2. Epilepsy are the most commonly encountered
neurological disorders.
DEFENITION OF EPILEPSY
1. Conceptual Definition – which are useful for patient
communication & neurology education
2.Operational Definition-which can be used in clinical practice
&research
YOUMANS& WINN
3.
4. Introduction
TBI accounts for 10-20% of symptomatic epilepsy in
the general population and 6% of all epilepsy.
TBI refers to a brain injury caused by an external
mechanical force.
Posttraumatic epilepsy (PTE) is defined as a recurrent
seizure disorder secondary to traumatic brain injury
(TBI).
5. Prevention of the development of PTE is a major
challenge in medicine.
Identification of critical molecular, cellular, and
network characteristics predicting epileptogenesis with
TBI remains incomplete.
As epileptogenesis occurs only in a subpopulation of
subjects, biomarkers for predicting risk for
epileptogenesis are needed.
6. Post traumatic seizures
1.Immediate, Contact, or Concussive seizures (IPTS)-
which occur within 24 hours after injury
2.Early (EPTS), Acute Symptomatic- Seizures those
occurring with in 1 week
• Late (LPTS), Remote Symptomatic-which occur after one
week after injury. Two or more unprovoked seizures
after 1 week
7. Immediate and early seizures belong to the group of
provoked seizures
they do not define epilepsy since they are not due to
underlying a pathogenic mechanism that chronically
predisposes the patient to manifest epileptic seizures
Post-traumatic epilepsy is determined by the
presence of late seizures and therefore unprovoked.
8. Epidemology
Post-traumatic epilepsy (PTE) is the most frequent cause
of epilepsy in young adults as they are more at risk of the
exposure to head injury
Estimated proportion of presumed causes of incident
epilepsy related to TBI range between 2% and 16% in
European Countries.
Early PTSs frequency comprised between 2.6% and
16.9%.
Annegers et al have published a prospective study with a
follow-up of over 10 years, reporting an average PTE
/LPTS frequency of 2.1% in TBI patients; the percentage
was significantly higher (12%) if considering only subjects
with severe TBI.
9.
10. Children
EPTS: 0.2 to 9.8%.
EPTS more common than LPTS
Younger children at increased risk of both
Younger children more likely to have status
epilepticus
11. Risk factors
EPTS
GCS <10
Contusion
Depressed fracture
SDH EDH ICH
Penetrating injury
need of surgery
infant age
amnesia lasting more than 30 minutes,
history of chronic alcoholism
Seizure <24 h of injury (IPTS)
12. RISK FACTORS FOR LPTS
Penetrating Injury
Intracranial Hematoma (ICH)
Compound Depressed Fracture
EPTS
Age over 35
transient amnesia which lasts more than 24 hours
male gender
the presence of early PTSs as a risk factor for late PTSs
13. Jennet et al showed that the presence of compound
depressed skull fractures was associated to a higher
general risk of early and late PTSs.
Compound Depressed Fracture
Early Seizures >50%
PTA >24 hours
Dural Tearing 20-40%
Focal Signs 5-20%
None <3%
14. Jennet. TB Head Injury 2005.
ICH
Intradural
Extradural
Operated NotOperated Operated
45% 23% 22%
15. Risks - Penetrating injury
~ 50% over 15 years
20% of adults within two years of TBI
Risk remains high for >5 years
Risk factors:
GCS
Motor deficit/ Aphasia
EPTS
Infection
16. Clinical types of seizures
Generalized-onset or secondarily generalized
seizures
– Nonpenetrating TBI
– Children
Partial-onset seizures
– Adults
– EPTS
– Focal lesions on CT
– Penetrating TBI
17. Clinical types of seizures
Transient behavioral change
Reminiscent of CPS
Sterotyped behaviours
Without the hypersynchronous EEG activity
Mild TBI
Respond to carbamazepine
NES(non epileptic seizures)
Episodic behavioral events that superficially
resemble epileptic attacks
– 33 – 40%
– Milder injury
– Usually manifestations of other conversion disorders
– Psychiatric histories that predate TBI
18. LOCALIZATION
Temporal 54%
Frontal 33%
Occipital 3%
Parietal 5%
The clinical characteristics of the seizures depend on the location
of the lesion and the precocity of the secondary generalization.
In patients with a history of trauma in childhood (less than five
years) can manifest mesial temporal lobe epilepsies, as a trauma
in the temporal region at an early age can induce the
appearance of mesial temporal sclerosis
Status epilepticus (SE) at onset is not uncommon; Jennett
calculated a frequency of 10% in patients with PTSs .
The infant population undoubtedly has a higher probability of SE
compared to the adult one.
19. COURSE (NATURAL
HISTORY)
EPTS
Only 50% patients have a recurrence
25% only 2-3 seizures
LPTS
20% of people who have a single LPTS never
have any further seizures
50-66% have seizure onset within first 1 year
75-80% have seizures by the end of 2nd year
About half the patients who develop LPTS have 3 or
fewer seizures and go into spontaneous remission
thereafter
20. LPTS
Remission over 3 years
– 35% became seizure-free
– 21% had > 1 seizure per week
After 5 years
– mild TBI no longer increased risk
– moderate or severe TBI or penetrating TBI remain at
increased risk
21. Increased risk of recurrence/ persistence
• Partial seizures
• Seizure frequency within the first year
• Combined seizure patterns
• AED noncompliance
• Alcohol abuse
• Seizures began later after injury
22. PATHOGENESIS
IPTS &EPTS are considered direct reactions of a brain
damage & they are correlated to
1. altered vessel regulation of the local
cerebral blood flow,
2. alteration of the hematic-encephalic
barrier
3. increase of the intracranial pressure
with focal or diffuse presence of
ischemic, hemorrhagic, inflammatory
or necrotic damage
23. animal models of PTE have suggested that late
seizures are caused by two main pathogenic pathways:
Oxidative Stress Mechanisms
Excitotoxic Mechanisms - Neuronal Hyper Excitability
24. mechanism of oxidative
stress
trauma is accompanied by a leakage of red blood cells,
formation of free radicals mediated by the iron contained
in hemoglobin;
these free radicals react with the methylene groups in the
double lipid layer of neuronal membranes
lipid peroxidation of the neuronal membranes and
mitochondria and the alteration of the function of the
sodium/ potassium pump ATPase activity.
The result of this sequence of events is a reduction of the
chronic convulsive threshold of a group of neuronal cells.
25. EXCITOTOXIC
MECHANISM
Is explained by the extra cellular increase of excitatory amino acids
immediately after injury, with increased levels of glutamate and
aspartatic acid
These traumatized cells tend to assume excitatory aminoacids more
readily than controls and present increased expression of the
sodium-coupled neutral amino acid transporters subtypes 1 (SNAT1)
and subtypes 2 (SNAT 2) .
Traumatized in vitro cells tend to form axonal sprouting with a
higher immunoreactivity to GAP 43 (Grown Associated Protein).
These cells show an altered excitability, evidenced by the presence of
synaptic potentials with prolonged post-synaptic components
26. Other factors
• Altered calcium-mediated second messenger
activity
• Changes in ionotropic receptor function and
composition
• Altered endogenous neuro protectant activity
• TBI-induced cortical dysplasia
27. MODELS FOR EPILEPTOGENESIS
• Ferric chloride model
• Kindling model
These animal models of designed to mimic three broad
classes of epileptic disorders : temporal lobe epilepsy ,
epilepsy associated with a brain malformation & focal
epilepsy
28. Kindling
are stimulus induced of temporal lobe epilepsy
Application of brief trains of weak electrical stimulation
over brain until a seizure is observed
Over a prolonged period of time spontaneous
seizures eventually appear
Kindling occurs best in neuroplastic areas of brain,
amygdala
Agents that retard or abort the kindling process are
considered antiepileptogenic
Agents that suppress or block seizures in fully
“kindled” brain are anticonvulsant
30. Ferrous Chloride Model
The use of focal application of ferrous chloride as a model of
epilepsy arose from the observation that deposits of iron on
brain tissue after head trauma or stroke can be a risk factor to
develop epilepsy
Ferrous chloride is injected in the cortex or amygdala of the
rat,after 5 to 7 days, more than 90% of the spontaneous seizures.
Histologic analysis of 6 weeks after the injection show neuronal
loss,activated astroglial cells, iron-positive macrophages, and
fibro-blasts surrounding the iron deposit.
Some of the surviving layer V pyramidal neurons stain positive
for iron, with loss of dendritic spines and decreased dendritic
branchingThe latter anatomic findings have clear
implications for synaptic excitability.
Interest-ingly, most of AEDs available are effective in
controlling the seizures induced by ferrous chloride
31. DIAGNOSIS
In patients with seizures at a short distance from cranial trauma it is
necessary to exclude other potential causes of provoked seizures
A trauma patient often presents conditions of metabolic and
circulatory instability, with high probability of alteration in the
biochemicaL parameters, such as hyponatremia, which may lower the
epileptogenic threshold.
EEG:- EEG in a patient with TBI is useful for the localization of the
lesion focus and for the measurements of the extent of damage,
but it is not able to define the probability to develop epilepsy
more than 20% of patients with PTE have a negative EEG during the
first three months after injury
32. Neuroimaging
Brain MRI represents the study of choice
It allows a better anatomy definition of the brain and
gives the exact outcome of any post-traumatic lesion.
T2-weighted images and gradient echo sequences may
well highlight the presence of hemosiderin deposits
that have a potential epileptogenic role.
Messori et al. through the analysis of T2 images from
more than 130 patients, showed how a precocious
formation of a gliotic scar around a hemosiderin
deposit reduces the risk of PTE.
33. Treatment and prophylaxis -
EPTS
The manifestation of immediate or early seizures can
affect the patient’s prognosis
since it may increase the cerebral perfusion pressure
and the intracranial pressure.
The prophylactic therapy of PTE is mainly intended to
block or delay epileptogenic mechanisms established
after TBI
AED given during the first 24 hours reduce the
occurrence of early seizures significantly
34. CHOICE OF AED:- While choosing AED, the cognitive,
motor and psychological problems related to TBI should
be kept in mind
Phenytoin is more cost-effective than
levetiracetam at all reasonable prices and at all clinically
plausible reductions in post-TBI seizure
potential.(Cotton, et al. J Trauma 2011.
Though with increased hypersensitivity phlebitis
hypotension arrhythmia drug interactions of PHT
compared to LVM , which has predictable
pharmacokinetic, does not require drug monitoring but
with a greater tendency to persistence of epileptiform
EEG abnormalities,evidence favours PHT
35. Carbamazepine (CBZ); only one true RCT reported and
this showed a good efficacy in the prevention of early
PTSs, but not in the late ones.
VPA however with less capacity to prevent early PTSs
compared with PHT.
36. The use of antiepileptic drugs (AEDs) at an early stage
in order to prevent PTE is rather controversial.
The results of RCTs seem to show a moderate effect
only on early PTEs, not on the late ones.
Temkin et al demonstrated that an early administration
of PHT prevented EPTS in an excellent way, while it did
not prevent the complete onset of LPTSs both during
the first year of therapy and in the following years
without therapy
37. In general, the recommendations for drug prophylaxis
of EPTS provide Phenytoin as frontline drug,
Levetiracetam &Carbamazepine as second choice
drugs;
Phenobarbital and Valproate are not considered
indicated for PTS prophylaxis.
No AED is effective in preventing LPTS
38. Treatment and prophylaxis -
LPTS
• No AED is effective in preventing LPTS
• Standard AEDs are effective for treatment
• Treatment guidelines similar to any other epileptic
patients
• Choice of AED – Cognitive effects , drug interaction &
efficacy
39. Treatment LPTS
Focal epilepsy:- CBZ extended release/ OXC/ PHT/LTG
Generalized epilepsy:- VPA/ PHT/ OXC/ LTG
• AED substitution is indicated
• Failure of seizure control
• Adverse drug reaction
• Cognitive decline
40. Prophylaxis in adults
Recommendation
Level II
Prophylactic use of phenytoin or valproate is not
recommended for preventing LPTS
Anticonvulsants are indicated to decrease the
incidence of EPTS (within 7 days of injury)
EPTS is not associated with worse outcomes.
41. Prophylaxis in Children
Phenytoin vs placebo
No significant differences in incidence of EPTS
(phenytoin = 7% vs. placebo = 5%)
Ineffective in reducing incidence of LPTS
Phenytoin does not reduce EPTS or LPTS in children
42. Prophylaxis in Children
Recommendation
Level III
Prophylactic treatment with phenytoin may be
considered to reduce the incidence of EPTS in pediatric
patients with severe TBI
Level II
Prophylactic use of antiseizure therapy is not
recommended for children with severe TBI for
preventing LPTS
43. SURGICAL TREATMENT OF PTE
-Refractory PTE with a well localized seizure focus can
be considered for epilepsy surgery.
-Results are especially good for unilateral temporal lobe
injury.
-However, multifocal lesions are common, many of which
could be epileptogenic. Invasive monitoring may be
required.
-Risk of additional deficits is probably higher.
44. REFERENCES
YOUMANN &WINN
Post-Traumatic Epilepsy: Review Edward Cesnik, Ilaria
Casetta, Enrico Granieri* Department of Medical and
Surgical Sciences of Communication and Behaviour,
University of Ferrara, Italy(Journal of Neurology &
Neurophysiology)
BRAIN INJURY MEDICINE:-PRINCIPLES &PRACTICE.
GREENBERG