Status Epilepticus

1. STATUS EPILEPTICUS
PATHOPHYSIOLOGY &
PROGNOSIS
ARUN MATHAI MANI

2. DEFINITION OF STATUS
EPILEPTICUS

3. • Gastaut - 1962 - first international meeting on
SE, the Xth Marseilles Colloquium
• defined SE - whenever a seizure persists for a
sufficient length of time or is repeated
frequently enough to produce a fixed or
enduring epileptic condition
• He suggested that the diagnosis of SE requires
30–60 min of enduring epileptic condition

4. • Traditionally defined as 30 minutes of
continuous seizure activity or multiple
seizures without return to neurologic baseline

5. Duration of seizures
• Why 30 min ???
• repetitive seizures become self-sustaining and
pharmacoresistant and can lead to neuronal
injury within 15–30 min
• 30 min - Epilepsy Foundation of America’s
Working Group on Status Epilepticus
• 10 min - Veterans Affairs Status Epilepticus
Cooperation Study

6. Operational / Working Definition
• need for definition of SE that does not delay
therapeutic intervention and thereby prevent
irreversible damage
• Typical seizures last up to 3 to 5 minutes
before being stopped by the intrinsic
inhibitory mechanisms
• Seizures lasting longer than 5 minutes are less
likely to end without an external intervention

7. • Operational / Working Defenition - Stipulates
the treatment of convulsive status epilepticus
within 5 min of seizure onset

8. Refractory and Super-refractory SE
• Refractory status epilepticus is defined as
seizures that continue despite first- and
second line treatments
• Super-refractory status epilepticus occurs
when third-line agents (IV anesthetics) fail

9. The sequential phases of SE
• Clark and Prout
• basic mechanisms of SE in animal models and
in clinical situations
• described the natural course of status
epilepticus in patients unaffected by
anticonvulsants
• impending SE
• established SE
• subtle SE

10. Early or impending status
epilepticus
• continuous or intermittent seizures lasting
more than 5 min, without full recovery of
consciousness between seizures
• need intravenous high-dose anticonvulsants -
risk of developing SE is high
• corresponds with the 5 min operational
definition of SE

11. • mean duration of generalised convulsive
seizures in adults ranges from 62·2 s to 52·9 s
(SD 14) for the behavioural symptoms, and
averages 59·9 s (SD 12) for the
electroencephalographic changes
• impending status - duration of seizures is 18–
20 SD away from the norm of a single seizure -
indicating that something distinctly unusual
and severe is happening

12. Established status epilepticus
• clinical or electrographic seizures lasting more
than 30 min without full recovery of
consciousness between seizures
• cut-off at 30 min –
• status has become self sustaining in
experimental animals
• status-epilepticus-induced damage is distinct
• pharmacoresistance has developed

13. • Animal data - after 30 min of perforant path
stimulation, all animals were in established
status epilepticus
• 30 min of continuous seizures - accepted as
the defining duration of status epilepticus in
both clinical practice and clinical trials

14. Subtle status epilepticus
• Subtle SE - prolonged SE, both the motor and
electroencephalographic expression of
seizures become less florid
• prognostic and therapeutic implications –
same as convulsive status epilepticus

15. Aetiology
• low blood concentrations of antiepileptic
drugs in patients with chronic epilepsy (34%)
• remote symptomatic causes (24%)
• cerebrovascular accidents (22%)
• anoxia or hypoxia (~10%)
• metabolic causes (~10%)
• Alcohol and drug withdrawal (~10%).

16. PATHOPHYSIOLOGY

17. Basic mechanisms: current
concepts
• fundamental principle - failure of endogenous
mechanisms to terminate a seizure
• Excessive abnormal excitation during a seizure
• Loss of endogenous inhibitory mechanisms
• allow a single seizure to transform into status
epilepticus
• contribute to the self-perpetuating nature and
pharmaco-resistance

18. • Excitation can come from many sources -
• established epileptogenic circuit from
preexisting epilepsy
• Region surrounding a structural lesion
• diffuse excitation from a toxic/metabolic state

19. Perforant Path in SE
• The entorhinal cortex provides the major
excitatory input to the hippocampus
• Travel through the perforant pathway along
the parahippocampal gyrus to the neurons in
the dentate gyrus

21. • The dentate is often the brake for excitatory
activity
• But when overwhelmed, excitatory activity
feeds back to the hippocampus and then back
to the parahippocampal gyrus
• Self-amplifying reverberating circuit that
perpetuates status epilepticus

22. classic example
• status epilepticus in people after the
accidental ingestion of mussels contaminated
with domoic acid (analogue the glutamate)
• Supported the notion - excess excitation can
contribute to the development of seizures and
status epilepticus

24. Pathophysiology and neuronal
injury
• continuum of maladaptive changes
• transition from a single seizure to status
epilepticus
• self-sustaining nature of SE

25. Self-sustaining SE
• distinguishing feature of SE - self sustaining
• In most electrical and chemical animal models
of SE - seizures rapidly become self-sustaining
despite the withdrawal of the epileptogenic
stimulus
• Human data - far less clear, seizures which last
more than 30 min rarely stop spontaneously

26. • The initiation of SSSE - easily blocked by many
drugs that increase inhibition or reduce
excitation
• which directly or indirectly inhibit
glutamatergic neurotransmission
• once SSSE is established - maintained by
underlying changes that do not depend on
continuous seizures activity

27. Animal Model
• After 30 min of intermittent stimulation of an
excitatory glutamatergic pathway (PPS) in the
rat
• stopping the stimulation no longer stops
electrographic or behavioral seizures

28. Features of SSSE induced by 30
min perforant path stimulation
(PPS)Representative course of
spikes
Electrographic
activity in the dentate gyrus

29. Time-dependent
pharmacoresistance
• Another unique feature
• progressive, time-dependent development of
pharmacoresistance
• the potency of benzodiazepines may decrease
20-fold in 30 min of SSSE
• Phenytoin also loses potency, but more slowly
• By contrast, even late in its course, NMDA
blockers continue to be effective in stopping
SSSE

30. Animal Model
• Pharmacological studies in animals - two
distinct phases of SSSE
• initiation phase and maintenance phase
• initiation phase - can be easily blocked by
many pharmacological agents which enhance
inhibition or reduce excitation

31. • SSSE- maintained by underlying changes
which do not depend on continuous seizure
activity
• effectively terminated by only a few agents,
most of which inhibit glutamatergic
neurotransmission

33. The effects of an NMDA receptor
blocker

34. Pathophysiology of self-sustaining
status epilepticus
• Repeated seizures produce broad and
complex cascades of pathophysiological and
biochemical changes in the brain
• The first milliseconds to seconds are
dominated by the
• consequences of protein phosphorylation
• Ionic channels open and close
• neurotransmitters and modulators are
released, and receptor desensitisation takes
place

35. Cascade of selected mechanisms
involved in the transition of a
single seizure to status epilepticus

36. RECEPTOR TRAFFICKING

37. Trafficking of GABA and glutamate
receptors
• receptor trafficking causes some key
adaptations
• mainly of the GABA and glutamate receptors
• Immunocytochemical studies of the gamma 2
and beta2–3 subunits of the GABAa receptors
• decrease in the number of subunits present
on the synaptic membrane and an increase in
the interior of the cell

38. Intracellular distribution of GABAa
in hippocampal neurons from
Control SE

39. • Endocytosis and the decrease in functional
GABAa receptors in the synaptic cleft
• failure of GABAa inhibition
• progressive, time-dependent
pharmacoresistance to benzodiazepines

40. • Immunocytochemical studies - NR1 subunits
of NMDA receptors move from subsynaptic
sites to the synaptic surface
• physiological investigations show -increase in
functional NMDA receptors per dentate
granule cell synapse

41. Subcellular distribution of NMDA
NR1 subunits with SE

42. • AMPA and NMDA receptor subunits are
recruited to the synaptic membrane
• form additional excitatory receptors
• further enhances excitability in the midst of
uninhibited seizures

43. Receptor trafficking in transition of single
seizures to status epilepticus
Endocytosis of GABAa
receptors Exocytosis of NMDA receptors

44. • NMDA blockers remain highly efficient in
stopping the disorder, even late in its course
• Extrasynaptic GABAa receptors - do not
endocytose
• neurosteroids - used to stimulate these
extrasynaptic receptors - might be useful in
the treatment of SE

45. Maladaptive changes in
neuropeptide expression
• During SSSE, depletion in hippocampus of the
predominantly inhibitory peptides
• Dynorphin
• Galanin
• Somatostatin
• neuropeptide Y

46. • expression of the proconvulsant tachykinins is
increased
• substance P
• neurokinin B
• slower to develop than the receptor
trafficking
• Tilt the balance between hippocampal
excitation and inhibition in favor of excitation
• play a role in maintaining self-sustaining

47. Galanin-like immunoreactivity in
the hippocampus

48. Genetic and epigenetic changes
• both increased and decreased expression of
numerous genes
• may contribute to the process of
epileptogenesis
• Epigenetic changes – genomewide alterations
in hippocampal cell DNA methylation, Altered
regulation of microRNA which regulates post-
transcriptional gene expression

49. Seizure-induced neuronal injury
and death
• seizures per se cause neuronal loss - results
from excessive neuronal firing through
excitotoxic mechanisms
• SSSE - induce widespread neuronal death,
mostly necrotic and associated with
mitochondrial dysfunction
• apoptotic death also does happen

50. Animal Studies
• convulsive seizures induced in baboons
-hyperthermia, hypotension, and hypoxia
• neuronal injury in the thalami, hippocampi,
and neocortex
• Paralysis of the baboons to prevent convulsive
activity - only partial protection against
neuronal injury
• non-convulsive electrographic seizures can
result in neuronal damage and cell death

51. • Evidence in human beings is largely anecdotal
• brain damage is often seen in patients who
die from status epilepticus
• Patients who die from SE show brain lesions
and decreased neuronal density in the
hippocampus
• Neuron-specific enolase, a marker of neuronal
death, is increased in the serum of patients
after SE

52. • MRI studies - cerebral edema acutely and
atrophy chronically after SE
• presence of focal atrophy in areas of intensive
seizure activity supports a causal link between
seizures and cell loss
• SE induced by domoic acid poisoning showed
neuronal loss at autopsy

54. PROGNOSIS

55. Factors associated with poor
outcome
• Age ≥60 years
• longer duration of SE
• lack of past history of seizures
• low Glasgow coma scale score at admission
• type of SE
• acute symptomatic aetiology
• presence of periodic lateralized epileptiform
discharges on EEG

56. Status
Epilepticus Severity Score
• Four outcome predictors
• Age
• History of seizures
• Seizure type
• extent of consciousness impairment
• easily and quickly measurable as well as
reproducible
• A favorable score is 0–2

59. Epidemiology-Based Mortality Score in Status Epilepticus
(EMSE)

60. References
• Chen JW, Naylor DE, Wasterlain CG. Advances
in the pathophysiology of status epilepticus.
Acta Neurol Scand Suppl 2007; 186: 7–15
• Betjemann JP, Lowenstein DH. Status
epilepticus in adults. Lancet Neurol. 2015
Jun;14(6):615-24
• Chen JW, Wasterlain CG. Status epilepticus:
pathophysiology and management in adults.
Lancet Neurol. 2006 Mar;5(3):246-56

61. • Rossetti AO, Logroscino G, Milligan TA,
Michaelides C, Ruffieux C,Bromfi eld EB.
Status Epilepticus Severity Score (STESS): a
tool to orient early treatment strategy. J
Neurol 2008; 255: 1561–66