Post traumatic seizure and epilepsy

POST TRAUMATIC SEIZURES (PTS)

Dhaval ShuklaAssoc. Prof. of Neurosurgery

NIMHANS, Bangalore

Glossary

Happen at or minutes after impact

• “Immediate,” “Contact,” or “Concussive” seizures (IPTS)

Seizures those occurring while the patient is still suffering from the direct effects of

the injury” (< 1 week)

• Early (EPTS), Acute Symptomatic

Seizures > 1 week

• Late (LPTS), Remote Symptomatic

Two or more unprovoked seizures after 1 week

• Post traumatic Epilepsy (PTE)

Episodic behavioral events that superficially resemble epileptic attacks

• Nonepileptic Seizures (NES)Teasell. ABIEBR 2012.

Neurotrauma 2012, Kochi

Burden of disease

• 30% ages 15 and 34 years

• 14% in children <14 years

• 8% in adults >65 years

Teasell. ABIEBR 2012.


Proportion of incidence cases of epilepsy by etiology

Relative risks for developing epilepsy

Lowenstein. Epilepsia, 2009.

Burden of disease

• EPTS: 2.1 to 16.9%

• LPTS: 1.9% to >30%.

– 9.1% (n=415)#

– 2.7% (n=520)*

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

Statler. Dev Neurosci 2006#Gururaj, et al. TBI Registry 2005

*Thapa, et al. Seizure 2010.


Burden of disease

38 (9.1%)

0 20 40 60 80 100

Locomotor

Headache

Behavior

Pains

Memory

PTE

Visual

Giddiness

Anxiety

Speech

Phobias

Hearing

N=415

Locomotor

Headache

Behavior

Pains

Memory

PTE

Visual

Giddiness

Anxiety

Speech

Phobias

#Gururaj, et al. TBI Registry 2005

Pathophysiology

• Cerebral insult

• Latency period

• Occurrence of spontaneous, recurrent seizures

Models for epileptogenesis

• Ferric chloride model

• Kindling model

Statler. Dev Neurosci 2006

Pathophysiology

Multi-factorial

• Involves changes in excitatory and inhibitory networks

• Altered calcium-mediated second messenger activity

• Changes in ionotropic receptor function and composition

• Altered endogenous neuroprotectant activity

• TBI-induced cortical dysplasia

Statler, Dev Neurosci 2006

PathophysiologyTherapeutic relevence

Kindling• 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

• Agents that retard or abort the kindling process are considered antiepileptogenic

• Agents that suppress or block seizures in fully “kindled” brain are anticonvulsant

Yablon. TB Brain Injury 2007.

PathophysiologyTherapeutic relevence

Anticonvulsant

• Phenytoin (PHT)

• Carbamazepine (CBZ)

• Topiramate (TPM)

• Lamotrigine (LTG)

Antiepileptogenic

• Valproate (VPA)

• Diazepam (DZP)

• Phenobarbitone (PB)

• Tiagabine (TGB)

• Levetirecetam (LEV)


Risk of EPTS

• GCS <10

• Contusion

• Depressed fracture

• SDH

• EDH

• ICH

• Penetrating injury

• Seizure <24 h of injury

Bullock, et al. J Neurotrauma 2007.


Risk of LPTS

• Penetrating Injury 35–50%

• Intracranial Hematoma (ICH) 22-45%

• Compound Depressed Fracture 3-50%

• EPTS 26%

• None <2%

Jennet. TB Head Injury 2005.


Risk of LPTS

Compound Depressed Fracture

• Early Seizures

• PTA >24 hours

• Dural Tearing

• Focal Signs

• None



>50%

20-40%

5-20%

<3%

Risk of LPTS



ICHIntradural

Operated

45%

Not Operated

23%

Extradural

Operated

22%

Risks - Penetrating injury

• ~ 50% over 15 years, 200 times

• 20% of adults within two years of TBI

• Risk remains high for >5 years

• Risk factors:

GCS Motor deficit/ Aphasia

EPTS Infection

Transventricular injury GOS

Aarabi, et al. Head Injury 2005.


Clinical types of seizures

• ~ 70% Unconscious

• ~ 40% Focal

• ~ 20% Temporal




• Generalized-onset or secondarily generalized seizures

– Nonpenetrating TBI

– Children

• Partial-onset seizures

– Adults

– EPTS

– Focal lesions on CT

– Penetrating TBI


• Transient behavioral change– Reminiscent of CPS

– Without the hypersynchronous EEG

– Mild TBI

– Respond to carbamazepine

• NES– 33 – 40%

– Milder injury

– Usually manifestations of other conversion disorders

– Psychiatric histories that predate TBI

Continuous video EEGN=127Yield

Types Subtypes Localization %

Nondiagnostic 18

NES 33

Epileptic 65

Generalized onset

9

Focal onset 91

Temporal 54

Frontal 33

Occipital 3

Parietal 5

Diaz-Arrastia. Epilepsia 2009.

Natural history - EPTS • Only 50% patients have a recurrence

• 25% only 2-3 seizures

Seizure precipitants

• Sepsis

• Hypoxia/ Hypocarbia

• Metabolic abnormalities

– Hypoglycemia

– Hyponatremia

• Hemorrhage

• Antibiotics: Imipenem and Quinolones

• 60% have precipitants Teasell. ABIEBR 2012.Yablon. TB Brain Injury 2007.

Natural history - 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




• 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




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



Complications - EPTS

Secondary brain damage

• Increased metabolic demands

• Increased intracranial pressure

• Excessive neurotransmitter release

• Impairment of neurologic recovery


Complications - LPTS

Cognitive and behavioral function• Persistent behavioral abnormalities

– Disinhibited behavior– Irritability– Aggressive behavior– Higher incidence of psychiatric-related hospitalizations

Functional status• Penetrating TBI: affects employment and cognitive

performance• Nonpenetrating TBI: not significantStatus Epilepticus• Infrequent


Complications -LPTS

Mortality• Mortality rates with epilepsy of any cause are 2-5

times

• N=508, 71 with LPTS, 8–15 years post-injury• 27% as compared to 10% of non-LPTS patients• LPTS died at a younger age (54.1 versus 67.7 years)• Males and patient with SDH more likely to die• No significant difference in time from injury to death• Causes variable and not specifically related to epilepsy• Only one death attributable to seizures

Teasell. ABIEBR 2012.Englander, et al. J Neurotrauma 2009.

Treatment and prophylaxis - EPTS

• Midazolam/ Lorazepam for acute seizure cessation

• Phenytoin 15 – 20 mg/ kg – 4-7mg/ day for 7 days

• AED given during the first 24 hours reduce the occurrence of early seizures significantly

• N=890

• AED reduce RR to 0.34 (95% CI 0.21, 0.54)

• NNT to keep 1patient seizure-free in acute phase -10

• AED do not reduce death and disability

Schierhout, et al. Cochrane Database, 2001

Choice of AED

Choice of AED

Phenytoin

• Hypersensitivity

• Phlebitis

• Hypotension

• Arrhythmia

• Drug interactions

Levetirecetam

• Predictable pharmacokinetics

• Does not require drug monitoring

Zafar et al. BMC Neurology 2012.

Levetiracetam

Zafar et al. BMC Neurology 2012.

Phenytoin is more cost-effective than levetiracetamat all reasonable prices

and at all clinically plausible reductions in post-TBI seizure potentialCotton, et al. J Trauma 2011.

Treatment and prophylaxis - LPTS

• No AED is effective in preventing LPTS

• Standard AEDs are effective for treatment

• Choice of AED

– Cognitive effects

• Treatment guidelines similar to any other epileptic patients


Treatment LPTS

Focal epilepsy

• CBZ extended release/ OXC/ PHT/LTG

Generalized epilepsy

• VPA/ PHT/ OXC/ LTG

• Duration – 2 years

• AED substitution• Failure of seizure control

• Adverse drug reaction

• Cognitive decline


Prophylaxis in adultsRecommendation

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.

Prophylaxis in Children

• Phenytoin vs placebo

• N=41 and N=102

• 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

Young et al. 2004Young et al. 1983

Prophylaxis in Children

• N=275, risk of EPTS

• Severe TBI: 8.7 times

• Non-accidental injury: 3.4 times

• Age <2 years: 3 times

• AED: 0.2 times

Liesemer, et al. J Neurotrauma 2011

Prophylaxis in ChildrenRecommendation

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

Kochanek, et al. Pediatr Crit Care Med 2012

Surgical treatment

Challenges

• Accurate localization

• Multiple and bilateral sites

• N=25

• Successfully localized in 9 patients– Hippocampus or neocortex

• All underwent surgical excision

• All seizure free 1-year post surgery

Marks, et al.1995

Issues in treatment

• Continuation of AED in EPTS

• Alcohol related seizures

• Cognitive side effects

• Drug interaction

• Adverse effects

• Continuous EEG monitoring

Continuation of AED in EPTS

• Onset (day 1 versus day 7)

• Severity

• Frequency

• Risk factors

• Monitored withdrawal of AED therapy

Most patients with nonpenetrating TBI and isolated EPTS will tolerate discontinuation of AED therapy

without seizure recurrence

Alcohol related

• 6-48 hours of withdrawal

• Lorazepam prevents recurrent seizures

• Phenytoin is ineffective in prevention

Gaughwin, et al. Head Injury 2005.


AED and cognition

• N=244, Phenytoin

• Severely injured impaired neuropsychological performance at 1 month

• Moderately injured no significant differences

• Patients who stopped receiving phenytoinbetween 1 and 2 years improved more

Dikmen et al. 1991

AED and cognition

• N = 82, Phenytoin or Carbamazepine

• Significant improvement in performance following cessation of AED

LTG extended release 300mg monotherapy useful for substitution

Smith. et al. 1994

AED and other adverse effects

• A trend towards an increased risk of skin rashes

• Inappropriate dose related

– Giddiness and ataxia

Schierhout & Roberts, 2001

PTS and other drugs interaction

• Early steroids may increase PTS• Antidepressant

– Tricyclic antidepressants: 19% developed seizures– Sustained-release formulations of buproprion– SSRIs lower proconvulsant activity

• Antipsychotics including clozapine• Bromocriptine and amantadine, dopamine

receptor agonists - anecdotal• Amphetamine,methylphenidate and

dextroamphetamine do not increase risk of PTS

Dikmen et al. 1991

Continuous EEG monitoring

• Should be monitored for 7 days

• Upto 50% are non-convulsive

• Help in titration of AED

• Detection of rebound seizures

• No correlation with clinical seizures

• Long term benefits of suppression of EPTS is not known

Vespa. Epilepsy and Intensive Care Monitoring 2010.

Future Investigation


• Additional studies to determine if reduction in early PTS has an effect on outcome.

• Continuous EEG monitoring to identify seizures

• PTS in patients treated with neuroprotectiveagents that have antiepileptic activity, such as magnesium and other NMDA receptor antagonists

Health & Medicine

Post traumatic seizure and epilepsy