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STATUS EPILEPTICUS
Definition and Pathophysiology
Presenter : Dr. Vamsi Krishna Koneru
DM Neurology (CMC Vellore)
PDF Epilepsy (JIPMER)
19/9/23
Status Epilepticus - Facts and Figures
• 10–41 per 100,000 per year .
• 4–16% of people with epilepsy will have at least one episode of status epilepticus
• Approximately half the episodes of status epilepticus occur in people with no prior history of
epilepsy.
• Status epilepticus is a risk factor in those without epilepsy for the development of chronic
epilepsy.
• Acute symptomatic SE has a three-fold risk of resulting in chronic epilepsy compared to acute
symptomatic seizures
Status Epilepticus - Facts and Figures
• Convulsive status epilepticus (SE) :
• Common neurological emergency
• Associated with a high mortality
• Survivors often have neurological and cognitive deficits
Status Epilepticus - Facts and Figures
Status epilepticus,Lancet 2015
Status Epilepticus - Facts and Figures
Status Epilepticus in the Pediatric Emergency Department
Jonathan E. Kurz et al
• Seizure threshold in the immature brain is lower than the mature brain
• Highest synaptic density is seen at around 2 months of age
• Excitatory synapses mature earlier than inhibitory synapses
• Stimulation of GABAA receptors in the immature brain results in depolarisation
(In adult brain it causes hyperpolarisation )
HISTORICAL INTRODUCTION
• Historically Status epilepticus (SE) is considered
the most extreme form of a seizure
• Trousseau, 1867:
“In the status epilepticus, when the convulsive
condition is almost continuous, something
special takes place which requires an
explanation ”.
HISTORICAL INTRODUCTION
• In 1876, Bourneville defined status epilepticus as more or less incessant seizures.
• In 1903 Clark and Prout described the natural course of status epilepticus
• They recognised three phases:
• Early pseudostatus phase,
• Convulsive status and
• Stuporous status
HISTORICAL INTRODUCTION
• First ILAE definition of status epilepticus (1970) :
• Seizure that persists for a sufficient length of time or is repeated
frequently enough to produce a fixed and enduring condition
HISTORICAL INTRODUCTION
• 1981 Revision of ILAE status epilepticus definition:
• Seizure that persists for a sufficient length of time or is repeated
frequently enough that recovery between attacks does not occur
HISTORICAL INTRODUCTION
• Observations from the work by Meldrum et al :
• Led to the definition for SE duration of 30 min.
• Experimental evidence from baboons
• Rationale : Irreversible neuronal injury may occur after 30 min of ongoing seizure
activity
HISTORICAL INTRODUCTION
HISTORICAL INTRODUCTION
• As the prognosis of SE worsens
with increasing duration
• Clinicians have rightfully argued
for earlier initiation of
treatment
HISTORICAL INTRODUCTION
• Review article by Bleck (1991) :
• Status epilepticus : continuous or repeated
seizures lasting >20 min
• Veterans Affairs status epilepticus cooperative study
group:
• Duration of 10 min as inclusion criterion for
status epilepticus
HISTORICAL INTRODUCTION
• Generalized convulsive SE in adults and children older than 5 years was operationally
defined as :
• “ ≥5 min of continuous seizure or two or more discrete seizures between which
there is incomplete recovery of consciousness”
2015 ILAE DEFINITION OF STATUS EPILEPTICUS
• Status epilepticus is a condition resulting either from :
• Failure of the mechanisms responsible for seizure termination or
• Initiation of mechanisms, which lead to abnormally, prolonged
seizures (after time point t1).
• It is a condition, which can have long-term consequences (after time
point t2), including neuronal death, neuronal injury, and alteration of
neuronal networks, depending on the type and duration of seizures.
2015 ILAE DEFINITION OF STATUS EPILEPTICUS
• This definition is conceptual, with two operational dimensions:
• Time point (t1) : beyond which the seizure should be regarded as
“continuous seizure activity.”
• Time point (t2) : time of ongoing seizure activity after which there is
a risk of long-term consequences
2015 ILAE DEFINITION OF STATUS EPILEPTICUS
• Time points of convulsive (tonic–clonic) SE :
• T1 : 5 min
• T2 : 30 min
• Based on animal experiments and clinical research
• This evidence is incomplete
• There is considerable variation
• Should be considered as the best estimates currently available
2015 ILAE DEFINITION OF STATUS EPILEPTICUS
2015 ILAE STATUS EPILEPTICUS
DEFINITION OF ELECTRICAL STATUS EPILEPTICUS
• ELECTRICAL STATUS EPILEPTICUS :
• More than or equal to 10 minutes
(or)
• 20% of the record
Refractory & Super Refractory SE
• Refractory status epilepticus :
• seizures that continue despite first- and second line treatments
• Super Refractory Status Epilepticus :
• Status epilepticus that continues or recurs 24 hours or more after
the onset of anesthetic therapy, including those cases where status
epilepticus recurs on the reduction or withdrawal of anesthesia
ILAE classification of SE
• The ILAE classification of SE consists of 4 axes, as follows:
• Semiology - including those with or without prominent motor findings
• Etiology - known and unknown causes
• EEG correlates - description of the EEG
• Age - neonatal, infancy, childhood, adolescent, adult, and elderly
Pathophysiology of status epilepticus
Pathophysiology of status epilepticus
• Why seizures start and stop is unknown
• Imbalance between excitatory and inhibitory neurotransmission
Normal Action Potential In A Neuron
Nerve action potential, Cambridge University Press
Paroxysmal Depolarizing Shift
Nerve action potential, Cambridge University Press
Paroxysmal Depolarizing Shift
• It is a sudden large depolarization of the resting membrane potential
• Magnitude of voltage change is in the range of 20 - 40 mV and lasts 50 - 200 ms
• At its peak triggers a flurry of action potentials with a frequency of several
hundred Hz.
• Paroxysmal depolarizing shift is followed by prolonged hyperpolarization
Ayala et al., 1973
Pathophysiology of status epilepticus
Pathophysiology of status epilepticus
Pathophysiology of status epilepticus
Pathophysiology of status epilepticus
Kandel and schwartz
• HYPEREXCITABILITY + HYPERSYNCHRONY + LOSS OF SURROUND
INHIBITION
• Leads to spread of seizure activity:
• Contiguous areas via local cortical connections,
• Distant areas via long association pathways such as the CC
Pathophysiology Of Status Epilepticus
• For seizure termination, different biological processes have been proposed :
• Neurotransmitter depletion
• ATP depletion
• Ionic changes
• Increased GABA-ergic drive
• Release of adenosine
• Release of peptides (e.g. Inhibitory Neuropeptide Y etc.)
• Suppression or failure of these processes may promote STATUS EPILEPTICUS
Pathophysiology of status epilepticus
• Much of the pathophysiology of status epilepticus :
• Poorly understood
• Animal models
• Fundamental principle :
• Failure of endogenous mechanisms to terminate a seizure
• Initiation of mechanisms leading to abnormally prolonged seizures
Important changes leading to status epilepticus
• GABA A receptor internalisation
• NMDA receptor increased expression
• AMPA receptors lose their GLUA 2 subunit
• Presynaptic adenosine A1 receptor is decreased
• Presynaptic GABA(B) receptor expression is decreased
• Increase in Substance P
• Decrease in Neuro-peptide Y
• Decrease in other inhibitory Neuro-peptides like Galanin, Dynorphin, Somatostatin
Status epilepticus,Lancet 2016
Seizure: European Journal of Epilepsy 68 (2019) 16
• Ability of diazepam to stop seizures progressively decreased from :
• 6 of 6 rats when administered early
• (mean: 7.3 minutes since seizure onset)
• 1 of 6 rats when administered late
• (mean: 36.7 minutes since seizure onset)
• A rat model of SE based on electrical stimulation of the hippocampus :
• Phenobarbital (70 mg/kg) administered :
• 15 min after stimulation , controlled seizures in 66% of animals(n= 6).
• 60 min after stimulation , controlled seizures in 25% of animals (n = 4)
• Ketamine (100 mg/kg) administered :
• 15 min after stimulation did not control seizures in any animal (n = 4)
• One hour after stimulation , controlled seizures in all animals (n = 4).
AMPA RECEPTOR
The essential role of AMPA receptor GluA2 subunit RNA editing in the normal and
diseased brain. Amanda Wright, Bryce Vissel. Frontiers Neurology
• During SE, there is rapid, ongoing plasticity of AMPARs
• Expression of GluA2-lacking AMPARs.
• They provide another source of Ca2+ entry into the principal neurons.
• Benzodiazepam-refractory SE can be terminated by AMPAR antagonism.
• The data identifies AMPARs as potential therapeutic target for the treatment of
SE
Role of GABAB RECEPTORS
Keeping the Balance: GABAB Receptors in the
Developing Brain and Beyond. Brain Sci. 2022
Role of Adenosine A1 Receptor
Adenosine A1 Receptor and Epilepsy.
https://doi.org/10.3390/ijms22010320
Role of Substance P
• Binding of SP to the NK-1 receptor will result in :
• Reduces inward rectifying K+ currents
• Increases the intracellular Ca2+concentration
• Removal of Mg2+ blockade and increased glutamate sensitivity
• Promotes protein kinase c-dependent phosphorylation of the NMDA
receptor
• All the above processes contribute to the maintenance phase of self-
sustaining status epilepticus
Role of Substance P
• SSSE results in a rapid and dramatic increase in the expression of Preprotachykinin A (a
precursor of Substance P) mRNA and SP in principal neurons in CA3, CA1, and the dentate
gyrus and in hippocampal mossy fibers
Substance P is expressed in hippocampal principal neurons during
status epilepticus and plays a critical role in the maintenance of status
epilepticus
https://doi.org/10.1073/pnas.96.9.5286
Role of Neuro-peptide Y
• Neuro-peptide Y exerts
• Potent anticonvulsive action
• Through presynaptic Y2 receptors
• By suppressing Glutamate release
• It’s level increases towards the end of the seizure
• However in SE, there will be insufficient replacement
Role of Neuro-peptide Y
Net effect
• GABA A receptor internalisation
• NMDA receptor increased expression
• AMPA receptors lose their GLUA 2 subunit
• Presynaptic adenosine A1 receptor is decreased
• Presynaptic GABA(B) receptor expression is decreased
• Increase in Substance P
• Decrease in Neuro-peptide Y
• Decrease in other inhibitory Neuro-peptides like Galanin, Dynorphin, Somatostatin
Status epilepticus,Lancet 2015
Pathophysiology of status epilepticus
• Neuronal death and dysfunction
• Specific groups of neurons seem to be more susceptible
• CA3 and CA1 regions
• Reason
• Physiological compromise including hypotension, hypoxia, hypoglycemia and acidosis
• Seizure itself
• Enzymes activated by intracellular calcium accumulation (Apoptosis through activation of
caspase 3)
• Mitochondrial dysfunction
• Reactive oxygen species
Pathophysiology of status epilepticus
• Seizure-induced re-modeling of neuronal networks
Neuronal loss and damage
Neurogenesis
Axonal sprouting
Reduced dendritic branching and spine loss Gliosis
Majak and Pitkänen, Epil Behav 2004
Pathophysiology of status epilepticus
Status epilepticus,Lancet 2015
THANK YOU

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Status epilepticus-Definition and Pathophysiology

  • 1. STATUS EPILEPTICUS Definition and Pathophysiology Presenter : Dr. Vamsi Krishna Koneru DM Neurology (CMC Vellore) PDF Epilepsy (JIPMER) 19/9/23
  • 2. Status Epilepticus - Facts and Figures • 10–41 per 100,000 per year . • 4–16% of people with epilepsy will have at least one episode of status epilepticus • Approximately half the episodes of status epilepticus occur in people with no prior history of epilepsy. • Status epilepticus is a risk factor in those without epilepsy for the development of chronic epilepsy. • Acute symptomatic SE has a three-fold risk of resulting in chronic epilepsy compared to acute symptomatic seizures
  • 3. Status Epilepticus - Facts and Figures • Convulsive status epilepticus (SE) : • Common neurological emergency • Associated with a high mortality • Survivors often have neurological and cognitive deficits
  • 4. Status Epilepticus - Facts and Figures Status epilepticus,Lancet 2015
  • 5. Status Epilepticus - Facts and Figures Status Epilepticus in the Pediatric Emergency Department Jonathan E. Kurz et al
  • 6. • Seizure threshold in the immature brain is lower than the mature brain • Highest synaptic density is seen at around 2 months of age • Excitatory synapses mature earlier than inhibitory synapses • Stimulation of GABAA receptors in the immature brain results in depolarisation (In adult brain it causes hyperpolarisation )
  • 7. HISTORICAL INTRODUCTION • Historically Status epilepticus (SE) is considered the most extreme form of a seizure • Trousseau, 1867: “In the status epilepticus, when the convulsive condition is almost continuous, something special takes place which requires an explanation ”.
  • 8. HISTORICAL INTRODUCTION • In 1876, Bourneville defined status epilepticus as more or less incessant seizures. • In 1903 Clark and Prout described the natural course of status epilepticus • They recognised three phases: • Early pseudostatus phase, • Convulsive status and • Stuporous status
  • 9. HISTORICAL INTRODUCTION • First ILAE definition of status epilepticus (1970) : • Seizure that persists for a sufficient length of time or is repeated frequently enough to produce a fixed and enduring condition
  • 10. HISTORICAL INTRODUCTION • 1981 Revision of ILAE status epilepticus definition: • Seizure that persists for a sufficient length of time or is repeated frequently enough that recovery between attacks does not occur
  • 11. HISTORICAL INTRODUCTION • Observations from the work by Meldrum et al : • Led to the definition for SE duration of 30 min. • Experimental evidence from baboons • Rationale : Irreversible neuronal injury may occur after 30 min of ongoing seizure activity
  • 13. HISTORICAL INTRODUCTION • As the prognosis of SE worsens with increasing duration • Clinicians have rightfully argued for earlier initiation of treatment
  • 14. HISTORICAL INTRODUCTION • Review article by Bleck (1991) : • Status epilepticus : continuous or repeated seizures lasting >20 min • Veterans Affairs status epilepticus cooperative study group: • Duration of 10 min as inclusion criterion for status epilepticus
  • 15. HISTORICAL INTRODUCTION • Generalized convulsive SE in adults and children older than 5 years was operationally defined as : • “ ≥5 min of continuous seizure or two or more discrete seizures between which there is incomplete recovery of consciousness”
  • 16. 2015 ILAE DEFINITION OF STATUS EPILEPTICUS • Status epilepticus is a condition resulting either from : • Failure of the mechanisms responsible for seizure termination or • Initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1). • It is a condition, which can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures.
  • 17. 2015 ILAE DEFINITION OF STATUS EPILEPTICUS • This definition is conceptual, with two operational dimensions: • Time point (t1) : beyond which the seizure should be regarded as “continuous seizure activity.” • Time point (t2) : time of ongoing seizure activity after which there is a risk of long-term consequences
  • 18. 2015 ILAE DEFINITION OF STATUS EPILEPTICUS • Time points of convulsive (tonic–clonic) SE : • T1 : 5 min • T2 : 30 min • Based on animal experiments and clinical research • This evidence is incomplete • There is considerable variation • Should be considered as the best estimates currently available
  • 19. 2015 ILAE DEFINITION OF STATUS EPILEPTICUS 2015 ILAE STATUS EPILEPTICUS
  • 20. DEFINITION OF ELECTRICAL STATUS EPILEPTICUS • ELECTRICAL STATUS EPILEPTICUS : • More than or equal to 10 minutes (or) • 20% of the record
  • 21. Refractory & Super Refractory SE • Refractory status epilepticus : • seizures that continue despite first- and second line treatments • Super Refractory Status Epilepticus : • Status epilepticus that continues or recurs 24 hours or more after the onset of anesthetic therapy, including those cases where status epilepticus recurs on the reduction or withdrawal of anesthesia
  • 22. ILAE classification of SE • The ILAE classification of SE consists of 4 axes, as follows: • Semiology - including those with or without prominent motor findings • Etiology - known and unknown causes • EEG correlates - description of the EEG • Age - neonatal, infancy, childhood, adolescent, adult, and elderly
  • 24. Pathophysiology of status epilepticus • Why seizures start and stop is unknown • Imbalance between excitatory and inhibitory neurotransmission
  • 25. Normal Action Potential In A Neuron Nerve action potential, Cambridge University Press
  • 26. Paroxysmal Depolarizing Shift Nerve action potential, Cambridge University Press
  • 27. Paroxysmal Depolarizing Shift • It is a sudden large depolarization of the resting membrane potential • Magnitude of voltage change is in the range of 20 - 40 mV and lasts 50 - 200 ms • At its peak triggers a flurry of action potentials with a frequency of several hundred Hz. • Paroxysmal depolarizing shift is followed by prolonged hyperpolarization
  • 34. • HYPEREXCITABILITY + HYPERSYNCHRONY + LOSS OF SURROUND INHIBITION • Leads to spread of seizure activity: • Contiguous areas via local cortical connections, • Distant areas via long association pathways such as the CC
  • 35. Pathophysiology Of Status Epilepticus • For seizure termination, different biological processes have been proposed : • Neurotransmitter depletion • ATP depletion • Ionic changes • Increased GABA-ergic drive • Release of adenosine • Release of peptides (e.g. Inhibitory Neuropeptide Y etc.) • Suppression or failure of these processes may promote STATUS EPILEPTICUS
  • 36. Pathophysiology of status epilepticus • Much of the pathophysiology of status epilepticus : • Poorly understood • Animal models • Fundamental principle : • Failure of endogenous mechanisms to terminate a seizure • Initiation of mechanisms leading to abnormally prolonged seizures
  • 37. Important changes leading to status epilepticus • GABA A receptor internalisation • NMDA receptor increased expression • AMPA receptors lose their GLUA 2 subunit • Presynaptic adenosine A1 receptor is decreased • Presynaptic GABA(B) receptor expression is decreased • Increase in Substance P • Decrease in Neuro-peptide Y • Decrease in other inhibitory Neuro-peptides like Galanin, Dynorphin, Somatostatin
  • 39. Seizure: European Journal of Epilepsy 68 (2019) 16
  • 40.
  • 41. • Ability of diazepam to stop seizures progressively decreased from : • 6 of 6 rats when administered early • (mean: 7.3 minutes since seizure onset) • 1 of 6 rats when administered late • (mean: 36.7 minutes since seizure onset)
  • 42. • A rat model of SE based on electrical stimulation of the hippocampus : • Phenobarbital (70 mg/kg) administered : • 15 min after stimulation , controlled seizures in 66% of animals(n= 6). • 60 min after stimulation , controlled seizures in 25% of animals (n = 4) • Ketamine (100 mg/kg) administered : • 15 min after stimulation did not control seizures in any animal (n = 4) • One hour after stimulation , controlled seizures in all animals (n = 4).
  • 43. AMPA RECEPTOR The essential role of AMPA receptor GluA2 subunit RNA editing in the normal and diseased brain. Amanda Wright, Bryce Vissel. Frontiers Neurology
  • 44.
  • 45. • During SE, there is rapid, ongoing plasticity of AMPARs • Expression of GluA2-lacking AMPARs. • They provide another source of Ca2+ entry into the principal neurons. • Benzodiazepam-refractory SE can be terminated by AMPAR antagonism. • The data identifies AMPARs as potential therapeutic target for the treatment of SE
  • 46. Role of GABAB RECEPTORS Keeping the Balance: GABAB Receptors in the Developing Brain and Beyond. Brain Sci. 2022
  • 47. Role of Adenosine A1 Receptor Adenosine A1 Receptor and Epilepsy. https://doi.org/10.3390/ijms22010320
  • 48. Role of Substance P • Binding of SP to the NK-1 receptor will result in : • Reduces inward rectifying K+ currents • Increases the intracellular Ca2+concentration • Removal of Mg2+ blockade and increased glutamate sensitivity • Promotes protein kinase c-dependent phosphorylation of the NMDA receptor • All the above processes contribute to the maintenance phase of self- sustaining status epilepticus
  • 49. Role of Substance P • SSSE results in a rapid and dramatic increase in the expression of Preprotachykinin A (a precursor of Substance P) mRNA and SP in principal neurons in CA3, CA1, and the dentate gyrus and in hippocampal mossy fibers Substance P is expressed in hippocampal principal neurons during status epilepticus and plays a critical role in the maintenance of status epilepticus https://doi.org/10.1073/pnas.96.9.5286
  • 50. Role of Neuro-peptide Y • Neuro-peptide Y exerts • Potent anticonvulsive action • Through presynaptic Y2 receptors • By suppressing Glutamate release • It’s level increases towards the end of the seizure • However in SE, there will be insufficient replacement
  • 52. Net effect • GABA A receptor internalisation • NMDA receptor increased expression • AMPA receptors lose their GLUA 2 subunit • Presynaptic adenosine A1 receptor is decreased • Presynaptic GABA(B) receptor expression is decreased • Increase in Substance P • Decrease in Neuro-peptide Y • Decrease in other inhibitory Neuro-peptides like Galanin, Dynorphin, Somatostatin
  • 54. Pathophysiology of status epilepticus • Neuronal death and dysfunction • Specific groups of neurons seem to be more susceptible • CA3 and CA1 regions • Reason • Physiological compromise including hypotension, hypoxia, hypoglycemia and acidosis • Seizure itself • Enzymes activated by intracellular calcium accumulation (Apoptosis through activation of caspase 3) • Mitochondrial dysfunction • Reactive oxygen species
  • 55. Pathophysiology of status epilepticus • Seizure-induced re-modeling of neuronal networks Neuronal loss and damage Neurogenesis Axonal sprouting Reduced dendritic branching and spine loss Gliosis Majak and Pitkänen, Epil Behav 2004
  • 56. Pathophysiology of status epilepticus Status epilepticus,Lancet 2015

Editor's Notes

  1. Mitochondria are one of the main buffers of cytosolic calcium, taking up calcium predominantly through the mitochondrial calcium uniporter[75]. Calcium uptake by mitochondria activates mitochondrial respiratory chain function and can increase mitochondrial ATP (and free radical) production through activation of calcium-dependent NADH dehydrogenases[75]. However, excessive mitochondrial calcium accumulation has two main detrimental effects. First, calcium accumulation can result in mitochondrial membrane depolarization[60]. Since the mitochondrial membrane potential is necessary for ATP production, this can result in decreased ATP production and consequently cellular energy failure[60]. Energy failure results in a decrease in the cell’s ability to maintain ionic gradients, and so results in cellular depolarization, hyperexcitability and eventually cell death