AntiEpileptic drugs Part 1
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Transcript of 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.