A 31-year-old male presented with a fever for one week and seizures and altered sensorium for three days. He experienced generalized tonic-clonic seizures that were initially uncontrolled. Imaging showed findings suggestive of viral or autoimmune encephalitis. Refractory status epilepticus was diagnosed and treated with high doses of multiple antiepileptic drugs, including lacosamide, which eventually controlled the seizures. Status epilepticus is defined as a seizure that persists for a sufficient length of time or is repeated frequently enough that recovery between attacks does not occur. The pathophysiology involves reductions in inhibitory GABA receptors and increases in excitatory glutamate receptors over time.

1. STATUS
EPILEPTICUS

2. Seizure
 A seizure is defined as “a transient occurrence
of signs and/or symptoms due to abnormal
excessive or synchronous neuronal activity in
the brain

3. Case -scenario
 A 31 years male presented with c/o fever - 1 week
 Seizures and Altered sensorium – 3 days
 Semiology – day 1 GTCS - 2 episodes with regaining of consciousness
 Day 2 - he had 3 episodes GTCS type
 He was taken to CMC hospital he was evaluated with CT scan and LP was
done.
 He was started on inj. Eptoin, Acyclovir and steroids .

4. Case scenario
 As seizures were not controlled they were referred to SVIMS------.
 During admission he had GTCS seizures initially 5-6 episodes with regaining of
consciousness. Inj levetiracetam was added along with loading doses of lorazepam . Inj
sodium valproate was started.
 Later seizures were continuous. He was intubated and midazolam infusion was started.
 Generalised seizures reduced but he had subtle seizures in the form eye blinking and lip
smacking. Doses of giving anti epileptics were escalated to high doses. Still he had subtle
seizures.
 Then Inj. Lacosamide was added. Seizures got controlled
 Imaging was suggestive of viral /autoimmune encephalitis

5. Incidence
 The incidence of GCSE among the general population ranges between
18 and 41 cases per 100,000, with a GCSE mortality rate in adults of
10% to 40% .
 Approximately 31% to 43% of status epilepticus episodes will become
refractory.
 The mortality of status epilepticus ranges from19% to 26% and rises
with increasing age.

6. Incidence
 The most common cause of GCSE in adults was cerebrovascular
disease (25.2%) whereas fever or infection(35.7%) was the most
common cause in children.
 A recent medication change was a major factor in all ages:
20% in children and 19% in adults

7. Status epilepticus - Definition
 ILAE 1970 -seizure that persists for a sufficient length of time or is repeated
frequently enough to produce a fixed and enduring condition.”
 1981, the definition was minimally changed into a “seizure” that “persists for a
sufficient length of time or is repeated frequently enough that recovery
between attacks does not occur.
 America’s Working Group on S.E., in 1993, defined SE as more than 30
minutes of continuous seizure activity, or two or more sequential seizures
without full recovery of consciousness

8. The ILAE Core Group on Classification group suggested the
 operational definition for SE in adults and children more than five years a)
Two or more discrete seizures without restoration of consciousness or
 b) Seizure lasting for more than five minutes (patients > 5 years
conceptual definition,
 “Generalized, convulsive status epilepticus refers to a condition in which there
is failure of the “normal” factors that serve to terminate a typical GTCS
[generalized tonic–clonic seizures].
Status epilepticus - Definition

9.  The ILAE Task Force on Classification of Status Epilepticus proposes a
definition that encompasses all types of SE,
 SE is a condition resulting either from the failure of the mechanisms
responsible for seizure termination or from the initiation of mechanisms which
lead to abnormally prolonged seizures (after time point t1).
 It is a condition that 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.

10.  The time point of operational dimension 1 determines the time at which
treatment should be considered or started, whereas
 The time point of operational dimension 2 determines how
aggressively treatment should be implemented to prevent long-term
consequences.
 The time domain may vary considerably between different forms of SE

12. Refractory Status Epilepticus
 Status Epilepticus (SE) Resistant to one first-line (benzodiazepines,
bdz) and one second-line (Phenytoin, Phenobarbital, or Valproic Acid)
Antiepileptic (AED) is labelled as Refractory Status Epilepticus (RSE).
 It develops in 23–44% Of SE patients and has a mortality of 16–39%.

13. Super refractory status
epilepticus
 Super-refractory status epilepticus is defined as status epilepticus that
continues or recurs 24 h or more after the onset of anesthetic therapy,
including those cases where status epilepticus recurs on the reduction or
withdrawal of anaesthesia .

14. NEW ONSET REFRACTORY
SEIZURES
NEW ONSET REFRACTORY SEIZURES (NORSE) is a rare condition
characterized by the occurrence of a prolonged period of refractory
seizures with no readily identifiable cause in otherwise healthy individuals.
(MC CAUSE AUTOIMMUNE ENCEPHALITIS)

15.  Seizure clusters, also called acute repetitive seizures and serial seizures,
are closely grouped seizures representing an increase in seizure
frequency compared to baseline, usually occurring over the span of
minutes to a couple days.
 May include any type of seizure and may vary in severity, but by
definition there is complete recovery in between seizures.
 Seen in patients with drug resistant epilepsy, particularly those with
remote symptomatic epilepsy and extra temporal epilepsy.

16. CLASSIFICATION
 A new diagnostic classification system of SE is proposed
 Provide a framework for clinical diagnosis, investigation, and
therapeutic approaches for each patient.
 There are four axes:
(1) Semiology;
(2) Etiology;
3) Electroencephalography (EEG) correlates; and
(4) Age

18. AXIS 2 :ETIOLOGY

19. AXIS 2 – UNDETERMINED CAUSE

20. Etiology
The main causes of status epilepticus are
 Low blood concentrations of AEDs in epileptics (34%)
 Remote symptomatic causes (24%)
 Cerebrovascular accidents (22%),
 Anoxia or hypoxia (~10%)
 Metabolic causes (~10%)
 Alcohol and drug withdrawal (~10%)
 Most recalcitrant cases - viral or paraneoplastic encephalitis, old traumatic injury
 Epilepsy with severe mental retardation.

22. AXIS 3: EEG
The following terminology to describe EEG patterns in SE:
 Location: generalized (including bilateral synchronous patterns),
lateralized, bilateral independent, multifocal.
 Name of the pattern: Periodic discharges, rhythmic delta activity or spike-
and-wave/sharp-and-wave plus subtypes.
 Morphology: sharpness, number of phases (e.g., triphasic morphology),
absolute and relative amplitude, polarity

23. AXIS 3: EEG
 Time-related features: prevalence, frequency, duration, daily pattern
duration and index, onset (sudden vs. gradual),and dynamics (evolving,
fluctuating, or static).
 Modulation: stimulus-induced vs. spontaneous.
 Effect of intervention (medication) on EEG

24. Criteria for Non-convulsive Seizures
 Any pattern lasting at least 10 seconds satisfying any one of the
following 3 primary criteria

25.  1. Repetitive generalized or focal spikes, sharp waves, spike and- wave,
or sharp-and-slow wave complexes at ≥3/sec.
 2. Repetitive generalized or focal spikes, sharp waves, spike and- wave,
or sharp-and-slow wave complexes at <3/sec and the secondary criterion.
 3. Sequential rhythmic, periodic, or quasi-periodic waves at ≥1/sec and
unequivocal evolution in frequency, morphology, or location
Criteria for Non-convulsive Seizures –
Primary Criteria

26.  Significant improvement in clinical state or appearance of previously
absent normal EEG patterns (such as a posterior dominant rhythm)
temporally coupled to acute administration of a rapidly acting AED.
 Resolution of the “epileptiform” discharges, leaving diffuse slowing without
clinical improvement and without appearance of previously absent normal
EEG patterns, would not satisfy the secondary criterion
Criteria for Non-convulsive Seizures –
Secondary Criteria

27. Axis 4: Age
 1 Neonatal (0 to 30 days).
 2 Infancy (1 month to 2 years).
 3 Childhood (> 2 to 12 years).
 4 Adolescence and adulthood (> 12 to 59 years).
 5 Elderly (≥ 60 years)

29. Pathophysiology

30. PATHOPHYSIOLOGY
 At the cellular level, receptors on the surface of axons are in a highly dynamic
state, moving onto (externalization), away from (internalization), and along the
axonal membrane.
 This “receptor trafficking” intensifies during SE, and the overall effect is a
reduction in the number of functional γ-aminobutyric acid (GABA) receptors in
the cells affected in the seizure discharge.
 As GABA is the principle inhibitory transmitter, reduction in GABAergic activity
may be an important reason for seizures to become persistent

31. PATHOPHYSIOLOGY
 Number of glutamatergic receptors at the cell surface also increases.
 The decreasing GABAergic receptor density may also render the GABAergic
drugs (benzodiazepines or barbiturates) inefficient in controlling SE.
 Mitochondrial failure or insufficiency may also be responsible for the failure
of seizure termination. Cellular damage and mitochondrial processes are
involved in cell necrosis and apoptosis.
 Another category of disease triggering persistent SE is an inflammatory
condition such as herpes simplex encephalitis (HSE).

32. Changes in neuropeptide expression in
status epilepticus
HIPPOCAMPUS
Decrease in
Inhibitory peptides
dynorphin
Galanin
Somatostatin
Neuropeptide Y
Increase in
Pro convulsant tachykinins
Substance P
Neurokinin B

33. Diagnostic Testing of SE
 The diagnostic studies should be done once the patient is stabilized and
appropriate pharmacotherapy for SE is initiated
 The diagnosis of convulsive status epilepticus is straightforward.
 The tonic phase is initially prolonged, and the clonic movements are
violent.
 The convulsive phase is accompanied by a massive sympathetic
outpouring manifested by pupillary dilatation, tachycardia, hypertension,
hyperglycemia, and increased cerebral blood flow

34.  As status epilepticus continues, the tonic phase shortens as the clonic
movements disperse and ultimately disappear, sometimes with ongoing
non-convulsive seizure activity. This is referred to as subtle status
epilepticus and is accompanied by metabolic failure
with decreased cardiac output, hypoglycemia, and decreased
cerebral blood flow

35.  To exclude a diagnosis of subtle status epilepticus, an EEG should be
obtained if the patient has not returned to his or her baseline within 10 to
20 minutes of the cessation of tonic clonic activity.
 Critically ill adults who are stuporous or comatose without an
alternative explanation require at least a routine EEG to
exclude non-convulsive status epilepticus

36.  If epileptiform activity is identified on routine EEG, the patient should
undergo continuous EEG monitoring of at least several hours’ duration.
Eg: Severe sepsis who are slow to recover consciousness
 Acute brain injury who have impaired consciousness out of proportion to
what would be expected based on the severity of the
brain injury

37.  Focal non-convulsive status epilepticus clinical presentation is highly variable
behavioral, cognitive, sensory, autonomic, or motor function .
 The patient is typically awake and confused and may appear to have
somewhat automatic behavior, such as walking or performing simple tasks
repetitively.
 The diagnosis of both focal and generalized non-convulsive status epilepticus
requires clinical suspicion, EEG confirmation, and both clinical and
electrographic improvements following a trial of a fast-acting AED

38. Laboratory studies
 Serum electrolytes, S.ca, S.mg
 Glucose,lactate
 RFT,LFT ,ABG,
 Toxicological screening when suspected
 If the patient is known to be taking an antiepileptic drug a
laboratory assay for drug levels.

39. Lumbar Puncture
 CNS infection.
 SAH is suspected.

40. Neuroimaging
 A head CT scan should be considered for all GCSE patients once they
have been stabilized.
 The MRI during and for days after a bout of status epilepticus may show
signal abnormalities in the region of a focal seizure or in the hippocampi.
 The MRI changes are most evident on FLAIR and diffusion-weighted
sequences

41. Sequence of EEG patterns in GCSE
 Discrete recurrent seizures separated by interictal slow activity
 Merging seizures with waxing and waning ictal discharge
 Continuous ictal discharge
 Continuous ictal discharge punctuated by generalized attenuation
 periodic epileptiform discharges on a relatively flat background

42. Indications for cEEG in ICU

43. Continuous EEG treatment endpoints

44. Cryptogenic SE
 Brain MRI, whole PET scan,Angiogram
 CT abdomen /chest/pelvis
 Ovarian /testicular ultrasound
CSF:
• JE Virus, EBV, entero, adeno, EEE, WEE, etc,,,
• Oligo clonal bands, IgG index, GAD AB
• Auto immune Abs ,Para neoplasticAbs,14-3-3 protein.

45. Cryptogenic SE
 serum for auto immune profile, vasculitis profile, ACE
 Heavy metals
 Porphyrins
 Genetic testing
 Brain SPECT or FDG-PET
 Brain /meningeal biopsy.

46. PRINCIPLES OF MANAGEMENT OF
ACUTE STATUS EPILEPTICS
 To Maintain vital functions
 To stop seizures & prevent recurrence
 To identify the cause & precipitating factors and treat
 To identify post ictal sequalae - cerebral or systemic and treat

47. MANAGEMENT

50. Stages of treatment of SE

51. Algorithm for management of Super Refractory Status
Epilepticus
General anesthesia including consideration of ketamine, antiepileptic drugs, full ICU
support and investigate urgently to identify the cause
No cause identified
Cause identified
Treat cause if possible
Give i.v magnesium and i.v pyridoxine in children
Consider steroids+/-IvIg+/-PEX Consider neurosurgery in lesional SE
Consider hypothermia
Consider ketogenic diet
Consider ECT, CSF drainage and other therapies

52.  Absence status must be managed by
IV lorazepam ,
Valporic acid or both
followed by ethosuximide.

53. Benzodiazepines
Lorazepam 0.1mg/kg upto 4mg/dose Diazepam 0.15mg/kg upto 10mg/dose
Less lipid soluble More lipid soluble
Csf ,brain concentrations rise at slow rate Rapid systemic absorption
Long duration of action
Rectal /im /iv Rectal/ im/iv
Midazolam is water soluble and rapidly absorbed from IM site .
Tachyphylaxis is more common 0.2mg/kg LD ,
infusion 0.05-0.6mg/kg/hr.(2mg/kg/hr)

54. Phenytoin Fosphenytoin
Extravasation –purple glove
syndrome
Prodrug, more water soluble,
non irritating
20mg/kg body wt 20mg/kg body wt
S/E- hypo tension ,cardiac arrythmias

55.  SODIUM VALPROATE -20-40 mg/kg @ 6mg/kg/min
Continuous infusion @1-5 mg/kg/h
DOC –myoclonic seizures, Lennox Gastaut syndrome, absence.
 PHENOBARBITONE -20mg/kg @100mg/min
produces respiratory and CNS depression, hypotension.

56. LEVETIRACITAM -30-60mg/kg
S/E -sedation and irritability broad spectrum of action, least drug interactions
and not metabolized in liver, this makes LEV a drug of choice in patients on
multiple drugs like oral anti-coagulants, hepatic disorders, porphyria
LACOSAMIDE bolus dose was 200-400 mg over 3-5min
Maintainance dose 100mg bd

57.  Propofol is a non-barbiturate anesthetic agent with hypnotic, antiemetic,
antioxidant, and anticonvulsant activity
 IV loading dose of 1to 3 mg/kg, although 3 to 5 mg/kg have also been
recommended. infusion ranging from 1 to 15 mg/kg/hr.
titrated to seizure control and maintained for 12 hours before an attempt
at a taper.
 Hypotension, hypertriglyceridemia, worsening of anemia, metabolic acidosis
and myocardial failure in children

59. Burst suppression
 In RSE and SRSE, burst suppression provides an arbitrary target for the
titration of barbiturate or anesthetic treatment with the drug dosing
commonly set in a way in which burst suppression is aimed at interburst
intervals of 2–30 s or even an isoelectric EEG.
 The optimal extent of burst suppression is not known.

60. rTMS
 Recurrent transcranial magnetic stimulation (rTMS) is a potential therapy for RSE.
 rTMS is a non invasive technique where pulsed intracranial electrical current is induced by
electromagnetic induction.
 In most patients, a continuous train of low frequency (≤1 Hz) pulses results in cortical
suppression, whereas intermittent trains of high frequency (≥5 Hz) pulses result in facilitation of
cortical excitability.
 Several case reports describe rTMS application in medication-refractory focal epilepsy or RSE
in non-ICU settings, with mixed results.
 rTMS is well-tolerated by patients with epilepsy without reports of seizure exacerbation.
 Seizure suppression can be achieved by low frequency rTMS.

61. Systemic complications of SE

62. PROGNOSIS
 Several prognostic factors are important in predicting outcome of status epilepticus:
cause -age, seizure duration, and response to treatment
High mortality :
 Patients with anoxia or multiple medical problems
 Elderly
 Prolonged status epilepticus and refractoriness to treatment are associated with poor
outcome
Low mortality :
 In patients with epilepsy and precipitating factors, such as low serum concentrations of
antiepileptic drugs.

63. Mortality and morbidity of RSE
 The short-term fatality rates for RSE have been between 16% and
39%
 Mortality after RSE is about three times higher than for non-
refractory SE
 So, the goal is to aggressively manage the SE and to institute the
protocol for RSE immediately when the first line drugs fail

64.  Status epilepticus is both a medical and neurologic emergency with significant
potential morbidity and mortality.
 Evaluation and management are aimed at:
(1) stabilization and avoidance of secondary injury,
(2) rapid control of seizures,
(3) rapid identification and treatment of the etiology.
 Rapid diagnosis of status epilepticus, treatment respecting a written protocol,
correction of the underlying etiology, and attention to potential complications
may limit sequelae.

65. References
 Status epilepticus – Recent advances in the management. Butchi Raju.
AP Neurocon 2014. Proceedings of the 21st Annual Conference of the
Andhra Pradesh Neuroscients Association. pp no: 22-37.
 Sara E. Hocker. Status Epilepticus Continuum (Minneap Minn)
2015;21(5):1362–1383.
 Eugen Trinka, Hannah Cock, Dale Hesdorffer, Andrea O. Rossetti, Ingrid
E. Scheffer, Shlomo Shinnar, et al. A definition and classification of status
epilepticus – Report of the ILAE Task Force on Classification of Status
Epilepticus. Epilepsia, 56(10):1515–1523, 2015.
 Harrison
 Bradley’s

66. THANK YOU