Intravenous valproic acid for the treatment of status epilepticus and seizure clusters

Abstract

Status epilepticus (SE) and seizure clusters (SCs) are emergency situations, which require immediate and effective treatment. This study aimed to investigate the efficacy and tolerability of intravenous (IV) administration of Valproic acid (IV VPA) in the treatment of SE and SCs. All patients treated in our department with IV VPA between January 2009 and February 2010, were retrospectively analyzed. Indications for IV VPA were SCs and SE refractory to first line therapy (benzodiazepines). Dose, responsiveness and adverse events were evaluated. 31 patients (19 males and 12 females, median age 54.2 years), were included in the study. Twenty one patients presented primary generalized SCs, 6 had focal motor status epilepticus and 4 had focal seizures with secondary generalization. All had previously been unsuccessfully treated with intravenous infusion of Diazepam. The treatment protocol implied a 25mg/kg b.w. of IV VPA loading dose over 30 minutes, followed by continuous infusion of 100 mg/h for at least 24h, continued by oral administration. In 80% of the cases (25 of 31), seizures stopped within 6 h, and general anesthesia was not required. Four patients (12%) required general anesthesia and 2 patients were resistant to all therapeutic attempts and died. SE was symptomatic in all cases, 16 with stroke, traumatic 6, toxic 4, infectious 3 and tumors 2. No serious side effects were reported considering that relevant medical history included cardiac arrhythmias, respiratory distress and hepatic disease. IV VPA proved to be a safe, effective treatment of status epilepticus and SCs, especially in patients with co-morbidities (cardiovascular diseases and respiratory insufficiency).

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INTRAVENOUS VALPROIC ACID FOR THE
TREATMENT OF STATUS EPILEPTICUS AND
SEIZURE CLUSTERS
CORINA ROMAN-FILIP1*, FELICIA GLIGOR2, AURELIAN
UNGUREANU3, LIIANA PRODAN3
1Department of Neurology, University “Lucian Blaga”, Pompeiu
Onofreiu St., No. 2-4, 550166, Sibiu, Romania
2Department of Biochemistry, University “Lucian Blaga”, Lucian Blaga
St., No. 2A, 550169, Sibiu, Romania
3Department of Neurology, Academic Emergency Hospital Sibiu,
Romania Pompeiu Onofreiu St., No. 2-4, 550166, Sibiu, Romania
*corresponding author: corinaromanf@yahoo.com
Abstract
Status epilepticus (SE) and seizure clusters (SCs) are emergency situations,
which require immediate and effective treatment. This study aimed to investigate the
efficacy and tolerability of intravenous (IV) administration of Valproic acid (IV VPA) in
the treatment of SE and SCs. All patients treated in our department with IV VPA between
January 2009 and February 2010, were retrospectively analyzed. Indications for IV VPA
were SCs and SE refractory to first line therapy (benzodiazepines). Dose, responsiveness
and adverse events were evaluated. 31 patients (19 males and 12 females, median age 54.2
years), were included in the study. Twenty one patients presented primary generalized SCs,
6 had focal motor status epilepticus and 4 had focal seizures with secondary generalization.
All had previously been unsuccessfully treated with intravenous infusion of Diazepam. The
treatment protocol implied a 25mg/kg b.w. of IV VPA loading dose over 30 minutes,
followed by continuous infusion of 100 mg/h for at least 24h, continued by oral
administration. In 80% of the cases (25 of 31), seizures stopped within 6 h, and general
anesthesia was not required. Four patients (12%) required general anesthesia and 2 patients
were resistant to all therapeutic attempts and died. SE was symptomatic in all cases, 16 with
stroke, traumatic 6, toxic 4, infectious 3 and tumors 2. No serious side effects were reported
considering that relevant medical history included cardiac arrhythmias, respiratory distress
and hepatic disease. IV VPA proved to be a safe, effective treatment of status epilepticus
and SCs, especially in patients with co-morbidities (cardiovascular diseases and respiratory
insufficiency).
Rezumat
Statusul epileptic și crizele epileptice subintrante reprezintă situații de urgență
neurologică majoră, care necesită tratament prompt și eficient. Studiul prezentat analizează
eficiența și tolerabilitatea valproatului administrat intravenos în tratamentul statusului
epileptic și al crizelor subintrante. Au fost analizați retrospectiv toți pacienții admiși în
clinica noastră și tratați cu valproat intravenos în perioada ianuarie 2009 - februarie 2010.
Indicațiile de tratament au fost crizele epileptice subintrante și statusul epileptic refractar la
tratamentul intravenous cu benzodiazepine. Au fost evaluate dozele, răspunsul terapeutic și
reacțiile adverse. Au fost incluși în studiu 31 de pacienți. Douăzeci și unu de pacienți au

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prezentat convulsii tonico-clonice primar generalizate cu caracter subintrant, 6 cu status
epileptic focal motor și 4 au prezentat convulsii focale cu generalizare secundară. Toți
pacienții au fost anterior tratați fără succes cu diazepam intravenos. Protocolul de tratament
a fost reprezentat de inițierea cu 25mg/kg corp a dozei de încărcare pentru valproat timp de
30 minute, urmată de perfuzie continuă de 100 mg / h pentru cel puțin 24 de ore, continuat
apoi per os. În 80% din cazuri, convulsiile au fost oprite în decurs de 6 ore, iar anestezia
generală nu a fost necesară. Patru pacienți (12%), au necesitat anestezie generală, iar 2
pacienți au fost refractari la toate încercările terapeutice și au decedat. Statusul epileptic a
fost simptomatic în toate cazurile, 16 prin accident vascular cerebral, 6 posttraumatice, 4
toxice, 3 infecțioase, două tumorale. Nu au fost raportate reacții adverse serioase având în
vedere istoricul medical relevant de aritmii cardiace, detresă respiratorie și insuficiență
hepatică. Administrarea intravenoasă de valproat s-a demonstrat a fi un tratament sigur și
eficient pentru cuparea statusului epileptic și al crizelor subintrante, mai ales la pacienții cu
comorbidități (boli cardiovasculare și insuficiență respiratorie).
Keywords: status epilepticus, valproic acid
Introduction
Status epilepticus (SE) and serial attacks also known as seizure
clusters (SCs) represent major neurological emergencies and the mortality
rate for SE is high, ranging from 3 to 25 %, depending on the cause and co-
morbidity [1]. Most recent literature agrees that any convulsions lasting for
more than 5 minutes, or two or more convulsions in a 5-minute interval
without return to preconvulsive neurological baseline, are sufficient to
qualify for the diagnosis of SE, (traditional requirement for seizures to last
for a minimum of 30 minutes has been abandoned by most authors) [2]. SCs
often end in SE, in which a series of grand mal seizures follow one another
with no conscious interval. The etiology is considered the major prognostic
factor in SE [3]. Anoxia, stroke, central nervous system infections and
metabolic dysfunctions are associated with the worst prognosis, but low
plasmatic levels of antiepileptic drugs (AEDs) in epileptic population,
alcohol intoxication and traumatic brain injury predict a better outcome [1].
This study aimed to investigate the efficacy and tolerability of intravenous
Valproic acid (IV VPA) in the treatment of SE and SCs which are
considered emergency situations, requiring immediate and effective
treatment in the neurological intensive care units.
Materials and Methods
We retrospectively analyzed all the patients treated with IV VPA in
the Neurology Intensive Care Department of Academic Emergency Hospital
Sibiu, Romania between January 2009 and February 2010. The study was

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approved by the Ethics Committee of the Hospital. Indications for IV VPA
were SCs and SE refractory to the first line of therapy (benzodiazepines
were immediately administered in the emergency room with intravenous
diazepam 5 mg at a dose rate of 2 mg/minute IV, repeated after 10 minutes).
Electroencephalographic monitoring was set for all the patients included in
this study. Dose responsiveness and adverse events were evaluated. The
treatment protocol was with 25 mg/kg b.w. of IV VPA loading dose over 30
minutes, followed by continuous infusion of 100mg/h for at least 24 hours,
then oral administration through nasogastric tube. If seizures were not
stopped, general anesthesia was performed, the anesthetic drug used was
thiopental (the loading dose was 20 mg/kg b.w. IV slow bolus followed by
3–5 mg/kg b.w./hour IV via continuous infusion).
Results and Discussions
During a period of 14 months, we have identified a total number of
31 patients with SE treated with IV VPA. The mean age of patients was
52.4 years old. All patients had been previously unsuccessfully treated with
Diazepam IV during the transportation and admission in our department.
The treatment protocol implied a 25 mg/kg b.w. of IV VPA loading dose
over 30 minutes, followed by continuous infusion of 100mg/h for at least 24
hours, then oral administration. In 81% of the cases (25 of 31 patients)
seizures were stopped within 6 hours and general anesthesia was not
required. In 13 % (4 patients) the general anesthesia was needed. The
anesthetic drug of choice was thiopental (the loading dose of thiopental was
20 mg/kg b.w. IV slow bolus followed by 3–5 mg/kg b.w./hour IV via
continuous infusion) (table I). Two patients (6 %) were resistant to all
therapeutic attempts and died. Deaths were attributed to the underlying
diseases – one case of encephalitis and one with cerebral metastasis. No
serious adverse effects were reported as relevant underlying medical
conditions included cardiac arrhythmias, respiratory distress and hepatic
failure (all patients were permanently monitored in the intensive care unit).
There were few temporary side-effects (slight transient increase of the ALT
and AST transaminases was reported in 4 patients – 13%) with restitution
after the IV VPA was finished. Typical adverse effects of standard AEDs
for SE, such as respiratory and circulatory insufficiency, drug interaction or
encephalopathy were not observed.

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Table I
Etiology, type of seizure and evolution under treatment in the studied group
Total
(31)
Total
(%)
Gender
Male
19
61.3
Female
12
38.7
Mean age
52.4
Etiology
Stroke
16
52.0
Trauma
6
19.0
Toxic
4
13.0
Infectious
3
10.0
Tumor
2
6.0
Type of seizure
Primary generalized serial attacks
21
67.7
Focal motor status epilepticus
6
19.4
Secondary generalized focal seizures
4
12.9
Evolution under treatment
Seizures stopped within 6h
25
81.0
Required anesthesia
4
13.0
Death (1 tumor and 1 encephalitis)
2
6.0
Benzodiazepines are widely accepted as the drugs of choice for
initial therapy in the early stage of status epilepticus [4]. The effectiveness
of benzodiazepines and especially diazepam decreases very rapidly probably
because of decrease of sensitivity of GABA receptors. A down-regulation
mechanism is supposed due to neuronal membrane modifications during a
seizure [4]. Cited disadvantages of diazepam are short redistribution half-
time (less than 1 h) and large volume of distribution (1-2 L/kg) [5]. These
pharmacologic properties of diazepam decrease the brain concentration
rapidly after initial intravenous administration, leading to potentially high
rates of seizures recurrence. Repeat boluses of diazepam, can lead to
significant accumulation and progressively greater peak levels. This may
result especially in respiratory depression, and cannot be recommended [4].
On the other hand, lorazepam has a lesser volume of distribution and a
smaller lipid solubility. Because of these properties the peaks levels are
reached within 30 minutes (with a therapeutic level reached as rapid as
diazepam) and the half-life time is considerably longer (2-3 h) [5]. The

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longer initial duration of action and a smaller risk of cardiorespiratory
depression make lorazepam the drug of choice in SE. A restriction in the
use of intravenous lorazepam is its absence in the Romanian pharmaceutical
market. If the therapy with benzodiazepines failed (the seizures continue
after 30 minutes after the first benzodiazepine was given), the patient is
situated in the stage of established status epilepticus. According to the
guidelines, it is recommended to administer phenytoin (or fosphenytoin). As
an alternative it is recommended to administer valproat or levetiracetam.
The disadvantages of phenytoin are that it crystallizes and precipitates in
solutions and it may cause thrombophlebitis (with extravasation), it is a
potent enzyme inductor and has variable biological effects related to genetic
variations of CYT2C9 [6]. Its vehicle, propylene glycol, can cause
hypotension. Cardiac monitoring is required for both phenytoin and
fosphenytoin and the dosing units of the drug are confusing and have caused
problems in practice [5]. Intravenous VPA administration in SE and SCs,
given in bolus, was well tolerated locally (no irritation signs to injection
site). VPA appears to be safe in patients with co-morbidities. No
cardiovascular changes were noted in these patients, no hemodynamic
changes also. Even to high doses of VPA with rapid infusion, nor
respiratory depression was noticed. Four patients (13 %) were non
responders to any kind of AED’s and they required pharmacological coma
induction with thiopental. IV administration of VPA efficacy is dependent
on time lapse between symptoms and VPA treatment and administration of
a sufficiently high loading dose [1]. Other studies suggested that the
efficacy of VPA is comparable to that of IV diazepam; seizure activity
remitted in 80% of children to whom IV VPA was given and 85% on IV
diazepam. The median time needed to control the refractory SE was
significantly shorter with VPA (5 minutes) then diazepam (17 minutes) [7,
8]. In a randomised open study [7], non-responding SE to diazepam, was
treated with IV VPA at doses of 20 mg/kg b.w. or phenytoin 20 mg/kg b.w.
in 50 patients for each group. Treatment success was 88% for IV VPA and
84% for the patients treated with phenytoin. These results are concordant
with our study. Some of the authors suggest higher doses (25 – 45 mg/kg
b.w.) of IV VPA [9]. Limitation of this study are due to the small and
heterogenous sample size, making possible just a descriptive statistic.
Conclusions
Intravenous VPA proved to be a safe, effective treatment of status
epilepticus and SCs, especially in patients with co-morbidities

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(cardiovascular disease and respiratory insufficiency) and side effects were
lower in comparison with other AEDs used in SE or SCs as confirmed in
other recent studies [10]. The percent of seizure free outcome within 6 hours
was relatively high in our group, which suggests that IV VPA for SE and
SCs can be an effective treatment, but this must be assessed in large group
studies to obtain more relevant data.
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Manuscript received: December 13th 2012