Crisis convulsiva & epilepsia:

mecanismos fisiopatológicos
básicos

José Luis Castillo

U. De Chile
Epilepsy may require chronic treatment (with antiepileptic medication and,
in some cases, surgery) whereas therapy for an isolated seizure is directed
toward the underlying cause and may not require antiepileptic drugs
(AEDs).

Introducción
Furthermore, epilepsy often has profound psychosocial ramifications for
the patient, and is thus a diagnosis to be assigned with care.

Crisis convulsiva (Seizure)

manifestación clínica de una descarga anormal, excesiva
e hipersincrónica de un grupo de neuronas

Epilepsia
trastorno del SNC caracterizado por la recurrencia de
crisis epilépticas; no provocadas por una condición
sistémica o un insulto neurológico agudo

Epileptogenesis
secuencia de eventos que transforma una red neuronal
normal a una red hiperexcitable
Epilepsia
Epilepsia heterogénea en términos:
• Expresión clínica
• Etiología subyacente
• Fisiopatología
Focal
Generalizada
Crisis convulsiva resultado de una
alteración del balance normal entre inhibición
y excitación de un área local o cerebral
difusa
Introducción

Actividad eléctrica aberrante

subyacente a la crisis epiléptica:
• Hiperexcitabilidad neuronal
• Hipersincronía neuronal
• Fenómeno que involucra grandes redes neuronales
Membrane potential thus varies with :

activation of ligand-gated channels,

whose conductance is affected bybinding to neurotransmitters;

Descarga neuronal normal

or with activation of voltage-gated channels,
whose conductance is affected by changes in transmembrane potential;

- or with changes in intracellular ion compartmentalization.

action potential can occur.

Activation of I causes an inhibitory postsynaptic potential (IPSP), which

also keeps the membrane potential further from threshold for action
potential generation.

Descarga neuronal normal

Inset (box) shows magnified portion of the neuronal membrane as a lipid
bilayer with interposed voltagegated Na+ and K+ channels; the direction of
ion fluxes during excitatory activation is shown. After firing, the membrane
bound Na+ –K+ pump and star shaped astroglial cells restore ionic
balance.

AHP: afterhyperpolarization; EPSP: exciatory postsynaptic potential; IPSP:

inhibitory postsynaptic potential; mV: millivolts.
can be found postsynaptically on excitatory principal cells as well as on
inhibitory interneurons, and have been demonstrated on certain types of
glial cells.

The ionotropic subclasses are the alpha-amino-2,3-dihydro-5-methyl-3-

Glutamato
oxo-4-isoxazolepropanoic acid (AMPA), kainate receptors, and N-methyl-
D-aspartate (NMDA); these allow ion influx upon activation by glutamate

NTs excitatorio más importante

Dos grupos de receptores de glutamato
• Ionotropic—fast synaptic transmission
– NMDA, AMPA, kainate
– Gated Ca++ and Gated Na+ channels
• Metabotropic—slow synaptic transmission
– Quisqualate
– Regulation of second messengers (cAMP and
Inositol)
– Modulation of synaptic activity
Modulación de los receptores de glutamato
• Glycine, polyamine sites, Zinc, redox site
The NMDA receptor also has a Ca++ channel that is blocked by Mg++ ions
in the resting state, but under conditions of local membrane depolarization,
Mg++ is displaced and the channel becomes permeable to Ca++; influx of
Ca++ tends to further depolarize the cell, and is thought also to contribute

Glutamato
to Ca++ mediated neuronal injury under conditions of excessive neuronal
activation (such as status epilepticus and ischemia), potentially leading to
cell death, a process termed excitotoxicity.
Glutamato

Receptores NMDA tienen canales Ca++

que se bloquea con Mg++ en estado de
reposo.
Mg++ desplazado, activación neuronal
excesiva (SE, isquemia), muerte celular
(excitotoxicidad)

B-Slide 9
subtypes of receptor: GABAA and GABAB receptors.

GABAA receptors are found postsynaptically, while GABAB receptors are

found presynapti-cally, and can thereby modulate synaptic release.

GABA
Neurotransmisor inhibitorio más
importante del SNC
Dos tipos de receptores
• GABAA—post-synaptic, specific
recognition sites, linked to CI- channel
• GABAB —presynaptic autoreceptors,
mediated by K+ currents
GABAB receptors are associated with second messenger systems rather
than Cl channels, and lead to attenuation of transmitter release due to their
presynaptic location. The second messenger systems often result in
opening of K+ channels, leading to a hyperpolarizing current. Certain
GABAB agonists, such as baclofen, have been reported to exacerbate

GABA
hyperexcitability and seizures.

Relevant to epilepsy, glutamate and GABA both require active reuptake to

be cleared from the synaptic cleft.
Transporters for both glutamate and GABA exist on both neurons and glia
(primarily astrocytes). Interference with transporter function has also been GABA site
shown to activate or suppress epileptiform activity in animal models,
depending on which transporter is being blocked. Barbiturate site

Benzodiazepine
site

Steroid site

Picrotoxin site

Diagram of the GABAA receptor

From Olsen and Sapp, 1995
Glutamato y GABA requieren
recaptación para limpiarse de la
hendidura sináptica.
Existen transportadores en las
neuronas y glía.
La interferencia con estos
transportadores puede activar o
suprimir actividad epiléptica,
dependiendo del transportador
bloqueado. B-Slide 12
increased excitatory synaptic neurotransmission,

Mecanismo celular de la
decreased inhibitory neurotransmission,

an alteration in voltage-gated ion channels,

generación de crisis epiléptica

or an alteration of intra- or extra-cellular ion concentrations in favor of
membrane depolarization.

Excitación (too much)

• Ionic—inward Na+, Ca++ currents
• Neurotransmitter—glutamate, aspartate

Inhibición (too little)

• Ionic—inward CI-, outward K+ currents
• Neurotransmitter—GABA
Factores Neuronales (intrínsecos) que
modifican la excitabilidad neuronal

Canales iónicos: tipo, número,

distribución

Receptores: modificaciones
bioquímicas

Activación de sistemas de segundos

mensajeros

Modulación de la expresión génica

(e.j., para proteínas de receptores)
Factores Neuronales (intrínsecos) que
modifican la excitabilidad neuronal

Modificaciones bioquímicas de
receptores:

Ej.: Fosforilación receptores NMDA

aumenta permeabilidad a Ca++, aumento
excitabilidad

B-Slide 15
Factores Neuronales (intrínsecos) que
modifican la excitabilidad neuronal

Activación de sistemas de segundos

mensajeros:

Por ej.: Unión de norepinefrina a receptor

alfa que activa GMP cíclico, que activa
proteína G, que abre canales de K y
disminuye excitabilidad.

B-Slide 16
Factores Neuronales (intrínsecos) que
modifican la excitabilidad neuronal

Modulación de expresión génica:

Por ej.: Edición de un par de RNA que

codifica una subunidad específica de
receptor de Glutamato que cambia
selectividad iónica del canal.

B-Slide 17
Factores extra-neuronales (extrínsecos)
que modifican la excitabilidad neuronal

Cambios en la concentración de iones

extracelulares

Remodelación sináptica por el input

aferente (localización o configuración)

Modulación del metabolismo de

neurotransmisores o recaptación de la
glia
Factores extra-neuronales (extrínsecos)
que modifican la excitabilidad neuronal

Cambios en la concentración de iones

extracelulares:

Por ej.: Disminución espacio extracelular

aumenta K extra que impide que salga K
para repolarizar y aumenta excitabilidad.

B-Slide 19
Factores extra-neuronales (extrínsecos)
que modifican la excitabilidad neuronal

Remodelación sináptica por el input

aferente:

Por ej.: Descarga de alta frecuencia de

estimulación (potencial post tetánico),
aumenta excitabilidad.

B-Slide 20
Factores extra-neuronales (extrínsecos)
que modifican la excitabilidad neuronal

Modulación del metabolismo de NT o

recaptación de la glía:

Por ej.: Disminución metabolismo de glía,

disminuye captación de NT como
Glutamato y aumenta excitabilidad.

B-Slide 21
Rol de la Glia

Restaura la homeostasis iónica luego

de actividad neuronal
• Captura de K extracelular (bloqueo de los canales
de K de la glia hiperexcitabilidad neuronal)
• Transporte de glutamato fuera del espacio
extracelular (bloqueo excitotoxicidad o epilepsia)
Regula excitabilidad, por otras vía:
• pH extracelular
• Liberación de agentes neuroactivos al espacio
extracelular
hippocampus consists of three major regions: subiculum, hippocampus
proper (Ammon's horn) and dentate gyrus.

Organización de red influye en la

The hippocampus and dentate gyrus have a three layered cortex. The
subiculum is the transition zone from the three to the six layered cortex.
Important regions of the hippocampus proper include CA1, CA 2, CA3.
excitabilidad neuronal: hipocampo
along the perforant path (PP) (1), where they synapse on granule cell

Inhibición sináptica en el
dendrites.

Next, dentate granule cells send their axons (called mossy fibers [MF]) to
synapse on cells in the hilus and in the CA3 field of Ammon’s horn (2).

hipocampo: dos circuitos

CA3 pyramidal cells, in turn, project to the CA1 field of Ammon’s horn via
Schaffer collaterals (SC) (3).

Finally, CA1 neurons send projections outward through the fornix to other
brain regions, as well as back to the subiculum. For simplicity, only the
classic "feed forward" projections of the trisynaptic pathway are shown.
The known "backward" projections and local circuit interactions are omitted
Feedback and
here for simplicity. feed-forward
inhibition, illustrated
via cartoon and
schematic of
simplified
hippocampal circuit

Babb TL, Brown WJ. Pathological Findings in Epilepsy. In: Engel J. Jr. Ed. B-Slide 24
Surgical Treatment of the Epilepsies. New York: Raven Press 1987: 511-540.
Mecanismos de generación de
redes hiperexcitables

Proliferación axonal excitatoria

“sprouting”

Pérdida de neuronas inhibitorias

Pérdida de neuronas excitatorias de

neuronas inhibitorias
(eg, 4, dashed lines), leaving axons of dentate neuron 1 without a
postsynaptic target. Those axons then "sprout" and innervate the dendrites
of granule neurons (thick curved arrow), creating the substrate for a

Sprouting axonal e hiperexcitabilidad

hyperexcitable circuit. Now, when dentate granule neuron 1 is activated,
multiple action potentials are fired in neurons 2 and 3, which fire
repetitively, a manifestation of their hyperexcitability.
hipocampal en epilepsia
This diagram represents a simplification; in fact, neurons of numerous
types in the dentate hilus (labeled H) may die as a consequence of status
epilepticus and the surviving neurons may become involved in seizure
induced synaptic plasticity. The resultant circuit function will depend upon
the balance of excitation and inhibition in the reorganized neuronal
network.
A close-up of the dentate granule-cell layer reveals several morphologic
changes characteristic of hippocampal sclerosis that may play a part in
epileptogenesis.

Esclerosis hipocampal
Newly sprouted mossy fibers from dentate granule cells can synapse on
dendrites of neighboring dentate granule cells, resulting in a recurrent
excitatory circuit. They can also sprout onto inhibitory interneurons.

Excitation interneurons, which normally activate inhibitory interneurons,

may be selectively vulnerable to brain insults. Finally, neurogenesis of new
dentate granule cells continues into adult life, and these neurons may
integrate themselves into abnormal circuits.
followed by the usual refractory period, thereby generating a prolonged
membrane depolarization (which is more prolonged than typically occurs in

PDS (paroxysmal depolarization

response to normal excitatory postsynaptic potentials [EPSPs]).

An interictal spike is caused by PDSs in large numbers of neurons that are

shift)
synchronized such that each involved neuron generates one PDS at the
same time. An electroclinical seizure occurs when large numbers of
neurons in one or more brain regions are repeatedly generating PDSs, in
sustained repetitive firing with synchronization. Repetitive neuronal firing
probably underlies the interictal and ictal unit and local field recording of
high- frequency oscillations.

Fenómeno fisiopatológico celular que

subyace a todos los tipos de crisis
epilépticas y las anomalías
electroencefalográficas interictales
• Potenciales de acción rápidos y repetidos, no
seguidos de período refractario, de una neurona
• Espiga interictal en el EEG PDS en un gran
número de neuronas (millones) que se sincronizan
en el tiempo
• Crisis electro-clínica ocurre cuando un gran
número de neuronas en una o más regiones,
generan repetidamente PDS, en forma sincronizada
"desynchronized" (neurons are not firing together in synchrony). In the
interictal condition, large "spikes" are seen focally at electrode 2 (and to a

Descarga neuronal anormal en

lesser extent at electrode 1, where they might be termed "sharp waves"),
representing synchronized firing of a large population of hyperexcitable
neurons (expanded in time below). The ictal state is characterized by a

epilepsia
long run of spikes.

(B) At the neuronal network level, the intracellular correlate of the interictal
EEG spike is the "paroxysmal depolarization shift" (PDS). The PDS is
initiated by a nonNMDAmediated fast EPSP (shaded area), and is
maintained by a longer, larger NMDAmediated EPSP. The postPDS
hyperpolarization (*) temporarily stabilizes the neuron. If this postPDS
hyperpolarization fails (right column, thick arrow), ictal discharge can occur.
The lowermost traces, recordings from neuron 2, show activity similar to
that recorded in neuron 1, with some delay (doubleheaded horizontal
arrow). Activation of inhibitory neuron 3 by firing of neuron 1 prevents
tracings).
(B) A primary generalized seizure begins simultaneously in both
hemispheres. The characteristic bilateral synchronous spikewave pattern
on EEG is generated by reciprocal interactions between the cortex and
thalamus, with rapid spread via corpus callosum (CC) contributing to
bilateral synchrony. One type of thalamic neuron (dark neuron) is a
GABAergic inhibitory cell that displays intrinsic pacemaker activity. Cortical
neurons (open triangles) send impulses to both thalamic relay neurons
(open diamond) and to inhibitory neurons, setting up oscillations of
excitatory and inhibitory activity, which gives rise to the rhythmic spike
waves on EEG.
CC: corpus callosum; EEG: electroencephalogram; GABA: gamma
aminobutyric acid.
Posibles mecanismos de
Epileptogénesis

Modelo de Kindling : estímulos

subconvulsivos o descargas breves
recurrentes, pueden generar cambios de
largo plazo
• Eventualmente se generarían crisis
clínicas inducidas por estímulos
• En algunos casos, determinan crisis
espontáneas (epilepsia)
• Aplicabilidad a epilepsia humana es
incierta
Posibles mecanismos de
Epileptogénesis
Algunos ejemplos de mecanismos
fisiopatológicos que determina epilepsia
Etiologías
Mutations in SCN1B, which encodes a voltage-gated sodium-channel
subunit, are associated with generalized epilepsy with febrile seizures plus
(Panel B). The apparent effect of these mutations is to allow passage of an
increased sodium current, which would lead to a greater depolarization

Canalopatías
during the action potential and an increased tendency to fire repetitive
bursts.

Mutations in KCNQ2 and KCNQ3, which both encode potassium channels,

are associated with benign familial neonatal convulsions (Panel C). These
mutations, which appear to decrease the potassium outflow underlying the
longer-lasting “M current,” are likely to cause a loss of spike-firing
adaptation and therefore an increase in neuronal firing frequency.
Causas secundarias
Causas secundarias