Epilepsy

Seizure: An sudden and temporary alteration in

brain function due to abnormal electrical discharges

of cerebral neurons resulting changes in motor,

sensory, psychomotor activity

A group of chronic syndromes : Recurrence of seizures – (periods of abnormal discharge of cerebral neurons)

Convulsions• A convulsion : body muscles contract and relax rapidly

and repeatedly results an uncontrolled shaking of the body.

• Because a convulsion is often a symptom of an epileptic seizure, the term convulsion is sometimes used as a synonym for seizure.

• However, not all epileptic seizures lead to convulsions, and not all convulsions are caused by epileptic seizures.

• Seizure may be associated WITH or WITHOUT CONVULSIONS.

• Site of origin of focus epileptic focus

• Epileptogenesis: previously normal brain is

functionally altered biased towards the generation

of the abnormal electrical activity chronic seizures.

• In simple words, it is the process by which normal

brains develops epilepsy.

• “Fit” term used alternatively an epileptic seizure

• The process of epileptogenesis is classically thought to occur in three phases:

Precipitating injury or event changes occurs in the structure and physiology of the brain (latent' period) results in the development of epilepsy Chronic, established epilepsy.

• During this latent period hyper-excitable neuronal network forms can lead to spontaneous seizures

• Experience abnormal behavior, symptoms and sensations, including loss of consciousness.

Antiseizure drugs

Antiepileptic: used on chronic basis for prevention of epileptic attacks.

Anticonvulsant: Used to stop the episode of convulsions.

An antiepileptic may be anticonvulsant (eg. Phenytoin sodium), but -Every anticonvulsant may not be antiepileptic (eg. Diazepam)

Classification

• 2 type of classification1. Based on seizure types & characteristic features2. Epilepsy syndrome

• Etiological factors• Frequency of attacks• Age, onset• Clinical manifestations

Focal or partial (1 hemisphere)Simple partial (Jacksonian )

Complex partial (psychomotor )

Secondary Generalized

Unilateral (min.spread)

localized focuscoffined to motorarea

abnormal movements

No loss of consciousness

First localized spreads

Temporal lobe behavioral changes

altered consciousnessDreamy state (Dien

focal spreads and generalizes,

lost consciousness

Generalized seizures:

• Arise from both cerebral hemispheres and diencephalon simultaneously, involving entire body.

• Types of generalized seizures:Tonic seizureClonic seizuresGrand mal epilepsy or tonic clonic epilepsyAkinetic (atonic) seizuresPetit mal epilepsy or absence seizureMyoclonic seizures

Grand mal epilepsy

• Usually associated with aura prior to seizure. • The pt. falls to the ground in stiff tonic phase (legs

extended) with an epileptic cry due to tonic contraction of laryngeal muscles.

• followed by clonic convulsions (repetitive bilateral muscle jerking) and then to coma which may last for 15-30 min.

• Recovery is associated with stupor, amnesia, mental confusion, postictal (post seizure) depression, incontinence and exhaustion.

• Status epilepticus: emergency condition

Petit mal epilepsy or absence seizures• Prevalent in children.• Last for 20-30 second• No aura present• Pt apparently freezes and stares in one direction. T• here is a trance-like state. Unresponsive and unaware to

surroundings. – If the patient is speaking, speech is slowed or interrupted;– If walking, he or she stands transfixed; – If eating, the food will stop on its way to the mouth.

• No muscular component or little bilateral jerking.• Absence seizures generally are not followed by a period of

disorientation or lethargy (post-ictal state), this is in contrast to the majority of seizure disorders.

Myoclonic seizures

• Bilateral epileptic myoclonus• Characterised by sudden and brief skeletal

muscle contraction that may involve entire body or one part of the body.

• Shock like momentary contraction of muscle of limb or the whole body

Akinetic or atonic seizures

• Unconsciousness with relaxation of all muscle due to excessive inhibitory discharge.

SensoryVisual changes. Examples:

Bright lights.Zigzag lines.Slowly spreading spots.Distortions in the size or shape of objects.Blind or dark spots in the field of vision.

Hearing voices or sounds (auditory hallucinations).Strange smells (olfactory hallucinations).Feelings of numbness or tingling on one side of your face or body.Feeling separated from your body.Anxiety or fear.Nausea.

Unclassified seizures

• Febrile : young children's with hyperpyrexia• Infantile spasm: progressive mental

retardation

PARTIAL(focal) SEIZURES(1 hemisphere)

Simple partial

Complex partial

Secondary generalized

GENERALIZED seizures(both hemispheres,

-Generalized tonic-clonic (Grand mal)

-Absence seizures (petit mal)-myoclonic jerking-Atonic seizures-Infantile spasm

To find real seizureSometimes twitching may miss diagnosed as epilepsy Non-epileptic seizures are paroxysmal events that mimic an

epilepetic seizure but do not involve abnormal, rhythmic discharges of cortical neurons. They are caused by eitherphysiological or psychological conditions.

• 1. Tongue bite• 2. Urinary incontinence • 3. Arching back• 4.limbis moving flailing (vigorously)• 5. Eye opening resisted or eye ball roll up

• Recent studies suggest :• Inc excitatory neurotransmitter: Ach,

Glutamate, Asparate (Over activity) or• inhibitory gamma amino butyric acid (GABA)

(decreased activity )• Or both

Mechanisms of actions

• Imbalance or defects in – Na+ or Ca2+ ion conductance in neuronal membranes – K efflux – GABA transmission – Excitatory mechanism involved in NMDA receptor

to produce depolarization (not yet available for clinical use)

Mechanism of action• 1 Sodium channel blockers • Phenytoin, Carbamazepine, Lamotrigine• Also phenobarbitone,valproate, topiramate

• 2 drugs affecting GABA transmission• Receptor: BZD, Barbiturates, topiramate• GABA transaminase: Valproate, vigabatrin• GABA uptake: Tiagabine, Gabapentin

Mechanism of action..continued3. T-type Calcium channel blockade:

Ethosuximide, Valproate (low threshold current in thalamic cortical rhytham)

4. Glutamate antagonism• Phenobarbital, Felbamate,• Topiramate (Kainate, AMPA receptors) • Also Valproate

• 5. K channel: Valproate

Classification• Aliphatic carboxylic acid: Valproic acid (sodium valproate)• Barbiturate : Phenobarbitone• Benzodiazepines: Clonazepam, diazepam, lorazepam, clobazam• Deoxybarbiturate : Primidone• Hydantoin : Phenytoin, fosphenytoin• Iminostilbene: Carbamazepine, Oxcarbamazepine • Phenyltriazine: Lamotrigine• Succinimide: Ethosuximide• Cyclic GABA analogues: Gabapentin, Pregabalin• Newer drugs: Topiramate, zonisamide, levtiracetam,

vigabatrin, tiagabin lacosamide

Parital seziures-Carbamazepine-Valproic acid Gen Tonic-clonic-valproic acid- Lamotrigine-carbamazepine-phenytoin-phenobarbitone

Absence seizures-Ethosuximide *-Valproic acid-lamotrigine, topiramate

Myoclonic seizures-Clonazepam-Valproic acid-Benzodiazepines-topiramate

AdjunctsFelbamate, gabapentin*Lamotrigine*, phenobarbitalTiagabine, topiramateVigabatrin, leveteracetam, zonisamide

PARTIAL SEIZURES(1 hemisphere)Valproate, phenytoin, carbamazepine-Simple partial

-Complex partial

-Secondary generalized

GENERALIZED seizures(both hemispheres, altered consciousness)

-Generalized tonic-clonic (Grand mal)

-Absence seizures (petit mal)-myoclonic jerking-Atonic seizures-Infantile spasm

Anticonvulsant drug therapy general considerations

• Anti epileptic drugs can control but nor cure• Obj of therapy : provide neuro protection by

minimizing from seizure attack. • Many pt have to take medication throughout

life to ensure control of seizure • Newer drugs are add on drug

Barbiturates: Phenobarbitone

• Long acting barbiturate• Phenobarbital was the main anticonvulsant

from 1912 till the development of phenytoin in 1938.

• Current status: Today, Phenobarbital is rarely used to treat epilepsy in new patients since there are other effective drugs that are less sedating.

MOA• GABAA receptors are the primary target for barbiturates in the

central nervous system.• By binding to GABAA receptor, barbiturates potentiate the effect

of GABA at this receptor (GABA facilitatory action). • Barbiturate potentiate GABAergic inhibition by increase in

lifetime of Cl- channel opening induced by GABA.• At high concentrations barbiturates directly increase Cl-

conductance (GABA mimetic action) and inhibit Ca+ dependent release of neurotransmitter.

• In addition, barbiturates depress glutamate induced neuronal depolarization through AMPA receptors (i.e. block AMPA receptors)

Adverse effects• Major drawback of phenobarbitone as an antiepileptic is its

sedative action.

• Long term administration may produce additional side effects– such as behavioural abnormalities, – diminution of intelligence,– impairment of learning and memory, – hyperactivity in children mental confusion in older patient.

• Rashes, megaloblastic anemia and osteomalacia

Uses • Phenobarbitone can be effective in all types of seizures

except absence seizure. Hence effective in GTC, SP, CP seizures.

• Dose : 60 mg 1-3 times daily.• Less popular than carbamazepine, phenytoin or

valproate because of its dulling and behavioural side effects.

• Drug interaction should also be taken into consideration while starting phenobarbitone (phenobarbitone is an enzyme inducer.)

Primidone

• Deoxybarbiturate• Convertated by liver to phenobarbitone and

phenylethyl malonamide.• Active drug --- active metabolite• Dose 250-500 mg BD

Phenytoin

• Introduced in 1938.• It is not a CNS depressant; some sedation occurs at

therapeutic dose.

MOA

• Phenytoin has stabilizing influence on neuronal membrane –by an action on voltage-dependent sodium channels

• which carry the inward membrane current necessary for the generation of an action potential.

• They block preferentially the excitation of cells that are firing repetitively, and the higher the frequency of firing, the greater the block produced.

• At higher dose/ toxic concentration:

Pharmacokinetics • Absorption – oral route is slow, mainly because its poor aqueous solubility.– Bioavailability of different market preparations may be differ.

• Metabolised – hydroxylation involving CYP 2C9 and 2C19 as well as

glucuronidation.• The kinetics of metabolism is capacity limited : changes

from 1st order to zero order over the therapeutic range. – hence plasma conc. rises suddenly even after small increase in the dose. Monitoring of plasma conc. Is very important

Adverse effect

• At therapeutic level:• Gum hypertrophy: commonest (incidence 20%), more in younger patients. It is

due to overgrowth of gingival collage fibers. Can be minimised by maintaining oral hygiene.

• Hirsuitism, acne.• Hypersensitivity reaction: rashes, lymphadenopathy.

Neutropenia is rare requires discontinuation of the therapy• Megaloblastic anaemia: decreases folate absorption, Inc.excretion.

• Osteomalacia: Interferes with metabolic activation of vit D with calcium absorption/ metabolism.

• Foetal hydantoin syndrome: hypoplastic phalanges, cleft palate, hare lip, microcephaly) – which is probably caused by its areneoxide metabolite.

• Facial expression: less

• At high plasma level (dose related toxicity): Cerebellar and vestibular manifestations: ataxia, vertigo, diplopia,

nystagmus are the most characterised features. Drowsiness, behavioural alternation, mental confusion, disorientation and

rigidity Epigastric pain, nausea, vomiting. These can be minimised by taking the

drug with meals. IV injection can cause local vascular injuary intimal damage and

thrombosis of the vein oedema and discolouration of the injected limb. Rate of injection should not exceed 50 mg/min. tissue necrosis occurs if the solution extravasates.

Fall in BP and cardiac arrhythmia on IV injection

• Drug interactions:

Uses of phenytoin

Draw backs :• GTC, SP, CP seizures but not effective in

absence seizures• Dose 100 mg BD …. Max. 400 mg/ day• Status epileptics: fosphenytoin used now.• Trigeminal neuralgia: 2nd choice

Fosphenytoin

• Water soluble prodrug of phenytoin• Introduce to overcome the difficulties in iv

administration of phenytoin.• Advantages:• less damage to intima • can be injected at faster rate (150 mg/ min)

but ECG monitoring is needed.

Carbamazepine

• Was introduced in 1960 for trigeminal neuralgia. Now it is 1st line antiepileptic drug

• MOA : similar to Phenytoin. • Antidiuretic action, probably by enhancing ADH

action on renal tubules. • Pharmacokinetics: • Interactions

Adverse effects • Dose related neurotoxicity: sedation, dizziness, vertigo,

diplopia and ataxia.• Acute intoxication:• GIT adverse effect• Hypersensitivity reaction: rashes, photosensitivity,

hepatitis, lupus like syndrome, rarely agranulocytosis and aplastic anaemia.

• Water retention and hyponatremia.• Foetal malformation

Uses • CPS, GTC, SP but not for absence seizure• Trigeminal and related neuralgias: Carbamazepine is

the DOC. • Second line drugs for trigeminal neuralgia: phenytoin,

lamotrigine, baclofen, gabapentin.• Manic depressive illness and acute mania:• Dose 200-400 mg TDS children 15-30 mg/kg/day

Oxcarbazepine

• Toxic effects due to epoxide metabolite are avoided.

• Less drug interactions and auto-induction

• Risk of hepato-toxicity is less but that of hyponatremia is more.

Ethosuximide• Clinically only effective in absence seizure.• The primary action appears to be exerted on

thalmocortical system.• Selectively suppresses/ inhibits T type Ca channel

without affecting other types and Na currents.• Use: only indication- Absence seizure but now

superseded by valproate.

Valproic acid (Na valproate)• Broad spectrum anticonvulsant action.• MOA• A phenytoin like frequency dependent prolongation of Na+

channel inactivation.• Ethosuximide like T type Ca2+ channel blocking action.• 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.

• Pharmacokinetics

Adverse effects• Toxicity is relatively low. • GIT: Anorexia, vomiting, loose motion, heart burn are common but

mild.• CNS: Drowsiness, ataxia, tremors.• Hypersensitivity reactions like rashes and thrombocytopenia. • Alopecia, curling of hair, weight gain, increased bleeding tendency.• Asymptomatic rise in serum transaminase is often noted;

monitoring of liver function is noted. • Teratogenic effect: • Rare adverse effects: Acute live failure, pancreatitis, In young girls –

PCOD menstrual abnormalitis.• Dose: 200-800 mg tds for adults. 15-30 mg/kg/day for children

USES• Doc for absence, GTCS, Myoclonic, Atonic, tonic, clonic

seizures• Mania and bipolar disorders: alternative to lithium.• DOC for bipolar disorder in pt. having rapid cycles (4 or more

cycles per year).• Have some prophylactic role in migraine. • Recently it has been used in tardive dyskinesia.• Alternative drug to carbamazepine in trigeminal neuralgia.

Benzodiazepines • Diazepam, lorazepam, clonazepam, clobazam are

benzodiazepines that act by GABA facilitatory action. These drug increase the frequency of Cl- channel opening.

• Diazepam, lorazepam, clonazepam are effective for the management of acute seizures.

• For status epilepticus lorazepam is DOC.• Diazepam (per rectally) DOC for febrile seizures.• Drawback prominent sedative effect• Tolerance develops to the antiepileptic effect so these are

not indicated for long term use.

Other antiepileptic drugs• Lamotrigine: broad spectrum antiepileptic have inhibitory

action on Na and Ca channel. Initially found effective as add on therapy in refractory cases. Recently found effective as monotherapy as well.

• Gapapentin: act by increasing synthesis and release of GABA. Gabapentin and its newer congener pregabalin exert a specific analgesic effect in neuropathic pain. Mainly used as add on drug in the treatment of epilepsy.

• Pregabalin : it is particularly used for neuropathic pain, such as diabetic neuropathy, postherpetic neuralgia, CRPS.

• Viagabatrin: irreversible inhibitor of GABA transaminase, thus increases GABAergic activity. Irreversible visual field defect is the characteristic adverse effect due to retinal atrophy.

• Tiagabine : act by inhibiting GABA transporter GAT -1.

• Topiramate : weak carbonic anhydrase inhibitory activity. Broad spectrum anticonvulsant action. MOA: prolongation of NA channel inactivation, GABA potentiation, antagonism of certain glutamate receptors and neuronal hyper polarization through certain K channels.

• Zonisamide: weak carbonic anhydrase inhibitory activity. MOA porolonation of NA channel inactivation and suppression of T type Ca currents in certain neurons.

Status epilepticus-

• Prolonged seizure• Recurrent • No consciousness bew seizures• Permanent damage• Semi prone position

Status epilepticus-• Lorazepam – IV 0.1 – 0.2 mg/kg bolus (5-10 mg) or • Diazepam- IV 0.1 – 0.2 mg/kg bolus (5-10 mg) or• slow IV infusion (2 mg/minute) – slow

redistribution, effect lasts longer• Fosphenytoin 100-150 mg/min in saline or glucose

Or Phenytoin 25-50 mg/min in a saline IV line • Phenobarbitone – 100-200 mg IM/IV• propofol/Valproate,midazolam/thiopentone/

curarization

DCO

• Partial seizure: Carba, Valproic• Partial to Gen: Lamotri, VA• General tonic clonic: VA, Lam• Absence: Etho, VA• Myoclonic : VA, Clonazepam

• Thank U

Phenytoin – diphenylhydantoin- dilantin

• Na channel blocker• Prolongs the inactivated state of voltage

sensitive Na channel• Prevents repetitive detonation of

neuronal cells• Inhibits high frequency discharge• Ca, glutamate, GABA – other mechanisms at higher

concentrations

Phenytoin – diphenylhydantoin- dilantin

• Partial, generalized tonic-clonic – 100 mg q 12 hrs – children 5-8 mg/kg/day• Status epilepticus• Trigeminal neuralgia

• worsens absence seizures

Phenytoin – diphenylhydantoin- dilantin

• Oral slow but 80-90% absorp.• low TI (10-20µg/ml)• Mixed order kinetics (10-20µg) first order (10-20µg)

than zero order– saturation kinetics• PPB90-92%- displacement • Induction – HMES• I/M: Tissue damage(Precipitated), necrosis• IV: Thrombophlebitis

• Fosphenytoin – IV, IM, water soluble • IV slow ( Cardio collapse)

INTERACTIONS– Binds to TBG – interference with T3, T4

Induction HES – anticoagulants, OCPs, quinidine, doxycycline, cyclosporine, mexiletine, INH, chloramphenicol, cimetidine inhibit phenytoin metabolism

Phenytoin –adverse effects• Gingival hyperplasia/hypertrophy• Coarsening of facial features• Hirsutism, acne• Megaloblastic anemia (folate defi),

Peripheral neuropathy, depletes vit D (osteomalacia), osteoporosis

Phenytoin –adverse effects• Hypersensitivity, rash, neutropenia, Aplastic

anemia, agranulocytosis, neutropenia, fever

• Pregnancy: • Neural tube defects • craniofacial abnormalities • cleft lip, cleft palate • fetal hydantoin syndrome• heart disease,• reduced growth, • mental retardation

• CNS depression, behavioral changes

Phenytoin –adverse effects–Vestibulocerebellar syndrome ataxia, –vertigo,– nystagmus, –diplopia

• GI discomfort, N, V• Behavioral changes, hallucinations,

confusion, disorientation• Cardiovascular toxicity only on iv admn

3 per second spike and wave pattern – absence seizure

Phenytoin –adverse effects• Gingival hyperplasia/hypertrophy• Coarsening of facial features• Hirsutism, acne• Megaloblastic anemia (folate defi),

Peripheral neuropathy, depletes vit D (osteomalacia), osteoporosis

B) Generalized• Both cerebral hemispheres • Involve entire bodyTonic-clonic (Grand mal)• Tonic: Continuous contraction• Clonic: Rapid contraction and relaxation• Associated with Aura • Epileptic cry (Contraction of laryngeal muscle)• Followed by clonic convulsions- coma• Last 15-30min• Recovery associated with stupor, amnesia, mental confusion• Status epilepticus: Recurrence of 2 or more seizures

without recovery of unconsciousness between the seizures• Clinical emergency

2) Petit Mal or Absence Seizures• No aura• No loss of consciousness (if loss for 5sec)• Short duration (lasts for few seconds)• Rapid blinking of eyelids• Chewing movements• Small amplitude clonic jerks of hands for sec• Main seizure type 15-20% of children's

3) TonicRigid violent muscular contractionStiff & fixed extended limbs Some pts, after dropping

4) Clonic: Repetitive muscle jerks

5) Atonic ( akinetic): Starts between the ages 2-5 yrs. sudden loss of postural or sudden fall

6) Myoclonic . Sudden, brief shock like contraction

which may involve the entire body or be confined to the face, trunk or extremities.

• Care should be supportive so as to minimize the damage from the floor and near by objectives

• Turn on one side • Place soft item below the head• Minimize tongue bite• Oxygen therapy

Infantile spasm

• Consists of a sudden jerk followed by stiffening.• Each seizure lasts only a second or two but usually in a

series.• Most common just after waking up and rarely occur

during sleep.• They typically begin between 3 and 12 months of age

and usually stop by 4 years old.• Steroid therapy and the antiseizure medicine Sabril

are the primary treatments.• Most children are developmentally delayed later in life.

Classification according MOA• Drugs acting Na:

– Phenotoin– Car– VC– Lamotrizine– fosphenytoin– Oxcarbazepine– Felbamate– Topiramate

• GABA– BZD : Clonazepam, diazepam,

lorazepam, clobazam– Barb: Phenobarbitone– VC

• Ca– Etho– VC

• K+– VC– retigabine,

T- type Ca2+

• Ca2+ Absence seizure • low threshold current in thalamic cortical

rhytham