Status epilepticus and refractory status epilepticus

1. Status Epilepticus
Dr Sooraj Patil
Moderator- Dr Abhishek Pathak

2. Introduction
• Status epilepticus (SE) is a series of
uninterrupted seizures which result in an
impairment of normal brain function, which
if not treated as a medical emergency results
in high morbidity and mortality
• Overall annual incidence of 10-41 per
100,000 people
• Bimodal peak distribution, with peaks in
children and elderly
J K Murthy Convulsive status epilepticus API India 2013 2013
• Frequency of refractory status
epilepticus in status epilepticus patients
= 31-44% & 20% RSE will bcm SRSE
• Approximately 50% cases, there is no
prior history of epilepsy(NORSE)
• Mortality rates range between 10.5-28%
for SE
• Neurological or cognitive sequelae in
convulsive SE occur in 11- 16 % patients

3. Definition
• SE was defined as more than 30 min of either
• (1) continuous seizure activity or
• (2) two or more sequential seizures without full recovery of consciousness
between them
• The International League Against Epilepsy (ILAE)
• Operational definition of SE, which suggests starting treatment if
seizures do not spontaneously stop within 5 min

4. The new definition of SE
• SE is a condition resulting either from the failure of the mechanisms
responsible for seizure termination
or
• From the initiation of mechanisms that 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

5. Classification of SE
With prominent motor symptoms
Convulsive SE (CSE, synonym: tonic–clonic SE)
• Generalized convulsive
• Focal onset evolving into bilateral convulsive SE
• Unknown whether focal or generalized
Myoclonic SE (prominent epileptic myoclonic jerks) With coma
& Without coma
Focal motor
• Repeated focal motor seizures (Jacksonian)
• Epilepsia partialis continua (EPC)
• Adversive status
• Oculoclonic status
• Ictal paresis (i.e., focal inhibitory SE)
Tonic status
Hyperkinetic SE
Without prominent motor symptoms
• NCSE with coma
• NCSE without coma
• Typical absence status
• Atypical absence status
• Myoclonic absence status
• Focal a Without impairment of consciousness (aura continua,
with autonomic, sensory, visual, olfactory, gustatory, emotional/psychic/experiential, or
auditory symptoms)
• Aphasic status
• With impaired consciousness
• Unknown whether focal or generalized
• Autonomic SE

6. Etiology of SE
• Known (i.e., symptomatic)
• Acute (e.g., stroke, intoxication, malaria, encephalitis, etc.)
• Remote (e.g., posttraumatic, postencephalitic, poststroke, etc.)
• Progressive (e.g., brain tumor, Lafora’s disease and other PMEs,dementias)
• SE in defined electroclinical syndromes
• Unknown (i.e., cryptogenic)

7. Epidemiology of status epilepticus in adults: A population‐based
study on incidence, causes, and outcomes (26 November 2018)
0

9. Etiology in SE
• According to an Indian study, the etiology of SE
• Infection in 53.8%, drug default in 7.9%, metabolic in 14.5%, Stroke in 12.8%
and miscellaneous in 11% of patients
• Infection as an etiology was more common in children, drug default
and metabolic causes in adult and stroke in elderly
• Mortality = 29% (elderly >> children)
A clinical, radiological and outcome study of status epilepticus, India J Neurology (2010) 257:224-2292013

10. Systemic and cerebral pathophysiological changes associated with
seizures and convulsive status epilepticus
Compensation (< 30 minutes)
• Increased cerebral blood flow
• Cerebral energy requirements matched by
supply of oxygen and glucose
• Increased glucose concentration in the
brain
• Increased catecholamine release
• Increased cardiac output
Decompensation (> 30 minutes)
• Failure of cerebral autoregulation
• Hypoglycaemia
• Hypoxia
• Acidosis
• Hyponatraemia
• Hypo/hyperkalaemia
• Disseminated intravascular coagulation
• Leucocytosis
• Falling blood pressure
• Falling cardiac output
• Rhabdomyolysis

11. Most sz stop, why
some will progress
to SE/RSE
Excitatory vs
Inhibitory
neurotransmitters
GABA apoptosis
within minutes of
sz onset
Loss of GABA
receptors on
neuronal surface
TIME is BRAIN
BZP, barbiturate
resistance after
initial time delay
Glutamate and
NMDA
neurotransmitter
toxicity
Neuronal death &
seizure
propagation to SE
Pathophysiology of SE

12. Time to Treatment in SE
• The sooner treatment is initiated, the better the chances of success, and
the lower the risk for adverse consequences

13. Factors associated with poor
outcome in SE
• Duration of seizures (most important)
• Sensorium at presentation
• Underlying aetiology (Stroke, Anoxic & infection)
• De novo development in hospitalised patients
• Older age
• Associated medical complication
• Focal neurological signs at onset
Symptomatic SE, young
patient, low AED levels
better prognosis

14. Predictor scoring in SE- STESS
Status Epilepticus Severity Score (STESS) A tool to orient early treatment strategy J Neurol (2008) 255:1561–1566

15. Predictor scoring in EMSE- EACE
Epidemiology-Based Mortality Score in Status Epilepticus (EMSE) Neurocritical Care 22(2) · November 2014

16. Major drugs in SE
Drug Latency in min Duration in hours
Lorazepam IV 3-10 12-24
Diazepam rectal 5-15 <1
Diazepam IV 1-5 <1
Midazolam IV 10-30 <1
Midazolam IM/buccal 5-10 <1
Phenytoin 10-30 12-24
Fosphenytoin 10-30 12-24
Phenobarbitone 5-30 48-72
Valproate <20 8-24

17. Goals of treatment in SE
• Termination of Status Epilepticus
• Prevention of Seizure Recurrence
• Management of Precipitating cause
• Management of complications

18. Approach: Diagnostic workup
All patients
• Monitor vital signs (ABC).
• Obtain IV access
• Head CT (appropriate for most cases)
• Labs: blood glucose, CBC, renal function tests, Calcium,
Magnesium, electrolytes, AED levels.
• cEEG monitoring (preferably)
Consider based on clinical presentation
• Brain MRI
• Lumbar puncture
• Toxicology panel (i.e. isoniazid, TCAs, theophylline,
cocaine,
sympathomimetics, organophosphates, cyclosporine)
• Other relevant investigations as per the need

19. STATUS EPILEPTICUS
Rapid IV access available
NO
IM Midazolam 0.2mg/kg (max 10mg)
OR
Buccal or Intranasal Midazolam
0.5mg/kg (max10mg)
YES
IV LORAZEPAM 0.1mg/kg slow push (max
4mg)
Rate- maximum rate of 2 mg/minute
Repeat IV LORAZEPAM
0.1mg/kg
slow push
If Seizure donot
stop in 5 minutes
If Seizure do not stop
in 5 minutes, Achieve
IV access
Shift to 2nd line drugs
If Seizure donot
stop in 5 minutes
IV Phenytoin 20mg/kg @ 50mg/min
OR
IV Fosphenytoin 30 mg/kg @ 150 mg/min
If Seizure do not stop in 20 minutes
If possibility of
subttherapeutic levels,
Valproate 20-40 mg/kg @
5-10 mg/kg/min max 3 gm
If Seizure
donot stop in
10 minutes
Airway-
Breathing-
Circulation
OXYGEN
+
POSITIONING
History- AED ,
DRUGS,
TRAUMA
RBS & Blood
tests, another IV
cannula

20. PHT @ 5mg/kg or fPHT @ 7.5
mg/kg
IV Phenobarbitone 20mg/kg @ 100mg/min f/by 3-5
mg/kg.hr cont infusion
OR
IV Midazolam 0.2 mg/kg loading dose f/by 0.1-0.4
mg/kg/hr cont infusion
OR
IV Propofol 2mg/kg bolus f/by 2-10 mg/kg/hr cont
infusion
OR
IV Pentobarbital 5 mg/kg loading dose f/by
1-3 mg/kg/hr cont infusion
If seizure persists after 24 hrs Super
refractory status epilepticus
Alternative drug
Valproate 40-
60 mg/kg @ 5-10
mg/kg/min
Alternative
Drug Levitiracetam
20-30mg/kg
@ 5 mg/kg/min
Seizure not
controlled
Seizure not
controlled
Refractory Status Epilepticus

23. 1998 Veteran’s Affairs SE study
Lorazepam vs Phenytoin
• Lorazepam (0.1 mg/kg), diazepam (0.15 mg/kg) followed by phenytoin (18
mg/kg), phenobarbital (18 mg/kg), and phenytoin alone (18 mg/kg) in adults
• Differential anticonvulsant efficacy was found in overt status epilepticus where
the four treatment arms had an overall difference (p = 0.02) for the primary
outcome variable.
• Only one head-to head comparison met the pre-specified statistical
significance difference: lorazepam was superior to phenytoin (p = 0.002)
Evidence-Based Guideline Epilepsy Curr. 2016 Jan-Feb; 16(1): 48–61.

24. 2001 Alldredge trial IV Lorazepam vs
Diazepam
• 205 adult patients with status epilepticus randomized to one of 3 different treatments
initiated outside the hospital by paramedics:
• IV lorazepam (2 mg, n=66)
• IV diazepam (5 mg, n=68)
• IV placebo (n=71)
• A repeat dose of study drug could be done if the seizure continued after 4 minutes
(for a maximum lorazepam dose of 4 mg and diazepam dose of 10 mg)
• Both lorazepam and diazepam were superior to placebo:
lorazepam (59.1%) > placebo (21.1%) (OR, 4.8; 95% CI: 1.9–13.0)
diazepam (42.6%) > placebo (21.1%) (OR, 2.3; 95% CI: 1.0–5.9)
Evidence-Based Guideline Epilepsy Curr. 2016 Jan-Feb; 16(1): 48–61.

25. 2012 RAMPART study
IM Midazolam (prehospital) vs IV
Lorazepam
• 893 participants with SE (748 adults and 145 children) were randomized to one of
two treatments in a non-inferiority comparison (pre-specified non-inferiority
margin of 10%):
• Intramuscular midazolam (10 mg or 5 mg in children weighing 13–40 kg, n=448)
• IV lorazepam (4 mg or 2 mg in children weighing 13–40 kg, n=445)
• Primary efficacy endpoint was achieved in 73% of subjects in the IM
midazolam group compared with 63% in the IV lorazepam group giving an
absolute difference between groups of 10% (95% CI: 4.0–16.1)
Evidence-Based Guideline Epilepsy Curr. 2016 Jan-Feb; 16(1): 48–61.

26. VA vs other AEDs RCTs
• Five open-label class III initial therapy RCTs examined the efficacy of
• IV valproic acid (n = 2) , IV phenytoin (n = 2) , IV phenobarbital (n = 1), IV
diazepam plus phenytoin (n = 1) , IV levetiracetam (n = 1) , rectal diazepam
(n = 1) , and IV lorazepam (n = 1)
• Valproic acid had higher efficacy than phenytoin in one study
(valproic acid, 66%, vs phenytoin, 42%; p = 0.046)
Sodium valproate vs phenytoin in status epilepticus: a pilot study. Misra UK, Kalita J, Patel R Neurology. 2006 Jul 25; 67(2):340-2
• VA similar to phenytoin in the other (valproic acid, 87.8%, vs
phenytoin, 88%)
Treatment of status epilepticus and acute repetitive seizures with i.v. valproic acid vs phenytoin Acta Neurol Scand. 2008

27. • IM midazolam, IV lorazepam, IV diazepam (with or without phenytoin) are
established as efficacious at stopping seizures lasting at least 5 minutes (level A).
• IM midazolam has superior effectiveness compared with IV lorazepam in adults
with convulsive status epilepticus without established IV access (level A).
• IV lorazepam is more effective than IV phenytoin in stopping seizures lasting at
least 10 minutes (level A).
Conclusion of studies
Evidence-Based Guideline Epilepsy Curr. 2016 Jan-Feb; 16(1): 48–61.

28. Conclusion of studies
• IV valproic acid has similar efficacy to IV phenytoin or continuous IV diazepam
as second therapy after failure of a benzodiazepine (level C).
• Insufficient data exist in adults about the efficacy of levetiracetam as either initial
or second therapy (level U).
Evidence-Based Guideline Epilepsy Curr. 2016 Jan-Feb; 16(1): 48–61.

29. Is IV Fosphenytoin More Effective
Than IV Phenytoin?
• A Class III single-dose, randomized, double-blind, class III tolerability study in patients
needing infusion of phenytoin compared
• Insufficient data exist about the comparative efficacy of phenytoin and fosphenytoin
(level U).
• Fosphenytoin is better tolerated compared with phenytoin (level B).
• When both are available, fosphenytoin is preferred based on tolerability, but phenytoin is
an acceptable alternative (level B)
Evidence-Based Guideline Epilepsy Curr. 2016 Jan-Feb; 16(1): 48–61.

30. Phenytoin Fosphenytoin
•15-20 mg/kg i.v.
@50mg/min
•100 mg phenytoin
• 20 mg PE/kg i.v @
150mg/min
Fosphenytoin 150 mg
pH 12
Extravasation causes severe tissue
injury
pH 8.6
Extravasation well tolerated
• Onset 10-30 min • Onset 5-10 min
•May cause hypotension,
dysrhythmia
(may be because of rapid administration and propylene
glycol which is used as diluent)
•less cardiac complications as it is water
soluble and propylene glycol is not used as
diluent.
• Cheap • Expensive

31. When Does Anticonvulsant Efficacy
Drop Significantly
• The efficacy of each successive blinded treatment was:
First AED 55.5%
Second AED 7.0%
Third AED 2.3%
Four or more AEDs 23.2%
No AED was successful 11.7%
• If the patient did not respond to lorazepam or phenytoin, the response rate to 3rd
AED was 2.3%
• the second anticonvulsant administered is less effective than the first “standard”
anticonvulsant, while the third anticonvulsant administered is substantially less
effective than the first “standard” anticonvulsant (level A).
After How Many Different Anticonvulsants Does Status Epilepticus Become Refractory?
1998 class I Veterans Affairs SE study

32. Refractory & Super-refractory SE
• Refractory status epilepticus -either clinical or electrographic seizures that
persist after adequate doses of an initial benzodiazepine and an acceptable
second-line antiseizure drug
• Super-refractory status epilepticus -seizures continue to recur 24hours or
more after the onset of anasthetic therapy
• Acute repetitive seizures- 3 or more seizures within 24 hours for patients
whose habitual seizure frequency is fewer than 3 seizures/day with
relatively preserved sensorium in between

33. Refractory status epilepticus
• Up to 23 - 30 % status epilepticus will turn out refractory, standard
definition 30-60 min will prolong neuronal injury
• Failure to respond to second AED (proper dose) should be treated as
RSE

34. Refractory status epilepticus
IV Phenobarbitone 20mg/kg @ 100mg/min f/by 3-5
mg/kg.hr cont infusion
OR
IV Midazolam 0.2 mg/kg loading dose f/by 0.1-0.4
mg/kg/hr cont infusion
OR
IV Propofol 2mg/kg bolus f/by 2-10 mg/kg/hr cont
infusion
OR
IV Pentobarbital 5 mg/kg loading dose f/by
1-3 mg/kg/hr cont infusion
If seizure persists after 24 hrs, try emerging novel therapies: Ketamine bolus 0.5-4.5
mg/kg infusion (upto 5 mg/kg/hr ) ; Immunomodulation IV Methylprednisolone or
IVIg; Resective surgery ; Ketogenic diet ; hypothermia
Review history
Examine for any
focality
Check records
Check dose and Drug
Counsel family
ICU call and shift

36. C-EEG in RSE
• Need for Continuous EEG
• 15- 20 % will bcm NCSE
• Difficult to differentiate post ictal vs NCSE
• Electromechanical dissociation in subtle GCS
• To titrate dose of IV anaesthetics
• Decide when to taper AEDs
• C-EEG should be started within 1 hours with frequent review
• EEG bursts are associated with phasic synaptic depolarizing cellular potentials (Action
potential)
• Target of EEG is to achieve burst suppression pattern

37. Burst suppression EEG
• EEG - brief bursts of spikes, sharp waves, or
slow waves of relatively high amplitude
alternating with periods of relatively flat EEG
or isoelectric period (usually >10 s IBI, <
10mvolt)
• No association between a specific interburst
interval and outcome has been identified
• Targeting clinical seizures is most important
• EEG characteristics of the bursts
rather than IBI on C-EEG
• Percent of bursts with epileptiform
features
• Maximum amplitude of bursts and
monomorphic bursts
• Burst suppression ratio or IBI doesn’t
effect outcome
EEG Characteristics of Successful Burst Suppression for Refractory Status Epilepticus Neuro crit 2016
Does burst-suppression achieve seizure control in refractory status epilepticus? BMC
Neurology 2017
Burst suppression doesn’t correlate with outcome or recurrence in RSE

38. Treatment of resistant SE
Drug Loading dose Maintenance dose Side effects
Midazolam 0.2–0.4 mg/kg
IV every 5 min until
Seizures controlled.
Maximum dose:
2 mg/kg
0.1–2.0 mg/kg/h Respiratory
depression,
hypotension
Propofol 2 mg/kg IV every 5 min
until seizures controlled.
Maximum dose:
10 mg/kg
30–200 mcg/kg/min
Avoid ≥ 80 mcg/kg/min
for ≥ 48 h
Hypotension, propofol infusion
Syndrome (PRIS)
Movement ds
Pentobarbitol 5 mg/kg IV up to 50 mg/min
every 5 min until seizures
are controlled or a
Maximum loading dose
of 15 mg/kg
0.5–5 mg/kg/h Hypotension, adynamic
ileus, respiratory
depression, hepatotoxicity,
Prolonged sedation
Ketamine 1 mg/kg loading
Maximum 5mg/kg
0.5 to 10 mg/kg/hour Hypertension, hallucination,
arrhythmia, increased ICP

39. Midazolam
• Rapidly acting, short duration 0.8 to 2.8 hours
• Most commonly used 3rd line agent, commonly available
• Associated with tachyphylaxis, necessitating gradually higher doses.
• Hypotension in 40-50 % and respiratory depression needs support
• 51% of patients had breakthrough seizures within the first 6 h of MDZ
treatment (vs 15% on propofol and 12% on pentobarbital)
• 63% of patients had withdrawal seizures when tapering MDZ (compared to
46% on propofol and 43% on pentobarbital)
High-dose midazolam infusion for refractory status epilepticus. Neurology 2014

40. Propofol
• Propofol IV anesthetic acts by direct activation of GABA-A receptors ,
inhibition of NMDA receptors.
• Rapid onset of action - decreases cerebral oxygen utilization - reduces ICP
• Hypotension required pressors in 22– 55% of patients.
• Propofol infusion syndrome (PRIS) - metabolic acidosis, rhabdomyolysis,
renal failure, hypertriglyceridemia, refractory bradycardia, and cardiac
failure

41. Barbiturates
• Thiopental & Pentobarbitone (active metabolite of thiopental)
• Augmenting transmission at the GABA receptor
• Lower body temperature - may have neuroprotective effects
• High doses - loss of brainstem reflexes and an isoelectric pattern on
EEG & long duration of effect
• Strong anaesthetic agent, almost always controls seizures up to 90 %
pentobarbital safe and efficacious in the treatment of super-refractory status epilepticus: a cohort study. Crit Car 2014

42. Role of Ketogenic diet
The Feasibility, Safety and Efectiveness of a Ketogenic Diet for Refractory Status Epilepticus in Adults in the Intensive Care Unit Neurocrit Care 2018
ketogenic diet (KD), a low carbohydrate diet that promotes
formation of ketone bodies (e.g., acetoacetate and beta
hydroxybutyrate)
ketogenic diet as a formula delivered via feeding tube
Once able to tolerate food by mouth, patients switched to a
modified Atkins diet
Although the study in children and adolescents is RCT, it is open
label and relies on parental reporting both of seizure frequency
and severity

43. Role of Ketogenic diet
• KD initiation and implementation is not always practical
• Randomized placebo controlled studies are needed to fully determine
if KD is safe and effective among patients with SRSE
• KD can be considered in pediatric patients in limited options but need
further well powered studies

44. Autoimmunity in SE
New-onset refractory status epilepticus or NORSE
Febrile infection-related epilepsy syndrome (FIRES) 40 % Refractory status epilepticus
Devastating epileptic encephalopathy in school-aged children (DESC)
(1) status epilepticus as presentation of new-onset seizures
(2) progression to refractory or super-refractory status epilepticus
(3) relatively recent but explosive onset of seizures
(4) the absence of established epilepsy history
(5) the presence of other neurological problems such as memory loss, autonomic or hypothalamic dysfunction, and ataxia or
movement disorder
(6) new psychiatric symptoms or behavioral changes
(7) known history of cancer
(8) lymphocytic pleocytosis on CSF examination

45. Autoimmunity in SE
Hashimoto encephalopathy and Rasmussen
encephalitis present with refractory status
epilepticus
CSF can be normal in up to 40–50% of
the patients
Treated best with Steroids/PLEX/IvIg
APE score of 4 or greater had a sensitivity of
82.6% and a specificity of 82.0% for detecting a
positive antibody
RITE
score of 7 or greater predicted a favorable
seizure outcome and had a sensitivity
of 87.5% and specificity of 83.8%

46. Therapies in SRSE

47. Management of NCSE
There is no universally accepted definition of nonconvulsive status epilepticus and there is no consensus on
how to treat it.
EEG, although critical to the evaluation of
nonconvulsive status epilepticus, can sometimes be
equivocal.
In these cases, a response to treatment (typically
IV-administered antiseizure drugs)
Patient’s clinical state, medical history, and
response to antiseizure drugs is often needed to
make the diagnosis.
Once the diagnosis of NCSE is made
How aggressively to treat ?
Patient’s mental
status and clinical course

48. EEG criteria for NCSE Salzburg
In patients without a known
epileptic encephalopathy
Repetitive generalized or focal spikes, polyspike,
sharp waves, spike-and-wave or sharp-and-slow
wave complexes at >2.5/second.
ED <2.5/second OR rhythmic delta/theta activity
And one of the below
Focal ictal phenomena (e.g., facial twitching, gaze
deviation, nystagmus, limb myoclonus)
EEG improvement after IV AED
Typical spatiotemporal evolution
In patients with known epileptic
encephalopathy
Frequent or continuous generalized spike-wave
discharges, which show an increase in profusion or
frequency when compared to baseline
EEG with observable change in clinical state.
Regression (improvement) of clinical or EEG features
with IV BZPs

49. Management of NCSE

50. 2013 to 2019 OCTOBER