1. Super-refractory Status Epilepticus
Utku Uysal, M.D. M.S.

2. Seizure: “a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. The term transient is used as demarcated in time, with a clear start and finish.”
Classical definition of SE: “a condition characterized by an epileptic seizure that is sufficiently prolonged or repeated at sufficiently brief intervals so as to produce an unvarying and enduring epileptic condition”
Gastaut H. Dictionary of epilepsy, part 1 definitions. Geneva: World Health Organisation; 1973.
Roger J, Lob H, Tassinari CA. Status epilepticus. In Magnus O, de Lorentz Haas AM (Ed) Handbook of clinical neurology, Vol. 15. The epilepsies. Amsterdam: North Holland Publishing Company, 1974:145–188.

3. Status epilepticus (SE)
Continuous clinical and/or electrographic seizure activity lasting more than five minutes or recurrent seizures without recovery between seizures
Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med 1998;338(14):970-6.
Life threatening emergency that requires immediate treatment.
The incidence of SE varies between per 100,000 population
Mortality rate of as high as 22%
Coeytaux A, Jallon P, Galobardes B, et al. Incidence of status epilepticus in French-speaking Switzerland: (EPISTAR). Neurology 2000;55(5):693-7.
DeLorenzo RJ, Hauser WA, Towne AR, et al. A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology 1996;46(4):
Hesdorffer DC, Logroscino G, Cascino G, et al. Incidence of status epilepticus in Rochester, Minnesota, Neurology 1998;50(3):
A seizure is defined as “a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. The term transient is used as demarcated in time, with a clear start and finish.” Classically SE was defined as a “a condition characterized by an epileptic seizure that is sufficiently prolonged or repeated at sufficiently brief intervals so as to produce an unvarying and enduring epileptic condition.”[7, 8]
Because the ILAE definitions of SE have not provided a precise definition of the duration of SE,[1-5] different operational definitions have been provided in textbooks, research papers, and clinical trials. The seminal work by Meldrum et al.[9] suggested that 82 min or longer of ongoing seizure activity in baboons can cause irreversible neuronal injury due to excitotoxicity. This observation led to the commonly used definition for SE as seizure duration of 30 min.[10, 11] The rationale behind this definition was that irreversible neuronal injury may occur after 30 min of ongoing seizure activity. This definition, therefore, remains useful for epidemiologic studies focused on consequences and prevention of SE. Clinicians have rightfully argued for the need to start treatment earlier, because the prognosis of SE worsens with increasing duration.[12, 13] Several suggestions of a shorter timeframe for SE have subsequently been made, but none has been based on scientific evidence provided by prospective studies.

4. Convulsive Status Epilepticus:
Defined as convulsions that are associated with rhythmic jerking of the extremities.
Characteristic findings of generalized convulsive status epilepticus (GCSE):
• Generalized tonic–clonic movements of the extremities
• Mental status impairment (coma, lethargy, confusion)
• May have focal neurological deficits in the post ictal period

5. Non-convulsive status epilepticus (NCSE)
Seizure activity seen on electroencephalogram (EEG) without clinical findings associated with GCSE.
Two distinct phenotypes :
the ‘‘wandering confused’’ patient
the acutely ill patient with severely impaired mental status, with or without subtle motor movements (subtle status)

6. Non-convulsive status epilepticus (NCSE)
Up to 37% of ICU patients with altered mental status, 8% of those in coma, and majority of patient with SE (Privitera et al., 1994; Rudin et al., 2011; Towne et al., 2000).
Particular subtypes – complex partial (CPSE) and absence SE (ASE) – may carry less risk of mortality.
Most studies demonstrate that mortality is associated with the underlying etiology:
higher rates noted in patients with acute medical conditions and acute brain injuries,
lower rates in patients with previous known history of epilepsy.
(Scholtes et al., 1996; Shneker and Fountain, 2003; Young et al., 1996).

7. Treatment of SE Emergent initial AED with BZD (Stage 1)
Lorazepam (0.1 mg/kg IV up to 4 mg per dose, may repeat in 5–10 min)
Midazolam (10 mg IM (>40 kg); 5 mg IM (13–40 kg); 0.2 mg/kg (intranasal))
Diazepam (0.15 mg/kg IV up to 10 mg per dose, may repeat in 5 min)
Urgent treatment (Stage 2)
Valproate sodium (20–40 mg/kg IV, may give an additional 20 mg/kg)
Phenytoin/fosphenytoin (18-20 mg PE/kg IV, may give additional 5 mg/kg)
Phenobarbital (20 mg PE/kg IV, may give additional 5-10 mg/kg)
Levetiracetam (1,000–3,000 mg IV Peds: 20–60 mg/kg IV)
Established Status Epilepticus Trial (fPHT, VPA, LEV)

8. Glauser T, Shinnar S, Gloss D, et al
Glauser T, Shinnar S, Gloss D, et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr Jan-Feb;16(1):48-61.

9. Refractory Status Epilepticus
The Neurocritical Care Society guideline: “patients who continue to experience either clinical or electrographic seizures after receiving adequate doses of an initial benzodiazepine followed by a second acceptable anticonvulsant will be considered refractory.”
Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012;17(1):3-23.
22–43 % of patients enter the refractory stage
There is no specific time or previous trial of anticonvulsants.

10. Who gets RSE? Risk factor OR, 95%CI Reference Acute SE etiology
2.02, ( )
(Sutter, Kaplan et al. 2015)
Coma/stupor
4.83, ( )
Serum albumin <35 g/l at SE onset
2.45, ( )
Encephalitis
6.43, ( )
(Holtkamp, Othman et al. 2005)
Severity of consciousness
N/A, ( )
(Novy, Logroscino et al. 2010)
De novo episodes
N/A, ( )
NCSE
11.6 ( )
(Mayer, Claassen et al. 2002)
Focal motor seizure at onset
3.1, ( )
(Mayer, Claassen et al. 2002)
Severe consciousness impairment
1.67, ( )
(Delaj, Novy et al. 2016)
Increasing age
1.01, ( )
Lack of remote symptomatic SE
0.48, ( )

11. Bolus dose should be given if continuous infusion is chosen.
“The main decision point at this step is to consider repeat bolus of the urgent control anticonvulsant or to immediately initiate additional agents.”
Mayer SA, et al. Refractory status epilepticus: frequency, risk factors, and impact on outcome. Arch Neurol. 2002;59(2):205–210.
Holtkamp M, et al. Predictors and prognosis of refractory status epilepticus treated in a neurological intensive care unit. J Neurol Neurosurg Psychiatry. 2005;76(4):534– 539.
Bolus dose should be given if continuous infusion is chosen.
Bolus dose can be repeated to breakdown the SE.
If the first agent fails, switching to or adding another agent is recommended.
Continuous agents:
Midazolam
Propofol
Pentobarbital
Thiopental
Brophy GM, et al. Guidelines for the Evaluation and Management of Status Epilepticus. Neurocrit Care (2012) 17:3–23

12. Brophy GM, et al. Guidelines for the Evaluation and Management of Status Epilepticus. Neurocrit Care (2012) 17:3–23

13. Treatment recommendations at this stage depend on retrospective case series and uncontrolled studies.
In two systemic reviews, none of the treatments currently available was superior to another
Propofol may be associated with an infusion syndrome, characterized by metabolic acidosis, rhabdomyolysis, renal failure, and heart failure.
Treatment duration of less than 48 h and doses of no more than 5 mg/kg/h are recommended.
The rate of cardiovascular and metabolic complications seemed to be lowest with midazolam and highest with barbiturates.
Claassen J, et al. Epilepsia. 2002;43(2):146–153
Ferlisi M, Shorvon S. Brain.2012;135:2314–2328

14. (Marchi, Novy et al. 2015)
(Kowalski, Ziai et al. 2012)
(Sutter, Marsch et al. 2014)

15. Super-refractory Status Epilepticus
SE that has continued or recurred despite therapy with general anesthesia for >24 hours
Shorvon S, Ferlisi M. Brain 2011:

16. Who gets SRSE? Failure in seizure termination mechanisms
Increased receptor trafficking of GABAR (internalization)
Increased glutaminergic receptors at the cell surface
Alterations in the extracellular environment changing inhibitory GABAR to excitatory.
Mitochondrial failure
Inflammatory processes
Disrupted BBB
Maladaptive response of the astrocytes to the BBB damage
Altered extracellular K and Glu
IL-1B, LPS, TNF-alpha, COX-2,
activation of toll-like receptor (TLR4) by high mobility group box-1 (HMGB1)
Genetic?

17. Determinants: In a recent Finnish population study :
Delaj, L., et al (2016). Refractory and super-refractory status epilepticus in adults: a 9-year cohort study. Acta Neurologica Scandinavica. doi: /ane.12605
In a recent Finnish population study :
the incidence was of 0.7/100,000 (95% CI: 0.6–0.9).
the median age of patients 57 years (17–84 years).
M/F: 51%/49%.
Kantanen AM, Reinikainen M, Parviainen I, et al. Incidence and mortality of super-refractory status epilepticus in adults. Epilepsy Behav 2015;49:131-4.
Determinants:
Encephalitis in developing countries
Severe impairment of consciousness
Younger age
Elderly
Lack of hx of epilepsy

18. Jayalakshmi S, et al. Determinants and predictors of outcome in super refractory
status epilepticus--a developing country perspective. Epilepsy Res 2014;108(9):
Delaj L, et al. Refractory and super-refractory status epilepticus in adults: a 9-year cohort study. Acta Neurol Scand 2016.

19. Mortality rates in SRSE
Tian L, et al. Super-refractory status epilepticus in West China. Acta Neurol Scand 2014.

20. Diagnosis Continuous-video EEG Serum for: Infectious Autoimmune
Paraneoplastic markers,
AED levels,
Toxicology including heavy metals
LP (viruses, parasites, fungi, syphilis/borrelia)
Neuroimaging

21. Treatment Aims: Control of seizures Prevent recurrence
Prevent systemic complications

22. civ Anesthetics

23. Intended recruitment 150 patient, only recruited 24
Propofol seemed to control RSE better though not significant
Both study drugs had similar functional outcome and mortality
Mechanical ventilation duration was longer in barbiturates
Rossetti AO, Milligan TA, Vulliemoz S, et al. A randomized trial for the treatment of refractory status epilepticus. Neurocrit Care 2011;14(1):4-10.

24. Ferlisi M, Shorvon S. The outcome of therapies in refractory and super-refractory convulsive
status epilepticus and recommendations for therapy. Brain 2012;135(Pt 8):
Claassen J, Hirsch LJ, Emerson RG, et al. Treatment of refractory status epilepticus with pentobarbital,
propofol, or midazolam: a systematic review. Epilepsia 2002;43(2):

25. civ Anesthetics
There are no controlled or randomized trial data to aid in selection of the appropriate anesthetic agent.
The choice is dependent on the individual patient profile and physician preference.
Single-center retrospective studies and a meta-analysis comparing midazolam, propofol, and pentobarbital failed to show a short-term benefit of one anesthetic over the others.
The choice of the anesthetic agent is probably less important than the goal of achieving rapid seizure control.
Neither titration goal nor choice of anesthetic infusion was associated with a change in overall outcome
Decreased metabolism and increased t1/2 in concomitant hypothermia

26. civ Anesthetics EEG background suppression: lower breakthrough seizure
significantly higher frequency of hypotension
EEG background activity does not predict seizure control.
Full functional recovery may occur after weeks or months.
The cumulative duration of treatment is not indicative of long term prognosis.

27. Stage 1
Intubated, mechanically ventilated patients, on complete hemodynamic support and under continuous electroencephalogram recording
 Continue all anti-epileptic drugs already started. Use IV formulations if available
 Anesthetics for 24–48 h:
 Midazolam 0.2 mg/kg IV bolus, which can be repeated every 5–10 min up to 2 mg/kg total and start infusion 0.1–0.2 mg kg−1 h−1
 Propofol 2 mg/kg bolus IV and 150 μg kg −1min−1 infusion
 Thiopental 4 mg/kg loading dose IV and 0.3–0.4 mg kg−1 min−1 infusion
 Pentobarbital 10 mg/kg IV loading dose, which can be repeated to burst-suppression 20–30 s effect. Start infusion at 1 mg kg−1 h−1 and titrate up to 10 mg kg−1 h−1
 Monitor and treat aggressively hypotension, sepsis, atelectasis, or pneumonia and deep venous thrombosis. May need total parenteral nutrition
Stage 2
 If seizure control fails or seizure recur after tapering the doses, use the same as above for longer period (1 week?) or go directly to stage 3
Stage 3
 If seizures are still not controlled or recur, use alternative therapies (in order first from top to bottom):
 Ketamine 0.5–4.5 mg/kg bolus IV and start infusion up to 5 mg kg−1 h−1
 Isoflurane or desflurane or gabapentin or levetiracetam (in acute intermittent porphyria)
 Topiramate 300–1600 mg/day per orogastric tube (if no increased stomach residuals)
 Magnesium 4 g bolus IV and 2–6 g/h infusion (keep serum levels <6 mEq/L)
 Pyridoxine 100–600 mg/day IV or via orogastric tube
 Methylprednisolone 1 g/day IV for 5 days, followed by prednisone 1 mg kg−1 day−1 for 1 week
 IVIG 0.4 g kg−1 day−1 IV for 5 days
 Plasmapheresis for 5 sessions
 Hypothermia 33–35 °C for 24–48 h and rewarming by 0.1–0.2 °C/h
 Ketogenic diet 4:1
 Neurosurgical resection of epileptogenic focus if any
 Electroconvulsive therapy
 Vagal nerve stimulation or deep brain stimulation or transcranial magnetic stimulation
Stage 4
 If several weaning attempts have failed over a period of weeks, consider end-of-life discussion with family or surrogate decision maker and withdrawal of life support with subsequent autopsy (if no etiology has been found)
Cuero MR, Varelas PN. Current Neurology and Neuroscience Reports. 2015;15;74

28. Ketamine Strong antagonistic effect on the NMDA-glutamate receptor.
Extensively metabolized by the hepatic cytochrome P450 pathway to its active metabolite, norketamine
Two retrospective case series and nine single case reports, reporting 80 episodes of refractory SE in treated with ketamine.
In total 23 CSE, 13 NCSE, five focal SE, 38 focal NCSE, and one SE of infantile spasms were treated with ketamine.
The overall success rate was 56 %
The bolus dose ranged from 0.5 to 2 mg/kg
Trinka E. Pharmacotherapy for status epilepticus. Drugs. 2015; 75: 1499–1521.

29. Infusion rate ranged from 0.6 mg/kg/h to a maximal 10 mg/kg/h.
The treatment duration of ketamine was at least 2 h and at most 27 days.
A median of five medications (min four, max nine) prior to ketamine were used.
More likely response when used as a third-line or fourth-line agent rather than late in the course.
Effective dose > 0.9 mg/kg/h.
Side effects:
dysarthria, drooling, and appendicular ataxia after treatment with ketamine; cerebellar atrophy in higher dose of Ketamine in one patient.
hypertension, with systolic blood pressure >220 mmHg for 10 min, after the initial bolus of 0.5 mg/kg in one patient
Propofol-infusion syndrome after 4 days of high-dose ketamine (4.5 mg/kg/h) and midazolam,
Supraventricular tachycardia in two
AF in one
Trinka E. Pharmacotherapy for status epilepticus. Drugs. 2015; 75: 1499–1521.

30. Likely responsible in 12% Possibly responsible 20%
Reference N
Response rate
Death
Outcome
Synowiec et al. 11
64%
18%
18% Home
27% ACF
9% SNF
27% IPR
Gaspard et al.
46 Adult
12 Children
60 RSE episodes
Likely responsible in 12%
Possibly responsible 20%
Transient control 13%
45%
4% of adults good outcome (mRS<=2)
1 of the children returned to baseline
Sabharwal et al. 67
91%
38%
N/A
1. Synowiec AS, Singh DS, Yenugadhati V, et al. Ketamine use in the treatment of refractory status epilepticus. Epilepsy Res 2013;105(1-2):183-8.
2. Gaspard N, Foreman B, Judd LM, et al. Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study. Epilepsia 2013;54(8):
3. Sabharwal V, Ramsay E, Martinez R, et al. Propofol-ketamine combination therapy for effective control of super-refractory status epilepticus. Epilepsy Behav 2015;52(Pt A):264-6.

31. Inhalational halogenated anesthetics
Total 19 studies: 28 adult, 18 pediatric cases
8 retrospective case series
1 prospective case series
10 retrospective case reports
Isoflurane (MAC of %) in majority of cases
Desflurane/isoflurane in adults; halothane/isoflurane, and xenon in pediatric cases.
Median duration of tx:
Median 30.3hours (5h-32 days) in adults
Median 29 hours (1h-85 days) in pediatrics

32. Inhalational halogenated anesthetics
Seizure response (adults):
Seizure response (pediatrics):
93% complete control (26/28) within minutes
Failure to isoflurane 7.7%
Desflurane was inferior to isoflurane in achieving seizure control and B-S pattern
Seizures returned upon cessation of the volatile gas treatment
94% complete control (17/18)
Failure to isoflurane was 7.7% as in adults
Seizures returned upon cessation of the volatile gas tx as in adults
Xenon in 5 children controlled seizures with return of seizures with cessation.
Zeiler FA, et al. Modern inhalational anesthetics for refractory status epilepticus. Can J Neurol Sci Mar;42(2):

33. Inhalational halogenated anesthetics
Limitations:
Rise in inorganic serum fluoride levels; with possible hepatic, renal, and pulmonary injury with isoflurane administration.
Hypotension
Calcium mediated myocardial depression in high doses
Isoflurane associated neurotoxicity and apoptotic-induced neuronal death in elevated concentrations

34. Antiepileptic Drugs Topiramate
A broad-spectrum AED with several mechanisms of action, including blockade of the ionotropic glutamatergic AMPA receptor.
No available IV formulation.
95 patients SRSE patients reported to date in the literature.
Dose range: 2 and 25 mg/kg/day in children, and up to 1600 mg/day in adults,
Efficacy: Clinical seizure cessation in 62/95 (65 %).
Metabolic acidosis was the most frequently reported side effect with its use.

35. Lacosamide Good tolerability of the IV formula.
A review of 19 studies (ten single case reports and nine case series):
136 episodes of refractory SE
50 % NCSE, 31 % focal SE, and 19 % CSE
Most commonly bolus dose 400 mg, followed 200–400 mg/day
The overall success rate of 56 % (76/136).
AE in 25 % (34/136) of patients:
mild sedation in 25 cases,
one patient with possible angioedema,
two with allergic skin reactions, four with hypotension,
one with pruritus,
one patient developed a third-degree atrioventricular (AV) block and paroxysmal asystole.

36. Magnesium Blocks NMDA receptor Evidence from limited case reports
Infusion is safe and without significant adverse events
Efficacy ???

37. Pyridoxine Effective in inborn error of pyridoxine metabolism
May be effective in super-refractory status epilepticus
Routinely given in cases of SRSE in young children
In non-pyridoxine-dependent patients case reports of low pyridoxine levels.
The infusion of pyridoxine alone carries no risk.
Dose: 180–600 mg/day.

38. Immunotreatment Autoimmune Status Epilepticus Intracellular targets
Indirectly pathogenic
T cell cytotoxicity responsible for the neuronal dysfunction
Extracellular targets
Directly pathogenic to neurons
Cell damage mediated by B cells and complement deposition
1. Lopinto-Khoury C, Sperling MR. Autoimmune status epilepticus. Curr Treat Options Neurol 2013;15(5):

39. Immunotreatment NORSE Previous good health Very long lasting SE,
Extensive negative work-up
No previous epilepsy
Similar disorders:
Devastating epilepsy in school-age children (DESC)
Acute nonherpetic encephalitis with refractory repetitive partial seizures
Acute encephalitis with refractory repetitive partial seizures (AERRPS)
Fever induced refractory epileptic encephalopathy syndrome (FIRES)
Febrile Infection-Related Epilepsy Syndrome (FIRES)

40. 18/45 favorable outcome Autoantibodies 7/45 3 anti-GAD65 2 anti-NMDAR
1 anti-VGKC
1 anti-VGCC
Khawaja AM, et al. New-onset refractory status epilepticus (NORSE)--The potential role for immunotherapy. Epilepsy Behav 2015;47:17-23.

41. Immunotherapy
AERPPS
Acute encephalitis with refractory, repetitive partial seizures
acute encephalitis of unknown origin, without underlying developmental delay or prior unprovoked seizures;
presenting with repetitive and refractory partial seizures during the acute phase, referred to as refractory partial SE,
continuous transition to intractable epilepsy without a latent period. Tx
12 with CS (2 responded)
13 IVIG with no response
1 PE with no response
Sakuma H., et al. Acta Neurol Scand 2010: 121: 251–256

42. Ketogenic Diet High-fat, low-carbohydrate, and adequate protein diet.
Antiepileptic action
Antiepileptogenic properties
Neuro-protection.
Antioxidant and anti-inflammatory effects
Potential disease-modifying intervention

43. N Age Start day Diet Response Cont’d diet Outcome
Wusthoff,2010 2
29 yo
34y o
101 18
4:1
Sz stopped on day 4
Sz stopped on day 8
Yes
Minimal assistance in ADL at 1 year
Returned to previous profession
Nabbaout, 2010 9
54-98 mo
4-55
Sz stopped in 7 in 4-6 days
Yes in 6/7
Sz recurrence in 1-6 mo in 6 patients
Cervenka, 2010 1
49 yo 58
N/A
Yes (MAD)
Residual weakness, otherwise neurologically intact
Nam, 2011 5
4-40 yo
15-485
Median 8 days
Yes 1-16 mo
1 Normal, 2 Mild MR, 1 MR, 1 Minimally responsive state
Strzelcyzk, 2013
21 yo 16
4:1 (iv)
3.5 days
Return to baseline
Thakur, 2014 10
23-51 yo
2-60
4:1 (9)
3:1 (1)
Sz stopped in 9 in 3 days (median)
Yes 5 MAD
2 died,4 intermittent sz, 3 sz free, 1 lost to follow-up,
Caraballo, 2014 yo
>50 reduction in 5-7 days
Yes 7/10
6 had sz recurrence, quality of life did not worsen
 Cobo, 2014  4
 9 9wks-16 yo
 19-67
 2:1-4:1
 No sz control but successful wean off from iv anesthetics
Yes 
 1 sz free with minor expressive language deficit, 1 died, 2 continued seizures without functional deficits

44. Hypothermia The ability of hypothermia to produce electrocortical
silence in humans has been described for over 50 year

45. Hypothermia
Focal cooling suppresses spontaneous epileptiform activity in human
Karkar KM et al. threshold Epilepsia, 43 (2002), pp. 932–935
Decreased number of limbic seizures in rats
Maeda et al. Brain Res., 818 (1999), pp. 228–235
50% decreased frequency and duration of ictal discharges and no cell loss in Kainic Acid induced SE.
Liu Z et alBrain Res., 631 (1993), pp. 51–58
Application of chilled saline to a spike focus of a
temporal lobe tumor was effective in aborting seizure
activity [

46. Hypothermia
Cooling in addition to low-dose diazepam significantly diminished amplitudes and frequencies of epileptic discharges
After rewarming the discharge frequency increased- reversibility of the findings.
Cooling,
particularly in conjunction with diazepam, diminished
the amplitude and frequency of epileptic discharges that
translated into an anticonvulsant effect in rats tested
Schmitt FC, et al.Anticonvulsant properties of hypothermia in experimental status epilepticus. Neurobiol Dis. 2006;23(3):689–96

47. Hypothermia Calcium overload, Cerebral metabolic rate
Free radical production and oxidative stress,
Permeability of the blood–brain barrier,
Pro-inflammatory reactions
Cerebral metabolic rate
Oxygen utilization,
ATP consumption,
Glutaminergic drive,
Mitochondrial dysfunction,
The anticonvulsant mechanism by which hypothermia
works is not fully understood. Hypothermia reduces excitatory
transmissions, decreases the global cerebral metabolic
rate for glucose and oxygen, reduces ATP breakdown, and
stimulates glycolysis by intracellular alkalinization
enhancing energy production [19, 26]. Its neuroprotective
qualities may stem from this energy conservation and its
attenuation of NO production [25].

48. Hypothermia 1984- Orlowski et al.
Three pediatric cases
Moderate hypothermia + thiopental infusion for h
Two of the patients made a total or near-total recovery without seizure recurrence
The third later died (Rassmussen’s Encephalitis at autopsy)
2008- Corry et al used endovascular induced HT as primary modality to stop RSE
In a case series of three pediatric patients
with SE unresponsive to therapy with conventional anticonvulsants,
moderate hypothermia (30–31C) was used
adjunctively with thiopental [17]. All 3 patients were first
treated with thiopental to a goal of burst suppression.
Hypothermia was then induced with surface cooling and
patients were kept in a state of burst suppression for
48–72 h, titrating their thiopental as necessary. After this
period, thiopental was discontinued and the patients were
slowly rewarmed. Two of the patients made a total or neartotal
recovery without seizure recurrence, while the third
later died and was diagnosed with Rassmussen’s Encephalitis
at autopsy.

49. series of four patients with RSE, hypothermia effectively
terminated seizures during the period of cooling, with
either seizure freedom or a substantial reduction in seizure
frequency being maintained in the postcooling period.
Upon reaching goal temperature, all patients had infusions
of anticonvulsant therapy (i.e., midazolam) weaned off and
could be maintained either in a state of burst suppression or
profound slowing without hemodynamic compromise.
Recurrent seizures occurred in two patients but only over
36 h after rewarming, and were more responsive to traditional
therapies.
Seizure control with antipyretics
Seizure control with low dose midazolam
Corry JJ ey al. Hypothermia for Refractory Status Epilepticus Neurocrit Care (2008) 9:189–197

50. Guilliams K, et al. Hypothermia for pediatric refractory status epilepticus. Epilepsia Sep;54(9):

51. Guilliams K, et al. Hypothermia for pediatric refractory status epilepticus. Epilepsia Sep;54(9):

52. Hypothermia
Excellent (burst suppression or absence of seizure activity electrographically) in 25 of 40 (62.5%) patients.
Reduction in seizure frequency, or a partial response, was documented in six (15%) of patients.
Failure of treatment nine (22.5%) patients.
After optimization of other AED’s, acute recurrence of seizures upon rewarming occurred in three (7.5%) patients
No correlation between target temperature and seizure response.

53. Vagal Nerve Stimulation
Chronic intermittent electrical stimulation of the vagus nerve, delivered by a programmable pulse generator.
Implanted subcutaneously in the chest wall and connected to a bipolar electrode that is wrapped around the vagus nerve in the neck.
Utilized for medically refractory epilepsy

54. Vagal Nerve Stimulation
>50% reduction in seizure frequency in >50% of the patients.
The mechanism of action is not well known.
Vagal nerve mediated diffuse EEG changes
Desynchronization of neuronal activity through activation of amygdala, limbic cortex and thalamus
Increased hippocampal theta activity
Increased noradrenergic secretion and serotonergic transmission in animal models
Increase in CSF GABA level, and upregulation of GABAA receptors in humans

55. Zeiler FA, et al. VNS for refractory status epilepticus
Zeiler FA, et al. VNS for refractory status epilepticus. Epilepsy Research. 2015;112:

56. Zeiler FA, et al. VNS for refractory status epilepticus
Zeiler FA, et al. VNS for refractory status epilepticus. Epilepsy Research. 2015;112:

57. Zeiler FA, et al. VNS for refractory status epilepticus
Zeiler FA, et al. VNS for refractory status epilepticus. Epilepsy Research. 2015;112:

58. Zeiler FA, et al. VNS for refractory status epilepticus
Zeiler FA, et al. VNS for refractory status epilepticus. Epilepsy Research. 2015;112:

59. Zeiler FA, et al. VNS for refractory status epilepticus
Zeiler FA, et al. VNS for refractory status epilepticus. Epilepsy Research. 2015;112:

60. Vagal Nerve Stimulation
Generalized RSE
Focal RSE
Duration of tx before VNS: days
Cessation of RSE in 19/24 (76%)
Time to response 3-14 days
No correlation between stimulation parameters and
1 study with 4 children.
Not SRSE
EPC
Mean duration before VNS months
Mean AED #: 5.8 (5-7)
Cessation of EPC in 4 patients with recurrence of severe seizures in 75%
Zeiler FA, et al. VNS for refractory status epilepticus. Epilepsy Research. 2015;112:

61. Electroconvulsive Therapy (ECT)
Transcutaneous electrical stimulation of the cerebral cortex to induce seizure.
Efficacy well-documented in medically refractory depression and schizophrenia.
A recent systematic review revealed 3 case series and 11 case reports.
Total 19 patients: 15 adults, 4 pediatric cases (median age 10)
Etiology: variable
Zeiler FA, et al. Electroconvulsive therapy for refractory status epilepticus: A systematic review. Seizure Feb;35:23-32.

62. Electroconvulsive Therapy (ECT)
Number of treatment session: Variable, most commonly 1/day
Duration of treatment before ECT: 9-10 days
Duration of ECT: 1 week
Number of AED: 2-14 (mean 7)
Response: 11/19 (58%); 21% partial, 37% complete resolution of seizures.
Duration of response: 2 days-8 years
Outcome: 10 out of 13 available outcome died or severely impaired.
Zeiler FA, et al. Electroconvulsive therapy for refractory status epilepticus: A systematic review. Seizure Feb;35:23-32.

63. Surgery

64. Surgery Reference N Age (y) Etiology EEG MRI PET SPECT Surgery
Age (y)
Etiology
EEG
MRI
PET
SPECT
Surgery
Pathology
Outcome
Molyneux , 1 19
Focal cortical dysplasia
Left central seizures
Norrmal
N/A
MST on left precentral and postcetral gyri with ECOG
RSE stopped, no recurrence of EPC, wheelchair bound on 9 months
Ma, 22 U
Right frontal seizures, bilateral PED, right frontal PLED
Left parasagittal frontal cortex increased FLAIR intensity without contrast enhancement
Right frontal, parietal and posterior temporal increased ictal perfusion
Right frontal resection + MST with ECOG on day 40
Astrogliosis
Occasional brief seizures, left hemiparesis 25
Generalized epilepsy
Generalized fast activity for 1-2 seconds every 30 seconds
Prior corpus callosotomy
CC on day 42
Seizure free, recovered to baseline functions 31
Focal epilepsy
Diffuse attenuation for 1-2 seconds
Right frontal T2 hyperintensity
SPECT-
Right frontal, superior temporal lobes and globus pallidus increased ictal perfusion
Anterior 2/3 CC on day 23,
then right frontal resection at 17th month
Gliosis
Seizure free
Costello, 36
Frequent and organized left frontal sharp and slow waves
Left midfrontal thickening of cortical mantle
Focal left frontal ictal hypermetabolism
Left middle frontal gyrus resection + MST with ECOG on day 51
inconclusive
Seizure free, cognitive impairment first then independent in activities of daily living at 16 months
Ng, 48
Astrocytoma
Right frontal continuous seizure activity
Previous right frontal biopsy with edema and contrast enhancement
Grid placement on day 4, Tumor resection + MST on day 10
Astrocytoma with anaplastic transformation
Seizure free without residual deficit
Weimer, 45
Limbic encephalitis
Right temporal ictal activity
T2 hyperintensities: pons, cerebral white matter and right temporal lobe
Right temporal lobectomy on day 11
Encephalitis
Seizure free, intact mental status, died at 6th months of metastatic lung cancer
Nahab,
200812 57
Left fronto-centralseizures
MRI: T2 hyperintensity in the left fronto-parietal region
Left frontal resection on day 22
Chronic inflammation of leptomeninges, perivascular spaces of cortex and white matter blood vessels
Seizures resolved, patient remained comatose and died on day 54
Weimer, 43
Right frontal seizures
MRI left temporal arachnoid cyst
R frontal resection + MST
Atkinson, 20
CNS vasculitis
MRI- increased T2 signal in right temporal, left insula, bilateral frontal lobes
Right lateral frontal resection with ECOG at week 8
Small vessel vasculitis in cortex and leptomeninged
Rare simple partial motor seizures, mild left hemiparesis, no cognitive impairment
Winkler, 5
1 Engel class I, 1, Engel class II, 2 Engel class III, 1 Engel class IV.
Oderiz, 21
Left hemispheric polymicrogyria
Frequent left frontal paroxysmal fast activity
Left hemispheric polymicrogyria, restricted diffusion in left frontal lobe
Left functional heispherectomy on day 20
Focal cortical dysplasia type IIA
Only 2 seizures, right hemiparesis 18
Parry Romberg Syndrome, focal epilepsy
Right frontotemporal epileptiform discharges and seizures
Right parietal and occipital T2 hyperintensity
Right hemispherectomy on day 39
Reactive gliosis
Seizure free with moderate left hemiparesis

65. Resective Surgery-Pediatric Cases
Pathology
The most common pathologic finding from postoperative
analysis is malformation of cortical development including cortical dysplasia and tuberous sclerosis.
Type of Intervention and Outcome
Resective surgical techniques have included focal cortical resection
(n 13), functional hemispherectomy (n 9), anatomic
hemispherectomy (n 5), lobar resection
Resolution of RSE
The overall outcome among all pediatric cases has been encouraging
with the immediate resolution of RSE in all cases
but one.11 However, these results may be limited by publication
bias of only good outcomes.
Seizure freedom at long-term follow up was achieved in 24 of
the 31 cases (77%) with available follow-up data (Table 1).
predictors for ongoing seizures included an MRI lesion
contralateral to the resection site.13 Of the 6 subjects who did not
become seizure free at follow-up, 2 had undergone focal resection7,10
(2 of the 13 focal resection cases), and 4 had undergone
functional hemispherectomy.9,13
Vendrame M, Loddenkemper T. Semin Pediatr Neurol 17:

66. Resective Surgery-Pediatric Cases
Vendrame M, Loddenkemper T. Semin Pediatr Neurol 17:

67. Conclusion SRSE is encountered in up to 25% of SE.
Carries high risk for mortality.
Extensive investigation for underlying cause should be performed.
Recovery after weeks or months is possible.
Alternative treatments along with AED’s and civ anesthetics may be considered early.