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Epilepsy is serious neural disorder that causes frequent
seizures.1 Seizures are physical changes that
can be observed during or after abnormal bursts of electrical activity in the
brain that alters brain function..2 Epilepsy
manifestation can be at any age, although it is more common in children and in adults
over 60.3 It is a lifelong disease, but with
the correct treatment, it gets better over time.3

 

HISTORY

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Epileptic seizures are caused by the disruption in the
electrical activity of the basic and most primitive components of the nervous
system.4 A logical conclusion can be drawn
from this observation that epileptic seizures may have existed in the earliest
stages of the human evolution.4

Scientists have associated prehistoric trephined skulls as a
possible method by which primitive physicians attempted to solve epilepsy.5 Many of these trephined skulls at
the time of their discovery had undergone bone apposition signifying survival
over a considerable amount of time6. Trephined skulls with other
fractures were related to traumas and the fracture-free trephined skulls were
said to belong to epileptic patients since no other explanation of the
intervention has been proposed.6 Proving this theory is almost
impossible since no literature has yet been found on it. 6 Literature however indicates that
the early scientists predicted that seizures were as a result of brain wounds
and many thought making holes in the skull could solve the issue7. This can be seen in the earliest
Hippocratic texts. Hippocrates knew epilepsy as a disease which originates in
the brain and in the second century, one of the early surgeons, Aretaeus the
Cappadocian suggested trephination as a remedy for the condition.7

As seen above, scientists tried to use rational thinking to
approach and treat epilepsy; the total contrast of the religious perspective.8 Many religious and superstitious
people believed epilepsy was a disorder sent by gods.8 Evidence of this can be found in a
Babylonian cuneiform tablet which directly equated epilepsy and associated
seizures to the influence of evil spirits.8

 

Even in the 21st century, there is still evidence that the confusion
in the varying explanations for epilepsy, the religious and scientific, still
exists with numerous people not knowing who to believe.9 This confusion however never affected
Hippocrates and in his famous pamphlet on “The sacred disease”, written around
450 BC, he was strongly against the religious explanations.9

 

EARLIER
CLASSIFICATION OF EPILEPSY

Two main historical classifications were recorded; One by
Hippocrates and the other by Galenus.10 Hippocrates classified according to
the multiplicity of natural causes for example climate and moon phases.7,10 Galenus however has an alternative
approach.10 Although he agreed that all
seizures had something to do with the brain, he believed it was not always the
primary source of the pathology.10 He further divided seizures into
idiopathic and sympathetic.10 The prior referred to conditions
originating from the brain and the latter, later renamed symptomatic did not
originate from the brain.10 Galenus’ classification is still
being used even though they have slightly different definitions now.10

 

CURRENT
CLASSIFICATION

 

BASIC
ANATOMY OF THE NEURON

Since it has been established that epilepsy is a
neurological disorder, a basic understanding of neuroanatomy would better
enable us to dissect the issues.

The nervous system is one of the systems in the human body.
The basic working unit of the nervous system is the neuron.11 The brain has as many as 100
billion neurons.11 A classic neuron has a cell body
and processes: an axon and dendrites.11 The cell body, also known as the
perikaryon is the site from which the axon and dendrites arise.11 Dendrites receive stimuli from the
surroundings of the neuron and sends impulses to the cell body while the axon
transmits the impulses from the cell body to the surroundings. Neurons are
classified into unipolar, bipolar and multipolar based on the number of
processes it has on its cell body. This classification is morphology based.
Others classify neurons based on the neurotransmitters they release. A neuron
axon may be myelinated or not and this affects the speed at which impulses are
transmitted. The conduction across a myelinated neuron is said to be saltatory.
The cell body has a plasma membrane, a nucleus and other organelles in its
cytoplasmic.11,12 
Neurons do not undergo division after initial formation hence their
inability to undergo repair.11

 

 

BASIC
NEUROPHYSIOLOGY OF THE NEURON

As stated earlier, the neuron transmits impulses. It does so
through its excitable plasma membrane which is an 8nm thick phospholipid
membrane.13 This membrane has proteins which
act as ion channels which allow movement of ions.

 

At rest, the neuron has a resting membrane potential of
about -80mV. 13 When the neuron gets excited and
the threshold is reached, the membrane becomes permeable to sodium ions in a
process called depolarization. The influx of the sodium ions causes an action
potential to occur during an overshoot. Repolarization occurs after where there
is the efflux of potassium ions. This process allows the transmission of
impulses down the neuron.13

At the terminal end of the axons, the impulse flowing causes
the influx on calcium ions into the axon. This leads to subsequent exocytosis
of the neurotransmitter stored in vesicles at the terminal.13

 

PATHOGENESIS
OF EPILEPSY

Science is yet to fully understand the various mechanisms by
which epilepsy develops. Also known as epileptogenesis, the development of epilepsy
can be said to be the process by which a normal neuron becomes chronically
hyper excitable.14–16 This can occur when there is an
injury to the brain slowly reducing the threshold for seizures. For a long
time, the scientific community believed that epilepsy was as a result of a
local area injury15. But current technology is pointing
more towards multiple hyper-excitable networks even though the local area
hypothesis is still relevant.17

 

These issues may be as a result of idiopathic and genetic
causes. A loss of inhibitory signals or an overstimulation of neurons and
genetic mutations affecting ion channels can lead to the hyper excitable
networks.15

 

 

 

TREATMENT
OPTIONS

As compared to the historical trephination approach of
treating epilepsy, current scientific research has led us to a wide range of
drugs and surgical procedures used to manage and treat epilepsy. The drugs are
generally known as anti-epileptic drugs.18 They are also called
anticonvulsants due to their ability to treat other forms of seizures. More
research is being carried out to better the drugs used. Surgery is used in
patients with severe epilepsy. The various methods will be further discussed in
the subsequent paragraphs.

 

ANTI-EPILEPTIC
DRUGS

There are many types of anti-epileptic drugs used in the
management of epilepsy. Out of the anti-epileptic drugs, some are more
effective and therefore are preferred. Some new drugs which are still
undergoing evaluation to determine its long term effects are being employed.19 Drugs in their various clinical trial
phases are also being researched.20 The various classes of
anti-epileptic drugs and how they work will be discussed below.

 

 

ANTI-SEIZURE BARBITURATES

 

A barbiturate is a drug that acts by slowing down brain
activity.18,21 The slowing down of neural activity
enables barbiturates to have anti-epileptic properties. It also has a sedative
effect.18 Through research, it has been
observed that phenobarbital has a maximal anti-epileptic effect. The mechanism
of action of phenobarbital involves the increased effect of the inhibitory neurotransmitters,
GABA.21 It is an agonist of the GABA
receptors and this allows the GABA response.21 This inhibits neuronal action
preventing over firing of the neurons. Phenobarbital can be obtained after the
metabolism of a drug such as primidone.21 It having a good anti-epileptic
effect also came with the sedative effect.21 Due to this side effect, many
physicians do not prefer this drug. Ataxia, irritability and confusion are all
side effects of the drug. Mephobarbital is also an anti-epileptic barbiturate
and functions similarly to phenobarbital.21

 

HYDANTOINS

Hydantoins are anticonvulsants that are used to treat a wide
range of seizure types. The most common anti-epileptic drug of the hydantoins
class is phenytoin. It is known to be effective in partial seizures,
tonic-clonic. It is however inactive in absence seizure.21 Hydantoins and barbiturates are
quite similar in structure and chemical properties. Phenytoin works by
inhibiting the firing of neuronal action potentials.22 This does so by delaying the sodium
ion recovery following an action potential.22 This increases the refractory
period of the action potential thereby reducing the transmission of impulses.22 This in turn greatly reduced the
probability of an epileptic attack.

 

Phenytoins have a wide range of side effects. A low dose can
lead to nystagmus, rare hematological toxicity and ataxia.19 A relatively higher dose can lead
to confusion and intellectual dysfunction.19 Sedation is not a side effect. When
used during pregnancy, the drug can lead to teratogenic effects on the fetus.
When it is administered with the intravenous route, it could result in cardiac
arrhythmia. Gingival hypertrophy is also a possibility.23 Other hydantoins are ethotoin and
peganone.24

 

TOPIRAMATE

Topiramate is an anti-epileptic drug used for patients between
the ages of 2 to 16 with partial-onset seizures.16 It is also effective in seizures associated
with Lennox–Gastaut syndrome.16

 

The anti-seizure mechanism of topiramate is yet to be
determined. Research however indicates that a certain concentrations, the drug blocks
sodium channels and interferes in the activities of GABA by acting as GABA
receptor agonist. 16 They enhance the work of GABA by
binding to its receptor. It also inhibits the carbonic anhydrase enzyme.16

 

Topiramate can cause anorexia, anxiety and loss of appetite.
Confusion, dizziness and diarrhea are adverse effects of the drug.16

 

IMINOSTILBENES

The most commonly used iminostilbenes is carbamazepine.25 It is so common and effective that
it is used as the primary drug for the treatment of both tonic-clonic and
partial seizures.25 It works similarly to phenytoins.
There is a reduction in the recovery period of the sodium channels thereby
extending the refractory period.25 This reduces the firing rate of the
neuron. Also 10,11-epoxycarbamazepine, which is the metabolite of carbamazepine
plays a role in limiting the firing of action potentials.26

 

The side effects of carbamazepine vary with dosage. Acute
toxic effects of the drug include hyponatremia, hepatotoxicity and rash.19 The long term side effects include leucopenia
and weight gain.19 This drug has other beneficial uses
including the treatment of neuropathic pain and manic-depressive illness.19 Other drugs in the iminostilbenes
class are Oxcarbamazepine and Eslicarbamazepine although the latter is still in
the developmental stages. 25

 

SUCCINIMIDES

The most commonly used succinimide is ethosuximide.27 It is used in the treatment of
absence seizures and seizures induced by pentylenetetrazol.19 Considering the pharmacokinetics of
the drug, it can be said to be well absorbed with a plasma half-life of about
60 hours.28

 

This is how the drug works: Ethosuximide reduces the
impulses from calcium ion channels in the thalamocortical neurons.16,28 This results in the reduction of
the firing rate of neuron.28 The drug has a number of side
effects including nausea, vomiting and dizziness.28 It also exerts a central effect
resulting in euphoria and inability to focus.28 Adverse effects include
Parkinsonian syndrome and bradykinesia.28 Another drug of this class is
methsuximide, but is less widely used.19

 

VALPROATE(VPA)

Valproic acid and sodium valproate are all forms of
valproate that is used in the prevention of seizures. It is employed in the
treatment of generalized seizures, partial seizures and complex absence
seizures.16 
Valproic acid is also used to treat bipolar disorders, migraine,
headache and other psychological conditions.16

Valproic acids mechanism of action is diverse and its anti-epileptic
mechanism is yet to be identified.16 It is however believed that the drug
increases the GABA concentration in the brain.16

 

The side effects of valproic acid include hepatic damage and
pancreatitis.16 When taken during pregnancy, it has
been found to be associated with spinal bifida and other developmental
anomalies due to its teratogenicity properties.16 Using this drug can cause the
patient to be suicidal and experience tremors.16  It also exerts a central effect by acting on
the central nervous system causing ataxia.16

 

 

CURRENT RESEARCH & PROSPECTIVE AGENTS

Pharmacogenomics

Recent
scientific research in the U.S. and Europe are primarily pharmacogenomics.19 This involves the search for biomarkers
in individual genes that make a person more susceptible to epilepsy. 29 Pharmacogenomics can also predict the
severity and therapeutic response of epilepsy.29 An individual-based treatment, specific
to the particular gene responsible for epilepsy is going to be the most
effective way of managing this disease.

 

The
existing drugs are currently ineffective in 1 out of every 3 cases.30 Newer drugs such as Lacosamide,
Rufinamide, Perampanel and many others have been found to be more effective in
the management of epilepsy.30 Ganaxolone, another anti-epilepsy drug is
still under review.30

All
these drugs vary in their mode of action.

 

SURGICAL OPTIONS

The primary aim of epilepsy surgeries is to pin-point the
region of the brain responsible of the epilepsy.31 A complete removal of this area is goal of this
treatment. Surgeons are very careful and avoid causing cognitive or neurologic
deficit.31 In situations where the epilepsy-causing lesion
is in an important part of the brain, the surgery is stopped in order to
prevent irreversible neurologic impairment.31 

Temporal lobectomy is the most common surgical treatment.31 Corpus callosotomy is done when the seizures are
observed to spread from one hemisphere to the other. Implantation of deep brain
stimulators is also effective in the treatment of epilepsy. 31

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