antiepileptic drugs part 1

Seizures & EpilepsyMBBS IV Group CTutor: Prof. V. Wong16th Feb 2004

Outline

Definitions Pathophysiology Aetiology Classification Video demonstration Diagnostic approach Treatment Quiz

Definition

Seizure (Convulsion)• Clinical manifestation of synchronised

electrical discharges of neurons

Epilepsy• Present when 2 or more unprovoked

seizures occur at an interval greater than 24 hours apart

Definition

Provoked seizures Seizures induced by somatic

disorders originating outside the brain E.g. fever, infection, syncope, head

trauma, hypoxia, toxins, cardiac arrhythmias

Definition

Status epilepticus (SE) Continuous convulsion lasting longer than

30 minutes OR occurrence of serial convulsions between which there is no return of consciousness

Idiopathic SE Seizure develops in the absence of an

underlying CNS lesion/insult Symptomatic SE

Seizure occurs as a result of an underlying neurological disorder or a metabolic abnormality

Aetiology of seizures

Epileptic Idiopathic (70-80%) Cerebral tumor Neurodegenerative disorders Neurocutaneous syndromes Secondary to

Cerebral damage: e.g. congenital infections, HIE, intraventricular hemorrhage

Cerebral dysgenesis/malformation: e.g. hydrocephalus

Aetiology of seizures

Non-epileptic Febrile convulsions Metabolic

Hypoglycemia HypoCa, HypoMg, HyperNa, HypoNa

Head trauma Meningitis Encephalitis Poisons/toxins

Aetiology of Status Epilepticus Prolonged febrile seizure

Most common cause Idiopathic status epilepticus

Non-compliance to anti-convulsants Sudden withdrawal of anticonvulsants Sleep deprivation Intercurrent infection

Symptomatic status epilepticus Anoxic encephalopathy Encephalitis, meningitis Congenital malformations of the brain Electrolyte disturbances, drug/lead

intoxication, extreme hyperpyrexia, brain tumor

Pathophysiology

Still unknownSome proposals:

Excitatory glutamatergic synapses Excitatory amino acid neurotransmitter

(glutamate, aspartate) Abnormal tissues — tumor, AVM, dead

area Genetic factors Role of substantia nigra and GABA

Pathophysiology

Excitatory glutamatageric synapsesAnd, excitatory amino acid

neurotransmitter (glutamate, aspartate) These are for the neuronal excitation In rodent models of acquired epilepsy and in human

temporal lobe epilepsy, there is evidence for enhanced functional efficacy of ionotropic N-methyl-D-aspartate (NMDA) and metabotropic (Group I) receptors

Chapman AG. Glutatmate and Epilepsy. J Nutr. 2000 Apr; 130(4S Suppl): 1043S-5S

Pathophysiology

Abnormal tissues — tumor, AVM, dead area These regions of the brain may promote

development of novel hyperexcitable synapses that can cause seizures

Pathophysiology

Genetic factors At least 20 % Some examples

Benign neonatal convulsions--20q and 8q Juvenile myoclonic epilepsy--6p Progressive myoclonic epilepsy--21q22.3

Pathophysiology

Role of substantia nigra Studies with 2-deoxyglucose indicate that a

marked increase in metabolic activity in SN is a common feature of several types of generalized seizures; it is possible that some of this increased activity is associated with GABAergic nerve terminals that become activated in an attempt to suppress seizure spread.

Because GABA has been shown to inhibit nigral efferents, it is likely that GABA terminals inhibit nigral projections that are permissive or facilitative to seizure propagation

From Gale K. Role of the substantia nigra in GABA-mediated anticonvulsant actions. Adv Neurol.1986;44:343-364

Pathophysiology

Premature brain It is more susceptible to specific seizures

than is the brain in older children and adults Kindling

Repeated subconvulsive stimulation (e.g. to the amygdala) will lead to generalized convulsion

This may explain the development of epilepsy after injury to the brain

One temporal lobe seizure -> contralateral lobe

Classification of seizures

Seizures

Partial– Electrical discharges in

a relatively small group of dysfunctional neurones in one cerebral hemisphere

– Aura may reflect site of origin

– + / - LOC

Generalized– Diffuse abnormal

electrical discharges from both hemispheres

– Symmetrically involved

– No warning– Always LOC

Simple Complex

Partial Seizures

1. w/ motor signs

2. w/ somato-sensory symptoms

3. w/ autonomic symptoms

4. w/ psychic symptoms

1. simple partial --> loss of consciousness

2. w/ loss of consciousness at onset

Secondary generalized

1. simple partial --> generalized

2. complex partial--> generalized

3. simple partial --> complex partial--> generalized

Simple partial seizureswith motor signs

Focal motor w/o march Focal motor w/ march Versive Postural Phonatory

Simple partial seizures with motor signs

Sudden onset from sleep

Version of trunk Postural

Left arm bent Forcefully stretched

fingers

Looks at watch Note seizure

Simple partial seizures with sensory symptomsSomato-sensoryVisualAuditoryOlfactoryGustatoryVertiginous

Simple partial seizures with sensory symptoms

Vertiginous symptoms“Sudden sensation of

falling forward as in empty space”

No LOC Duration: 5 mins

Simple partial seizures with autonomic symptomsVomitingPallorFlushingSweatingPupil dilatationPiloerection Incontinence

Simple partial seizures with autonomic symptoms

Stiffness in L cheek Difficulty in articulating R side of mouth is dry Salivating on the L

side Progresses to tongue

and back of throat

Simple partial seizures with psychic symptomsDysphasiaDysmnesicCognitiveAffective IllusionsStructured hallucinations

Simple partial seizure with pyschic symptoms

Dysmnesic symptoms “déjà-vu”

Affective symptoms fear and panic

Cognitive Structured

hallucination living through a scene

of her former life again

Complex Partial SeizuresSimple partial onset followed by

impaired consciousness with or without automatism

With impairment of consciousness at onset with impairment of consciousness only with automatisms

Simple Partial Seizures followed by Complex Partial Seizures

Seizure starts from awake state

Impairment of consciousness

Automatisms lip-smacking right leg

Complex Partial Seizures with impairment of consciousness at onset

Suddenly sit up Roll about with

vehement movement

Partial Seizures evolving to Secondarily Generalised Seizures

Simple Partial Seizures to Generalised Seizures

Complex Partial Seizures to Generalised Seizures

Simple Partial Seizures to Complex Partial Seizures to Generalised Seizures

Simple Partial Seizures to Generalised Seizures

Turns to his R with upper body and bends his L arm

Stretches body LOC Tonic-clonic seizure Relaxation phase Postictal sleep

Simple Partial Seizures to Complex Partial Seizures to Generalised Seizures

Initially unable to communicate but understands

Automatism Smacking Hand-rubbing

Abolished communication

Generalised tonic-clonic seizure

Generalized seizures

AbsenceMyoclonicClonicTonicTonic-clonicAtonic

Absence seizures Sudden onset Interruption of ongoing activities Blank stare Brief upward rotation of eyes Duration: a few seconds to 1/2 minute Evaporates as rapidly as it started

Absence seizures Stops

hyperventilating Mild eyelid clonus Slight loss of neck

muscle tone Oral automatisms

Myoclonic seizures Sudden, brief, shock-like Predominantly around the hours of going to

or awakening from sleep May be exacerbated by volitional

movement (action myoclonus)

Myoclonic seizures Symmetrical

myoclonic jerks

Clonic seizures Repetitive biphasic

jerky movements Repetitive vocalisation

synchronous with clonic movements of the chest (mechanical)

Venous injection of diazepam

Passes urine

Tonic seizures Rigid violent muscle contraction Limbs are fixed in strained position

patient stands in one place bends forward with abducted arms deep red face noises - pressing air through a closed mouth

Tonic seizures Elevates both hands Extreme forward

bending posture Keeps walking

without faling Passes urine

Tonic-clonic seizures(grand mal)

Tonic Phase Sudden sharp tonic

contraction of respiratory muscle: stridor / moan

Falls Respiratory inhibition

cyanosis Tongue biting Urinary incontinence

Clonic Phase Small gusts of grunting

respiration Frothing of saliva Deep respiration Muscle relaxation Remains unconscious Goes into deep sleep Awakens feeling sore,

headaches

Tonic-clonic seizures Tonic stretching of

arms and legs Twitches in his face

and body Purses his lips and

growls Clonic phase

Atonic seizures Sudden reduction

in muscle tone Atonic head drop

Epilepsy syndrome Epilepsy syndromes may be classified

according to: Whether the associated seizures are partial

or generalized Whether the etiology is idiopathic or

symptomatic/ cryptogenic Several important pediatric syndromes can

further be grouped according to age of onset and prognosis

EEG is helpful in making the diagnosis Children with particular syndromes

show signs of slow development and learning difficulties from an early age

Category Localization-related Generalized

Idiopathic Benign epilepsy of childhood with centrotemporal spikes(benign rolandic epilepsy)Benign occipital epilepsy

Benign myoclonic epilepsy in infancyChildhood absence epilepsyJuvenile absence epilepsyJuvenile myoclonic epilepsy

Symptomatic (of underlying structural disease)

Temporal lobeFrontal lobeParietal lobeOccipital lobe

Early myoclonic encephalopathyCortical dysgenesisMetabolic abnormalitiesWest syndromeLennox-Gastaut syndrome

Cryptogenic Any occurrence of partial seizures without obvious pathology

Epilepsy with myoclonic absencesWest syndrome (with unidentified pathology)Lennox-Gastaut syndrome (with unidentified pathology)

Table 1. Modified ILAE Classification of Epilepsy Syndromes

Special syndromes Febrile convulsionsSeizures occurring only with toxic or metabolic provoking factorsNeonatal seizures of any etiologyAcquired epileptic aphasia (Landau-Kleffner syndrome)

Table 1. Modified ILAE Classification of Epilepsy Syndromes

(cond’)

Three most common epilepsy syndromes:1. Benign childhood epilepsy2. Childhood absence epilepsy3. Juvenile myoclonic epilepsy

Three devastating catastrophic epileptic syndromes:1. West syndrome 2. Lennox-Gastaut syndrome 3. Landau Kleffner Syndrome

Benign childhood epilepsy with centrotemporal spike

(Benign Rolandic Epilepsy)

1. Typical seizure affects mouth, face, +/- arm. Speech arrest if dominant hemisphere, consciousness often preserved, may generalize especially when nocturnal, infrequent and easily controlled

2. Onset is around 3-13 years old, good respond to medication, always remits by mid-adolescence

Childhood absence epilepsy1. School age ( 4-10 years ) with a peak age of onset at 6-7

years2. Brief seizures, lasting between 4 and 20 seconds3. 3Hz Spike and wave complexes is the typical EEG abnorm

ality

4. Sudden onset and interruption of ongoing activity, often with a blank stare.

5. Precipitated by a number of factors i.e. fear, embarrassment, anger and surprise. Hyperventilation will also bring on attacks.

Juvenile myoclonic seizure 1. Around time of puberty2. Myoclonic ( sudden spasm of muscles ) jerks →

generalized tonic clonic seizure without loss of consciousness

3. Precipitated by sleep deprivation

West’s syndrome (infantile spasms)Triad: 1. infantile spasms2. arrest of psychomotor development3. hypsarrhythmia

Spasms may be flexor, extensor, lightning, nods, usually mixed. Peak onset 4-7 months, always before 1 year.

Lennox-Gastaut syndrome Characterized by seizure, mental retardation and

psychomotor slowing Three main type:1. tonic2. atonic3. atypical absence

Landau- Kleffner syndrome ( acquired aphasia )

Diagnosis in epilepsyAims:

Differentiate between events mimicking epileptic seizures

E.g. syncope, vertigo, migraine, psychogenic non-epileptic seizures (PNES)

Confirm the diagnosis of seizure (or possibly associated syndrome) and the underlying etiology

Diagnosis in epilepsyApproach:

History (from patient and witness) Physical examination Investigations

History Event

Localization Temporal relationship Factors Nature Associated features

Past medical history Developmental history Drug and immunization history Family history Social history

Physical ExaminationGeneral

esp. syndromal or non-syndromal dysmorphic features, neurocutaneous features

NeurologicalOther system as indicated

E.g. Febrile convulsion, infantile spasm

Investigations I. Exclusion of differentials:

Bedside: urinalysis Haematological: CBP Biochemical: U&Es, Calcium, glucose, ABGs Radiological: CXR, CT head Toxicological: screen Microbiological: LP(Always used with justification)

Investigations II. Confirmation of epilepsy:

Dynamic investigations : result changes with attacks

E.g. EEG Static investigations : result same

between and during attacks E.g. Brain scan

Electroencephalography (EEG)EEG indicated whenever epilepsy

suspectedUses of EEG in epilepsy

Diagnostic: support diagnosis, classify seizure, localize focus, quantify

Prognostic: adjust anti-epileptic treatment

International 10-20 System of Electrode Placement in EEG

Electroencephalography (EEG) EEG interpretation in epilepsy

Hemispheric or lobar asymmetries Periodic (regular, recurring) Background activity:

Slow or fast Focal or generalized

Paroxysmal activity: Epileptiform features – spikes, sharp waves Interictal or ictal Spontaneous or triggered

Electroencephalography (EEG) Certain epilepsy syndromes have characteristic or

suggestive features E.g.

Infantile spasms Hypsarrhythmia

Childhood absence epilepsy Generalized 3-Hz spike-wave

Juvenile myoclonic epilepsy Generalized/ multifocal 4-5 Hz spike-wave and polyphasic-wave

Benign occipital epilepsy Unilateral/ bilateral occipital sharp/ sharp-slow activity that attenuates on eye opening

Lennox-Gastaut syndrome Generalized/ bianterior spike-wave activity at <2.5 Hz

Electroencephalography (EEG)

E.g. Brief absence seizure in an 18-year-old patient with primary generalized epilepsy

Electroencephalography (EEG)Note:

Normal in 10-20% of epileptic patients Background slowed by:

AED, diffuse cerebral process, postictal state Artifact from:

Eye rolling, tremor, other movement, electrodes

Interpreted in the light of proximity to seizure

NeuroimagingStructural neuroimagingFunctional neuroimaging

Structural NeuroimagingWho should have a structural

neuroimaging? Status epilepticus or acute, severe

epilepsy Develop seizures when > 20 years old Focal epilepsy (unless typical of benign

focal epilepsy syndrome) Refractory epilepsy Evidence of neurocutaneous syndrome

Structural Neuroimaging Modalities available:

Magnetic Resonance Imaging (MRI) Computerized Tomography (CT)

What sort of structural scan? MRI better than CT CT usually adequate if to exclude large tumor MRI not involve ionizing radiation

I.e. not affect fetus in pregnant women (but nevertheless avoided if possible)

Functional NeuroimagingPrinciples in diagnosis of epilepsy:

When a region of brain generates seizure, its regional blood flow, metabolic rate and glucose utilization increase

After seizure, there is a decline to below the level of other brain regions throughout the interictal period

Functional Neuroimaging Modalities available:

Positron Emission Tomography (PET) Single Photon Emission Computerized

Tomography (SPECT) Functional Magnetic Resonance Imaging

(fMRI) Mostly used in:

Planning epilepsy surgery Identifying epileptogenic region Localizing brain function

Venn Diagram

Seizure Therapy

Anticonvulsant Surgery

Specific Treatments

Reassurance and Education

General Treatment

Seizure

Education & Support

Information leaflets and information about support group

Avoidance of hazardous physical activities

Management of prolonged fits Recovery position Rectal diazepam

Side effects of anticonvulsants

Anticonvulsants

Suppress repetitive action potentials in epileptic foci in the brain Sodium channel blockade GABA-related targets Calcium channel blockade Others: neuronal membrane

hyperpolarisation

Anticonvulsants

CabamazepinePhenytoin

Valproic acid

Tonic-clonic and partial

EthosuximideValproic acidClonazepam

Absence seizures

Valproic acidClonazepam

Myoclonic seizures

DiazepamLorazepam

Short term control

PhenytoinPhenobarbital

Prolonged therapy

Status Epilepticus

CorticotropinCorticosteroids

Infantile Spasms

Drugs used in seizure disorders

Adverse EffectsTeratogenicity

Neural tube defects Fetal hydantoin syndrome

Overdosage toxicityLife-threatening toxicity

Hepatotoxicity Stevens-Johnson syndrome

Abrupt withdrawal

Medical Intractability

No known universal definition Risk factors

High seizure frequency Early seizure onset Organic brain damage

Established after adequate drug trials

Operability

SurgeryCurative

Catastrophic unilateral or secondary generalised epilepsies of infants and young children

Sturge-Weber syndrome Large unilateral developmental

abnormalities

Palliative Vagal nerve stimulation

Surgical Outcome

Medical IntractabilityA well-localised epileptogenic zone

EEG, MRILow risk of new post-operative

deficits

References

1. Stedman’s Medical Dictionary.2. MDConsult: Nelson’s textbook.3. Illustrated Textbook of Pediatrics.4. Video atlas of epileptic seizures – Classical

examples, International League against epilepsy.

5. Guberman AH, Bruni J, 1999, Essentials of Clinical Epilepsy, 2nd edn. Butterworth Heinemann.

6. Manford M, 2003, Practical Guide to Epilepsy, Butterworth Heinemann.