Washington University School of Medicine

I. Acute Symptomatic Seizures

by Michael Wong, MD, PhD

I. ACUTE SYMPTOMATIC SEIZURES

A. FEBRILE SEIZURES

1. Epidemiology
a. Cumulative Incidence: 2-4% of children; slightly more common in males.
b. Age: generally between 6 months to 6 years, most common in 2nd year of life.
c. Risk Factors for First Febrile Seizure: family history of febrile seizures, complicated neonatal course (>28 days in hospital), developmental delay, child care attendance, very high fever, hyponatremia (Berg et al. 1995, Bethune et al. 1993).

2. Etiology/Pathophysiology
a. Febrile Illness: most commonly otitis media, tonsillitis, or viral URIs (Stokes et al. 1977); also associated with HHSV-6;
immunizations (e.g. pertussis) may induce seizure via fever.
b. Fever may lower seizure threshold in young children who already have a relatively low seizure threshold.
c. Genetics:
- Increased prevalence of febrile seizures in close relatives (~10-20% of siblings develop febrile seizures).
- Linkage studies have identified possible genes for febrile seizure susceptibility (Kugler and Johnson 1998).
- Generalized epilepsy with febrile seizures plus is a recently-identified autosomal dominant genetic epilepsy syndrome, localized to
chromosome 19 and due to a mutated sodium channel beta subunit (Singh et al. 1999).

3. Diagnostic Evaluation
a. History: Differentiate between simple and complex (atypical) febrile seizures.
- Simple: generalized tonic-clonic seizure, brief (<15 min), only one per febrile illness.
- Complex: partial seizure, prolonged (>15 min), multiple. The initial febrile seizure is complex in ~35% of patients: ~16% partial,
~14% multiple, ~10% prolonged, ~5% status epilepticus (Berg and Shinnar 1996).
b. Physical exam to look for source for fever.
c. Evaluate for meningitis clinically (mental status, meningismus);
- AAP Practice Parameter(1996) recommends LP for all patients <12 mo due to poor reliability of meningeal signs; clinical judgement
should be used for patients >12 mo.
- But, one study (Green et al. 1993) of 115 patients with seizures due to meningitis found no cases with a simple febrile seizure as the
only sign - 93% of patients were obtunded or comatose, the remaining had meningismus or prolonged or multiple seizures.
d. Routine labs, CT/MRI, or EEG are not recommended for a simple febrile seizure (AAP Practice Parameter 1996). EEG is also of
limited value in complex febrile seizures (Maytal et al. 2000).

4. Treatment
a. Antipyretics as prophylaxis during febrile illness. Not shown to be effective (van Stuijvenberg et al. 1998).
b. Antiepileptic medications generally not indicated for simple febrile seizures. For recurrent complex febrile seizures:
- Short-term Intermittent Prophylaxis: Intermittent diazepam prophylaxis (0.5mg/kg q12hr x4) during febrile illnesses is effective in
reducing recurrence (Rosman et al. 1993).
- Continuous Prophylaxis: phenobarbital or valproate are effective in reducing the recurrence of febrile seizures (Newton 1988,
Knudsen and Vestermark 1978, Rantala et a. 1997, Wolf et al. 1977).
c. Treatment of febrile seizures with antiepileptic medications does not change the risk of developing epilepsy (Knudsen et al. 1996,
Rosman et al. 1993).

5. Prognosis
a. Recurrence of Febrile Seizures
- Meta-analysis (Berg et al. 1990): A meta-analysis of 14 studies found two strong predictors of febrile seizure recurrence: age < 1
year and FHx of febrile seizure. Complex febrile seizures had only a small increased risk and FHx of epilepsy was not consistently
associated with increased risk.
- Prospective study #1 (Knudsen 1985): overall 35% had recurrence, 10% had 3 or more; risk factors 1) age <15 mo, 2) FHx
epilepsy, 3) FHx febrile seizure, 4) day care, 5) complex febrile sz; 0 risk factors - 10%, 1 risk factor - 25%, 2 risk factors -50%,
3-5 risk factors - 80-100%.
- Prospective study #2 (Berg et al. 1992,1997): overall 32% had recurrence, 6% had 3 or more; risk factors 1) age <18 mo, 2) FHx
febrile sz, 3) shorter duration (<1hr) fever, 4) lower fever in ED.
- Recurrence of complex febrile seizures: If the initial febrile seizure was prolonged, the risk of recurrent seizures also being prolonged
is increased by 2-4 fold compared to an initial simple febrile seizure (Berg and Shinnar 1996).
b. Future Unprovoked Seizures
- Study #1 (Nelson & Ellenberg 1976): overall risk 2-3%; risk factors 1) neurodevelopmental abnormalities, 2) complex febrile
seizure, 3) FHx epilepsy; 0 risk factors - 1-2%, 1 risk factor - 5%, 2-3 risk factors - 10%.
- Study #2 (Annegers et al. 1987): overall risk 2.4%; risk factors 1) complex febrile sz components, 1 (6-8%), 2 (17-22%), 3 (49%),
2) age <12 mo, 3) recurrent febrile szs
- Study #3 (Berg & Shinnar 1996): overall risk 6.1%; risk factors 1) neurodevelopmental abnormalities (35%), 2) complex febrile
seizure, 3) FHx epilepsy (18%), 4) recurrent febrile szs (20% for 4 or more), 5) shorter duration fever (11% for <1 hr).
c. Relationship to Mesial Temporal Sclerosis
- Retrospective studies and anecdotal cases have found an association between mesial temporal sclerosis/temporal lobe epilepsy and a history of prolonged febrile seizures (Cendes et al. 1993, Kuks et al. 1993, Sagar and Oxbury 1987).
- Population-based and prospective studies have not found this association (Annegers et al. 1987, Lee et al. 1981).
d. Neurodevelopmental Outcome: patients with febrile seizures generally have normal neuro-developmental outcome and treatment with AEDs does not affect neurodevelopmental outcome (Knudsen et al. 1996, Nelson and Ellenberg 1978).

B. (AFEBRILE) ACUTE SYMPTOMATIC SEIZURES

1. Epidemiology (Annegers et al. 1995)
a. Distinction from Febrile Seizures: Since febrile seizure have unique properties of age-specificity, high incidence, and universality of
stimulus exposure, other types of acute symptomatic seizures are generally classified and analyzed separately from febrile seizures.
b. Incidence: The overall (age-adjusted) incidence of (afebrile) acute symptomatic seizures in the US is ~40/100,000 person-years.
Cumulative (lifetime) incidence is ~4%, accounting for ~40% of all new-onset afebrile seizures.
c. Age-dependence: Incidence is highest in the neonatal period (200-300/100,000), drops precipitiously during the first year of life, and
reaches a nadir in early adulthood (15/100,000). After age 35 years, incidence gradually increases and reaches a second peak among
the elderly (100-150/100,000).
d. Sex: Men have a higher cumulative incidence of acute symptomatic seizures (~5%) than women (~3%).

2. Etiology
a. Overall: In the Rochester study (Annergers et al. 1995), the etiologies of acute symptomatic seizures included head trauma (16%),
CVA (16%), CNS infection (15%), drug withdrawal (14%), metabolic (9%), brain tumor (8%), toxic (6%), encephalopathy (5%),
eclampsia (2%), and other (10%).
b. Age-dependence:
- neonates: high incidence of infectious and metabolic causes.
- elderly: CVA accounts for ~50%.
c. Timing: 75-90% of acute symptomatic seizures occur within the first 24 hours following head trauma or CVA (Annegers et al. 1980,
Hahn et al. 1988, So et al. 1996).

3. Treatment
a. Acute Treatment:
- Correction of the underlying etiology, if possible, represents the most direct, effective treatment.
- Temporary use of AEDs may help suppress seizures while the underlying etiology is still active. For example, prophylactic AED
treatment decreases the risk of post-traumatic seizures in the first week following the head trauma (Temkin et al. 1990).
b. Chronic Treatment: Similar to febrile seizures, there is no evidence that treatment of other types of acute symptomatic seizures, such as
post-traumatic seizures, decreases the risk of developing epilepsy (Temkin et al. 1990).

4. Prognosis: Acute symptomatic seizures most likely represent a sign of disease severity, rather than a cause. The underlying etiology,
rather than the seizure, is probably the most important factor in dictating prognosis.
a. Epilepsy:
- Metabolic etiologies: The risk of subsequent epilepsy in patients with acute symptomatic seizures from metabolic causes is not well-
documented, but is hypothesized to not be elevated.
- Other etiologies: For most other etiologies, including trauma, infection, and CVA, patients with acute symptomatic seizures are at
higher risk for subsequent epilepsy than patients without acute seizures (Annegers et al. 1980, Annegers et al. 1988, Hauser et al.
1984, So et al. 1996).
b. Mortality:
- Patients with acute symptomatic seizures following a CVA had a higher inpatient mortality than patients with CVA without seizures
(Arboix et al. 1996).
- In general, acute symptomatic seizures are associated with a relatively high mortality rate, but again the seizures may simply be a
marker of a more serious underlying etiology, rather than a causative factor of mortality.

C. REFERENCES

American Academy of Pediatrics. Practice parameter: the neurodiagnostic evaluation of the child with a first simple febrile seizure. Pediatrics 1996;97:769-772.

Annegers JF, Grabow JD, Groover RV, et al. Seizures after head trauma: a population study. Neurology. 1980;30:683-689.

Annegers JR, Hauser WA, Beghi E, Kurland LT. The risk of seizures after encephalitis and meningitis. Neurology 1988;38:1407-1410.

Annegers JR, Hauser WA, Coan SO, Rocca WA. A population-based study of seizure disorders after cerebral infarction. Neurology 1996;46:350-355.

Annegers JF, Hauser WA, Lee JR, Rocca WA. Acute symptomatic seizures in Rochester, Minnesota, 1935-1984. Epilepsia 1995;36:327-333.

Annegers JF, Hauser WA, Shirts SB, Kurland LT. Factors prognostic of unprovoked seizures after febrile convulsions. N Eng J Med 1987;316:493-498.

Arboix A, Comes E, Massons J, et al. Relevance of early seizures for in-hospital mortality in acute cerebrovascular disease. Neurology 1996;47:1429-1435.

Berg AT, Shinnar S. Unprovoked seizures in children with febrile seizures: short-term outcome. Neurology 1996;47:562-568.

Berg AT, Shinnar S. Complex febrile seizures. Epilepsia 1996;37:126-133.

Berg AT, Shinnar S, Darefsky AS, Holdford TR, Shapiro ED, Salomon ME, Crain EF, Hauser AW. Predictors of recurrent febrile seizures: a prospective cohort study. Arch Pediatr Adolesc Med 1997;151:371-378.

Berg AT, Shinnar S, Hauser WA, Alemany M, Shapiro ED, Salomon ME, Crain EF. A prospective study of recurrent febrile seizures. N Engl J Med 1992;327:1122-1127.

Berg AT, Shinnar S, Hauser WA, Leventhal JM. Predictors of recurrent febrile seizures: a metaanalytic review. J Ped 1990;116:329-337.
Berg AT, Shinnar S, Shapiro ED, Salomon ME, Crain EF, Hauser WA. Risk factors for a first febrile seizure: a matched case-control study. Epilepsia 1995;36:334-341.

Bethune P, Gordon K, Dooley J, Camfield C, Camfield P. Which child will have a febrile seizure? Am J Dis Child 1993;147:35-39.

Cendes F, Andermann F, Dubeau F, et al. Early childhood prolonged febrile convulsions, atrophy and sclerosis of mesial structures, and temporal lobe epilepsy: an MRI volumetric study. Neurology 1993;43:1083-1087.

Green SM, Rothrock SG, Clem KJ, Zurcher RF, Mellick L. Can seizures be the sole manifestation of meningitis in febrile children? Pediatrics 1993;92:527-534.

Hahn YS, Fuchs S, Flannery AM, et al. Factors affecting posttraumatic seizures in children. Neurosurgery 1988;22:864-867.

Hauser WA, Ramirez-Lassepas M, Rosenstein R. Risk for seizures and epilepsy following cerebrovascular insults. Epilepsia 1984;25:666.

Knudsen FU. Recurrence risk after first febrile seizure and effect of short-term diazepam prophylaxis. Arch Dis Child 1985;60:1045-1049.

Knudsen FU, Paerregaard A, Andersen R, Andresen J. Long-term outcome of prophylaxis for febrile convulsions. Arch Dis Child 1996;74:13-18.

Knudsen FU, Vestermark S. Prophylactic diazepam or phenobarbital in febrile convulsions: a prospective controlled study. Arch Dis Child 1978;53:660-663.

Kugler SL, Johnson WG. Genetics of the febrile seizure susceptibility trait. Brain Dev 1998;20:265-274.

Kuks JB, Cook MJ, Fish DR, Stevens JM, Shorvon SD. Hippocampal sclerosis in epilepsy and childhood febrile seizures. Lancet 1993;342:1391-1394.

Lee K, Diaz M, Melchior JC. Temporal lobe epilepsy - not a consequence of childhood febrile convulsions in Denmark. Acta Neurol Scand 1981;63:231-236.

Maytal J, Steele R, Eviator L, Novak G. The value of early postictal EEG in children with complex febrile seizures. Epilepsia 200;41:219-221.

Nelson KB, Ellenberg JH. Predictors of epilepsy in children who have experienced febrile seizures. N Engl J Med 1976;295:1029-1033.

Nelson KB, Ellenberg JH. Prognosis in children with febrile seizures. Pediatrics 1978;61:20-727.

Newton RW. Randomised controlled trials of phenobaritone and valproate in febrile convulsions. Arch Dis Child 1988;63:1189-1191.

Rantala H, Tarkka R, Uhari M. A meta-analytic review of the preventive treatment of recurrences of febrile seizures. J Pediatr 1997;131:922-925.

Rosman NP, Colton T, Labazzo J, et al. A controlled trial of diazepam administered during febrile illnesses to prevent recurrence of febrile seizures. N Engl J Med 1993;329:79-84.

Rosman NP, Labazzo JC, Colton J. Factors predisposing to afebrile seizures after febrile convulsions and preventive treatment. Ann Neurol 1993;329:79-84.

Sagar HJ, Oxbury JM. Hippocampal neuron loss in temporal lobe epilepsy: correlation with early childhood convulsions. Ann Neurol 1987;22:334-340.

Singh R, Scheffer IE, Crossland K, Berkovic SF. Generalized epilepsy with febrile seizures plus: a common childhood-onset genetic epilepsy syndrome. Ann Neurol 1999;45:75-81.

So EL, Annegers JR, Hauser WA, et al. Population-based study of seizure disorders after cerebral infarction. Neurology 1996;46:350-355.

Stokes MJ, Downham MA, Webb JK, McQuillin J, Gardner PS. Viruses and febrile convulsions. Arch Dis Child 1977;52:129-133.

Temkin NR, Dikmen SS, Wilensky AJ, et al. A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med 1990;323:497-502.

van Stuijvenberg M, Derksen-Lubsen G, Steyerberg EW, Habbema JD, Moll HA. Randomized, controlled trial of ibuprofen syrup administered during febrile illnesses to prevent febrile seizure recurrences. Pediatrics 1998;102:e51.

Wolf SM, Carr A, Davis DC, et al. The value of phenobarbital in the child who has had a single febrile seizure: a controlled prospective study. Pediatrics 1977;59:378-385.