eMedicine Specialties > Neurology > Seizures and Epilepsy

Posttraumatic Epilepsy

Ewa Posner, MD, MRCP, Consultant Pediatrician, Department of Pediatrics, University Hospital of North Durham, UK
Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants

Updated: Oct 22, 2009

Introduction

Background

Posttraumatic epilepsy (PTE) refers to a recurrent seizure disorder, the cause of which is believed to be injury to the brain. This injury can be a result of head trauma or a sequel to an operation on the brain. The term PTE must be differentiated from the term posttraumatic seizure (PTS), which signifies any seizure that occurs as a sequel to brain injury. If the seizures occur within 24 hours of the injury, they are called immediate PTSs. A PTS that occurs within 1 week of injury is termed early PTS, and a seizure that occurs more than 1 week after injury is termed late PTS. About 20% of people who have 1 late PTS never have any more, and these people should not be described as having PTE.

Pathophysiology

The mechanism by which trauma to the brain tissue leads to recurrent seizures is unknown. Cortical lesions seem important in the genesis of the epileptic activity. Early seizures are likely to have a different pathogenesis than late seizures; early PTS are thought to be a nonspecific response to the physical insult. In the pathophysiology of the PTE kindling model of epilepsy, damage by free radicals caused by iron deposition from extravasated blood and damage by excitotoxicity due to accumulation of glutamate have been postulated. Animal studies suggest that blood brain barrier is disrupted in PTE and this is likely to contribute to the generation of seizures.

Some natural antioxidants, such as alpha-tocopherol and condensed tannins, have been demonstrated to be prophylactic for the occurrence of epileptic discharge in the iron-injected animal brain.¹ Studies suggest that antioxidants like phosphate diester of vitamin E and C, vanillyl alcohol, and melatonin may be useful alternative medications for preventing PTE.

Frequency

United States

Although the incidence of epilepsy in the general population is estimated at 0.5-2%, the incidence of PTS for all types of head injuries is 2-2.5% in civilian populations. This incidence increases to 5% in hospitalized neurosurgical patients. When only severe head injuries (usually Glasgow Coma Scale score <9) are considered, the incidence is 10-15% for adults and 30-35% for children. The incidence of PTS is as high as 50% in military series, as these studies include many patients with penetrating head injuries. The incidence of seizures (excluding early seizures) after uncomplicated mild head injury is the same in the military population as in the general population.

International

The data above are based on studies from the United States and Europe. In Japan, the occurrence of PTE is approximately 150,000 annually; this equals 10% of all hospitalized patients with head injury and 1% of all outpatients with head injury. In a study from Norway, the incidence of PTE in a mixed age group of patients with severe head injuries was 23% and there was significant correlation with severity of injury and intracranial surgery.²

Mortality/Morbidity

Approximately 80% of first PTS occur within 2 years of the injury.

Age

In the United States, the incidence of brain injury is highest among young adults; this is reflected in the incidence of PTE in the relevant age group. Early PTS are more common in children, while late PTS are more common in adults.

Clinical

History

The seizures are usually partial (focal) or generalized tonic-clonic. Often, both types coexist. Most early PTS are partial seizures, whereas most late PTS, especially when part of PTE, are generalized and either primary or secondary.

Physical

No specific findings are noted on physical examination.

Causes

By definition, PTE is a result of injury to the brain. Recent data suggest that neuroimaging and genomic information (eg, haptoglobin genotypes, apolipoprotein E levels) may be helpful in predicting an individual's risk for PTE. Early PTSs are more common in children younger than 5 years, in patients with focal neurologic deficits, and in patients with a linear or depressed skull fracture than in others.

Factors that increase the risk of PTE are as follows:

• Severity of trauma
• Penetrating head injuries
• Intracranial hematoma
• Depressed skull fracture
• Hemorrhagic contusion
• Coma lasting more than 24 hours
• Early PTS

Differential Diagnoses

Other Problems to Be Considered

Seizures due to causes other than brain injury

Workup

Laboratory Studies

• In a patient who is still hospitalized after a recent head injury, investigation of a seizure should focus on determining whether an intracranial bleed or a change in clinical condition (eg, hyponatremia) cause the seizure.
• In a patient in otherwise stable condition whose serum electrolytes are within the normal range and whose neurologic findings are the same as those before the seizure, further laboratory studies are not needed.
• In a patient presenting some time after the injury, the usual investigations that are applicable for the first epileptic seizure should be performed.
• Serum prolactin measurement can be done after the seizure to help differentiate pseudoseizures from seizures. However, this is still more of a research point rather then a well-recognized standard test.

Imaging Studies

• Brain MRI is the study of choice, and many clinicians perform it in all patients with PTS.
• If MRI is not readily available, head CT can be substituted. CT is less sensitive than MRI, but should be able to depict all pathology (eg, intracranial bleed) that needs urgent intervention.

Other Tests

• EEG is useful mainly for localizing seizure foci and for prognosticating their severity.
• EEG is not helpful in predicting the likelihood of PTS in a given patient. However, it may be helpful in predicting relapse before anticonvulsant medication is withdrawn.
• Video EEG may be helpful in differentiating between pseudoseizures and posttraumatic epilepsy seizures.

Treatment

Medical Care

Treatment of PTE does not require hospitalization. Admission may be needed for the treatment of status epilepticus or for videotelemetry to assist in the diagnosis.

Surgical Care

Surgical treatment is an option for PTE refractory to medication. The aim is precise identification and excision of the epileptogenic focus. This is often more difficult in cases of PTE than in other types of epilepsy.

Consultations

• Consult a neurologist to confirm the diagnosis.
• Consult a neuropsychologist to document the patient's baseline function before antiepileptic medication is started. Consultation with a neuropsychologist should be a part of the workup if surgery is considered.

Medication

Early PTS is treated with phenytoin, sodium valproate, or carbamazepine. In most cases, administering the medication via the intravenous (IV) route is desirable, as the patient is still in the recovery stage from the head injury; phenytoin is the drug of choice for IV administration. No evidence suggests that antiepileptic drugs (AEDs) influence the incidence of late PTS; therefore, prophylaxis has no place in caring for patients with head injuries. However, AEDs are effective in patients who develop PTE.

The main drugs used for PTE are valproate and carbamazepine. To the authors' knowledge, no randomized controlled studies have been performed to prove that one is better than the other. Some also recommend phenytoin⁴ , but it seems to increase the risk of impairing cognitive function. A retrospective study that compared phenytoin and levetiracetam in patients after craniotomy found that levetiracetam was better tolerated and therefore more likely to be used long term.⁵ Levetiracetam has also been studied in patients with severe traumatic brain injuries; a recent small study suggested that it was as effective as phenytoin in preventing early seizures, but the amount of seizure activity seen on EEG monitoring was higher in the levetiracetam group.

Anticonvulsants

These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.

Sodium valproate (Depakote, Depakene, Depacon

Chemically unrelated to other antiseizure drugs. Mechanism of action not established; may be related to increased brain levels of GABA or to enhanced GABA action. May potentiate postsynaptic GABA responses, affect potassium channel, or have direct membrane-stabilizing effect. For conversion to monotherapy, concomitant AED dose ordinarily reduced by about 25% q2wk. Reduction may start with therapy or delayed 1-2 wk if seizures possible with reduction; closely monitor patients during this time for increased seizure frequency.
As adjunctive therapy, may be added to regimen at 10-15 mg/kg/d. May increase by 5-10 mg/kg/wk for optimal clinical response. Optimal clinical response usually achieved at <60 mg/kg/d.

Dosing

Adult

600 mg/d PO divided bid, preferably after food; increase by 200 mg/d at 3-d intervals; not to exceed 2.5 g/d (20-30 mg/kg/d)

Pediatric

<2 years: Not recommended; risk of fatal hepatotoxicity
>2 years: 20 mg/kg/d PO initially in divided doses; can be increased, not to exceed 35 mg/kg/d

Interactions

Cimetidine, salicylates, felbamate, and erythromycin may increase toxicity; rifampin may reduce levels significantly; in children, salicylates decrease protein binding and metabolism; may result in variable changes of carbamazepine concentrations, with loss of seizure control; may increase diazepam and ethosuximide toxicity (monitor closely); may increase phenobarbital and phenytoin levels, and either may decrease levels; may displace warfarin from protein-binding sites (perform coagulation tests); may increase zidovudine levels in HIV-positive patients

Contraindications

Documented hypersensitivity; active liver disease; porphyria; family history of hepatic dysfunction

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Thrombocytopenia and abnormal coagulation reported; risk of thrombocytopenia increases significantly at total trough plasma concentrations >110 (women) or >135 (men) mcg/mL; before therapy, periodically, and before surgery, determine platelet counts and bleeding time; reduce dose or discontinue if hemorrhage, bruising, or hemostasis or coagulation disorder occur. Monitor for hepatotoxicity (perform LFTs periodically); hyperammonemia may occur, resulting in hepatotoxicity; monitor closely for malaise, weakness, facial edema, anorexia, jaundice, and vomiting; may cause drowsiness

Carbamazepine (Tegretol)

Indicated for complex partial seizures. May block posttetanic potentiation by reducing summation of temporal stimulation. After therapeutic response, may reduce dose to minimum effective level or discontinue at least once q3mo.

Dosing

Adult

100-200 mg PO qd/bid; slowly increase to usual dose of 0.8-1.2 g/d in divided doses; not to exceed 1.6-2 g/d

Pediatric

<1 year: 100-200 mg/d PO in divided doses
1-5 years: 200-400 mg/d PO in divided doses
10-15 years: 0.6-1g/d PO in divided doses

Interactions

Danazol may increase serum levels significantly (avoid within 30 d if possible); cimetidine may increase toxicity, especially if taken in first 4 wk; may decrease primidone, lamotrigine (via hepatic enzyme induction), and phenobarbital levels (coadministration may increase levels); lamotrigine may increase levels of active metabolites, leading to symptoms of cerebellar dysfunction

Contraindications

Documented hypersensitivity; AV conduction abnormalities (unless paced); porphyria; history of bone marrow depression; concurrent MAOIs

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

In first trimester, risk of teratogenesis, including neural tube defects, may be increased; in third trimester, manufacturer advises prophylactic vitamin K-1 for mother before delivery (and for neonate) because of risk of neonatal bleeding; counseling, screening, and folate supplements advised. Initiation should be gradual; caution with increased IOP; obtain CBC counts and serum iron level before treatment, during first 2 mo and then yearly or biyearly; can cause drowsiness, dizziness, and blurred vision; caution while driving or performing other tasks requiring alertness

Phenytoin (Dilantin)

May act in motor cortex, inhibiting spread of seizure activity; may inhibit activity of brainstem centers responsible for tonic phase of grand mal seizures.
Individualize dose. Administer larger dose before sleep if cannot be divided equally. To minimize GI irritation, administer with or immediately pc. Rapid injection or direct IV injection may cause severe hypotension or CNS depression.

Dosing

Adult

IV loading dose for patients who have not received phenytoin in preceding 7 days: 10-15 mg/kg; rate not to exceed 50 mg/min (25 mg/min in elderly)
Maintenance dose: 4-7 mg/kg/d PO/IV

Pediatric

IV loading dose: 15-18 mg/kg; rate not to exceed 0.5-1 mg/kg/min or 50 mg/min; in infants, do not give via scalp vein
Maintenance dose: 5 mg/kg/d PO/IV divided bid, adjust on basis of clinical signs and serum concentrations

Interactions

Amiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimides, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (acute ingestion), trimethoprim, and valproic acid may increase toxicity; barbiturates, diazoxide, ethanol (chronic ingestion), rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate may decrease effects; may decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, metyrapone, mexiletine, oral contraceptives, valproic acid

Contraindications

May aggravate typical absence seizures; reduce dose in hepatic impairment; sinoatrial block; Adams-Stokes syndrome; second- or third-degree AV block

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Rapid IV infusion may cause death from cardiac arrest marked by QRS widening; narrow therapeutic index, and relationship between dose and plasma concentration nonlinear (must monitor plasma levels); avoid abrupt withdrawal; perform CBC counts and urinalyses at start and monthly for several months to monitor for blood dyscrasias; discontinue if skin rash occurs and do not resume if exfoliative, bullous, or purpuric; caution in acute intermittent porphyria and diabetes (may elevate blood glucose level); discontinue if hepatic dysfunction occurs

Follow-up

Further Outpatient Care

Regular follow-up should be performed for a review of medications; for neuropsychological assessment; and for monitoring of adverse effects, drug levels if indicated, and the patient's neurologic status.

Inpatient & Outpatient Medications

• Prophylaxis
  • Findings of the latest Cochrane Review are that prophylactic treatment in the acute phase does not reduce death or disability rates.
  • Treatment of early PTS does not decrease the risk of late PTS.
• Treatment
  • Early PTS: The recommendation is that early PTS should be treated promptly, as seizure activity is likely to further damage the already-compromised brain. IV phenytoin and sodium valproate are the drugs of choice and usually effective in stopping the seizure.
  • Late PTS: Treatment is not mandatory, as some patients with a low frequency of seizures may choose not to take regular medication. Compliance with long-term treatment is often poor in this group of patients. The anticonvulsant usually prescribed is sodium valproate, phenytoin, or carbamazepine. Among the newer anticonvulsants, levetiracetam has been used successfully after craniotomy.

Deterrence/Prevention

• A large percentage of PTEs should be viewed as preventable. Encourage preventive strategies, such as use of child seats and the use of helmets when cycling.
• Current evidence suggests that the treatment of early PTS does not influence the incidence of PTE. Routine preventive anticonvulsants are not indicated for patients with head injuries.
• Some have proposed the existence of a therapeutic window of opportunity of about 1 hour after traumatic brain injury. During this period, an agent (eg, sodium valproate), if delivered, may prevent or abort the epileptogenic process. Studies to explore such treatment are underway.

Complications

• Posttraumatic status epilepticus, which is more common in children than adults, is a complication of PTE.
• Psychological problems related to social isolation and the stigma of epilepsy are common and must be addressed.

Prognosis

• The risk of PTS decreases with time and reaches the normal value for the population at 5 years after the head injury.
• About half the patients who develop late PTS have 3 or fewer seizures and go into spontaneous remission thereafter.

Patient Education

• As in any seizure disorder, patients must be warned to exercise caution during bathing, swimming, and climbing heights. They should never be alone during these activities. In all situations, appropriate steps should be taken to ensure the safety of the person if a seizure occurs.
• Patients must also be counseled about the limitations in obtaining a driver's license.
• For excellent patient education resources, visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education article Epilepsy.

Miscellaneous

Medicolegal Pitfalls

• The medical/legal aspect is an important issue in cases of PTE, as some patients pursue legal actions against various authorities and individuals responsible for the circumstances of the accident.
• Clinicians are often asked to estimate the risk of a patient developing PTE in the future as a result of sustained brain injury. This is a difficult task and should be left to an experienced senior specialist.

Special Concerns

• Many patients are not able to obtain a driving license.

References

1. Mori A, Yokoi I, Noda Y, Willmore LJ. Natural antioxidants may prevent posttraumatic epilepsy: a proposal based on experimental animal studies. Acta Med Okayama. Jun 2004;58(3):111-8. [Medline].

2. Skandsen T, Ivar Lund T, Fredriksli O, Vik A. Global outcome, productivity and epilepsy 3--8 years after severe head injury. The impact of injury severity. Clin Rehabil. Jul 2008;22(7):653-62. [Medline].

3. Hudak AM, Trivedi K, Harper CR, Booker K, Caesar RR, Agostini M, et al. Evaluation of seizure-like episodes in survivors of moderate and severe traumatic brain injury. J Head Trauma Rehabil. Jul-Aug 2004;19(4):290-5. [Medline].

4. Temkin NR, Dikmen SS, Wilensky AJ. A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med. Aug 23 1990;323(8):497-502. [Medline].

5. Milligan TA, Hurwitz S, Bromfield EB. Efficacy and tolerability of levetiracetam versus phenytoin after supratentorial neurosurgery. Neurology. Aug 26 2008;71(9):665-9. [Medline].

6. Angeleri F, Majkowski J, Cacchio G, et al. Posttraumatic epilepsy risk factors: one-year prospective study after head injury. Epilepsia. Sep 1999;40(9):1222-30. [Medline].

7. Annegers JF, Hauser WA, Coan SP, et al. A population-based study of seizures after traumatic brain injuries. N Engl J Med. Jan 1 1998;338(1):20-4. [Medline].

8. Beghi E. Overview of studies to prevent posttraumatic epilepsy. Epilepsia. 2003;44 Suppl 10:21-6. [Medline].

9. Chang BS, Lowenstein DH. Practice parameter: antiepileptic drug prophylaxis in severe traumatic brain injury: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. Jan 14 2003;60(1):10-6. [Medline].

10. Chang BS, Lowenstein DH. Practice parameter: antiepileptic drug prophylaxis in severe traumatic brain injury: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. Jan 14 2003;60(1):10-6. [Medline].

11. D'Ambrosio R, Perucca E. Epilepsy after head injury. Curr Opin Neurol. Dec 2004;17(6):731-5. [Medline].

12. Frey LC. Epidemiology of posttraumatic epilepsy: a critical review. Epilepsia. 2003;44 Suppl 10:11-7. [Medline].

13. Garga N, Lowenstein DH. Posttraumatic epilepsy: a major problem in desperate need of major advances. Epilepsy Curr. Jan-Feb 2006;6(1):1-5. [Medline].

14. Schierhout G, Roberts I. Anti-epileptic drugs for preventing seizures following acute traumatic brain injury. Cochrane Database Syst Rev. 2001;CD000173. [Medline].

15. Temkin NR. Prophylactic Anticonvulsants After Neurosurgery. Epilepsy Curr. Jul 2002;2(4):105-107. [Medline].

16. Temkin NR, Dikmen SS, Anderson GD, et al. Valproate therapy for prevention of posttraumatic seizures: a randomized trial. J Neurosurg. Oct 1999;91(4):593-600. [Medline].

Keywords

PTE, head injury, head trauma, posttraumatic seizure, PTS, traumatic brain injury, TBI

Contributor Information and Disclosures

Author

Ewa Posner, MD, MRCP, Consultant Pediatrician, Department of Pediatrics, University Hospital of North Durham, UK
Ewa Posner, MD, MRCP is a member of the following medical societies: European Paediatric Neurology Society and Royal College of Paediatrics and Child Health
Disclosure: Nothing to disclose.

Coauthor(s)

Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Nicholas Y Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology
Disclosure: Nothing to disclose.

Medical Editor

Joseph F Hulihan, MD, Vice President, Medical Affairs, Ortho-McNeil Janssen Scientific Affairs, LLC
Joseph F Hulihan, MD is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, American Headache Society, and American Medical Association
Disclosure: Johnson & Johnson Salary Employment; Johnson & Johnson Stock Employment

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Jose E Cavazos, MD, PhD, FAAN, Associate Professor with Tenure, Departments of Neurology, Pharmacology, and Physiology, University of Texas Health Science Center at San Antonio; Co-Director, South Texas Comprehensive Epilepsy Center; Director of the Epilepsy Center, Audie L Murphy Veterans Affairs Medical Center
Jose E Cavazos, MD, PhD, FAAN is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, and Society for Neuroscience
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

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