Valparin & Epilepsy

8/11/2019 Valparin & Epilepsy

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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-dependentepilepsy 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


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Seven in 1000 individualsin 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 ofneurotransmitters, 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.


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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 seizureso

Unprovoked seizures

o Prior head injury

o

Infections or toxic episodes

o

Family history of any seizures or

neurological disorders

Clinical examination is done withparticular

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, positronemission 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 testslike EEG, CT Scan, MRIand 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


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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 onecombination 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


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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


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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 tonormal 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


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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 forepilepsy 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

LamotrigineLevetiracetam

Oxcarbazepine

Topiramate

Absence Sodium valproate

Ethosuximide

Lamotrigine

Myoclonic Sodium valproate

LevetiracetamTopiramate

Tonicclonic Sodium valproate

Carbamazepine

Clobazam

Lamotrigine

Treatment options for different types of epileptic

seizures


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Levetiracetam

Oxcarbazepine

Topiramate

Tonic or

Atonic

Sodium valproate

LamotrigineaAt 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 EpilepticSurgery

Removal of the brain tissue

from where the seizure arises

or blockade of the neuronalpathways through which the

impulses navigate may help inpreventing seizure

recurrences.

Vagus Nerve StimulationThis is a type of treatment, in

which short spurts of electricalenergy are directed into the

brain through the vagus nerve (a

large nerve in the neck) with the

help of a small battery placedunder the skin, on the chest.


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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 levelswithin 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 ketosishas been found to be

effective in the treatment of

drug-resistant seizures.


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Sodium valproate, a

broad-spectrum AED, iseffective against all types

of seizures.

85 % was theresponse 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/partialresponse).

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 tonicclonicseizures.

Useful in Diverse Populations

Sodium valproate is considered to be the first choice for the treatment of

epilepsy in children.


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Sodium

valproate IV

VALPARIN 400 Sodium valproate I.P. 400mg/4 mL

VALPARIN EC

VALPARINALKALETS are enteric-coated tablets containing sodiumvalproate in 200 and 500 mg strengths.

Enteric-coated sodium valproate has been shown to yield promising results,

with predictable drug release and improved effectiveness.

VALPARINCHRONO

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 matrixtechnology.

This technology employs a hydrophilic matrix system, with hydroxypropylmethylcellulose (HPMC) and ethyl cellulose for controlling the release of

the drug.

I nnovative Drug Release Profi le

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 interiorand disintegration of the tablet core.

This outer protective gel layer controls the penetration of additional waterinto 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.


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De iction of dru release rofile 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.


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Intravenous sodium valproate was found

to be well-tolerated and effective optionfor 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 wasfound 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 VALPARINI.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.


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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 dextrosesaline.

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.


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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 patientswith newly-diagnosed epilepsy.

Study Design

The study design

Study design

Study type Patientdemography Clinicalcharacteristics Therapyregimen Primaryendpoints

52-week,unblinded,

randomized,

two-parallel

group, stratifiedtrial

n=1688

Age 16years

Mean age:

41 years;females 44%

2

unprovoked

seizures in 2years

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


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KOMET Study

Sodium valproate extended-release was found to be noninferior

to levetiracetam monotherapy in time-to-treatment withdrawal

in atients with newl -dia nosed e ile s .

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 epilepticsyndromes.

Study Design

The study design.

Study design

Study type Patientdemography

Clinicalcharacteristics

Treatmenthistory

Therapyregimen

Primaryendpoints

Unblinded,randomized,

controlledtrial from

Jan 1999 toAug 2004

n=716

Mean age:

22.5 years

Idiopathicpartial

Symptomatic

partial

Idiopathicgeneralized

Othersyndromes

Unclassified

Untreated

Monotherapy

(notoptimum)

Recentseizures after

remission

VPA

LMT

TPR

(1:1:1)

Time-totreatmen

failure

Time-to

1-yearremissio

Principle Findings


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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 forfirst-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 ofchildren and adolescents with focal and generalized epilepsy (except absence

seizures)

Why was this study done?


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To identify the therapy failure rate with newer agent(like levetiracetam whose

usage has been growing lately as an initial anticonvulsant) vs establishedagents(Like Valproate and oxcarbazepine) as initial anticonvulsant therapy.

How was the study done?

Study type: Retrospective chart reviewStudy population:Children and adolescents >6months and


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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 inchoosing an initial anticonvulsant, that is EFFECTIVENESS. This study showsthat 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 ofeffectiveness.

Valproate and Oxcarbazepine were not more frequently abandoned because of

ADEs than levetiracetam

Valparin & Epilepsy

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