This presentation focuses on the management of generalised convulsive status epilepticus

1. STATUS EPILEPTICUS
Dr Pramod Krishnan
Consultant Neurologist and Epileptologist
Manipal Hospital, Bengaluru

2. DEFINITION
• “more than 30 minutes of a continuous seizure or two or more
sequential seizures without full recovery of consciousness’
Working Group on Status Epilepticus of the Epilepsy Foundation of America.
• In clinical practice, a single or sequential seizures continuing for
more than >5 min should be considered as status epilepticus.
Lowenstein DH et al. NEJM 1998; 338: 970-6.
• Patient still convulsing on arrival to the ER should be considered
as status epilepticus.

3. blood flow
glucose conc in brain
glucose metabolism
oxygen supply to
brain
cardiac output.
catecholamine output
Stage of decompensation
(seizures > 30 min)
Failure of cerebral
autoregulation
Hypoxia, hypoglycemia
Acidosis,
dyselectrolytemia
DIC, Leucocytosis
Falling BP, Falling CO
Stage of compensation
(seizures < 30 min)
Cherian A, Thomas SV. Ann Indian Acad Neurol 2009; 12: 140-53

4. Classification of SE
Generalised
Partial
Aura status
Autonomic
status
Dyscognitive
status
Motor status
Special
status
Simple
motor
Complex
motor
Generalised
NCSE
(13%)
Convulsive
status
Focal Motor
status (10%)
Generalised
convulsive
status (77%)

5. Clinical stages of Status epilepticus
Stage Duration
Premonitory Confusion, myoclonus, increasing seizure
frequency
Incipient 0-5 min
Early 5- 30 min
Established 30 -60 min
Refractory > 60 min
Super refractory > 24 hrs
Post ictal

6. EEG progression of status epilepticus
Discrete seizures with
inter-ictal slowing
Waxing and waning of
inter- ictal discharges
Continuous ictal
discharges
Continuous ictal discharges
punctuated by flat periods
PED on a flat background
Lateralised Bilateral
Cherian A, Thomas SV. Ann Indian Acad Neurol 2009; 12: 140-53

7. MANAGEMENT

8. ICU
care

9. PRE-HOSPITAL TREATMENT

10. Randomised, double-blind trial. Definition of duration of SE was ≥ 5 min.
End point was termination of seizures on arrival at Emergency Department.

11. Pre-Hospital Management (PHTSE trial)
San Francisco Emergency
Medical Services Study, N= 205
Inj Lorazepam
2 mg IV (n=66)
Inj Diazepam 5
mg IV (n= 68)
Placebo (n=71)
Identical dose was repeated if required.
42.6 % had
seizure control
59.1 % 21.1 %
Lorazepam and Diazepam were significantly safer and efficacious than placebo.
Trend of Lorazepam being superior to Diazepam (not statistically significant).

12. Lorazepam Vs Diazepam
Lorazepam Diazepam
Longer duration of action (>6 hrs). Shorter duration (20 min) due to rapid
redistribution.
Onset of action upto 5 min. 1 min.
Risk of respiratory depression is less. Risk is more.
Light proof storage. Not required.
Refrigeration is recommended. Not required.

13. Midazolam vs Diazepam
Study Type N Conclusion
McIntyre et
al 2005
Buccal Midazolam (0.5
mg/kg) vs Rectal
Diazepam (0.5 mg/kg)
177 56% of Midazolam group had
seizure control compared to 27%
for diazepam.
Mpimbaza et
al 2008
Buccal Midazolam Vs
rectal Diazepam.
330 Midazolam was
as well tolerated and more
effective than diazepam.

14. • Double blind, randomised, non-inferiority trial of IM Midazolan Vs IV Lorazepam
• Administered by paramedics in prehospital setting for seizures lasting > 5 minutes
in adults and children.

15. RAMPART trial. Seizures lasting > 5 min and
patient convulsing when seen by paramedics
IM Midazolam 10
mg + IV placebo
IV Lorazepam 4
mg + IM placebo
End points:
Termination of clinical seizures prior to arrival to ER.
Need for a second rescue medication, intubation.
329/448 (73.4%) had
seizure termination
(282/445)
63.4%
Statistically significant (p<0.001). No difference in seizure
recurrence (11.4 Vs 10.6%), adverse effects, intubation rates

16. Results
• The proportion of subjects admitted was significantly lower, and
the proportion discharged from the Emergency dept was
significantly higher) in the midazolam group (P = 0.01).
• Among admitted subjects, the lengths of stay in the ICU and in
the hospital did not differ significantly between the groups.
• Median time to administration of IM Midazolam was significantly
shorter than IV Lorazepam (1.2 vs. 4.8 minutes).
• Onset of action (i.e., termination of convulsions) occurred sooner
after IV Lorazepam than IM Midazolam (1.6 vs. 3.3 minutes).

17. STAGE 1
Early GCSE

18. Initial management
in hospital
• Initial AEDs
• Maintenance
AEDs
• Treat:
Hypothermia
Hypotension
Thiamine
Investigations:
ABGA
Electrolytes
CBC
AED levels
ECG
Airway protection.
Oxygen.
IV line and IVF (NS).
Intubation +/-
Further etiological
work up.
Correction of metabolic
causes and specific
treatment.Transfer to ICU or
high dependency

19. • 5 year, randomised, double blind, multi-centre trial of LZP vs PHT vs PB
vs DZP+PHT.
• In GCSE, Lorazepam was significantly superior to phenytoin (p=0.002)
• No difference noted in the treatment arms for 134 NCSE patients.
• No differences among the treatments noted with respect to recurrence
during the 12 hour study period, adverse reactions, or outcome at 30 days.
Treiman DM et al. NEJM 1998; 339: 792-8

20. Veterans Affairs Cooperative Trial
N= 384 GCSE
Inj Phenobarbital
15 mg/kg
Inj Phenytoin
18 mg/kg
Inj Diazepam
0.15 mg/kg +
Inj Phenytoin 18 mg/kg
Inj Lorazepam
0.1 mg/kg
64.9% 43.6% 58.2% 55.8%
Cessation of seizures within 20 min of starting infusion, and no
recurrence in next 40 min..
Treiman DM et al. NEJM 1998; 339: 792-8

21. Stage 1: Early GCSE
Once seizure duration > 5 min
Midazolam:
im or rectal: 5–10 mg
iv bolus: 0.1–0.3 mg/kg at < 4 mg/min
Buccal/ intranasal: 10 mg.
Lorazepam (max 4 mg/dose):
iv push: 0.1 mg/kg (<2 mg/min)
Diazepam (max 10 mg/dose):
IV: 0.15-0.2 mg/kg, at < 5 mg/min
Rectal: 10–30 mg
Repeat once if seizures
continue beyond 5-10
min and RR> 8/min.

22. STAGE 2
ESTABLISHED GCSE

23. This study compared parenteral Phenytoin, Phenobarbitone, Sodium Valproate,
Levetiracetam and Lacosamide.

24. Results of the meta analysis
AED Efficacy Comment
Sodium Valproate 75.7% (95% CI: 63.7–84.8%). Follow-up seizure freedom is higher.
Phenobarbitone 73.6% (95% CI: 58.3– 84.8%) Wide confidence interval- ?significance. May
be neuroprotective. Significant side effects.
Levetiracetam 68.5% (95% CI: 56.2–78.7%) Well tolerated in all patient groups.
Phenytoin 50.2% (95% CI: 34.2–66.1%) Poor result could be due to inadequate drug
levels (not reported in most studies).
Lacosamide May be beneficial but
evidence is insufficient.
Small studies suggest good efficacy and
tolerability.
• Valproate, levetiracetam and phenobarbital can all be used as first line
therapy in BZD resistant status epilepticus.
• The evidence does not support the first-line use of phenytoin.

25. Phenytoin Vs Fosphenytoin
Fosphenytoin Phenytoin
Can be given IV or IM. Cannot be given IM.
Less cardiac toxicity. More cardiac adverse effects.
Dextrose containing fluids can be
used.
Cannot be used.
Can be infused at a faster rate. Slower infusion
More expensive Cheaper

26. • 3 studies with phenytoin as
comparator were included.
• VPA does not lead to significantly
higher seizure cessation (OR 1.00;
95% CI: 0.36-2.76) compared to PB.
• VPA has fewer adverse effects than
PB, but not statistically significant.
(OR 0.17; 95% CI: 0.04-0.71).

27. • Only generalised convulsive SE were included, with duration defined as
10 minutes.
• Most common etiology was encephalitis, metabolic/ toxic
encephalopathy.
• Statistically significant efficacy was noted in favour of VPA for seizure
control after infusion, but not for 24 hour seizure freedom.

28. GCSE
n= 68
Inj Valproate
30 mg/kg (n=35)
Inj Phenytoin
18 mg/kg (n=33)
Inj Valproate
30 mg/kg
Inj Phenytoin
18 mg/kg
66% 42%25% 79%
Not
controlled
Seizures controlled following AED infusion
Misra UK et al. Neurology 2006; 67: 340-2.

29. Stage 2 GCSE.
Failure of BZD.
Inj Fosphenytoin (max 1500 mg/dose):
15-20 mg PE/ kg. Upto 100 mg PE/min
Inj Phenytoin:
15-20 mg/kg. Upto 50 mg/min.
Valproate (max 3000 mg/dose):
20-40 mg/kg infusion.
Inj Phenobarbital:
15-20 mg/kg, upto 100 mg/min.
Levetiracetam (max 4500 mg/dose):
20-60 mg/kg infusion.

30. STAGE 3
REFRACTORY STATUS EPILEPTICUS (RSE)

31. DEFINITION
• Continuous or repetitive seizures (lasting more than 60 minutes)
despite treatment with a benzodiazepine and another standard
anticonvulsant.
Shorvon S. Status Epilepticus. Cambridge University Press, 1994: p201.
• RSE develops in 30-40% of patients with status epilepticus.
Brophy GM, et al. Neurocrit Care. 2012;17:3–23.
• Intrahospital mortality ranges form 19-67%.
• Claassen J, et al. Epilepsia. 2002;42:146–53

32. NORSE SYNDROME
New onset refractory status epilepticus (NORSE)
• Patients who develop refractory status epilepticus with no prior
history of epilepsy, or identifiable causative factors.

33. Veteran Affairs Study
2nd study drug
1st study drug
Effective in
55.5% of
patients
3rd Study drug
Effective in
additional 7%
Effective in
additional 2.3%
Intensive ‘non-study’ drug therapy was
needed in 23.2% of patients to stop SE.
LZP vs PHT vs PB vs DZP+PHT
• LZP -> PHT -> PB
• PHT -> LZP -> PB
• PB -> PHT -> LZP
• DZP+PHT -> LZP -> PB

34. RSE
Intubate,
ventilate, ICU care
Investigate cause, and
specific therapy
Hydration, and
supportive care
One of Inj Valproate/ LEV/PHT
Phenobarbitone/ Lacosamide
Anesthetic
agents
By 40 min of seizure onset

35. Continuous EEG
monitoring
Seizures aborted but
sensorium remains poor,
suspicion of NCSE.
EEG end points:
Burst suppression
pattern.
Suppression of
electrographic seizures.
Taper anesthetic
agents after 12-24 hrs
Maintain burst
suppression for 12-
24 hours, interburst
interval of 10 sec
Seizure
Recurrence
Restart
same agent

36. ANESTHETIC AGENTS
Features Propofol Midazolam Pentobarbitone
Loading dose 1-2 mg/kg, at 20
mcg/kg/min
0.2 mg/kg, with 0.2-0.4 mg/kg
increments every 5 min till seizures
stop or a max dose of 2.9 mg/kg is
reached.
5 mg/kg, with 5 mg/kg
increments till seizures
stop. Max bolus rate is
25-50 mg/min.
Maintenance 30-200 ug/kg/min 0.05-2 mg/kg/hr. 0.5-5 mg/kg/hr.
Breakthrough
seizures
Additional 1-3
mg/kg
Additional bolus and 20% increase
in maintenance infusion

37. ANESTHETIC AGENTS
Propofol Midazolam
Rapid onset and offset of action- no
accumulation.
Rapid onset, but slow offset due to
accumulation.
Highly lipophilic Water soluble
No dose reduction required in hepatic or
renal disease
Metabolised by liver, excreted by kidney.
Lower doses with concomitant BZD use Propofol sparing effect.
Multiple mechanisms of action. GABA-A receptor
Propofol infusion syndrome. Tachyphylaxis
Risk of acidosis with ZSN, TPM Longer time to awakening.

38. • 51 refractory status epilepticus patients were studied.
• Anoxic encephalopathy patients were excluded.
• Midazolam induced burst suppression was achieved in 26 patients
(51%).

39. Results
• Breakthrough seizure was less in the burst suppression group.
• Weak evidence of an association between BS and increased
withdrawal seizures.
• No difference noted with regard to intra-hospital complications,
mortality or functional outcomes between the two groups.
• Higher mortality was noted in BS group (53.8% vs. 24.0%), but
not statistically meaningful after controlling for confounding
factors.

40. Early use of Anesthetic Agents
Disease condition
Post-operative patients, especially cardiac and neurosurgery.
Raised ICP, brain tumor, trauma, hematoma, SAH
Stroke
CNS infections
Hepatic or multi-organ failure
Hyperthermia, hyperthyroidism.
Metabolic disorders prone to raised ICP, DKA, organic acid disorders.

41. SUPER REFRACTORY
STATUS EPILEPTICUS

42. DEFINITION
• Status epilepticus that continues or recurs 24 h or more after the
onset of anaesthetic therapy, or recurs on the reduction or
withdrawal of anaesthesia. (Shorvon and Ferlisi, 2011)
• 15% of all the cases with status epilepticus admitted to hospital
will become super-refractory.
• Typically seen in acute severe brain injury or as NORSE.
• Mortality is >50%.

43. Treatment of super-refractory SE
• Continued general anesthesia is the bedrock of therapy.
• Continue anesthesia for 24 h and then slowly reverse it. If seizures
recur, anesthesia is re-established.
• This is repeated in 24-48 hr cycles, and later 5-7 day cycles.
• Anesthesia is administered till the point of burst suppression and
is used to maintain clinical stability till the epilepsy settles down.
• Propofol, midazolam, thiopental are preferred agents in that order.
• Continue 2-3 appropriate AEDs at high doses.

44. Other Treatments

45. Non pharmacological treatments in RSE

46. Simon Shorvon, 2011

47. Common reasons for treatment failure
• Inadequate drug treatment
• Failure to initiate or continue maintenance antiepileptic drug
therapy.
• Medical factors can exacerbate seizures.
• Failure to treat (or identify) the underlying cause
• Misdiagnosis- pseudostatus epilepticus.

48. GCSE in special situations
Patient group Treatment
Eclampsia Magnesium. Phenytoin can be used.
GCSE in pregnancy unrelated
to eclampsia
Standard protocol.
Elderly Valproate may be safer than DPH.
Respiratory depression risk with lorazepam is
higher.
Cardiac patients Avoid phenytoin, fosphenytoin.
Renal disease Standard protocol, but monitor AED levels
closely.

49. MgSo4
Vasodilatation
Reverses vasospasm
of eclampsia and
reduces ischemia
Loading dose: 4-6 g
over 15- 20 min.
Maintenance: 2 g/hr
as continuous IV
Signs of toxicity:
loss of DTRs,
weakness, diplopia,
dysarthria.
Respiratory
depression/ arrest at
levels >14 mg/dl.
Reduces calcium
entry and
excitability

50. • 63 consecutive pts aged 70 years or more, with status epilepticus.
• Compared to 189 controls without epilepsy matched for age, gender and
comorbidity.

51. Results
Risk factors for status encephalitis Factors associated with in-hospital mortality
Acute decompensation Younger age
History of epilepsy Higher comorbidity index
Chronic cerebrovascular disease De novo status epilepticus
Nonvascular dementia
Dysnatremia
• The most common seizure type was complex partial SE/ non-
convulsive SE (85%).
• Mortality rate was 22%

52. GCSE in special situations
Patient group Treatment
Wilson Disease,
INH toxicity
Pyridoxine supplementation at 25 mg/day
(Penicillamine dependent pyridoxine deficiency).
Porphyrias Use non enzyme inducing AEDs like LEV.
Mg, Lorazepam can be used.
Coexisting liver disease Avoid VPA. LEV is best.
Hepatic encephalopathy AEDs are largely ineffective.

53. PROGNOSIS
• Mortality rate: 7.6-39%
• Refractory RSE: mortality is 50%
• Medical complications.
• No difference in mortality was noted between groups treated with
different agents.
• Mortality was 19% within first 30 days, but cumulative mortality
was 43% over 10 years.
• Long term mortality risk increased with SE duration of 24 hrs,
acute symptomatic etiology and myoclonic SE.
Neligan A, Shorvon SD. Arch Neurol 2010;67(8):931–40

54. Studied 2 scores:
Status epilepticus severity score (STESS) and Epidemiology based mortality score in SE
(EMSE)

55. STESS
Parameter Item
Age < 65 yrs: 0 pt.
≥ 65 yrs: 2 pts.
Etiology Previous seizure: 0 pt.
No previous seizure: 1 pt.
Level of consciousness (pretreatment) Alert/ somnolent/ confused: 0 pt.
Stuporous/ coma: 1 pt.
Semiology SPS, CPS, absence, myoclonus of IGE: 0 pt.
Generalised convulsive seizure: 1 pt.
NCSE in coma: 2 pt.
STESS is good at predicting bad outcome but has a ceiling effect especially in
patients > 65 years without pre-existing epilepsy

56. EMSE
Parameter and item Parameter and item
Age:
21-30 yrs: 1 pt.
31-40 yrs: 2 pt.
41-50 yrs: 3 pt.
51-60 yrs: 5 pt.
61-70 yrs: 7 pt.
71-80 yrs: 8 pt.
> 80 yrs: 10 pt.
CNS-anomalies, Multiple sclerosis: 2 pt.
Drug reduction/withdrawal, poor compliance: 2 pt.
Remote cerebrovasc. dis, brain injury: 7 pt.
Hydrocephalus: 8 pt. Alcohol abuse: 10 pt.
Drug overdose: 11 pt. Head trauma: 12 pt.
Cryptogenic: 12 pt. Brain tumor: 16 pt.
Sodium imbalance: 17 pt. Metabolic disorders: 22 pt.
Acute cerebrovascular dis: 26 pt.
Acute CNS infection: 33 pt. Anoxia: 65 pt
EEG findings:
Spont. burst suppression: 60 pt
ASID, LPD, GPD: 40 pt.
No LPD, GPD, ASIDs: 0 pt.
Comorbidity:
AMI, CHF, PVD, CVA, CTDs, dementia, COPD, ulcer disease,
mild liver disease, diabetes: 10 pt.
Hemiplegia, moderate or severe renal disease, diabetes with end
organ damage, tumors: 20 pt.
Moderate or severe liver disease: 30 pt.
Metastatic solid tumor, AIDS: 60 pt.

57. Predicting prognosis
• EMSE is superior to STESS at detection of both bad and good
outcomes and therefore, is highly qualified for individual risk
assessment.
• STESS of 3 or more indicates bad outcome.
• EMSE score of 64 or more indicates bad outcome.

58. Netherlands Study.
N= 346
Favourable
outcome.
263/346
Sequelae.
45/346
Death
38/346
Sequelae
due to SE
itself
Death due
to SE itself
Inadequate treatment:
Wrong AED dose or route
Unnecessary delay
Mech Vent not used on time
NM paralysis without EEG
monitoring
10.3% 22.2% 50%
55.3%
62%
Scholtes FB, Renier WO, Meinardi H. Epilepsia 1994; 10: 1528-57

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