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FEBRILE SEIZURES

 

DEFINITION:

 

     "An event in infancy or childhood, usually occurring between 3 months and 5 years of age, associated with fever but without evidence of intra-cranial infection or other definable cause. Seizures with fever in children who have suffered a previous non febrile seizure are excluded. Febrile convulsions are to be distinguished from epilepsy, which is characterized by recurrent, non febrile seizures." (Consensus Development Panel on febrile convulsions 1980)

     This definition is 1) old and 2) opens to serious criticism.

1) It dates from 1980 but to my knowledge there has not been any better definition proposed.

2) Serious criticisms:

     1. The term "event" is much too vague, and even the term "seizure" is not precise enough. Indeed, FC (Febrile Convulsions) can be of epileptic etiology (i.e.: associated with epileptic EEG discharges) but some attacks can be anoxic or syncopal (therefore NOT epileptic in nature).

     2. The degree of fever is not specified.

     3. Absence of intra-cranial infection remains an unproved assumption. Some acute febrile encephalitis with normal CSF may be impossible to distinguish from FC. Some diseases are known to be capable of producing brain damage through vascular injuries or toxic mechanisms, (pneumonia, salmonellosis, shigellosis, Haemolytic Uremic Syndrome....).

 

     FC include at least 3 different subgroups.

     *First and largest group: children who have a seizure in response to fever, and as a result of an individual susceptibility that is genetically determined.

     *Second group: patients who convulse with fever as a result of an unrecognized brain insult caused by their febrile illness.

     *Third group: children in whom the fever merely acts as a triggering factor to unmask an epileptic disorder. In this subgroup one can easily identify children with a Symptomatic Epilepsy (although not always- unrecognized TS for example-) but it will be very difficult to distinguish children with an Idiopathic Epilepsy entering the epilepsy at the time of a febrile disorder.

Furthermore there are lots of possible overlaps. Small brain lesions otherwise silent, pure febrile convulsion and epilepsy triggered by fever, (e.g. Rolandic epilepsy and Febrile convulsions). One can also argue that a genetic predisposition for febrile seizure does not "immunize" against brain insults and both can coexist in the same patient.

These distinctions are more than a semantic exercise since the prognostic is highly dependant on subgroup classification.

     Livingston (1968) distinguished "simple FC" and "Atypical FC". Brief and generalized seizure with no family history vs. prolonged and often focal seizures. This is still true in the majority of cases but:

     some true FC are prolonged and or focal while some complex febrile seizures may, at least initially be undistinguishable from a typical Febrile seizure.

     Furthermore, although it is true that a severe, complex FC carries a higher risk for residual epilepsy, 90% of patients who go on to develop epilepsy have had a simple FC.

 

     INCIDENCE:

 

FC are the most common single neurological problem in children. 2 to 5% of all children will experience one or more convulsion associated with fever before the age of 5 years. Male: female ratio is 1.4:1

 

     PATHOPHYSIOLOGY.

 

Genetic predisposition to convulse in the presence of fever at a certain age.

 

     Genetic predisposition.

There is clearly a familial tendency. 17% of parents and 22% of siblings have seizures. Other authors report as much as 31% family history of convulsion. Probably autosomal dominant with variable penetrance and expression. EEG of children with FC often shows same pattern as other genetically determined epileptic syndromes (monomorphous parietal theta rhythm in the wake state). In epilepsy this rhythm will be associated with spike and wave complexes. A sibling of a child with FC runs approximately 10% chances of developing FC. It is a bit more if it is the child of a parent who had a FC and it is almost 50% if both the parent and the sibling had FC. 80% of monozygotic (identical) twins are concordant for FC.

 

     Fever.

Most often caused by Upper Respiratory Infections, Otitis Media, flu, GastroEnteritis, Urinary Tract Infections, etc... FC usually occur during the earliest hours of the acute infection. (The vast majority within the first 24 hours). Hence the name "initial" convulsion often given to FC. It also reflects the fact that one must be very cautious with convulsions occurring later in the course of an acute febrile illness, they are more likely to be the expression of an encephalitis. The degree of fever has no correlation with the likelihood of convulsion. 65% of patients will not have any further seizure even when the temperature remains very high. It has been thought that it was the rate of rise of fever which was important, but there is no finite evidence of its importance. The cause of the fever may have a role in the occurrence of FC. My former partner and role model, Dr J Parker always said that he had never seen a febrile seizure associated with pyelonephritis. Bacterial infections are less likely to cause febrile seizures.

 

     Age-dependence.

FC are strongly age-dependent. Very few infants have FC before 5 or 6 months of age while 85% of them have had their first FC before the age of 4 years. Median age 17 to 23 months. Although possible up to 8 years, one should be very cautious in case of a first FC after the age of 6 years.

 

              An interpretation of the physiopathology could be the following:

     In a genetically predisposed child in the right age group, the FC occurs when there is a significant discrepancy between the thermostat setting and the actual temperature. We know that viral infections create a CNS response at the level of the hypothalamus to reset the thermostat at a higher level. This in turn leads to all sorts of physiological phenomenons in order to raise the temperature: peripheral vasoconstriction, shivering and tremor being the usual ones. Until the temperature reaches the thermostat setting value, the patient will feel cold. This is why patients will shiver, ask for blankets when their temperature is at 39 or even 40 c. Their thermostat is set at a higher level and they feel cold. It is also very well known that seizures create a lot of heat. Any patient who had a seizure for whatever reason will have an elevation of his/her central temperature as a result of muscular contractions during the convulsion. And in fact the most efficient way of raising central temperature is to have a convulsion. In genetically predisposed patients the convulsion occurs as a very efficient way of raising central temperature. Whether the problem lies at the level of the thermostat centre which will respond too fast to the pyrogenes or whether it is an inability of the body to respond appropriately to the elevation of the thermostat remains obscure. This pathophysiological explanation is not recognized and is my own personal explanation.

 

 

     CLINICAL MANIFESTATIONS

 

     The great majority of FC are brief, bilateral, clonic or tonico-clonic. Usually they are NOT followed by a postictal state, unless it is very brief. However long-lasting and/or partial true FC do exist. Some of the unilateral seizures may be followed by a Todd's hemiplegia that usually lasts a few hours, may persist for several days. While prolonged partial seizures carry a higher risk of sequelae, they may be simple FC.

     15 to 20% of patients will have more than one FC within 24 hours. The repetition of the FC within the same febrile episode is associated with a higher risk of later development of epilepsy.

 

     EEG

      EEG paroxysms recording of a FC are mainly generalized but focal anomalies may be seen in up to 10% of cases.

     EEG tracing recorded within a week show anomalies in 33% of the patients. Posterior slowing, or parietal slowing. Commonly bilateral the theta activity can be asymmetrical or even unilateral. The early slow activity (EEG within 24 or 48 hours) have no prognostic value.

     Spikes and spikes-waves are seldom recorded before the age of 2 and their presence in this age group is of more value for later onset of epilepsy.

     Some focal paroxysms resemble in shape and location the CentroTemporal spikes of later childhood. These children with Rolandic discharges may be a subgroup of FC.

     THERE IS NO CORRELATION BETWEEN EEG PAROXYSMS AND LATER ONSET OF EPILEPSY, therefore EEG has little practical value in the evaluation of a child with FC, and should be reserved to selected cases where an epileptic syndrome is suspected (eg: Severe myoclonic epilepsy of childhood, Mesial temporal sclerosis etc...).

 

     DIAGNOSIS

      The diagnosis of FC is not always easy. Clearly one has to rule out a CNS infection. Severe FC may raise the problem of an encephalopathy. Syncope or anoxic seizures can also be triggered by fever. Epileptic syndrome triggered by a fever is a major diagnostic difficulty.

     Non epileptic phenomenons such as febrile delirium, febrile shivering can be confused with FC, mostly when associated with autonomic phenomenons such as pallor, perioral cyanosis, ...

 

     PROGNOSIS

      Depending on the definition of what is a febrile convulsion, the frequency of residua varies widely (0 to 100%).

     Certainly in the subgroup of true simple febrile convulsions (patient with a simple seizure, no underlying epilepsy, no CNS infection, no neurological pathology) the outcome is almost invariably favorable (>98%). However there is clear evidence that convulsive activity is harmful (Mesial Temporal Sclerosis).

 

     Mental and Neurological Development:

The vast majority of brief FC recover completely even after several recurrences. A minority will develop epilepsy.

"Complex" FC, may recover completely but may also evolve toward an epileptic syndrome such as Hemi convulsion-Hemiplegia-Epilepsy syndrome, or Severe Myoclonic Epilepsy of Childhood.

As previously stated the main difficulty is that the majority of children who later develop an epileptic activity had a "simple" FC.

The clinician is left with his/her own experience and the so called "soft signs" take more value. Behaviour disturbances prior or following a FC, exophoria, imitation synkinesia, language anomaly,...are all examples of these soft signs.

Intellectual dysfunction and learning disorders are uncommon complications of FC. In contrast, children who develop afebrile convulsions following FC have a fivefold increase in frequency of mental retardation (IQ<70 at 7 years). One study found that in twins (both mono and dizygotic) discordant for FC, the affected one scored 7 points less than the unaffected mate on IQ testing.

 

     Non Febrile Seizures following FC:

2 to 5% of FC develop non febrile seizures. That is 2 to 10 times the rate in the general population.

Again this is probably due to the fact that there are several different subgroups who present with a FC. Furthermore the subgroups of patients who are destined to develop non febrile seizures are over-represented.

Classically risk factors for later onset of epilepsy are:

     *developmental anomaly prior to the FC

     *first degree relative with epilepsy

     *non simple FC

6% of children with FC have 2 or more risks factors and they have 10% risk of later epilepsy.

The 34% of children with only one risk factor have 2% risk of later epilepsy (still higher than the general population).

But, again, 75% of later onset epilepsy occur in children who had one or no risk factor.

All types of epilepsies can be observed after FC. Generalized motor seizures are the most common. Typical absences are also relatively common, but complex partial seizures or atypical absences can also be observed.

One third of patients with "temporal lobe epilepsy" had FC. It has been recently recognized that Mesial Temporal Sclerosis does occur in children at a much earlier age than it was previously thought.

 

     Recurrence:

2 thirds of patients with FC will never have any other seizure.

30 to 35% of them will have at least one more episode of FC, but only 9% of them will have more than 3 recurrences.

If the first FC occurs before 1 year of age the recurrence rate goes up to 50%. Recurrence of FC is not a major risk factor for later onset epilepsy, but they may induce a decrease in IQ points.

 

     MANAGEMENT

      Investigations:

The Lumbar Puncture dilemma!! It is easy to advise LP in all first febrile seizures. Rightly, most physicians perform a LP only in selected cases. MENINGITIS MUST REMAIN ON THE TOP OF THE LIST. Only when the physician is clinically convinced that there is no evidence of meningitis, will the LP be avoided. Under 6 months of age a seizure associated with fever IMPOSES a LP, which may be repeated in the following hours, particularly if the first LP was negative, if the child does not improve. (watch the puffy child who does not pee). Between 6 and 18 months is a difficult moment! Most children will show clinical findings if they have meningitis but not all of them. Admission for observation is recommended. After 18 months the clinician can rely on the clinical findings.

Investigations to elucidate the etiology of the febrile illness are indicated: CBC, Blood Cultures, Urine, etc...

BS, Ca, lytes and other metabolic work up for seizures are of no value. I personally do lytes as a means of ruling out an inappropriate ADH, frequently seen in meningitis.

EEG is not routinely indicated and should be reserved to selected cases.

 

     Acute treatment:

The vast majority of FC will arrive in the ER after the seizure has spontaneously stopped. The child is alert and there is no need for any intervention. Treatment of the acute febrile illness when indicated is the only management required. Under 18 months admission for observation is appropriate for a first FC. Repeated seizures within the same febrile episode account for 16 to 20% of FC. Parental anxiety must be taken into account in the decision to admit or not.

Control of the temperature remains advocated. Tylenol to lower the thermostat, followed by cooling the child. There is no evidence that control of the temperature in subsequent febrile illnesses does anything to prevent recurrence of FC.

If the child arrives in the ER convulsing, the FC is not simple any more and can be described as prolonged. (In our society, it takes at the best 10 to 15 minutes to reach an ER). One needs to stop the seizure. This by itself has been recognized as a risk factor for later onset of epilepsy as well as recurrence of FC. Rectal valium at the dose of 0.3 mg per kilogram is usually very efficient. See also management of status epilepticus.

 

     Antiepileptic Prophylaxis

Who?

3 or more risks factors: most likely yes.

less than 3 risks factors: maybe

no risks factors: no.

But this will miss the vast majority of children who will develop non febrile seizures. Furthermore, there is no evidence that prevention of recurrence of FC affects at all the occurrence of non febrile seizures.

The recent reports of increased incidence of Mesial Temporal Sclerosis (MTS) in children with repeated FC complicates the problem even further.

In fact since we are unable to distinguish within the population of children with "simple" FC who is going to develop non FC or MTS, we are unable to say who should be given prophylaxis. Once more clinical judgment remains the gold standard.

1) Intermittent prophylaxis: Diazepam (Valium) intrarectally  0.1 to 0.3 mg per Kilogram every 8 hours from the onset to the end of each febrile illness. This a very safe approach. It is not certain that it is very efficient since a lot of FC in fact are the opening event of the febrile illness. Furthermore 2 thirds of FC do not recur and one never knows if the diazepam does anything at all. Although there is a reduction from 26% to 6% in recurrence.

2) Prevention of prolonged seizures or of immediate repeated seizure. Rectal diazepam given after the first FC or if the FC is still occurring when the child presents in ER, is often the most effective management of FC. This can be repeated every 8 hours for the first 24 or 48 hours or until the fever has subsided. It is a safe and effective management.

3) Continuous daily prophylaxis with AED's. Phenobarbital or Valproate are the only two AED's proven to prevent febrile seizures. Note that Phenytoin (Dilantin) and Carbamazepine (Tegretol) do not prevent febrile seizures. The balance of risk vs. benefit does not seem to favour continuous prophylaxis. PHB has immediate side effects such as hyperactivity, and long term side effects such as loss of IQ points, that makes this drug difficult to prescribe. It remains however the drug of choice in younger children on whom prophylaxis has been decided. VPA is much better tolerated but it has been associated with fatal liver damage and is not recommended in younger children. After 2 or 3 years of age it is probably the drug of choice in cases selected for prophylaxis. The doses should be individualized to obtain control. (see drug dosage sheet). When daily prophylaxis has been decided it should be continued for 2 years free of seizures.

 

     CONCLUSION

 

FC are the single most common neurological problem in children.

FC are brief bilateral tonico clonic or clonic, between 6 months and 6 years, associated with fever.

FC children have a genetic predisposition.

Long term outcome of FC is favourable in more than 95%. Epilepsy rate varies from 2 to 5%. Long lasting brain damage may occur very rarely but more if the FC was not "simple".

Recurrences of FC occur in 35%. They may increase the risk of later epilepsy and decrease IQ.

The risk of later epilepsy is higher when:

     *previous abnormal neurological development

     *non "simple" seizure (prolonged, lateralised, repeated)

     *positive family history of epilepsy.

Prophylaxis does not prevent later epilepsy which will be treated when/if it occurs

.  

BIBLIOGRAPHY

Aicardi 1986: Febrile Seizures in Epilepsy in Children, pp 212-232. Raven Press N-Y.

Aicardi and Chevrie. 1976: Febrile Convulsions... in :Brain Dysfunction in Infantile Febrile Convulsions, edited by MAB Brazier and Coecani, pp 247-257,. Raven Press, N-Y.

Al-Eissa, 1995: Febrile Seizures, Journal Of Child Neurology 10:4 pp 315-319.

Camfield & Camfield 1993, Febrile Seizures, Contemporary Pediatrics: Nov/Dec 1993 pp 8-19.

Consensus Development Panel on Febrile Convulsions 1980: Pediatrics, 66: 1009-1012.

Doose et Al. 1983. EEG in Febrile Convulsions. Neuropaediatrics 14: 81-87.

Freeman 1992, Febrile Seizures. Pediatric Annals 21:6, pp 355-361.

Hauser 1981: in: Febrile Seizures, edited by KB Nelson pp5-17, Raven Press N-Y.

Lennox-Buchtal 1971: Febrile and Nocturnal Convulsions in monozygotic twins. Epilepsia, 12: 147-156.

Livingston 1968. Dev. Med. Child Neurol., 10:374-376.

Nelson and Ellenberg 1983 Febrile Seizures in Pediatric Epileptology, Edited by Dreyfuss, pp 173-198. J Wright, Boston.

Zhao Liu, 1995: Mesial Temporal Sclerosis, Pediatric Neurology 12:1, pp 5-14.