EPILEPSY:

CLASSIFICATION, PATHOGENESIS AND MANAGEMENT

DR AGABI OSIGWE P. MBBS(Benin), MWACP SENIOR REGISTRAR NEUROLOGY UNIT. LAGOS UNIVERSITY TEACHING HOSPITAL.

6TH AUGUST,2013

BIBLICAL REFERENCE
A man in the crowd answered, Teacher I brought you my son, who is possessed by a spirit that has robbed him of speech ,whenever it seizes him, it throws him to the ground. He foams in the mouth, gnashes his teeth and becomes rigid. I asked your disciples to drive out the spirit but they could not. MARK 9(NIV)
6TH August,2013

DEFINITION OF EPILEPSY
The occurrence of two or more unprovoked seizures New:
a disorder of the brain characterized by an enduring
predisposition to generate epileptic seizures requires occurrence of at least 1 unprovoked seizure

6TH August,2013

DEFINITION OF SEIZURES
Abnormal electrical discharge from a network of neurons within the brain Clinical features are determined by function of brain region affected Convulsive and non-convulsive seizures
Convulsive (jerky movements) Non-convulsive (no jerky movements)
6TH August,2013

CLASSIFICATION
Generalized and focal seizures Concept:
GS originate from neural networks in both hemispheres FS originate within networks limited to one hemisphere

Classified as
Generalized seizures Focal seizures Unknown origin
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NPMCN UPDATE 2012

CLASSIFICATION ii
GENERALIZED Tonic-clonic Absence (typical; atypical;
absence with special features myoclonic absence, eyelid myoclonus)

FOCAL (PARTIAL) Simple partial

Motor
Somatosensory Psychic Autonomic

Myoclonic (myoclonic;
myoclonic atonic; Myoclonic tonic

Complex partial
With automatisms

Clonic Tonic Atonic

Without automatisms

Secondary generalized
EPILEPSY CME 2011

6TH August,2013

ILAE 2010 Revised terminology

AETIOLOGY
Genetic
Directly resulting from a known or presumed genetic defect(s) in which sz are core symptom

Structural / metabolic
Epilepsy due to a distinct dx associated with substantially increased risk of epilepsy Structural lesions may be inherited (e.g. tuberous sclerosis)or acquired (e.g. stroke, trauma, infection)

Unknown cause
6TH August,2013

PATHOGENESIS - concepts
Seizure initiation Seizure propagation Epileptogenesis Genetics of epilepsy

Mechanism of action of AEDs

6TH August,2013

SEIZURE INITIATION
Hyperexcitability
The tendency of a neuron to discharge repetitively to a stimulus that normally causes a single action potential influx of extracellular calcium (Ca2+) causing prolonged membrane depolarization leads to opening of voltage-dependent sodium (Na+) channels, influx of Na, and generation of repetitive action potentials Followed by hyperpolarizing afterpotential (mediated by GABA receptors or potassium (K+) channels

Hypersynchronization
the property of a population of neurons to discharge together independently.

SEIZURE PROPAGATION
Spread of activity is usually prevented by hyper-polarization and surrounding inhibition (by inhibitory neurons) However, high level activation (repetitive discharges) leads to recruitment of surrounding neurons via several mechanisms:
Increased extracellular K+ (blunts hyperpolarization and depolarizes neighbouring neurons) Accumulation of Ca2+ in presynaptic terminals (resulting in enhanced neurotransmitter release) Activation of NMDA excitatory amino acid receptors, causing Ca2+ influx and neuronal activation Recruitment of neurons with loss of surrounding inhibition and propagation of seizure activity into contiguous areas via local cortical connections, and distally via long commisural pathways (e.g. corpus callosum)

Absence seizures
Normally, the thalamo-cortical circuits generate oscillatory rhythms during sleep

This oscillatory behaviour involves interaction between GABA B receptors (pacemakers), T-type Ca2+ channels, and K+ channels within the thalamus
Modulation of this interaction causes absence seizures

Activation of transient Ca channels (T channels) and GABA B mediated hyperpolarization results in 3-4 Hz oscillations

MECHANISMS OF EPILEPTOGENESIS
Transformation of a normal neuronal network over time, into one that is chronically hyperexcitable. Insult initiates a process that gradually lowers seizure threshold in affected region, until spontaneous seizure occurs. Mechanism:
Structural changes in neural networks (e.g. in MTLE, selective loss of inhibitory neurons to dentate gyrus; accompanied by reorganization (sprouting) of surviving neurons, with change (increase) in excitability Local hyperexcitability results in further structural changes over time, until clinically evident seizures occur. Also, functional (and metabolic) changes in receptor function occur

MECHANISM OF AED
Mainly block initiation or propagation of seizures Via modification of ion channel or neurotransmitter function Mechanisms Inhibition of Na+-dependent action potential (phenytoin, carbamazepine, lamotrigine, topiramate, zonisamide) Inhibition of voltage-gated Ca2+ channels (phenytoin) Decreased glutamate release (lamotrigine) Potentiation of GABA receptor function (benzodiazepines and barbiturates) Increased availability of GABA (valproic acid, gabapentin, tiagabine) Inhibition of T-type Ca2+ channels in thalamic neurons (ethosuximide and valproic acid)

MANAGEMENT
Differential diagnosis of epileptic seizures Diagnosis
Clinical evaluation investigations

Treatment
Pharmacological Non-pharmacological Surgical

DIFFERENTIAL DIAGNOSIS
Syncope (cardiac (e.g. arrhythmias; non-cardiac (e.g. vasovagal, orthostatism) Sleep disorders (narcolepsy, OSA, parasomnias) Transient ischaemic attacks and transient global amnesia Dizziness/vertigo

Paroxysmal (intermittent) movement disorders

Migraine (complex) Metabolic (hypoglycaemia, alcohol) / delirium Psychiatry base: panic/anxiety, conversion/psychogenic seizures, dissociative states, malingering, hyperventilation, etc).
EPILEPSY CME 2011

DIAGNOSIS i
History
Careful and detailed Eye-witness account valuable Exclude differentials Risk factor evaluation Seizure type: partial or generalized; type of generalized or partial seizure
Aura Loss of consciousness (G) or impairment (CPS) Sequence of events
EPILEPSY CME 2011

DIAGNOSIS ii
Electroencephalography
To identify electrical (potential) abnormalities Ictal (during seizure) and interictal

Neuroimaging
To identify structural lesions MRI is superior to brain CT in seizure evaluation Normal in idiopathic epilepsy Abnormality is common in partial epilepsies e.g. TLE (hippocampal sclerosis)

Blood tests
Baseline biochemical and haematologic parameters
EPILEPSY CME 2011

EEG Normal

EPILEPSY CME 2011

EEG Generalized spike and SW

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EEG Absence seizures

NPMCN UPDATE 2012

TREATMENT i
Early diagnosis and treatment
improves long-term quality of life Reduces morbidity and mortality Early referral

Decision to treat
Patient and physician interaction in decision making Explain pros and cons of treatment Offer treatment for epilepsy Single seizures: consider risk of recurrence (abnormal neuro exam, abnormal imaging, abnormal EEG)
EPILEPSY CME 2011

TREATMENT ii
Choice of AED should be rational
Monotherapy to maximal tolerable dose Alternative monotherapy Polytherapy (rational)

Use medications that are accessible to the patient on the long-term

EPILEPSY CME 2011

TREATMENT iii
Important considerations Treatment options Pharmacological (first-line before second line) Surgical (refractory seizures: resection, hemispherectomy, vagus nerve stimulation)

Women of child-bearing age: folic acid 5mg daily

Comorbidities: mood disorders, medical illness Treatment duration: 2 years initially (relapse 11-14%) Psychosocial and cultural issues: driving, marriage, employment, belief systems, cross-referrals
EPILEPSY CME 2011

Table 1. Drug options for seizure treatment (NICE)

EPILEPSY CME 2011

EPILEPSY CME 2011

TREATMENT iv
Improving adherence
Patient and caregiver education Reducing stigmatization Simple medication regimes
Monotherapy and serial monotherapy
Controlled release formulations

Enhanced relationship between physician and patient/caregiver

EPILEPSY CME 2011

TREATMENT v

EPILEPSY CME 2011