Chang P, Walker MC, Williams RS. Seizure-induced reduction in PIP3 levels
contributes to seizure-activity and is rescued by valproic acid. Neurobiol Dis 2014;
62: 296–306.
The use of VPA in the prophylaxis of migraine 2. Wolfgang Löscher. Mechanisms of drug resistance in status epilepticus. Epilepsia 2007;
headaches is approved by US – Food and Drug 48: [s8], 74–77.
3. Ahamed Zawab, John Carmody. Safe use of sodium valproate. Aust Prescr 2014;
Administration [FDA] and EME due to its ability 37:124–127.
to inhibition of glutamatergic hyperexcitability of 4. Kammerer M, Rassner MP, Freiman TM, Feuerstein TJ. Effects of antiepileptic
drugs on GABA release from rat and human neocortical synaptosomes. Naunyn
cortex. However, there is only moderate evidence Schmiedebergs Arch Pharmaco. 2011; 384(1):47-57.
for efficacy of VPA in the treatment of neuropathic 5. McNamara [Link] 19. Pharmacotherapy of epilepsies. In Brunton LL, Lazo JS,
Parker KL (Eds): Goodman & Gilman’s The Pharmacological Basis of Therapeutics.
pain where it produces altered pain sensitivity for 11th Edition. The Mc Grwa-Hill Companies Inc. New York. 2005.
which it is being explored in - diabetic neuropathy, 6. Cecilie Morland, Kaja Nordengen, Vidar Gundersen. Valproate causes reduction of
the excitatory amino acid aspartate in nerve terminals. Advances in Gene Therapy
post-herpetic neuralgia and in trigeminal neuralgia9, for Disorders of the Nervous System. Neuroscience Letters 2012: 527 [2], 100–104.
10 7. Large CH, Kalinichev M, Lucas A et al. The relationship between sodium channel
. VPA is also under investigation for use in inhibition and anticonvulsant activity in a model of generalised seizure in the rat.
Alzheimer’s disease.11 Epilepsy Research 2009; 85: 96–106.
8. Wolfgang Löscher. Pharmacological effects and mechanisms of action. In-Mile stones
Non-neurological conditions in drug therapy Valproate, Ed: W Loscher. Indian Reprint 2007: 7-45.
9. Robert H. Dworkin et al. Recommendations for the Pharmacological Management
of Neuropathic Pain: An Overview and Literature Update. Mayo Clinic Proceedings
The blocking of sodium channels as a mechanism, 2010: 85;S3–S14.
appears to be implicated in a psychiatric condition 10. Shirra Moch. Therapeutic uses of antiepileptic drugs in non-epileptic disorders:
Review SA Pharmaceutical Journal 2010: 77[5]18-20, 22-24, 26-27.
namely — bipolar affective disorder.12,13,14 The am- 11. Nalivaeva NN, Belyaev NCD, Turner AJ. Sodium valproate: an old drug with new
plifying dopaminergic activty aggravates schizo- roles. THIPS 2009: 30; 509–514.
12. Malhi GS, Adams D, Porter R et al. Special Issue: Clinical Practice Recommendations
phrenia is proposed to improve the symptoms by for Mood Disorders. Acta Psychiatrica Scandinavica 2009: 119 [s439], 5–46.
potentiating GABA activity.15 Further, conditions 13. Weisler RH, Cutler AJ, Ballenger JC, Post RM, Ketter TA. The use of antiepileptic
drugs in bipolar disorders: A review based on evidence form controlled trials. CNS
like cocaine craving, alcohol withdrawal16 and im- Spectr 2006; 11:788–799.
pulsivity/aggression are hypothesized due to gluta- 14. Fountoulakis KN. An update of evidence-based treatment of bipolar depression:
Where do we stand? Current Opinion in Psychiatry 2010: 23 [1], 19-24.
mate-induced synaptic plasticity. VPA by reducing 15. Ettinger AB, Argoff CE. Use of antiepileptic drugs for non-epileptic conditions:
Psychiatric disorders and chronic pain. Neurotherapeutics 2007; 4(1):75-83.
glutamate transmission and increasing GABAergic
16. Johannessen LC. Antiepileptic drugs in non-epilepsy disorders: Relations between
‘lagging’ of pathological firing is known to have ben- mechanisms of action and clinical efficacy. CNS Drug 2008; 22(1):27-47.
eficial effects.16 The use of VPA in conditions such 17. Mackey C. The anticonvulsants market. Nat Rev Drug Discov 2010; 9:265–266.
18. Venkataramani V, Rossner C, Iffland L et al. Histone deacetylase inhibitor valproic
as fibromyalgia and extra-pyramidal dysfunction are acid inhibits cancer cell proliferation via down-regulation of the alzheimer amyloid
precursor protein. J Biol Chem. 2010; 285(14):10678-89.
being investigated.17 19. McIntyre, J., Moral, M.A., Bozzo, J. Combination therapy with valproic acid in
The mechanism of action of VPA such as histone cancer: Initial clinical approach. Drugs Fut 2007; 32(1): 45.
20. Sun L, Coy DH. Anti-Convulsant Drug Valproic Acid in Cancers and in Combination
deacetylase [HDAC] inhibition is said to offer Anti-Cancer Therapeutics. Mod Chem appl 2014; 2: 11
opportunities for its use in cancer treatment.18 21. Berendsen S, Broekman M, Seute T, et al. Valproic acid for the treatment of malignant
gliomas: Review of the preclinical rationale and published clinical results. Expert Opin
Many Phase III studies are underway to evaluate Investig Drugs 2012; 21(9):1391-415.
its activity against breast, glioblastoma, endometrial 22. Lomia M, Chapichadze Z, Pruidze M, Platonov P. Efficacy Of Monotherapy With
Carbamazepine And Valproic Acid In Patients With Bronchial Asthma: Is Asthma A
and prostate cancer.19,20,21 Neurological Disease?The Internet Journal of Neurology. 2004; 4, 1.

13
 PK – Parameters of VPA1, 2
ABSORPTION DISTRIBUTION ELIMINATION
Bioavailability Peak con- Food delays Therapeutic con- Distributed Protein Detected Metabolism Mainly in Increased
centration absorption of centration range – Rapidly binding is in CSF & in liver urine as clearance
oral prepa- 50-100 mcg/mL Detected concen- saliva by beta metabo- in children
Rapid & com- 1 – 4 hrs
rations but Toxic - in CSF and tration Crosses & omega lites 3 months
plete absorption
not extent of saliva depend- placenta & oxidation Small to 10 yrs.
oral Valproic > 150 mcg/mL
absorption ent eliminated and glucu- amounts Decreased
acid [Concentrations in milk ronidation in feces clearance
from GI tract DO NOT correlate Half-life & expired in neonates
Oral divalproex 3 – 5 hrs well with its 5-20 hrs air & geriatric
sodium therapeutic population.
Oral divalproex - effects]
Reduced
sodium-Delayed
clearance
Release[DR]
in hepatic
Oral divalproex 6 – 14 hrs and renal
sodium-Extend- impairment.
ed Release [ER]
Valproic acid IV Similar to -
injection above
NOTE - Divalproex Sodium Extended Release [ER]
• Dosing frequency of ER is – once a day compared to delayed release [DR].
• Twice a day ER dosing, increases steady state trough concentration to higher values making it efficacious and safer by reaching
plateau levels.

References
1. Adapted and extracted from:[Link] › Professionals › FDA PI
2. [Link]
3. On-line version ISSN 1980-5365 J. epilepsy clin. neurophysiol. vol.13 no.2 Porto Alegre June 2007

Preparations of VPA with storage instructions

Routes Dosage Forms Strengths Storage

Oral Solution 250 mg (of valproic acid) per 5 mL* Tight containers at <30°C; avoid freezing

Parenteral Injection, for IV use 100 mg (of valproic acid) per mL* 15–30°C. Discard unused portions of the solution

Oral Capsules, delayed-release 125 mg

250 mg 25°C; may be exposed to 15–30°C
Tight containers at 15–25°C.
500 mg
Capsules, liquid-filled 250 mg*
Capsules (containing equivalent to valproic acid 125 mg* <25°C
coated particles)
equivalent to valproic acid 125 mg* Tight, light-resistant containers at a temperature <30°C
Tablets, delayed-release
equivalent to valproic acid 250 mg*
Oral
equivalent to valproic acid 500 mg*
equivalent to valproic acid 250 mg* 25°C, but may be exposed to temperatures ranging from
Tablets, extended-release equivalent to valproic acid 500 mg* 15–30°C

REF: Adapted from - [Link]

*available from one or more manufacturer, distributor, and/or re-packager by generic (non-proprietary) name

14
Valproic Acid – Role in Idiopathic
Generalized Epilepsy (IGEs)
Sanjib Sinha, P. Satishchandra

Introduction Valproic acid; treatment of Idiopathic Generalized

Epilepsy, and, for MeSH terms in PubMed, Epilepsy,
VPA has been used extensively as an antiepileptic Generalized; Epilepsy, Idiopathic Generalized;
drug (AED) over the past four decades, and occupies Diagnosis and Therapeutics
an important place as a first-line therapy for many
epilepsy syndromes in adults, notably Idiopathic Classification of Clinical Trial Evidence
Generalized Epilepsy (IGEs).1,2 In spite of the lack of
randomized, double-blind studies in JME , the efficacy Evidence of AED efficacy in the literature is divided
of valproic acid monotherapy has been documented into four classes::
in many clinical series. Despite availability of newer  Class I evidence requires results from randomized
AED like levetiracetam, the efficacy of VPA in JME controlled studies. They are of 2 types:-
is unparalleled. Valproic acid is of particular interest – Class IA: It is a meta-analysis of double blind,
in IGEs as AEDs like carbamazepine, oxcarbazepine, randomized controlled trials (RCTs).
lamotrigine and phenytoin may aggravate seizures in – Class IB: It is at least one RCT in a series.
certain cases and thus these AEDs should only be  Class II evidence requires results from matched,
used with caution in generalized epilepsies. controlled, but not randomized trials.
This position has been acquired because valproic  Class III evidence comprises uncontrolled
acid has been recognized as a generally safe and comparisons involving groups of patients and
effective therapy. A workshop was held in Goteborg case studies.
in June 2005 in which epilepsy experts from around  Class IV evidence comprises additional efficacy
the world discussed the place of valproic acid in information, including expert opinions.
treating adult epilepsies, evaluating the epilepsy types
for which the drug is most suitable and addressing Treatment of IGE
issues in the use of valproic acid in women of child-
So far, no AED has Class I or Class II evidence
bearing age, in men and in patients with psychiatric
regarding efficacy or effectiveness in adults with
comorbidity. This issues discussed and the consensus
IGEs.4 Recently, four RCTs which examined initial
positions of this meeting have been summarized in
monotherapy of adults with IGEs were considered
an article by Ben-Menachem et al.3
class III studies because of either an open-label
The objective is to develop consensus guidelines for
design5,6, too brief treatment duration5,7 or lack of an
the use of valproic acid (VPA) in IGEs. The objective
adequate comparator.8
was to provide useful and shared information for
VPA in the treatment of IGE: VPA is the most
physicians, healthcare professionals, patients and
effective anti-epileptic drug (AED) in patients with
their caregivers.
IGEs and is considered to be the drug of choice.6 This
Data Sources is especially true if it is given as the sole antiepileptic
drug.9,10 There is Class III evidence that VPA is more
Data were retrieved from PubMed and Cochrane effective than lamotrigine and better tolerated than
review; the terms used were: Idiopathic Generalized topiramate in generalized or unclassified epilepsy.6
Epilepsy; Idiopathic Generalized Epilepsy and There is also Class III evidence that if the daily dose

15
 does not exceed 40 mg/kg or 2.5g, it is singularly 8. Epilepsy With Generalized Tonic–Clonic Seizures
free from serious side effects.11 Valproic acid is of Only (IGEs With GTC Only)
particular interest in IGEs, as many other AEDs This document deals with guidelines for CAE, JAE,
such as carbamazepine, oxcarbazepine, lamotrigine, JME, IGEs with GTC Only and IGEs NOS.
vigabatrin and phenytoin may aggravate seizures
in certain cases and thus should only be used with Absence Epilepsy (AE)
caution in generalized epilepsies.12 Valproic acid
can also be recommended as first-line monotherapy VPA and Ethosuximide (ESM) are established
in IGEs with multiple seizure types.13 In addition, (level A) and lamotrigine (LTG) is possibly (level C)
valproic acid could be prescribed as an initial efficacious as initial monotherapy for children with
conservative treatment option in newly diagnosed newly diagnosed or untreated absence seizures.4
patients in whom the nature of the epilepsy This was indicated by a Class 1A superiority trial
syndrome (i.e. focal vs. generalized) has not yet comparing VPA, ESM, and LTG in 446 children with
been determined14, as the risk of seizure aggravation absence seizures.20 The initial report focused on the
is low and the chances of improving seizure control short-term (16–20 weeks) freedom from failure rate,
are relatively good. There is also Class III evidence an effectiveness outcome measure defined as seizure
that VPA reduced seizure-related morbidity and freedom without intolerable side effects; the rate
improved educational and occupational functioning was 58% for VPA and 53% for ESM (no significant
in patients with IGEs.15 difference between VPA and ESM), both of which
Problems with VPA: Valproic acid rates lowest were higher than the rate for LTG (29%; p <0.001
with respect to favorable pharmacokinetic for both comparisons). These findings persisted over
characteristics, mostly because of its non-linear the first 12 months of double-blind therapy, allowing
pharmacokinetics, extensive hepatic metabolism, this study to qualify as a successful Class IA study.
and its high propensity to interact both with other A Class 1B trial done on the EEG readings of 25
AEDs and non-AEDs.16 VPA is also well known to patients with absence seizures treated with valproic
have teratogenic side effects. It causes dose dependent acid (VPA) in doses of 17–62.5 mg/kg/day showed
damage to the fetus related to the exposure to AEDs that 19 (76%) patients experienced a reduction in
during pregnancy.17,18 However, failure to prescribe spike-and-wave charges, and 11 (58%) of the 19 had
valproic acid for IGEs, particularly when another a spike-and-wave discharge reduction of >75%, a
first-line treatment has failed, may not be in a young statistically significant (p < 0.02) reduction. Twenty-
woman's best interests, particularly when they are one (84%) patients had a reduction of the total time
most vulnerable to sequelae from uncontrolled of spike-and-wave discharge, and 19 (76%) patients
seizures.15 had fewer absence seizures. The authors noted that
clinical improvement occurred in the patients when
According to the ILAE Classification of plasma levels of VPA reached 50–60 μg/ml.21 In a
Epilepsies and Epileptic Syndromes (1989) multicenter, open study was conducted on patients
(19), there are Eight IGE Syndromes with IGEs on VPA monotherapy. In this study,
21 patients had absence seizures and were given
1. Benign Myoclonic Epilepsy In Infancy (BMEI) a mean daily dose of 20 mg/kg of VPA. After 18
2. Generalized Epilepsy With Febrile Seizures Plus months receiving VPA monotherapy, 20 (95%) of
(GEFS +) the 21 patients remained seizure free. The authors
3. Epilepsy With Myoclonic Absences (EMA) concluded that VPA monotherapy was effective in
4. Epilepsy With Myoclonic-Astatic Seizures (Doose controlling absence seizures and should be given
Syndrome; DS) an adequate trial to ensure that patients derive the
5. Childhood Absence Epilepsy (CAE) greatest possible benefit before adding another AED
6. Juvenile Absence Epilepsy (JAE) or switching to a different AED.22 However, a case
7. Juvenile Myoclonic Epilepsy (JME) study reported a patient with early-onset absence

16
seizure with onset at age 11 months, whose seizures suggests that CBZ (carbamazepine) and PHT may
increased in frequency after the introduction of precipitate or aggravate generalized-onset tonic–
valproic acid (VPA) treatment and substantially clonic seizures.28-30
improved upon cessation of treatment.23
Combination therapy with ESM and VPA should Juvenile Myoclonic Epilepsy (JME)
be considered in patients whose absence seizures do
not respond to standard therapeutic measures.24 Low- Among anticonvulsants, valproic acid still stands
dose lamotrigine added to valproic acid appears to out as the most efficacious drug in JME, but may be
be effective in typical absence seizures. A therapeutic poorly tolerated by some, and is considered unsafe
interaction of the two drugs seems likely.25 for the fetuses of pregnant women. The interest of
A study assessed the value of VPA in 25 patients valproic acid in treating this epilepsy syndrome
(11 males and 14 females, aged 14–73 years) with is reinforced by the fact that most other AEDs
recurrent ASE who had failed to respond to other available, including phenytoin, carbamazepine,
anticonvulsants, including ethosuximide and CZP lamotrigine, oxcarbazepine, vigabatrin, tiagabine
(clonazepam).26 All of the patients had absence status and gabapentin may aggravate myoclonic seizures.31
demonstrated by EEG and were grouped according The open case-series that has been published using
to EEG criteria as having primary generalized VPA shows a 41–88% seizure-free rate for patients
epilepsy, generalized epilepsy with cerebral damage, receiving VPA, either as an add-on medication or as
or generalized epilepsy with focalization. The monotherapy.32,33
frequency of absence status in these patients before A Class III randomized open label trial compared
treatment with VPA was retrospectively determined topiramate (TPM) and VPA monotherapy in
and compared with the frequency observed during both newly diagnosed and previously treated JME
treatment with individually titrated doses of VPA. patients.34 There were only 16 newly diagnosed
The most frequently administered dose was 1,500 previously untreated patients among the 28 children
mg/day, given in an open and unblinded manner. in the study. These 16 children were randomized
Among the 25 patients, 18 had primary generalized between TPM (n = 12) and VPA (n = 4). The low
epilepsy with a mean frequency of 5.7 absence status number of previously untreated patients prevents
attacks per year. After a mean follow-up period of drawing conclusions from this study. Case studies
4.4 years, the frequency of attacks was reduced to have also shown that a low, once-daily dose (500 mg)
0.6 per year. Fourteen patients had no recurrence, of VPA can effectively control JME and keep patients
three had rare attacks with noncompliance, and seizure free for as long as 2 years.35, 36
one had an incomplete response, probably due Acute treatment for most myoclonic seizures
to gastrointestinal intolerance. The response to starts with a BZD, such as CZP (clonazepam) or
treatment by patients with diffuse cerebral damage nitrazepam. Another BZD, clobazam, was found to
or generalized epilepsy with focalization was not as be less effective.37 As a second step, intravenous VPA
good as that of patients with primary generalized (i.v.-VPA) can be administered at a high loading
epilepsy. These findings suggest that VPA is the drug dose to rapidly achieve therapeutic levels.38 Sheth
of choice for the prevention of ASE recurrence.26 and Gidal described two female patients, aged 15 and
28, with JME that presented with myoclonic status.39
Generalized Tonic-Clonic Seizures (GTCS)
One was on baseline therapy with phenytoin (PHT),
A meta-analysis by Marson et al. specifically and the other was on lamotrigine (LTG). When they
reviewed the use of VPA and CBZ (carbamazepine) presented with SE, both were successfully treated
in GTCS. There was a non-statistically significant with 500 mg i.v.-VPA given over 30 min, a relatively
trend toward a better response with VPA compared modest dose and a fairly slow infusion rate. Within
with CBZ (carbamazepine), and the authors 5 min. of the end of the infusion, both patients were
concluded that trials should be conducted with seizure free, their myoclonic jerks stopped, and
VPA in GTCS management.27 Class IV evidence follow-up EEG readings were normal.

17
 Epilepsy With Generalized Tonic–Clonic had one fit every 6 months with 3 doses, had fits with
Seizures Only (IGE With GTC Only; EGTCS) the same frequency with the single dose treatment.
There were no side effects.46 They concluded that the
VPA monotherapy is very effective for both seizure efficacy of a single dose might result from the action
outcome control and photosensitivity (PS) reduction of VPA, which increases the intra-cerebral levels of
in adolescents with EGTCS.40 GABA, which are delayed and prolonged.
Studies Looking at VPA Efficacy in Multiple Cochrane Reviews
IGE Groups
1. Relationship between valproic acid, lamotrigine
Of 84 children having a diagnosis of IGEs [33 and topiramate and IGEs prognosis
(35%) of the children having Childhood Absence Valproic acid may be the most effective
Epilepsy (CAE)], 48 (57%) became seizure-free on antiepileptic drug in the treatment of the IGEs.
valproic acid monotherapy and another 10 patients Combination therapy should be initiated if an
became seizure-free but discontinued VPA because adequate trial of valproic acid monotherapy is
of adverse effects. The mean dose in seizure-free not effective, rather than switching to alternative
children was 15.7 mg/kg/day and over 95% of IGEs monotherapy. Antiepileptic drug treatment needs
patients will respond below 25 mg/kg/day.41 A study to be lifelong in many adult patients with IGEs.
done prospectively to assess the response to low- 2. Primary outcomes of SANAD study
dose valproic acid (VPA) treatment (<1000 mg/ Time to treatment failure: valproic acid was
day) together with plasma VPA levels in a cohort of significantly better than topiramate (hazard
44 patients with IGEs [23 (42.6%) having JME, 17 ratio 1·57 [95% CI 1·19–2·08]), but there was no
(31.5%) having JAE and 14 (25.9%) having GTCS significant difference between valproic acid and
only] found that low-dose VPA was a highly effective lamotrigine (1·25 [0·94–1·68]).
treatment for the majority of those with JME and For patients with IGEs: valproic acid was
GTCS only. The seizures in JAE tended to be more significantly better than both lamotrigine (1·55
resistant to treatment, usually requiring higher doses [1·07–2·24] and topiramate (1·89 [1·32–2·70]).
of VPA or polytherapy.42 For time to 12-month remission: valproic acid was
There is Class III evidence that VPA treatment significantly better than lamotrigine overall (0·76
in patients with IGEs (1) reduces spontaneous [0·62–0·94]), and for the subgroup with IGEs
generalized spikes and waves but not photo [0·68 (0·53–0·89)]. But there was no significant
paroxysmal reactions43; (2) decreases EEG difference between valproic acid and topiramate
synchronization in the delta and theta frequency in either the analysis overall or for the subgroup
bands in a use-dependent manner44; (3) normalizes with IGEs.
EEG functional connectivity.45 But there was no significant difference between
valproic acid and topiramate in either the analysis
Place of valproic acid in children with overall or for the subgroup with IGEs.
idiopathic generalized epilepsy
Current NICE Guidelines
A study was done to test the efficacy and
innocuousness of a single dose of VPA for the Treatment of IGEs in children, young people and
treatment of IGEs, as compared with 3 daily doses. adults
It was found that twenty patients (57.14%) who were  First line treatment: valproic acid, lamotrigine (if
well controlled with 3 daily doses had no fits with valproic acid is not suitable)
the single dose treatment. Ten patients (28.57%)  Cautions: be aware of potential effect of valproic
who had had one fit every 6 months during the acid in pregnancy. If the person has myoclonic
observation year had no convulsions during the year seizures or may have juvenile myoclonic epilepsy
on a single dose: however, 5 (14.28%) others who had lamotrigine may worsen myoclonic seizures

18
 Alternative first line: carbamazepine,  Despite availability of newer AED like
oxcarbazepine levetiracetam, the efficacy of VPA in JME is
 Cautions: be aware that these drugs may worsen unparalleled
myoclonic or absence seizures  Combination with lamotrigine: only proven
 Adjunctive treatment (if 1st line treatment synergistic combination
is ineffective or not tolerated): clobazam,
lamotrigine, levetiracetam, topiramate References
 Cautions: be aware of potential effect of valproic 1. Groupe C. [Treatment of newly diagnosed epileptic crises. A French experience]. Revue
neurologique. 2001 Dec;157(12):1500-12. PubMed PMID: 11924446. Traitement des
acid in pregnancy. If the person also has absences crises epileptiques nouvellement diagnostiquees. Une experience francaise.
or myoclonic seizures, or may have juvenile 2. Semah F, Picot MC, Derambure P, Dupont S, Vercueil L, Chassagnon S, et al. The
choice of antiepileptic drugs in newly diagnosed epilepsy: A national French survey.
myoclonic epilepsy do not offer carbamazepine, Epileptic disorders : international epilepsy journal with videotape. 2004 Dec;6(4):255-
gabapentin, oxcarbazepine, phenytoin, pregabalin, 65. PubMed PMID: 15634622.
3. Ben-Menachem E, Schmitz B, Tomson T, Vajda F. Role of valproate across the ages.
tiagabine or vigabatrin Treatment of epilepsy in adults. Acta neurologica Scandinavica Supplementum.
2006;184:14-27. PubMed PMID: 16776493.
AAN Guidelines 4. Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Chadwick D, Guerreiro C, et al.
ILAE treatment guidelines: Evidence-based analysis of antiepileptic drug efficacy and
effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia.
 Valproic acid is effective in the treatment of 2006;47(7):1094-120.
5. Steinhoff BJ, Ueberall MA, Siemes H, Kurlemann G, Schmitz B, Bergmann L, et al.
primary generalized-onset tonic–clonic seizures The LAM-SAFE Study: lamotrigine versus carbamazepine or valproic acid in newly
especially Juvenile Myoclonic Epilepsy. diagnosed focal and generalised epilepsies in adolescents and adults. Seizure : The
journal of the British Epilepsy Association. 2005 Dec;14(8):597-605. PubMed PMID:
 Topiramate is effective for the treatment of 16278088.
refractory generalized-onset tonic–clonic seizures 6. Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW,
et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for
in adults and children (recommendation level A). generalised and unclassifiable epilepsy: An unblinded randomised controlled trial.
 A small study with lamotrigine used as add-on Lancet. 2007 Mar 24;369(9566):1016-26. PubMed PMID: 17382828. Pubmed Central
PMCID: 2039891.
therapy in patients with refractory IGEs and a 7. Ramsay E, Faught E, Krumholz A, Naritoku D, Privitera M, Schwarzman L, et al.
Efficacy, tolerability, and safety of rapid initiation of topiramate versus phenytoin in
combination of seizure types is mentioned in the patients with new-onset epilepsy: A randomized double-blind clinical trial. Epilepsia.
guidelines. 2010 Oct;51(10):1970-7. PubMed PMID: 20633037.

 AAN cautions about use of VPA like FDA. 8. Brodie MJ, Perucca E, Ryvlin P, Ben-Menachem E, Meencke HJ, Levetiracetam
Monotherapy Study G. Comparison of levetiracetam and controlled-release
carbamazepine in newly diagnosed epilepsy. Neurology. 2007 Feb 6;68(6):402-8.
PubMed PMID: 17283312.
Conclusions 9. Sullivan JE, Dlugos DJ. Idiopathic Generalized Epilepsy. Current treatment options in
neurology. 2004 May;6(3):231-42. PubMed PMID: 15043806.
 Valproic acid has been demonstrated to be the 10. Patsalos PN. Properties of antiepileptic drugs in the treatment of idiopathic
generalized epilepsies. Epilepsia. 2005;46 Suppl 9:140-8. PubMed PMID: 16302888.
most efficacious and safe AED in adult males and
11. Covanis A, Gupta AK, Jeavons PM. Sodium valproate: Monotherapy and polytherapy.
post-menopausal with IGEs and multiple seizure Epilepsia. 1982 Dec;23(6):693-720. PubMed PMID: 6816580.
types. 12. Perucca E, Gram L, Avanzini G, Dulac O. Antiepileptic drugs as a cause of worsening
seizures. Epilepsia. 1998 Jan;39(1):5-17. PubMed PMID: 9578007.
 VPA is considered as 1st line therapy for many 13. Karceski S, Morrell MJ, Carpenter D. Treatment of epilepsy in adults: Expert opinion,
epilepsy syndromes in adults, notably IGEs – 2005. Epilepsy & behavior : E&B. 2005 Sep;7 Suppl 1:S1-64; quiz S5-7. PubMed
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JME, Absence Epilepsy 14. Trinka E, Marson AG, Van Paesschen W, Kalviainen R, Marovac J, Duncan B, et al.
 Although VPA is highly efficacious in women KOMET: An unblinded, randomised, two parallel-group, stratified trial comparing the
effectiveness of levetiracetam with controlled-release carbamazepine and extended-
with IGEs, it should be used with caution in release sodium valproate as monotherapy in patients with newly diagnosed epilepsy.
Journal of neurology, neurosurgery, and psychiatry. 2013 Oct;84(10):1138-47.
young women and those in childbearing age. PubMed PMID: 22933814.
 Valproic acid is often said to be more suitable in 15. Mole TB, Appleton R, Marson A. Withholding the choice of sodium valproate to
young women with generalised epilepsy: Are we causing more harm than good?
children with epileptic encephalopathies and in Seizure : the journal of the British Epilepsy Association. 2015 Jan;24:127-30. PubMed
PMID: 25223837.
those with multiple seizures
16. Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy:
 Valproic acid is of particular interest in IGEs interactions between antiepileptic drugs and other drugs. The Lancet Neurology. 2003
Aug;2(8):473-81. PubMed PMID: 12878435.
as AEDs like carbamazepine, oxcarbazepine,
17. Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Perucca E, et al. Dose-
lamotrigine and phenytoin may aggravate seizures dependent teratogenicity of valproate in mono- and polytherapy: An observational
study. Neurology. 2015 Jun 17. PubMed PMID: 26085607.
in certain cases and thus these AEDs should only
18. Bromfield EB, Dworetzky BA, Wyszynski DF, Smith CR, Baldwin EJ, Holmes LB.
be used with caution in generalized epilepsies Valproate teratogenicity and epilepsy syndrome. Epilepsia. 2008 Dec;49(12):2122-4.

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 PubMed PMID: 18557775. 34. Levisohn PM, Holland KD. Topiramate or valproate in patients with juvenile
19. ILAE. Proposal for revised classification of epilepsies and epileptic syndromes. myoclonic epilepsy: A randomized open-label comparison. Epilepsy & behavior : E&B.
Commission on Classification and Terminology of the International League Against 2007 Jun;10(4):547-52. PubMed PMID: 17482520.
Epilepsy. Epilepsia. 1989 Jul-Aug;30(4):389-99. PubMed PMID: 2502382. 35. Karlovassitou-Koniari A, Alexiou D, Angelopoulos P, Armentsoudis P, Dimitrakoudi
20. Glauser TA, Cnaan A, Shinnar S, Hirtz DG, Dlugos D, Masur D, et al. Ethosuximide, E, Delithanasis I, et al. Low dose sodium valproate in the treatment of juvenile
valproic acid, and lamotrigine in childhood absence epilepsy. The New England myoclonic epilepsy. Journal of neurology. 2002 Apr;249(4):396-9. PubMed PMID:
journal of medicine. 2010 Mar 4;362(9):790-9. PubMed PMID: 20200383. Pubmed 11967642.
Central PMCID: 2924476. 36. Panagariya A, Sureka RK, Sardana V. Juvenile myoclonic epilepsy--an experience
21. Villarreal HJ, Wilder BJ, Willmore LJ, Bauman AW, Hammond EJ, Bruni J. Effect from north western India. Acta neurologica Scandinavica. 2001 Jul;104(1):12-6.
of valproic acid on spike and wave discharges in patients with absence seizures. PubMed PMID: 11442437.
Neurology. 1978 Sep;28(9 Pt 1):886-91. PubMed PMID: 99687. 37. Badhwar A, Siren A, Andermann E, Andermann F. Myoclonic status epilepticus:
22. Bourgeois B, Beaumanoir A, Blajev B, de la Cruz N, Despland PA, Egli M, et al. video presentation. Movement disorders : Official journal of the Movement Disorder
Monotherapy with valproate in primary generalized epilepsies. Epilepsia. 1987;28 Society. 2002 Mar;17(2):409-11. PubMed PMID: 11921135.
Suppl 2:S8-11. PubMed PMID: 3121293.
38. Venkataraman V, Wheless JW. Safety of rapid intravenous infusion of valproate
23. Belcastro V, Caraballo RH, Romeo A, Striano P. Early-onset absence epilepsy loading doses in epilepsy patients. Epilepsy research. 1999 Jun;35(2):147-53. PubMed
aggravated by valproic acid: a video-EEG report. Epileptic disorders : International PMID: 10372567.
epilepsy journal with videotape. 2013 Dec;15(4):440-3. PubMed PMID: 24169439.
39. Sheth RD, Gidal BE. Intravenous valproic acid for myoclonic status epilepticus.
24. Rowan AJ, Meijer JW, de Beer-Pawlikowski N, van der Geest P, Meinardi H. Neurology. 2000 Mar 14;54(5):1201. PubMed PMID: 10720302.
Valproate-ethosuximide combination therapy for refractory absence seizures. Archives
of neurology. 1983 Dec;40(13):797-802. PubMed PMID: 6416232. 40. Verrotti A, Grosso S, D'Egidio C, Parisi P, Spalice A, Pavone P, et al. Valproate in
adolescents with photosensitive epilepsy with generalized tonic-clonic seizures only.
25. Ferrie CD, Robinson RO, Knott C, Panayiotopoulos CP. Lamotrigine as an add-on
European journal of paediatric neurology : EJPN : official journal of the European
drug in typical absence seizures. Acta neurologica Scandinavica. 1995 Mar;91(3):200-
Paediatric Neurology Society. 2014 Jan;18(1):13-8. PubMed PMID: 23891468.
2. PubMed PMID: 7793236.
26. Berkovic SF, Andermann F, Guberman A, Hipola D, Bladin PF. Valproate prevents 41. Holland KD, Monahan S, Morita D, Vartzelis G, Glauser TA. Valproate in children
the recurrence of absence status. Neurology. 1989 Oct;39(10):1294-7. PubMed PMID: with newly diagnosed idiopathic generalized epilepsy. Acta neurologica Scandinavica.
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2834532.
27. Marson AG, Williamson PR, Clough H, Hutton JL, Chadwick DW, Epilepsy
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meta-analysis. Epilepsia. 2002 May;43(5):505-13. PubMed PMID: 12027911. dose sodium valproate in the treatment of idiopathic generalized epilepsies. Acta
neurologica Scandinavica. 2014 May;129(5):e20-3. PubMed PMID: 24372179.
28. Guerrini R, Belmonte A, Genton P. Antiepileptic drug-induced worsening of seizures
in children. Epilepsia. 1998;39 Suppl 3:S2-10. PubMed PMID: 9593229. 43. Muhle H, Ettle E, Boor R, Stephani U, Siniatchkin M. Valproate reduces spontaneous
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1998 Feb;7(1):63-6. PubMed PMID: 9548228. d'une dose quotidienne unique de valproate de sodium chez l'enfant.

Table showing choice of AEDs in patients with IGE syndromes as NICE guidelines
Preferred AEDs GTCS Absence seizures Myoclonic seizures
1st line AEDs Valproic acid Ethosuximide lamotrigine
/lamotrigine
Alternate 1st line AEDs lamotrigine lamotrigine levitiracetam topiramate
Adjunctive AEDs clobazam, levetiracetam, or Any of the above
topiramate
Avoid AEDs carbamazepine, gabapentin, carbamazepine, gabapentin, carbamazepine, gabapentin,
oxcarbazepine, phenytoin, oxcarbazepine, phenytoin, oxcarbazepine, phenytoin,
pregabalin, tiagabine or pregabalin, tiagabine or pregabalin, tiagabine or
vigabatrin vigabatrin vigabatrin

20
Valproic Acid in Focal Epilepsy
Manjari Tripathi

The International League Against Epilepsy (ILAE) controlled-release carbamazepine and extended-
published their updated ILAE evidence review of release valproic acid as monotherapy in patients
anti-epileptic drug efficacy and effectiveness as initial with newly diagnosed epilepsy. The results showed
monotherapy for epileptic seizures and syndromes that in a study design where the clinician decided
in 2013. whether VPA or CBZ (carbamazepine) would be the
The below table summarises the role of valproic standard 1st line treatment. Within the VPA stratum,
acid (VPA) clearly in partial onset seizures (POS): pts were randomised (1:1) to treatment with LEV
or VPA-ER. 1698 patients were randomised 1266
Seizure Class Class Class Level of efficacy and
type or I II III effectiveness evidence patients were still taking the drug at the end of the
epilepsy (in alphabetical order) study. The primary outcome measure was the time
syndrome to withdrawal from study medication (treatment
POS: 2 1 30 Level A: CBZ, PHT, LEV withdrawal). This was calculated from randomisation
Adults Level B: VPA to the day after the last intake of study medication for
Level C: GBP, LTG, OXC, PB,
TPM, VGB
the overall comparison of LEV with standard AEDs.
The secondary outcome measure was time to first
POS: 1 0 17 Level A: OXC
Adults Level B: None
seizure calculated from randomisation, treatment
Level C: CBZ, PB, PHT, TPM, withdrawal and seizure freedom rates at 6 and 12
VPA months. Time to treatment withdrawal was longer in
POS: 1 1 2 Level A: GBP, LTG (CBZ CR) patients treated with LEV compared with standard
Elderly Level B: None AEDs, but the difference was not significant. Time
Level C: CBZ to first seizure was significantly longer for patients
in the standard AEDs group compared with the LEV
Based on this VPA would not be the drug of first
group.
choice.
About 30% of the patients received levetiracetam
Seizure Class I Class II Class III Level of versus valproic acid for focal seizures. Time to
type or efficacy and
treatment withdrawal was similar for LEV and
epilepsy effectiveness
VPA-ER (HR 1.02, 95% CI 0.74 to 1.41). When
syndrome evidence
(in alphabetical comparisons were done according to seizure type,
order) no significant differences were found, but trends
BECTS 0 0 2 Level A: None favoured LEV in those with focal seizures (HR 0.73,
Level B: None 95% CI 0.37 to 1.44). Estimated seizure freedom rates
Level C: CBZ, VPA at 6 and 12 months were higher with VPA-ER than
LEV, for all patients. Discontinuation of treatment
The summary of recommendations for syndromes due to AEs was similar in patients treated with LEV
put this as one of the options for benign rolandic (6.1%) and VPA-ER (4.7%). The study found LEV
epilepsy with centrotemporal spikes (BECTS). to be non-superior to both VPA-ER and CBZ-CR
One of the more recent multicenter studies (carbamazepine) for the global outcome and time to
KOMET by Trinka et al. in 2012 which was an treatment withdrawal.
unblinded, randomised, two parallel-group, stratified Nolan in the Cochrane review studying the role
trial compared the effectiveness of levetiracetam with of valproic acid versus phenytoin monotherapy in

21
 focal seizures. Outcomes were time to (a) treatment References
withdrawal (b) 12-month remission (c) six-month
1. Glauser T, Ben-Menachem, Bourgeois B, et al. Updated ILAE evidence
remission and (d) first seizure post randomisation. review of anti-epileptic drug efficacy and effectiveness as initial
Individual patient data were available for 669 monotherapy for epileptic seizures and syndromes. Epilepsia 2013; 54:1-
individuals out of 1119 eligible individuals from 5 13.
out of 11 trials, 60% of the potential data. The results 2. Trinka E, Marson AG, Van Paesschen W, et al. & KOMET Study Group.
did not suggest that valproic acid was better in focal KOMET: An unblinded, randomised, two parallel-group, stratified trial
comparing the effectiveness of levetiracetam with controlled-release
seizures. carbamazepine and extended-release sodium valproate as monotherapy
in patients with newly diagnosed epilepsy. J Neurol Neurosurgy Psychiatry.
Conclusion 2013 Oct; 84(10):1138-47.
3. Nolan SJ, Marson AG, Pulman J, Tudur Smith C. Phenytoin versus
There should be no reason to use valproic acid as valproate monotherapy for partial onset seizures and generalised
a drug of choice for focal seizures at all with better onset tonic-clonic seizures. Cochrane Database Syst Rev. 2013 Aug 23;
treatment options available for the same. 8:CD001769.

22
Valproic Acid in Epileptic Syndromes with
Special Reference to Juvenile Myoclonic
Epilepsy
Satish Jain, Manjari Tripathi

The International League Against Epilepsy (ILAE) 500, 89%), and 28 (6%) required another AED in
published a review of all relevant studies that addition to VPA, 24 (5%) were never treated with
were aimed to provide evidence based answers VPA and had good seizure control on other AEDs,
to the specific question: “For patients with newly and the current information on AEDs of one patient
diagnosed or untreated epilepsy, which anti-epileptic was not available. Additionally, 41 of 42 JME patients
drugs (AEDs) have the best evidence for long term who had a photo-paroxysmal response on the EEGs
efficacy or effectiveness as initial monotherapy.1 had responded very well to VPA alone.4
This review article has been updated by the ILAE The International league Against Epilepsy (ILAE)
subcommission of AED guidelines, mainly based published their updated ILAE evidence review of
on the impact of the initial publication and the anti-epileptic drug efficacy and effectiveness as initial
information that was made available in several of monotherapy for epileptic seizures and syndromes
the published randomized controlled trials (RCTs) in 2013.
on the efficacy and effectiveness of AEDs in patients The below table summarises the role of VPA in
with new-onset epilepsy.2 generalised seizures tonic-clonic (GTC) and other
generalised seizure types/syndromes:
Juvenile Myoclonic Epilepsy (JME)
Seizure Class I Class II Class III Level of
A review of the evidence available at the time of type or efficacy and
initial publication in 2006 revealed that there were no epilepsy effectiveness
syndrome evidence
RCTs that had studied the efficacy and effectiveness of
(in alphabetical
AEDs as initial monotherapy for patient having JME. order)
The two RCTs that had not reported on the efficacy
GTC: 0 0 27 Level A: None
and effectiveness as the primary outcome measure
Adults Level B: None
were not included in this report.1 Subsequently, one Level C: CBZ, LTG,
RCT compared the role of topiramate (TPM) and OXC, PB, PHT,
valproic acid (VPA) monotherapy in only 16 newly TPM, VPA
diagnosed children having JME. This study (Class GTC: 0 0 14 Level A: None
III DB, n=1) was interpreted to show that VPA and Children Level B: None
TPM are potentially (level D) efficacious/effective for Level C: CBZ, PB,
patients with newly diagnosed JME.3 PHT, TPM, VPA
In one of the largest study of phenotypic analysis of Absence 1 0 7 Level A: VPA
JME among Indian families, information on clinical seizures Level B: VAL
and EEG features, family history and response to Level C: LTG
AEDs was collected on 500 probands with JME. JME 0 0 1 Level A: None
Level B: None
The seizures among majority of patients having JME
Level C: None
were successfully treated with VPA alone (447 of

23
  One of the more recent multicenter studies Conclusion
KOMET by Trinka et al. in 2013 which was
an unblinded, randomised, two parallel-group, VPA is an effective anticonvulsant for generalized
stratified trial compared the effectiveness seizures in terms of efficacy and should be used
of levetiracetam with controlled-release where there are no contraindications and side effect
carbamazepine and extended-release VPA as profile is acceptable to the patient after a shared
monotherapy in patients with newly diagnosed decision making process.
epilepsy. This study showed that in the stratum
comparing LEV and VPA-ER, the HR (95%
References
CI) for time to treatment withdrawal was 1.02 1. Glauser T, Ben-Menachem, Bourgeois B, et al. ILAE treatment guidelines:
(0.74 to 1.41), suggesting similarity between Evidence-based analysis of anti-epileptic drug efficacy and effectiveness as
the two. Subgroup analysis of only the patients initial monotherapy for epileptic seizures and syndromes. Epilepsia 2006;
47:1094-1120.
classified with generalised seizures gives an HR
2. Glauser T, Ben-Menachem, Bourgeois B, et al. Updated ILAE evidence
for treatment withdrawal of 1.16 (95% CI 0.79
review of anti-epileptic drug efficacy and effectiveness as initial
to 1.71) suggesting a non-significant advantage monotherapy for epileptic seizures and syndromes. Epilepsia 2013; 54:1-
for VPA-ER. For time to first seizure in the VPA 13.
stratum, (HR 1.19) results were similar to the 3. Levishon PM, Holland KD. Topiramate or valproate in patients with
overall results, suggesting an advantage for VPA- juvenile myoclonic epilepsy: A randomized open-label comparison.
ER. Epilepsy Behav 2007; 10:547-552.

 Nolan in the Cochrane review studying the 4. Jain S, Tripathi M, Srivastava AK, et al. Phenotypic analysis of juvenile
role of VPA versus phenytoin monotherapy in myoclonic epilepsy in Indian families. Acta Neurol Sacnd 2003; 107:356-
362.
generalised seizures. Outcomes were time to (a)
5. Trinka E, Marson AG, Van Paesschen W, et al. & KOMET Study Group.
treatment withdrawal (b) 12-month remission
KOMET: an unblinded, randomised, two parallel-group, stratified trial
(c) six-month remission and (d) first seizure comparing the effectiveness of levetiracetam with controlled-release
post randomisation. Individual patient data were carbamazepine and extended-release sodium valproate as monotherapy
available for 669 individuals out of 1119 eligible in patients with newly diagnosed epilepsy. J Neurol Neurosurgy Psychiatry.
individuals from 5 out of 11 trials, 60% of the 2013 Oct; 84(10):1138-47.

potential data. The results suggested that there 6. Nolan SJ, Marson AG, Pulman J, Tudur Smith C. Phenytoin versus
valproate monotherapy for partial onset seizures and generalised
was no evidence against or for the use of VPA in
onset tonic-clonic seizures. Cochrane Database Syst Rev. 2013 Aug 23;
generalised seizures. 8:CD001769.

24
Valproic Acid in Status Epilepticus
Usha Kant Misra, Jayantee Kalita, Sanjeev Bhoi, Deepanshu Dubey

Status epilepticus (SE) is a common neurological 15-18 mg/kg IV or equivalent dose of fosphenytoin
emergency second only to acute stroke. The is recommended.4 Each of the recommended
management of SE has been evolving. Benzodiazepines treatment has its advantage and disadvantage.
have now been established as the first line treatment Benzodiazepines although are highly effective, result
of SE. There are many drugs like phenytoin (PHT), in sedation, hypotension and respiratory suppression
levetiracetam (LEV), valproic acid (VPA) and whereas PHT (Phenytoin) though has no sedating
lacosamide as possible second line agents for SE. An effect but has serious side effects such as cardiac
ideal antiepileptic drug (AED) for SE should act arrhythmia, hypotension and phlebitis. The first line
rapidly without cardiorespiratory depression, with AED fails to control 25-45% of patients with SE.5
a half-life long enough to prevent relapse, protein Additional treatment therefore is needed though
binding such that the pharmacokinetics are not high quality evidence is lacking. Valproic acid (VPA)
affected by systemic illness, metabolism not affected acid has been elevated second line antiepileptic drug
by renal or hepatic impairment and a linear dose (AED).6-10 US FDA has approved IV SVA in 1996
response relationship. and since its introduction several case studies and
uncontrolled studies have been published evaluating
Pharmacokinetics the role of VPA in SE.11 Intravenous VPA is an
emerging alternative in SE patients who are resistant
VPA potentiates γ-aminobutyric acid (GABA)
to 1st line drugs (BDZ). The safety data has also been
inhibitory effects in the central nervous system. In
encouraging for VPA.
addition, it also acts through attenuation of N-methyl
D-aspartate (NMDA) receptor mediated excitation, The First Case Series Reporting Efficacy of
although this does not explain the effect of valproic VPA in SE was by
acid on absence seizures. It has also been proposed
that VPA exerts its effect via blockade of voltage Vajda et al. who administered VPA per rectum in
dependent sodium channels.1 VPA is about 90% 6 patients resistant to diazepam and/or amobarbital
bound to plasma proteins, and the degree of binding were administered SVA 200-800 mg per rectum. The
decreases with increasing drug concentration within plasma levels of SVA reached the therapeutic level
the clinically occurring range. VPA is extensively within 36 hours. SE was controlled in 5 patients and
metabolized by microsomal glucuronide conjugation, a 75% reductions in seizures was noted in the 6th
mitochondrial beta-oxidation and cytochrome P450- patient.12
dependent oxidation.2 Elimination of VPA appears to The review of published literature including
follow a monophasic exponential course: biological randomized controlled trials (RCT), non RCT
half-life is 8 to15 hours, but shorter values (5 to 12 prospective and retrospective case series received and
hours) are observed in patients receiving enzyme- presented to the group of experts. The conclusions
inducing agents. Valproic acid appears to have a opinion is summarized in the following section
relatively restricted distribution ranging from 0.15
to 0.40/Kg. There are large individual differences Randomized Controlled Trials
in clearance rates. The therapeutic range of VPA is
between 50 and 100 mg/l.2,3 There are 3 RCTs comparing VPA with PHT
For treatment of status epilepticus, lorazepam 4 mg (Phenytoin) 8,9,10 and 2 with diazepam13,14 and 1 with
or diazepam 10 mg followed by phenytoin (PHT) phenobarbitone.15 These studies include 361 patients,

25
 183 were randomized to VPA. The dose of VPA was higher relapse rate in 24 hour was observed (12/23)
20-30 mg/kg. in phenobarbital compared to VPA group 4/27.15
In the study by Misra et al. seizure cessation at (Table 1).
the end of infusion was significantly higher in VPA
(66%) compared to PHT (Phenytoin) (42%; P=0.06). Controlled Non-randomized Studies
15 of the non-responses were treated to the other
Four studies have compared VPA with PHT
study drug. 15 out of 19 (79%) non-responds to
PHT (Phenytoin) responded to VPA compared to (Phenytoin) and LEV16-19. Tripathi et al. compared
3/12, (12%, P<0.001). 24 hour seizure freedom was LEV with VPA in refractory SE (>1 hour) in the
obtained in 29 patients irrespective of treatment patients who had received benzodiazepine or PHT
group or sequence.8 Gilad et al. in 2007 found no (Phenytoin). Clinical seizure cessation occurred
significant difference in seizure cessation after in 26/41 (68.3%) in VPA group and 28/41 (73.2%)
infusion of VPA or PHT (Phenytoin) after 20 min. in LEV group which was not significant. Seizures
infusion (13/18, 72.2% Vs 7/9, 77.8 NS). Seizure were refractory to VPA in 31.7% and to LEV 26.8%
freedom was obtained in all the patients in both the and patients required mechanical ventilation and
groups.9 Agarwal et al. compared seizure cessation anesthetics.17 In a retrospective study, VPA was
clinically and EEG was done within 20 minutes compared with PHT (76%) as first line drug. SE was
of VPA or PHT (Phenytoin) infusion and rate of controlled by VPA in 75% and by PHT in 46%.16
seizure recurrence within 12 hour in 50 patients was In a prospective study 65 patients received VPA
noted. There was no significant difference in seizure and 52 PHT for SE. Seizures of 56% on VPA and
cessation between VPA and PHT (Phenytoin) (88% 44% on PHT were controlled. Crossing over the
vs. 84%). Seizure cessation was high if patients were
patients with uncontrolled seizure resulted in seizure
treated within 2 hours (P<0.005).10
control in 41 additional patients whereas 35 (30%)
The efficacy of VPA was compared to diazepam: in
patients remained refractory to both VPA and PHT.18
generalized convulsive SE in 66 patients. Significant
A retrospective analysis of VPA vs. PHT or LEV as
difference between diazepam (56%) and VPA (50%)
2nd line AED revealed failure by VPA in 25.4%, PHT
with respect to seizure cessation was not observed.
41.4% and LEV 48.3%. In this study even without
Relapse of seizure in 24 hour occurred in 25% in
diazepam and 20% in valproic acid group which was statistical power LEV was less effective than VPA to
also not significant.14 control SE resistant to benzodiazepine.19(table 2)
In a study on children comparing VPA and The results of two published trials, one evaluating
diazepam, the median time to abrogation of seizures the efficacy and safety of VPA and PHT (group I) and
were shorter with valproic acid (5 min.) compared to the other LOR and LEV (group II) were compared.
diazepam (17 min.) (P<0.0001).13 Group I had 117 and Group II 79 patients. As first
In a systematic review IV VPA and IV PHT choice, LOR controlled SE in 75.1%, LEV in 76.2%,
(Phenytoin) comparing PHT (Phenytoin) to VPA VPA in 55.4% and PHT in 44.2%. As second choice,
there was no significant difference in seizure LEV was effective in 88.9%, LOR in 70%, VPA in
cessation (RR 1.31 95% CI 0.3–1.84) and in 24 hour 74%, and PHT in 28%. Refractory SE was more
seizure freedom (PR 0.96, 95% CI 0.80-1.06).11 commoner in group I (27.9%) than group II (10.5%).
The complications and death were more in group II.
Valproic Acid Compared to LOR and LEV combination was better than PHT
Phenobarbitone and VPA in reducing refractory seizures but at the
In the study comparing IV VPA vs. phenobarbitone cost of higher complications and death.20
in children, seizure termination was higher in those There are a large number of uncontrolled studies
receiving IV VPA (27/30, 90%) compared to IV and case reports which have little importance in
phenobarbital (23/30, 77%) (P=0.189). A significantly light of the above mentioned studies.

26
 VPA in Different Types of SE Safety
VPA has been evaluated mainly in generalized There are a large number of dedicated safety
convulsive SE. Evaluation of 10 studies (both studies, adverse event responding in efficacy studies,
retrospective and prospective) has revealed a response case reports and pharmacovigilance reporting which
rate of 71.7%.21 In simple and complex partial SE, the provide information about the safety and side effects
response to VPA was 77.6% (83/107). In absence SE, of VPA.
the experience is limited and based 16 patients 12 Dedicated safety studies revealed safety of IV
(75%) of whom responded. In 2 patients, valproic VPA. Though all the patients were not of SE but the
acid was given in absence SE after benzodiazepine information is relevant to evaluate the safety of VPA
failure and both responded.16 In myoclonic SE in SE. In a study of 318 adults and children with
seizures VPA in a dose of 15 mg/kg/6 hourly was
response rate to VPA was 71% (5/7) and post anoxic
evaluated. The median dose was 375 mg injected in
myoclonus 60% patients responded.21
1h .Transient adverse events were noted in 54 (17.5%)
and included headache, injection site reactions,
Order of VPA and seizure outcome nausea, somnolence, vomiting, dizziness and
2 randomized and 1 non-randomized trials altered taste. There was no change in hematological
parameters, serum chemistry and vital signs.24 In
have evaluated VPA as first line AED instead of
another study on 1.5 mg vs. 3 mg/kg/min infusion
benzodiazepine. SE was controlled in 66%-72%
was compared in 112 children. There was no change
patients in randomized and 68.3%-75% in non
in their mean BP, 2 patients on 3 mg/kg/min had
RCTs. 4 randomized studies evaluated VPA as 2nd transient hypotension. The commonest side effects
time drug. SE was controlled in 50%-90% in RCT were somnolence, paresthesia, dizziness and nausea.
and 56% patients non RCT.21 The possibility of treatment related encephalopathy
was reported in 1 patient receiving VPA at the rate
Treating SE with One or Two Drugs in the of 3 mg/kg/min which resolved on discontinuation
Beginning of VPA. A study on 40 patients receiving 20-30 mg/
kg/min at the rate of 6 and 10 mg/kg/min resulted
There is evidence that LOR alone, PB in asymptomatic hyperammonemia in 30 out of 40
(Phenobarbitol) alone or PHT plus diazepam can patients 1 hour after infusion. None of the patients
be used of treatment of SE.5 This study compared had any alteration of consciousness or increase in
LOR 0.1mg/kg, with PHT+diazepam 0.15 mg/ serum transaminase.25 On rapid infusion of VPA,
kg. Since LOR is several times more potent than BP changes and adverse events were evaluated in 36
diazepam hence the comparison was between patients who were infused VPA at the rate of 3 mg/
LOR and PHT with ineffective dose of diazepam. kg/min up to a maximum of 15 mg/kg. 24 patients
Hence, the question whether to administer 2 drugs were infused at the rate of 3 mg/kg/min upto 30 mg
simultaneously or sequentially remains unanswered. and 6 patients 6 mg /kg up to 15 mg/kg and did not
Some authorities recommend 2 drugs with different reveal any increase in adverse events at higher dose
mechanism of action because of the following or at faster infusion rate and no change in BP was
reasons: 1) The time dependent loss of potency of observed. Later infusion rate up to 11 mg/kg/min
BDZ documented experimentally22 hence the drugs have been reported in paediatric patients without
acting on GABA receptors should not be used when any toxicity.26 Hypotension is a concern in IV AEDs
SE is treated more than 30 min. after the onset of in treatment of SE. A retrospective analysis revealed
seizure. This time is sufficient to cause a decline in the that IV VPA was used to control SE in 13 patients,
potency of BDZ.23 2) SE is a heterogeneous disorder revealed hypotension or cardiovascular instability 12
and attacking two mechanisms of action may have of these patients who were above the age of 64 years,
a better chance of success. In such a situation VPA mean dose of VPA was 25.1 + 5 mg/kg infused at
or PHT may be used in addition to BDZ especially rate of 36.6 + 25 mg/kg/min. All of these but one
in the patients with long standing or established SE. patient received vasopressors; no significant change

27
 in BP was observed during or after VPA infusion convulsive status epilepticus. New England J. Med. 1998; 339:792–798.
6. Sinha S, Naritoku DK. Intravenous valproate is well tolerated in unstable
and increase in vasopressor dose was not required. patients with status epilepticus. Neurology. 2000; 55: 722–724.
No other cardiovascular adverse event or arrhythmia 7. Trinka E. What is the relative value of the standard anticonvulsants:
was observed.6 In an open labeled study, VPA infusion Phenytoin and fosphenytoin, phenobarbital, valproate, and levetiracetam?
Epilepsia. 2009; 50(Suppl 12):S40–43.
in 40 patients with epilepsy who received VPA in a 8. Misra UK, Kalita J, Patel R. Sodium valproate vs. phenytoin in status
dose of 20 or 30 mg/kg/min at the rate of 6 or 10 epilepticus: A pilot study. Neurology. 2006; 67:340–342.
9. Gilad R, Izkovitz N, Dabby R, Rapoport A, Sadeh M, Weller B et al.
mg/min. VPA was well tolerated without any cardiac Treatment of status epilepticus and acute repetitive seizures with i.v.
arrhythmia or cardiovascular side effects and there valproic acid vs. phenytoin. Acta Neurol Scand. 2008; 118:296–300.
was no alteration in consciousness although 7.5% 10. Agarwal P, Kumar N, Chandra R, Gupta G, Antony AR, Garg N.
Randomized study of intravenous valproate and phenytoin in status
patients reported sedation and 2.5% had nausea.27 epilepticus. Seizure. 2007; 16:527–532.
Local irritation with VPA infusion was also less than 11. Brigo F, Storti M, Del Felice A, Fiaschi A, Bongiovanni LG. IV Valproate
that in PHT (18% vs. 25%) in a retrospective study in generalized convulsive status epilepticus: A systematic review. Eur J
Neurol. 2012; 19:1180–1191.
in head injury patients.28 12. Vajda FJ, Symington GR, Bladin PF. Rectal valproate in intractable status
Randomized controlled trials: There are 6 RCTs epilepticus. Lancet. 1977; 1:359–360.
13. Mehta V, Singhi P, Singhi S. Intravenous sodium valproate versus
including 183 patients in whom the side effects of diazepam infusion for the control of refractory status epilepticus in
VPA have been reported in comparison to diazepam, children: A randomized controlled trial. J Child Neurol. 2007; 22:1191–
PHT and phenobarbitone. They revealed lower 1197.
14. Chen WB, Gao R, Su YY, et al. Valproate versus diazepam for generalized
incidence of serious side effects following VPA convulsive status epilepticus: A pilot study. Eur J Neurol. 2011; 18:1391–
administration (Table 3). 1396.
Valproic acid therefore seems to have better 15. Malamiri RA, Ghaempanah M, Khosroshahi N, Nikkhah A, Bavarian
B, Ashrafi MR. Efficacy and safety of intravenous sodium valproate
toxicity profile compared to other 1st line AEDs. versus phenobarbital in controlling convulsive status epilepticus and
In a metaanalysis VPA has significantly lower risk acute prolonged convulsive seizures in children: A randomised trial. Eur
of adverse events (RR 0.31) (95% CI 0.12-0.85).11 J Paediatr Neurol. 2012; 16: 536–541.
16. Tiamkao S, Sawanyawisuth K. Predictors and prognosis of status
Controlled non-randomized trials also document epilepticus treated with intravenous sodium valproate. Epileptic Disord.
cardiovascular and respiratory safety of VPA 2009; 11:228–231.
17. Tripathi M, Vibha D, Choudhary N, Prasad K, Srivastava MV, Bhatia R,
compared to other AEDs.17 A case report has reported et al. Management of refractory status epilepticus at a tertiary care centre
to association of VPA with acute pancreatitis.29 in a developing country. Seizure. 2010; 19:109–111.
18. Kalita J, Nair PP, Misra UK. A clinical, radiological and outcome study
of status epilepticus from India. J Neurol. 2010; 257: 224–229.
Conclusion 19. Alvarez V, Januel JM, Burnand B, Rossetti AO. Second-line status
epilepticus treatment: Comparison of phenytoin, valproate, and
1. Intravenous valproic acid seems to be effective and safe in SE patients
levetiracetam. Epilepsia. 2011; 52:1292–1296.
who have failed IV benzodiazepine
20. Misra UK, Kalita J. A comparison of four antiepileptic drugs in status
2. The recommended dose of VPA is 15-45 mg/kg bolus (6mg/kg /min )
epilepticus: experience from India. International Journal of Neuroscience
followed by 1-3 mg/kg in infusion
2015; 0(0): 1–7 (in the press).
3. The incidence of adverse reaction is below 1% and includes, dizziness,
21. Eugen Trinka, Julia Ho¨fler, Alexander Zerbs, Francesco Brigo Efficacy
mild hypotension which is independent of infusion rate. VPA has good
and Safety of Intravenous Valproate for Status Epilepticus: A Systematic
cardiovascular and respiratory tolerability.
Review. CNS Drugs 2014;28: 623–639.
4. High quality RCTs of VPA in SE are needed.
22. Mazarati AM, Baldwin RA, Sankar R, Wasterlain CG. Timedependent
decrease in the effectiveness of antiepileptic drugs during the course of
References self-sustaining status epilepticus. Brain Res 1998; 814: 179–85
23. Chen JW, Wasterlain CG. Status epilepticus: pathophysiology and
1. Peterson GM, Naunton M. Valproate: A simple chemical with so much to management in adults. Lancet Neurol. 2006 Mar; 5(3):246-56.
offer. J Clin Pharm Ther. 2005; 30:417-421. 24. Devinsky O, Leppik I, Willmore LJ, et al. Safety of intravenous valproate.
2. Perucca E. Pharmacological and therapeutic properties of valproate: A Ann Neurol. 1995; 38:670–674.
summary after 35 years of clinical experience. CNS Drugs. 2002; 16:695– 25. DeWolfe JL, Knowlton RC, Beasley MT, Cofield S, Faught E, Limdi NA.
714. Hyperammonemia following intravenous valproate loading. Epilepsy Res.
3. Biton V, Levisohn P, Hoyler S, Vuong A, Hammer AE. Lamotrigine versus 2009; 85:65–71.
Valproate monotherapy-associated weight change in adolescents with 26. Morton LD, O’Hara KA, Coots BP, Pellock JM. Safety of rapid intravenous
epilepsy: Results from a post hoc analysis of a randomized, double-blind valproate infusion in paediatric patients. Pediatr Neurol. 2007; 36: 81–83.
clinical trial. J Child Neurol 2003;18:133-139. 27. Limdi NA, Faught E. The safety of rapid valproic acid infusion. Epilepsia.
4. Meierkord H, Boon P, Engelsen B, Göcke K, Shorvon S, Tinuper P, 2000; 41:1342–5.
Holtkamp M. EFNS guideline on the management of status epilepticus. 28. Anderson GD, Lin Y, Temkin NR, Fischer JH, Winn HR. Incidence of
Eur J Neurol. 2006; 13:445-450. intravenous site reactions in neurotrauma patients receiving valproate or
5. Treiman DM, Meyers PD, Walton NY, Collins JF, Colling C, Rowan phenytoin. Ann Pharmacother. 2000; 34:697–702.
AJ, Handforth A, Faught E, Calabrese VP, Uthman BM, Ramsay 29. Grosse P, Ru¨sch L, Schmitz B. Pancreatitis complicating treatment with
RE, Mamdani MB. A comparison of four treatments for generalized intravenous valproic acid. J Neurol. 2002; 249:484–485.

28
Table 1: Randomised controlled trials comparing efficacy of VPA with other drugs

Author No. of patients Patients Type of seizures Statistical difference

Misra et al.8 VPA=35, PHT=33 Adults and children Convulsive SE NS

Agarwal et al. 9 VPA=50, PHT=50 Adults and children Generalized SE NS

Gilad et al. 10 VPA=18, PHT=9 Adults > 18 yrs Generalized SE NS

Chen et al.14 VPA=30, D=36 Adults and children> 15 yrs Generalized SE NS

Mehta et al.13 VPA=20, D=20 Children (B12 y) Generalised SE NS

Malamiri et al.15 V: 30, B: 30 Children ([2 y) Convulsive SE NS

B: phenobarbital, D: diazepam, PHT: phenytoin, SE: status epilepticus, VPA: valproic acid

Table 2: Non-randomized trials of SE using i.v. Valproic acid

Author N Age Type SE Outcome

Tripathi et al.17 VPA 41, Lev 41 >14 Ref GCSE VPA 68.3% vs Lev 73.2 NS

Tiamkao & VPA 12, PHT 37 >15 GCSE VPA 75% PHT 46% NS
Sawanyawisuth16

Kalita et al.18 VPA 65 PHT 52 Ad & ch GCSE,NCSE VPA 56% PHT 44%

Alvarez et al.19 VPA 59, PHT70, Lev 58 >16 All Failure VPA 25.4%, PHT 41.4, Lev 48.3%

VPA: Valproic acid, Lev: levetiracetam, PHT: phenytoin, GCSE: Generalized convulsive status epilepticus

Table 3: Reported incidence of serious adverse events of VPA compared to PHT

Severe adverse events VPA PHT Diazepam PB
Hypotension (%) 0.5 8.7 21.4 0%
Respiratory impairment (%) 0.5 4.3 25.0 3.3%
Liver failure (%) 3.8 2.2 - -

29
 Efficacy of Valproic Acid – Comparison with
other Anti-Epileptic Drugs
SudhindraVooturi, Sita Jayalakshmi

Abstract The earliest reported trials on efficacy of VPA

date back to 1960s in patients with epilepsy that
Valproic acid (VPA) is one of the most widely was refractory to other AEDs available at that time;5
prescribed anti-epileptic drugs (AED) globally. where VPA reportedly reduced the incidence of
Among available AEDs, VPA is distinguished by both generalised and partial seizures. Pinder et al. in
its broad spectrum of efficacy against all seizure 1977 reported that VPA used as adjunctive therapy
types and syndromes. It has low risk of causing reduced seizure frequency by >75% in nearly two-
paradoxical seizure exacerbation and good CNS thirds of the patient.6 Similar findings were reported
tolerability. In all types of epilepsy, the efficacy of by Davies,7 in 70% of the patients who received
VPA is comparable with that of alternative AEDs, VPA mono-therapy for a variety of seizure types.
and it is mainly the differences in tolerability profile However, both the above reviews were based on
that determine which drug has to be preferentially non-comparative and non-randomized trials.
used. The current review aims to summarize the
efficacy of VPA in comparison to other AEDs in the Efficacy of VPA in Partial Seizures
management of partial and generalized epilepsies
and also in childhood epilepsies. Randomised trials comparing VPA, phenytoin and
carbamazepine as initial monotherapy in adults with
Introduction previously untreated epilepsy reported that, no major
differences in efficacy were found between the drugs.8
Nearly half a decade since its introduction, valproic However, phenytoin was more frequently associated
acid (VPA) is one of the most widely prescribed anti- with idiosyncratic adverse reactions leading to
epileptic drugs (AED) globally. Increased gamma withdrawal.8, 9 Additionally, complete seizure control
aminobutyric acid (GABA) – ergic transmission, was observed less commonly in the carbamazepine
blockage of voltage-gated sodium channels and group.9 Moreover, response rates to VPA were
modulation of dopaminergic and serotoninergic higher in patients with generalised tonic-clonic
transmission are the established pharmacological seizures (GTCS) than in those with partial seizures.9
effects of VPA.1-3 Clinical and electrophysiological These findings were consistent with the reports
studies have reported a wide spectrum action of from randomised follow-up trial in 243 patients,
VPA against different types of seizures suggesting randomised to treatment with VPA, carbamazepine,
a combination of mechanisms involved. Different phenytoin or phenobarbital and followed up for 3
dosages of VPA are available both for parenteral years.10 The reported discontinuation due to adverse
and oral use (with almost complete bioavailability).4 effects were found in 3, 5, 11 and 22% of patients
Among available AEDs, VPA also has the advantage randomised to phenytoin, VPA, carbamazepine and
of good central nervous system (CNS) tolerability phenobarbital, respectively.10
and low risk of paradoxical seizure exacerbation.5 Similar findings of efficacy were reported in
The current review aims to summarize the efficacy children where no major differences were identified
of VPA in comparison to other AEDs in the between VPA, carbamazepine and phenytoin,
management of epilepsy. but withdrawals as a result of adverse effects were

30
more common in the phenytoin group (9%).11 The followed by topiramate, with lamotrigine being most
findings were consistent with reports from paediatric likely.
study carried out in India where tolerability findings Aldenkamp et al.,18 compared the tolerability
tended to favour VPA.12 Three additional, larger and prevention of cognitive dysfunction of VPA or
scale randomised monotherapy trials focused on a TPM given as first-line add-on therapy to steady-
comparison of valproic acid with carbamazepine. state treatment with CBZ (carbamazepine), in a
Verity et al., in 260 children at 63 centres in the multicenter, randomized, observer-blinded, parallel-
UK and Ireland, reported a trend for superiority group clinical trial. The authors reported that, none
of valproic acid in the 12- and 24-month remission of the mood tests or the test for subjective complaints
rates.13 The same study also reported that increased shows statistically significant differences between the
appetite was more common in the VPA group, whereas treatments, although more scores are in the negative
somnolence and dizziness were more common in the direction for TPM during titration.
carbamazepine group. The Veterans Administration Other adjunctive therapy trials, evaluating efficacy
(VA) Collaborative Group,14 in a double-blind of VPA in the management of refractory partial
trial that included patients with complex partial seizures reported VPA superior to placebo.19 In
seizures and secondary GTCS reported that mean patients with refractory epilepsy, the best responses
dosage of VPA was as effective as carbamazepine are often found when VPA is combined with either
in controlling generalised tonic-clonic seizures, but carbamazepine or with lamotrigine.20 Zonisamide,
carbamazepine provided better control of complex is relatively a new AED with a broad spectrum of
partial seizures and had fewer long-term adverse anticonvulsant activity, usually used in treatment
effects. The conclusions of this study, however, have of refractory epilepsy, very often as an add-on
been largely debated, in view of the high dosages therapy. Furthermore, the updated ILAE report has
used, high number of patients (about one-third) lost established level A efficacy/effectiveness evidence
to follow-up in the first 12 months and recruitment for zonisamide as initial monotherapy for adults
of patients with a more severe partial epilepsy. The with partial-onset seizures.21,22 However, the data on
Cochrane Collaboration Group in a meta-analysis of polytherapy is still inconsistent and needs further
randomised, controlled, comparative trials of VPA, investigation.
phenytoin and carbamazepine given as monotherapy
to patients with newly diagnosed partial and Efficacy of VPA in Generalised Seizure Types
primarily generalised tonic-clonic seizures, reported
no overall difference between the drugs for the main The effectiveness of VPA in patients with
outcomes examined.15 For primary GTCS, efficacy generalised epilepsies is supported by decades of
endpoints tended to favour VPA. extensive clinical experience, even though controlled
On comparison of VPA monotherapy with comparative trials are rarely conducted in these
oxcarbazepine monotherapy in the management of patients. In idiopathic and symptomatic generalised
patients with newly diagnosed, previously untreated, epilepsy syndromes associated with multiple seizure
partial and primarily GTCS, followed up for 12 types, prescription of a broad-spectrum drug such as
months, the two drugs were found to have comparable VPA becomes a reasonable choice.5 In fact, in patients
efficacy, and no significant differences were found with idiopathic generalised epilepsy syndrome, VPA
in their overall tolerability.16 The Standard And has been shown to be significantly better than both
New Antiepileptic Drugs (SANAD) trial,17 reported topiramate and lamotrigine for seizure control.17
VPA as the first choice treatment in patients with The same study also concluded that based on cost
either partial or generalised onset seizures. When per seizure avoided, VPA should remain the first
evaluating for time to treatment failure, VPA was the choice drug for idiopathic generalised or unclassified
most effective drug and topiramate was least effective. epilepsy.
Furthermore, VPA was least likely to be associated In patients with typical and atypical absence
with treatment failure for inadequate seizure control, seizures, the efficacy of VPA has been demonstrated

31
 by reduced frequency and duration of discharges of children”. The author further stated that; VPA
in the EEG;23,24 suppressing seizures in at least 80% can increase plasma concentrations of concomitant
of patients with childhood or juvenile absence drugs, such as phenobarbital and lamotrigine, by
epilepsy.23,24 However, VPA is usually considered the inhibiting their metabolism. Moreover, as a result
drug of choice as it is also effective in preventing of its broad spectrum of efficacy in a wide range
generalised tonic-clonic seizures, which may coexist of seizure types and epilepsy syndromes, VPA is a
or develop at a later time in these patients and also drug of choice for children with newly diagnosed
prevents recurrence of absence status.25 Valproic epilepsy, idiopathic generalized epilepsy, epilepsies
acid is efficacious against all types of seizures with prominent myoclonic seizures or with multiple
associated with juvenile myoclonic epilepsy, where seizure types, and photosensitive epilepsies.
it is treatment of choice for this condition. Other Dudley et al.,30 in 48 children with idiopathic
syndromes where VPA has been found to be useful epilepsy compared VPA and carbamazepine to
include the Lennox-Gastaut26 and West syndromes.27 evaluate failure of treatment with first AED. The
The SANAD trial identified VPA as the first line authors reported that, treatment failure was due to
of drug in generalized epilepsies.17 Subsequently, adverse effects in 12/30 children (40.0%), due to
the Keppra vs. Older Monotherapy in Epilepsy Trial lack of efficacy in 11/30 (37.9%), and due to both
(KOMET), compared the effectiveness of extended adverse effects and lack of efficacy in 7/30 (24.1%).
release VPA (VPA-ER) versus levetiracetam (LEV).28 Furthermore, approximately one third of children
The study reported that, time to treatment withdrawal newly diagnosed with epilepsy experienced treatment
was similar for LEV and VPA-ER. Furthermore, failure with the first antiepileptic drug used. Lack of
the authors reported trends favouring VPA-ER in efficacy and unacceptable adverse effects contributed
patients with primary generalised seizures. The equally to these treatment failures. The authors
estimated overall withdrawal rates as reported by the also reported that, AED choice, maximum drug
authors at 12 months were 22.0% (18.0–26.7) with dose, etiology of epilepsy, and particular epilepsy
LEV and 21.6% (17.7–26.4) with VPA-ER. However, syndromes had no effect on treatment failures.
time to first seizure favoured VPA-ER over LEV. Importantly, when compared to carbamazepine,
Importantly, estimated seizure freedom rates at 6 phenytoin, and phenobarbital in focal epilepsy and
and 12 months were higher with VPA-ER than LEV, with ethosuximide in absence epilepsy, VPA was as
both for all patients and in those with generalised effective and showed a favorable tolerability profile.31
seizures only.28 Moreover, serious adverse events Intravenous VPA may be effective for the treatment
were reported by 11.3% patients treated with LEV of convulsive and non-convulsive status epilepticus
and 5.8% with VPA-ER.28 Although VPA might be that is refractory to conventional drugs.31 The
the most efficacious drug in idiopathic generalized reviewer cautioned that, in infants, potential benefits
epilepsies, it should be avoided in women of should be carefully weighed against the risk of liver
childbearing age due to its safety profile with toxicity, gastrointestinal intolerance.31
concerns of teratogenesis and weight gain.29
Conclusions
VPA in Childhood Epilepsies Among available AEDs, VPA is distinguished by its
broad spectrum of efficacy against all seizure types
Most idiopathic generalized epilepsies (IGEs) begin
and syndromes, low risk of causing paradoxical
in childhood and treatment with the first prescribed seizure exacerbation and good CNS tolerability. In all
antiepileptic drug fails in approximately 20% and types of epilepsy, the efficacy of VPA is comparable
40%.30 Guerrinni,31 in a review of literature on VPA with that of alternative AEDs, and it is mainly the
in children reported that “valproic acid remains a differences in tolerability profile that determine
gold standard antiepileptic drug for the treatment which drug has to be preferentially used.

32
 References 15. Tudur Smith C, Marson AG, Williamson PR. Phenytoin versus valproate
monotherapy for partial onset seizures and generalized onset tonic-clonic
1. Loscher W. Valproate: A reappraisal of its pharmacodynamic properties seizures. Cochrane Database Syst Rev 2001:CD001769.
and mechanisms of action. Prog Neurobiol 1999;58:31-59. 16. Christe W, Kramer G, Vigonius U, et al. A double-blind controlled clinical
2. Loscher W. Effects of the antiepileptic drug valproate on metabolism trial: Oxcarbazepine versus sodium valproate in adults with newly
and function of inhibitory and excitatory amino acids in the brain. diagnosed epilepsy. Epilepsy Res 1997;26:451-460.
Neurochem Res 1993;18:485-502. 17. Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of
3. McLean MJ, Macdonald RL. Sodium valproate, but not ethosuximide, effectiveness of valproate, lamotrigine, or topiramate for generalised and
produces use- and voltage-dependent limitation of high frequency unclassifiable epilepsy: An unblinded randomised controlled trial. Lancet
repetitive firing of action potentials of mouse central neurons in cell 2007;369:1016-1026.
culture. J Pharmacol Exp Ther 1986;237:1001-1011. 18. Aldenkamp AP, Baker G, Mulder OG, et al. A multicenter, randomized
4. Gugler R, von Unruh GE. Clinical pharmacokinetics of valproic acid. Clin clinical study to evaluate the effect on cognitive function of topiramate
Pharmacokinet 1980;5:67-83. compared with valproate as add-on therapy to carbamazepine in patients
5. Perucca E. Pharmacological and therapeutic properties of valproate: A with partial-onset seizures. Epilepsia 2000;41:1167-1178.
summary after 35 years of clinical experience. CNS Drugs 2002;16:695- 19. Richens A, Ahmad S. Controlled trial of sodium valproate in severe
714. epilepsy. Br Med J 1975;4:255-256.
6. Pinder RM, Brogden RN, Speight TM, et al. Sodium valproate: A review 20. Brodie MJ, Yuen AW. Lamotrigine substitution study: Evidence for
of its pharmacological properties and therapeutic efficacy in epilepsy. synergism with sodium valproate? 105 Study Group. Epilepsy Res
Drugs 1977;13:81-123. 1997;26:423-432.
7. Davis R, Peters DH, McTavish D. Valproic acid. A reappraisal of its 21. Kwan SY, Chuang YC, Huang CW, et al. Zonisamide: Review of Recent
pharmacological properties and clinical efficacy in epilepsy. Drugs Clinical Evidence for Treatment of Epilepsy. CNS Neurosci Ther;21:683-
1994;47:332-372. 691.
8. Turnbull DM, Howel D, Rawlins MD, et al. Which drug for the adult 22. Glauser T, Ben-Menachem E, Bourgeois B, et al. Updated ILAE
epileptic patient: Phenytoin or valproate? Br Med J (Clin Res Ed) evidence review of antiepileptic drug efficacy and effectiveness as initial
1985;290:815-819. monotherapy for epileptic seizures and syndromes. Epilepsia;54:551-563.
9. Callaghan N, Kenny RA, O'Neill B, et al. A prospective study between 23. Braathen G, Theorell K, Persson A, et al. Valproate in the treatment
carbamazepine, phenytoin and sodium valproate as monotherapy in of absence epilepsy in children: a study of dose-response relationships.
previously untreated and recently diagnosed patients with epilepsy. J Epilepsia 1988;29:548-552.
Neurol Neurosurg Psychiatry 1985;48:639-644. 24. Villarreal HJ, Wilder BJ, Willmore LJ, et al. Effect of valproic acid on
10. Heller AJ, Chesterman P, Elwes RD, et al. Phenobarbitone, phenytoin, spike and wave discharges in patients with absence seizures. Neurology
carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: 1978;28:886-891.
A randomised, comparative monotherapy trial. J Neurol Neurosurg 25. Berkovic SF, Andermann F, Guberman A, et al. Valproate prevents the
Psychiatry 1995;58:44-50. recurrence of absence status. Neurology 1989;39:1294-1297.
11. de Silva M, MacArdle B, McGowan M, et al. Randomised comparative 26. Covanis A, Gupta AK, Jeavons PM. Sodium valproate: Monotherapy and
monotherapy trial of phenobarbitone, phenytoin, carbamazepine, polytherapy. Epilepsia 1982;23:693-720.
or sodium valproate for newly diagnosed childhood epilepsy. Lancet
27. Siemes H, Spohr HL, Michael T, et al. Therapy of infantile spasms with
1996;347:709-713.
valproate: Results of a prospective study. Epilepsia 1988;29:553-560.
12. Thilothammal N, Banu K, Ratnam RS. Comparison of phenobarbitone,
28. Trinka E, Marson AG, Van Paesschen W, et al. KOMET: An unblinded,
phenytoin with sodium valproate: Randomized, double-blind study.
randomised, two parallel-group, stratified trial comparing the effectiveness
Indian Pediatr 1996;33:549-555.
of levetiracetam with controlled-release carbamazepine and extended-
13. Verity CM, Hosking G, Easter DJ. A multicentre comparative trial
release sodium valproate as monotherapy in patients with newly
of sodium valproate and carbamazepine in paediatric epilepsy. The
diagnosed epilepsy. J Neurol Neurosurg Psychiatry;84:1138-1147.
Paediatric EPITEG Collaborative Group. Dev Med Child Neurol
1995;37:97-108. 29. Rheims S, Ryvlin P. Pharmacotherapy for tonic-clonic seizures. Expert
14. Mattson RH, Cramer JA, Collins JF. A comparison of valproate with Opin Pharmacother;15:1417-1426.
carbamazepine for the treatment of complex partial seizures and 30. Dudley RW, Penney SJ, Buckley DJ. First-drug treatment failures in
secondarily generalized tonic-clonic seizures in adults. The Department children newly diagnosed with epilepsy. Pediatr Neurol 2009;40:71-77.
of Veterans Affairs Epilepsy Cooperative Study No. 264 Group. N Engl J 31. Guerrini R. Valproate as a mainstay of therapy for pediatric epilepsy.
Med 1992;327:765-771. Paediatr Drugs 2006;8:113-129.

33
 Valproic Acid – Adverse effects and
Tolerability Profile
Bindu Menon, Gagandeep Singh
Valproic acid (VPA) is a widely used antiepileptic Idiosyncratic reactions: Adverse effects not
drug (AED) for generalized and partial seizures in straightly related with pharmacodynamic
adults and children. The broad range of effects and mechanisms of the drug and can take place on
clinical efficacy with a wide therapeutic window unpredictable way by abnormal interaction between
makes it a broad-spectrum antiepileptic drug. the drug and the organism, usually mediated by
Adverse effects of antiepileptic drugs remain the immunologic or cytotoxic effects triggered by the
most common cause of treatment failure. However, drug or its metabolites. Some of the most important
the most common adverse effects are dose dependent idiosyncratic reactions also occur at the start of
and reversible. AED treatment. Idiosyncratic reactions after the
The knowledge of side effects also plays an start of treatment, such as hypersensitivity reactions
important role in choosing the AED of choice. The and hepatic adverse effects, are most likely to occur
possible effects of AED could be divided as side within 2 to 8 weeks.
effects, adverse effects and idiosyncratic reactions. For practical purposes the use of word side effects
The side effects could also be acute and long-term and adverse effects are used as one.
side effects. The side effects profile of valproic acid can be
divided as follows:
Definitions 1) General Effects
2) Gastrointestinal
Side effect: Unintended effect occurring at normal
3) Dermatological
dose related to the pharmacological properties.
4) Neurological
Adverse event: Medical occurrence temporally
5) Metabolic
associated with the use of a medicinal product, but
6) Hematological
not necessarily causally related.
7) Hepatic and Pancreatic
Adverse reaction: A response to a drug which is
8) Reproductive and Endocrine
noxious and unintended, and which occurs at doses
9) Teratogenic effects
normally used in man for the prophylaxis, diagnosis,
or therapy of disease, or for the modifications of General
physiological function.
Unexpected adverse event: Not consistent with Common symptoms are asthenia, back pain,
applicable product information or characteristics of deafness, ear disorder, ear pain, facial edema, fever,
drug. malaise, arthralgia, arthrosis, leg cramps, myalgia,
Serious adverse event or reaction. Any untoward twitching.
medical occurrence at any dose. Weight gain is a frequent side effect which may
• Results in death lead to drug withdrawal. Weight gain has been found
• Life threatening to occur in 57% of adults1 and 58% of older children
• Requires inpatient hospitalization or prolongation and teenagers2 treated with VPA. Weight gain was
of existing hospitalization more in women as compared to men.3 Weight gain
• Results in persistent or significant disability or is an important risk factor for the development of
incapacity non-alcoholic fatty liver disease and endocrine

34
abnormalities in women. Caloric restriction does Neurological
not necessarily eliminate the problem.4 Potential risk
Neurological side effects are very common.
factors for VPA induced weight gain are puberty,
females, long duration of treatment, pre-treatment Drowsiness occurs at the beginning and is usually
overweight status, moderate intellectual disability, transient. Patients also experience giddiness,
physical inactivity and physical disabilities, excessive headache, drowsiness, ataxia, disturbance in
eating in individuals. attention and dysarthria. Confusion and irritablity
can also occur. Tremor is an important dose related
Gastrointestinal side effect. It occurs in about 10% of patients. The
character of the tremor resembles essential tremor.
Gastrointestinal side effects are the most common Usually appears within a month of starting therapy, or
for AED’s. Dose-dependent side effects are nausea, else 3 to 14 months after the start of therapy. In some
vomiting, dyspepsia, dry mouth, eructation and patients, when the tremor has a ‘flapping’ pattern,
indigestion. Rarely diarrhea, abdominal cramps and an underlying VPA-induced hyperammonemia
constipation also occur. These effects are usually at may contribute to its etiology. Tremor is seldom
initiation of treatment. They are usually transient severe enough to warrant treatment withdrawal.
and do not generally require discontinuation of Propranolol has the most therapeutic value.13
treatment. The effects could be minimized by using
Extrapyramidal side effects are rare. There are only
an enteric-coated formulation or by administering
few reports and a few case series of VPA-induced
the drug slowly or at meal times.5
reversible parkinsonism and cognitive decline. The
Dermatological first report was by Lautin et al. in 1979.14 The cases of
VPA-induced parkinsonism probably go unnoticed
Alopecia has been reported in 12-28% in a dose and unreported and hence the actual prevalence is
dependent manner.6 Abnormal hair texture, abnormal not known. VPA induced parkinsonism is likely to
hair growth, hair color changes, sweating are also be dose related. There is a cause effect relationship as
reported. Mechanism of hair loss is still debated. the side effect is reversed after either dose reduction
Deficiencies of trace elements like copper, zinc, and
or stopping the drug. Hence the effect is called
magnesium and inhibition of metallic enzymes that
reversible parkinsonism. The exact mechanism
are essential for hair growth and keratinization have
is unknown, however oxidative stress and
been suggested. Increased synchronization of hair
mitochondrial dysfunction has been postulated.15
maturation is the other presumed mechanism.7 Hair
Parkinsonism usually responds to levodopa but drug
growing back tends to be curlier.
Allergic skin rash is the lowest with VPA.8 withdrawal or substitution remains the best strategy.
Discoid lupus erythematosus, dry skin, ecchymosis, Cognitive problems for VPA have also been
furunculosis, maculopapular rash, petechia, pruritus, reported. A study done on 76 adult patients showed
rash, seborrhea, drug rash with eosinophilia and that cognitive domains involved were memory (17%),
systemic symptoms (DRESS) syndrome, erythema speech (7%), attention (10%), psychomotor slowing
multiforme, Stevens-Johnson syndrome, toxic (3%), confusion (3%), language (7%) or other (3%).16
epidermal necrolysis have been rarely reported.9 However few other studies failed to demonstrate any
Ethnicity has been shown to be a contributing cognitive effects. 17
risk factor regarding antiepileptic drug. A study A study on 453 children showed that attention
analyzing 154 patients with AED-induced severe dysfunction was more common with VPA than
cutaneous adverse drug reactions (SCARs) found with ethosuximide (in 49% of the children vs. 33%;
none with VPA.10 odds ratio, 1.95; 95% CI, 1.12 to 3.41; P = 0.03).18
A case report with DRESS with fulminant hepatic A reversible, dementia like syndrome has been
failure has been reported.11 Stomatitis and cutaneous reported. This syndrome is at times associated
leukoclastic vasculitis has been reported.12 with magnetic resonance imaging (MRI) of the

35
 cortical atrophy. The syndrome is rare. Treatment is Hyperammonemia is a rare and serious side
reduction or discontinuation of VPA which results effect of VPA. This often gets missed especially in
in reversal of mental and MRI changes.19 the setting of normal liver function tests and VPA
VPA induced encephalopathy is an important and levels. This may be present in 20-50% of patients on
severe side effect of AED-therapy and is seen to occur VPA therapy. In some patients, it is asymptomatic,
early in the course of treatment. This rare side effect but in others elevated ammonia can be associated
is in most cases associated with hyperammonemia. with encephalopathy. Symptoms include acute
Rarely, it is associated without hyperammonemia. confusional state, lethargy, drowsiness, ataxia,
A study reviewed 19 cases of valproic acid induced reduced cognitive abilities, stupor, triphasic waves in
encephalopathy between 1994 and 2003 and found EEG, and increased seizure frequency.24 In chronic
that this side effect is also prevalent in adults. Clinical therapy, onset can be insidious.
manifestations are varied and patients present with Hyperammonemia without clinical or laboratory
irritability, agitation, lethargy, drowsiness, coma, and evidence of hepatoxicity is an
occasionally paradoxical seizures. important idiosyncratic side effect of VPA
They proposed that VPA induced encephalopathy treatment.25 Timely diagnosis can reverse the
could be four types:20 condition and hence a high index of suspiion is
1) Encephalopathy with normal ammonia, a direct required. Changes in mentation especially after
effect on neurotransmitters. addition of topiramate should prompt the clinician to
2) Encephalopathy with hyperammonemia without think of this condition. Untreated, this can progress
liver failure, an inhibition of urea cycle. to life-threatening coma.
3) Encephalopathy with hyperammonemia and liver Several mechanisms have been proposed to explain
failure. VPA-induced hyperammonemic encephalopathy.
4) Encephalopathy without hyperammonemia but There is inhibition of the mitochondrial carbamoyl
liver failure. phosphate synthetase enzymes in the liver by
There is a temporal relation between VPA active metabolites of VPA, which is necessary
administration and the development of for ammonia elimination via urea cycle. Chronic
encephalopathy and its reversal following VPA VPA therapy increases the amount of VPA
withdrawal establishes the diagnosis.21 oxidation and production of active metabolites
in the liver. These metabolites interfere with
Metabolic effects
several biochemical pathways in the mitochondria,
Valproic acid produces an increase in glucose- leading to disruption of the urea cycle and thereby
stimulated pancreatic insulin secretion. This can causing hyperammonemia.26 Chronic VPA therapy
lead to an increase in body weight and obesity. The enhances urinary excretion of L-carnitine, resulting
metabolic disturbances associated with the weight in depletion of blood carnitine stores leading to
gain include hyperinsulinemia and insulin resistance, reduced capacity of ammonia metabolism.27
hyperleptinemia and leptin resistance.22 In the acute stage hyperammonemia produces
Metabolic syndrome (MS) has been seen to excessive activation of
occur in 41% of women treated with VPA.23 MS as NMDA receptors. The increased ammonia
indicated by centripetal obesity, glucose intolerance, conjugates with glutamate to form glutamine. The
hypertension, elevated triglycerides, low high-density increased glutamine level in the astrocytes increases
lipoprotein cholesterol, and hyperandrogenism/ intracellular osmolarity leading to astrocyte swelling
polycystic ovaries. It was seen to occur exclusively in and cerebral edema.28
those who develop obesity during VPA use.4 Longer Increase in activation of gamma-aminobutyric acid
duration of treatment appears to be a risk factor for (GABA) by ammonia induces somnolence.29 Risk
developing MS. factors of developing hyperammonemia is mental

36
retardation, carnitine deficiency, urea cycle defects, Hypofibrinogenemia occur because of decreased
concomitant use of other AEDs, young age, multiple synthesis (inherited hypofibrinogenemia, liver
neurological disabilities, and poor nutritional disease) or increased consumption (fibrinolytic
intake.30 therapy, protein loss). There are usually no bleeding
Treatment consists of supportive care, dose symptoms. Routine coagulatin tests may show
reduction or at times stopping the drug. Complete pathologic PT, aPTT.41 High serum concentration of
recovery often occurs within few days. L-carnitine VPA is associated with bone marrow suppression.
supplementation can help in faster resolution of Aplastic anemia, pure red cell aplasia, macrocytosis,
symptoms.31 VPA has also been reported to cause and leukopenia are some of the hematological adverse
a syndrome of inappropriate antidiuretic hormone effects of valproic acid therapy. Some of these effects
secretion (SIADH) or hyponatraemia.32 VPA may can lead to life-threatening complications.
also cause a decrease in plasma carnitine levels.33
L-carnitine supplementation is currently Liver and pancreas
recommended for VPA-induced liver toxicity, VPA Idiosyncratic reactions to VPA includes pancreatitis
overdose, other acute metabolic disorders associated and liver failure. They are rare complications, however
with carnitine deficiency and primary plasmalemmal are serious.35,42 Serious hepatic dysfunction following
carnitine transport defect.34 Alterations in lipid VPA use is a Type B (idiosyncratic) reaction, i.e., it is
metabolism and reduced bone mineral density have unpredictable and occurs in genetically predisposed
been reported.35, 36 individuals only.
Hematological Overall, the risk of VPA induced serious hepatic
dysfunction is low – about 1 in 100,000 people using
Valproic acid–associated thrombocytopenia is the medication.43,44 However, in at-risk, predisposed
generally mild and asymptomatic. The incidence individuals (see below), the risk may be as high as
varies from 5% to 60% is more often seen in children 1 in 500. The predisposed individuals are less than
than in adults.37 Most patients recover completely two years of age and harbour the polymerase gamma
after dosage reduction or discontinuation of VPA. 1 (POLG1) mutation. The mutation is a feature of
Recovery is seen within 1 week in most patients. Alpers-Huttenlocher syndrome, a mitochondrial
Thrombocytopenia is usually transient and self- disorder with progressive downhill course. VPA-
limiting. The interval between the initiation of induced hepatitis in children less than two years
VPA treatment and platelet nadir is variable among of age is invariably fatal. Hence, screening of high-
patients with thrombocytopenia, ranging from 8 risk individuals for the POLG1 mutation before
days to 16 months.38 Thrombocytopenia is dose commencing VPA treatment should be considered.45
related and often pronounced with intercurrent viral There has been mild increase in serum
illness. Mechanism of thrombocytopenia is either a transaminases without any evidence of liver disease
direct toxic effect on bone marrow39 or formation of in 10-15%. The complication has been noted to
autoantibodies against platelets.40 occur more in children younger than 2 years
Acquired Von Willebrand disease has been reported receiving polytherapy, the risk of valproate-induced
and in such cases desmopressin, a synthetic arginine liver toxicity is as high as 1: 600 or 1: 800, but the
vasopressin analogue is recommended before surgery. incidence decreases with increasing age.46,47
Deficiency of vitamin K–dependent coagulation Risk factors for developing hepatitis are age below
factors has also been reported. Hemorrhagic 2 years, use of VPA as polytherapy, children with
symptoms may range from mild bruising to severe mental retardation, evidence of any pre-existing liver
ecchymoses, serious mucous membrane bleeding, disease or elevated liver enzyme levels, coexistence of
suffusions, or post-traumatic bleeding. Laboratory certain metabolic defects (e.g. β-oxidation disorders
findings include prolonged PT and aPTT. and mitochondrial diseases.

37
 The mechanism of VPA induced hepatic performed in the required setting. Children with
failure has now been elucidated. The failure is suspected hereditary mitochondrial disorder over
characterised by microvesicular steatosis and is two years should be treated with VPA only if other
related to the accumulation of 4-en valproic acid antiepileptics have failed. Further patients should
instead of 2-en valproic acid, which is ordinarily always be asked to report if they have any nausea,
formed as a result of VPA metabolism.48,49 VPA vomiting, icterus. Regular clinical and laboratory
largely undergoes glucoronidation in the level; assessment for older patients for noting any signs of
however, a small proportion of the molecule is also liver injury must be done.
oxidised. This oxidation preferentially occurs in
the mitochondrion and requires the transport of Pancreatitis
VPA to the mitochondrial matrix from the cytosol. VPA induced acute pancreatitis is a severe
When this does not occur as a result of carnitine idiosyncratic adverse effect. The common symptoms
deficiency or due to the mitochondrial defect are abdominal pain, nausea, and vomiting. It is
associated with POLG1 mutation, VPA oxidation noted during the first year of therapy but can occur
occurs predominantly in the cytoplasm leading to after years of treatment.52
the formation of 4-en valproic acid. The mechanism of pancreatitis postulated was
Symptoms include apathy, somnolence, anorexia, there is depletion of free radical scavengers such
nausea, vomiting and increased seizure frequency, as superoxide dismutase, catalase, and glutathione
especially in the presence of febrile infections. In peroxidase. The free radicals accumulation results
some patients there will be jaundice and bleeding in endothelial permeability and lipid peroxidation,
tendency. These warning signs should immediately ultimately leading to tissue damage.53
prompt the clinician for the withdrawal of the drug. VPA induced mitochondrial oxidation is another
Management involves rapid discontinuation of the theory for VPA-induced pancreatitis.54 Acute
offending drug, and the use of intravenous carnitine pancreatitis can be fatal. Patients with acute abdomen
has also been advocated.50 Liver transplantation has should undergo serum amylase and lipase as well as
been undertaken in the past for irreversible hepatic radiology imaging in suspect cases.
failure due to VPA but the outcome is invariably Endocrine, reproductive and teratogenic effects are
poor as the patients succumb to the widespread discussed elsewhere.
effects of mitochondrial dysfunction associated with Table 1: Effects of VPA according to severity
the POLG1 mutation.51
Minor Moderately severe Severe
VPA induced hepatotoxicity can be avoided if the
drug is used as monotherapy whenever possible Gastroin- Thrombocytopenia Fatal hepatitis
especially in children under 3 years, to keep minimal testinal side Bone marrow suppres- Pancreatitis
effects sion Teratogenesis
possible dose required for seizure control, salicylates
Somnolence Neutropenia Hyperammonae-
to be avoided, avoiding use of VPA in patients Tremor Red cell aplasia mic encephalop-
with liver disease or metabolic disorders involving Hair loss or Hyperammonemia athy
the urea cycle, organic acidaemias, mitochondrial thinning Excessive weight gain
disorders, free radical scavenger deficiencies, Polycystic ovaries
carnitine or medium chain acyl coenzyme A Decreased bone miner-
al density
deficiency. Screening for POLG mutation should be

38
Table 2: Common and rare effects of Valproic acid
Common Rare
General/Dermatological General/Dermatological
Weight gain, hair loss, Arthralgia, leg cramps, Rash, Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome
myalgia, bronchitis pharyngitis, acne Facial and limb edema,
Gastrointestinal Nocturnal eneuresis (not life threatening)
Nausea, vomiting, dyspepsia, dry mouth, Gastrointestinal
eructation and indigestion, diarrhea, Hepatotoxicity with liver failure
Abdominal cramps, constipation. Pancreatitis
Hyperammonemia, hypercarnitenemia, CNS
elevated liver enzymes (asymptomatic)
Reversible dementia, brain atrophy parkinsonism, asterixis, chorea, sensorineural hearing loss,
CNS encephalopathy
Tremor, drowsiness, Lethargy, giddiness, Metabolic
ataxia, asthenia, headache.
Insulin resistance, hyperleptinemia and
Metabolic
leptin resistance
Hypocarnitinemia
Hematological
hyperglycinaemia, hyperammonaemia
Neutropenia
Hematological
Bone marrow depression (life threatening)
Anemia, thrombocytopenia
Von Willebrand disease type 1, decreased factor XIII, abnormal platelet function, bleeding,
Reproductive and Endocrine: haemolytic anaemia, leukopenia, leucocytosis, eosinophilia, thrombocytosis, prolonged
Polycystic ovary morphology, hirsutism, prothrombin and thromboplastin times, fibrinogen and hematoma
menstrual abnormalities, overweight Reproductive and Endocrine
, obesity, polycystic ovary syndrome,
Hyperandrogenism (hirsutism, virilism,
anovulary cycles
acne, male pattern alopecia, and/or androgen increased) and Syndrome of Inappropriate
Teratogenic
Secretion of ADH (SIADH)
Teratogenic
Major and minor malformations, including a 20-fold increase in neural tube defects, cleft
lip and palate, cardiovascular abnormalities, genitourinary defects, developmental delay,
endocrinological disorders, limb defects, and autism.
Fetal valproic acid syndrome
Learning disability and behavioural problems in offsring
Common means 1 in 100 to 1 in 10 people will get it.
Rare means 1 in 1000 will get it.
Very rare means less than 1 in 10,000 people will get it.

Table 3: Early and late side effects of Valproic acid

EARLY LATE
1. Gastrointestinal (42%). 1. Reversible dementia with brain atrophy and Parkinsonism.
Higher in children. Anorexia, nausea, vomiting, 2. Psychiatric and cognitive side effects emotional upset,
indigestion, abdominal discomfort. depression, psychotic reactions, aggression, hyperactivity and
2. Elevated SGPT behavioral deterioration, insomnia, hypersomnia, lassitude,
(5%) and SGOT (25%), four fold increase in GGT. (Dose and hyperactivity.
related with no increase in serum bilirubin) 3. Hearing loss.
3. Acute liver failure. 4. Metabolic: Hyperinsulinemia, polycystic ovaries,
4. Somnolence, tremors. hyperandrogenism.
5. Drowsiness, lethargy, acute or subacute 5. Endocrine and reproductive dysfunction: Irregular mensus,
encephalopathy. secondary amenorrhea, breast enlargement, galactorrhea and
6. Asymtomatic hyperammonemia. parotid enlargement.

39
 Table 4: Dose related and idiosyncratic side effects of Valproic acid
Dose related Idiosyncratic
Tremor Thrombocytopenia
Weight gain Hamehorrhagic pancreatitis
Anorexia Acute hepatic failure
Nausea and vomiting Bone marrow aplasia
Dizziness
Drowsiness
Alopecia/hair loss/curly hair
Encephalopathy

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Differential cognitive and behavioural effects of topiramate and 13.
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following 3-month topiramate or valproate treatment revealed by event- associated with valproic acid: four case reports from the Netherlands and
related potential. Int Psychophysiol 2008; 68: 235–241 a case/non-case analysis of vigibase. Drug Safety Vol.33, No.1, pp. 47-55

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33. Beghi E, Bizzi A, Codegoni AM, et al. Valproate, carnitine metabolism, 45. Saneto RP, Lee IC, Koenig MK, et al. POLG DNA testing as an emerging
and biochemical indicators of liver function. Epilepsia 1990; 33: 346-52 standard of care before instituting valproic acid therapy for pediatric
34. Bourgeois BFD. Valproic acid: clinical efficacy and use in epilepsy. In: seizure dis orders. Seizure 2014; 19: 140–146.
Levy RH, Mattson BS, Meldrum BS, et al., editors. Antiepileptic drugs.
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S. Valproate-associated coagulopathies are frequent and variable in
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43. Dreifuss FE. Fatal liver failure in children on valproate. Lancet 1987; 1:
47–48. 54. Eyer F, Felgenhauer N, Gempel K, Steimer W, Gerbitz KD, Zilker T.
44. Koeing SA, Buesing D, Longin E, et al. Valproic acid induced hepatopathy: Acute valproate poisoning: pharmacokinet- ics, alteration in fatty acid
nine new fatalities in Germany from 1994 to 2003. Epilepsia 2006; 47: metabolism, and changes during therapy. J Clin Psychopharmacol
2027–2031. 2005;25: 376-80.

41
 Pharmacoeconomics of Valproic Acid
Param S. Kharbanda
Pharmacoeconomics essentially deals with The daily cost was calculated depending on the
scientific comparison between the value of different defined daily dose of the drugs, as prescribed by
pharmaceutical drugs or drug regimens, with the World Health Organization. To get as accurate
focus on the cost. In the present day scenario, a cost as possible, the price was averaged from the
when pharmacotherapy is becoming increasingly various brands available on the internet; with some
expensive, this discipline has gained even more counterchecking from the printed prices on the
importance. Whether the medicines are state strips on a given day (subject to change anytime).
subsidised or the patient pays out of pocked, society
Table 1: Comparison of VPA with other AEDs
has to bear the huge cost burden. Though the per
Drug Defined daily Ave. daily Annual % of PC
capita (PC) income of our country has been steadily dose (mg) cost (INR) cost (INR) income
going up (~ INR 90,000/annum), a large population VPA-sustained 1,500 33 12,045 13.4
still lives below the poverty line, due to the huge release
disparity between different economic groups. In VPA-immediate 1,500 24 8,760 9.7
addition to this, most of the people here pay out of release
pocket; and antiepileptic medicines require a long LEV 1,500 36 13,140 14.6
term commitment. LTG 300 39 14,235 15.8
Overall it is the cost-effectiveness which would CBZ 1,000 8 2,920 3.2
guide the choosing of one treatment modality over OXC 1,000 27 9,855 10.95
another; where effectiveness consists of efficacy and PHT 300 5 1,825 2
tolerance. However, this can be a complex process. PB 100 5 1,825 2
When we discuss the relative Pharmacoeconomics of As mentioned in table, the average daily cost of
Valproic Acid (VPA) here, we will confine ourselves VPA was around INR 24 for the immediate release
to the economics of it all; as the comparative and INR 33 for the sustained release. Compared to
effectiveness of valproic acid to other similar this the other commonly used AEDs for generalized
antiepileptic drugs (AEDs) in different settings epilepsies, LEV and LTG had an average daily
will be dealt with in the other write-ups in this expenditure of INR 36 and 39 respectively. As for focal
monograph. epilepsies cheaper AEDs like CBZ (carbamazepine)
Valproic acid is a broad spectrum AED and is and PHT are available for use.
effective in both focal and generalized seizures. The This cost analysis however has to be viewed
cost analysis can be done both against drugs used in concurrence with the efficacy and tolerability
for focal epilepsies and those used for generalized analysis. The best choice of AED may also depend
epilepsies. In our country, the cost of VPA differs upon other factors in addition to the type of epilepsy,
depending on the price set by various manufacturers. e.g. special situations like pregnancy, allergies, co-
It also varies with the preparation – whether it is morbidities, co-medication etc.
immediate release or sustained release; the latter Box Points:
being more expensive (this is significant, as VPA is a • VPA is a relatively economical AED for Generalized
long half life molecule). Epilepsies
• Immediate release preparation is significantly cheaper
The below mentioned table shows the average
than the sustained release
cost of some of the commonly used AEDs in • More economical AEDs are available for treatment of
comparison to VPA, namely Carbamazepine (CBZ), Focal Epilepsies
Oxcarbazepine (OXC), Phenytoin (PHT), Phenobarb • For best choice of AED-specific setting, efficacy and
(PB), Levetiracetam (LEV) and Lamotrigine (LTG). tolerability to be viewed in concurrence to the cost

42
Valproic Acid – A Paediatric Perspective
Nandan Yardi, Sheffali Gulati, Suvasini Sharma

Introduction serendipitously discovered its anticonvulsant activity

in the lab of C. Carraz in 1962. In the experiment,
The story of antiepileptic drugs (AEDs) began VPA was being used as a solvent carrier to dissolve
on 11th May 1857, when Sir Charles Locock the water-insoluble khelline derivatives (synthesized
used potassium bromide in a young women with by Eymard) to test them to abort seizures in rabbits.
hysterical epilepsy and reported it in Lancet. When all the compounds were found to abort
This was followed by serendipitous discovery of seizures “surprisingly”, it was found that the solvent
antiepileptic properties of phenobarbitone in 1912 by per se (VPA) possesses anticonvulsant activity.
Alfred Hauptmann, a young resident psychiatrist, Similarly Meunier found VPA’s anticonvulsant
who lived above a ward of people with epilepsy. activity at the rabbit test after dissolving coumarin
The patients used to fall out of bed during the night derivatives in VPA. VPA’s first clinical trial was
due to tonic-clonic seizures, thereby keeping him published in 1964 and in 1967. It was approved for
awake. Phenobarbitone, marketed the previous year marketing in France and marketed worldwide. VPA
as a hypnotic (Luminal) by F. Bayer and Company was approved by the US-FDA in 1978.
was used by Hauptmann to sedate his patients, so
that they could get a good night’s sleep. His patients Chemistry
responded by reducing their seizures not only during
night but also during daytime, so Phenobarbital Valproic acid is n-propyl pentanoate (di-n-propyl
created history by being recognized and used as a acetate), a branched chain fatty acid. It is marketed
potent AED. More than 20 years later, in 1936, Tracy in free acid form or the corresponding sodium
Putnam and Houston Merritt carried out a series of salt, and also as divalproex sodium, a combination
experiments on cats with electrical seizures and the of valproic acid and valproic acid. VPA is water-
result was launching of phenytoin in 1938.3 The next insoluble {(water solubility - 1.27 mg/mL) weak acid
major AEDs to be launched were carbamazepine pKa = 4.8)} whose sodium salt is freely water soluble
(mid 1960s) followed by valproic acid thereafter and very hygroscopic. Chemically, VPA is one of
benzodiazepines. Valproic acid since then has grown the simplest drugs currently available in therapeutic
in stature and is currently on the World Health arsenal with eight carbons and without any nitrogen
Organization’s List of Essential Medicines, a list of atom or cyclic ring.
the most important medications needed in a basic
health system. Mechanism of Action
The modern era of AED development was ushered VPA potentialising the inhibitory activity of
in after 1975 with the developemnt of Anticonvulsant GABA through several mechanisms, including
Drug Development Programme by the National inhibition of GABA degradation, inhibition of
Institute of Neurological Disorders and Stroke in GABA Transaminobutyrate (ABAT), increased
the United States, resulting in the licensing of an GABA synthesis, and decreased turnover by altering
increasing list of AEDs. the activity of the neurotransmitter Gamma Amino
Valproic acid (VPA, di-n-propylacetic acid) was first Butyrate (GABA).
synthesized in 1882 by Burton as a lipophilic solvent VPA also attenuates N-Methyl-D-Aspartate-
to dissolve the water insoluble substrates. There mediated excitation8, 9 and blocks Na+ channels,
was no known clinical use of VPA until P. Eymard Ca2+ channels (voltage-dependent L type CACNA1

43
 type C, D, N, and F), and voltage-gated K+ channels • Children and Adolescents 2 to 14 years: 9 hours
(SCN).10 Also, more recently VPA has been described (range: 3.5 to 20 hours)
as an HDAC inhibitor. • Adults: 9 to 16 hours
An almost concurrent study showed that the me-
Pharmacokinetics tabolites of VPA are also different in different age
groups. Here Leppik and colleagues12 demonstrated
All formulations of VPA are completely absorbed
that relative amount of VPA metabolized to 4-ene is
with enteric-coated formulation slowly, with a
more than twofold less in adults than in children,
2-3-hour time lag and peak levels from enteric-
which explains the different profile of hepatotoxicity
coated tablets occur 3-5 hours after intake. After
seen by age. In addition, metabolism of valproic acid
rectal administration peak plasma levels have been
is influenced by several cytochrome P450 and uridine
comparable to those after oral intake. Valproic acid
diphosphoglucuronosyltransferase (UGT) polymor-
has high affinity for plasma albumin and so a small
phisms.
volume of distribution with a free fraction value of
10%, at higher total valproic acid concentrations. The
Clinical Indications
therapeutic blood concentrations of VPA are 50-100
æg/ml with a half-life of 6-15 hours. Being highly VPA has been approved for the following clinical
lipophilic, it concentrates in the liver and crosses the settings (Table).
BBB to give high concentrations in the brain. Seizure Disorders: VPA is a broad spectrum AED
Clearance is increased at high doses, due to that has been used for almost all types of seizures.
the higher free fraction of valproic acid and is The recommendations and guidelines for use of VPA
higher in patients receiving CYP enzyme inducers. in epilepsy have been illustrated in Table.
Neonates have a low and immature microsomal drug Epilepsy: Valproic acid is the drug of choice for
metabolizing system, but eliminate valproic acid the idiopathic generalized epilepsy, absence seizures
at the same rate as adults, despite having a larger (along with myoclonic seizures, juvenile myoclonic
circulating free fraction. epilepsy, and atonic seizures. It is effective against
Valproic acid is extensively metabolized, through focal less so than carbamazepine. VPA has even been
oxidative and conjugation mechanisms. Conjugation found to be effective in febrile seizure prophylaxis
with D-glucuronic acid is the major pathway but is not recommended for the same due to the self-
of biotransformation, accounting for 30-40% limiting and benign nature of the disease.
of the dose. Similar to fatty acids, valproic acid Epileptic Encephalopathies: For management of
is sequentially oxidized by mitochondrial beta- children with West syndrome, the drug of choice is
oxidation to yield 3-oxo-valproate. Other pathways ACTH (non-tuberous sclerosis complex) or Vigabatrin
are also involved, yielding numerous metabolites. (tuberous sclerosis complex). However, in limited
Omega and omega-1 oxidative pathways have been literature, valproic acid has been effective for treating
described. The metabolites are biologically inactive. infantile spasms (Class IV evidence stiripentol along
Since valproic acid is a protein bound drug, its with valproic acid and clobazam has been proposed
volume of distribution closely parallels the serum as the most effective therapy for Dravet syndrome.
albumin concentration and also the body weight of VPA has also been reported be effective in children
the child. Also, since it is primarily metabolized in with Lennox-Gastaut syndrome (LGS). It has been
liver via the Cyp450 system, the maturation of liver suggested as the first line treatment for children with
enzymes improves valproic acid clearance. The major LGS myoclonic astatic epilepsy. Among patients with
study by Cloyd in 1993 showed that half-life of continuous spike and wave during sleep (CSWS;
valproic acid in various age groups is different. First line – clobazam, corticosteroids), and Landau
• Neonates 1st week of life: 40 to 45 hours Klefner syndrome (First line-corticosteroids), VPA
• Neonates <10 days: 10 to 67 hours has been proposed as an adjunctive AED.
• Infants and Children >2 months: 7 to 13 hours Status Epilepticus: Limited data have shown

44
efficacy of valproic acid in children with status aforementioned clinical settings VPA is being tried
epilepticus. In one retrospective study, an initial in various other disorders as well.4 They have been
loading dose of 25 mg/kg was effective in stopping listed in the Table.
seizure activity within 20 minutes after the end of
the infusion in all 18 patients treated epilepticus. A Drug Interactions
separate retrospective trial found a higher efficacy
To date a total of 606 drugs are known to interact
rate in paediatric patients who received an initial
with VPA, 12 major, 546 moderate, and 48 minor
loading dose of 30 mg/kg (73.3%, n=15) compared
interactions ([Link] List of
to 20 to 30 mg/kg (46.2%, n=26) or >40 mg/kg
commonly used drugs that can alter serum valproic
(40%, n=10) (24). In an open-label, randomized
acid levels have been depicted in table 4.6 Co-
comparative trial, loading dose of 30 mg/kg was
administration of VPA with other AEDs can influence
administered (n=20; age range: 7 months to 10
pharmacokinetics both VPA and other AEDs (Table
years of age; mean age: 3 years); a repeat bolus of 10
5 Adverse Reactions).
administered if seizures were not controlled within
The adverse effects of VPA have been illustrat-
10 minutes; mean required dose: 37.5 ñ 4.4 mg/kg;
ed.28 The most common adverse effects include
median required dose.
sleep disturbances, dizziness,abdominal pain/ dys-
Dosing of Valproic Acid pepsia, rash, increased appetite/ weight gain, trem-
ors, alopecia, and hirsutism. The more serious ad-
Seizure disorders: It is started at a dose of 10 verse effects include hepatotoxicity (idiosyncratic
mg/kg/day in two divided doses. The drug is then Reye’s like syndrome), hyperammonemic encepha-
increased in increments of 10 mg/kg/day every 3 lopathy, mitochondrial toxicity, pancreatitis, Stevens
days to reach the maintenance dose of 20-40mg/ Johnson syndrome/toxic epidermal necrolysis and
kg/day. In special circumstances of refractory aplastic anemia.
epilepsy doses up to 60 mg/kg/day have also been
administered. However, caution is advised at doses Hepatotoxicity
above 40 mg/kg/day with regular monitoring of liver
5 to 10% of persons develop asymptomatic and
function tests and plasma ammonia.
naturally resolving ALT elevations during long-term
Status epilepticus: Loading dose of VPA, 20- valproic acid therapy, needing no discontinuation of
30 mg/kg, is administered by intravenous infusion drug as shown by several prospective studies.
@ ó 6 mg/kg/min, which should be followed by Besides this simple aminotransferase elevation,
maintenance VPA administration at a dose of 20 mg/ three clinically distinguishable forms of
kg/day. VPA maintenance is initiated 12 hours after hepatotoxicity can occur with valproic acid.
the loading dose. All three forms of valproic acid hepatotoxicity
Migraine prophylaxis: In children aged 7 years have features of mitochondrial injury and liver
and adolescents aged 16 years, VPA is initiated at histology, usually demonstrate microvesicular
10 to 15 mg/kg/day in 2 divided doses (maximum steatosis with variable amounts of inflammation
initial mg/dose). Thereafter, it can be titrated and cholestasis. Young age (<2 years), presence
as needed over 4 to 6 weeks to 40 to 45 mg/kg/ of other neurological conditions and concurrent
day in 2 divided doses (maximum daily dose: use of anticonvulsants appear to be important risk
1,000 adolescents >16 years). VPA is started factors for acute liver failure due to valproic acid.
at 250 mg twice daily and increased based on The first syndrome is hyperammonemia with
patient’s response to maximum of 1000 mg/day. minimal or no evidence of hepatic injury. Syndrome
Bipolar disorders: VPA is started at 10-15 mg/kg/day typically presents with progressive and episodic
in two divided doses and increased to 60 mg/kg/day confusion followed by obtundation and coma.
for desired effects. The time to onset is often within a few of starting
Potential Therapeutic Targets: Apart from the valproic acid or increasing the dose, but it can

45
 present months or even years after starting the Monitoring
medication. The diagnosis is made by finding of
elevations in serum ammonia with normal (or near Some clinicians recommend monitoring complete
normal) serum aminotransferase and bilirubin blood counts (including platelet counts) at baseline,
levels. Valproic acid levels are usually normal or then monthly for three months, and every three months
minimally high. The syndrome resolves within a thereafter. However, currently routine monitoring
few days of stopping valproic acid, but may reverse of drug levels and hematological/biochemical
more rapidly with carnitidine supplementation parameters are not recommended. In an event of
and or renal hemodialysis. The second form of features of an adverse effect, the following tests
injury from valproic acid is an acute hepatocellular should be performed: complete blood count, liver
injury with jaundice, typically accompanied function tests, serum electrolytes, plasma ammonia
by hepatocellular or mixed pattern of enzyme and serum valproic acid levels.
elevations. This acute liver injury pattern usually Contraindications are important and must be
has its onset within 1 to 6 months of pattern of known to everyone and thought of by all who use
serum enzyme elevations, can be hepatocellular valproic acid.
or mixed; sometimes the serum aminotransferase Contraindications to VPA include:
levels are not markedly elevated, despite the Known mitochondrial disorders caused by
severity of injury. Prospective studies using historical mutations in mitochondrial DNA polymerase
controls suggest that carnitine (particularly gamma (POLG; e.g., Alpers-Huttenlocher syndrome
intravenously) may be beneficial if given soon after [AHS]) or children years of age suspected of having
presentation. a POLG-related disorder.
The third form of hepatic injury due to valproic Urea Cycle Defect
acid is a Reye-like syndrome described in children Hypersensitivity to valproic acid, divalproex, deriv-
on valproic acid that develop fever and lethargy atives, or any component of the formulation
(suggestive of a viral infection) followed by confusion, Hepatic disease or significant hepatic impairment
stupor and coma, with raised ammonia levels and Special Considerations
marked ALT elevations but normal or minimally Children up to 2
elevated bilirubin levels. Metabolic acidosis is also Neonates, infants, and children <2 years
common and the syndrome can be rapidly. of age are at considerably increased risk for
hepatotoxicity/hepatic failure, especially those
Valproic Acid and Liver : 4 Clinical scenarios
on anticonvulsant polytherapy, with congenital
and manifestations:
metabolic disorders, with severe seizure disorders
Characteristics Common Confusion- Hepatocel- Reye’s and mental retardation, or with organic brain
coma luar Like
disease. It is imperative to monitor these patients
(children)
Liver Enzymes Mild to Near normal Raised Markedly <2 years closely for appearance of malaise,
(ALT/AST) moderately minimally or raised loss of seizure control, weakness, facial edema,
raised significantly jaundice, and vomiting; to monitor liver enzymes
Ammonia Normal Raised Normal Raised
prior to therapy and at 4-6 weeks intervals, especially
Bilirubin Normal Normal Raised Near nor-
mal during the first 6 carnitine is clearly indicated for
Clinical Normal Confusion/ Signs of he- Confusion/ the management of valproic acid overdose and
presentation coma patocellular coma and hepatotoxicity, with the available evidence the
failure metabolic
acidosis routine prophylactic carnitine supplementation
Action Continue VPA Stop VPA Stop VPA Stop VPA is not recommended.30, 31 In this age group of less
Treatment Nil reassure ORAL/IV IV carnitine Support- than years, a valproic acid-associated Reye’s-like
parents / Carnitine or ive, alkali syndrome has also been reported.
doctors hemodial-
ysis Rare multiorgan hypersensitivity reactions have

46
been reported in paediatric patients in association References
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drug related eosinophilia and systemic symptoms Pharmacodynamic properties of dipropylactic acid. 1. Anticonvulsive
(DRESS); valproic acid and derivatives should action. Therapie. 1963; 18:435-8.
6. Vajda FJ, Eadie MJ. The clinical pharmacology of traditional antiepileptic
be discontinued in patients suspected of having drugs. Epileptic disorders: international epilepsy journal with videotape.
multiorgan hypersensitivity reactions. 2014; 16(4):395-408.
7. Mesdjian E, Ciesielski L, Valli M, Bruguerolle B, Jadot G, Bouyard P,
Adolescent girls: et al. Sodium valproate: kinetic profile and effects on GABA levels in
The adverse effects including hirsutism, weight various brain areas of the rat. Progress in neuro-psychopharmacology &
biological psychiatry. 1982; 6(3):223-33.
gain and polycystic ovarian syndrome (risk 8. Zeise ML, Kasparow S, Zieglgansberger W. Valproate suppresses
x1.95 times) assumes greater significance among N-methyl-D-aspartate-evoked, transient depolarizations in the rat
neocortex in vitro. Brain research. 1991; 544(2):345-8.
adolescent girls.32 These should be balanced against 9. Gean PW, Huang CC, Hung CR, Tsai JJ. Valproic acid suppresses the
the therapeutic benefits and discussed with the synaptic response mediated by the NMDA receptors in rat amygdalar
slices. Brain research bulletin. 1994; 33(3):333-6.
family before initiating VPA among adolescent girls. 10. VanDongen AM, VanErp MG, Voskuyl RA. Valproate reduces excitability
Pregnancy and lactation: by blockage of sodium and potassium conductance. Epilepsia. 1986;
27(3):177-82.
VPA intake during pregnancy is contraindicated.33,34 11. Cloyd JC, Fischer JH, Kriel RL, Kraus DM. Valproic acid pharmacokinetics
It has been associated with increased risk of in children. IV. Effects of age and antiepileptic drugs on protein binding
and intrinsic clearance. Clinical pharmacology and therapeutics. 1993;
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and diaphragmatic hernia.35 Also, it has been 12. Leppik IE. Metabolism of antiepileptic medication: newborn to elderly.
Epilepsia. 1992; 33 Suppl 4:S32-40.
shown that low doses of VPA are secreted 13. Jain P, Shastri S, Gulati S, Kaleekal T, Kabra M, Gupta N, et al.
in breast milk. However, these VPA levels in Prevalence of UGT1A6 polymorphisms in children with epilepsy on
valproate monotherapy. Neurology India. 2015; 63(1):35-9.
breast milk are insignificant and do not impact 14. Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Guerreiro C,
infant’s growth or development.36 Nonetheless, it is Kalviainen R, et al. Updated ILAE evidence review of antiepileptic drug
efficacy and effectiveness as initial monotherapy for epileptic seizures and
recommended that infant’s breast-feeding on mothers syndromes. Epilepsia. 2013; 54(3):551-63.
taking VPA should be monitored for jaundice and 15. Nunes VD, Sawyer L, Neilson J, Sarri G, Cross JH. Diagnosis and
management of the epilepsies in adults and children: Summary of
petechial rash. The intake of combination AEDs updated NICE guidance. BMJ. 2012; 344:e281.
rather than VPA monotherapy among breast 16. Dominguez-Carral J, Garcia-Penas JJ, Perez-Jimenez MA, Fournier-Del
Castillo MC, Carreras-Saez I, Jimenez-Echevarria S. [Benign myoclonic
feeding mothers may be more hazardous. FDA epilepsy in infancy: natural history and behavioral and cognitive
has labeled VPA as category “2” for lactation (i.e., outcome]. Revista de neurologia. 2014; 58(3):97-102.
17. Bourgeois B. Clinical use of drugs useful in the treatment of atonic
use with caution), while for pregnancy it has been seizures. Adv Neurol. 1995; 67:361-7.
provided with Category “D/X” label (i.e., should not 18. Baumann RJ, Duffner PK. Treatment of children with simple febrile
seizures: The AAP practice parameter. American Academy of Pediatrics.
be used in pregnancy). Pediatric neurology. 2000; 23(1):11-7.
19. Go CY, Mackay MT, Weiss SK, Stephens D, Adams-Webber T, Ashwal
Conclusion S, et al. Evidence-based guideline update: medical treatment of infantile
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VPA is a broad spectrum of AED with a beneficial American Academy of Neurology and the Practice Committee of the
Child Neurology Society. Neurology. 2012; 78(24):1974-80.
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is important to avoid its use in children with proven Bogaert P, et al. Summary of recommendations for the management
of infantile seizures: Task Force Report for the ILAE Commission of
or suspected mitochondrial disorders. Also, its use Pediatrics. Epilepsia. 2015; 56(8):1185-97.
should be cautious in children less than two years 21. Lemmon ME, Kossoff EH. New treatment options for lennox-gastaut
of age and among those on lamotrigine co-therapy. syndrome. Current treatment options in neurology. 2013; 15(4):519-28.

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 22. Vigevano F, Arzimanoglou A, Plouin P, Specchio N. Therapeutic approach 32. Hu X, Wang J, Dong W, Fang Q, Hu L, Liu C. A meta-analysis of
to epileptic encephalopathies. Epilepsia. 2013; 54 Suppl 8:45-50. polycystic ovary syndrome in women taking valproate for epilepsy.
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intravenous valproate in paediatric status epilepticus and acute repetitive 33. Harden CL, Pennell PB, Koppel BS, Hovinga CA, Gidal B, Meador
seizures. Epilepsia. 2003; 44(5):724-6. KJ, et al. Practice parameter update: management issues for women
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valproic acid therapy. The Annals of pharmacotherapy. 2000; 34(5):630-8. htm.

Table 1. Indications and dose of valproic acid

No. Indication Dose
1. Seizures/ Epilepsy Start: 10 mg/kg/day
Increase by 10 mg/kg/day every 3 days
Maintenance: 40 mg/kg/day
In refractory seizures maintenance dose of 60 mg/kg/day can been
administered
Dose to be administered in two divided doses
2. Status Epilepticus Initial: 20-30 mg/kg IV infusion @ 6 mg/kg/min
Additional 20 mg/kg can be administered after 15-20 minutes if required to a
maximum of 40 mg/kg
3. Migraine prophylaxis Children ≥7years and adolescents ≤16 years:
Initial: 10 to 15 mg/kg/day in 2 divided doses; maximum initial dose: 250 mg/
dose. Titrate as needed over 4 to 6 weeks to 40 to 45 mg/kg/day in 2 divided doses;
maximum daily dose: 1,000 mg/day
Adolescents >16 years:
Initial: 250 mg BD; titrate as needed to maximum of 1000 mg/day
4. Bipolar Disorders Initial: 10-15 mg/kg/day
Titrate upwards to maximum of 60 mg/kg/day
• Dose escalation is at a rate of 5-10 mg/kg/day every 3-5 days
• Monitor for side effects at doses >40 mg/kg/day

48
Table 2. Guidelines for use of valproic acid in epilepsy
No. Type of Seizure ILAE (2013) recommendations (14) NICE recommendations (15)
1. GTCS • VPA is possibly efficacious as monotherapy (Level C). • VPA as first line treatment
• Others including CBZ, PB, PHT, and TPM are possibly
(level C) and OXC is potentially (level D) efficacious/
effective for children with newly diagnosed or untreated
generalized-onset tonic–clonic seizures.
2. Absence seizures • VPA (and ETM) are efficacious as monotherapy as initial • VPA as the first line
monotherapy for children with newly diagnosed or treatment
untreated absence seizures (Level A).
3. Benign childhood • VPA (and CBZ) are efficacious as monotherapy (Level C). • VPA as the first line
epilepsy with • GBP, LEV, OXC, and STM are potentially (level D) treatment (along with CBZ,
centrotemporal spikes efficacious/effective as initial monotherapy for children LTG, OXC, LEV)
(BECTS) with BECTS.
4. Juvenile Myoclonic • VPA (and TPM) are potentially efficacious/effective for • VPA as the first line
Epilepsy patients with newly diagnosed JME (Level D). treatment (along with LTG,
LEV, TPM)
5. Partial Seizures • OXC is established (level A); CBZ, PB, PHT, TPM, VPA, • Offer CBZ or LTG as first
and VGB are possibly (level C); and CLB, CZP, LTG, line treatment.
and ZNS are potentially (level D) efficacious/effective as • VPA can be offered as
initial monotherapy for children with newly diagnosed or adjunctive treatment
untreated partial-onset seizures.
6. Myoclonic Not mentioned separately - VPA as the first line drug
7. Atonic seizures Not mentioned separately • - VPA as the first line drug
Levels of Evidence (For ILAE recommendations):
1. Class A: ≥1 Class I studies or meta-analysis meeting class I criteria sources OR ≥2 Class II studies
2. Class B: 1 Class II study or meta-analysis meeting class II criteria
3. Class C: ≥2 Class III double-blind or open-label studies
4. Class D: 1 Class III double-blind or open-label study OR ≥1 Class IV clinical studies OR Data from expert committee
reports, opinions from experienced clinicians
Other seizures/epileptic encephalopathies where VPA has been found to be effective:
1. West syndrome (Class IV Evidence) (19)
2. Dravet syndrome (along with Stiripentol and CLB) (20)
3. Benign myoclonic epilepsy of infancy (20)
4. Lennox-Gastaut syndrome (22)
5. Myoclonic astatic epilepsy (22)
6. Continuous spike and wave during sleep (CSWS; First line- CLB, corticosteroids) (22)
7. Landau Klefner syndrome (First line-corticosteroids) (22)
Abbreviations: CBZ: Carbamazepine; CLB: Clobazam; CZP: Clonazepam; LEV: Levetiracetam; LTG: Lamotrigine; OXC: Oxcarbazepine;
PB: Phenobarbitone; PHT: Phenytoin; TPM: Topiramate; VBG: Vigabatrin; VPA: Valproic Acid; ZNS: Zonisamide

49
 Table 3. Ongoing clinical studies with valproic acid
Neurological Disorders
1. Spinal muscular atrophy type I
2. Autism
3. ADHD
4. Bipolar disorder
5. Cluster headache
6. Dementia
7. Depression
8. Mood disorder
9. Neuralgia
10. Schizophrenia
11. Amyotrophic lateral sclerosis
Malignancies
1. Autoimmune lymphoproliferative syndrome
2. CNS tumors
3. Breast cancer
4. CLL
5. HTLV-1 associated myelopathy
6. Nasopharyngeal carcinoma
7. Sarcoma
Dependences
1. Alcohol abuse or dependence
2. Cocaine dependence
3. Marijuana abuse
Others
1. Asthma
2. Hypersplenism
3. Insulin resistance

Table 4. Interaction of valproic acid with other commonly used drugs

Drugs that may decrease valproic acid levels Carbapenems, Ethosuximide, Mefloquine, Protease inhibitors,
Rifampicin
Drugs that may increase valproic acid levels Chlorpromazine, Felbamate, Salicylates, Topiramate
Drugs whose levels may increase with valproic acid intake Barbiturates, Carbamazepine, Lamotrigine, Lorazepam,
Risperidone, Rufinamide, Zidovudine
Drugs whose levels may decrease with valproic acid intake Phenytoin/Fosphenytoin, Olanazipine, Oxcarbazepine

Table 5. Effect of other antiepileptics on valproic acid

Antiepileptic Drugs Effect on Valproic Acid
Carbamazepine Valproic acid levels decrease to 75% of pre-polytherapy level
Phenytoin Valproic acid levels decrease to 75% of pre-polytherapy level
Phenobarbitone Valproic acid levels decrease to 75% of pre-polytherapy level
Levetiracetam Valproic acid levels unchanged
Ethosuximide Valproic acid levels decrease to 28-37% of pre-polytherapy level

50
Table 6. Effects of Valproic acid on other antiepileptic drugs
Antiepileptic drug Effect on its level on co-administration with valproic acid
Lamotrigine Lamotrigine levels increase by 85%
Topiramate Topiramate levels stay unchanged
Felbamate Felbamate levels increase by 27%

Table 7. Adverse effects of valproic acid

Very common (10% or Common Uncommon (0.1% to Rare Frequency not
more) (1% to 10%) 1%) (< 0.1%) reported
Gastro-Intestinal
a. Abdominal pain a. Constipation a. Pancreatitis (life-
b. Diarrhea b. Dry mouth threatening)
c. Dyspepsia c. Eructation
d. Gingival disorder d. Fecal incontinence
e. Nausea e. Flatulence
f. Vomiting f. Gastroenteritis
g. Glossitis
h. Periodontal abscess
i. Hematemesis
j. Stomatitis
Hepatic
a. Increased liver a. Severe liver damage
enzymes (ALT and (including hepatic
AST) particularly early failure sometimes
in treatment resulting in death),
increased serum
bilirubin
Neurological
a. Dizziness a. Gait abnormality a. Ataxia a. Cognitive a. Cerebral atrophy
b. Headache b. Amnesia b. Coma disorder b. Dementia
c. Somnolence c. Catatonic reaction c. Encephalopathy b. Reversible
d. Tremor d. Disturbance in d. Lethargy dementia
attention e. Reversible associated
e. Dysarthria parkinsonism with reversible
f. Extrapyramidal cerebral
disorder atrophy
g. Hypertonia
h. Hypokinesia
i. Incoordination
j. Increased reflexes
k. Memory impairment
l. Nystagmus
m. Paresthesia
n. Speech disorder
o. Stupor
p. Tardive dyskinesia
q. Taste perversion

51
 Very common (10% or Common Uncommon (0.1% to Rare Frequency not
more) (1% to 10%) 1%) (< 0.1%) reported
Dermatologic
a. Alopecia a. Discoid lupus a. Abnormal hair a. Drug rash with a. Acne
erythematosus texture eosinophilia b. Hirsutism
b. Dry skin b. Abnormal hair and systemic c. Angioedema
c. Ecchymosis growth symptoms d. Generalized
d. Furunculosis c. Hair color changes (DRESS) pruritus
e. Maculopapular rash d. Sweating syndrome e. Photosensitivity
f. Petechiae b. Erythema
g. Pruritus multiforme
h. Rash c. Stevens-Johnson
i. Seborrhea syndrome
d. Toxic epidermal
necrolysis
Endocrine
a. Hyperandrogenism a. Hypothyroidism a. Abnormal thyroid
b. Syndrome of in- function tests
appropriate ADH b. Elevated serum
secretion testosterone
concentrations
c. Parotid gland
swelling
Genitourinary
a. Amenorrhea a. Breast enlargement
b. Cystitis b. Galactorrhea
c. Dysmenorrhea c. Polycystic ovary
d. Dysuria disease
e. Enuresis
f. Metrorrhagia
g. Urinary incontinence
h. Urinary frequency
i. Vaginal hemorrhage
j. Vaginitis
Hematologic
a. Thrombocytopenia a. Anemia a. Leucopenia a. Abnormal coag- a. Aplastic anemia
b. Hemorrhage b. Pancytopenia ulation tests (e.g., b. Bone marrow sup-
prolonged PT, pression
aPTT, INR) c. Bruising
b. Agranulocytosis d. Eosinophilia
c. Decreased coagu- e. Frank hemorrhage
lation factors f. Hypofibrinogen-
d. Pure red cell emia
aplasia g. Anemia including
e. Macrocytosis macrocytic with or
without folate defi-
ciency
h. Relative lympho-
cytosis

52
Very common (10% or Common Uncommon (0.1% to Rare Frequency not
more) (1% to 10%) 1%) (< 0.1%) reported
Metabolic
a. Weight gain a. Increased appetite a. Hyperam- a. Acute intermittent
b. Hyponatremia monemia porphyria
b. Minor elevations of
LDH (dose related)
c. Decreased carnitine
concentrations
d. Hyperglycinemia
Psychiatric
a. Nervousness a. Abnormal dreams a. Abnormal a. Behavioral
b. Agitation behavior deterioration
c. Anxiety b. Learning disorder b. Psychosis
d. Aggression c. Psychomotor
e. Confusion hyperactivity
f. Depression
g. Emotional lability
h. Hallucinations
i. Insomnia

Figure 1. Chronological evolution of antiepileptic Figure 2. Major valproic acid metabolic pathways.
drugs (1) The inactive forms are shown in lighter shade. (6)

53
 Valproic Acid Use in Girls and Women with
Epilepsy
Sanjeev V. Thomas

Introduction management of epilepsy in pregnancy. This paper

will be focussing on the safety of using valproic acid
It is estimated that there are about 1.2 million during pregnancy.
women with epilepsy in India who are in the
reproductive age group. There is a complex Indications for Valproic Acid
interaction between the reproductive sex hormones,
AEDs and epilepsy that makes women more prone to Valproic acid is a broad spectrum antiepileptic drug
seizures during certain periods of their reproductive that is effective against a variety of seizure types and
cycle or menstrual cycle. Several studies have shown epilepsy syndromes starting in infancy to adulthood
that seizure freedom is the single most important (Table 1). As a result it is not uncommon to find girls
predictor of good quality of life for people with who are started on valproic acid continue it in to
epilepsy. Most women with active epilepsy would adolescence and womanhood, when the pregnancy
require continuation of treatment with antiepileptic related concerns commence.
drugs during pregnancy in order to remain seizure Table 1: Epilepsy/Seizure Types
free. Antenatal exposure to anti-epileptic drugs can
Absence seizures
increase the risk of fetal malformations and long
term neurocognitive developmental problems to Myoclonic seizures
the babies. Hence safety of the mother and baby is Generalised tonic-clonic seizures
a major concern for women with epilepsy as they Epilepsy syndromes
prepare for pregnancy. Considering the special
Febrile seizures
situation of pregnancy, it is unlikely that prospective
controlled clinical trials of antiepileptic drugs (Class Idiopathic Generalized Epilepsies
I studies) would be undertaken. The pregnancy Childhood Absence Epilepsy
outcome of women with epilepsy had been under Juvenile Absence Epilepsy
systematic studies for the past two decades. The
Juvenile Myoclonic Epilepsy
prospective pregnancy registries had been set up in
the UK (1996), North America (1997), Kerala (1998), Idiopathic Generalized Epilepsy
Europe (1999) and Australia (2000) in order to Localization related (Focal) Epilepsies
address this research theme. The enrolment policies, Benign childhood epilepsy with Centrotemporal Spikes
methods and timing of ascertainment and definition Other localization related epilepsies
of outcome measures vary between the registries
to some extent. The neurocognitive outcome of the Epileptic encephalopathies
children born to women with epilepsy had been West syndrome (infantile spasms)
under scrutiny in the UK, North America (NEAD Lennox-Gastaut Syndrome (LGS)
study) and Kerala (KREP). The observations from Landau-Kleffner syndrome (LKS)
these registries and other studies have helped us
to develop evidence based recommendations on Progressive myoclonic epilepsies

54
 Adverse Effect Profile of Valproic Acid exposure to valproic acid.8 The data from the KREP
had shown that children with antenatal exposure
Valproic acid can cause several adverse effects that to AEDs performed significantly poorer than
can be particularly bothersome to women (Table 2). those without any exposure when examined at one
Table 2. Adverse effects of valproic acid that can year,9 six years10 and twelve years11 of age. Those
be of major concern to women with epilepsy exposed to valproic acid had a trend towards poorer
performance, when compared to those exposed
Hair loss to other AEDs in monotherapy. The data from the
Tremor NEAD study had confirmed that antenatal exposure
to valproic acid carried a dose dependent increased
Obesity risk of lower IQ at three years12 and six years of age.13
Menstrual irregularity The data from this registry had further confirmed
the dose dependency of the cognitive developmental
Polycystic ovarian syndrome
delay.
Infertility
Importance of Seizure Control for Women with
Osteoporosis
Epilepsy
Teratogenic effects and impaired cognitive develop-
ment in prenatally exposed offspring The very objective of treatment of epilepsy is
control of seizures, which is particularly relevant
for women. The impact of social stigma is more
Fetal adverse effects of Valproic Acid for women than for men. Their social position,
The potential risk of fetal malformations and late prospects of marriage, integration in the family
cognitive developmental problems of children are and society at large depend on complete control of
the most serious concern for girls and women with seizures. Occurrence of even breakthrough seizures
epilepsy. in the middle of prolonged seizure freedom can
jeopardize their functional status and add to their
Birth defects disability. Women with epilepsy who were married
on the understanding that they are in remission may
Data from the retrospective population based find their marriage at stake, if seizures recur during
studies in Norway1 and Denmark2 have shown that pregnancy or otherwise.
children of women with epilepsy who had used Women with idiopathic generalized epilepsy
valproic acid carried increased risk of birth defects. (generalized genetic epilepsy) are a subgroup that
The prospective cohort studies through the major often achieve complete remission of seizures with
pregnancy registries in UK3, USA4, Europe5, India6 medications and have normal cognitive functioning.
and Australia7 have confirmed the increased risk Their prospects of education, employment and
of neural tube defects and other major congenital successful marriage are higher than others with
malformations for children with antenatal exposure frequent seizures or cognitive impairments. Those
to valproic acid. The data from UK, EURAP and with juvenile myoclonic epilepsy are the typical
India have further shown that the risk of major prototypes of this subgroup.
malformations is proportionate to the dosage of Previous studies have shown that valproic acid is
valproic acid during pregnancy.5 one AED that successfully controls seizures in JME
Cognitive Adverse Effects and other types of IGEs.14 It is a broad spectrum
drug that is effective against myoclonus, generalized
Recent studies from UK had for the first time seizures and focal seizures with or without secondary
pointed towards increased risk of educational generalization. It has no interaction with oral
backwardness for older children with antenatal contraceptives.

55
 The therapeutic efficacy of valproic acid vis-a-vis too restrictive for women to access health care for
its adverse effects on the mother and the fetus has led epilepsy. The lack of economic autonomy for women
to wide debate on its precise role in the treatment of with epilepsy can limit the access to expensive
epilepsy in girls and women. The various regulatory investigations or therapy. A major proportion
bodies and professional organizations have been of pregnancies in India are unplanned as the
attempting to bring in standardized guidelines on proportion of women who access effective methods
when and how to use valproic acid in women with of contraception and plan pregnancy in India are less
epilepsy (See Table 3). than the desired levels. These special situations need
to be kept in mind while recommending treatment
Indian Scenario of epilepsy in women of reproductive age group.

A modest estimate shows that there are at least 15 Management of Epilepsy in Women who are
million women with epilepsy in the reproductive age Planning their Pregnancies
group. The treatment gap of epilepsy ranges from 35
- 85% in certain areas of the country. Cost of the The clinicians need to initiate discussion on the
drugs, lack of continuous availability of AEDs in impact of epilepsy and continuation of treatment
local dispensaries and hospitals, poor understanding with antiepileptic drugs for girls in their late teens
of the illness and social stigma are important barriers as some of them may get married early. Since a large
to good compliance with treatment of epilepsy in proportion of pregnancies in India are unplanned
India. This is further aggravated by the gender related the clinician should take time to discuss with
restrictions for women to travel to hospitals for the woman and her relatives the possible adverse
epilepsy care. The social stigma of epilepsy is often effects of antiepileptic drugs vis-a-vis the need for

Table 3: Summary of recommendations from major guideline organizations

Guideline Year of Main recommendation
updating
ILAE Commission July 2015 Valproic acid to be avoided in women with focal epilepsies. When used in women of child
on European Affairs bearing potential, lowest effective dose of valproic acid should be used aiming at a dosage
Recommendations15 less than 600 mg per day. Women of childbearing potential who are not planning pregnancy
and continue treatment with valproic acid should utilize effective contraception methods or
otherwise ensure that unplanned pregnancies can be avoided.
NICE Guidelines16 Jan 2015 We are assessing the impact of this on the guideline. In the meantime, healthcare professionals
are advised to use the guideline in conjunction with the latest MHRA advice.
European Nov 2014 Doctors in the EU are now advised not to prescribe valproic acid for epilepsy or bipolar disorder
Union (EMA) in pregnant women, in women who can become pregnant or in girls unless other treatments
recommendations17 are ineffective or not tolerated. Those for whom valproic acid is the only option for epilepsy or
bipolar disorder should be advised on the use of effective contraception and treatment should
be started and supervised by a doctor experienced in treating these conditions.
US FDA June Valproic acid contraindicated for migraine prevention in pregnant women. It is a category X
recommendations18 2013 drug for migraine prevention.
With regard to valproic acid use in pregnant women with epilepsy or bipolar disorder, valproic
acid products should only be prescribed if other medications are not effective in treating the
condition or are otherwise unacceptable. Valproic acid products will remain in pregnancy
category D for treating epilepsy and manic episodes associated with bipolar disorder.
With regard to women of childbearing age who are not pregnant, valproic acid should not
be taken for any condition unless the drug is essential to the management of the woman's
medical condition. All non-pregnant women of childbearing age taking valproic acid products
should use effective birth control.

56
continued medical treatment to maintain seizure morbidities and women who had undergone
freedom. It is important to carefully balance the sterilization or have become menopausal).
efficacy of valproic acid in controlling epilepsy and 8. All women and caregivers for girls should receive
maintaining seizure freedom with the potential full information of the benefits and risks prior to
adverse effects on the fetus including risk of birth treatment with valproic acid.
defect and long term cognitive developmental issues. 9. All women with childbearing potential need to be
A shared decision making in which the clinician prescribed folic acid 5 mg daily.
invites the patient and if possible the responsible
family members to participate in the decision Management of Pregnancy in Women who are
making with regard to the choice of antiepileptic on Valproic Acid
drugs. It is important that the physician explains in
simple terms the potential risk from breakthrough Once a woman is identified to be pregnant,
seizures as well as the adverse effects to the fetus and there is little benefit from attempting to switch
help the patients and their family members to make to other monotherapy/polytherapy. However, a
informed choices. The priorities of the patients with dose reduction to less than 600 mg per day can be
regard to need for seizure control, cost of treatment, considered in early pregnancy in those who are in
access to medications and care, impact of relapse remission.
of seizure on social stigma, family relationships, All Women with Epilepsy (WWE) need to continue
driving, employment and adverse effects on fetus folic acid 5 mg daily throughout pregnancy although
need to be given due considerations. its beneficial effects are not proven.
As general guidelines it can be stated that: All pregnant women with epilepsy need to have a
1. Valproic acid should preferably be avoided as the screening of serum alpha feto protein and a level III
first line drug for treatment of epilepsy in girls antenatal ultrasonography to carefully evaluate the
and women of reproductive age. fetal organs for any malformations.
2. Valproic acid may be avoided in obese women
Breastfeeding by Women who are Using
with history of menstrual irregularities or
Valproic Acid
polycystic ovarian syndrome.
3. Whenever possible valproic acid dosage need to The benefits of breast feeding outweigh the
be maintained below 600 mg per day for adult potential risk from the exposure to valproic acid
women. through breast milk. There was no correlation
4. Valproic acid can be continued (preferably in low between the child’s IQ and exposure to antiepileptic
dose) in women in reproductive age group who drugs through breast milk.
are already in long term remission of epilepsy
while on valproic acid. Should a Woman Avoid Pregnancy if she is
5. Low dose valproic acid (<600 mg per day) may be Using Valproic Acid as an Antiepileptic Drug?
considered under certain circumstances as one of
the first line drugs for treating newly diagnosed The likelihood of achieving seizure remission and
generalized epilepsy in girls and women of AED withdrawal within a reasonable period of time
reproductive age group after a full discussion on vis-a-vis the risk from AED exposure need to be taken
its risk to the patient. considered carefully and weighed while reaching
6. Valproic acid can be used as a first line drug to a decision regarding timing of pregnancy. The
treat age specific epilepsies of childhood such as indefinite postponement of pregnancy anticipating
absence or BECT that are known to resolve before AED withdrawal may not be wise as pregnancies
puberty. beyond 30–35 years of age carry higher maternal
7. Valproic acid can be used in girls and women and fetal adverse effects. The social commitments,
who are unlikely to become pregnant (girls with other health conditions of the women are important
epileptic encephalopathies or significant co- aspects that can influence decisions regarding

57
 planning of pregnancy. These factors have important exposure in utero. Acta Neurol Scand. 2013 Oct; 128(4):228-34.
8 Adab N, Jacoby A, Smith D, Chadwick D. Additional educational needs
bearing on the long term cognitive/behavioral in children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry.
outcomes of the children also. The woman and/or 2001; 70:15-21.
her caregiver should receive full information about 9 Thomas SV, Ajaykumar B, Sindhu K, Nair MK, George B, Sarma PS.
Motor and mental development of infants exposed to antiepileptic drugs
the benefits and adverse effects of use of valproic in utero. Epilepsy Behav. 2008; 13:229-36.
acid during pregnancy so that they can participate 10 Thomas SV, Sukumaran S, Lukose N, George A, Sarma PS. Intellectual
and language functions in children of mothers with epilepsy. Epilepsia.
in the shared decision making with the clinician. 2007; 48:2234-40.
These consensus statements on the use of valproic 11 Neelima Gopinath, Anila K. Muneer, Syam Unnikrishnan, Ravi Prasad
Varma, Sanjeev V. Thomas Children (10 - 12 years age) of women with
acid in girls and women would require further epilepsy have lower intelligence, attention and memory: Observations
assessment after three years as considerable amount from a prospective cohort case control study Epi Res 2015: DOI: http://
of new data are emerging from the various registries [Link]/10.1016/[Link].2015.09.003
12 Meador KJ, Baker GA, Browning N, Clayton-Smith J, Combs-Cantrell
and cohort studies on the maternal and fetal adverse DT, Cohen M, Kalayjian LA, Kanner A, Liporace JD, Pennell PB,
effects of use of valproic acid in the antenatal period. Privitera M, Loring DW; NEAD Study Group. Cognitive function at 3
years of age after fetal exposure to antiepileptic drugs. N Engl J Med. 2009
Apr 16; 360(16):1597-605.
References 13 Baker GA, Bromley RL, Briggs M, Cheyne CP, Cohen MJ, García-Fiñana
M, Gummery A, Kneen R, Loring DW, Mawer G, Meador KJ, Shallcross
1 Veiby G, Daltveit AK, Engelsen BA, Gilhus NE. Fetal growth restriction R, Clayton-Smith J; Liverpool and Manchester Neurodevelopment Group.
and birth defects with newer and older antiepileptic drugs during IQ at 6 years after in utero exposure to antiepileptic drugs: A controlled
pregnancy. J Neurol. 2014; 261:579-88. cohort study. Neurology. 2015 Jan 27; 84(4):382-90.
2 Kilic D, Pedersen H, Kjaersgaard MI, Parner ET, Vestergaard M, Sørensen
14 Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA,
MJ, Olsen J, Bech BH, Christensen J, Pedersen LH. Birth outcomes after
Chadwick DW, Cramp C, Cockerell OC, Cooper PN, Doughty J, Eaton
prenatal exposure to antiepileptic drugs--a population-based study.
B, Gamble C, Goulding PJ, Howell SJ, Hughes A, Jackson M, Jacoby A,
Epilepsia. 2014; 55:1714-21.
Kellett M, Lawson GR, Leach JP, Nicolaides P, Roberts R, Shackley P, Shen
3 Campbell E, Kennedy F, Russell A, Smithson WH, Parsons L, Morrison PJ,
J, Smith DF, Smith PE, Smith CT, Vanoli A, Williamson PR; SANAD
Liggan B, Irwin B, Delanty N, Hunt SJ, Craig J, Morrow J. Malformation
Study group. The SANAD study of effectiveness of valproate, lamotrigine,
risks of antiepileptic drug monotherapies in pregnancy: updated results
or topiramate for generalised and unclassifiable epilepsy: An unblinded
from the UK and Ireland Epilepsy and Pregnancy Registers. J Neurol
randomised controlled trial. Lancet. 2007 Mar 24; 369(9566):1016-26.
Neurosurg Psychiatry. 2014; 85:1029-34.
15 Tomson T, Marson A, Boon P, Canevini MP, Covanis A, Gaily E,
4 Hernández-Díaz S, Smith CR, Shen A, Mittendorf R, Hauser WA,
Kälviäinen R, Trinka E. Valproate in the treatment of epilepsy in girls
Yerby M, Holmes LB; North American AED Pregnancy Registry; North
and women of childbearing potential. Epilepsia. 2015 Jul; 56(7):1006-19.
American AED Pregnancy Registry. Comparative safety of antiepileptic
drugs during pregnancy. Neurology. 2012; 78:1692-9. 16 Epilepsies: Diagnosis and management [Link]
5 Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Sabers A, Perucca cg137 accessed on 28 October 2015
E, Vajda F; EURAP study group. Dose-dependent risk of malformations 17 CMDh agrees to strengthen warnings on the use of valproate
with antiepileptic drugs: An analysis of data from the EURAP epilepsy medicines in women and girls. [Link]
and pregnancy registry. Lancet Neurol. 2011 Jul; 10(7):609-17. jsp?curl=pages/news_and_events/news/2014/11/news_detail_002220.
6 Begum S, Sarma SP, Thomas SV. Malformation in index pregnancy jsp&mid=WC0b01ac058004d5c1 accessed on 28 October 2015
in women with epilepsy is not followed by recurrence in subsequent 18 FDA Drug Safety Communication: Valproate Anti-seizure Products
pregnancy. Epilepsia. 2013; 54:e163-7. Contraindicated for Migraine Prevention in Pregnant Women due to
7 Vajda FJ, O'Brien TJ, Graham J, Lander CM, Eadie MJ. Associations Decreased IQ Scores in Exposed Children [Link]
between particular types of fetal malformation and antiepileptic drug Drugs/DrugSafety/[Link] accessed on 28 October 2015

58
Valproic Acid in Epilepsy with Various
Comorbidites and Systemic Disorders
Atma Ram Bansal and Neeraj N. Baheti

Epilepsy is a chronic disorder in majority. As with to note whether AEDs with positive psychotropic
other chronic disorders, co-morbid conditions can properties (i.e., carbamazepine, lamotrigine, and
frequently occur in epilepsy and may significantly valproic acid) have recently been discontinued, or
affect epilepsy and its treatment. A person with whether AEDs with negative psychotropic properties
epilepsy can have other systemic disorders requiring (i.e., benzodiazepines, felbamate, levetiracetam,
other medications. A detailed understanding of the phenobarbital, primidone, tiagabine, topiramate,
interrelationships between comorbidities, systemic vigabatrin, and zonisamide) have been recently
disorders and their treatments is optimal for effective added or the dosage increased. Valproic acid
management of patients. Valproic acid is a first line increases extracellular serotonin5 and also stimulates
broad spectrum antiepileptic drug which is useful brain dopamine turnover thus making it an
across all age groups and multiple seizure types. In antiepileptic of choice in persons with concomitant
this chapter we will review usefulness of valproic mood disorders.6 Following points need attention in
acid in persons with epilepsy and comorbidities and/ a patient with epilepsy and mood disorders.
or systemic disorders. • During discontinuation of valproic acid, the
person with epilepsy may show features of
Valproic Acid in Epilepsy with Various affective disorder like mania or depression and
Comorbidities should be taken care of accordingly.
• Valproic acid can be a good choice in patient
Mood disorders (see Table 1) with affective disorder especially mania or
Depression is a very common undiagnosed and bipolar disorder in view of its mood stabilizing
untreated comorbidity in patients with epilepsy property. It is particularly effective in bipolar
especially refractory epilepsy with occurrence rate affective disorder especially with rapid cycling
of 3 to 10 times more than general population.1 The and dysphoric mania.7
frequency of depression among medically refractory • Valproic acid is helpful in certain psychological
epilepsy populations can be as high as 50%, while symptoms like hostility, impulsivity, and
in patients with controlled seizures the frequency is aggression.
closer to 10%.2 Depression in patients with epilepsy
may relate to dysfunction in the prefrontal, inferior Migraine
frontal, striatal, and mesial temporal regions.3 Migraine and epilepsy are two neurological
Antiepileptic drugs (AEDs) are also known to disorders with many similarities like episodic
exacerbate depression. Common such AEDs are attacks, chronic disorders with associated autonomic
phenobarbital, primidone, tiagabine, vigabatrin, and gastrointestinal symptoms. There are similarities
and the benzodiazepines can exacerbate depression. in pathophysiology and treatment as well. Kindling,
Felbamate, levetiracetam, topiramate, and zonisamide a pathological change characterized by lowering
have also been associated with depression.4 Certain the threshold for subsequent attacks in epilepsy,
AEDs like carbamazepine, lamotrigine and valproic has some similarities with sensitization of pain
acid have mood stabilizing property. When assessing in migraine.8 The people with epilepsy are more
an epilepsy patient with depression, it is important likely to have migraine and at the same time

59
 epilepsy is more common in people with migraine Polycystic ovarian syndrome
than general population.9, 10 In 1988, an open label Increased rates of polycystic ovarian syndrome,
study showed the effectiveness of valproic acid in decreased libido, infertility, and early menopause have
migraine prevention.11 Subsequently there have been been described in women with epilepsy. Polycystic
double blind randomized studies on valproic acid ovarian syndrome has been more frequently
monotherapy for migraine prophylaxis including reported in association with genetic (idiopathic)
extended release of valproic acid.12,13 generalized than focal epilepsy syndromes, although
Valproic acid mainly acts via GABA mediated more women with generalized epilepsy received
transmission in epilepsy as well as in migraine. It valproic acid treatment. Randomised study has
inhibits GABA transaminase inhibitor and activates shown that polycystic ovarian syndrome features
glutamic acid decarboxylase which leads to reduction developed more frequently during valproic acid than
in inflammation seen in migraine.14 lamotrigine treatment and these metabolic changes
are partially reversible on discontinuing valproic
As per AAN guidelines, valproic acid and divalproex
acid.19,20
sodium, both have level A recommendation (more
Renal Failure
than 2 class I trials) for use in migraine prophylaxis
More lipophylic high protein bound AEDs like
in adults.15 In the recent Cochrane review, valproic
carbamazepine, phenytoin, and valproic acid are
acid is found to be effective in reducing headache
little affected by renal disease. Hemodialysis has
frequency and is reasonably well tolerated in adult
little impact on valproic acid levels as they are highly
patients with episodic migraine.16 Parentral valproic
protein bound.21 Although valproic acid is safe in
acid is also effective in aborting acute attack of
mild-to-moderate renal failure, there are reports of
headache in status migrainosus.17 However, due to
acute tubular necrosis following valproic acid use
its potential teratogenic effects, it should be avoided
and Fanconi’s syndrome.22
in young women of 3 child bearing age group.
Hepatic Failure
Systemic Disorders and Role of Valproic Acid Valproic acid is a wide-spectrum isoenzyme
inhibitor and increases its own serum level and
Thyroid disorders that of other drugs sometimes causing toxicity thus
There are conflicting reports of effects of valproic dose reduction may be required in setting of hepatic
acid on thyroid functions. Majority of the reports dysfunction. Valproic acid can lead to hepatotoxicity
mention minimal (subclinical) suppression of and Rey’s syndrome as idiosyncratic reaction.23
thyroid functions with valproic acid. But the changes Further details are given in the chapter of side effects.
are transient and reversible with withdrawal of Osteoporosis
medication.18 Bone mineral density measurements reveal
osteopenia or osteoporosis in 38% to 60% of people
Obesity with epilepsy receiving AEDs in specialty clinics.24
Weight gain is a well-known adverse effect of Both men and women with epilepsy have elevated
VPA treatment, occurring in 40% of children and rates of fractures (two-to six fold higher) compared
nearly 50% of women especially in younger age to the general population. Evidence suggests that
group. Pathophysiologically, an increase in serum AEDs have negative effects on bone mineral density
insulin and insulin/glucose levels may cause weight through a variety of mechanisms including induction
gain, possibly by stimulating appetite. Although of cytochrome P-450 system enzymes. Valproic acid
usually reversible, the weight gain can sometimes although is an enzyme inhibitor but it has a strong
be progressive leading to hyperandrogenism and association with osteoporosis. For a patient who
polycystic ovaries. Valproic acid should be used with needs to be started on AEDs preferably newer non-
caution in obese with an advice regarding dietary enzyme inducing AEDs may be a better choice. If
and life style modifications with frequent weight such a person requires valproic acid or is already on
monitoring. the same, calcium and vitamin D supplementation

60
may be prescribed. In elderly population, a regular of acute intermittent porphyria have been reported
interval Dexa scan may help to detect bone loss at with valproic acid.35 In the presence of underlying
early stage. primary hematological disorders it is best to avoid
HIV Infection/AIDS valproic acid.
The American Academy of Neurology in Cardiovascular disorders
conjunction with ILAE published guidelines for AED Although safe in patients with cardiac comorbidities,
use in HIV.25 Although there is laboratory evidence valproic acid being highly protein bound can displace
that valproic acid may increase HIV replication in warfarin, digoxin, and amiodarone from its binding
vitro and thus it might lead to accelerated sites. It can lead to cardiac arrhythmias, increased
destruction by HAART but these findings needs to anticoagulation. Hence close monitoring is needed
be replicated.26 Valproic acid has been associated in this situation.
with hepatic and multiorgan failure when used with Valproic Acid in ICU Care
antiretroviral drugs.27 Valproic acid also increases Valproic acid is a well proven and effective drug
the level of zidovudine. Hence taking all the things in status epilepticus. Valproic acid is an alternative
into consideration, valproic acid should be used with agent to phenytoin and can be used in status
caution in the treatment of epilepsy in patients with epilepticus even in cases where phenytoin has failed.
HIV/AIDS. The detail of VPA use in status is mentioned in detail
Neuropathic pain syndromes in status epilepticus chapter. It is a preferred agent
Valproic acid is of uncertain efficacy for treating in cases of primary generalized epilepsy with status
neuropathic pain syndromes and in this situation or patient with myclonic status (post-hypoxic state
sodium channel blockers should be used preferably.28 like Lance Adam Syndrome) and in patients with
Stroke absence or non-convulsive state. There is no effect
The risk for development of epilepsy is 17-fold of VPA on QT interval and hence can be used in
higher after stroke than in the age matched general patients with cardiac arrhythmia. Valproic acid is
population; it is estimated that 10-15% stroke patients quite safe in mild-to- moderate renal dysfunction.
develop epilepsy.29 Phenytoin, phenobarbitone and However, in cases of seizures/status epilepticus with
benzodiazepines interfere with stroke recovery and preexisting significant hepatic dysfunction VPA is
hence are best avoided. Among the antiepileptics, better avoided.
valproic acid has less stroke risk than phenytoin.30 If any patient already on valproic acid is admitted
There is an increased risk of insulin resistance and in ICU for any systemic issues then monitoring of
metabolic syndrome31 and hence should be used liver function tests and ammonia may be useful.
with caution in such group of patients. If a patient There is a very significant drug interaction with
is on long term anticoagulation, VPA may have carbapenem antibiotics. There are several case reports
significant interaction due to enzyme inhibition and on carbapenem antibiotics, especially meropenem
hence should be avoided. causing decrease in the plasma concentrations of
Malignancies and patients on chemotherapy valproic acid (VPA), thus decreasing its therapeutic
Valproic acid exerts an antiproliferative effect activity.36 The reported decrease in plasma level of
on cancer cells in vitro and vivo due to histone VPA is more than 80% within 24 hours of starting
deacyetylase inhibition. There are preliminary meropenem. Hence, there is a high risk of withdrawal
reports of use of valproic acid in hematological and seizure in a patient who is well controlled on VPA
solid tumors including glioblastoma multiforme.32,33 after starting meropenem. It is advised that both the
Valproic acid may aggravate hematologic and other drugs should not be administered concomitantly.
toxicities of chemotherapeutic agents due to enzyme CNS infections
inhibition hence it should be best avoided.34 CNS infections like tubercular meningitis
Hematological disorders commonly present with seizures especially in adults.
Thrombocytopenia, leukopenia, bone marrow For acute management of seizure in TBM, VPA can
suppression, lymphadenopathy and exacerbation be used however for long term management it is not

61
 a very good choice in view of risk of drug interaction Implications for the cognitive-emotional features of mood disorders. Curr
Opin Neurobiol 2001; 11:240-249.
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 Notes

64
Notes

65
 Notes

66