Status Epilepticus- Neurophysiology, Evaluation & Management, Surgical options. Refractory Status Epilepticus.

1. Dr Robin Thomas
Manipal Hospital
Bangalore

2.  Seizure
 paroxysmal disorder of CNS (grey matter) –abnormal
neuronal discharge- change in function of pt.
 Excessive hypersynchronous discharge of cortical
neurons in grey matter.
 Risk factors- fever, hyponatremia, hypoglycemia,
hypocalcemia, meningitis, head trauma, toxins,
ethanol.
 DDs- syncope, breath holding spells, movement
disorders, hyperventilation syndrome.

3.  Status epilepticus
Old defn.
seizure lasting > 30 min
recurrent seizures lasting >30 min, without pt. regaining
consciousness.
 Current defn.
seizure >= 5 min of continuous seizures.
or
2 or more discrete seizures - incomplete recovery of
consciousness .

4. Classification of SE
 Gen. Convulsive- overt
(CSE) - subtle
Non convulsive SE
(NCSE ) - assoc. coma or paralysis
- following prolonged convulsion
- Absence SE
 Focal - simple
- complex

5.  Classification of SE- cause
 Symptomatic SE- known cause for SE (structural or
metabolic ).
 Acute symptomatic SE - < 7 days to acute systemic
metabolic or toxic insult or acute CNS insult.
 Remote symptomatic SE - > 1 week , remote CNS injury-
infection, trauma, cerebrovascular d/s, cortical dysgenesis.

 Idiopathic SE- no known or suspected cause for seizures.

6. Proportional incidences for symptomatic
epilepsies
 Cerebral malformations- 40-45 %
 Infections- 25 %
 Head trauma- 15 %
 Strokes- 5-7 %
 Others- 10-12 %
 ( Major P, Thiele EA. Seizures in children determining
the variation. Pediatr Rev. 2007; 28: 363-371 )

7. Physiological derangements in status
epilepticus
 Blood pressure: Hypertension, Hypotension
 PaO2: Hypoxia
 PCO2: Increased ICP
 Serum pH: Acidosis
 Automatic: Arrhythmias
 Potassium: Arrhythmias
 Creatine kinase: Renal failure
 Cerebral blood flow: Central nervous system bleed
 Cerebral metabolic rate of O2 consumption: Ischemia
 ( Textbook of Pediatric intensive care
medicine.Baltimore: Williams & Wilkins; 1987:618. )

8. Causes
Causes of SE in Children ( Richmond, Virginia,
1996 study )
 Infection with fever.
 Remote symptomatic cause.
 Low anti convulsant drug levels.
 Causes of SE in adults
 Low anti convulsant levels.
 Remote symptomatic cause.
 Stroke.

9. Common causes of seizures in PICU
 1. stroke / arteriovenous malformation/
hemorrhage.
 2. Tumour.
 3. Meningitis/ encephalitis/ abscess.
 4. Vasculitis
 5. Traumatic brain injury.
 6. Preexisting epilepsy.
 7. Antiepileptic agent withdrawal or change.
 8. Post operative craniotomy.
 9. Genetic CNS disorders.

10. Common causes of seizures in PICU
 10. Cerebral malformation
 11. Hypoxia & ischemia
 12. Metabolic : glucose
sodium
calcium
serum osmol

11.  16. Hypertensive encephalopathy
 17. Neurocutaneous syndrome
 12. Fever & febrile seizures
 13. Drug toxicity & withdrawal
 14. Renal or hepatic dysfunction

12.  Epilepsy
 Chronic seizure disorder- recurrent (more than two )
unprovoked seizures –predisposition-underlying state.
 Long term complication of SE, refractory SE, SRSE.


14.  Super refractory SE
 SE continues 24 hours or more after onset of
anesthetic therapy OR
 SE recurs during reduction or withdrawal of
anesthesia.

15.  Non convulsive status epilepticus (NCSE)
 Clinically subtle or non convulsive seizures –common
in ICU pts. –following prolonged convulsive seizures.
 Needs cEEG monitoring.

16. Neurophysiology

17. Normal neuronal firing
 Neuron with one Excitatory (E) & one Inhibitory (I)
input.
 Right side of graph –Membrane potential (mV) –
beginning at Resting membrane potential (-70 MV)
 Activation of E- graded Excitatory post synaptic
potential ( epsp )- larger one reaches threshold (-40
MV)- Action potential.

18.  Action potential- followed by After
hyperpolarization (AHP).
 Magnitude of AHP – determines next action potential.
 Activation of I- Inhibitory post synaptic potential
( ipsp ).

19. Neuronal membrane
 Magnified portion of neuronal membrane- lipid
bilayer- interposed voltage gated Na & K channels.
 Direction of ion fluxes Na to inside & K to outside.
 Membrane bound Na K pump & astroglial cells-
restore ionic balance, after firing.

20. Abnormal neuronal firing

21. Abnormal neuronal firing
 Abnormal neuronal firing- at levels of Brain &
Neuronal network.
 Two Excitatory neurons (1 & 2) and one Inhibitory
neuron (3).
 EEG & intracellular recordings –shown for normal,
interictal & ictal conditions.

22. Abnormal neuronal firing
 Brain
 Three EEG electrode record activity –from superficial
neocortical neurons.
 Normal case- low voltage activity & desynchronized-
neurons are not firing .
 Interictal cond.- large spikes focally at electrode 2-
electrode 1 , lesser extent- sharp waves.
 Ictal state- long run of spikes.

23. Abnormal neuronal firing
 Neuronal network
 Paroxysmal depolarization shift (PDS)-
intercellular correlate of interictal EEG spike.
 PDS – initiated by Non NMDA mediated fast epsp &
maintained by longer NMDA mediated epsp.
 Post PDS hyperpolarization- stabilizes neuron.
 Post PDS hyperpolarization fails- ictal discharge
occurs.

24.  Lower most traces- recordings from neuron 2- activity
similar to neuron 1.

25. Neurophysiology
 Seizures- abnormal synchronous electrical discharge
(depolarization)- of a group of neurons in CNS.
 Depolarization- influx of Na into neuron .
 Repolarization- egrees of K from cell- restoration of
resting negative electrical potential.
 Electrical potential- regulated by sodium potassium
pump- ATP driven.

26.  GABA- major inhibitory neurotransmitter in CNS.
 GABA receptors have chloride ion channel complex &
binding sites for barbiturates & benzodiazepines.
 Glutamate- excitatory neurotransmitter of CNS-
effects on NMDA & non NMDA receptors & secondary
messenger systems.

27. Pathophysiology
 Inhibitory neurotransmission ( GABA )
 Excitatory mediators ( glutamate – NMDA
, AMPA )

28. Neurologic injury in SE
1. Hypoxic ischemic injury
2. Excitotoxicity – accumulation of intracellular Ca2+

29. Diagnosis of SE
 CSE – straightforward
 NCSE v/s post ictal state – challenging
(may need continuous EEG monitoring for Dx )

30. EEG

31. Different wave patterns of EEG

32. EEG
 Abnormal waveforms on EEG- 2 types
 Epileptiform & Non epileptiform abnormalities.
 Epileptiform abn.
 Abnormal discharges - assoc. increased risk of seizures.
 a). sharp waves
 b). spikes & polyspikes
 c). spikes & slow wave discharges .
 Interictal abnorm.- waveforms when present b/w seizures.

37.  Seizures- ictal EEG abnormalities- hallmark is
rhythmicity & evolution in frequency.
 Generalized seizures – widespread b/l rhythmic
epileptiform discharges.
 Focal seizures– rhythmic epileptiform discharges
confined to one brain region.
 Secondary generalization- focal seizures spreading
to involve both cerebral hemispheres.

39. Generalized seizure

40. Left focal seizure

41. BURST SUPPRESSION EEG
 EEG pattern- high voltage electrical activity-
alternating with periods of no activity in brain.
 Brief bursts- mixture of spikes, sharp waves,
alternating with very low voltage.
 Inactivated brain states- general anesthesia, coma,
hypothermia.
 Marker for level of coma , a pt. is in.

43. Burst suppression pattern

44. ISOELECTRIC EEG PATTERN
 Complete loss of cortical electrical activity –with
maximal amplification .
 If sustained for 1 hour or more- cerebral death

45. ISOELECTRIC EEG

47.  Non epileptiform abnormalities- not necessarily
assoc. with seizure- suggest CNS dysfunction.
 Slow waves – nonspecific ( may show structural or
functional abnormality )- seen after a seizure or SE.
 Location of slow waves- differentiation b/w
generalized & focal seizures.
 Generalized slow waves- assoc. diffuse encephalopathy
– metabolic disturbance, hypoxia-ischemia, post ictal
state.

48. Sustained Refractory SE
 SE > 24 hrs.
 Prolonged therapy may be needed for days to weeks
 High dose seizure suppression medications.

49. Rx of SE - goal
 Abort seizure before irreversible neuronal injury
occurs .
 SE may be difficult to control once its duration
increases .

50. General supportive measures
 Airway
 Breathing
 Circulation
 In case of intubation ( use only short acting relaxant
and sedative ).
 Check vitals – HR , RR , BP, Temp, O2 saturation.
 GRBS –finger stick blood glucose- Rx if needed.

51.  Peripheral iv access.
 Medical & neurologic examination.
 Labs: Basal metabolic panel, Mg, PO4, CBC, LFT,
coagulation tests, ABG, anticonvulsant level.

52. EMERGENT INITIAL THERAPY
 Lorazepam IV- 0.1 mg/kg iv (max 4 mg)- may repeat if
seizures persist.
 No IV:
 Diazepam 2-5 yrs 0.5 mg/kg
 6-11 yrs 0.3 mg/kg
 12 yrs 0.2 mg/kg
 Midazolam IM , if 13-40 kg 5 mg.
 >40 kg 10 mg.
 Intranasal 0.2 mg/kg.
 Buccal 0.5 mg/kg

53. URGENT MANAGEMENT
 Diagnostic testing: LP, CT, MRI, toxicology labs, IEM .
 EEG monitoring
 Neurologic consultation.

54. URGENT CONTROL THERAPY
 Phenytoin 20mg/kg iv (another 10mg/kg if needed) –
may cause arrhythmia, hypotension, purple glove
syndrome.
 OR Fosphenytoin 20 PE/kg iv (another 10 PE/kg if
needed).
 OR consider Phenobarbital, Valproate sodium, or
Levetiracetam.
 If <2 yrs , consider Pyridoxine 100 mg iv.

55. REFRACTORY STATUS EPILEPTICUS
 If seizures continue after Benzodiazepines & second
antiseizure medication.
 Continuous EEG monitoring.
 Leviteracetam 20-60 mg/kg iv.
 Valproate sodium 20-40 mg/kg iv – ( contraindicated
if liver disease, thrombocytopenia, metabolic d/s).
 Phenobarbital 20-40 mg/kg iv- (cause respiratory
depression, hypotension).

56. REFRACTORY SE
 PHARMACOLOGICAL COMA MEDICATIONS
 Midazolam 0.2 mg/kg bolus (max 10 mg) & infusion
0.1 mg/kg/hr.
 Pentobarbital 5 mg/kg bolus & infusion 0.5
mg/kg/hr.
 Others: Isoflurane

57. REFRACTORY SE
 PHARMACOLOGICAL COMA MANAGEMENT
 Titrate to seizure suppression or burst suppression
based on EEG.
 Continue pharm. coma for 24-48 hrs.
 Modify antiseizure medications – for infusion
wean.
 Continue diagnostic testing & etiology directed
therapy.

58. REFRACTORY SE
 Add on options
 Medications: Phenytoin, Phenobarbital, levetiracetam,
Valproate sodium, Topiramate, Lacosamide, Ketamine,
Pyridoxine.
 Others: Epilepsy surgery, Ketogenic diet, Vagus nerve
stimulator, Immunomodulation, Hypothermia,
Electroconvulsive therapy.
( Pediatric status epilepticus management. Curr Opin
Pediatr.2014;26:668-674 )

62. BENZODIAZEPINES
 Lorazepam, Diazepam, Midazolam.
 1st line agents- RX of SE.
 Enhances inhibitory neurotransmission.
 Binds to specific BZD site on GABAa receptor.
 DOC – Lorazepam ??
 Less respiratory depression
 Prolonged antiepileptic effect- more than 6 hrs.
 Diazepam- less than 1 hr.
 Less lipophilic ( as diaz is highly protein bound )
 Preferred route – IV
 Diazepam –IM, PR
 Midazolam –IM, intranasal spray, buccal.

63. Barbiturates
 Increase inhibitory neurotransmission at GABAa.
 Phenobarbital, Pentobarbital, Thiopental.
 Phenobarbital– 2nd line drug after bzd do not abort
seizure.
 Good efficacy against – GTCS, AS, myoclonic & focal
seizures.
 Drawbacks – sedation , resp. depression , hypotension.

64. Phenytoin
 Inhibits voltage gated sodium channels
 Blocks fast repititive firing of neurons
 Adv – minimal sedation & resp depression
 Adverse effects– dysarthria, ataxia, hypotension,
cardiac arrhythmias , infusion site pain ,
thrombophlebitis and extravasation causing Purple
glove syndrome .
 Max infusion rate is 1 mg/kg/min (max 50 mg/min )

66. Fosphenytoin
 Water soluble disodium phosphate ester of phenytoin.
 IM / IV
 Devoid of propylene glycol- administered at faster
rate- no cardiovascular risks & no extravasation.
 15-20 mg PE/kg iv – initial dose.
 Max infusion rate of 150 mg PE/min.
 No side effects of phenytoin.

67. Paraldehyde
 Alternative to phenytoin and pheno in early SE or RSE.
 Wide spectrum & efficacy
 200-400 mg/kg PR.
 Irritant effect on rectal mucosa ( disadv)
 No IV
 Pulmonary toxicity

68. REFRACTORY SE
 Continued SE despite administration of multiple first
& second line agents – benzodiazepines,
fosphenytoin, phenytoin, phenobarbitone.
 SE persists beyond 1 yr despite AED therapy.
 Continuous seizure activity ( clinical or
electrographical) for hours.
 24 hr cEEG monitoring.

70. Rx of RSE
 Role of conventional AED’s ( Topiramate, CBZ,
Levetiracetam ).
 Therapeutic options in RSE – high dose BZD ,
barbiturates , propofol , valproic acid , ketamine ,
lidocaine & inhalational anaesthetic agents.

71. Goals of RSE
 Termination of all clinical & electrographic seizure
activity .
 Achieve burst suppression pattern on EEG – maintain
for at least 12 hrs before tapering medication.
 If seizure recurs while tapering – maintain therapy for
48hrs before tapering.
 Also titrate conventional AED’s to high therapeutic
doses.

72. High dose barbiturates
 Pentobarbital, Thiopental, Phenobarbital.
 Pentobarbital – loading dose- 5-10 mg/kg IV &
continuous infusion 1 mg/kg/hr ( max 10 mg/kg/hr).
Rx of break through seizure - 3-5 mg/kg bolus.
 High dose Phenobarbital – incremental boluses of 10
mg/kg.
(no max level or dose . give until seizures are
suppressed). serum levels- 344 mg/ml ( 1490 mmol/l).
 Drawbacks : cardiovascular depression & hypotension
and immunosuppression.

73. High dose BZD
 Midazolam – 0.15 mg/kg LD & continuous infusion @
1 mcg/kg/min ( max of 24 mcg/kg/min)
 Rapid onset , short half life , less CVS depression
 Adverse effects : tachyphylaxis.

75. Propofol
 GABAa agonist.
 Rapid onset of action , short half life.
 Bolus dose of 1-2 mg/kg & continuous infusion of 1-2
mg/kg/hr.
 Adverse effects – resp. depression & hypotension-
myocardial depression.
 Propofol infusion syndrome ( metabolic acidosis,
lipemia ,rhabdomyolysis , bradyarrhythmias & death ).

77. Valproic acid
 Role in RSE.
 Generalized convulsive & nonconvulsive seizures.
 Loading dose- 20 mg/kg & infusion @ 1-4 mg/kg/hr
depending on pts hepatic induction.

78. Inhalational anaesthetics
 Halothane, Isoflurane.
 Halothane- advantage of easily titrable.
 Risk of organotoxicity on prolonged use.
 Hemodynamic compromise.
 Isoflurane- achieves isoelectric EEG at 1.5 %- 2 %.

79. Ketamine and lidocaine
 Ketamine – NMDA antagonist having both
anticonvulsant & neuroprotective properties
 Good therapeutic option - refractory SE - failed to
high dose BZD & barbiturates.
 Lidocaine- IV bolus & continuous infusion.

80. Pyridoxine
 Vitamin B6
 Cofactor for glutamic acid & decarboxylase & GABA
transaminase.
 Trial of pyridoxine - child < 3 yrs with recurrent
seizures or SE - if seizures refractory to conventional
anticonvulsants .
 Isoniazid poisoning –effective anticonvulsant.

81. Therapeutic Hypothermia
 Treat RSE & SRSE.
 Body cooling to 32 to 35.3 C .
 Transient effect
 Temporizing measure.

82. Therapeutic Hypothermia

83. Ketogenic diet
 High fat, low carbohydrate & adequate protein diet.
 Rx of RSE & SRSE.

86. Surgical options- Focal cortical resection

87. Investigations before surgical resection
 FDG-PET scans
 MEG
 Implantation of subdural grid & strip electrodes

88. Fluoro deoxyglucose PET scan

89. Fluoro-deoxyglucose PET scan

90. FDG-PET scan

91. FDG-PET scan
 Fluorodeoxyglucose PET
 Demonstrate interictal hypometabolism or ictal
hypometabolism of epileptogenic focus.
 Medically stable pts.

92. MAGNETOENCEPHALOGRAPHY (MEG)

93. MEG

94. MEG

95. MEG

96. MEG

97. MEG

98. MEG
 Magnetoencephalography-
 Delineates epileptogenic zone- detects magnetic
fields produced by interictal epileptiform activity.

99. Invasive monitoring- Subdural grid & Strip
electrodes

100. Surgical Rx
 1. Focal cortical resections
focal structural abnormality ,identified on
neuroimaging.
 2. Temporal lobectomy
 3. Hemispherectomy

101.  4. Corpus callosotomy
 5. Multiple subpial transaction
 6. Placement of Vagal nerve stimulator (VNS)

102. INDICATIONS FOR SURGICAL
INTERVENTION
 Cortical dysplasia
 Tuberous sclerosis complex
 Polymicrogyria
 Hypothalamic hamarthoma
 Hemispheric syndromes
 Sturge weber syndrome
 Rasmussen syndrome
 Landau kleffner syndrome

103. Focal cortical resection

104. Hemispherectomy

105. FUNCTIONAL HEMISPHERECTOMY

106. Implantation of subdural grid & strip
electrodes

107. CORPUS CALLOSOTOMY

108. MULTIPLE SUBPIAL TRANSECTION

111. VNS

112. VNS

113. Vagal nerve stimulation