1. Post-Traumatic Seizures and Epilepsy in the Developing Brain
Michael J. Esser MD, PhD, FRCPC
Pediatric Neurologist
Alberta Children’s Hospital
University of Calgary

2. Disclosure Faculty/Presenter Disclosure; Michael J. Esser
Grants/Research Support: CIHR, CIMVHR, ACH, ACHF, Brain Canada

3. Objectives Ascertain the epidemiology of pediatric PTS and PTE
Consider the evidence for the “need” of seizure prophylaxis in pediatric TBI
Consider the balance of seizure treatment versus drug (neuro)toxicity

4. Central question Should we treat children with TBI Is there a need?
Balance the developmental impact of seizures/epilepsy with those of seizure medications

6. Numbers and what they mean
PTS and PTE – measures of Incidence, epidemiology, outcomes, treatment
Incidence is dependent on “common” classification/terminology
No accepted nomenclature of seizure types and blurring of time stratification
Epidemiology is dependent on accurate capture and categorization.
Outcomes – affected by classification and treatment
Guidelines are based on adults and incomplete data
Treatment – kids are not little adults, and one-size doesn’t fit all

7. TBI Leading cause of morbidity and mortality in Pediatric age group
~>50% of childhood deaths (Mazzola and Adelson, 2002)
1.4 million TBIs in US, 626,000 are in children up to age 19 (Aitken et al., 2009)

8. Post-Traumatic Seizures (PTS)
Dependent on several factors
Nature of injury (NAT greatest), severe TBI, age (<2 highest),
prolonged LOC, prolonged post-traumatic amnesia, intracranial hemorrhage, depressed or open skull fracture
Aggregate incidence** of PTS is from % ( ) (Arnt et al., 2015; Tanaka and Litofsky, 2016))
Mild-TBI (1-5%), moderate (10-20%), severe ( %) (Tanaka and Litofsky, 2016)
NAT (33-73%)
Recurrence risk within the first week – 35-65% (Arnt et al., 2015)
Most are focal (54-80%)
Post-traumatic status epilepticus %
Younger children > older children
Clinical and subclinical PTSE associated with increased LOS and lower global outcome scores (Arnt et al., 2013)
The 42.5% comes from one study – arndt et al., 2013 that looked ate cEEG in TBI and found a high incidence of electrographic seizures
CT risk factor associations – acute lesion - ~ 3 fold increased risk. Subdural or intraparenchymal blood (15 times more likely).
Children at greater risk (age range 1-7 years), Female > Male (OR 2.6), children <7 =30%, 8-16=20%, >16 8.4%
Delay in presentation to hospital increases rsik – link to hypoxia and hypotension as contributing

9. Seizure characteristics
Seizure within the first 7 days
25% PTS <60 min, 50% PTS < 7days,
Most are 2o GTC – 60-85% (Pagni and Zenga, 2005)
Focal symptoms related to region affected
In pediatrics, hypomotor is more prevalent in severe TBI (Park and Chugani, 2015) - ? Due to large number of NAT patients
The later in onset from injury the more likely it will be focal
>50%
~ 18.4 % PICU TBI will progress to status epilepticus (Tanaka and Litofsky, 2016)
Post traumatic epilepsy
17-33% with PTS will develop PTE
PTE literature is very controversial – not sure that PTS is an independent risk factor or a marker of combined other risk factors – Annegars et al., 1999 – NEJM; Temkin et al., 2003

10. Evaluation Diagnosis Clinical
Limited as a significant proportion of PTS are subclinical
Neuroimaging
Not prognostic, but can help with risk stratification for PTS
CT – not associated with risk of EPTS, but SDH found in more kids with EPTS (Liesemer et al., 2011)
MRI – early changes with DTI or SWI, later with structural (Gupta et al., 2005; Messori et al., 2005)
Can help distinguish etiology and suggest treatment – NSx, seizure drugs
Biomarkers
Inconclusive as of yet
EEG
abnormalities do not predict risk of PTE or type of seizure
Increase yield and ability to detect events especially in younger children at risk for non-convulsive seizures/status epilepticus
Identification of other abnormal EEG patterns (BS, non-reactive, abn sleep)

11. 87 pediatric (1 month -18 years), two centers, all severities
Prospective study with cEEG (minimum 24 hours)
37/87 (42.5%) had seizures,
14/87[37] (16.1%[37.8%]) had subclinical seizures
6/87 [37] (6.9% [16.2%]) had subclinical seizures only,
16/87 [37] (18.4% [43.2%]) had SE,
12/87[16] (13.8%[75%]) had subclincal SE
Treatment - was not related to seizure incidence ( BDZ, fosPheny/Pheny, Phenobarb, Topamax, Keppra)
Outcomes - greater hosp-LOS (SE, subclinical-SE) and lower KOSHI score (subclinical seizures and subclinical SE)
SE equals ongoing seizure >15 minutes, or repeated seizures occurring at a rate of >3/hr
But we don’t know the time of the seizure detection – classification
All patients with subclinical only were less than 1 year of age
Subclincial were seen in …. younger children, NAT, subdurals, intraxial hemmorhage,
Only 4/33 given neuromuscular blockade had subclinical
SE – age was associated with SE (1.5 vs 7.5) , NAT – 54.5% had SE versus 10% in others, intraaxial bleed
Subclinical SE – younger (<1 year), NAT, intra-axial blood
KOSHI – Kings Outcome Scale for Childhood Head Injury -

12. (Arnt et al., 2013; O’Neill et al., 2015)
Comparison
Adult (Vespa et al., 1999)
Pediatric
(Arnt et al., 2013; O’Neill et al., 2015)
42.5%, 30% of mod-severe TBI had seizures,
16.2%, 27.7% had subclinical seizures
6.9%, 11.8% had subclinical seizures only,
18.4%, 53% had Status Epilepticus,
13.8% had subclinical SE
22% had seizures
12.7% had subclinical seizures only
6.4% had Status Epilepticus
All patients with on
For O’Neill paper SE defined as 30 of continuous activity or multiple seizures exceeding 50% of the recording

13. Post-Traumatic Epilepsy
5% of all epilepsy and 20% of structural epilepsies are due to PTE (Lowenstein et al., 1999; Lamar et al., 2014)
General prevalence of PTE in children is 0.2 to 16.8%
17-33% with PTS will develop PTE
unclear if there is a difference between early or late PTS and risk for PTE
Risk factors are similar to those for PTS
Cumulative incidence (per 100 persons)** (Annegars, 1996; Englander, 2003; Lamar et al., 2014)
Mild – 4.4
Moderate 1.2 – 7.6
Severe 4.3 – 17
PTE onset
40% < 6 months; % < 1 year; 80% < 2 years
May begin as late as 15 years after (Raymont et al., 2010; Lamar et al., 2014)
Treatment of PTS does NOT seem to affect rate of PTE****
Englander – hospitalised patients with abnormal neuroimaging – CTs
Pederson -  Risk of epilepsy was increased after a mild brain injury (RR 2.22, 95% CI ), severe brain injury (7.40, ), and skull fracture (2.17, ). The risk was increased more than 10 years after mild brain injury (1.51, ), severe brain injury (4.29, ), and skull fracture (2.06, ). RR increased with age at mild and severe injury and was especially high among people older than 15 years of age with mild (3.51, ) and severe (12.24, ) injury. The risk was slightly higher in women (2.49, ) than in men (2.01, ). Patients with a family history of epilepsy had a notably high risk of epilepsy after mild (5.75, ) and severe brain injury (10.09, ).

14. Treatment in Kids “Strength of recommendations: WEAK”
“Quality of Evidence: LOW”
“Recommendation” for prophylactic treatment when high risk of EPTS (Adelson et al., 2003, Kochanek et al., 2012)

15. Treatment
Treatment
Adults - Early (<1 week) administration of anti-seizure medication (Phenytoin) is supported (Level IIA) in severe TBI
Insufficient evidence to recommend Keppra over Phenytoin/fospheny
Pediatrics – Data is limited and based on extrapolation (Adelson et al., 2003)
Neurobehavioral effect of Keppra is hard to extract from neurobehavioral outcomes due to TBI (and its influencing factors) alone.
--- neurobehavioral effect of Keppra is known in the epilepsy population – irritability, aggression, depression , suicidality, and somolence (impaired sleep-wake cycles), headache
Keppra may be neuroprotective – shown in animal studies of seizure induced apoptosis – by preventing overactivation of the brain and hippocampus – demonstrated in Alzheimer's patients
Does delay in treatment affect ability to control similar to that seen in other forms of epilepsy of in neuropathic [pain for that matter
Keppra has also been found to be of benefit after intracranial hemorrhage in kids from 1month to 18years
Tanaka and Litofsky, 2016

16. Treatment in Kids Goal is to minimise secondary injury
“Strength of recommendations: WEAK”
“Quality of Evidence: LOW”
“Recommendation” for prophylactic treatment when high risk of EPTS (Adelson et al., 2003, Kochanek et al., 2012)
Goal is to minimise secondary injury
Paradox of PTS – product of the injury and contributor to secondary physiological, neurochemical and metabolic insult
Reduce hypoxia, hypercarbia, systemic hypotension, increased metabolic stress, raised ICP

17. What about kids……….
Balance the developmental impact of drug neurotoxicity
against harm of recurrent seizures and epilepsy

18. PTE and epileptogenesis
Hunt et al., 2012
Epileptogenesis – multi-layered process from primary injury --- secondary injury --- repair mechanisms.
Effect of structural lesions – site and mode dependent – hippocampal atrophy, neocortical gliosis, shear injury at gray-white junction
Lead to hyperexcitability, hypersynchronicity, and network re-organisation
Process not well understood

19. Developmental Toxicity
Seizures and epilepsy
SE has high morbidity and mortality
Prolonged SE becomes refractory (Mayer et al., 2002)
Many hypothesis about consequences
GABA and Chloride
Dentate gyrus cell loss
Mossy fiber sprouting
[Ca]i accumulation
Adenosine receptor
Cortical dysplasia
Seizure medications
ASDs interact with ion channels, metabolic enzymes, neurotransmitter receptor systems and transporters
Interfere with neuronal migration, differentiation, and myelination, as well as impair plasticity and cause cell death
Phenobarb, Phenytoin, VPA, Diazepam, Midazolam, Clonazepam – induce apoptotic neurodegeneration
?? Topiramate, Levetiracetam
Requires a knowledge of the role of ontogeny in the disposition and action of the drugs (Kaindl et al., 2006)
Treatment of SE withih 20 minutes have better outcomes
Different brain regions develop at different rates and even within brain regions, differemnt populations of neurons develop at different rates
-- most research is an extrapolation between animals to human
-- interference with cell migration affects network orgabnistaion as it alters important contact and develppment of conection
-- neurotransmitters are important for synaptic organisation and cross talk as part of synaptogenesis
--- however they also modulate proliferation of neural stem cells, neuroblasts and glioblasts, regulate migration and induce differentiation – thus anything that interferes with the programmed development of neurotransmitter systems can impact on development
-- most of this studies on the drug related effects were at very high doses relative to what we use for kids – but it was dose dependent and nonetheless was at doses that were effective in controlling the seizures. However, to put it in context with pediatric TBI, kids may have developmental and injury related alteractions in pharmacology that could expose the brain to similar levels – this may not be accurately captured in the blood.
Alos need to consider the balance between neuronal protection and induced apoptosis that may be develomental epoch related.

20. Kearns GL et al. N Engl J Med 2003;349:1157-1167.
Drug metabolism and distribution in children
Figure 1. Developmental Changes in Physiologic Factors That Influence Drug Disposition in Infants, Children, and Adolescents. Physiologic changes in multiple organs and organ systems during development are responsible for age-related differences in drug disposition. As reflected by Panel A, the activity of many cytochrome P-450 (CYP) isoforms and a single glucuronosyltransferase (UGT) isoform is markedly diminished during the first two months of life. In addition, the acquisition of adult activity over time is enzyme- and isoform-specific. Panel B shows age-dependent changes in body composition, which influence the apparent volume of distribution for drugs. Infants in the first six months of life have markedly expanded total-body water and extracellular water, expressed as a percentage of total body weight, as compared with older infants and adults. Panel C shows the age-dependent changes in both the structure and function of the gastrointestinal tract. As with hepatic drug-metabolizing enzymes (Panel A), the activity of cytochrome P-450 1A1 (CYP1A1) in the intestine is low during early life. Panel D summarizes the effect of postnatal development on the processes of active tubular secretion — represented by the clearance of para-aminohippuric acid and the glomerular filtration rate, both of which approximate adult activity by 6 to 12 months of age. Panel E shows age dependence in the thickness, extent of perfusion, and extent of hydration of the skin and the relative size of the skin-surface area (reflected by the ratio of body-surface area to body weight). Although skin thickness is similar in infants and adults, the extent of perfusion and hydration diminishes from infancy to adulthood. Data were adapted from Agunod et al.,4 Rodbro et al., 5 Poley et al., 9 Gibbs et al., 21 Okah et al., 24 West et al., 27 Friis-Hansen, 38 Young and Lietman, 39 Hines and McCarver, 40 Treluyer et al., 41 Kinirons et al., 42 Pynnönen et al., 43 Aranda et al., 44 Miller et al., 45 Barrett et al., 46 Murry et al., 47 and Robillard et al. 48
Kearns GL et al. N Engl J Med 2003;349:

21. Neurodevelopment
Caveat is that different regions develop at different rates and within a single region subpopulations of neurons develop at different rates – exposure is relative
Neurotransmitters are important to synapse formation but also to modulate proliferation of neural stem cells – therefore any drug that affects transmitter levels has the potential to cause permanent deficits.

22. Summary Risk of: PTS - 30-40%, of NCS - 15-30%, of SE is ~ 20%
Risk of PTE - True incidence and treatment effect/need is unclear
Consistent Risk factors
NAT, severe TBI, age < 2,
SDH or parenchymal haemorrhage, contusions, length of PTA/LOC, penetrating injury, depressed skull fracture,
“ future research should be randomized and prospective, and should intervene during pre-trauma center care with initiation of continuous EEG monitoring as soon as possible” (Liesemer et al., 2011)
Treatment - ASD are effective at preventing early seizures and should be used in those at risk
Future trials to determine if Keppra is main drug and the duration

23. Acknowledgements ACH-TBI program Lab Funding
Dr. K. Barlow, Dr. L. Burkholder, Dr. V. Gnanakumar, Lisa Bodell
Lab
Dr. T. Shutt, Dr. Q. Pittman, Dr. R. Mychasiuk, Sydney Candy, Alyson Farran, Erik Fraunberger, Harleen Hehar, Alon Gilad
Funding
CIHR, ACH, ACHF, ACHRI, CIMVHR

24. END

25. Select References
Pagni CA, Zenga F (2005) Posttraumatic epilepsy with special emphasis on prophylaxis and prevention. Acta Neurochir Suppl. 2005;93:27.
Annegers JF et al., A population-based study of seizures after traumatic brain injuries. NEJM 338(1):20.
Arrango et al., Post-traumatic seizures in children with sever TBII. Child Nerv Syst 28:1925.
Englander et al., Analyzing risk factors for late posttraumatic seizures: a prospective, multicenter investigation. Arch Phys Med Rehabil. 84(3):365.
Christensen et al., Long-term risk of epilepsy after traumatic brain injury in children and young adults: a population-based cohort study. Lancet. 373(9669):1105.
Raymont et al., Correlates of posttraumatic epilepsy 35 years following combat brain injury. Neurology. 75(3):224.
Frey LC (2003) Epidemiology of posttraumatic epilepsy: a critical review. Epilepsia. 2003;44 Suppl 10:11.
Gallentine WB (2013) Utility of CEEG in children wit acute TBI. J Clin Neurophysiol 30(2): 126.
Kochanek et al., 2012 – Chapter 17. Antiseizure prophylaxis. Pediatric Crit Care Med 13(1): S72.
Abend et al., (2013). Electrographic seizures and status epilepticus in critically ill children and neonates with encephalopathy. Lancet Neurology 12:
Ostahowski et al., Variation in seizure prophylaxis in severe pediatric traumatic brain injury. JNS Pediatrics, June:1.
Adelson et al., Guidelines for the acute medical management of severe TBI in infants, children and adolescents. Ped Crit Care Med 4(3): S72-S75
Gupta et al., 2005 Diffusion Tensor Imaging in late post-traumatic epilepsy. Epilepsia 46:1465.
Messori et al., Predicting post-traumatic epilepsy with MRI: prospective longitudinal morphological study in adults. Epilepsia 46:1472.
Mayer et al., Refractory status epilepticus :frequency risk factors and impact on outcome. Ach Neurol 59:205.
Kaindel et al., 2006 Seizure meds and the developing brain, Cell Mol Life sci 63:399.
Kearns et al., Developmental Pharmacology – drug disposition, action, and therapy in infants and children. NEJM 349:1157.
Lowenstein et al., Epilepsy after head injury: an overview. Epilepsia 50 (Suppl 2):4.
Liesemer et al., 2011 Early psot-traumatic seizures in moderate to severe pediatric traumatic brain injury: rates, risk factors, clinical feature. J neurotrauma 28:755..
Oneill et al., Incidence of seizures on continuous EEG monitoring following traumatic brain injury in children. JNS Pediatrics 16:187.
Tanaka and Litofsky, Anti-epileptic drugs in pediatric brain injury. Expert Reviews Nuerotherapeutics Oct 16(10):1229.

26. Arnt et al., 2015; J Child Neurol 1-11.

27. Retrospective analysis – 2002-2006 275 children (0-15 years)
34 with seizures (12%)
23/34 (68%) had EPTS within 12hours
Risk factors
Pre-hospital hypoxia, age, NAT, severe injury, impact seizure, subdural
Independent risk factors – age <2 (OR 3), GCS <8 (OR 8.7), NAT (OR 3.4)
EPTS occur within 7 days but not associated with impact

28. NCSE
NAT - Electrographic seizures and NCSE common - 57% with 67% of those being NCSE (Hasbani et al., 2013)
NCSE
Small sample size and selection bias
Abend et al., 2013

30. However……. Most data is from:
retrospective studies with heterogeneous data sets
Adults
PTS/PTE - biased by suspicion of seizures
Treatment -
based on
adult healthy pharmacology
“whole event” philosophy
on older drugs – phenytoin
Variation in treatment between centres may contribute to in-accurate interpretation of seizure prophylaxis outcomes (Ostahowski et al., 2016)

31. 94 patients (21-80 years old) with moderate-severe TBI
Prospectively had cEEG (from admission up to 14 days)
21/94 (22%) had seizures
12/94[21] (12.7% [52%]) had non-convulsive seizures
6/94 [21] (6.4% [29%]) had status epilepticus
Seizures occurred despite prophylactic treatment (phenytoin)
Outcomes – all with SE died, no difference in LOS or in GOS between seizure and non-seizure patients
Only prospective study
Did a follow up in 2010 with similar numbers – seizures detected in 23%

32. Risk Factors Ongoing seizures and development of PTE
Injury severity (esp NAT)
Age < 2 (or>65) at time of the injury
Seizures within the first 7 days
Intracranial hemorrhage
Brain contusion
Penetrating injury (↑ risk by 50%),
Blunt injury with contusion or hemorrhage (↑ risk by 30%)
Development of PTE seems to be related to intrinisic risk factors