Catastrophic Case Report
Encephalitis/Refractory Status Epilepticus Death
ENCEPHALITIS AND REFRACTORY STATUS
EPILEPTICUS: FAILURE TO RESCUE
A Report from the FH Patient Safety Review Committee
Report Prepared May 2008
CONFIDENTIAL for Quality Improvement Purposes only.
BRIEFING NOTES
16 year old with three-day history of fever, nausea, vomiting and mild headache. The patient was treated
with antibiotics and observed in hospital while cultures were pending. Approximately 72 hours into admission,
the patient became delirious, seized and required intubation and ventilation. Unsuccessful attempts were
made to transfer the patient to another site for critical care and EEG monitoring. The patient was admitted to
the ICU, had further work up and treatment with antiviral agents.
Twelve hours later, the patient had another seizure and subsequently developed localized twitching. This was
assessed by both ICU staff and MRP to be muscular jerking or myoclonus. Through the night the patient
experienced increasing frequency and severity of twitching. This was often one sided affecting facial muscles.
The dose of Midazolam was increased incrementally to a maximum of 36 mg per hour in a combination of IV
infusion and bolus doses. Ultimately the MRP elected to paralyze the patient. The patient was transferred to a
tertiary site. At arrival the patient was in Refractory Status Epilepticus (RSE). Despite aggressive intervention
the patient died from from brain injury due to refractory status epilepticus likely secondary to viral
encephalitis.
RSE triggered by an inflammatory CNS condition carries a very high mortality.
Questions that arose with regard to the management of this case were ;

appropriateness of care of a 16 year old in an overflow unit;
availability of critical care beds for patients between the ages of 16-18;
availability of EEG monitoring for comatose patients who may be seizing;
applicability of the LLTO policy and its failure to cover cases such as this; and
•
availability of physicians and handover, with special reference to after-hours medical
bedside attention.
•
•
•
Intensive supportive therapy in coma is a key contributor to improved outcome in many cases.
Aggressive seizure control and prevention of recurrent seizures/status epilepticus is critical to
reduce the cascade of cerebral parenchymal trauma that can result from oxidative injury.
Results-Recommendation 2
“That a standard guideline for the management of
protracted seizures be developed and shared with FH
clinicians; in particular, to focus on
Status epilepticus(SE)/Refractory status
epilepticus (RSE).”
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Table 1. Guidelines for management of SE/ RSE in adult patients. (estimated times)
Time zero
Seizure
Manage ABC’s, obtain history, check
vital signs (including SAO2 and glucose
meter), monitor temperature frequently
Perform neuro exam and obtain blood work (CBC, electrolytes,
anticonvulsant levels and tox screen)
Time zero-20 minutes
Prolonged Seizure
Insert IV NS one or two lines
In first IV:
Administer Lorazepam 0.1mg/kg/dose IV bolus at 2mg/min –
preferred benzodiazepine as it has longer half-life than Diazepam
and Midazolam
Repeat Lorazepam bolus after 5 minutes- prepare IV phenytoin
In second IV:
If seizure persist, begin to administer Phenytoin 15-20mg/kg/dose
IV infusion as a loading dose (max rate: 50mg/min with monitor)
Time 20-30 minutes – if seizure
persists
Status Epilepticus
FH 300-500 cases per year
Paralyze (short acting agent) and
intubate
Administer Phenobarbital 15-20 mg/kg/dose IV infusion as a
loading dose (max rate: 60 mg/min with monitor);
Control hyperthermia; Support BP/ventilation
Time 30-60 minutes (approx
with drug admin)
Refractory Status Epilepticus
FH 60-100 cases/year
Terminate RSE as soon as possible
Admit to ICU with continuous EEG
monitoring if available
Administer General Anaesthetic doses of midazolam, propofol or
thiopental
Midazolam 0.2mg/kg slow IV bolus, then 0.05-0.5mg/kg/h
preferably in ICU with EEG monitoring if available or
Propofol 1-2mg/kg IV loading dose then 2-10mg/kg/hour
preferably in ICU with EEG monitoring
Greater than 60 minutes
Severe Refractory Status Epilepticus
FH 12-20 Cases/year
LLTO Transfer
Using 2.5% Thiopental infusion (5g in 200mL SWFI glass bottle)
give 15 mg/kg/hr for first hour, then 7.5 mg/Kg/hr for 4 hours,
then 5mg/kg/hr for 20 hrs
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ENCEPHALITIS AND REFRACTORY STATUS EPILEPTICUS
Case Report
A 16 year old with three-day history was hospitalized for fever, nausea, vomiting and mild headache-Dx
“Suspect Viral syndrome/Rule out bacteremia”. The patient was treated with antibiotics and observed while
cultures were pending. Approximately 72 hours into admission, the patient became delirious, had major motor
seizure and required intubation. The patient was admitted to the ICU, had further work up and was
administered antiviral medication. In the ensuing 12 hours, the patient remained obtunded because of
sedative medications and progressive brain injury. 10-12 hours later the patient started twitching then
developed myoclonus and seizures, despite high doses of benzodiazepine anti-seizure medication the patient
proceeded to refractory status epilepticus (RSE). The patient was transferred and despite aggressive
interventions, died.
Diagnosis: Refractory status epilepticus likely secondary to viral encephalitis.
Encephalitis and Refractory Status Epilepticus
Encephalitis is an acute inflammation of the brain tissue characterized by fever, headache, nausea, vomiting,
weakness and altered mental status. The clinical presentation can be florid or subacute. The development of
seizures is a bad prognostic sign with mortality up to 30% and permanent morbidity (cognitive/motor
problems) in many of survivors.
This paper will review the current understanding of Encephalitis and the management of Convulsive Status
Epilepticus / Refractory Status Epilepticus
Encephalitis Clinical Presentation
Many cases of Encephalitis are indolent and progress over days to weeks with fever in almost all cases.
Common findings include headache, nausea, vomiting, general weakness, drowsiness, photophobia and
confusion. “Flu-like” symptoms may last for 2-3 weeks. Seizures can present at any time and may be focal or
generalized. Cognitive impairment and seizures define a high risk group.
Etiology:
Viral infections are the most frequent causative agents while bacteria (mycoplasma) and parasites are
implicated in a small number. Precipitant organisms can be identified in up to 40% of cases. Infections cause
cerebral inflammation via a direct insult or an autoimmune mechanism. Common organisms are Herpes,
Epstein Barr, CMV, enterovirus, mumps, measles, varicella and influenza. Arboviruses transmitted by
mosquitoes and ticks are common in some parts of the world. West Nile virus is increasingly implicated in
some cases throughout North America.
Incidence:
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2-4 cases per 100,000 population may be affected annually. This translates to 30-60 cases in FH per year.
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Clinical approach:
A detailed history with secondary information from relatives or friends suggesting altered cognitive function
should trigger suspicion of Encephalitis. Diagnostic testing has limited value. CT scan is not helpful, except to
rule out other causes of raised intracranial pressure. MRI is occasionally useful with Diffusion-weighted MRI
potentially demonstrating hyper-densities scattered through temporal and inferior frontal lobes. LP and CSF
analysis should be performed once contraindications are excluded. Changes are minimal but may demonstrate
lymphocytic pleocytosis with normal glucose and mildly raised protein. CSF can be sent for viral PCR testing.
This is typically only useful for Herpes virus and not as specific as brain biopsy. EEG is recommended though
findings are usually non specific with up to 75% of cases demonstrating epileptiform abnormalities.
Management:
Acyclovir 10mg/kg/dose IV Q8H should be started as soon as the diagnosis of encephalitis is considered. The
recommended course length is 14 days for immunocompetent patients and 21 days for immune
compromised. This treatment is only effective for HSV encephalitis. Without Acyclovir treatment only 3% of
HSV encephalitis patients make a full recovery. With early prolonged Acyclovir administration mortality drops
from 70% to 30%. Corticosteroids have shown some promise in reducing negative sequelae of autoimmune
encephalitis.
Intensive supportive therapy in coma is a key contributor to improved outcome in many cases.
Aggressive seizure control and prevention of recurrent seizures/status epilepticus is critical to
reduce the cascade of cerebral parenchymal trauma that can result from oxidative injury.
Prognostic Factors:
Poor prognosis is associated with untreated HSV encephalitis, leucopenia, coma, focal neurologic signs,
recurrent seizures, status epilepticus, prolonged EEG abnormalities and focal cortical hyperdensities on MRI
scanning.
Morbidity:
Cognitive impairment, motor problems epilepsy, developmental delay (children), emotional and behavioural
changes reflect the span of post infectious complications.
Recurrent Seizures and Status Epilepticus
In a 2005 published article, Kramer reviewed the outcome of eight children (2-15 years) who presented with
Encephalitis and severe refractory status epilepticus. All were treated with usual IV anti-seizure medications
and burst suppression coma with pentothal, midazolam, propofol or ketamine. The mean duration of
anesthesia was 28 days. Two died, four had persistent seizure disorder, one experienced mild developmental
delay and one made a full clinical recovery, though MRI demonstrated cerebral atrophy.
General Remarks:
Seizures are a common occurrence and can reflect underlying epilepsy, brain or metabolic disorder. Seizures
are usually brief with a postictal period differentiating them from simple faint with clonic activity. Most
seizures are self limited though patients are at risk for further seizures in the period shortly after an episode.
Status Epilepticus (SE) is defined as two or more sequential seizures without full recovery of consciousness
between seizures, or more than 30 minutes of continuous seizure activity. Seventy percent of episodes of
status epilepticus are preceded by a partial onset seizure. There are about 15,000 cases of SE/year in Canada
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translating to 1500 in British Columbia or 500 for FH. Overall mortality in children is 3-5 % while adults have
up to 20% mortality. One third of cases occur in epileptic patients with poor control. Another one third
develop status epilepticus as their first onset of seizure disorder (epilepsy). A host of other conditions cause
the balance of cases. Theses include toxic/metabolic (hypoglycaemia, electrolyte abnormalities, drugs, toxins
(including alcohol) and primary CNS triggers (bleed, tumour, CVA, prior brain injury, encephalitis and other
infections).
Status epilepticus persisting beyond 30 minutes is associated with significant neuronal injury and a
phenomenon of “seizures begetting seizures”. This creates the milieu for the development of Severe or
Refractory Status Epilepticus (RSE).
There is no consensus on the definition of RSE, some define RSE as seizures that fail to respond to 2
standard antiepileptic agents while others define RSE on the basis on seizure duration (i.e. 60-120 minutes of
seizure activity). (Dhar R et al., 2006) RSE is further subclassified to Convulsive RSE (CRSE), which describes
patients with tonic, clonic, or myoclonic movements; whereas Nonconvulsive RSE (NCRSE) refers to patients
without overt motor manifestations of ongoing seizures, despite evidence of ictal discharges on the EEG. RSE
constitutes about 31% to 40% of status epilepticus cases, with a high mortality rate ranging from 23% to
>40%. (Young, GB. 2006)
Pathophysiology:
Status Epilepticus results from the failure of body’s normal mechanisms to terminate seizures. Normal
termination processes include the activation of Na +/K+ ATPase system, acidification of extracellular
environment to stabilize membrane potential, blockade of NMDA channels by Mg +2, and activation of K+
conductance for membrane repolarization. (Dhar R et al., 2006) Possible mechanisms in propagation of
seizures leading to RSE include changes in the GABA receptor composition and loss of benzodiazepine
efficacy, excessive glutamate excitation and possible activation of drug resistance genes. (Murthy JMK, 2006)
Therefore in RSE, benzodiazepine receptors may lose its affinity for its ligands, and therapeutic agents with
mechanisms other than GABA inhibition may be more effective.
Management of SE and RSE:
Published guidelines for the Management of Status Epilepticus have been available for many years. The initial
approach in managing SE patients are consistent among evidence-based guidelines recommending
benzodiazepines such as lorazepam or diazepam as the drug of choice, followed by phenytoin or
fosphenytoin, or Phenobarbital. (Walker M, 2005; Meierkord H et al., 2006; Minicucci F et al., 2006) A recent
Cochrane Systematic Review of anti-epileptic drugs (AEDs) for status epilepticus found that lorazepam was
better than diazepam or phenytoin alone for cessation of seizures and has a lower risk of continuation of
status epilepticus requiring a different drug or general anaesthesia.(Prasad K et al., 2008)
In RSE, patients fail to respond to the above agents and treatment becomes more difficult. The longer the
duration of seizures, the less likely the seizures will abort spontaneously. To date, there has been no studies
that directly compared ongoing non-anaesthetising anticonvulsants vs. general anaesthesia after patients
failed to respond to 2 AEDs. Surveys among neurologist/ ED physicians in the United States and in Europe
revealed the majority are more comfortable with trial of a non-anaesthetising anticonvulsant first (e.g.
Phenobarbital IV) before instituting general anaesthesia (e.g. propofol, high dose midazolam or thiopental).
Unfortunately, some of the non-anaesthetising anticonvulsants that have been studied or used in RSE such as
IV sodium valproate and IV levetiracetam are not available in Canada.
Barbiturates (e.g. thiopental or pentobarbital) have traditionally been used for RSE; however, they are
associated with increased risk of pulmonary infections and severe hypotension, prolonged awakening after
discontinuation and increased length of ICU stay. (Dhar R et al., 2006) As well, pentobarbital is only available
in Canada through a special access program and unless onsite is not a useful consideration. Propofol has
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favourable pharmacokinetic profile with rapid onset, short duration of action and can be easily titrated.
Propofol has been studied in RSE patients and has shown quick onset of seizure control compared to
barbiturates with effective burst suppression of seizures. (Stecker MM et al. 1998) (Parvianen I et al. 2006) In
a retrospective review of 31 RSE episodes using propofol, all episodes of RSE were terminated and brought to
burst suppression. The overall success rate for propofol in controlled RSE was 68% and overall mortality was
22.5%. (Rossetti AO et al, 2004). In a Systematic Review of continuous IV infusions of pentobarbital, Propofol
and midazolam for the treatment of RSE (Claassen J et al., 2002), mortality was not different among patients
treated with Propofol, midazolam or pentobarbital. Mortality was related to the patient’s age, higher APACHE2 scores and duration of SE rather than the choice of therapy. The authors concluded that target of EEG burst
suppression may lead to better outcomes in RSE. Studies of drug therapies used for RSE are summarized in
Appendix 1.
SE progressing to RSE is a medical emergency with a high mortality rate. The approach to managing patients
should be standardised and dependent on patient’s response to standard therapies. A systematic approach to
managing these patients are consistent in the published guidelines, these are summarized in Table 1:
Table 1. Guidelines for management of SE/ RSE in adult patients. (estimated times)
Time zero
Seizure
Manage ABC’s, obtain history, check
vital signs (including SAO2 and glucose
meter), monitor temperature frequently
Perform neuro exam and obtain blood work (CBC, electrolytes,
anticonvulsant levels and tox screen)
Time zero-20 minutes
Prolonged Seizure
Insert IV NS one or two lines
In first IV:
Administer Lorazepam 0.1mg/kg/dose IV bolus at 2mg/min –
preferred benzodiazepine as it has longer half-life than Diazepam
and Midazolam
Repeat Lorazepam bolus after 5 minutes- prepare IV phenytoin
In second IV:
If seizure persist, begin to administer Phenytoin 15-20mg/kg/dose
IV infusion as a loading dose (max rate: 50mg/min with monitor)
Time 20-30 minutes – if seizure
persists
Status Epilepticus
FH 300-500 cases per year
Paralyze (short acting agent) and
intubate
Administer Phenobarbital 15-20 mg/kg/dose IV infusion as a
loading dose (max rate: 60 mg/min with monitor);
Control hyperthermia; Support BP/ventilation
Time 30-60 minutes (approx
with drug admin)
Refractory Status Epilepticus
FH 60-100 cases/year
Terminate RSE as soon as possible
Admit to ICU with continuous EEG
monitoring if available
Administer General Anaesthetic doses of midazolam, propofol or
thiopental
Midazolam 0.2mg/kg slow IV bolus, then 0.05-0.5mg/kg/h
preferably in ICU with EEG monitoring if available or
Propofol 1-2mg/kg IV loading dose then 2-10mg/kg/hour
preferably in ICU with EEG monitoring
Greater than 60 minutes
Severe Refractory Status Epilepticus
FH 12-20 Cases/year
LLTO Transfer
Using 2.5% Thiopental infusion (5g in 200mL SWFI glass bottle)
give 15 mg/kg/hr for first hour, then 7.5 mg/Kg/hr for 4 hours,
then 5mg/kg/hr for 20 hrs
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Appendix 1. Summary of Studies in RSE treatment
Use of Non-Anaesthetising anticonvulsants in RSE
Sodium Valproate IV – Not available in Canada
Limdi NA et al. Neurol
- Retrospective review of adult patients with RSE. N=63.
2005.
- VPA 10-78 mg/kg (mean 31.5 mg/kg).
- Overall treatment efficacy 63.3% with time to treatment and comorbidity
as strong predictors of treatment success.
- improved treatment success with time to treatment <24h
- VPA level not done; cannot establish serum drug concentration
correlation with efficacy.
- overall well tolerated.
Agarwal P. et al. Seiz
2007.
- Prospective, randomized, comparator-controlled study, (?blinding)
- N=100 adult patients with SE refractory to IV diazepam
- mean age 27, mean cause of SE drug noncompliance
- Intervention:
Group A (n=50): IV VPA 20 mg/kg bolus (max rate 40mg/min)
Group B (n=50): IV PHT 20 mg/kg (max rate 50 mg/min)
- Endpoint: Sz control defined as Sz termination per clinical or EEG Sz
activity w/n 20 min of drug infusion with no recurrence in following 12 h.
- Results:
Sz control in VPA 88% vs PHT 84% (NSS)
ADEs not different between 2 regimens
- Conclusion:
IV VPA as effective as IV PHT in RSE control.
- Limitations: study powered? Study not designed for equivalence trial. Sz
recurrence time frame too short?
Phenobarbital IV/ Pentobarbital IV – Not available in Canada
Mostly anecdotal evidence.
Levetiracetam IV – Not available in Canada
Knake S. et al. J Neurol
Retrospective review of SE patients treated with ivLEV between May 2006Neurosurg Psych 2008.
Feb 2007. N=18
-
seizure controls in 18/18 episodes.
all patients treated with different combination of AEDs
ivLEV was last resort in 16/18 episodes.
Mean loading dose 944 mg ivLEV.
Mean maintenance dose 2166 mg/24h.
well-tolerated (no respiratory failure, arrhythmia, Sz worsening).
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Anaesthetic Agents for RSE
Propofol IV
Stecker MM. et al.
Epilepsia 1998.
- Retrospective, comparative study. N=16 RSE patients
- N=8 received high-dose barbiturate
- N=8 received propofol
- Results:
- Sz control with propofol 63% vs high-dose barbiturate 82% (NSS)
- time to Sz control with propofol 2.6 min vs barbiturates 123 min
(p=0.002)
- Limitation: small study, not powered to see difference in efficacy between
propofol & barbiturates. RSE definitions? Study subject to bias given trial
design.
Parvianen I. et al. Int Care
Med 2006.
- prospective observational study, N=10
- propofol IV titration to target of burst suppression EEG pattern x 12h
- Results:
- time to burst suppression ~35 min
- median rate of peak propofol infusion = 9.5 mg/kg/h
- median total dose = 195 mg/kg/24h
- Sz termination in all but recurred (EEG burst) in 3/10 patients.
- 5/10 patients died, cause no attributed to propofol.
- 7/10 received NE to maintain BP
- retrospective review of 31 RSE episodes (N=27 adults)
- propofol with clonazepam administration treated RSE in 67% case
- median propofol @ 4.8 mg/kg/h, median propofol duration 3d, median
ICU stay 7d.
- no major ADEs observed.
Rossetti AO. Et al.
Epilepsia 2004.
Midazolam IV
Prasad A. et al. Epilepsia
2001.
Ulvi H. et al. Neurol Sci
2002.
- retrospective chart review of consecutive patients treated for RSE
between 1995-1999.
- N=14 propofol
- N=6 midazolam
- Results:
- clinical seizure suppression in propofol 64% vs Midaz 67%
- EEG seizure suppression in propofol 78% vs Midaz 67%
- mortality in propofol 57% vs Midaz 17% (NSS – difference driven by
high APACHE II score in propofol group)
- Conclusion:
- Propofol & Midaz equivalent
- patients with high APACHE II score might be better with Midaz
- prospective, open-label study
- N=19 pt with RSE (failed diazepam, POHT, phenobarb)
- midaz IV bolus 200 mcg/kg followed by 1 mcg/kg/min & increase by 1
mcg/kg/min q15 min until seizure termination
- mean time to seizure control ~45 min, mean infusion rate of 8
mcg/kg/min
- seizure persistence found in 1 patient
- no significant changes in BP, HR, O2Sat, respiratory status with midaz
use
- mean infusion duration of idaz 14.5h
- Limitations: endpoint too short? Would not capture seizure recurrence as
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med being tapered off.
Systematic Review
Classen J. et al. Epilepsia
2002.
N=28 studies, total of 193 patients between 1970-2001
Interventions: pentobarbital, propofol or midazolam.
Outcomes: 1) frequency of immediate treatment failure 1-6 hour after
starting AED, 2) mortality
Results:
- overall mortality 48% (not associated with agents used)
- Pentobarbital associated with lower frequency of short-term treatment
failure (8 vs 23%, p<0.01), breakthrough seizure (12 vs. 42%, p<0.001),
change to a different AEDs (3 vs 21%, p,0.001), & increased incidence of
hypotension (77 vs 34%, p<0.001)
++ heterogeneity between studies: Pentobarb studies target EEG
background suppression while propofol and midazolam studies attained
goal of clinical seizure termination.
Conclusion: target of EEG burst suppression perhaps lead to better
outcome in RSE.
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