State of the Art Meeting - Intensive Care Society 2015

1. Super refractory status epilepticus
how long should we persevere?
Nicholas Hirsch
Neuromedical Intensive Care Unit
The National Hospital for Neurology and Neurosurgery
Queen Square London
State of the Art Meeting 2015

2. Super refractory status epilepticus
This lecture aims to:
• Define super refractory status epilepticus
• Discuss the various aetiology of super refractory
status epilepticus
• Discuss the association between aetiology and
outcome
• Illustrate the management by discussing
autoimmune encephalitis

3. Refractory status epilepticus
Definitions:
• Refractory status epilepticus (RSE) – status epilepticus
that continues despite first and second line therapies
(typically a benzodiazepine followed by phenytoin,
valproate etc)
• Super-refractory status epilepticus – SE that reappears
whenever general anaesthesia (e.g. propofol, thiopental)
is withdrawn
• Other terms used include new onset status epilepticus
(NORSE) and prolonged refractory status epilepticus
(PRSE)

4. Super refractory status epilepticus
The scale of the problem
• Although relatively rare they are increasingly
seen in specialised neurointensive care units
and may take up bed space for many months
• Morbidity and mortality is high due to the
general complications of ICU
• Recovery is variable and therefore discussions
regarding futility are often raised

5. Aetiology of super-refractory status
epilepticus
• Encephalitis
• Presumed encephalitis
• Hypoxic brain injury
• CNS inflammatory conditions e.g. cerebral
vasculitis
• Metabolic encephalopathy
• Mitochondrial disease
• Autoimmune encephalitis

6. Typical case history and management plan
• A young patient presents with a prodrome of a few
days of behavioral abnormalities
• Patient then presents with status epilepticus which
does not respond to lorazepam and phenytoin
• Following transfer to ICU the intubated patient is
anaesthetised with propofol or thiopental
• Continuous EEG monitoring aiming for burst
suppression
• Longer acting agents (e.g. phenytoin, phenobarbital,
valproate etc) are introduced and plasma levels
optimised

7. Typical case history and management plan
• General anaesthetic agent is slowly withdrawn
looking for clinical of EEG evidence of
continuing status
• If SE continues, add in other agents being
mindful of their mode of action

8. Investigations
• Imaging – MRI may give clue e.g. typical
temporal lobe changes of herpes encephalitis
• CSF – cells, protein, viral PCR etc
• Blood – viral studies, antineuronal antibodies,
HIV, cerebral vasculitis markers etc
• Brain biopsy if vasculitis, lymphoma etc
suspected
• Muscle biopsy if mitochondrial disease
suspected

9. Aetiology is all important for prognosis
• Aetiology appears to more important for
determining prognosis than duration of status
or age of the patient
• For example refractory status epilepticus
associated with hypoxic brain injury has an
almost universally dismal outlook
• Patients with autoimmune encephalitis (e.g.
anti-NMDA receptor encephalitis) can make a
full recovery

10. Syndrome of NMDAR-Ab encephalitis
• Incidence unknown but increasingly recognised
• Characteristic syndrome:
Prodromal stage - headache, fever, URTI, GI upset
Psychiatric stage – anxiety, paranoia, fear, mania,
mutism. Accompanied by seizures, status
epilepticus. After 10-20 days:
Decreased responsiveness stage –
encephalopathy, catatonia, oro-
facial dyskinesias, limb writhing, eye movement
disorders, central pyrexia
• Accompanied by autonomic dysfunction, hypoventilation
requiring IPPV

11. Effect of reduction of NMDARs
• Effect on dopaminergic & cholinergic
transmission Autonomic instability
• Possibly inactivates GABAergic neurones
disinhibiting excitatory pathways Psychosis,
dystonia, catatonia, rigidity, rhythmic
bulbar, ocular and limb movements
• Disruption of brainstem pontine and
medullary respiratory control
Hypoventilation, respiratory failure
• Symptoms and signs similar to those seen
with phencyclidine - an antagonist at the
NMDAR

12. Autoimmunity in NMDAR Encephalitis
• 80% of patients are women
• 50% have associated ovarian teratomas – suggested
molecular mimicry as tumour expresses NMDAR
teratomas most commonly seen in patients < 18y
high proportion of non-Caucasians – suggests
genetic susceptibility
• Oophorectomy improves outcome significantly
• Other tumours described include Hodgkin’s lymphoma
and T cell lymphoma

13. Diagnosis of anti-NMDAR encephalitis
Investigations
• CSF abnormal in majority of
cases: lymphocytosis,
increased protein, oligoclonal
bands
• EEG shows characteristic
‘extreme delta brush’ pattern
• MRI/brain biopsy findings non-
specific
• Definitive diagnosis requires
detection of serum and/or CSF
NMDA antibodies
Extreme delta brush

14. ITU and anti-NMDAR encephalitis
• Overall estimated mortality of disease 5%
• Mortality exclusively in those requiring ITU care
• Reasons for ITU admission include coma requiring
airway protection, refractory status epilepticus,
uncontrolled dystonic movements, respiratory failure
• Mortality of ITU patients high ( > 50%)
• Patients often spend months in ITU and mortality
often related to sepsis etc.

15. ITU management of anti-NMDAR
encephalitis
• Have a high suspicion of anti-NMDAR encephalitis in
any patient who presents with psychiatric symptoms
associated with refractory status, orofacial and limb
dyskinesias, autonomic instability or hypoventilation
• Establish diagnosis with positive NMDAR antibodies
• Give supportive care including adequate sedation to
allow effective ventilation and abolish abnormal
movements. Often high doses of
propofol/midazolam needed
• Treat seizures and status epilepticus

16. ITU management of anti-NMDAR
encephalitis
• Immunosuppressive treatment – high dose iv
methylprednisolone, intravenous
immunoglobulin, plasma exchange
• Second line treatment includes rituximab or
cyclophosphamide
• Hunt for ovarian tumours – CT, MR, transvaginal
ultrasound
• Repeat scans regularly as macroscopic teratoma
may arise later
• Early oophorectomy probably improves outcome

17. Take home messages
• Super refractory status epilepticus is a rare ITU
condition but patients may remain in ITU for
long periods
• Although it has a high morbidity and mortality
complete recovery may occur even after
months of status epilepticus
• Aetiology is all important when considering
how long to persevere

18. Further reading
Shorvon S, Ferlisi M. The outcome of therapies in refractory and super-
refractory convulsive status epilepticus and recommendations for
therapy. Brain 2012; 135: 8: 2314-28.
Kilbride RD, Reynolds AS, Szaflarski JP, Hirsch LJ. Clinical outcomes
following prolonged refractory status epilepticus. Neurocrit Care 2013;
18: 374-85.
Dalmau J, Lancaster E et al. Clinical experience and laboratory
investigations in patients with anti-NMDAR encephalitis. Lancet Neurol
2011; 10: 63-74
Zuliani L, Graus F et al. Central nervous system neuronal surface
antibody associated syndromes: review and guidelines for recognition.
J Neurol Neurosurg Psychiatry 2012; 83: 638-45
Davies G, Irani SR et al. Anti-N-methyl-D-aspartate receptor antibodies:
a potentially treatable cause of encephalitis in the intensive care unit.
Crit Care Med 2010; 38: 679-82