IV-Pharm.D, Pharmacotherapeutics-III, pathophysiology and treatment of epilepsy

1. PATHOPHYSIOLOGY &
MANAGEMENT OF EPILEPSY
T. SOUJANYA
PHARM.D

2. DEFINITION:
Epilepsy is a common neurological condition characterized by recurrent seizures (that usually
occur unpredictably), loss of consciousness with or without body movements. It is derived from a
Greek word Epi-upon, Leptos-seizures. It is also known as seizure disorder.
Seizure is a phenomenon characterized by an excessive, hypersynchronous discharge of
cortical neuronal activity (measured by EEG), featured by disturbances in consciousness, sensory
motor systems, subjective well-being and objective behaviour.

3. EPIDEMIOLOGY:
• Incidence of epileptic seizures is around 50 cases per 1,00,000 of the
population. Around 50 million people worldwide have epilepsy.
• Higher risk observed in extremes of age.
• Prevalence in European countries is 0.5%, prevalence in developing countries is
higher due to parasitic illnesses like cysticercosis.

4. ETIOLOGY:
In 20% cases cause can be determined, rest 72% are idiopathic (of unknown cause).
1. Inherited/genetic causes: Single gene mutation (<2%), multiple genes +
environmental factors, genetic disorders (down, dravet etc.), >200genes have the
capability of causing epilepsy.
2. Acquired causes: Head trauma, neurosurgery, cerebrovascular disease, infections
(meningitis, influenza, toxoplasmosis, mumps, measles, syphilis), metabolic
disorders (such as hypoglycemia and hypocalcemia), intracranial neoplasms.
3. Congenital causes: Inborn error of metabolism.
4. Withdrawal of drugs: Alcohol, benzodiazepines, barbiturates, antiepileptics.
5. Drugs that induce seizures: Some of the antibiotics, antidiabetics, anesthetics,
antimalarials, antispastics, antidepressants, antipsychotics, mood stabilizers.

5. PATHOPHYSIOLOGY:
 Neurons are inter-connected in a complex network. Each individual neuron is linked
with hundreds of other neurons via synapses.
 Neurons discharge electrical current and neurotransmitters are released at synaptic
levels and permits inter-communication.
 Neurotransmitters are of two types: Inhibitory neurotransmitters (INT) and Excitatory
neurotransmitters (ENT).
 Inhibitory neurotransmitters (GABA): GABA (Gamma amino butyric acid) acts on ion
channels and increases chloride outflow & decreases chances of action potential
formation.
 Excitatory neurotransmitters (aspartate, glutamate): Aspartate and glutamate allows
sodium and calcium influx which paves way for action potential formation.

6. CONTD…
 In this manner, information is conveyed, transmitted and processed throughout the CNS.
Seizures occur due to the imbalance between the above inhibition and excitation.
 A normal neuron discharges repetitively at low baseline frequencies. If neurons are damaged,
injured/suffer a chemical/metabolic insult, the changes in discharge pattern develops.
 During epilepsy, regular low frequency discharges are replaced by bursts of high frequency
discharges followed by periods of inactivity.
 A single neuron discharging in an abnormal manner is usually not clinically significant. But
when a whole population of neurons discharge synchronously in an abnormal manner,
epileptic seizure is precipitated. This abnormal discharge may remain localized or it may
spread to adjacent areas, recruiting more neurons as it expands.

7. CONTD…
Abnormalities in ion channel (Na+, K+, Ca+2) or
decreased INT activity/inactivation of INT activity
Increased ENT activity
Rhythmic & repetitive hypersynchronous discharge of neurons
Seizures focus
Seizures
Repetitive seizures
Epilepsy

8. TYPES OF EPILEPSIES INCLUDING CLINICAL
MANIFESTATIONS:
Based on International League Against Epilepsy (ILAE), they are classified into:
1. Partial seizures (focal seizures)
2. Generalized seizures

9. 1. PARTIAL/FOCAL SEIZURES (SEIZURES BEGIN
LOCALLY):
It is the most common type of seizures, localized to a neuronal system, limited to part of one
cerebral hemisphere. Types of partial seizures include:
a) Simple partial seizures (without impairment of consciousness):
It is not associated with loss of consciousness. It is associated with motor signs (convulsive
jerking, lip smacking), sensory and somatosensory signs (paresthesias, auras), autonomic signs
(sweating, flushing, behavioural manifestations (dysphasia, structured hallucinations).
b) Complex partial seizures (with impairment of consciousness):
It is associated with impaired consciousness, impairment proceeds/follows seizures. It is also
associated with purposeless behaviour, glassy stare, aimless walking, hallucinations (visual,
auditory), aggressive behaviour.
c) Secondary generalized seizures: Partial onset evolving to generalized tonic-clonic seizures.

10. 2. GENERALIZED SEIZURES:
a) Absence seizures:
It is also known as ‘petit mal’ seizure. It happens exclusively in childhood and early
adolescence. It is associated with alterations of consciousness, staring with occasional
eye-blinking, enuresis. These attacks last only for few seconds and often go
unrecognized.
b) Myoclonic seizures:
It is also known as ‘bilateral massive epileptic myoclonus’. It is associated with
involuntary, rhythmic jerking of facial, limb/trunk muscles.
c) Clonic seizures: It is associated with sustained muscle contractions, altering with
relaxation.
d) Tonic seizures: It is associated with sustained muscle contractions (stiffening).

11. CONTD…
e) Generalized tonic-clonic seizures:
It is also known as ‘grand mal’ seizure. It leads to sudden loss of conscious, the
individual becomes rigid and falls to the ground. It is associated with interrupted
respirations, extended legs, rapid bilateral muscle jerking, heavy salivation, tongue
biting, headache, confusion. It lasts for one minute.
In some cases, grand mal seizure occurs repeatedly with no recovery of
consciousness between attacks, leading to state known as ‘status epilepticus’.
f) Atonic seizures:
It is also known as ‘drop attack’. It occurs mainly in children. It is associated with
sudden loss of postural tone and the individual falls to the ground.

12. RISK FACTORS:
1. Sleep deprivation.
2. Missed doses of anti-epileptic drugs (AEDs) in treated patients.
3. Alcohol withdrawals, recreational drug misuse.
4. Physical and mental exhaustion.
5. Flickering lights (includes TV, computer screens; comes under generalized
epilepsy syndrome).
6. Intercurrent infections.
7. Metabolic disturbances.
8. Uncommon reasons like loud noises, very hot baths etc.

13. DIAGNOSIS:
• Neurological examination/neuropsychological tests: Doctor tests for behavior,
motor abilities, mental function and other symptoms.
• Medical history.
• Genetic testing.
• Electroencephalogram (EEG): Tracks electrical signals from the brain.
• CT scan, MRI scan: Used to detect abnormalities in brain (tumors, bleeding,
cysts).

14. CONTD…
• fMRI: Used to measure the changes in blood flow.
• PET (Positron Emission Tomography): Used to visualize active areas of brain and
detect abnormalities.
• SPECT (Single Photon Emission Computerized Tomography): Used when MRI
and ECG did not pinpoint the location in brain where the seizures are
originating.
• SISCOM (Subtraction Ictal SPECT Categorized to MRI): A form of SPECT test
which may provide even more detailed results.

15. TREATMENT:
Goals of treatment:
To control and reduce seizure frequency.
To focus on minimum possible dosage of AEDs
To minimize ADRs associated with therapy.
To ensure patient medication compliance.
To ensure that the person lives a normal life as far as possible.
To reduce morbidity and mortality, to improve quality of life.

16. NON-PHARMACOLOGICAL TREATMENT:
1) Ketogenic diet:
Ketogenic diet containing high content of fats, followed by proteins, carbohydrates
were found to reduce seizures in some children.
Side effects: Constipation, slow growth because of nutritional deficiencies, build up of
uric acid in blood, kidney stones.
2) Surgeries:
• Medications can control seizures in most people with epilepsy, but they don’t work
for everyone.
• About 30% of people taking the drugs can’t tolerate the side effects. In such cases,
brain surgery may be an option.

17. CONTD...
i) Lobe resection:
• The lobe within which seizures focus is located is cutoff.
• Extemporal resection involves brain tissue from areas outside of the temporal
lobe.
ii) Lesionectomy:
• This surgery removes brain lesions, areas of injury or defect like a tumor or
malformed blood vessel that cause seizures. Seizures usually stop once the
lesion is removed.

18. CONTD…
iii) Corpus callostomy or split-brain surgery:
• Corpus callosum is a band of nerve fibers connecting the two halves (called
hemispheres) of the brain. In this operation, corpus callosum is cut off and the
communication between hemispheres is prevented, no spread of seizures from
one side to other side.
• It works best for people with extreme forms of uncontrollable epilepsy who have
intense seizures that can lead to violent falls and serious injury.
iv) Functional hemispherectomy:
• Entire hemisphere or half of the brain is removed. It is mostly used for children
younger than 13 who have one hemisphere that doesn’t work like it should.

19. CONTD…
v) Multiple subpial transection (MST):
• This procedure can help to control seizures that began in areas of the brain that
can’t be safely removed.
• The surgeon makes a series of shallow cuts in the brain tissue. These cuts
interrupt the flow of seizure impulse but don’t disturb normal brain activity.
vi) Vagus nerve stimulation (VNS):
• A device implanted under skin sends an electronic jolt to the vagus nerve, which
controls activity between brain and major internal organs. It lowers seizure
activity in some people with partial seizures.

20. CONTD…
vii) Responsive neurostimulation device (RNS):
• Doctor’s implant a small neurostimulator in skull, just under your scalp. They link
it to one or two wires that they place either in the part of brain where seizures
start or on brain surface.
• This device detects abnormal electrical activity in the area and sends an electric
current.
• It can stop the process that leads to a seizure.

21. PHARMACOLOGICAL TREATMENT:
Classification of anti-epileptic drugs:
1. Barbiturates: Phenobarbitone
2. Hydantoins: Phenytoin, Fosphenytoin
3. Succinimide: Ethosuximide
4. Benzodiazepines: Clonazepam, Diazepam, Lorazepam, Clobazam
5. Deoxybarbiturate: Primidone
6. Iminostilbenes: Carbamazepine, oxcarbazepine
7. Aliphatic carboxylic acid: Valproic acid (valproate sodium), Divalproex
8. Phenyl triazine: Lamotrigine
9. Cyclic GABA analogues: Gabapentin, Pregabalin
10. Newer drugs: Topiramate, Zonisamide, Levetiracetam, Vigabatrin, Tiagabine, lacosamide

22. CONTD…
1. Barbiturates (phenobarbitone):
MOA: Phenobarbitone acts on GABA(A) receptors and enhances the action of
inhibitory neurotransmitters (e.g. GABA) and suppresses the excitatory
neurotransmitters (Ach), opens Cl- ion channels and decreases the seizures.
ADRs: hyperactivity, behavioural changes, metabolic bone disorders, ataxia,
unsteadiness, blood, dyscrasias, sedation, headache, respiratory depression (when
given i.v.)
Dose: Phenobarbitone- 60mg OD (child 3-6mg/kg/day), 100-200mg i.m./i.v.
Uses: It is used in the treatment of febrile convulsions, neonatal seizures, status
epilepticus (SE), generalized tonic-clonic seizures.

23. CONTD…
2. Hydantoins (phenytoin):
MOA: Phenytoin acts by blocking the voltage-dependent sodium channels in post
synaptic neuron and reduces the influx of sodium ions across cell membrane and also
reduces high-frequency neuronal discharge/inhibits the action potential of neurons.
ADRs: Gingival hyperplasia, hirsutism, megaloblastic anaemia, diabetes mellitus, visual
blurring, ataxia, behavioural changes, foetal hydantoin syndrome (drug when used in
pregnancy causes cleft lips, microcephaly in neonates).
Dose: 100-200mg BD (child 5-8mg/kg/day) oral, 25mg/min slow i.v. injection (max
1.0g).
Uses: It is mainly used in the treatment of generalised tonic-clonic seizures, status
epilepticus, partial seizures etc.

24. CONTD…
3. Succimides (ethosuximide):
MOA: Ethosuximide acts by blocking the voltage-sensitive T type Ca+2 channels in
thalamic neurons (the T type Ca+2 current is thought to provide a pacemaker
current in thalamic neurons responsible for generating the rhythmic cortical
discharge of an absence attacks) and reduces the low-threshold (T-type) current.
ADRs: GI disturbances, dizziness/drowsiness, unsteadiness, hiccoughs etc.
Dose: 500mg/day (20-30mg/kg/day)
Uses: It is commonly used in the treatment of absence seizures.

25. CONTD…
4. Benzodiazepines (clonazepam, diazepam, lorazepam, clobazam):
MOA: Benzodiazepines work by increasing the efficiency of a natural brain chemical,
GABA, to decrease the excitability of neurons. Binding of benzodiazepines to GABAA
receptor complex promotes binding of GABA, which in turn increases of chloride ions
across the neuronal cell membrane, resulting in inhibition of neuronal firing.
ADRs: Blood disorders, respiratory depression, hypotension, jaundice etc.
Dose: clonazepam-1.5mg/day, diazepam- 4-40mg PO or 5-10mg IV, lorazepam-
10mg/day or 0.044mg/kg/day IV, clobazam- 10-20mg/day (max 60mg/day).
Uses: They are used in the treatment of panic disorder, seizure disorder, status
epilepticus, pre-operative medication, insomnia associated with anxiety etc.

26. CONTD…
5. Deoxybarbiturate (primidone):
MOA: Primidone after entering into the body metabolized by the liver to
phenobarbitone (active anticonvulsant) and shows anti-epileptic activity.
ADRs: Slow or slurred speech, loss of control of bodily movements, vertigo,
blurred vision, skin rashes, loss of appetite etc.
Dose: Primidone- 250-500mg BD (child 10-20mg/kg/day)
Uses: It is generally used in combination with other anticonvulsants to treat
generalised tonic-clonic seizures (GTCS), partial epilepsy.

27. CONTD…
6. Iminostilbenes (carbamazepine, oxcarbazepine):
MOA: Carbamazepine is a tricyclic compound. It has good anti-seizure activity; its
mechanism of action and anti-epileptic action are similar to phenytoin.
ADRs: Drowsiness, vertigo, nausea & vomiting, ataxia, hepatitis, pancreatitis,
arrhythmia, hyponatremia, rashes, CHF etc.
Dose: Carbamazepine- 200-400mg/day (children 15-30mg/kg/day);
oxcarbazepine- 300-600mg BD.
Uses: They are mainly used in the treatment of trigeminal neuralgia, generalized
tonic-clonic seizures, bipolar disorder, simple & complex, partial seizures etc.

28. CONTD…
7. Aliphatic carboxylic acids (valproic acid, divalproex):
MOA: Valproic acid enhances the level of GABA (reduces the metabolism of
GABA), blocks the sodium channels which decreases low threshold Ca+2 in
thalamus and reduces seizure activity.
ADRs: Stevens-Johnson syndrome (SJS), pancreatitis, thrombocytopenia, increased
bleeding time, encephalopathy, dementia etc.
Dose: Valproic acid- 200-800mg; divalproex- 250-500mg
Uses: Valproic acid is mainly used as a single drug therapy for treating patients
with a combination of generalized tonic-clonic, absence or myoclonic seizures.

29. CONTD…
8. Phenyl triazines (lamotrigine):
MOA: Lamotrigine inactivates/inhibits voltage-sensitive Na+ channels and inhibits
the release of glutamate and aspartate (excitatory neurotransmitters) and
therefore reduces the seizure activity.
ADRs: Ataxia (inability to coordinate voluntary muscle movements), diplopia,
unsteadiness, skin rash (Steven-Johnson syndrome) etc.
Dose: Lamotrigine- 25mg/day for initial 14 days; then 50mg/day for next 14 days;
then increase dose to 50-100mg/day for next 7-14 days.
Uses: Lamotrigine is commonly used in the treatment of bipolar disorders and
generalized tonic-clonic seizures.

30. CONTD…
9. Cyclic GABA analogues (gabapentin, pregabalin):
They are structurally similar to GABA, but has no effect on binding, uptake/
degradation of GABA.
MOA: These drugs act by modulating voltage sensitive calcium channels and
decreases the entry into presynaptic neurons, decreases glutamate release which
in turn decreases neuronal excitability.
ADRs: Steven-Johnson syndrome (SJS), acute renal failure, hepatitis, primary AV
block, CHF etc.
Dose: Gabapentin- initial dose 300mg OD (max 300-600mg); Pregabalin-75-
150mg BD (max 600mg/day).

31. DRUGS OF CHOICE FOR SPECIFIC-SEIZURE
DISORDERS:
Seizure type First line drugs Alternative drugs
Partial seizures Carbamazepine, phenytoin,
lamotrigine, valproic acid,
oxcarbazepine
Gabapentin, topiramate,
levetiracetam, Zonisamide,
tiagabine, primidone,
phenobarbital, felbamate
Absence seizures Valproic acid, ethosuximide Lamotrigine, levetiracetam
Myoclonic seizures Valproic acid, clonazepam Lamotrigine, levetiracetam,
topiramate, Zonisamide
Tonic-clonic
seizures
Phenytoin, Valproic acid Lamotrigine, topiramate,
oxcarbazepine,
levetiracetam

32. Treatment algorithm for epilepsy

33. REFERENCES/BIBLIOGRAPHY:
1. Text book of pathology by Harsh Mohan
2. Clinical Pharmacy and Therapeutics – Roger and Walker, Churchill Livingstone
publication
3. Pharmacotherapy: A Pathophysiologic approach – Joseph T. Dipiro
4. www.slideshare.net