MECHANISM
OF SRSE

The complex brain

The exact causes of super-refractory status epilepticus (SRSE) are unknown. However, SRSE is defined by seizures that continue or recur after initiation of anesthesia.1,2 In other words, the seizures are drug-resistant and self-sustaining or self-perpetuating.1 Let’s look at several key insights into the neurobiological mechanisms of self-sustaining seizures.

Neurons in the brain

Cognition and behavior emerge from the coordinated activity of neurons in the brain. Connected neurons convey information through electrical signals at a specialized junction point, the synapse. Neurons are organized into neural circuits, which mediate information processing in the nervous system.3

A synapse is a connection between two neurons3:

  • Presynaptic neuron – cell that transmits information
  • Postsynaptic neuron – cell that receives information

Neuronal information is encoded in electrical signals. The firing of electrical signals causes neurotransmitter (i.e., glutamate or ɣ-aminobutyric acid [GABA]) release from the presynaptic neuron. Neurotransmitters then bind to their proper receptors on the postsynaptic neuron. A synapse can be excitatory or inhibitory depending on the neurotransmitter and the receptor.3

Status epilepticus induces functional changes in the GABA receptors

For illustrative puposes only. Images are not exact representations.

Self-sustaining seizures may be characterized by the imbalance of excitatory and inhibitory brain activity4

The exact cause of self-sustaining seizures is unknown. However, it is believed that these seizures are the result of abnormal electrical activity, or uncontrolled neuronal excitation, in the brain, which can be caused by1:


  • Failure of inhibitory mechanisms
  • Unchecked proliferation of excitatory mechanisms

Failure to terminate seizures can result in neuronal death,5-7 neuronal injury,5-7 and altered neuronal networks1,2 depending on the type and duration of seizures.5,8

Excitatory brain activity is mediated by the binding of glutamate, the principal excitatory neurotransmitter, to glutamate receptors on neurons. Inhibitory brain activity is mediated through the binding of GABA, the principal inhibitory neurotransmitter, to GABA receptors on neurons.3

Changes in the availability of specific types of GABA receptors are postulated to facilitate benzodiazepine resistance in cases of prolonged seizure.9 In contrast, glutamate receptors mediate excitatory neurotransmission, and unchecked increased activity of excitatory glutaminergic neurotransmission may lead to neuronal damage.3,7,10

Synaptic dysfunction, and other cellular processes, are thought to be among the important events involved in the mechanism of prolonged or self-sustaining seizures2,4,11,15,16

Reduction in principal inhibitory neurotransmitters

During status epilepticus (SE), increased receptor internalization leads to an overall reduction in functional GABA receptors, making receptors unavailable for GABA to bind to. This may be involved in the reduction in inhibitory neural activity observed in animal models.11,17

Status epilepticus induces functional changes in the GABA receptors

Changes in GABAergic inhibition

As shown in animal studies, SE may alter GABA receptors on the postsynaptic membrane of neurons.11,17 In addition, SE can alter the flow of ions through the receptors.18.19

Glutaminergic receptor over-activity

Increased glutaminergic receptor activity causes calcium influx into the cells, which may lead to necrosis and apoptosis. This process of increasing excitatory drive leading to cell damage or death, called “excitotoxicity,” is the principal cause of neuronal cell death associated with prolonged SE episodes.2,3,5-7,10

Rapid identification
and action is needed

Though the exact mechanism of SRSE is unknown, when excitatory mechanisms proliferate, cell damage and neuronal death may follow, underscoring the clinical importance of early diagnosis and effective disease management.2,20

References:

  1. Hocker S, Tatum WO, LaRoche S, Freeman WD. Refractory and super-refractory status epilepticus – an update. Curr Neurol Neurosci Rep. 2014;14:452.
  2. Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain. 2011;134(10):2802-2818.
  3. Kandel ER, Schwartz JH, Jessell TM, Siegelbaum SA, Hudspeth AJ. Principles of Neural Science. 5th ed. New York, NY: McGraw Hill Medical; 2013.
  4. Cuero MR, Varelas PN. Super-refractory status epilepticus. Curr Neurol Neurosci Rep. 2015;15(11):74.
  5. Scholtes FB, Renier WO, Meinardi H. Generalized convulsive status epilepticus: causes, therapy, and outcome in 346 patients. Epilepsia. 1994;35(5):1104-1112.
  6. Payne T, Bleck TP. Status epilepticus. Crit Care Clin. 1997;13(1):17-38.
  7. Meldrum B. Excitotoxicity and epileptic brain damage. Epilepsy Res. 1991;10:55-56.
  8. Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus – Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia. 2015;56(10):1515-1523.
  9. Deeb T, Maguire J, Moss S. Possible alterations in GABA(A) receptor signaling that underlie benzodiazepine-resistant seizures. Epilepsia. 2012;53(suppl 9):79-88.
  10. Naylor DE, Liu H, Niquet J, Wasterlain CG. Rapid surface accumulation of NMDA receptors increases glutamatergic excitation during status epilepticus. Neurobiol Dis. 2013;54:225-238.
  11. Joshi S, Kapur J. GABAA receptor plasticity during status epilepticus. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV. Jasper’s Basic Mechanisms of the Epilepsies. 4th ed. Bethesda, MD: National Center for Biotechnology Information (US); 2012.
  12. Naylor DE, Liu H, Wasterlain CG. Trafficking of GABAA receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. J Neurosci. 2005;25(34):7724-7733.
  13. Naylor DE, Liu H, Niquet J, Wasterlain CG. Rapid surface accumulation of NMDA receptors increases glutamatergic excitation during status epilepticus. Neurobiol Dis. 2013;54:225-238.
  14. Wasterlain CG, Liu H, Mazarati AM, et al. Self-sustaining status epilepticus: a condition maintained by potentiation of glutamate receptors and by plastic changes in substance P and other peptide neuromodulators. Epilepsia. 2000;41(suppl 6):S134-S143.
  15. Cock HR. The role of mitochondria in status epilepticus. Epilepsia. 2007;48(suppl 8):24-27.
  16. Hocker S, Nagarajan E, Rabinstein AA, Hanson D, Britton JW. Progressive brain atrophy in super-refractory status epilepticus. JAMA Neurol. 2016;73(10): 1201-1207.
  17. Luscher B, Fuchs T, Kilpatrick CL. GABAA receptor trafficking-mediated plasticity of inhibitory synapses. Neuron. 2011;70:385-409.
  18. Raimondo JV, Burman RJ, Katz AA, Akerman CJ. Ion dynamics during seizures. Front Cell Neurosci. 2015;9:419.
  19. Meldrum B, Chapman A. Metabolic consequences of seizures. In: Siegel GJ, Agranoff BW, Albers RW, et al, eds. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th ed. Philadelphia, PA: Lippincott-Raven; 1999.
  20. Chen JW, Wasterlain CG. Status epilepticus: pathophysiology and management in adults. Lancet Neurol. 2006;5:246-256.