Epilepsy is a group of clinical

syndromes characterized by
at least two episodes of
unprovoked seizures.
CNS Skill workshop learning module

Epilepsy & Valparin
Definition of Epilepsy
Epilepsy is not a single entity but a group of different clinical syndromes.
It is one of the common neurological disorders characterized by the occurrence
of repeated unprovoked episodes of seizures.
Seizure is a sudden, brief disturbance in the
consciousness of an individual and in the
way he/she moves, feels, behaves or
perceives.
Seizure occurs owing to an abnormal
excessive activity of the brain cells (neurons).
Seizure is actually a symptom of epilepsy and at least two episodes of seizures
are required for the diagnosis of epilepsy.
A practical clinical definition of epilepsy(new)
International League Against Epilepsy(ILAE)2014
Epilepsy is a disease of the brain defined by any of the following conditions
o At least two unprovoked (or reflex) seizures occurring >24 h apart
o One unprovoked (or reflex) seizure and a probability of further seizures
similar to the general recurrence risk (at least 60%) after two unprovoked
seizures, occurring over the next 10 years
o Diagnosis of an epilepsy syndrome

Epilepsy is considered to be resolved for individuals who had an age-dependent
epilepsy syndrome but are now past the applicable age or those who
have remained seizure-free for the last 10 years, with no seizure medicines for
the last 5 years.
Prevalence
Seven in 1000 individuals
in the general population
have epilepsy.
5

Epilepsy usually begins in childhood.
5

At any one time, about 7 in 1000 people in the general population have
epilepsy.
5

The incidence of seizures is about 70100 per 1 lakh individuals, annually.
6

Acute seizures account for 1% of all emergency visits.
6

The incidence is the highest in the first year of life and in individuals aged over
60 years.
1

Average chances for an 80 year old to have epilepsy in his lifetime is about
3%.
1







Pathophysiology

Seizures occur due to a disturbance in the electrical system of the brain.
Normally, the neurons discharge electrical
impulses to communicate with each other.
These impulses stimulate the release of
neurotransmitters, the excitatory and inhibitory
actions of which help control the physical and
mental functioning.
When there is a constant increase in the levels of
excitatory neurotransmitters and decrease in the
inhibitory transmitters, there is an uncontrolled
firing of impulses that is manifested in the form of a seizure.

Diagnosis
The diagnosis of epilepsy is based on the history, clinical examination and
investigations.
Detailed information of the events, the onset, course, time of the day and the
duration is obtained from the patient or the observer of the event. It also
includes information about
o Seizures in the new-born period
o Febrile seizures
o Unprovoked seizures
o Prior head injury
o Infections or toxic episodes
o Family history of any seizures or
neurological disorders
Clinical examination is done with particular
emphasis on neurological and psychiatric status.
Some of the chief investigations are as follows-
o Electroencephalogram (EEG): It is a vital tool used in the diagnosis of
epilepsy. It records electrical signals from the brain with the help of wires
taped to the head and represents in the form of wavy lines.
o Magnetic resonance imaging (MRI)
o Computer tomogram
o Head radiograph
o Blood tests
o Other tests: Single-photon emission computed tomogram, positron
emission tomogram, magnetoencephalography.
What is the usual approach to diagnosing epilepsy?
Diagnosis involves:

A careful and detailed account of the patients history.
Neurological examination - Changes in sensory, motor or size perception
examined which can all be indicative of epilepsy.
Diagnostic tests like EEG, CT Scan, MRI and analyses of blood and CSF.
Sophisticated imaging modalities such as MRS (Magnetic Resonance
Spectroscopy), Functional MRI, SPECT (Single Photon Emission
Computerized Tomography) and PET (Positron Emission Tomography) are
being increasingly used for investigating patients with Epilepsy





What is Intractable / Refractory epilepsy?
Definition
Not completely controlled by medical therapy

Seizures despite treatment with 1st line AED as monotherapy or at least one
combination with an adjuvant medication.

Criteria

Frequency
> 1/month after optimal therapy with minimum 2 AEDs

Duration
6 months after optimal therapy

Adequate AED therapy
Appropriate drugs (at least 3 drugs, including a newer antiepileptic
and rational polytherapy with 2 conventional AEDs)
optimal doses
Rational drugs
The rule is what we call the rule of two. That means if we try two drugs for two
years and the epilepsy is not under control. Secondly, if the seizures are more than
two per month, going on for two years, then also we call it intractable epilepsy.


Classification of Epileptic Seizures
There are several types of epileptic seizures. Some of the common types of
seizures and their clinical features
Common types of epileptic seizures
Epileptic seizure type Clinical features
1. Partial seizure Affects only a part of one side of
the brain
Most common type of seizure
a. Simple partial seizure Lasts for 3060 seconds
Consciousness not impaired
Uncontrolled bodily movements
depending on the part of the brain
involved
Transient weakness
Loss of sensation
May see, feel, hear, smell, taste
something that does not exist
Bouts of sudden anger, laughter
or crying
b. Complex partial seizure Lasts for 12 min
Consciousness impaired
Trance-like state
Repeated, unorganized
movements such as lip smacking,
picking at clothes, fumbling,
chewing etc.
Unaware of the surroundings
May wander
Loss of memory of the seizure
event
Mild-to-moderate confusion
during the event
Sleepiness after the event
c. Partial seizures evolving
into generalized seizure

Partial seizure spreads to other
parts of the brain resulting in a
(Secondary generalized
seizure)
generalized seizure
2. Generalized seizure Affects both sides of the brain
Consciousness impaired for short
or long duration
a. Absence seizure More common in children
Lasts for a few seconds
May stare vacantly without
responding to surroundings
Repeated unorganized
movements
Can occur occasionally more than
100 times a day
Often goes unnoticed
b. Myoclonic seizure May occur as a single seizure or a
cluster of seizures
Rapid, brief muscle contractions
on both sides of the body
Sudden, involuntary muscle
movements
c. Clonic seizure Repeated jerking movement of
muscles on both sides of the body
d. Tonic seizure Abrupt stiffening of muscles
resulting in a fall
Lasts for less than a minute
Rapid recovery
e. Tonicclonic seizure Most common type of generalized
seizure
Incontinence
Biting of the tongue or inside of
the mouth
Involves tonic and clonic phases
Tonic phase:
o Stiffening of the limbs
o Breathing may decrease or
cease
o Cyanosis (bluish
discoloration) of the lips,
nail beds and face
Clonic phase:
o Jerking of the limbs and the
face
o Breathing will return to
normal or may be irregular
o Lasts for less than a minute
f. Atonic seizure Abrupt loss of muscle tone
Sudden head drops; also called
drop attacks
Loss of posture
Sudden collapse
Recovers fast
3. Non-epileptic seizure Seizure not related to the
abnormal activity of the brain
Considered psychological in
origin
4. Status epilepticus

Prolonged and recurrent seizures
without returning to baseline
Medical emergency requiring
hospitalization

Management of Epilepsy
The goal of epilepsy management is to prevent the occurrence of seizures and
enable the individual to lead an active life.
4
Different treatment options for
epilepsy are as follows.
Antiepileptic Drugs
Antiepileptic drugs (AEDs) prevent seizures in majority of the population.
4

About 50% of patients with epilepsy are found to gain a complete control over
seizures with antiepileptic medications.
The choice of antiepileptic medications for the treatment of different types of
seizures.


Seizure type AEDs
Partial Sodium valproate
Carbamazepine
Clobazam

Gabapentin
Lamotrigine
Levetiracetam
Oxcarbazepine
Topiramate
Absence Sodium valproate
Ethosuximide
Lamotrigine
Myoclonic Sodium valproate
Levetiracetam
Topiramate
Tonicclonic Sodium valproate
Carbamazepine
Clobazam
Lamotrigine
Treatment options for different types of epileptic
seizures
Levetiracetam
Oxcarbazepine
Topiramate
Tonic or
Atonic
Sodium valproate
Lamotrigine
a
At the time of publication (January 2012) this drug did not have the UK
marketing authorization for this indication and/or population.

Epileptic Surgery


Vagus Nerve Stimulation



Rationale behind Epileptic
Surgery
Removal of the brain tissue
from where the seizure arises
or blockade of the neuronal
pathways through which the
impulses navigate may help in
preventing seizure
recurrences.

Vagus Nerve Stimulation
This is a type of treatment, in
which short spurts of electrical
energy are directed into the
brain through the vagus nerve (a
large nerve in the neck) with the
help of a small battery placed
under the skin, on the chest.
Sodium valproate may
increase the levels of the
inhibitory
neurotransmitter,
GABA.
Sodium valproate
exhibits rapid oral
absorption and attains
peak blood levels within
14 h.
14

Ketogenic Diet


Management of Epilepsy: Focus on Sodium Valproate
Sodium Valproate: Pharmacodynamics and Pharmacokinetics
Pharmacodynamics
Sodium valproate is a simple eight-carbon branched-chain fatty acid.
Several studies have demonstrated an increase in the
levels of a inhibitory neurotransmitter known as -
aminobutyric acid (GABA) with the administration
of sodium valproate although the exact mechanism
is unclear.
Sodium valproate may also cause blockade of the
voltage-gated sodium channels, thereby limiting the neuronal firing of impulses.
There are several other mechanisms through which sodium valproate attenuates
the excitation of neurons however, they are quite complex and not very well-
understood.
Pharmacokinetics
Absorption of valproate is rapid if taken orally, achieving the peak blood levels
within 14 h.
Therapeutic blood levels of sodium valproate
have been found to be 50100 g/mL with an
adult daily dosage of 12001500 mg.
Ketogenic Diet
A high-fat and low-
protein/carbohydrate diet to
maintain long-term ketosis
has been found to be
effective in the treatment of
drug-resistant seizures.

Sodium valproate, a
broad-spectrum AED, is
effective against all types
of seizures.
85 % was the
response rate with
intravenous sodium
valproate in a study
conducted in 26
epileptic children.
15

Sodium valproate has high affinity to bind to plasma proteins (about 90%).
Sodium valproate is metabolized in the liver and has a half-life of 1012 h.
Sodium valproate is excreted mainly in urine with traces in bile, feces and
expired air.
Advantages of Sodium Valproate in Epilepsy Management
Broad Spectrum of Activity
Sodium valproate is a broad-spectrum AED and hence effective against all
types of seizures.
In epileptic syndromes with multiple seizure types,
use of a broad-spectrum AED such as sodium
valproate has added benefits.
Sodium valproate has been found to be particularly
useful in the treatment of absence seizures, tonic
clonic, myoclonic and complex partial seizures.
In absence seizures, sodium valproate may be considered as a first line therapy.
Good Response Rate
In a study conducted in 26 children with epilepsy, intravenous sodium valproate
was found to exhibit a response rate of 85% (including complete/partial
response).
An excellent response rate of 80% has been found
to be achieved with sodium valproate in patients
with juvenile myoclonic epilepsy.
16

Several studies have demonstrated a good
response rate for sodium valproate in patients with
generalized tonicclonic seizures, thereby
establishing valproate as the first drug of choice in the treatment of tonicclonic
seizures.
Useful in Diverse Populations
Sodium valproate is considered to be the first choice for the treatment of
epilepsy in children.
Sodium valproate has
shown a favorable
tolerability profile with
fewer cognitive and
central nervous
systemeffects.
It has been found to be an effective treatment of choice in children with newly-
diagnosed epilepsy, idiopathic generalized epilepsy, epilepsies with prominent
myoclonic seizures or with multiple seizure types.
In elderly individuals with epilepsy, valproate, due to its broad spectrum of
action and dosing schedule, has been found to be a useful choice.
Better Tolerability
In children with partial epilepsy, sodium
valproate has shown a favorable
tolerability profile with fewer cognitive
and central nervous system effects.
Rapid administration of sodium valproate
was found to be well-tolerated, favoring its
use in epileptic emergencies.
Intravenous valproate was found to be effective and well-tolerated in patients
with acute repetitive seizures.



VALPARIN

(Sodium Valproate) Formulations

Various VALPARIN

formulations have been shown in Table 9.

VALPARIN formulations
Formulation Strengths Composition
Sodium
valproate tablets
I.P.
VALPARIN

200 ALKALETS Sodium valproate IP 200 mg
VALPARIN 500 ALKALETS Sodium valproate IP 500 mg
Controlled-
release tablets of
sodium valproate
and valproic acid


VALPARIN CHRONO 200

Sodium valproate I.P. 133 mg
Valproic acid I.P. 58 mg
VALPARIN CHRONO 300

Sodium valproate I.P. 200 mg
Valproic acid I.P. 87 mg
VALPARIN CHRONO 500

Sodium valproate I.P. 333 mg
Valproic acid I.P. 145 mg
Sodium
valproate oral
solution I.P.
VALPARIN 200

Sodium valproate I.P. 200
mg/5 mL
Sodium
valproate IV
VALPARIN 400 Sodium valproate I.P. 400
mg/4 mL

VALPARIN EC
VALPARIN

ALKALETS are enteric-coated tablets containing sodium
valproate in 200 and 500 mg strengths.
Enteric-coated sodium valproate has been shown to yield promising results,
with predictable drug release and improved effectiveness.
VALPARIN CHRONO
Controlled Manufacturing Process with Innovative Technology

Active Ingredients

Active ingredients of VALPARIN CHRONO (sodium valproate and valproic acid)
are manufactured at France. Sodium valproate is manufactured by spray dry
technology to ensure finer and more consistent size of the tablets.

Matrix Technology

Release of the drug in VALPARIN CHRONO is controlled by the matrix
technology.
This technology employs a hydrophilic matrix system, with hydroxypropyl
methylcellulose (HPMC) and ethyl cellulose for controlling the release of
the drug.

I nnovative Drug Release Profile

Drug release profile of VALPARIN CHRONO is depicted.
The hydration of HPMC polymer on the outer tablet skin results in the rapid
formation of a gelatinous layer, which prevents the wetting of the interior
and disintegration of the tablet core.
This outer protective gel layer controls the penetration of additional water
into the tablet.
Following the hydration and dissolution of the outer gel layer, an inner
cohesive layer is formed, which retards the influx of water and controls drug
diffusion.

Depiction of drug release profile of VALPARIN CHRONO.


Advantages of CHRONO sodium valproate formulations


Significantly increased seizure freedom.
Significantly higher response rate (seizure reduction >50%).
Reduced side-effects.
Once-daily dosing; improved patient compliance.
Enhanced patient satisfaction rate.




















Clinical Evidences

Clinical evidence exists in favor of chrono formulations for the management of
epilepsy.


Intervenes Valparin

Parenteral Sodium Valproate: Role in the Management of Epilepsy

Sodium valproate is available in different formulations.
Intravenous sodium valproate was found
to be well-tolerated and effective option
for the treatment of various types of
status epilepticus.
An intravenous formulation of sodium valproate was approved in the United
States in the year 1996 for use in epileptic patients.
Since then, intravenous valproate has gained popularity in situations demanding
immediate effects.
Intravenous sodium valproate is being used in the management of status
epilepticus in the recent years with encouraging results.
Several studies have been conducted to study the efficacy, safety and
tolerability of intravenous valproate in various epileptic seizures.
Intravenous sodium valproate was found to exhibit higher efficacy compared to
phenytoin in patients with convulsive status epilepticus.
Intravenous sodium valproate was found to be a well-tolerated and effective
option in the treatment of nonconvulsive and myoclonic status epilepticus.
Intravenous sodium valproate had no effect on the blood pressure and was
found to be well-tolerated in status epilepticus patients with cardiovascular
instability.
Intravenous infusion of sodium valproate was found to arrest seizures in less
than 30 minutes in 80% of the status epilepticus patients with generalized
tonicclonic seizures or simple partial motor seizures (1998)





Introducing VALPARIN

I.V.
Indications
VALPARIN I.V. (Sodium valproate) injection is indicated for the treatment of
generalized epilepsy and partial epilepsy in patients for whom oral therapy is
temporarily not possible.

Dosage
Daily dosage requirements should be established according to age and body
weight.
In children, daily requirement is usually in the range 20-30 mg/kg/day.


If an adequate control is not achieved, the dose may be increased to 40
mg/kg/day only in those patients in whom plasma valproic acid levels can be
monitored.
In elderly, the dosage should be determined by seizure control as the volume of
distribution is high in elderly.
In elderly patients with renal insufficiency, dosage should be decreased.
Dosage of valproate should be adjusted based on clinical monitoring and not the
plasma concentrations of the drug.


Salicylates should not be used along with valproate as they employ the same
metabolic pathway.


Concomitant use of salicylate and valproate in children under 3 years of age can
increase the risk of liver toxicity.


Administration
Valproate may be given by direct slow intravenous injection or by infusion
using a separate intravenous line in normal saline, dextrose 5%, or dextrose
saline.


Valproate injection should not be administered via the same IV line as other IV
additives.


Patients already satisfactorily treated with valproate injection may be continued
at their current dosage using continuous or repeated infusion.


Other patients may be given a slow intravenous injection over 35 minutes,
usually 400800 mg depending on body weight (up to 10mg/kg) followed by
continuous or repeated infusion up to a maximum of 2500 mg/day.





KOMET Study
Study Aim
Trinka et al., conducted an unblinded, randomized trial to compare the
effectiveness of levetiracetam (LEV) with controlled-release carbamazepine (CBZ-
CR) and extended-release sodium valproate (VPA-ER) as monotherapy in patients
with newly-diagnosed epilepsy.
Study Design
The study design

Study design
Study type Patient
demography
Clinical
characteristics
Therapy
regimen
Primary
endpoints
52-week,
unblinded,
randomized,
two-parallel
group, stratified
trial
n=1688
Age 16
years
Mean age:
41 years;
females 44%
2
unprovoked
seizures in 2
years
1
unprovoked
seizures in the
past 6 months
VPA-ER
(or)
CBZ-CR
(n=847)

LEV
(n=841)

Time-to-
treatment
withdrawal

Principal Findings
No significant difference was observed in time-to-treatment withdrawal
between LEV and standard AEDs.
Time-to-first seizure was found to be significantly longer for the standard AEDs
as compared to LEV.
Twelve-month seizure-free rates were found to be significantly greater in the
VPA-ER group compared to LEV (64.5% vs. 58.7%).
Each group reported at least one adverse event with the percentage being
smaller in the VPA-ER group compared to LEV group (62% vs. 66.1%).

Study Conclusions

KOMET Study

Sodium valproate extended-release was found to be noninferior
to levetiracetam monotherapy in time-to-treatment withdrawal
in patients with newly-diagnosed epilepsy.
The VPA-ER group was found to be noninferior to the LEV monotherapy in time-
to-treatment withdrawal in patients with newly-diagnosed epilepsy.






SANAD Study
Study Aim
In the Standard and New Antiepileptic Drugs (SANAD) study, Marson, et al.,
compared the long-term efficacy of broad-spectrum drugs, valproate (VPA),
lamotrigine (LMT) and topiramate (TPR) in various types of seizures and epileptic
syndromes.

Study Design
The study design.
Study design
Study type Patient
demography
Clinical
characteristics
Treatment
history
Therapy
regimen
Primary
endpoints
Unblinded,
randomized,
controlled
trial from
Jan 1999 to
Aug 2004
n=716
Mean age:
22.5 years


Idiopathic
partial
Symptomatic
partial
Idiopathic
generalized
Other
syndromes
Unclassified
Untreated
Monotherapy
(not
optimum)
Recent
seizures after
remission
VPA
LMT
TPR
(1:1:1)


Time-to-
treatment
failure
Time-to-
1-year
remission


Principle Findings
SANAD Study

Sodium valproate was found to be superior to topiramate in
terms of tolerability and to lamotrigine in terms of efficacy.
Time-to-treatment failure for VPA was found to be significantly better than
TPR [hazard ratio 1.57 (95% CI 1.192.08)].
In patients with IGE, VPA was found to be significantly better than both LMT
[hazard ratio 1.55 (95% CI 1.072.24)] and TPR [hazard ratio 1.89 (95% CI
1.322.70)] for time-to-treatment failure.
For overall time-to-1-year remission, VPA was found to be significantly better
than LMT [hazard ratio 0.76 (95% CI 0.620.94)].
In patients with IGE, time-to-1-year remission for VPA was found to be better
than LMT [hazard ratio 068 (95% CI 0.530.89)].
Study Conclusion
Sodium valproate was found to have a better tolerability profile than topiramate
and was more efficacious compared to lamotrigine and hence, a better choice for
first-line therapy in patients with generalized and unclassified epilepsies.






Newest Evidence comparing Valparin Chrono/Syrup over Levetiracetam in
Childhood epilepsy (European Journal of Pediatrics 11th Aug 2013)
Bertsche et al

Study design:

Retrospective review on Initial anticonvulsant monotherapy in routine care of
children and adolescents with focal and generalized epilepsy (except absence
seizures)
Why was this study done?

To identify the therapy failure rate with newer agent(like levetiracetam whose
usage has been growing lately as an initial anticonvulsant) vs established
agents(Like Valproate and oxcarbazepine) as initial anticonvulsant therapy.

How was the study done?

Study type: Retrospective chart review
Study population: Children and adolescents >6months and <18yrs with
generalized and focal epilepsy(except absence seizures) who were started on
anticonvulsant monotherapy with Levetiracetam, Valproate and
oxcarbazepine(only focal epilepsies for OXC) between 1 Jan 2007 31 Dec 2011.
Objective: To analyse failure of monotherapy and defined as add on of second
anticonvulsant, switch to other anticonvulsant or final discontinuation of therapy.

Primary outcome: Failure of anticonvulsant monotherapy during first year
Secondary outcome: Assessment of failure by lack of effectiveness or by adverse
drug events

Results:
Failure of initial monotherapy with levetiracetam and valproate in generalized and
focal epilepsies.

Lack of effectiveness (p0.05):
A. 25/61 (41 %) patients treated with levetiracetam
B. 11/49 (22 %) patients treated with valproate.
Modifications in therapy caused by ADEs (n.s.):
A. 4/61 (7 %) patients treated with levetiracetam
B. 7/49 (14 %) patients treated with valproate
It is important to note there was no significant difference in the
discontinuation due to adverse events between Valproate and
levetiracetam!

Failure of initial monotherapy of levetiracetam and oxcarbazepine in focal
epilepsies
Lack of effectiveness (p0.05):
A. 17/42 (40 %) patients treated with levetiracetam
B. 6/34 (18 %) patients treated with Oxcarbazepine
Modifications in therapy caused by ADEs (n.s.):
A. 4/42 (10 %) patients treated with levetiracetam
B. 4/34 (12 %) patients treated with oxcarbazepine

Conclusion:

It is a pragmatic study which shows the clinical reality better and considers effectiveness.
As we know friends due to the profile of ADEs being considered advantageous, there is increasing use of


Why is this study important

levetiracetam as an initial monotherapy for pediatric patients with newly diagnosed
focal and generalized epilepsies. This study raises an important consideration in
choosing an initial anticonvulsant, that is EFFECTIVENESS. This study shows
that Levetiracetam failed more frequently as an initial monotherapy versus
Valproate in generalized and partial epilepsies due to lack of effectiveness.


An initial levetiracetam monotherapy failed more frequently than an initial
valproate monotherapy and initial oxcarbazepine monotherapy due to a lack of
effectiveness.
Valproate and Oxcarbazepine were not more frequently abandoned because of
ADEs than levetiracetam