A REVIEW OF EPILEPSY

1. AIM AND OBJECTIVE:

Aim:

Review of pathophysiology and pharmacotherapeutics of Epilepsy.

Objectives:

1. To identify the treatment and pharmacotherapeutic treatment alternative for a patient

with a specific seizure disorder.

2. To describe significant adverse effect and drug interaction.

3. To develop pharmacotherapeutics.

4. To study monitoring parameter for agent used to treat the seizure.

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2. INTRODUCTION

Hardly any other illness can be traced back in medical history as far as epilepsy

can. Many pointers from early history indicate that this condition has been part of the

human lot from the very beginning. Then as now, it is one of the most common chronic

diseases that there are: 0.5% of all human beings suffer from epilepsy, which means that

in the U.K. alone around 300 000 to 600 000 people are affected.

When someone repeatedly has epileptic seizures then we say that that person is

suffering from epilepsy. An epileptic seizure itself is one of the many pathological forms

of reaction which can take place in the brain; it is the brain’s "response" or reaction to a

disturbing, irritating or damaging stimulus. This reaction to the stimulus is accompanied

by abnormal electro-chemical excitatory processes in the cerebral nerve cells. This

pathological process takes place when suddenly an unnaturally large number of nerve

cells are stimulated simultaneously, causing a difference in voltage between the outer

side of the cell wall and the inside of the cell (membrane potential).

These seizures are transient signs and/or symptoms of abnormal, excessive or

synchronous neuronal activity in the brain. About 50 million people worldwide have

epilepsy, with almost 90% of these people being in developing countries. Epilepsy is

more likely to occur in young children, or people over the age of 65 years, however it can

occur at any time. Epilepsy is usually controlled, but not cured, with medication,

although surgery may be considered in difficult cases. However, over 30% of people with

epilepsy do not have seizure control even with the best available medications. Not all

epilepsy syndromes are lifelong some forms are confined to particular stages of

childhood. Epilepsy should not be understood as a single disorder, but rather as

syndromic with vastly divergent symptoms but all involving episodic abnormal electrical

activity in the brain.(1)

A seizure is a short episode of symptoms caused by a burst of abnormal electrical

activity in the brain. Typically, a seizure lasts from a few seconds to a few minutes.

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(Older words for seizures include convulsions and fits.) The brain contains millions of

nerve cells (neurones). Normally, the nerve cells are constantly sending tiny electrical

messages down nerves to all parts of the body. Different parts of the brain control

different parts and functions of the body. Therefore, the symptoms that occur during a

seizure depend on where the abnormal burst of electrical activity occurs. Symptoms that

may occur during a seizure can affect your muscles, sensations, behaviour, emotions,

consciousness, or a combination of these.

If you have a single seizure, it does not necessarily mean that you have epilepsy.

About 1 in 20 people has a seizure at some time in their life. It may be the only one that

occurs. The definition of epilepsy is 'more than one seizure'. The frequency of seizures in

people with epilepsy varies. In some cases there may be years between seizures. At the

other extreme, in some cases the seizures occur every day. For others, the frequency of

seizures is somewhere in between these extremes. Epilepsy can affect anyone at any age.

Around 456,000 people in the UK have epilepsy. Epileptic seizures arise from within the

brain. A seizure can also be caused by external factors which may affect the brain. For

example, a high fever may cause a 'febrile convulsion’. (2)

2.1 Definition

According to the Epilepsy Foundation of America, epilepsy is a physical

condition that occurs when there is a sudden, brief change in how the brain works. When

brain cells are not working properly, a person's consciousness, movement, or actions may

be altered for a short time. These physical changes are called epileptic seizures. Epilepsy

is therefore sometimes called a seizure disorder. Epilepsy affects people in all nations and

of all races. (3)

2.2 History:

The Greek physician Hippocrates writes the first book on epilepsy, On the Sacred

Disease. Refuting the idea that epilepsy is a curse or a prophetic power, Hippocrates

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proves the truth: It's a brain disorder. "It is thus with regard to the disease called Sacred:

it appears to me to be nowise more divine nor more sacred than other diseases, but has

a. .natural cause like other affections.(4)

2.3 What is a seizure?

A seizure is a short episode of symptoms caused by a burst of abnormal electrical

activity in the brain. Typically, a seizure lasts from a few seconds to a few minutes. It is

a hyperexcitation of neurons in the brain leading to altered behaviour with or without

violent motor activity. The term describe varies experiences and behaviours. Two third of

people experience a siezure never have another while rest go on to have reccurent

siezures.

The changes seen during siezure depends upon on which part of is affected.Ideally

anything that irritates the brains, can produce sensation. A seizure usually last for 02-05

min. when it stops, the persons may have a headache, confusion, fatigue, unusual and

unpleasant sensation.

2.4 What is epilepsy?

It is disorder characterised by periodic and unpredictable occurrence of siezure

followed by spontaneous resolution. It is known as epileptic seizure It often causes

transient impairment of consciousness, leaving indivisual at risk bodily harm.

About 1-2%of whole population have epileptic seizure. In about 25% of these patients the

causes can be make out with the help of EEG and MRI. Rest of 75% are labelled as

idiopathic.

Scaring in small areas of brains due to injury at birth or later can leads to epilepsy.

The common factor that can precipitate the epileptic seizre are repetitive sound, flashing

lights video games low level of oxygen in blood, hypoglycemia.(2)

2.5 Characteristics:

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Although the symptoms listed below are not necessarily indicators of epilepsy, it is wise

to consult a doctor if you or a member of your family experiences one or more of them:

"Blackouts" or periods of confused memory;

Episodes of staring or unexplained periods of unresponsiveness;

Involuntary movement of arms and legs;

"Fainting spells" with incontinence or followed by excessive fatigue; or Odd

sounds, distorted perceptions, episodic feelings of fear that cannot be explained. (3)

3. NEURAL BASIS OF EPILEPSY:

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The exact neural basis of epilepsy is not clear and attributed to following mechanism

as per experimental findings.

The reduction in inhibitory synaptic activity or enhanced excitatory synaptic activity may

lead to seizures. The neurotransmitters like certain amino acids, GABA (inhibitory) and

glutamate (excitatory) are prominently involved.

The potassium stimulated glutamate release also plays role in epilepsy.

The state of Na+ ion channels plays an important role during neuronal firing, as

recovery from inactivated Na+ channel is essential for generation of action potential.

The fast recovery from inactivated form to activated form is seen in epilepsy.

Thus the epilepsy could be collective result of above mentioned neuronal alteration. (5)

Fig. No.1 Neural basis of epilepsy (5)

4. DIFFERENT TYPES OF SEIZURES

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Seizures are divided into two main types - generalised and partial. (There are also

other uncommon types of seizure.) If you have epilepsy you usually have recurrences of

the same type of seizure. However, some people have different types of seizure at

different times.

4.1 Generalised seizures:

Fig. No. 2 Generalised seizure (6)

These occur if the abnormal electrical activity affects all or most of the brain. The

symptoms tend to be 'general' and involve much of your body.

There are various types.

4.1.1 Atonic-clonic seizure:

It is the most common type of generalised seizure. With this type of seizure your

whole body stiffens, you lose consciousness, and then your body shakes (convulses) due

to uncontrollable muscle contractions

4.1.2 Absence seizure:

It is another type of generalised seizure. With this type of seizure you have a

brief loss of consciousness or awareness. There is no convulsion, you do not fall over,

and it usually lasts only seconds. Absence seizures mainly occur in children.

4.1.3 A myoclonic seizure:

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It is caused by a sudden contraction of the muscles, which causes a jerk. These

can affect the whole body but often occur in just one or both arms.

4.1.4 A tonic seizure:

It causes a brief loss of consciousness, and you may become stiff and fall to the

ground.

4.1.5 An atonic seizure:

Causes you to become limp and to collapse, often with only a brief loss of

consciousness.

4.2 Partial seizures:

Fig. No.3 Partial seizure(6)

In these types of seizures the burst of electrical activity starts in, and stays in, one

part of the brain. Therefore, you tend to have localised or 'focal' symptoms. Different

parts of the brain control different functions and so symptoms depend on which part of

the brain is affected:

4.2.1 Simple partial seizures: are one type. You may have muscular jerks or strange

sensations in one arm or leg. You may develop an odd taste, or pins and needles in one

part of your body. You do not lose consciousness or awareness.

4.2.2 Complex partial seizures:. These commonly arise from a temporal lobe (a part of

the brain) but may start in any part of the brain. Therefore, this type is sometimes called

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'temporal lobe epilepsy'. Depending on the part of the brain affected, you may behave

strangely for a few seconds or minutes. For example, you may fiddle with an object, or

mumble, or wander aimlessly. In addition, you may have odd emotions, fears, feelings,

visions, or sensations. These differ from simple partial seizures in that your

consciousness is affected. You may not remember having a seizure. (2)

5. CLASSIFICATION OF EPILEPSY:

The epilepsy is classified into four type:

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5.1 Juvenile myoclonic epilepsy:

It is common among the age of 8-20 years and show characteristic myoclionic jerk

followed by generaalised tonic-clonic seizure.

5.2 Benign partial epilepsy in childhood:

It is common upto age 12 and starts with partial seizure which may result

generalized tonic-clonic seizure.The attack is more severe during sleep.

5.3 Solitary parenchymal cysts:

Single small cysts, a common form neurocystercosis is responcible. This is well

controlled by antiepileptic drug. Sometime therapy need augmentation of cysticidal (e.g.-

albendazol)

5.4 Reflex epilepsy:

In this type specific sensory stimuli or responsible for evoke the attack.

Photosensitivity, hot water is common stimuli. (3)

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6. EPILEPSY SYNDROMES:

There are over 40 different types of epilepsy, including: Absence seizures, atonic

seizures, benign Rolandic epilepsy, childhood absence, clonic seizures, complex partial

seizures, frontal lobe epilepsy, Febrile seizures, Infantile spasms, Juvenile Myoclonic

Epilepsy, Juvenile Absence Epilepsy, lennox-gastaut syndrom, Landau-Kleffner

Syndrome , myoclonic seizures, Mitochondrial Disorders, Progressive Myoclonic

Epilepsies, Psychogenic Seizures , Reflex Epilepsy, Rasmussen's Syndrome, Simple

Partial seizures, Secondarily Generalized Seizures, Temporal Lobe Epilepsy, Toni-clonic

seizures, Tonic seizures, Psychomotor Seizures, Limbic Epilepsy, Partial-Onset Seizures,

generalised-onset seizures, Status Epilepticus, Abdominal Epilepsy, Akinetic Seizures,

Auto-nomic seizures, Massive Bilateral Myoclonus, Catamenial Epilepsy, Drop seizures,

Emotional seizures, Focal seizures, Gelastic seizures, Jacksonian March, Lafora Disease,

Motor seizures, Multifocal seizures, Neonatal seizures, Nocturnal seizures,

Photosensitive seizure, Pseudo seizures, Sensory seizures, Subtle seizures, Sylvan

Seizures, Withdrawal seizures, Visual Reflex Seizures amongst others.

Each type of epilepsy presents with its own unique combination of seizure type, typical

age of onset, EEG findings, treatment, and prognosis. The most widespread classification

of the epilepsies [9] divides epilepsy syndromes by location or distribution of seizures (as

revealed by the appearance of the seizures and by EEG) and by cause. Syndromes are

divided into localization-related epilepsies, generalized epilepsies, or epilepsies of

unknown localization.

Localization-related epilepsies, sometimes termed partial or focal epilepsies, arise from

an epileptic focus, a small portion of the brain that serves as the irritant driving the

epileptic response. Generalized epilepsies, in contrast, arise from many independent foci

(multifocal epilepsies) or from epileptic circuits that involve the whole brain. Epilepsies

of unknown localization remain unclear whether they arise from a portion of the brain or

from more widespread circuits.

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Epilepsy syndromes are further divided by presumptive cause: idiopathic, symptomatic,

and cryptogenic. Idiopathic epilepsies are generally thought to arise from genetic

abnormalities that lead to alteration of basic neuronal regulation. Symptomatic

epilepsies arise from the effects of an epileptic lesion, whether that lesion is focal, such

as a tumor, or a defect in metabolism causing widespread injury to the brain.

Cryptogenic epilepsies involve a presumptive lesion that is otherwise difficult or

impossible to uncover during evaluation.

Some epileptic syndromes are difficult to fit within this classification scheme and fall in

the unknown localization/etiology category. People who only have had a single seizure,

or those with seizures that occur only after specific precipitants ("provoked seizures"),

have "epilepsies" that fall into this category. Febrile convulsions are an example of

seizures bound to a particular precipitant. Landau-Kleffner syndrome is another epilepsy

which, because of its variety of EEG distributions, falls uneasily in clear categories. More

confusingly, certain syndromes like West syndrome featuring seizures such as Infantile

spasms can be classified as idiopathic, syndromic, or cryptogenic depending on cause and

can arise from both focal or generalized epileptic lesions.

Below are some common seizure syndromes:

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an idiopathic

localization-related epilepsy that is an inherited epileptic disorder that causes

seizures during sleep. Onset is usually in childhood. These seizures arise from the

frontal lobes and consist of complex motor movements, such as hand clenching,

arm raising/lowering, and knee bending. Vocalizations such as shouting,

moaning, or crying are also common. ADNFLE is often misdiagnosed as

nightmares. ADNFLE has a genetic basis. These genes encode various nicotinic

acetylcholine receptors.

Benign centrotemporal lobe epilepsy of childhood or Benign rolandic epilepsy is

an idiopathic localization-related epilepsy that occurs in children between the ages

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of 3 and 13 years with peak onset in prepubertal late childhood. Apart from their

seizure disorder, these patients are otherwise normal. This syndrome features

simple partial seizures that involve facial muscles and frequently cause drooling.

Although most episodes are brief, seizures sometimes spread and generalize.

Seizures are typically nocturnal and confined to sleep. The EEG may demonstrate

spike discharges that occur over the centrotemporal scalp over the central sulcus

of the brain (the Rolandic sulcus) that are predisposed to occur during drowsiness

or light sleep. Seizures cease near puberty. Seizures may require anticonvulsant

treatment, but sometimes are infrequent enough to allow physicians to defer

treatment.

Benign occipital epilepsy of childhood (BOEC) is an idiopathic localization-

related epilepsy and consists of an evolving group of syndromes. Most authorities

include two subtypes, an early subtype with onset between 3–5 years and a late

onset between 7–10 years. Seizures in BOEC usually feature visual symptoms

such as scotoma or fortifications (brightly colored spots or lines) or amaurosis

(blindness or impairment of vision). Convulsions involving one half the body,

hemiconvulsions, or forced eye deviation or head turning are common. Younger

patients typically experience symptoms similar to migraine with nausea and

headache, and older patients typically complain of more visual symptoms. The

EEG in BOEC shows spikes recorded from the occipital (back of head) regions.

The EEG and genetic pattern suggest an autosomal dominant transmission as

described by Ruben Kuzniecky et al. Lately, a group of epilepsies termed

Panayiotopoulos syndrome that share some clinical features of BOEC but have a

wider variety of EEG findings are classified by some as BOEC.

Catamenial epilepsy (CE) is when seizures cluster around certain phases of a

woman's menstrual cycle.

Childhood absence epilepsy (CAE) is an idiopathic generalized epilepsy that

affects children between the ages of 4 and 12 years of age, although peak onset is

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around 5–6 years old. These patients have recurrent absence seizures, brief

episodes of unresponsive staring, sometimes with minor motor features such as

eye blinking or subtle chewing. The EEG finding in CAE is generalized 3 Hz

spike and wave discharges. Some go on to develop generalized tonic-clonic

seizures. This condition carries a good prognosis because children do not usually

show cognitive decline or neurological deficits, and the seizures in the majority

cease spontaneously with onging maturation.

Dravet's syndrome Severe myoclonic epilepsy of infancy (SMEI). This

generalized epilepsy syndrome is distinguished from benign myoclonic epilepsy

by its severity and must be differentiated from the Lennox-Gastaut syndrome and

Doose’s myoclonic-astatic epilepsy. Onset is in the first year of life and

symptoms peak at about 5 months of age with febrile hemiclonic or generalized

status epilepticus. Boys are twice as often affected as girls. Prognosis is poor.

Most cases are sporadic. Family history of epilepsy and febrile convulsions is

present in around 25 percent of the cases.

Frontal lobe epilepsy, usually a symptomatic or cryptogenic localization-related

epilepsy, arises from lesions causing seizures that occur in the frontal lobes of the

brain. These epilepsies can be difficult to diagnose because the symptoms of

seizures can easily be confused with nonepileptic spells and, because of

limitations of the EEG, be difficult to "see" with standard scalp EEG.

Juvenile absence epilepsy is an idiopathic generalized epilepsy with later onset

that CAE, typically in prepubertal adolescence, with the most frequent seizure

type being absence seizures. Generalized tonic-clonic seizures can occur. 3 Hz

spike-wave or multiple spike discharges can be seen on EEG. Prognosis is mixed,

with some patients going on to a syndrome that is poorly distinguishable from

JME.

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Juvenile myoclonic epilepsy (JME) is an idiopathic generalized epilepsy that

occurs in patients aged 8 to 20 years. Patients have normal cognition and are

otherwise neurologically intact. The most common seizures are myoclonic jerks,

although generalized tonic-clonic seizures and absence seizures may occur as

well. Myoclonic jerks usually cluster in the early morning after awakening. The

EEG reveals generalized 4–6 Hz spike wave discharges or multiple spike

discharges. Interestingly, these patients are often first diagnosed when they have

their first generalized tonic-clonic seizure later in life when they experience sleep

deprivation (e.g., freshman year in college after staying up late to study for

exams). Alcohol withdrawal can also be a major contributing factor in

breakthrough seizures as well. The risk of the tendency to have seizures is

lifelong; however, the majority have well-controlled seizures with anticonvulsant

medication and avoidance of seizure precipitants.

Lennox-Gastaut syndrome (LGS) is a generalized epilepsy that consists of a triad

of developmental delay or childhood dementia, mixed generalized seizures, and

EEG demonstrating a pattern of approximately 2 Hz "slow" spike-wave. Onset

occurs between 2–18 years. As in West syndrome, LGS result from idiopathic,

symptomatic, or cryptogenic causes, and many patients first have West syndrome.

Authorities emphasize different seizure types as important in LGS, but most have

astatic seizures (drop attacks), tonic seizures, tonic-clonic seizures, atypical

absence seizures, and sometimes, complex partial seizures. Anticonvulsants are

usually only partially successful in treatment.

Ohtahara Syndrome is a rare but severe form of epilepsy syndrome combined

with cerebral palsy and characterised with frequent seizures which typically start

in the first few days of life. Sufferers trend to be severely disabled and their lives

short (they are unlikely to reach adulthood).

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Primary reading epilepsy is a reflex epilepsy classified as an idiopathic

localization-related epilepsy. Reading in susceptible individuals triggers

characteristic seizures.

Progressive myoclonic epilepsies define a group of symptomatic generalized

epilepsies characterized by progressive dementia and myoclonic seizures. Tonic-

clonic seizures may occur as well. Diseases usually classified in this group are

Unverricht-Lundborg disease, myoclonus epilepsy with ragged red fibers

(MERRF syndrome), Lafora disease, neuronal ceroid lipofucinosis, and sialdosis.

Rasmussen's encephalitis is a symptomatic localization-related epilepsy that is a

progressive, inflammatory lesion affecting children with onset before the age of

10. Seizures start as separate simple partial or complex partial seizures and may

progress to epilepsia partialis continuata (simple partial status epilepticus).

Neuroimaging shows inflammatory encephalitis on one side of the brain that may

spread if not treated. Dementia and hemiparesis are other problems. The cause is

hypothesized to involve an immulogical attack against glutamate receptors, a

common neurotransmitter in the brain.

Symptomatic localization-related epilepsies Symptomatic localization-related

epilepsies are divided by the location in the brain of the epileptic lesion, since the

symptoms of the seizures are more closely tied to the brain location rather than

the cause of the lesion. Tumors, atriovenous malformations, cavernous

malformations, trauma, and cerebral infarcts can all be causes of epileptic foci in

different brain regions.

Temporal lobe epilepsy (TLE), a symptomatic localization-related epilepsy, is the

most common epilepsy of adults who experience seizures poorly controlled with

anticonvulsant medications. In most cases, the epileptogenic region is found in the

midline (mesial) temporal structures (e.g., the hippocampus, amygdala, and

parahippocampal gyrus). Seizures begin in late childhood and adolescence. Most

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of these patients have complex partial seizures sometimes preceded by an aura,

and some TLE patients also suffer from secondary generalized tonic-clonic

seizures. If the patient does not respond sufficiently to medical treatment, epilepsy

surgery may be considered.

West syndrome is a triad of developmental delay, seizures termed infantile

spasms, and EEG demonstrating a pattern termed hypsarrhythmia. Onset occurs

between 3 months and 2 years, with peak onset between 8–9 months. West

syndrome may arise from idiopathic, symptomatic, or cryptogenic causes. The

most common cause is tuberous sclerosis. The prognosis varies with the

underlying cause. In general most surviving patients remain with significant

cognitive impairment and continuing seizures and may evolve to another

eponymic syndrome, Lennox-Gastaut syndrome.(1)

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7. CAUSES

The diagnosis of epilepsy usually requires that the seizures occur spontaneously.

Nevertheless, certain epilepsy syndromes require particular precipitants or triggers for

seizures to occur. These are termed reflex epilepsy. For example, patients with primary

reading epilepsy have seizures triggered by reading. Photosensitive epilepsy can be

limited to seizures triggered by flashing lights. Other precipitants can trigger an epileptic

seizure in patients who otherwise would be susceptible to spontaneous seizures. For

example, children with childhood absence epilepsy may be susceptible to

Fig. No. 4 The Causes of Epilepsy(6)

hyperventilation. In fact, flashing lights and hyperventilation are activating procedures

used in clinical EEG to help trigger seizures to aid diagnosis. Finally, other precipitants

can facilitate, rather than obligately trigger, seizures in susceptible individuals. Emotional

stress, sleep deprivation, sleep itself, and febrile illness are examples of precipitants cited

by patients with epilepsy. Notably, the influence of various precipitants varies with the

epilepsy syndrome. Likewise, the menstrual cycle in women with epilepsy can influence

patterns of seizure recurrence. Catamenial epilepsy is the term denoting seizures linked to

the menstrual cycle. (1)

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8. PATHOPHYSIOLOGY

Mutations in several genes have been linked to some types of epilepsy. Several genes that

code for protein subunits of voltage-gated and ligand-gated ion channels have been

associated with forms of generalized epilepsy and infantile seizure syndromes. Several

ligand-gated ion channels have been linked to some types of frontal and generalized

epilepsies. One speculated mechanism for some forms of inherited epilepsy are mutations

of the genes which code for sodium channel proteins; these defective sodium channels

stay open for too long thus making the neuron hyper-excitable. Glutamate, an excitatory

neurotransmitter, may thereby be released from these neurons in large amounts which—

by binding with nearby glumtamanergic neurons—triggers excessive Ca++ release in these

post-synaptic cells. Such excessive calcium release can be neurotoxic to the affected cell.

The hippocampus, which contains a large volume of just such glutamanergic neurons is

especially vulnerable to epileptic seizure, subsequent spread of excitation, and possible

neuronal death. Another possible mechanism involves mutations leading to ineffective

GABA (the brain's most common inhibitory neurotransmitter) action. Epilepsy-related

mutations in some non-ion channel genes have also been identified.

Epileptogenesis is the process by which a normal brain develops epilepsy after an insult.

One interesting finding in animals is that repeated low-level electrical stimulation to

some brain sites can lead to permanent increases in seizure susceptibility: in other words,

a permanent decrease in seizure "threshold." This phenomenon, known as kindling (by

analogy with the use of burning twigs to start a larger fire) was discovered by Dr.

Graham Goddard in 1967. Chemical stimulation can also induce seizures; repeated

exposures to some pesticides have been shown to induce seizures in both humans and

animals. One mechanism proposed for this is called excitotoxicity. The roles of kindling

and excitotoxicity, if any, in human epilepsy are currently hotly debated.

Other causes of epilepsy are brain lesions, where there is scar tissue or another abnormal

mass of tissue in an area of the brain.

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The complexity of understanding what seizures are have led to considerable efforts to use

computational models of epilepsy to both interpret experimental and clinical data, as well

as guide strategies for therapy.(1)

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9. EPIDEMIOLOGY

Epilepsy is one of the most common of the serious neurological disorders. Genetic,

congenital, and developmental conditions are mostly associated with it among younger

patients; tumors are more likely over age 40; head trauma and central nervous system

infections may occur at any age. The prevalence of active epilepsy is roughly in the range

5–10 per 1000 people. Up to 5% of people experience non febrile seizures at some point

in life; epilepsy's lifetime prevalence is relatively high because most patients either stop

having seizures or (less commonly) die of it. Epilepsy's approximate annual incidence

rate is 40–70 per 100,000 in industrialized countries and 100–190 per 100,000 in

resource-poor countries; socioeconomically deprived people are at higher risk. In

industrialized countries the incidence rate decreased in children but increased among the

elderly during the three decades prior to 2003, for reasons not fully understood.[41]

Beyond symptoms of the underlying diseases that can be a part of certain epilepsies,

people with epilepsy are at risk for death from four main problems: status epilepticus

(most often associated with anticonvulsant noncompliance), suicide associated with

depression, trauma from seizures, and sudden unexpected death in epilepsy Those at

highest risk for epilepsy-related deaths usually have underlying neurological impairment

or poorly controlled seizures; those with more benign epilepsy syndromes have little risk

for epilepsy-related death.

The NICE National Sentinel Audit of Epilepsy-Related Deaths, led by "Epilepsy

Bereaved" drew attention to this important problem. The Audit revealed; "1,000 deaths

occur every year in the UK as a result of epilepsy" and most of them are associated with

seizure. (1)

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10. MANAGEMENT

Epilepsy is usually treated with medication prescribed by a physician; primary caregivers,

neurologists, and neurosurgeons all frequently care for people with epilepsy. In some

cases the implantation of a stimulator of the vagus nerve, or a special diet can be helpful.

Neurosurgical operations for epilepsy can be palliative, reducing the frequency or

severity of seizures; or, in some patients, an operation can be curative.

10.1 Responding to a seizure

In most cases, the proper emergency response to a generalized tonic-clonic epileptic

seizure is simply to prevent the patient from self-injury by moving him or her away from

sharp edges, placing something soft beneath the head, and carefully rolling the person

into the recovery position to avoid asphyxiation. In some cases the person may seem to

start snoring loudly following a seizure, before coming to. This merely indicates that the

person is beginning to breathe properly and does not mean he or she is suffocating.

Should the person regurgitate, the material should be allowed to drip out the side of the

person's mouth by itself. If a seizure lasts longer than 5 minutes, or if the seizures begin

coming in 'waves' one after the other - then Emergency Medical Services should be

contacted immediately. Prolonged seizures may develop into status epilepticus, a

dangerous condition requiring hospitalization and emergency treatment.

Objects should never be placed in a person's mouth by anybody - including paramedics -

during a seizure as this could result in serious injury to either party. Despite common

folklore, it is not possible for a person to swallow their own tongue during a seizure.

However, it is possible that the person will bite their own tongue, especially if an object

is placed in the mouth.

With other types of seizures such as simple partial seizures and complex partial seizures

where the person is not convulsing but may be hallucinating, disoriented, distressed, or

unconscious, the person should be reassured, gently guided away from danger, and

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sometimes it may be necessary to protect the person from self-injury, but physical force

should be used only as a last resort as this could distress the person even more. In

complex partial seizures where the person is unconscious, attempts to rouse the person

should not be made as the seizure must take its full course. After a seizure, the person

may pass into a deep sleep or otherwise they will be disoriented and often unaware that

they have just had a seizure, as amnesia is common with complex partial seizures. The

person should remain observed until they have completely recovered, as with a tonic-

clonic seizure.

After a seizure, it is typical for a person to be exhausted and confused. (this is known as

post-ictal state). Often the person is not immediately aware that they have just had a

seizure. During this time one should stay with the person - reassuring and comforting

them - until they appear to act as they normally would. Seldom during seizures do people

lose bladder or bowel control. In some instances the person may vomit after coming to.

People should not be allowed to wander about unsupervised until they have returned to

their normal level of awareness. Many patients will sleep deeply for a few hours after a

seizure - this is common for those having just experienced a more violent type of seizure

such as a tonic-clonic. In about 50% of people with epilepsy, headaches may occur after a

seizure. These headaches share many features with migraines, and respond to the same

medications.

It is helpful if those present at the time of a seizure make note of how long and how

severe the seizure was. It is also helpful to note any mannerisms displayed during the

seizure. For example, the individual may twist the body to the right or left, may blink,

might mumble nonsense words, or might pull at clothing. Any observed behaviors, when

relayed to a neurologist, may be of help in diagnosing the type of seizure which occurred.

10.2 Pharmacologic treatment

The mainstay of treatment of epilepsy is anticonvulsant medications. Often,

anticonvulsant medication treatment will be lifelong and can have major effects on

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quality of life. The choice among anticonvulsants and their effectiveness differs by

epilepsy syndrome. Mechanisms, effectiveness for particular epilepsy syndromes, and

side effects, of course, differ among the individual anticonvulsant medications. Some

general findings about the use of anticonvulsants are outlined below.

10.2.1 History and Availability-

The first anticonvulsant was bromide, suggested in 1857 by Charles Locock who used it

to treat women with "hysterical epilepsy" (probably catamenial epilepsy). Potassium

bromide was also noted to cause impotence in men. Authorities concluded that potassium

bromide would dampen sexual excitement thought to cause the seizures. In fact, bromides

were effective against epilepsy, and also caused impotence; it is now known that

impotence is a side effect of bromide treatment, which is not related to its anti-epileptic

effects. It also suffered from the way it affected behaviour, introducing the idea of the

'epileptic personality' which was actually a result of the medication. Phenobarbital was

first used in 1912 for both its sedative and antiepileptic properties. By the 1930s, the

development of animal models in epilepsy research lead to the development of phenytoin

by Tracy Putnam and H. Houston Merritt, which had the distinct advantage of treating

epileptic seizures with less sedation. By the 1970s, an National Institutes of Health

initiative, the Anticonvulsant Screening Program, headed by J. Kiffin Penry, served as a

mechanism for drawing the interest and abilities of pharmaceutical companies in the

development of new anticonvulsant medications.

Currently there are 20 medications approved by the Food and Drug Administration for

the use of treatment of epileptic seizures in the US: carbamazepine (common US brand

name Tegretol), clorazepate (Tranxene), clonazepam (Klonopin), ethosuximide

(Zarontin), felbamate (Felbatol), fosphenytoin (Cerebyx), gabapentin (Neurontin),

lacosamide (Vimpat), lamotrigine (Lamictal), levetiracetam (Keppra), oxcarbazepine

(Trileptal), phenobarbital (Luminal), phenytoin (Dilantin), pregabalin (Lyrica), primidone

(Mysoline), tiagabine (Gabitril), topiramate (Topamax), valproate semisodium

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(Depakote), valproic acid (Depakene), and zonisamide (Zonegran). Most of these

appeared after 1990.

Medications commonly available outside the US but still labelled as "investigational"

within the US are clobazam (Frisium) and vigabatrin (Sabril). Medications currently

under clinical trial under the supervision of the FDA include retigabine, brivaracetam,

and seletracetam.

Other drugs are commonly used to abort an active seizure or interrupt a seizure flurry;

these include diazepam (Valium, Diastat) and lorazepam (Ativan). Drugs used only in the

treatment of refractory status epilepticus include paraldehyde (Paral), midazolam

(Versed), and pentobarbital (Nembutal).

Some anticonvulsant medications do not have primary FDA-approved uses in epilepsy

but are used in limited trials, remain in rare use in difficult cases, have limited

"grandfather" status, are bound to particular severe epilepsies, or are under current

investigation. These include acetazolamide (Diamox), progesterone, adrenocorticotropic

hormone (ACTH), various corticotropic steroid hormones (prednisone), or bromide.

10.2.2 Effectiveness:

The definition of "effective" varies. FDA-approval usually requires that 50% of

the patient treatment group had at least a 50% improvement in the rate of epileptic

seizures. About 20% of patients with epilepsy continue to have breakthrough epileptic

seizures despite best anticonvulsant treatment.

10.2.3 Safety and Side Effects:

88% of patients with epilepsy, in a European survey, reported at least one

anticonvulsant related side effect. Most side effects are mild and "dose-related" and can

often be avoided or minimized by the use of the smallest effective amount. Some

examples include mood changes, sleepiness, or unsteadiness in gait. Some anticonvulsant

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medications have "idiosyncratic" side-effects that can not be predicted by dose. Some

examples include drug rashes, liver toxicity (hepatitis), or aplastic anemia. Safety

includes the consideration of teratogenicity (the effects of medications on fetal

development) when women with epilepsy become pregnant.

10.2.4 Principles of Anticonvulsant Use:

The goal for individual patients is, of course, no seizures and no side effects, and

the job of the physician is to aid the patient to find the best balance between the two

during the prescribing of anticonvulsants. Most patients can achieve this balance best

with monotherapy, the use of a single anticonvulsant medication. Some patients,

however, require polypharmacy; the use of two or more anticonvulsants.

Serum levels of AEDs can be checked to determine medication compliance, to assess the

effects of new drug-drug interactions upon previous stable medication levels, or to help

establish if particular symptoms such as instability or sleepiness can be considered a drug

side-effect or are due to different causes. Children or impaired adults who may not be

able to communicate side effects may benefit from routine screening of drug levels.

Beyond baseline screening, however, trials of recurrent, routine blood or urine

monitoring show no proven benefits and may lead to unnecessary medication adjustments

in most older children and adults using routine anticonvulsants.

If a person's epilepsy cannot be brought under control after adequate trials of two or three

(experts vary here) different drugs, that person's epilepsy is generally said to be

medically refractory. A study of patients with previously untreated epilepsy

demonstrated that 47% achieved control of seizures with the use of their first single drug.

14% became seizure free during treatment with a second or third drug. An additional 3%

became seizure-free with the use of two drugs simultaneously. Other treatments, in

addition to or instead of, anticonvulsant medications may be considered by those people

with continuing seizures.

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10.3 Surgical treatment

Epilepsy surgery is an option for patients whose seizures remain resistant to treatment

with anticonvulsant medications who also have symptomatic localization-related

epilepsy; a focal abnormality that can be located and therefore removed. The goal for

these procedures is total control of epileptic seizures, although anticonvulsant

medications may still be required.

The evaluation for epilepsy surgery is designed to locate the "epileptic focus" (the

location of the epileptic abnormality) and to determine if respective surgery will affect

normal brain function. Physicians will also confirm the diagnosis of epilepsy to make

sure that spells arise from epilepsy (as opposed to non-epileptic seizures). The evaluation

typically includes neurological examination, routine EEG, Long-term video-EEG

monitoring, neuropsychological evaluation, and neuroimaging such as MRI, Single

photon emission computed tomography (SPECT), positron emission tomography (PET).

Some epilepsy centers use intracarotid sodium amobarbital test (Wada test), functional

MRI or Magnetoencephalography (MEG) as supplementary tests.

Certain lesions require Long-term video-EEG monitoring with the use of intracranial

electrodes if noninvasive testing was inadequate to identify the epileptic focus or

distinguish the surgical target from normal brain tissue and function. Brain mapping by

the technique of cortical electrical stimulation or Electrocorticography are other

procedures used in the process of invasive testing in some patients.

The most common surgeries are the resection of lesions like tumors or arteriovenous

malformations which, in the process of treating the underlying lesion, often result in

control of epileptic seizures caused by these lesions.

Other lesions are more subtle and feature epilepsy as the main or sole symptom. The most

common form of intractable epilepsy in these disorders in adults is temporal lobe

epilepsy with hippocampal sclerosis, and the most common type of epilepsy surgery is

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the anterior temporal lobectomy, or the removal of the front portion of the temporal lobe

including the amygdala and hippocampus. Some neurosurgeons recommend selective

amygdalahippocampectomy because of possible benefits in postoperative memory or

language function. Surgery for temporal lobe epilepsy is effective, durable, and results in

decreased health care costs.. Despite the efficacy of epilepsy surgery, some patients

decide not to undergo surgery owing to fear or the uncertainty of having a brain

operation.

Palliative surgery for epilepsy is intended to reduce the frequency or severity of seizures.

Examples are callosotomy or commissurotomy to prevent seizures from generalizing

(spreading to involve the entire brain), which results in a loss of consciousness. This

procedure can therefore prevent injury due to the person falling to the ground after losing

consciousness. It is performed only when the seizures cannot be controlled by other

means. Multiple subpial transection can also be used to decrease the spread of seizures

across the cortex especially when the epileptic focus is located near important functional

areas of the cortex. Resective surgery can be considered palliative if it is undertaken with

the expectation that it will reduce but not eliminate seizures.

Hemispherectomy involves removal or a functional disconnection of most or all of one

half of the cerebrum. It is reserved for people suffering from the most catastrophic

epilepsies, such as those due to Rasmussen syndrome. If the surgery is performed on very

young patients (2–5 years old), the remaining hemisphere may acquire some rudimentary

motor control of the ipsilateral body; in older patients, paralysis results on the side of the

body opposite to the part of the brain that was removed. Because of these and other side

effects it is usually reserved for patients who have exhausted other treatment options.

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10.4 Other treatment

10.4.1 Ketogenic diet:

A high fat, low carbohydrate diet developed in the 1920s, largely forgotten with

the advent of effective anticonvulsants, and resurrected in the 1990s. The mechanism of

action is unknown. It is used mainly in the treatment of children with severe, medically-

intractable epilepsies.

10.4.2 Electrical stimulation:

Methods of anticonvulsant treatment with both currently approved and

investigational uses. A currently approved device is vagus nerve stimulation (VNS).

Investigational devices include the responsive neurostimulation system and deep

brain stimulation.

10.4.3 Vagus nerve stimulation (VNS):

The VNS consists of a computerized electrical device similar in size, shape and

implant location to a heart pacemaker that connects to the vagus nerve in the neck. The

device stimulates the vagus nerve at pre-set intervals and intensities of current. Efficacy

has been tested in patients with localization-related epilepsies demonstrating that 50% of

patients experience a 50% improvement in seizure rate. Case series have demonstrated

similar efficacies in certain generalized epilepsies such as Lennox-Gastaut syndrome.

Although success rates are not usually equal to that of epilepsy surgery, it is a reasonable

alternative when the patient is reluctant to proceed with any required invasive

monitoring, when appropriate presurgical evaluation fails to uncover the location of

epileptic foci, or when there are multiple epileptic foci.

Responsive Neurostimulator System (RNS) (manufacturer Neuropace) consists of an

computerized electrical device implanted in the skull with electrodes implanted in

presumed epileptic foci within the brain. The brain electrodes send EEG signal to the

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device which contains seizure-detection software. When certain EEG seizure criteria are

met, the device delivers a small electrical charge to other electrodes near the epileptic

focus and disrupt the seizure. The efficacy of the RNS is under current investigation with

the goal of FDA approval.

Deep brain stimulation (DBS) (US manufacturer Medtronic) consists of computerized

electrical device implanted in the chest in a manner similar to the VNS, but electrical

stimulation is delivered to deep brain structures through depth electrodes implanted

through the skull. In epilepsy, the electrode target is the anterior nucleus of the thalamus.

The efficacy of the DBS in localization-related epilepsies is currently under investigation.

Noninvasive surgery- The use of the Gamma Knife or other devices used in radiosurgery

are currently being investigated as alternatives to traditional open surgery in patients who

would otherwise qualify for anterior temporal lobectomy.

Avoidance therapy- Avoidance therapy consists of minimizing or eliminating triggers in

patients whose seizures are particularly susceptible to seizure precipitants For example,

sunglasses that counter exposure to particular light wavelengths can improve seizure

control in certain photosensitive epilepsies.

Warning systems- A seizure response dog is a form of service dog that is trained to

summon help or ensure personal safety when a seizure occurs. These are not suitable for

everybody and not all dogs can be so trained. Rarely, a dog may develop the ability to

sense a seizure before it occurs. Development of electronic forms of seizure detection

systems are currently under investigation.

Alternative or complementary medicine- A number of systematic reviews by the

Cochrane Collaboration into treatments for epilepsy looked at acupuncture, psychological

interventions, vitamins and yoga and found there is no reliable evidence to support the

use of these as treatments for epilepsy.(1)

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11. ANTIEPILEPTIC DRUG

Classification (7)

The antiepileptic drug may be classified according to chemical structure as under:

11.1. Anticonvulsant Barbiturates:

Phenobarbital, Mephobarbital, Methabital.

11.2. Hydantoins:

Phenytoin, Ethatoin, Mephenytoin.

11.3. Oxazlidinediones:

Trimthadione. Paramethadione.

11.4. Succinimides:

Ethosuximide, Methsuximide, Phensuximide.

11.5. Iminostilbines:

Carbamazepine.

11.6. Benzodiazepines:

Clonazepam, Diazepam, Nitrazepam.

11.7. Valproic acid derivatives:

Valproic acid, Valproate

11.8. Chemically unrelated anticonvulsant:

Primidone, Acetozolamide.

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11.1 Anti convulsant barbiturates:

11.1.1 Phenobarbital

All barbiturates can abolish seizures at doses sufficient to produce

anesthesia. Phenobarbital is effective antiepileptics at sub hypnotic doses.They exert a

prolong action. (7)

Fig. No. 5. Structure of Phenobarbital(8)

Mode of action :

The antiepileptic activity of barbiturates involved several mechanisms,

1. The excitability of the nerve cell is reduced due to their increased firing threshold.

2. Decreased neuronal excitability limits the spread of the abnormal discharge.

3. The active transport of ion across the neuronal membranes is impaired, which lowers

their firing rate.

Therapeutic uses:

1. Treatment of grand mal seizures used alone in infants and children’s and in

combination with phenytoin in adults.

2. Generalized myoclonic jerks and cortical focal seizures.

3. Control of status epilepticus.

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Adverse reactions:

Drowsiness, Lethargy and Dizziness are most frequently noted side effects. Less

common adverse reactions are bradycardia, hypotension, hypoventilation, bronchospasm,

laryngospasm, skin rash, confusion, hallucinations and aggressive behavior. (7)

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11.2 Hydantoins:

11.2.1 Phenytoin

The hydantoins are the most effective drugs for the treatment of grand mal

seizures and can also be used to control psychomotor epilepsy. Phenytoin is the most

frequently prescribed drug out of the hydantoins. (7)

Fig. No.6. Structure of Phenytoin(9)

Availability Form:

Phenytoin sodium has been marketed as:

Phenytek by Mylan Laboratories, previously Bertek Pharmaceuticals

Dilantin Kapseals and Dilantin Infatabs in the USA,

Eptoin by Abbott Group in India and PhydumTM in form of tab./inj. by Quadra labs

pvt. ltd. in India.(9)

Mechanism of action

The hydantoins inhibit the spread of seizures activity to neurons surrounding the

seizures focus. The motor cortex is the primary site of action These drugs produce a

stabilization of the neuronal membrane, i.e. the threshold of excitability is increased and

the duration of after-discharge is reduced. Perhaps by increasing Na+-K+ adenosine

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triphosphatase (ATPase) activity, sodium efflux from neuronal cells is stimulated,

blocking post-titanic potentiation (PTP). This prevent focal seizure activity to spread to

adjacent areas. Increased released or activity of GABA has been postulated asan

additional possible mechanism of action.

Therapeutic Uses

1. Control of grand mal seizures.

2. Treatment of psychomotor epilepsy

3. Adjunctive treatment of trigeminal neuralgia and alcohol withdrawal syndrome.

Adverse reaction

The side effects sluggishness, slurred speech nystagmus and confusion.

The other adverse reactions include:

GI- nausea, vomiting, dysphagia.

CNS- headache, tremors, behavioural disturbances.

Dermatology- skin rashes, urticaria

Haematopoietic- megaloblastic anaemia. bone marrow depression.

Other- gingimal hyperplasia hepatitis hyperglycaemia pulmonary fibrosis. (7)

11.3 Oxazolidinediones

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11.3.1 Trimethadione

These are effective drugs for the control of simple absence seizure.but incident of adverse

reactionis high. Their use reversed for patients who are intolerant or refractory to other

less toxic agents. (7)

Fig. No. 7. Structure of trimethadione (10)

Mechanism of action

Repetitive discharge in the thalamocortical system are responsible for absence

seizure. The drug which prolong the recovery period of the postsynapticneurons in these

systems, thereby exerting an antiseizure effect. They elevate the seizure threshold in the

thalamus, and interfere with prolongation pf seizure activity. They posses little sedative-

hypnotic effect and have an analgesic effect.

Therapeutic Use

The drug is used in treatment of simple absence (petit mal) seizures.

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Adverse reaction

Common side effect are drowsiness GI distress hiccup and photophobia.

The other adverse reactions are

GI- nausea, vomiting, anorexia

CNS-vertigo irritability, personality changes, precipitation of grand mal seizures.

Haematologic- mucosal bleeding, neutropenia.

Others- skin rashes exfoliative dermatitis, albimnuria.

This drug should not be used during pregnancy. (7)

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11.4 Succinimides

11.4.1 Ethosucximide:

The succinimides are the drug of choice for treatment of absence (petit mal)

seizures. They are not more effective than the oxazolidinediones, but are less toxic

compare to other alternative drugs. (7)

Fig. No. 8. Structure of Ethosuximide(11)

Availability:

Ethosuximide is marketed under the trade names Emeside and Zarontin.

However, both capsule preparations were discontinued from production, leaving only

generic preparations available. Emeside capsules were discontinued by their

manufacturer, Laboratories for Applied Biology, in 2005.[1] Similarly, Zarontin capsules

were discontinued by Pfizer in 2007.[2] Syrup preparations of both brands are still

available (11).

Mechanism of action :

The succinimides resemble oxazolidinediones in that they suppress the 3/sec.

spike wave EEG pattern characteristic of absence seizures. They have a dippresant effect

on the motor cortex and elevate the firing threshold of cortical neurons. In addition, the

succinimides depress inhibitory mechanisms descending from the reticular formation.

Therapeutic uses:

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1) They are drugs of choice for simple absence (petit mal ) seizures.

2) It is also used as adjunctive treatment of psychomotor and other minor motor seizures.

Adverse reaction:

Common side effect are GI distress, Drowsiness, Ataxia and Dizziness

Other adverse effect include :

CNS: Nervousness, Euphria, Hyperactivity, Aggresivness, Confusion, Dipression,

Sleep disturbance.

Ocular: Myopia, Blurred vision, Photophobia, Periorbital oedema.

Haematologic: blood dyscrasias.

Dermatologic: Urticaria, Systemic lupuserythematosus.

Others : Vaginal bleeding, Hirsutisn and swelling of the tongue.(1)

11.5 Immunostilbines:

11.5.1 Carbamazepine:

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Carbamazepine is structurally related to tricyclic antidepressant and has

actions similar to phenytoine. It is a fairly toxic agent and used for the treatment of grand

mal and psychomotor seizures in patient refractory to other less toxic drug. (7)

Fig.No.9. Structure of Carbamazepine(12)

Availability:

Carbamazepine has been sold under the names Tegretol, Biston, Calepsin, Carbatrol,

Epitol, Equetro, Finlepsin, Sirtal, Stazepine, Telesmin, Teril, Timonil, Triaminic,

Epimaz, Carbama/Carbamaze (New Zealand), Amizepin (Poland), Degranol (South

Africa).(12)

Mechanism of action:

Carbamazepine increases latency, decreases responsivety and suppresses

after discharge in polysynaptic pathways associated with cortical and limbic function. It

also reduce post titanic potentiation in addition carbazepamine has anti cholinergic, anti

depressant and muscle relaxant actions.

Therapeutic uses :

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1) Treatment of psychomotor seizures.

2) Treatment of grand mal seizures with phenytoin.

3) Adjunctive treatment of mixed seizures or complex partial seizures.

4) Relief of pain associated with trigeminal neuralgia.

Adverse reactions :

Common side effect are Drowsiness, Ataxia , Dizziness, nausea.

Other adverse reaction include :

CNS: Confusion, Incordination, Speech disturbances, Visual hallucinations,

Dipression.

Dermatologic: sweating, urticaria, Dermatits.

GI: Abdominal pain, Xerostomia.

CVS: Hypotension, Arrhythmias, AV block, hypertension, Congestive cardiac failure.

Others: Abnormal liver function, Jaundice, Osteomalasia. (7)

11.6 Benzodiazepines:

11.6.1 Clonazepam: (Clonopin)

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Clonazepam is a benzodiazepine derivative with anticonvulsant, muscle relaxant, and

anxiolytic properties. It is marketed by Roche under the trade-names Klonopin in the

United States, and Ravotril in Chile. Other names like Rivotril or Rivatril are known

throughout the large majority of the rest of the world. Clonazepam is a chlorinated

derivative of nitrazepam[3] and therefore a nitrobenzodiazepine.

Fig. No. 10. Structure of Clonazepam(13)

Availability:

Clonazepam was approved in the United States as a generic drug in 1997 and is now

manufactured and marketed by several companies.Clonazepam is available in the U.S. as

tablets (0.5, 1.0, and 2 mg) and orally disintegrating tablets (wafers) (0.125, 0.25, 0.5,

1.0, and 2 mg). In other countries, clonazepam is usually available as tablets (0.5 and

2 mg), orally disintegrating tablets (0.25, 0.5, 1 and 2 mg) oral solution (drops,

2.5 mg/ml), as well as solution for injection or intravenous infusion, containing 1 mg

clonazepam per ampoule (e.g. Rivotril inj.).

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Klonopin 0.5 mg Klonopin 1 mg

Fig. No.11.Tablets Available In Market.

Mechanism of action

Clonazepam exerts its action by binding to the benzodiazepine site of the GABA

receptors, which causes an enhancement of the electric effect of GABA binding on

neurons, resulting in an increased influx of chloride ions into the neurons. This results in

an inhibition of synaptic transmission across the central nervous system.

Benzodiazepines, however, do not have any effect on the levels of GABA in the brain.

Clonazepam has no effect on GABA levels and has no effect on gamma-aminobutyric

acid transaminase. Clonazepam does however affect glutamate decarboxylase activity. It

differs insofar from other anticonvulsant drugs it was compared to in a study.

Benzodiazepine receptors are found in the central nervous system but are also found in a

wide range of peripheral tissues such as longitudinal smooth muscle-myenteric plexus

layer, lung, liver and kidney as well as mast cells, platelets, lymphocytes, heart and

numerous neuronal and non-neuronal cell lines.

Pharmacology

Clonazepam's primary mechanism of action is via modulating GABA function in the

brain, via the benzodiazepine receptor, which, in turn, leads to enhanced GABAergic

inhibition of neuronal firing. In addition clonazepam decreases the utilization of 5-HT

(serotonin) by neurons and has been shown to bind tightly to central type benzodiazepine

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receptors. Because of its strong anxiolytic, anticonvulsant and euphoric properties, it is

said to be among the class of "highly potent" benzodiazepines. The anticonvulsant

properties of benzodiazepines are due to enhancement of synaptic GABA responses and

inhibition of sustained high frequency repetitive firing.

Benzodiazepines, including clonazepam, bind to mouse glial cell membranes with high

affinity. Clonazepam decreases release of acetylcholine in cat brain and decreases

prolactin release in rats. Benzodiazepines inhibit cold-induced thyroid stimulating

hormone (also known as TSH or thyrotropin) release. Benzodiazepines acted via

micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly

inhibit depolarization-sensitive calcium uptake in experimentation on rat brain cell

components. This has been conjectured as a mechanism for high-dose effects on seizures

in the study.

Clonazepam therapeutically used as :

Epilepsy

Anxiety disorders

Panic disorder

Initial treatment of mania or acute psychosis together with firstline drugs such as

lithium, haloperidol or risperidone

Hyperekplexia

Bruxism

Restless legs syndrome and some other forms of parasomnia ; Rapid eye

movement behavior disorder (low doses).

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Side-effects

Common

Drowsiness

Impairment of cognition, judgment, or memory

Irritability and aggression

Psychomotor agitation

Lack of motivation

Loss of libido

Impaired motor function

o Impaired coordination

o Impaired balance

o Dizziness

o Diarrhea

Cognitive impairments

o Increased sleepwalking (If used in treatment of sleepwalking)

o Auditory hallucinations

o Short-term memory loss(13)

11.7 Valproic acid derivatives :

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11.7.1 Valproic acid (sodium valproate)

It is branched chain aliphatic carboxylic acid with a broad spectrum anti

conversant action. It is more potent in blocking PTZ seizures than in modified maximal

electroshock(14)

Fig. No. 12. Structure of Valproic Acid(15)

Availability Form:

Branded products include:

Depakene (Abbott Laboratories in U.S. & Canada)

Convulex (Pfizer in the UK and in South Africa)

Deprakine (Sanofi Aventis Finland)

Epival (Abbott Laboratories U.S. & Canada)

Epilim (Sanofi Synthelabo in Australia)

Encorate (Sun Pharmaceuticals in India)

Valcote (Abbott Laboratories in Argentina)(15)

Mechanism of action :

Valproate appears to act by multiple mechanisms ……

1) A phenitoin like frequency dependant prolongation of sodium channel inactivation.

2) Weak attenuation of Ca2+ mediated current (Ethosuximide like).

3) Augmentation of release of inhibitory transmitter GABA by inhibiting its degradation

(by GABA transaminase) as well as probably by increasing its synthesis from

glutamic acid however, responses to exogenously applied GABA are not altered.

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Therapeutic uses :

1) Valproic acid is the drug of choice for absence seizures.

2) Myoclonic and atonic seizures control is often incomplete, but valproate is the drug

of choice.

4) Valproate has some prophylactic efficacy in migraine.

Adverse reaction :

The toxicity of valproate is low. Anorexia, vomiting, heart burn are common . The

drowsiness, atexia, triemor are dose relayed side effect. Alopecia, Curling of hairs and

increased bleeding tendency has been observed. The rashes and thrombocytopenia are

infrequent hypersensitivity phenomena. Used during pregnancy, It has spina bifida and

other neural tube defects in the offspring. (14)

11.8 Other unrelated anticonvulsants :

11.8.1 Primidone (mysoline):

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Primidone is an anticonvulsant of the pyrimidinedione[4] class whose active metabolites,

phenobarbital (major) and phenylethylmalonamide (PEMA) (minor), are also

anticonvulsants. It is used mainly to treat complex partial, simple partials, generalized

tonic-clonic seizures, myoclonic, akinetic seizures and since the 1980s it has been a

valuable alternative to propranolol in the treatment of essential tremor. Unlike other

anticonvulsants such as carbamazepine and valproic acid, primidone is rarely used in the

treatment of bipolar disorder or any other psychiatric problem. It is also not widely used

in treatment of neuropathic pain, trigeminal neuralgia, or migraine. Primidone has been

occasionally used to treat long QT syndrome, cerebral palsy, and athetosis.

Fig. No.13. Structure of Primidone(16)

Available forms

Primidone is available as a 250 mg/5mL suspension, and in the form of 50 mg, 125 mg,

and 250 tablets. It is also available in a chewable tablet formulation in Canada.

It is marketed as several different brands including:

Mysoline (Canada, Ireland, Japan, the United Kingdom, and the United States,

Prysoline (Israel, Rekah Pharmaceutical Products, Ltd.).

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Primidone has been available in the United States as a generic drug from Lannett since

1978.

Mechanism of action

The exact mechanism of primidone's anticonvulsant action is still unknown after over

fifty years. It is believed to work via interactions with voltage-gated sodium channels

which inhibit high-frequency repetitive firing of action potentials. The effect of

primidone in essential tremor is not mediated by PEMA.

Therapeutic uses :

, primidone is approved for adjunctive (in combination with other drugs) and

monotherapy (by itself) use in generalized tonic-clonic seizures, simple partial seizures,

and complex partimple partial seizures, and myoclonic seizures. In juvenile myoclonic

epilepsy. it is a second-line therapy, reserved for when the vaporizes and/or lamotrigine

do not work and when other second-line therapies—[acetazolamid work either].

Adverse Effects

Primidone can cause drowsiness, listlessness, ataxia, visual disturbances, nystagmus,

headache, and dizziness. These side effects are the most common, occurring in more than

1% of users. Transient nausea and vomiting are also common side effects.

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Fig. No. 14. Dupuytren's contracture of the fourth digit (ring finger).

Dupuytren's contracture, a disease of the fasciae in the palm and fingers that permanently

bends the fingers (usually the little and ring fingers) toward the palm, was first noted to

be highly prevalent in epileptic people in 1941 by a Dr. Lund, fourteen years before

primidone was on the market. Lund also noted that it was equally prevalent in individuals

with idiopathic and symptomatic epilepsy and that the severity of the epilepsy did not

matter. However, only one quarter of the women were affected vs. half of the men.

Less than 1% of primidone users will experience a rash. Compared to

carbamazepine, lamotrigine, and phenytoin, this is very low. The rate is comparable to

that of felbamate, vigabatrin, and topiramate. Primidone also causes exfoliative

dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

Fig. No. 15. Radiograph of a rickets sufferer

Primidone, along with phenytoin and phenobarbital, is one of the anticonvulsants most

heavily associated with bone diseases such as osteoporosis, osteopenia (which can

precede osteoporosis), osteomalacia and fractures. The populations usually said to be

most at risk are institutionalized people, postmenopausal women, older men, people

taking more than one anticonvulsant, and children, who are also at risk of rickets.

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Primidone is one of the anticonvulsants associated with anticonvulsant hypersensitivity

syndrome, others being carbamazepine, phenytoin, and phenobarbital. This syndrome

consists of fever, rash, peripheral leukocytosis, lymphadenopathy, and occasionally

hepatic necrosis. (16)

12. CONCLUSION

Many people with epilepsy lead productive and outwardly normal lives. Many

medical and research advances in the past two decades have led to a better understanding

of epilepsy and seizures than ever before. Advanced brain scans and other techniques

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allow greater accuracy in diagnosing epilepsy and determining when a patient may be

helped by surgery.

More than 20 different medications and a variety of surgical techniques are now

available and provide good control of seizures for most people with epilepsy. Other

treatment options include the ketogenic diet and the first implantable device, the vagus

nerve stimulator. Research on the underlying causes of epilepsy, including identification

of genes for some forms of epilepsy and febrile seizures, has led to a greatly improved

understanding of epilepsy that may lead to more effective treatments or even new ways of

preventing epilepsy in the future.

13. REFERENCE

1) http://en.wikipedia.org/wiki/epilepsy

2) http://www.patiant.w.uk/health/epilepsy-A Genaral-Introduction.htm

3) http://www.kidneeds.com/diagnostic_catagories/articles/epilepsy definition.com

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4) http:/www.epilepsy.com/epilepsy/history

5) Bodhankar S. L.,Vhywahare N. S. “pathophysiology” Nirali prakashan Pragati book

PVT. Ltd. Page no.3.4-3.5

6) http://www.epilepsiemuseum.de/alt/introen.html

7) Barar.F,S,K. “Essentials of Pharmacotherapeutics”, Chand S. and Company LTD.,

Ram Nagar,New Delhi,Page no.96-101

8) http://en.wikipedia.org/wiki/phenobarbital

9) http://en.wikipedia.org/wiki/phenytoin

10) http://en.wikipedia.org/wiki/trimethadione

11 ) http://en.wikipedia.org/wiki/ethosuximide

12) http://en.wikipedia.org/wiki/carbamazepine

13) http://en.wikipedia.org/wiki/clonazepam

14) Tripathi K, D. “Essentials of Medical Pharmacolgy” Jaypee Brothers medical

Publisher, 6th Edition, Page no. 407.

15) http://en.wikipedia.org/wiki/valproic acid

16) http://en.wikipedia.org/wiki/primidone

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