Transcript Super-refractory Status Epilepticus

Super-refractory Status Epilepticus
Utku Uysal, M.D. M.S.
• 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.
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 9.9-41.0 per 100,000 population
• Mortality rate of as high as 22%
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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):1029-35.
Hesdorffer DC, Logroscino G, Cascino G, et al. Incidence of status epilepticus in Rochester, Minnesota, 1965-1984. Neurology
1998;50(3):735-41.
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
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)
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).
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)
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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)
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. 2016 Jan-Feb;16(1):48-61.
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.
Who gets RSE?
Risk factor
OR, 95%CI
Reference
Acute SE etiology
2.02, (1.01-4.07)
(Sutter, Kaplan et al. 2015)
Coma/stupor
4.83, (2.42-9.68)
(Sutter, Kaplan et al. 2015)
Serum albumin <35 g/l at SE onset
2.45, (1.16-5.16)
(Sutter, Kaplan et al. 2015)
Encephalitis
6.43, (1.27-32.5)
(Holtkamp, Othman et al. 2005)
Severity of consciousness
N/A, (1.03-6.61)
(Novy, Logroscino et al. 2010)
De novo episodes
N/A, (1.03-6.62)
(Novy, Logroscino et al. 2010)
NCSE
11.6 (1.3-111.1)
(Mayer, Claassen et al. 2002)
Focal motor seizure at onset
3.1, (1.1-9.1)
(Mayer, Claassen et al. 2002)
Severe consciousness impairment
1.67, (1.24-2.46)
(Delaj, Novy et al. 2016)
Increasing age
1.01, (1.01-1.02)
(Delaj, Novy et al. 2016)
Lack of remote symptomatic SE
0.48, (0.32-0.72)
(Delaj, Novy et al. 2016)
• “The main decision point at this step is to consider repeat bolus of the urgent
control anticonvulsant or to immediately initiate additional agents.”
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Mayer SA, et al. Refractory status epilepticus: frequency, risk factors, and impact on outcome. Arch Neurol. 2002;59(2):205–210.
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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:
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Midazolam
Propofol
Pentobarbital
Thiopental
Brophy GM, et al. Guidelines for the Evaluation and Management of Status Epilepticus. Neurocrit Care (2012) 17:3–23
Brophy GM, et al. Guidelines for the Evaluation and Management of Status Epilepticus. Neurocrit Care (2012) 17:3–23
• Treatment recommendations at this stage depend on retrospective case series
and uncontrolled studies.
Claassen J, et al. Epilepsia. 2002;43(2):146–153
Ferlisi M, Shorvon S. Brain.2012;135:2314–2328
• 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.
(Marchi, Novy et al. 2015)
(Kowalski, Ziai et al. 2012)
(Sutter, Marsch et al. 2014)
Super-refractory Status Epilepticus
• SE that has continued
or recurred despite
therapy with general
anesthesia for >24
hours
Shorvon S, Ferlisi M. Brain 2011:134-2802-2818
Who gets SRSE?
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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
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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?
• Determinants:
Delaj, L., et al (2016). Refractory and super-refractory status epilepticus in adults: a 9-year cohort study. Acta
Neurologica Scandinavica. doi:10.1111/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.
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Encephalitis in developing countries
Severe impairment of consciousness
Younger age
Elderly
Lack of hx of epilepsy
Jayalakshmi S, et al. Determinants and predictors of outcome in super refractory
status epilepticus--a developing country perspective. Epilepsy Res 2014;108(9):1609-17.
Delaj L, et al. Refractory and super-refractory status epilepticus in adults: a 9-year cohort study. Acta Neurol Scand 2016.
Mortality rates in SRSE
Tian L, et al. Super-refractory status epilepticus in West China. Acta Neurol Scand 2014.
Diagnosis
• Continuous-video EEG
• Serum for:
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Infectious
Autoimmune
Paraneoplastic markers,
AED levels,
Toxicology including heavy metals
LP (viruses, parasites, fungi, syphilis/borrelia)
Neuroimaging
Treatment
• Aims:
Control of seizures
Prevent recurrence
Prevent systemic complications
civ Anesthetics
• 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.
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):146-53.
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):2314-28.
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
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.
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
Ketamine
• Strong antagonistic effect on the NMDA-glutamate receptor.
• T1/2: 2–3 h
• 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.
• 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.
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
Likely responsible in 12%
45%
4% of adults good outcome
(mRS<=2)
12 Children
Possibly responsible 20%
Sabharwal et al.
60 RSE episodes
Transient control 13%
67
91%
1 of the children returned to
baseline
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):1498-503.
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.
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 0.5-5.0%) 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
Inhalational halogenated anesthetics
Seizure response (adults):
Seizure response (pediatrics):
• 93% complete control (26/28) within
minutes
• 94% complete control (17/18)
• Failure to isoflurane was 7.7% as in adults
• 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
• 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. 2015 Mar;42(2):106-15.
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
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.
Lacosamide
• Good tolerability of the IV formula.
• A review of 19 studies (ten single case reports and nine case series):
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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:
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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.
Magnesium
• Blocks NMDA receptor
• Evidence from limited case reports
• Infusion is safe and without significant adverse events
• Efficacy ???
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.
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):545-56.
Immunotreatment
NORSE
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Previous good health
Very long lasting SE,
Extensive negative work-up
No previous epilepsy
Similar disorders:
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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)
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.
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
Ketogenic Diet
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High-fat, low-carbohydrate, and adequate protein diet.
Antiepileptic action
Antiepileptogenic properties
Neuro-protection.
Antioxidant and anti-inflammatory effects
Potential disease-modifying intervention
Wusthoff,2010
N
Age
Start day
Diet
Response
Cont’d diet
Outcome
2
29 yo
101
4:1
Sz stopped on day 4
Yes
Minimal assistance in ADL at 1 year
34y o
18
4:1
Sz stopped on day 8
Yes
Returned to previous profession
Nabbaout, 2010
9
54-98 mo
4-55
4:1
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
4:1
N/A
Yes (MAD)
Residual weakness, otherwise neurologically intact
Nam, 2011
5
4-40 yo
15-485
4:1
Median 8 days
Yes 1-16 mo
1 Normal, 2 Mild MR, 1 MR, 1 Minimally responsive state
Strzelcyzk, 2013
1
21 yo
16
4:1 (iv)
3.5 days
N/A
Return to baseline
Thakur, 2014
10
23-51 yo
2-60
4:1 (9)
Sz stopped in 9 in 3 days
(median)
Yes 5 MAD
2 died,4 intermittent sz, 3 sz free, 1 lost to follow-up,
3:1 (1)
Caraballo, 2014
10
0.5-16 yo
N/A
4:1
>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
Hypothermia
Hypothermia
• Focal cooling suppresses
spontaneous epileptiform
activity in human
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Karkar KM et al. threshold Epilepsia, 43 (2002), pp. 932–935
• Decreased number of limbic
seizures in rats
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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.
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Liu Z et alBrain Res., 631 (1993), pp. 51–58
Hypothermia
• Cooling in addition to low-dose
diazepam significantly
diminished amplitudes and
frequencies of epileptic
discharges
• After rewarming the discharge
frequency increasedreversibility of the findings.
Schmitt FC, et al.Anticonvulsant properties of hypothermia in experimental status epilepticus. Neurobiol Dis.
2006;23(3):689–96
Hypothermia
• Cerebral metabolic rate
• Calcium overload,
• Oxygen utilization,
• Free radical production and
oxidative stress,
• ATP consumption,
• Glutaminergic drive,
• Mitochondrial dysfunction,
• Permeability of the blood–brain
barrier,
• Pro-inflammatory reactions
Hypothermia
• 1984- Orlowski et al.
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Three pediatric cases
Moderate hypothermia + thiopental infusion for 48-120h
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
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
Guilliams K, et al. Hypothermia for pediatric refractory status epilepticus. Epilepsia. 2013 Sep;54(9):1586-94.
Guilliams K, et al. Hypothermia for pediatric refractory status epilepticus. Epilepsia. 2013 Sep;54(9):1586-94.
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.
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
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
Zeiler FA, et al. VNS for refractory status epilepticus. Epilepsy Research. 2015;112:100-113
Zeiler FA, et al. VNS for refractory status epilepticus. Epilepsy Research. 2015;112:100-113
Zeiler FA, et al. VNS for refractory status epilepticus. Epilepsy Research. 2015;112:100-113
Zeiler FA, et al. VNS for refractory status epilepticus. Epilepsy Research. 2015;112:100-113
Zeiler FA, et al. VNS for refractory status epilepticus. Epilepsy Research. 2015;112:100-113
Vagal Nerve Stimulation
Generalized RSE
Focal RSE
• Duration of tx before VNS: 4-12
days
• Cessation of RSE in 19/24 (76%)
• Time to response 3-14 days
• No correlation between
stimulation parameters and
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1 study with 4 children.
Not SRSE
EPC
Mean duration before VNS 6-60
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;112:100-113
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. 2016 Feb;35:23-32.
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. 2016 Feb;35:23-32.
Surgery
Surgery
Reference N
Age (y)
Etiology
EEG
MRI
PET
SPECT
Surgery
Pathology
Outcome
Molyneux 1
, 199811
19
Focal cortical dysplasia
Left central seizures
Norrmal
N/A
N/A
MST on left precentral and
postcetral gyri with ECOG
Focal cortical dysplasia
RSE stopped, no recurrence
of EPC, wheelchair bound on
9 months
Ma,
200110
1
22
U
Right frontal seizures,
bilateral PED, right frontal
PLED
N/A
Right frontal, parietal and
Right frontal resection + MST Astrogliosis
posterior temporal increased with ECOG on day 40
ictal perfusion
Occasional brief seizures,
left hemiparesis
1
25
Generalized epilepsy
N/A
N/A
CC on day 42
N/A
Seizure free, recovered to
baseline functions
1
31
Focal epilepsy
Generalized fast activity for
1-2 seconds every 30
seconds
Diffuse attenuation for 1-2
seconds
Left parasagittal frontal
cortex increased FLAIR
intensity without contrast
enhancement
Prior corpus callosotomy
Right frontal T2
hyperintensity
N/A
Right frontal, superior
temporal lobes and globus
pallidus increased ictal
perfusion
N/A
Anterior 2/3 CC on day 23,
Gliosis
Seizure free
Previous right frontal biopsy N/A
with edema and contrast
enhancement
T2 hyperintensities: pons,
N/A
cerebral white matter and
right temporal lobe
MRI: T2 hyperintensity in the N/A
left fronto-parietal region
N/A
Grid placement on day 4,
Tumor resection + MST on
day 10
Right temporal lobectomy
on day 11
N/A
Seizure free, intact mental
status, died at 6th months of
metastatic lung cancer
Left frontal resection on day Chronic inflammation of
Seizures resolved, patient
22
leptomeninges, perivascular remained comatose and died
spaces of cortex and white on day 54
matter blood vessels
N/A
R frontal resection + MST
SPECTCostello,
20069
then right frontal resection
at 17th month
1
36
U
Frequent and organized left Left midfrontal thickening of Focal left frontal ictal
frontal sharp and slow waves cortical mantle
hypermetabolism
Ng, 200713 1
48
Astrocytoma
Right frontal continuous
seizure activity
Weimer,
200823
1
45
Limbic encephalitis
Right temporal ictal activity
Nahab,
1
57
Limbic encephalitis
Left fronto-centralseizures
1
43
U
Right frontal seizures
MRI left temporal arachnoid N/A
cyst
Atkinson, 1
20126
20
CNS vasculitis
Right frontal seizures
MRI- increased T2 signal in
right temporal, left insula,
bilateral frontal lobes
N/A
Winkler,
201316
5
U
U
U
U
N/A
N/A
U
Oderiz,
201517
1
21
Left hemispheric
polymicrogyria
Frequent left frontal
paroxysmal fast activity
N/A
N/A
Left functional
heispherectomy on day 20
1
18
Parry Romberg Syndrome,
focal epilepsy
N/A
N/A
Right hemispherectomy on
day 39
200812
Weimer,
201215
Left hemispheric
polymicrogyria, restricted
diffusion in left frontal lobe
Right frontotemporal
Right parietal and occipital
epileptiform discharges and T2 hyperintensity
seizures
N/A
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
Astrocytoma with anaplastic Seizure free without residual
transformation
deficit
Encephalitis
U
Seizure free
Right lateral frontal resection Small vessel vasculitis in
with ECOG at week 8
cortex and leptomeninged
Rare simple partial motor
seizures, mild left
hemiparesis, no cognitive
impairment
U
1 Engel class I, 1, Engel class
II, 2 Engel class III, 1 Engel
class IV.
Focal cortical dysplasia type Only 2 seizures, right
IIA
hemiparesis
Reactive gliosis
Seizure free with moderate
left hemiparesis
Resective Surgery-Pediatric Cases
Vendrame M, Loddenkemper T. Semin Pediatr Neurol 17:182-189
Resective Surgery-Pediatric Cases
Vendrame M, Loddenkemper T. Semin Pediatr Neurol 17:182-189
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.