Febrile seizures

Definition

The most recent International League Against Epilepsy (HAE) report on classification and terminology lists febrile seizures as conditions with epileptic seizures that do not require a diagnosis of epilepsy. Febrile seizures are invari-ably associated with a rise in body temperature, which is usually at least 38°C. A previous area of contention related to seizures which were a complication of an intracranial infection, particularly bacterial meningitis. Some authors[1, 2] excluded children with meningitis and/or encephalitis from their studies, whereas others[3, 4] suggested that the actual seizure was no different. However, the Consensus Conference defined febrile seizures as 'an event in infancy or childhood, usually occurring between 3 month and 5 years of age, associated with fever but without evidence of intracranial infection or defined cause'[5] and this has ken generally accepted. Febrile seizures are considered 'simple' when they are generalized, do not recur within a defined illness, and are of less than 15 min duration. Complex, complicated or severe febrile seizures have focal features, are repeated within the same illness and/or are prolonged.

Epidemiology

Between 2 and 4 per cent of children have at least one febrile seizure before the age of 5 years. In a study of 21 544 children aged up to 6 years, 115 newly diagnosed cases were identified over a period of 20 months.[6] In the same period, district nurses, physicians and the neurophysiology laboratory identified 128 children.[7] The risk rate in the age group up to 4 years was 500/100 000 and the annual incidence rate 460/100 000. The cumulative incidence was 4.1 per cent. Factors that influence the prevalence are listed in Table below.

Table: Risk factors for Febrile seizures
Social class	Not relevant
Race	Not relevant
Child of parent(s) with febrile seizures	Increased risk (X4)
Child of parent(s) with epilepsy	Risk slightly raised (to 5 per cent)
Sibling of child with febrile seizures	Increased risk (X3.5)
Male:Female	1.72:1

Age

Febrile seizures occur most often between 6 and 36 months of age and are particularly common during the second year. A temporary age-related imbalance between the normal development of excitatory and inhibitory mechanisms of brain function seems likely. The demonstration of age-dependent spatiotemporal evolution of hyperpolarization-activated, cyclic nucleotide-gated channels in rat hippocampus[8] could lead to better understanding of the functioning of ion channels in critical periods of human brain development. Factors associated with an early age at onset are listed below. The age at each recurrence has predictive value for subsequent episodes.[9]

Factors associated with an early age at onset of febrile seizures

• Negative family history of febirile seizures
• Greater risk of complex febrile seizures, but not necessarily
• febrile status epilepticus
• Recurrence of febrile seizures
• Later non-febrile seizures
• Later cognitive problems

Genetic factors

Inheritance of febrile seizures is complex in most children. Advances in molecular genetics have clarified some of the inheritance patterns and facil itated our understanding of the place of febrile seizures within a number of epilepsies.[10] Table lists the epilepsies with proven genetic relationships to febrile seizures. In families with autosomal dominant inheritance, genes for febrile seizures have been mapped to chromosomes 19p and 5q and possibly 8q. Another locus, found on chromosome 2q, is considered to be identical to one of those for generalized epilepsy with febrile seizures plus (GEFS + ). Both this and the other gene for GEFS+ on 19q are involved in sodium channel regulation, with mutations in one of them also reported in severe myoclonic epilepsy in infancy (SMEI). Such mutations have also been found in individuals with febrile seizures and nonfebrile partial seizures.[11] A mutation has also been identified in the benzodiazepine binding domain of the GABA recep tor subunit GABRG2 in a large family with absence epilepsy and febrile seizures,[12] and in some families with GEFS + .[13]

Table: Familial factors and febrile seizures

• Epilepsies with proven genetic relationship to febrile seizures
  • Generalized epilepsy with febrile seizures plus (GEFS---)
  • Absence epilepsy and febrile seizures
  • Febrile seizures and hippocampal sclerosis
  • Febrile seizures and non-febrile partial seizures
• Patients with positive family histories for febrile seizures
  • Complex features less likely15
  • Recurrence risk of febrile seizures increased

Significant increases have been observed in the incidences of febrile seizures in mothers (p < 0.001) and fathers (p < 0.002), but not in siblings (p<0.49), although the risk to siblings was increased by 3.5 times. In the same study[6] 24 per cent of children with febrile seizures, but only 5 per cent of controls, had a parent or sibling with febrile seizures (p < 0.001). Both patients with febrile seizures and controls had a similar incidence of afebrile seizures in parents and siblings. Intrapair simi larity is much greater in monozygotic than dizygotic twins. The genetic influences on the characteristics of febrile seizures are summarized in Table.

Table: Pre- and perinatal factors that predispose to febrile seizures [2, 14, 15, 16]

• Chronic maternal ill-health, often associated with reduced fertility
• Smoking and alcohol
• Early, repeated, slight vaginal bleeding
• Toxemia
• Maternal therapeutic drug use
• Maternal seizures
• Delivery other than by the vertex
• Relative reduction of birthweight for gestation
• Neonatal sepsis
• Errors of metabolism in the neonatal period

Members of families with febrile seizures and hip pocampal sclerosis may have brief and bilateral febril seizures, [17] but preceding febrile seizures are often comple where there is heterogeneity in familial temporal lob epilepsy.[18] Interestingly, some completely seizure-free members of families with febrile seizures and subsequent hippocampal sclerosis demonstrate a unilateral small hippocampus with a blurred internal pattern.[19] Digen inheritance could be the explanation.[20]

Predisposing factors from the pre and perinatal periods

Some factors predipose children to febrile seizures, including maternal renal disease, thyrotoxic sis, mental disorders, epilepsy, hypertension and air immune disorders.[14, 15] A positive family history for seizure adds to the risk of febrile seizures if perinatal problems have occurred.[14] Birth order, durations of gestation and labor, and prolonged rupture of the membranes and fetal distress are unimportant.[2, 14, 16] Children with adverse pre-and perinatal events have increased risks of complex initial febrile seizures, and of later afebrile seizures. Neonatal seizures predispose to febrile status epilepticus.[21]

Postnatal development before the first seizures

Most children with febrile seizures are healthy and their prior neurologic development is normal. Table lists factors found more commonly than expected. Fewer than 3 per cent have seriously disabling conditions and prior mental retardation is rare. Later cognitive impair ment correlates with earlier onset of febrile seizures but it is not always easy to determine whether the development was delayed before the initial seizure if the seizure occurs at an early age. Prior neurologic abnormality predisposes to complex febrile seizures,[14, 16, 21] recurrence of febrile seizures, development of afebrile seizures, cognitive delay and later EEG abnormalities. Death, albeit extremely rare, is commoner in those with prior neurological abnormalities.

Table: Postnatal factors found more commonly prior to febrile seizures[1, 5, 7, 14, 22] Upper and lower respiratory tract infections, otitis media 'Soft' neurological signs Delay in walking Delay in talking Mental retardation Larger or smaller than usualoccip itofrontal head circumferences

Precipitating factors

The ultimate height of the fever seems more important than the rate of rise of the temperature.1 The commoner underlying illnesses associated with febrile seizures are listed below. Viral invasion of the CNS can be implied from CSF immunoglobulin estimations and confirmed by demonstration of viral DNA in CSF cell pellets.[4, 14, 23, 24] Primary human herpesvirus (HHV)-6 infection has been found in 10-20 per cent of patients with febrile seizures, of whom the majority had exanthem subitum clinically. HHV-7 may also precipitate febrile seizures. Both HHV-6 and HHV-7 can invade the CNS[24] and it has been postulated that reactivated latent infections may be the cause of further seizures. Following vaccination, a signifi cantly increased risk of seizures exists only within 24 h for diphtheria, pertussis and tetanus (DPT) vaccine, and only from 8-14 days later for measles, mumps and rubella (MMR):[25] the numbers of febrile seizures attributable to DPT are 6-9 per 100 000 children and to MMR 25-34 per 100,000 children.

Table:illnesses associated with febrile seizures

• Commonest clinical diagnosis
• Upper respiratory tract infection
• Less common clinical diagnoses
• Otitis media
• Bronchopneumonia
• Pertussis
• Gastroenteritis
• Pyuria
• Measles
• Exanthem subitum
• Scarlet fever

Table: Factors associated with complex initial febrile seizure[14, 17, 21, 22, 26, 27]

• Young age
• Negative family history
• Adverse perinatal events
• Neonatal seizures
• Prior neurologic dysfunction
• Abnormal neurologic development
• Infection with malaria or HHV-6
• Short duration of fever prior to seizure
• Relatively low fever

The initial seizures

A complex febrile seizure is either focal, repeated within the same illness or prolonged.[28] The criteria of the National Collaborative Perinatal Project (NCPP)[1] considered a seizure lasting more than 15 min as prolonged. Table lists factors associated with complex febrile seizures. Careful characterization of the initial seizure is important because complex febrile seizures are associated with a poorer prognosis than simple febrile seizures. Although approximately 30 per cent of febrile seizures are considered to be focal, a higher incidence is found when focal features are specifically sought. In a study of 100 febrile seizures, inter-rater agreement on classification was only fair to good on focality.[29] Difficulties related to lateral eye deviation, staring episodes and motor asymmetries in bilateral seizures. All observers agreed that 60 of 100 seizures were completely generalized. Subsequent partial epilepsy and neurologic and cognitive problems occur in at least one third of children who have complex febrile seizures.

Acute neurologic problems

Prolonged disturbance of consciousness occurs in 31 per cent of children and can be secondary to the underlying infection, related to the pyrexia or a consequence of a prolonged seizure. Where careful examination is conducted and minor asymmetries are included, about one third of children show neurologic abnormalities when examined following a febrile seizure, usually asymmetric pyramidal tract signs. Cerebellar ataxia and upper motor neuron facial palsies may also occur. Acute, transient hemi paresis following a prolonged, lateralized febrile seizure is associated with a significantly higher risk of subsequent complex partial seizures.

Investigation at presentation

Investigation aims to identify the underlying illness and highlight features that might lower the seizure threshold. In children under 3 years of age with fever more than 39°C and no obvious cause, a complete blood count, blood culture and urinalysis should be performed unless the child looks well and can be monitored carefully. Routine blood studies are not helpful.

It has been suggested that signs other than seizures are always present in bacterial meningitis,[30] but there are difficulties with establishing absolute clinical criteria in younger children. Lumbar puncture is considered essential when there is meningism or when the child is less than 18 months at presentation.

Plain skull radiographs are unhelpful. A CT head scan should be performed before lumbar puncture in children with seizures associated with fever when the child has a prolonged postictal focal deficit or does not recover consciousness within several hours of the seizure.

The EEC is of no benefit in the management of children with simple febrile convulsions and is not helpful in prognosis. Paroxysmal abnormalities tend to be age-related.

Acute therapy

Prevention of prolonged seizures is paramount. Ninety per cent of febrile seizures are self-limiting but those lasting more than 5-10 min are unlikely to stop spontaneously within the next few minutes. Thus, seizures lasting longer than 10 min should be treated in a similar fashion to status epilepticus. Intramuscular phenobarbi tal followed by oral phenobarbital and rectal diazepam have been used in the prevention of repeated attacks during the same illness.[31] Treatment of the fever and the underlying illness are also important. Antipyretic medication, preferably with paracetamol, is better than physical cooling. Underlying infections should be treated appropriately.

Pathologic and pathophysiologic features

Table 8.8 lists the biochemical abnormalities observed in the CSF of patients following a febrile seizure. Similar CSF histamine levels are observed in afebrile, noncon vulsing children, children with afebrile seizures and those with febrile seizures. This is consistent with the hypothe sis that the central histaminergic neuron system may be involved in inhibition of seizures associated with febrile illnesses. Children in whom the CSF histamine does not rise when they become febrile may be more susceptible to febrile seizures.[32]

A well-recognized association exists between prolonged or lateralized febrile seizures and later mesial temporal sclerosis.[33] Diffusion-weighted MRI within 2 days of a prolonged febrile seizure has demonstrated unilateral acute edema of the head, body and tail of the hippocampus.[34] MRI demonstrated changes consistent with acute unilateral hippocampal edema in 4 of 13 children with complex febrile convulsions within several days of the seizure.[35] Those with hippocampal edema had prolonged lateralized convulsions. Hippocampal atrophy has been demonstrated within 2 months in patients with hippocampal edema following a prolonged febrile seizure.[34] Reduced N-acetyl aspartate levels in the hippocampus within 2 days of a febrile seizure also suggest the occurrence of irreversible damage to the hippocampus following a febrile seizure.[34] Complex febrile seizures can occur in association with pre-existing temporal lobe anomalies[35, 36] and extratemporal heterotopias[37, 38] MRI confirms loss of mesial temporal structures when seizures of temporal lobe origin occur following febrile seizures.

Recurrence of febrile seizures and role of prophylaxis

The overall recurrence risk of a recurrent febrile convulsion is approximately 30-40 per cent.[7, 9, 14, 39, 40, 41] Table below describes factors known to influence the recurrence risk. The risk of recurrence increases with the number of factors present.[42] Having a first-degree relative with a history of a febrile seizure increases the risk of a recurrent febrile seizure from 27 to 52 per cent.[41] A multivariate analysis has found children at most risk (48 per cent risk) had a temperature of less than 40°C, a positive family history of febrile seizures, or multiple seizures at the time of the first febrile seizure, whereas those at least risk (15 per cent) had a fever of more than 40°C, a negative family history or a simple initial febrile seizure.[9] In a meta analysis of the predictors of recurrent febrile seizures, age at onset less than or equal to 1 year and a family history of febrile seizures were the most useful predictors and were each associated with a 50 per cent risk of recurrence.[39] Following initial complex febrile seizures, the risk that any further episodes will be complex rises to 40 per cent as the number of recurrences increases.[28]

Table: Factors known to influence risk of recurrent febrile seizures

• Increased risk
  • Age less than 1 year
  • Family history of febrile seizure in firstdegree relative
  • Low social class
  • Persistent neurologic aibnormality
  • Complex febrile seizure initially
• decreased risk
  • Fever of >40°C
  • Ho relevance
  • EEG findings
  • Proven viral infection

    

Drug therapy may aim to prevent recurrent febrile seizures or to ensure that they are not prolonged. There is no evidence that drugs used to prevent recurrent febrile seizures reduce the risk of later epilepsy. A meta-analysis of preventive treatment demonstrated that both continuous oral phenobarbital and valproic acid are effective in preventing recurrent febrile seizures but that their potential side-effects limited their use.[43] Intermittent use of rectal or oral diazepam, rectal or oral clonazepam and oral clobazam at times of fever have all been described, although failure to recognize pyrexia before the seizure and the sedation associated with these drugs are potential complications of intermittent therapy. Patients in whom the initial febrile seizure was prolonged are at greater risk of prolonged febrile seizures if there is a recurrence. The preferred management in these children is to treat with rectal diazepam at the onset of the seizure. Intranasal or buccal midazolam may replace this regime in the future. The child should be placed in the recovery position, and excessive heating and cooling avoided.

Development of afebrile seizures and epilepsy

The risk of subsequent afebrile seizures is significantly increased. Between 2-3 per cent of children with febrile seizures have an afebrile seizure by 7 years of age[1] and 7 per cent do so by 25 years of age.[44] However, afebrile seizures may present between 1 month and 28 years after the initial febrile seizure. The most common afebrile seizure types are generalized tonic-clonic, absence and partial seizures with automatisms and other motor symp tomatology.[14, 22, 45] Complex partial seizures occurring in patients with mesial temporal lobe sclerosis are the most classical seizure type following febrile convulsions. Hippocampal malformations[19] have been demonstrated in patients with familial febrile convulsions and temporal lobe epilepsy.[20] A mutation in the GABAA receptor has been demonstrated in a large family in which affected individuals had childhood absence epilepsy and febrile seizures.[12] In GEFS + , the seizure phenotype can be very variable[46] and may even include SMEI.[27]

Long term neurologic outlook

The neurologic status following a febrile seizure is influenced mainly by the neurologic development prior to the attack. New neurologic deficits are uncommon even following febrile status epilepticus. Most patients with neurologic impairment following a prolonged febrile seizure have a pre-existing neurologic deficit.[47]

Long-term EEG changes

Generalized paroxysmal EEG abnormalities may be observed later in childhood in children with febrile seizures. Some 20-50 per cent patients who have serial EEGs starting at least 2 years after the initial febrile seizure demonstrate spikes or spike-waves.[14] Eight to ten years after single febrile seizures, 60 per cent had paroxysmal theta activity, asymmetries or intermittent focal slow waves although only 5 per cent had spikes or spike-wave on their EEGs. Those with prolonged, lateralized febrile seizures were more likely to show early asymmetries or focal slow waves, with or without spikes, which persisted and evolved into frank epileptic foci in some patients.

In a separate study of children with febrile convulsions followed up to the age of 11-13 years with on average 12 EEG records per individual, a genetically determined EEG pattern was observed in 81 per cent of patients:[48] Theta rhythms were observed in 54 per cent, spikes and waves in 49 per cent and photosensitivity in 42 per cent. The occurrence of these abnormalities peaked at 5-6 years of age. Centrotemporal spikes are much more frequent than expected, but do not necessarily imply clinical epilepsy.[49]

Cognitive abilities

Cognitive abilities of children with febrile seizures are generally comparable to those of unaffected children. Hospital-based studies have demonstrated poor speech and language abilities, problems with short-term memory and difficulties with copying shapes and/or drawing pictures of people. Hospital-based studies have also demonstrated that 12-19 per cent have specific difficulties with reading accuracy and/or comprehension when tested 8-10 years later and that attention deficits are significantly increased. Poor cognitive abilities correlated with low social class, repeated febrile seizures, continuing neurologic handicap and later nonfebrile seizures. However, population-based studies have demonstrated that children with simple, complex or recurrent febrile seizures did not differ significantly from controls at 10 years of age in measures of academic progress, intelligence and behavior.[50] Special schooling was required slightly more often for children who had febrile seizures in the first year of life.[50]

Behavioral problems

A higher incidence of behavioral difficulties has been described in hospital-based studies,20 but behavioral outcome at 10 years was similar to that of the general childhood population in a population-based study.[50]

Social aspects

Although febrile seizures have an excellent medical prognosis, they often have a profound emotional effect on the parents. They occur unexpectedly when parents are likely to be relatively young and inexperienced. Seventy-seven per cent of parents think that their child is dead or dying, and 15 per cent imagine that their child has suffocated or has meningitis.[51] Only 21 per cent position the child correctly. They may subsequently sit and watch the child at night and during fevers, and suffer from restless sleep and/or dyspepsia. These parental behaviors and symptoms do not relate to the child's sex or age, the seizure characteristics, the presence of cyanosis, previous

knowledge of febrile seizures, their thoughts during the seizure or the appropriateness of their management. Further seizures cause a significant exacerbation of the parental symptoms. It is important therefore to educate parents on the excellent prognosis, and on how to manage subsequent episodes of fever.

Key points

• Febrile seizures occur in a minority of children who have acute infections in the first 5 years of life

• Febrile seizures occur most often between 6 and 42 months of age

• Genetic factors are important, and sodium channel and GABA-receptor mutations have been identified in studies of large families

• The precipitating infection is usually viral

• Recurrences of simple febrile seizures occur in 30-50 per cent of children and are more common in those with a first degree relative who has had febrile seizures and in those with a first febrile seizure under 1 year of age

• A complex febrile seizure is one that lasts longer than 15 min, is focal, or is repeated in the same illness. Approximately 30-40 per cent of febrile seizures are complex

• A complex febrile seizure and abnormal neurologic development are risk factors for the subsequent development of epilepsy. Children with no risk factors have approximately a 2 per cent risk of developing epilepsy and those with two risk factors have approximately a 15 per cent risk of developing epilepsy

• Long-term prognosis for neurologic development, educational achievement and behavior is generally good

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Main sources for this article: [54]

54. edited by Sheila J. Wallace and Kevin Farrell. Epilepsy in children. London: Arnold, 2004. isbn:0340808144.

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