Patrick VAN BOGAERT, MD, PhD

Clinique de Neurologie PédiatriqueLaboratoire de Cartographie Fonctionnelle du Cerveau

Université Libre de BruxellesHôpital Erasme

Status epilepticus in infancy

What is status epilepticus (SE)?

• ILAE 1993 (guidelines for epidemiologic studies):– Single epileptic seizure > 30-min duration– Or series of epileptic seizures during which function is

not regained between ictal events in a > 30-min period

• ILAE 2001 (glossary of descriptive terminology for ictal semiology)– Seizure that shows no clinical signs of arresting after a

duration encompassing the great majority of seizures of that type in most patients

– Or recurrent seizures without interictal resumption of baseline central nervous system function

From Raspall-Chaure et al, 2007

So the concept of SE relies on the occurrence of seizures

• An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain (ILAE 2005)

• Different types of SE according to the type of seizure:– Convulsive SE (CSE)– Non-convulsive SE

• Absence SE (typical or atypical)• Myoclonic SE• Focal SE• (Electrical SE during slow-wave sleep)• (Hypsarrhythmia)

Myoclonic SE in infancy

• In the course of a non-progressive encephalopathy– Psychomotor retardation from 3-4 m, no regression– Myoclonic sz may be confounded with a movement

disorder– Important etiologies: Angelman, Rett, other

chromosomal deletions

• In the course of a progressive encephalopathy: progressive myoclonic epilepsy (PME) of infancy

Clinical case 1

• M, 15 m• Admitted for febrile

seizure (GTCS)• Global psychomotor

delay from age 4 m, no regression

• Exam: jerky movements, possible ruptures of contact

Absence of hybridation signal on 15q11.2: Angelman syndrome

Clinical case 2

• F, 4y• Sz from age

3y (GTCS, absences), refractory to AED

• Mental deterioration, progressive ataxia

Curvilinear intracellular inclusions:late infantile neuronal ceroid lipofuscinosis

Epidemiology of SE

From Raspall-Chaure et al, 2007

Peak age < 1 year: related to febrile SE

Classification of SE according to etiology (ILAE 1993)

• Acute symptomaticin a previously normal child

• Remote symptomaticin the absence of an identified acute insult but with a history of a pre-existing CNS abnormality

• Idiopathic epilepsy relatedin children with prior diagnosis of idiopathic epilepsy

• Cryptogenic epilepsy relatedin children with prior diagnosis of cryptogenic epilepsy

Limits of this classification for CSE, particularly relevant in infants

• Acute symptomatic = 2 very different conditions that need to be individualized:– Febrile (excluding CNS infection)

– Due to an identified neurological insult (infection, trauma,...) = true acute symptomatic!

• Some children with CSE associated with fever have pre-existing neurological abnormalities, including epilepsy, while others are previously neurologically normal acute vs acute on remote

Distribution of etiologies

From Raspall-Chaure et al, 2007

• About 1/2 cases occurs without history of prior seizures

• Fever-associated SE is the most frequent situation in infants (Chin et al 2005; 95 cases)

– Febrile: 59%– Previous neurological abnormality (acute on

remote): 21%– CNS infection (acute symptomatic): 20%

bacterial meningitis: 12%viral encephalitis: 8%

Treatment: rationale for early intervention

From Raspall-Chaure et al, 2007

1. CSE may lead to brain injury

• Animal model: Kainate induced SE leading to hippocampal sclerosis

• SE-induced MRI changes:usually reversible but irreversible changes reported (focal atrophy, mesial temporal sclerosis, hemispheric damage)

Huang et al, 2009

CSE and hippocampal injury

• Relationship between MTS and prolonged febrile sz controversial (cause or consequence)

• MRI after CSE (Provenzale et al, 2008)

– Acute hypersignal in hippocampus: 7/11– Subsequent hippocampal atrophy: 5/7 (with sz in 4)

Clinical case: M, 10 years -Age 2 years: Febrile convulsive status epilepticus-Refractory epilepsy since age 4 years, R hemiparesis, severe mental retardation-Sz-free after hemispherotomy

HHE syndrome: hemiconvulsions-hemiplegia-epilepsy

2. GABAergic mechanisms fail and seizures become self-sustaining and

pharmacoresistant

Miniature IPSCs from dentate gyrus granule cells of SE (dotted line) and controls (solid line) demonstrating smaller amplitude and prolonged decay in SE

Naylor, 2005

The change of mIPSCs with SE reflects a decrease in the number of functional postsynaptic GABA-A receptors

The four phases for CSE management

• Prehospital• First-line treatment in emergency room• Second-line treatment after failure of

benzodiazepine• General anesthesia

Prehospital:Buccal MDZ to replace rectal DZ

Authors Design specificities

N

(ages)

EfficacySF at 10m for 1h

(MDZ vs DZ)

Safety Conclusion

McIntyre Lancet 2005

Emergency room

219 (>6m)

56 vs 27% p<.01

relapse 8 vs 17%

Respiratory depression 5%

(12 pts, intubation in 5)

MDZPO > DZIR

Mpimbaza

Pediatrics 2008

Emergency room, data for children without malaria

108 (3m-12y)

73.5 vs 44%p=0.02

Respiratory depression 1%

MDZPO > DZIR

RCT comparing buccal midazolam and rectal diazepam (both 0.5 mg/kg)

L Herd April 2007 Reviewed A Harrison Sept 2007 Review Date Nov

2009

Administration

• Following time frames in care plan

• Ensure patients head is upright and in the midline to ensure solution is given (and stays in the buccal space)

Administration 2

• It is accepted best practice that the medicine dose should be split equally between both spaces

• If it is a very small dose this may not be practical

Administration 3

• Carefully insert the syringe between the lower jaw and the cheek

• Ensure it is in the buccal space by pointing it downwards

• Give half of medicine in one space then transfer the syringe to other buccal space and complete dose

Administration tips

• Do not massage gums as you are likely to move the solution out of the buccal space

• Keep patient wherever possible in that position for 5-10 minutes

• If medicine is lost or swallowed –do not repeat

• Always remember to Time seizure

• Note any differences from normal

• Keep patient safe throughout

• All guidelines say not to put anything in patients mouth – this is the exception

Who is at risk for SE?

• In children with epilepsy (2 unprovoked sz):– Risk = 9.5%– Risk factors: history of SE, younger age ar

onset, symptomatic etiology

Berg et al, 2004

First-line treatment in emergency room: generalities

• Maintenance of adequate airways, breathing and circulation (ABC)IV access with saline, not glucose

• Termination of seizure and prevention of recurrence

• Diagnosis and initial therapy of life-threatening causes (e.g. hypoglycemia, meningitis, cerebral space-occupying lesion)

First-line treatment in emergency room: benzo IV

• 2 RCT, MDZ nasal against DZ IV, both at 0.2 mg/kg (Lahat 2000, Mahmoudian, 2004)

– NS in terms of safety and efficacy– Sz controlled more quickly with IV DZ

• Prospective population-based treatment of CSE (Chin et al, 2008)

– Prehospital treatment (DZ IR) efficient in 22%– IV lorazepam 3.7 times greater likehood of sz termination

than DZ IR– for each minute delay from onset of CSE to arrival at

emergency room, 5% cumulative increase in the risk of the episode lasting > 60 min.

Second-line treatment after failure of benzodiazepine: phenytoin

• > 2 doses BZP associated with– SE lasting > 60 min– respiratory

depression

• IV phenytoin 9 times greater likehood of sz termination than paraldehyde IR

(Chin et al, 2008)

Second-line treatment: VPA as an alternative to PHT?

• Phenobarbital:probably similar efficacy than PHT but:– greater incidence of respiratory depression– same mechanism of action than benzos

• Paraldehyde:no experience, interesting if no IV access

• Valproate: one randomized trial against PHT (Agarwal et al, 2007)

– Same success rate (88% VPA vs 84% DHT)– No difference for AE or recurrences

Refractory CSE

• Definition: SE refractory to 2 drugs(usually benzo and PHT, or benzo and VPA)

• Alternatives (no RCT in children!):– VPA or PB if not used previously– Benzo continuous infusion– Barbiturates: thiopental or pentobarbital– Propofol– New AEDs: levetiracetam, topiramate– Ketogenic diet

Thiopental (pentothal°)

• Ter Maaten et al 1998 n=10– EEG « clean » but death 10/10

• Gestel et al 2005 n=34 – propofol efficacy 64% death 2/22– thiopental efficacy 55% death 6/20

• Rantala et al 1999 n=54 – complications during thiopental : 50%– seizure relapse after thiopental : 53/54– back to previous seizure frequency : 78%– significantly more drugs needed

Thiopental & cerebral blood flow

• Wada et al 1996– decrease from 123 to 84ml/mn (19%) for regional CBF in rat

• De Bray et al 1993– significant decrease for CBF (Doppler) in children– more important for brain trauma than for controls

• Drummond et al 1995, Guo et al 1995. – Anesthesia : protection of brain and brainstem in a context of

ischemia

Thiopental-induced CBF decrease: – is beneficial if infarct or oedema (occasionnal SE, trauma)– is deleterious if epilepsy (CBF increase is needed if SE)

Refractory SE : new AEDs

• Levetiracetam IV– Gamez-Leyva et al 2009

• 34 (11-90y), no response to PHT/VPA• SE stopped in 71% by LVT

– Gallentine et al 2009• 11 (2d-9y), 15-70mg/kg/d (m=30mg/kg/d)• SE stopped in 45% by LVT (m=40mg/kg/d)

• Topiramate– Kahrima, et al 2003

• TPM by tube effective in 3 children

Ketogenic diet

• Diet resulting in a continuous cetosis– Low carbohydrates, high fat– Ratio Lipides / (Protides + Glucides)= 3:1 or 4:1– Now ready to give (Ketocal°)

• Encouraging preliminary data in children– Francois et al 2003

• SE stopped in 3/6 RSE, maintained for 2 y– Villeneuve et al 2009

• 11/22 children with RPE were responders• Better response in patients with SE (p<.04)

– Nabbout et al, 2010• FIRES: 7/9 were responders within 48 h following ketonuria

Recommendations in different countries

Country 1st line 2nd line 3rd line

Cochrane (UK)

MDZPO/IN LRZ VPA, PHT, DZIV

US* BZ, PHT VPA, LVT anesthesia

Denmark** DZIR DZIV, VPA FosPHT, MDZIV,

anesthesia

France*** DZIR DZIV, CNZIV PHT, PB

* Clonazepam IV non available, ** Lorazepam non available, *** Midazolam and Lorazepam non available

Protocol of CSE proposed by the Canadian

Paediatric Society • First-line: MDZ 0.5 mg/kg IB, or LRZ 0.1 mg/kg IV• After 5 min, repeat 1 time benzo• After 10 min: PHT 20 mg/kg IV over 20 min• After 20 min: PB 20 mg/kg IV over 20 min (but VPA

20 mg/kg IV over 5 min probably better alternative!)• After 40 min: intubation and midazolam continuous

infusion– 0.15 mg/kg bolus then 2 g/kg/min infusion– Increase as needed by 2 g/kg/min q5 min– Bolus 0.15 mg/kg with each increase in infusion rate– Maximum infusion rate: 24 g/kg/min– Taper after 24 hours• After 1 hour and 40 min: thiopental/pentobarbital

Friedman 2011, http://www.cps.ca

Outcome: seems to be more related to etiology (?)

• Mortality 5%, no death in febrile SE• Morbidity (new deficits):

– Acute symptomatic: > 20%– Febrile and unprovoked: < 15%

• In the epilepsy related group, occurrence of SE does not affect social and educational outcomes

• The relationship of CSE with mesial temporal sclerosis or subtle neurocognitive dysfunction, and the effect of age at CSE, seizure duration, or treatment on outcome have not yet been clarified.

From Sillanpää et al (2002) and Raspall-Chaure et al (2007)

Conclusions

• Establish your protocol according to drugs available in your country

• Among benzos, MDZ should be encouraged both for prehospital (buccal) and refractory SE (continuous infusion) because half-life short (1-3 h)

• PB should be avoided• Monitor EEG in continuous if possible in

each case of refractory CSE