1. Desperate Maladies, Desperate Remedies
Au Shek Yin
QEH ICU
Interhospital Grand Round
19/7/2011

2. Presented with fever and seizure
18M
Student in PolyUniversity
Good past health
No family history of epilepsy
No history of drug abuse
TOCC –ve apart from mosquito bites at home

3. Collateral history No rash in patient / family members / classmates
No retroocular pain
No parotitis/ testicular pain/ abdominal pain
No ear pain/ facial pain/ purulent ear/ nasal discharge/ No dental caries
No previous complaints of strange smells
No recent vaccination
( mump )
( Frontal temporal involvement in HSV )

4. On 14/5/2011
Presented with high fever and generalized malaise 5 days before admission
Attended AED of hospital A on 14/5/2011 with sore throat, cough, running nose and nausea
Given ampicillin, paracetamol and discharged home

5. On 19/5/2011
Patient subjectively felt better. He attended a meeting with his classmates on 19/5/2011 since 7pm
Tired looking throughout the meeting and was found collapse with facial twitching at 10pm
GCS 8/15 when attended QEH AED
Intubated at AED for airway protection
Still noted facial twitching

6. Urine for toxicology kit and ketamine –ve
Urgent CT brain done and direct admission to ICU

8. Arrived at ICU at 00:10 Intubated, GCS E1M1VT Afebrile
BP 100/46 pulse 100 Hstix 8
No rash / No needle marks
No LN
Neck soft
Pupil 4-5mm equal with sluggish response
4 limb flaccid on arrival
Repeated attacks of GTCs

9. Initial investigations
ECG sinus HR 100 with normal QT and QRS
Blood test taken at AED
WBC 8.2 plt 155
INR 1.01 APTT 34.5
ABG: pH 7.18 PCO2 6.3 PO BE -11
Blood for electrolytes unremarkable

10. Boluses of dormicum and propofol given and started dormicum infusion
phenytoin was given with loading and maintenance
Needed to start noradrenaline to maintain BP
Clinical seizure only transiently aborted
Toxicology saved and proceeded to LP

11. LP
OP 13cm CSF
Clear CSF
Started empirical acyclovir, rocephin, penicillin G
Later pen G shifted to ampicillin for better listeria monocytogenes cover
Added IVIG for possible EV71 and enterovirus rhomboencephalitis
Also added tamiflu for possible influenza encephalitis

12. Still repeated seizure attacks 20min after admission at 00:30
Recurrent seizure again
in less than 10 min with boluses of propofol, dormicum, dilantin and on dormicum infusion were given

13. Is it a case of status epilepticus (SE) ?

14. History
The earliest description of SE is between BC during Neo-Babylonian era.
Clark and Prout described the natural course of SE in 38 patients unaffected by anti-convulsants.
Clark LP, Prout TP. Status epilepticus: a clinical and pathological study in epilepsy. Am J Insanity 1903;60: , 60:645-75, 61:

15. Classification
Gastaut: there are as many types of status as there are types of epileptic seizures
The term status is used “when a seizure persists for a sufficient time and is repeated frequently enough to produce a fixed or enduring epileptic condition”
Gastaut H. Classification of status epilepticus. Adv Neurol 1983;

16. A definition is needed :30min
More than 40% of seizures lasting from min stops spontaneously without treatment
Mortality of seizures from min vs seizures more than 30 min
2.6% versus 19% (p<0.001)
DeLorenzo RJ, Hauser WA, Towne AR, and et al. A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology 1996;46:

17. Strong statistical reasons for using 5 min as time limit criterion
Mean duration of generalized convulsive seizures in adults ranges from 52.9 sec to 62.2 sec (with SD 14). None of these seizures exceed 2 min.
Wasterlain CG. Definition and classification of status epilepticus. The international meeting on status epilepticus, Santa Monica, CA; 1997(Abstract)
Lowenstein DH. Bleck T, Macdonald RL. It’s time to revise the definition of status epilepticus. Epilepsia 1999;40:
Meldrum BS. The revised operational definition of generalized tonic-clonic status epilepticus in adults. Epilepsia 1999;40:
Shorvon S. The management of status epilepticus. J Neurol Neurosurg Psychiatry 2001;70 (suppl 2):

18. Reasons for 5 min as the time limit
With 5 min, there will be standard deviations away from the norm. This indicates that SE is something distinct and unusual. This definition will unlikely generate confusion or delay in treatment
Theodore WH, Porter RJ, Albert P and et al. The secondarily generalized tonic-clonic seizure: a videotape analysis. Neurology 1994;44:
Kramer R, Levisohn P. The duration of secondarily generalized tonic-clonic seizures. Epilepsia 1992;33:68 (abstract)

19. Pathogenesis of SE

21. 3 cellular mechanisms of SE
Membrane instability: Further classified to increase excitability (pentylenetetrazol model), or decrease inhibitory influences (picrotoxin model) the latter more common
Post-synaptic receptor alterations: Either increase in stimulation of excitatory receptors or decrease inhibitory receptors
Neurotransmitter: Excitatory transmitter may cause seizure upon release, and absence of inhibitory transmitters, e.g.γaminobutyric acid or GABA may lead to seizure activities
Michael J. Neurolgic intensive care: status epilepticus. Crit Care Med 1993 Sep (Supl);21:9: S335-S336.
Drislane FW. Evidence against permanent neurologic damage from nonconvulsive status epilepticus. J Clin Neurophysiol 1999;16:
Kaplan PW. Prognosis in non-convulsive status epilepticus. Epileptic Disorder 2000;2:

22. Brain injury
Cell damage due to excessive excitatory neurotransmitter release, which activates N-methyl-D-asparate receptors and voltage-activated calcium channels, allowing calcium to enter into the cells.
Lipton SA, Rosenberg PA. Excitatory amino acids as final common pathway for neurologic disorders. N Eng J Med 1994;330:63-22.

23. A high Ca concentration leads to generation of reactive oxygen species via activation of nitric oxide synthase, uncouples oxidative phosphorylation in mitochondria and activates lipase, protease, endonuclease and many others catabolic enzymes that adversely affect cell function.
Holmes GL, Ben-Ari Y. The neurobiology and consequences of epilepsy in the developing brain. Pediatr Res 2001;49:

24. Self perpetuating nature of SE
First recognized in 19th century by Trousseau.
Well demonstrated in animal models
Initial SE can be easily blocked by drugs
However once established, it will be perpetuated.
SE causes neuronal damage from ongoing electographic activities, particularly in hippocampus, leading to excessive activation of glutamate receptors

25. Pathophysiology of self-sustaining status epilepticus
a speculative mechanism with three phases
First phase (between a few seconds to a few minutes):
Existing receptors move from the synaptic membrane into the endosomes, or be mobilized from storage sites to the synaptic membrane, hence drastically change the excitability by altering the number of inhibitory and excitatory receptors in the synaptic cleft.

26. Receptor changes

27. Neuropeptides change Second phase (between minutes to hours):
There are plastic changes in neuropeptide modulators, with increase expression of proconvulsive neuropeptides and depletion of inhibitory neuropeptides, hence contributing to a state of raised excitability.
Liu H, Mazarati AM, Katsumori H, Sanker R, Wasterlein CG. Substance P is expressed in hippocampal principal neurons during status epilepticus and plays a critical role in the maintenance of status epilepticus. Proc Natl Acad Sci USA 1999;96:
Vezzani A, Sperk G, Colmers WF. Neuropeptide Y: emerging evidence for a functional role in seizure modulaton. Trends Neurosci 1999;22:25-30.

28. Gene expression change
Final phase (hours, days and more):
Long term change in gene expression. The change in gene expression is a result of seizure-induced neuronal death and neuronal reorganization, with plastic adaptation to seizure activity
Wasterlein CG. Inhibition of cerebral protein synthesis by epileptic seizures without motor manifestations. Neurology 1974;24:

29. Back to Our patient It is now 30 min after admission to ICU
SE not controlled
We have already given boluses of dormicum, propofol, phenytoin and put on dormicum infusion

30. What else could be done?

31. Added regular sodium valproate (Epilim) and phenobarbitone (Luminal)
Seizure still not yet aborted!

32. It was then 01:00, about 50 min after ICU admission What could be done further?

33. Started thiopentone with loading and infusion and stopped dormicum and propofol after thiopentone infusion
( I hoped … )
Seizure finally aborted…

34. Recurrent seizure again at around 01:30, ~ 1 hr 20 min after ICU admission

35. Thiopentone stepped up to 12ml/ hr ( ~ 5mg/kg/ hr )
Resumed propofol and dormicum infusion
Also started clobazem
Seizure finally aborted

36. EEG 20/5/2011

37. Where to stop ? When to stop ?
Controversy about whether both clinical and EEG seizures should be completely controlled
Many use burst-suppression on EEG and aim for complete control of both, whereas some aim for control of clinical seizures (without EEG monitoring).
Bleck TP. Management approaches to prolonged seizures and status epilepticus. Epilepsia 1999;(40 Suppl 1):S59-S63.
Bleck TP. Refractory status epilepticus in Arch Neurol 2002;59:

38. In a survey, 56% aimed at burst-suppression while 41% titrated for seizure elimination.
Claassen J, Hirsch LJ, Mayer SA. Treatment of status epilepticus: a survey of neurologists. J Neurol Sci 2003;211:37-41.
But even with burst suppression, the degree of suppression is unclear. Some used a burst-suppression pattern as endpoint, aiming for inter-burst interval of at least 5 seconds in duration.
Sahin M, Menache C, Holmes GL and et al. Outcome of severe refractory status epilepticus in children. Epilepsia 2001:42:
Sahin M, Riviello JJ. Prolonged treatment of refractory status epilepticus in a child. J Child Neurol 2001;16:

39. Persistent seizure control is better with electrocerebral inactivity on EEG (17/20) than burst suppression pattern (6/12).
Krishnamurthy KB, Drislane FW. Relapse and survival after barbiturate anaesthetic treatment of refractory status epilepticus. Epilepsia 1996;37:

40. However hypotension often occurs when titration for electrocerebral inactivity.
Claassen J, Hirsch LJ, Emerson RG and et al. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia 2002;43:

41. High dose suppression therapy
HDST usually for 12 to 24 hours, and then tapered the infusion. If SE recurs, HDST can be started
Prolonged HDST considered if potential good prognosis: healthy patient before the SE, self-limiting disease, no disease in work up including neuroimaging study.
Mirski MA, Williams MA, Hanley DF. Prolonged pentobarbital and Phenobarbital coma for refractory generalized status epilepticus. Crit Care Med 1995;23:

42. However in one study, 7 out of 22 (32%) returned to baseline
However in one study, 7 out of 22 (32%) returned to baseline. But all 7 subsequently developed refractory epilepsy: epilepsy recurrence upon tapering, within 1 to 16 months.
Hence prognosis must be taken into account when using such extreme therapy.
Sahin M, Menache CC, Holmes GL. Outcome of acute symptomatic refractory status epilepticus in children. Neurology 2003;61:

43. Finally the patient was stabilized at around 02:45

44. What are the treatments for status epilepticus (SE)?

46. Double-blind Randomized Comparison of 4 i. v
Double-blind Randomized Comparison of 4 i.v. Treatments in Overt of Generalized Convulsive Status (n=384)

47. Stage 1 Premonitory/Early Status (0-30/60 minutes)
Benzodiazepines drugs of choice:
Lorazepam, 4 mg iv, may be repeated after 10 min
Diazepam, mg iv (5 mg/min), may be repeated after 10 minutes
midazolam, clonazepam
Out-of-hospital therapy
Rectal diazepam
Buccal/intranasal/im midazolam

48. Benzodiazepine- the drug of choice
Class 1 evidence
Although IV lorazepam and diazepam have similar complication rates, lorazepam is the preferred therapy because of efficacy.
Although diazepam rapidly enters the brain because of its high-lipid solubility, its clinical effect is diminished by its rapid systemic distribution. Lorazepam has a longer duration of action and a lower risk of seizure recurrence.

49. The Veterans Affairs Status Epilepticus Cooperative Study Group report:
at least one-third of the time, initial benzo fails to stop SE. And a second medication is usually also unsuccessful
Nevertheless, American and European protocols call for a second treatment, a non benzodiazepine, to be given for persistent SE. The most commonly used options are fosphenytoin or phenytoin.

50. Stage 2 Established Status Epilepticus
Conventional treatment:
Phenytoin/fosphenytoin iv at 50 mg/min
Fosphenytoin iv at 150 mg of phenytoin equivalents /min
Phenobarbitone, 10mg/kg iv at 100 mg/min
Alternatives:
Valproate, levetiracetam, benzodiazepine infusion
Courtesy of T. Tomson, 2010

52. Phenytoin/ Fosphenytoin

53. Second line in status
Risks: hypotension, cardiac dysrhythmias, puruple glove syndrome

54. Purple Glove Syndrome
Distinctive discolouration and swelling of the hands caused by intravenous administration of phenytoin
Characterized by intense pain, purplish black discolouration and edema at the site of injection which progresses to rest of the limb
Reported incidence between 1 and 7%
Should be differentiated from extravasation of intravenous fluid, injection site infection and intra-arterial injection.
Pathophysiology not fully understood –alkaline pH and irritation caused by PEG can be a factor

56. Fosphenytoin
Phosphate ester water-soluble prodrug of phenytoin, formulated in aqueous solution (Tris buffer, ph 8.8).
Rapidly converted to phenytoin by phosphatases in liver, red cells and other tissues
Same indications as i.v. phenytoin. May be given i.m.
After iv infusion at 150 mg of phenytoin equivalents/min, free phenytoin levels are superimposable to those achieved with phenytoin 50 mg/min
Lower risk of local irritation including purple glove syndrome -however, cost is an issue

57. Barbiturates

58. Phenobarbital
Useful as replacement therapy for patients unable to take oral medication
Second-line choice in SE unresponsive to benzodiazepines
Often used to treat ongoing seizures in neonates and infants

59. Valproate

60. An increasingly used second-line choice in SE unresponsive to benzodiazepines
Concerns: liver toxicity, teratogenicity, altered platelet function and coagulation defect

63. Thiopentone

64. Barbiturate, effects mediated via GABA receptors
Indications:
General anesthesia
Status epilepticus
Raised intracranial pressure

65. Adverse effects:
Hypotension, myocardial depression, tachycardia, dysrhythmia
Respiratiry depression, bronchospasm
Local effects: pain, swelling, ulceration, gangrene, necrosis
Allergic reaction, shivering

66. Contraindications:
Porphyria
Status asthmaticus

67. Levetiracetam (Keppra)

69. Levetiracetamin in the Treatment of Refractory SE
Several reports suggested efficacy in refractory SE by nasogastric tubes
Several more cases reported after the introduction of the i.v. formulation in 2006
Most successful cases reported in focal and non-convulsive (NCSE) status

74. Approved as replacement therapy for patients unable to take oral medications
An increasing number of reports suggest efficacy in patients with SE unresponsive to benzodiazepines
Good tolerability makes it an attractive candidate for further investigation as an emergency anti-seizure medication

75. Loosening of efficacy with time
Barbiturates and other GABAergic drugs have decreased efficacy and require higher doses. And side effects increased
Pharmacoresistance: Benzodiazepine will decrease in its potency by 20 times within 30 minutes of self-sustaining SE.
Other anticonvulsant such as phenytoin will also lose their potency, but much more slowly

76. NMDA blockers remain effective
The SE highly depends on function of glutamate receptors
Hence the novel approach is to develop new agents targeting at affinity for NMDA receptors
3 NMDA receptor blockers: 5,7-DCK, MK-801, ketamine can block SE with great effectiveness
Mazarati AM, Wasterlain CG. N-Methyl-D-asparate receptor antagonists abolish the maintainance phase of self-sustaining status epilepticus in rat. Neurosci Lett 1999;265:

77. Back to our patient

78. Lab results – To find the causes of SE
LP glucose 4.4 ( blood glucose 8.8 )
CSF protein 0.44
No organisms seen on gram stain
Later C/ST also –ve
Throat swab and septic work up –ve
TA for respi virus and H1N1 –ve  tamiflu off
Immune marker later turned back unremarkable
Toxicology turned out –ve
Dengue and Jap B encephalitis serology turned out –ve
Tumour markers –ve
HIV –ve

80. While waiting for some Ix results
Monitor clinical seizure, put on continuous EEG monitoring
Monitor electrolyte esp K, monitor CK
Monitor AED drug level
Monitor ammonia level while on epilim
FAST HUG

81. MRI 20/5/2011

83. Formal MRI brain report
Abnormal T2/FLAIR hyperintensity is noted at splenium of corpus callosum.
There is also suspected increased hyperintensity of cerebral sulci on FLAIR images, especially at posterior part of bilateral cerebral hemisphere.
No definite hyperenhancement is noted.
Overall features are suspicious of meningo-encephalitis in veiw of clinical context.
Sinusitic changes are noted, worse at left maxillary sinus.
Dx: Meningo-encephalitis is suspected

84. cEEG Day 2-3 ICU while on thiopentone coma

85. Started to gradually tail down thiopentone infusion because all the stock of thiopentone in HK has been exhausted for use in this patient
Kept on dormicum infusion and on AEDs: phenobarbitone, phenytoin, valproate

88. Repeated EEGs
EEG still showed bursts of PLEDS and sharp wave activites over both hemisphere
Added keppra on 25/5
Added trileptal on 30/5

91. Continuous EEG monitoring
A junior doctor on call in ICU was called to see the EEG tracing at 2am.

93. Role of continuous EEG monitoring in SE pt

94. cEEG
cEEG continuously displayed at the bedside for moment-to-moment on-line observation
Seizures detected in one of three ways: 1. On-line identification
2. By the total power trend seizure detection method
3. By detection during regularly scheduled EEG segment review

95. Continuum Academy Aermican of Neurology

96. EEG to predict response to initial treatment
The DVA trial: EEG stage of SE to predict response to treatment.
Earliest EEG stage of SE (discrete convulsions) patients have a 75% chance of success with the initial agent
With a waxing and waning pattern, falls to 30%
Continuous ictal activity, 25 %
Brief suppressions, 8%,

97. To complicate the issue…
Rhabdomyolysis and AKI requiring CVVH
Ileus and failed post pyloric feeding
Tense abdominal distension with abdominal compartment syndrome
AED level fluctuating due to RRT and difficult drug titration
Cranial DI requiring DDAVP
Small Grade 2 sore over head and sacral regions
Splinting to prevent contracture

98. Further Ix results Dengue IgM –ve PCR TB –ve VDLR non reactive
CSF HSV PCR Mumps measles VZV HSV -ve
Copper 14.0 ( ) umol/ L
Ceruloplasmin 230 ( ) mg/L
24 hr urine copper 1.25 umol/d

99. Screening for Inborn errors of metabolism –ve
Increased ammonia level notes since 1/6
Increased lactate level
To arrange aminoacid pattern for any evidence of beta-oxidative mitochrondrial defect: unremarkable
MELA screening –ve ( plan for genetic counseling if +ve )

100. Autoimmune screen -ve VGKC ab test -ve
( for a course of pulse steroid if 2nd viral titre not raised and Ab test suggested autoimmune encephalitis )

102. FU MRI brain 2/6/2011
Increased hyperdensity in T2/FLAIR over bilateral occipital, temporal lobes and right insular, sulci still preserved with no hydrocephalus, maxillary sinusitis especially over left side

106. CT paranasal sinus

107. Blood for galactomannan Ag +
ENT consulted and suspected fungal sinusitis 5/6/2011
FESS done on 6/6/2011:
Copious amount of frank pus filling up left antrum and anterior ethmoid and posterior ethmoid sinus
Grossly polypoid mucosa in all sinuses on left side
Right side antrum and posterior ethmoid filled with thick mucus
Polypoidal mucosa over right antrum

108. Nasal biopsy: chronic inflammation
Pus swab 5/6/2011: Acintobacter and ESBL klebsiella
Given a course of antibiotics / antifungal therapy

109. Further Ix LP repeated on 7/6/2011 Protein 0.14 glucose 5.3 WBC < 1
Second viral titre not raised

110. Tracheostomy performed

111. Latest condition Pupil 5mm fixed and dilated
Still on 5 AED with midazolam infusion at 10mg/ hr
Myoclonic jerks upon stimulation

112. Latest EEG

113. So far, what we know about our patient……
1. I failed to find a case report that the status can be so prolonged
2. Prolonged intractable seizure likely have poor prognosis
3. Efficacy of dormicum infusion decreases with time and may need to consider other therapy if recurrent seizure

114. What else we can do?

115. To review the approach to possible viral encephalitis

116. Encephalitis inflammation of brain parenchyma and neuronal cells
Directly caused by virus, protozoa (Toxoplasma gondii), bacteria (Listeria monocytogenes) and MTB
Autoimmune mediated: ADEM following infections/ vaccination, paraneoplastic limbic encephalitis, voltage gated potassium channel limbic encephalitis
Viral encephalitis can be infectious or post infectious

117. Encephalitis is a pathological diagnosis
Autopsy or brain biopsy

118. Presentations nonspecific
Dysphagia, pharyneal spasm, hydrophobia ( rabies )
Tremor of eyelids, tongue , lips and extremoities ( St Louis encephalitis, WNE )
Unilateral sensorimotor dysfunction ( PIE )
Flaccid paresis ( WNE )
Vesicles, keratoconjunctivitis ( HSE )

119. Epidemiology Etiology different in different regions
Overall HSV encephalitis most common one ( 57% in HK )
Japanese encephalitis common in Asia
Nipah and enterovirus emerging in Malays, Singapore and Taiwan

120. Changing / Emerging epidemiology around the world
CMV, EBV, HHV 6 more in immunocompromised host ( HIV, transplant, chemotherapy )
Arbovirus ( WNV and JE ) outbreaks in America, Europe and Asia ? Climate change
EV 71 with recent massive outbreaks of HFM disease with aseptic meningitis, encephalitis or myelitis in Asia
Nipah virus outbreak in Malaysia and Bangladesh
Measles and mumps resurging in UK probably related to reduced vaccine uptake

121. Treatment for various viral encephalitis
Viruses
Cytomegalovirus
Ganciclovir plus Foscarnet
Epstein-Barr
No specific treatment
Herpes B virus
Valgancyclovir
Herpes Simplex
Acyclovir
Human Herpesvirus 6
Gancyclovir or Foscarnet
Human immunodeficiency virus
HAART
JC virus
Reversal of immunosuppression if possible
Measles
Ribavirin
Nipah
St. Louis encephalitis
Interferon-2 alpha
Varicella-Zoster
West Nile

122. Brain Biopsy ? Gold standard Need eg SPECT scan for localization
99% sensitive and 100% specific (Whitley, RJ, Lakeman, F. Herpes simplex virus infections of the central nervous system: Therapeutic and diagnostic considerations. Clin Infect Dis 1995; 20:414. )
Last resort and invasive

123. PROGNOSIS OF STATUS EPILEPTICUS
The main determinants of mortality and morbidity are age, etiology, and duration of SE
Most mortality is secondary to the underlying etiology of SE rather than seizures themselves

124. Short-term mortality is highest when SE occurs due to an acute insult.
In particular, anoxic encephalopathy and stroke have high mortality rates
In one study of NCSE, acute medical and neurological etiologies had a mortality of 27%, cryptogenic etiologies 18%, and previous epilepsy 3%.

125. Duration of SE
SE duration greater than 2 hours is associated with a significant increase in mortality
Patients with continuous SE have higher mortality than those with intermittent seizures, possibly because of more prolonged duration of actual seizures
Seizures lasting 10 to 29 minutes have lower mortality (4.4%) than SE lasting more than 30 minutes (22%)

126. Prolonged SE is more likely to result in long-term deficits
Chronic encephalopathy and brain atrophy may occur in 6-15% of adult patients with generalized convulsive SE, presumably because of diffuse cortical injury and neuronal death.
Developmental deterioration reported in 34% of children with SE lasting from 30 to 720 minutes
New onset of epilepsy reported in 20-36% of survivors of GCSE

127. Other desperate remedies……
Role of hypothermia in SE?
Role of ketogenic diet in adults?
Role of ketamine in SE?

128. Role of Hypothermia? Use not proven yet
Corry JJ, Dhar R, Murphy T, Diringer MN. Hypothermia for refractory status epilepticus. Neurocrit Care. 2008;9(2):

129. Role of ketogenic diet?
Anecdotal reports documenting the success of fasting or starvation in the treatment of seizures exist as far back as the 5th century B.C.
The classic ketogenic diet, developed at Johns Hopkins, contains fats in a 4:1 ratio to carbohydrates. The amount of protein regulated so that 90% of calories derived from fat
This diet used as treatment for epilepsy fairly commonly in the 1920s and 1930s in children
In the late 1930s and 1940s, phenytoin and phenobarbital were introduced to practice, so ketogenic diet was largely replaced by drug therapy

130. Mechanism not well understood
1) direct stabilizing effect of ketone bodies on the central nervous system
2) resulting acidosis accompanying ketosis modifies the seizure threshold
3) changes in fluid and electrolyte balance
result in reduced seizures
4) change in lipid concentration induced by the diet has an antiseizure effect.

132. More established in childhood status
Acute encephalopathy with inflammation-mediated status epilepticus (AEIMSE) or many other different names.
a group of children (4-15 yrs) with fever & then refractory SE, but negative workup (including extensive infective, autoimmune, inborn error of metabolism, mitochondrial disease, autoimmune disease, etc).  Brain biopsy did not reveal any abn.
MRI: half has mesial temporal signal change. 
Refractory to even barbiturate anaesthesia.
this group of pt may respond to ketogenic diet.

133. Few experience in Adult
Wusthoff CJ, Kranick SM, Morley JF, Christina Bergqvist AG. The ketogenic diet in treatment of two adults with prolonged nonconvulsive status epilepticus. Epilepsia Oct 20.

135. Evidence of ketamine use in SE

136. Epilepsia, Vol. 47, Suppl. 1, The Management of Refractory Status Epilepticus: An Update Daniel H. Lowenstein
In addition to blocking seizure activity, ketamine has a potential neuroprotective effect, and can increase blood pressure due to its sympathomimetic properties. … clinical use to date appears to be very limited.
Bleck and colleagues described their experience with the use of ketamine in seven critically ill patients with RSE. Their main observation was that ketamine produced electrographic seizure control in over half the patients without causing hemodynamic instability.
A case report by Sheth and Gidal also provides evidence for the potential utility of ketamine in extremely refractory cases.
However, another anectdotal report has raised concern about the development of cerebellar toxicity when ketamine is used for prolonged periods.

137. Epilepsy Research 2008;82; Ketamine successfully terminates malignant status epilepticus Harald Prüssa and Martin Holtkamp
A case report, the SE was controlled with a trial IV ketamine in combination with midazolam (0.6 mg/(kg h)).
ketamine infusion started with 0.4 mg/(kg h) and gradually increased within 3 h to 1.6 mg/(kg h). As clinical and electrographic SE sustained after 48 h of ketamine treatment, the dose was increased to 2.4—3.2 mg/(kg h) for another 8 days.
With gradual decline and eventually disappearance of both continuous subtle motor phenomena and EEG epileptiform discharges, the ketamine infusion was titrated down over a period of 4 days without clinical or electrographic SE recurrence.

138. Epilepsy Behav. 2003 Feb;4(1):70-5
Epilepsy Behav Feb;4(1):70-5. Ketamine for refractory status epilepticus: a case of possible ketamine-induced neurotoxicity. Ubogu EE, Sagar SM, Lerner AJ, Maddux BN, Suarez JI, Werz MA.
A 44-year-old man with treated neurosyphilis presented with subclinical status epilepticus (SE) refractory to intravenous high-dose lorazepam, phenytoin, and valproic acid over 4 days.
Ketamine infusion was instituted after low-dose propofol sedation with gradual control of electrographic seizures over 72h.
Reevaluation 3 months later revealed diffuse cerebellar and worsened cerebral atrophy, consistent with animal models of N-methyl-D-aspartate antagonist-mediated neurotoxicity.

139. Side effects of ketamine
Cardiovascular
Elevated blood pressure and pulse rate
Hypotension and Bradycardia have been observed
Arrhythmia reported
Respiratory
Stimulated respiration, although severe depression of respiration or apnea may occur following rapid intravenous administration
Laryngospasms
Ocular
Slight elevation in intraocular pressure
Gastrointestinal
Anorexia, nausea, and vomiting.

140. Side effects of ketamine
Musculoskeletal
Enhanced skeletal muscle tone manifested by tonic and clinic movements sometimes resembling seizures
Local
Pain and exanthema at the injection site
Dermatologic
Transient erythema and/or morbilliform rash
Psychiatric
Anxiety, dysphoria, disorientation, insomnia, flashbacks, hallucinations, and psychotic episodes
withdrawal syndrome with psychotic features following discontinuation of long-term ketamine use.

141. What else we can do?
Your input on the management of this patient is most welcome !

142. Thank you very much !