Introduction

Epilepsy is one of the prevailing neurological disorders which affect more than 50 million people
in the most developing countries. Malaysia is one of the countries recorded with high numbers of
cases epilepsy and it is becoming a main concern to search for an antidote for it. The definition
of epilepsy is seizures that are recurrent and from an unprovoked aggression which is caused by
unusual firing of cerebral cortical neurons. Febrile convulsions is statistically proved as the main
cause of epilepsy followed by status epilepticus and etc. (Steven C 2013)
Epileptic patients undergo many significant effects in their lives. Their working and social life
are disturbed which in turns affect them badly in financial, physical and emotional terms. This
lowers down their self-esteem which in turn leads to many bad decisions. Hence preventive
measures should be taken in medical and psychological terms to cure and treat the epileptic
patients. (Buchanan 1992)
In this study we would like to highlight the prevalence of status epilepticus. Status epilepticus is
described as two or more seizures in sequence without full recovery of consciousness between
seizures, or continuous seizure activity which lasts more than 30 minutes which is clearly shown
in Figure 3. The types of status epilepticus and the drug of choice is shown in FIGURE 1 .
According to the Malaysias consensus guidelines on the management of status epilepticus which
is recently updated on 2010, various first line, second line and third line treatment as well as
quality of life adjustments were stated to treat epileptic condition with correct prescribing of
antiepileptic drugs (AED). Since management of epilepsy shows a positive result due to the
consumption of antiepileptic agents, various studies are conducted to study the tolerability,
adherence clinical efficacy and safety issues of those medications. (Joseph 2003)
Different types of combinations, monotherapy as well as polytherapy are used to treat status
epilepticus. But first line drugs are the drugs chosen as first choice of treatment due to their high
efficacy, tolerability, cost effectiveness and other factors. The ultimate goal of the treatment will
be controlling seizures with lowest number of adverse events and reoccurrence. This study is
conducted to study the Drug Utilization (DU90%) pattern of first line antiepileptic drugs in line
with assessing the efficacy of those AEDS. When discussing the drug utilization it is important
to know the choice of first line drugs for various types of status epilepticus as what have shown

in FIGURE 1 and TABLE 1 . Hence when filtering the first line drugs, the most commonly
used ones are Benzodiazepines, Carbamazepines, Phenytoin, Valproate and Lamotrigine. Hence
this study is conducted based on the utilization of these mentioned drugs and their efficacy in
controlling seizures resulting status epilepticus condition. (Martins, Alonso, Guilhoto, Guaranha,
Yacubian 2009)
This study will give a clearer picture on the relationship between the drug utilization and the
efficacy of those mentioned AEDS. By discussing this aspect we can also get to know whether
efficacy is the main concern or the other factors which affect the utilization.

FIGURE 1 :CLASSIFICATION AND DRUG OF CHOICE OF STATUS EPILEPTICUS.

Sourcefrom:http://www.neuro.org.my/MSN_GUIDELINE/MSN_GUIDELINE_Consensus
%20Guidelines%20on%20the%20Management%20of%20Epilepsy%202010.pdf
TABLE 2 : CHOICES OF FIRST LINE DRUGS AND SECOND LINE DRUGS USED IN
STATUS EPILEPTICUS

M- Monotherapy
A-Adjunctive therapy
Source from :

http://www.neuro.org.my/MSN_GUIDELINE/MSN_GUIDELINE_Consensus%20Guidelines
%20on%20the%20Management%20of%20Epilepsy%202010.pdf

Figure 3 :
Definition
and stages of
status
epilepticus
Source from :

file:///C:/Users/031610/Downloads/jcm-05-00049.pdf

Literature Review
There were a huge number of researches done and journals published on investigating the
efficacy of Anti-epileptic Drugs(AED) since it is proved that almost 70% people which is (7 in
10) diagnosed with epilepsy , with the use of AEDs they could completely control their
seizures.
According to a research conducted by (Loiseau, Yuen, Duch, Mnager, & Arn-Bs, 1990), the
efficacy and safety of lamotrigine which is one of the important first line drugs for status

epilepticus was tested using a randomized controlled trial using 23 patients who are in adult
category and have partial seizures. The results show that 15 patients showed a marked
improvement with lamotrigine treatment. It is also portrayed in the results that 7 patients total
seizure count drops to less than half of the number before the treatment. It is also said the drugs
tolerance level was good over the two months treatment period. No serious adverse events were
noted and the chemical and hematological level of the body remained normal among all the
patients.
In discussing benzodiazepines-resistant status epilepticus, a study was conducted by (Yasiry &
Shorvon, 2014) using five antiepileptic drugs. Their efficacy as a first line antiepileptic drug was
investigated. The tested drugs are phenobarbital, valproate, phenytoin, levetiracetam and
lacosamide. 70 patients with status epilepticus and have resistance to benzodiazepines initial
therapy as well who are with different type of seizures, severity are investigated in this study.
The results showed that phenobarbital, valproate as well as the levetiracetam are the most
efficacious first line treatment for patients with benzodiazepine-resistant status epilepticus. The
results didnt show much evidence on the efficacy of phenytoin and lacosamide, hence RCT
studies are recommended to further support the results.
Besides that, a research was carried out by (Marson, Kadir, & Chadwick, 1996) studying about
the newly developed AEDs mainly concentrating on their efficacy as well as their tolerability.
The drugs evaluated in this study were lamotrigine, gabapentin, topiramite, vigabatrine,
tiagabine, as well as zonisamide. Total of 28 trials were conducted using 3883 patients with
status epilepticus seizures by using methods of randomized controlled and placebo controlled
trials, parallel and crossover studies. The variable which tested was the 50% drop in the seizure
frequency and the results showed that all the tested 6 drugs were efficient in reducing the
frequency of seizures when compared to placebo.

There is a research conducted generally on the Drug Utilization 90% profile of the drugs acting
on the nervous system. This includes the use of carbamazepine as an antiepileptic drug. The
results showed the highly used drugs were the antiepileptic agents as followed by the drugs used
as psych analeptics. Moreover it also stated in the results that diazepam, phenobarbital and

carbamazepines are the most highly prescribed drug. The DU90% tested leads to better
understanding of the prescribing quality of those medications. (Markovi-Pekovi, Stoisavljeviatara, & krbi, 2009)
Moreover there is also a research conducted on the drug utilization pattern and tolerability of
AEDs in Oman. The use of therapeutic drug monitoring was also assessed in this study. The
duration of the mentioned study was for 6 months and the age group of patients tested was above
14 years old and they all were prescribed with AED . The results show that sodium valproate
with 49% was the most commonly prescribed drug followed by phenytoin as well as the
lamotrigine with 12% and 11% respectively. The efficacy profile and the selection of
antiepileptic agents showed a good relationship. It was concluded in the research that
monotherapy was the best treatment as it is the gold standard and the most frequently used AED
is sodium valproate with the highest percentage of use. (Hanssens Y, 2016)

A hospital based study was conducted in Dhaka Medical College Hospital (DMCH) from
October 1998 to February 2013 to study about the efficacy of low cost AEDs. The tested
number of subjects was 854 patients who has a follow up data completion of 2 years. The results
proved that although phenobarbital and phenytoin has the lowest cost but their tolerability is low
and the ADR(adverse reaction) profile is high which makes carbamazepine and valproate better
first line AEDs with good efficacy and tolerability profile. (Habib et al., 2013)
Although many researches and studies were done in overseas testing the efficacy and the drug
utilization profile , still there are only a very limited trials conducted in Malaysian hospital
setting. This study will also give a clearer insight whether is there a relationship between the
efficacy and the DU90% profile of AEDs in specific to status epilepticus. By studying this we
can get to know other factors which may influence the drug utilization pattern in public and
private hospitals in Malaysia.

Objectives

To study the efficacy of first line antiepileptic drugs (Benzodiazepines, Carbamazepines,

Phenytoin, Valproate and Lamotrigine) in a hospital setting.

To evaluate the Drug Utilization 90% profile (DU90%) of those mentioned antiepileptic

drugs in a public hospital

To study the relationship between the efficacy of the drug and the Drug Utilization 90%
profile of the first line antiepileptic drugs

Scope
Substantial morbidity and mortality is associated with status epilepticus disease which is a
worldwide main health issue. Statistical analysis have proved that the disease can be treated and
kept in control with the potential use of antiepileptic drugs. Initially benzodiazepines are
classified as the most common first line drug given for this condition. But eventually paroxysmal
benzodiazepine-resistant status epilepticus have emerged hence the need to study about other
potential first line antiepileptic agents have become essential. Thus this study will give an insight
on the efficacy of benzodiazepines and other first line AEDs which can be used for
benzodiazepine-resistant staus epilepticus patients. Moreover this study will enlighten on the
drug utilization pattern practiced in the public hospitals in Malaysia. We can evaluate whether
the efficacy is the main concern when choosing the AED or the factors play an important role as
well.

Research Methodology
A prospective cross sectional study and 2 year randomized controlled trial methods were chosen
to carry out the research on testing the efficacy and DU90% of antiepileptic dugs.
Hospital Universiti Kebangsaan Malaysia, Kuala Lumpur was the local tertiary hospital that
proposed to be selected to carry out the research. Ethical approval has to be obtained from the
Epileptic Committee of the mentioned hospital. Most importantly informed consent should be

collected from the selected subjects and it is important to explain the purpose of this research to
the patients so that they can fully understand the objective and agree to the study.
Inclusion criteria
Total number of 500 patients(n=500) who are recently diagnosed with status epilepticus and still
in the premonitory stage . The age group selected was 16-70 years old adults.
Exclusion criteria
Patients with

isolated partial seizures

more than 1 seizure within a day
recurrence of seizure before randomization being carried out
seizures occur from stroke or traumatic condition
other neurological diseases
alcohol / drug addicts
liver and kidney complications
metabolic problems

Intervention
Randomization methosd were carried out among the patients to receive immediate AED
treatment or only after seizure recurrence . Benzodiazepins, lamotrigine, phenytoin
Physicians chose carbamazepine, phenytoin, phenobarbital, or sodium valproate at their
discretion and modified doses to bring plasma levels to the therapeutic range within 1 month.

Search strategy
Databases such as Medline, The Cochrane library, BMJ Clinical Evidence and Psych Info
up to June 2016 were used to identify relevant systemic reviews .Figure 2 shows the
examples of search is carried out in those databases .

Source from : http://www.who.int/mental_health/mhgap/evidence/resource/epilepsy_q13.pdf

Type of studies
Trials Cross over studies
In this method patients receiving the drug and placebo (not the epileptic patients) should be
randomly placed in treatment phases which were divided into two by including a washout period.
This allows the study of the efficacy of the drug in patients receiving the first line drug treatment.
The seizure numbers before the treatment and after the treatment should be recorded.

Parallel-group study
In this study randomisation will be carried out so that patients will receive of of the few selected
dose range of drugs or the matched placebo. This study will help to assess the efficacy of the first
line antiepileptic drugs as an adjunctive therapy. Number and type of baselines must be limited to
minimise pk and pd related problems.
MONOTHERAPY TRIALS
It is proved that most patients who have untreated have epilepsy can be treated with
monotherapy to reduce their seizure frequency. Only one drug is given to a patient and their
frequency of seizures after the treatment were recorded for the whole period of research

STATISTICAL ANALYSIS
IBM SPSS system were used to conduct the statistical analysis. For each result collected
Standard errors were estimated for each trial and 95% confidence intervals (CIs) for the effect
measures were calculated using the SPSS system. It should be evident that odd ratios which has a
value more than 1 indicates the patients receiving the AEDs not the placebo. In determining the
heterogeneity p-value less than or equals 0.05 confirms heterogeneity in the 2 test. Regression
analysis is used to study the relationship between the efficacy of the the AEDs and the drug
Utilization 90% profile of the AEDs (St. Louis, Rosenfeld and Bramley 77-82)

Clinical end points

Seizure frequency : In the recorded data analysis should be done whether there is a significant
reduction in the seizure frequency.
Responders proportion : Seizure reduction of 50% also analyzed in this factor.
Number of seizure free days : Upon receiving the treatment , how many days patients do not
have seizure completely should be recorded

Severity of the seizures : If some patients do not have seizure free days , analyzing the severity
of the seizures could help in evaluating the efficacy of the AEDs

The complete guidelines in measuring the efficacy is shown in Figure 4

Figure 4: source :
http://www.who.int/selection_medicines/committees/expert/17/application/lamotrigine_inclusion
.pdf

OUTCOME
Direct outcome

The efficacy of the antiepileptic drugs as a first line therapy will be known based on the
50% reduction in frequency
The drug utilization pattern of AEDs in public hospitals will be known
The relationship between the two factors can be studied
Insight to other factors that affecting the DU90% profile of AEDs

Alternative first line treatment for benzodiazepines-resistant status epilepticus can be

known as well.

Indirect outcome

It will promote further investigations done on the efficacy of these AEDs with lesser
adverse events in the aim to increase the cure rate of status epileptics as well as reducing
the mortality rate .

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