FEBRILE CONVULSIONS AND THEIR PROPHYLAXIS: CHANGING TRENDS
Matloob Azam*
Paediatric Neurologist, Associate Professor of Paediatrics, Childrens Hospital, Pakistan Institute of Medical ,Sciences, lslamabad
Abstract
Introduction
Febrile convulsions are an age related disorder characterized by generalized or occasionally partial seizures occuring during an acute febrile illness. Most febrile convulsions are brief and uncomplicated, but some may be prolonged and followed by transient or permanent neurological sequelae. Febrile convulsions tend to recur in about one third of affected patients. Controversy about the risks of developing epilepsy later has largely been resolved by some large studies. The overall risk is probably not more than 5 percent. The indications for prolonged drug prophylaxis against recurrence of febrile convulsions are now more clearly defined, and most children do not require prophylaxis. Essentially, this condition is a relatively benign disorder of early childhood. In this review risk factors for developing febrile and subsequent afebrile seizures, use of anticonvulsant as prophylaxis against recurrent febrile fits, their benefits and side effects will be discussed.
Febrile convulsions have four basic features; I) Fits with fever, 2) young age, 3) individual susceptibility and 4) favourable prognosis. In 1980 National Institute of Health (Bethesda, USA) Consensus Development Conference on Febrile Seizures' stated that "a febrile seizure (an abnormal, sudden, excessive electrical discharge of neurons [gray matter] which propagates down the neuronal processes [white matter] to affect an end organ in a clinically measurable fashion) is an event in infancy or childhood, usually occurring between 3 months and S years of age, associated with fever but without evidence of intracranial infection or defined cause. Seizures with fever in children who have suffered a previous nonfebrile seizure are excluded Febrile seizures are to be distinguished from epilepsy, which is characterized by recurrent nonfebrile seizures.
Febrile seizures are the most common type of seizures and two to five percent of children experience at least one febrile seizure before the age of five years '. About 30% to 50% children will have one or more recurrent convulsions. They occur more frequently in males than in females, and the reason is not known. Fifty percent of children with febrile seizures experience their first fit before the age of 2 years, and 90% before their third birthdays. They are rare as first event in the first G months of life and uncommon (as first event) after the age of 3 years. They are of two types, simple and complex. Most febrile seizures are brief (less than 15 minutes) and about 10% last longer than 15 minutes. Less than 10% febrile fits are focal in nature. It is now known that most of these children do very well indeed.
Risk factors
Over the years researchers have identified several risk factors for developing fits and recurrent febrile and subsequent afebrile seizures. Factors significantly associated with first febrile seizure are family history of febrile or afebrile seizures, prenatal maternal smoking premature birth. apartment dwelling. and frequent infectious diseases in preceding G months. Day care attendance has been linked with an increased risk of infectious diseases, particularly respiratory infections, diarrhoea, cytomegalovirus, and haemophilus infueniae type B13 14, Verity et all', in a National cohort study found that children with history of discharging ears, frequent sore throats, or pneumonia were more likely to have had a febrile seizure. Forsgren et al also found that children with febrile fits more often had infectious diseases than did control. These factors equally apply to children of this country where vast majority of them live in unhygienic, overcrowded environments, and therefore, more exposed and vulnerable to infectious diseases. Neonatal difficulties and delayed neonatal discharge from nursery arc associated with subsequent febrile convulsions. The risk of recurrence is higher if the first fit occurs before the age of 18 months and at lower temperature' 1`. Other factors associated with increased risk include family, history of febrile convulsions or epilepsy, complex febrile seizure as the first seizure and neurodevelopmental abnormalities' '6 ". However, Berg et al" in a large prospective trial concluded that initial complex febrile seizure and neurodevelopmental abnormalities are not associated with increased risk of recurrent febrile seizures.
There have been several studies in which children who experienced seizures with .fever were followed to ascertain as to how many of them subsequently, developed epilepsy. Risk factors include young age at the time of first fit. presence of an underlying neurological disorder, unilateral or focal origin of fit, total number of seizures and repeated episodes the same day, duration of seizure, postictal paralysis, family history and abnormal interictal EEG'°. The risk of developing epilepsy after febrile seizures is generally low. This ranged from 2.7% among children with simple febrile convulsions to G to 8°/a among children with a single complex feature, i.e. focal or prolonged seizures or repeated fits during the same illness. Annegers et al', found that children with febrile convulsions overall had a fivefold excess of unprovoked seizures, and risk until the age of 25 years was 7 percent. Current data indicate that anticonvulsant prophylaxis against febrile seizures does not alter the risk of unprovoked seizures in future.
Prophylaxis
Children who suffer a febrile seizure generally enjoy normal health after the episode. However, they are at some risk in several respects. Thirty to 40% of children who have one febrile fit and do not receive prophylaxis will experience a second fit'. The seizure itself is frightening and frequently emotionally disturbing to the parents. During the convulsion, there is a minimal chance of physical injury. Therefore it is desirable to prevent recurrent febrile convulsions and prophylaxis has been used for several years. Four types of prophylactic treatment options are available: 1) antipyretics to lower the temperature, 2) continuous prophylaxis by administering daily anticonvulsant drugs, 3) intermittent prophylaxis given at the time of febrile illness and, 4) prevention of prolonged seizures, by immediate administration of an anticonvulsant agent at the time of fit. Frequent febrile episodes appear to be most powerful factor for subsequent febrile fits. Therefore preventing high fever in susceptible
children to some extent may prevent new convulsive episodes. Paracetamol and acetylsalicylic acid are two equally effective antipyretic drugs and have been used extensively to lower temperature in febrile children. Continuous antipyretic prophylaxis after febrile convulsions has not been evaluated, nor it is advisable. Camfield et al studied the efficacy of intermittent prophylaxis with Paracetamol and acetylsalicylic acid given at the time of fever in reducing the recurrence of' febrile fits. Their results suggest that antipyretic treatment at the time of fever does not reduce the recurrence significantly. In a recent placebo controlled double blind trial. routine use of Paracetamol (10 mg/kg four times per day) was also not effective to prevent febrile seizures `. However it was suggested that prostaglandin inhibitors or larger doses of Paracetamol may be more effective.
Continous prophylaxis
Several anticovulsants arc used as prophylaxis against febrile convulsions: phenobarbitone and sodium valproate for continuous and diazepam for intermittent prophylaxis. There was a time when continuous phenobarbitone prophylaxis was routinely used even for a single febrile fit '' In 1980 Consensus Development Panel for Febrile Seizures' devised guidelines for decreasing the use of drug prophylaxis and identified the circumstances it is appropriate it) consider prophylactic treatment. Circumstances included were:
1. Presence of abnormal neurological development (e.g. cerebral palsy, mental retardation. microcephaly)
2. Fits longer than 15 minute, focal or followed by
transient or persistent neurological abnormalities.
3. History of nonfebrile seizures of genetic origin in a parent or sibling.
4. Occasionally, one can use continuous prophylaxis when patient has multiple febrile seizures or his/her age is under one year. Prevention of epilepsy is not an indication for continuous prophylaxis of febrile fits.
However, recent epidemiological data from several cohort studies document a normal long term outcome for most children with febrile fits' Therefore, some Paediatric neurologists argue strongly against longTerm therapy even for complex
or recurrent febrile convulsions. There is no justification for treating a child after a single febrile seizure, even if neurodevelopmental problems are present. Therefore continuous prophylaxis for years with antiepileptic drugs has been abandoned'°. Nevertheless, treatment with phenobarbitone is still popular in United States, being prescribed nationwide by one third of child neurologists, paediatricians and general practitioners". In a survey of members of Child Neurology of North America, long term phenobarbitone prophylaxis was used by 89% of respondents for the prevention of complex febrile seizures and by 43% for simple febrile seizures32. Parental anxiety was a major factor in the prescription of prophylaxis. As a personal practice, author also considers continuous prophylaxis if adequate health care facilities are not easily accessible to the family near their residence.
Phenobarbitone has long serum half life, therefore, single daily dose provides adequate seizure control and reliable scrum level though, many paediatricians continue to use two or more daily doses. When prophylaxis is instituted, it is usually continued for at least two years or one year after the last seizure, whichever is the longer period. Therapy should be discontinued slowly over a period of one to two months.
However, merits of continuous prophylaxis should be assessed on the basis of benefits vs side effects. The side effects of phenobarbitone are many. Behaviour disorders with hyperactivity, irritability and sleep disturbances occur in about 40% of the treated children. Phenobarbitone may affect the higher cortical function on a long tern basis. Availability of phenobarbitone in the house may be responsible for accidental ingestion of drug by the child or other siblings. Moreover, abrupt discontinuation of phenobarbitone may provoke a seizure. The available alternatives to phenobarbitone for the treatment of febrile seizures are few and sodium valproate is one33 Sodium valproate is a highly effective, first line antiepileptic agent, which is especially useful in the treatment of primary generalized epilepsy. It is well tolerated with few side effects. The main serious effect is rare but fatal hepatotoxicity, seen most often in young (less than 3 years) retarded children who are taking several drugs concurrently". During recent years, incidence of such fatalities has decreased
significantly, probably because of increased awareness of this side effect. Haematological side effects include anemia, thrombocytopenia, neutropenia and pure red cell aplasia.
Intermittent prophylaxis
It is now widely recognized that continuous prophylaxis with anticonvulsants is rarely justified. There is growing evidence of adverse effects of phenobarbitone and risk of fatal hepatotoxicity with sodium valproate. Therefore intermittent prophylaxis has been evaluated. Intermittent prophylaxis consists of given medication only at the time of illness and fever. Diazepam as intermittent prophylaxis has been used extensively with variable results. Knudsen and co workers'5 were the first to use this drug as prophylaxis. Diazepam can be used in the form of rectal solution, suppositories or orally. Many studies have shown that rectal diazepam solution (Stesolid) is rapidly and completely absorbed '6 ". Bioavailability is close to 100%, however for suppositories it is slightly lower. Rectal diazepam in solution has been effectively used". The most commonly used dose schedule for intermittent diazepam prophylaxis is 0.5 mg/kg 12 hourly. Others have used diazepam suppositories at the time of fever and with satisfactory results'". Recommended dosage regimen is 0.5 mg/kg as soon as fever is recognized and can be repeated after 8 hours if fever is more than 38.5 C. Oral diazepam prophylaxis is also being prescribed to prevent febrile seizures. In a prospective controlled trial, short tern diazepam prophylaxis effectively reduced the recurrent seizures to one third'°. It is given 0.5 mg/kg 12 hourly for two to three days and first dose is administered whenever child develops fever (> 38.5 C) at the beginning of the illness.
Knudsen et al in a recent cohort study compared intermittent diazepam prophylaxis (diazepam at the fever time) with diazepam given at the time of seizures only (no prophylaxis). The diazepam prophylaxis effectively reduced the recurrence of febrile seizures in early childhood. However, they concluded that long-term prognosis in terms of occurrence of epilepsy. neurological, motor, intellectual and cognitive functions were not different in both groups. At present diazepam rectal solution (Stesolid) and suppositories are not available in Pakistan. Diazepam (Valium. Reche) intravenous solution has been used rectally to treat epileptic children successfully. This mode oftreatment in some children with recurrent febrile
convulsions and status epilepticus have been used with
encouraging results (Personal observations). Procedure
is simple and without any harmful effects. Diazepam
solution (Valium injection, 10 mg/2 ml) is pushed into
the rectum through a soft polythene catheter (Feeding
tubes No.8 10). Few cms of tube are lubricated with
liquid paraffin or commonly used oils and depending
upon the age, 8 to 10 cm of catheter is gently pushed
into rectum. Once the desired dose of valium solution
has been administrated, tube should be flushed with 2
3 ml of saline or air. Dosage schedule is same as used
for rectal solution. Information sheet for Valium
injection (Ruche) dose not mention rectal use. Concern
has been expressed that diazepam may induce severe
respiratory depression or arrest. It is widely recognized
that benzodiazepines are extremely safe drugs. Case
reports of deaths following benzodiazepines ingestion
are exceedingly rare, even after massive overdoses.
It has been argued that intermittent prophylaxis often
fails because parents are unable to recognize the
child's fever before the seizure occurs. This may be
true in communities with low maternal literacy rates
such as Pakistan. Some mothers of children with
febrile convulsions fail to appreciate fever and they
only recognize the fever after child already had fit/s
(personnel observations). In educated societies, 86% to
90% mothers correctly identified that their child was
unwell and febrile without the use of thennometer4'.
Phenobarbitone has been used most widely as
continuous prophylaxis against febrile convulsions, yet
phenobarbitone at the time of fever provides no seizure
control at all. The pharmacokinetic properties of the
drug rule out any oral anticonvulsant effect when
given intermittently in the usually recommended
doses44. Phenytoin and carbmazepine are not effective
as long or short term prophylaxis.
Parental education is of utmost importance. Every
child's parents especially mother who suffers from
febrile seizures, should be explained in simple
language about the nature of febrile seizures, the
recognition and management of fever, what to do
when child has actual fit, when to seek emergency
treatment, use of medication and its complication
Conclusion
The long term prognosis is excellent, so in
majority of children continuous anticonvulsant prophylaxis
is not required. However, febrile convulsions have high recurrence rate, disrupt the family life and may have emotional consequences for the family. Therefore no treatment at all for every child with febrile fits may not be appropriate either.
Thus several therapeutic strategies are available to deal with febrile seizures, and they include:
1) No anticonvulsant therapy, only control of fever and parents education;
2) No prophylaxis, but rectal diazepam in solution at
the time of fit;
3) Intermittent diazepam prophylaxis with rectal
diazepam in solution. by suppository or orally
given only at the time of fever or first sign of
illness;
4) Combination of 2 and 3 and
5) Continuous prophylaxis with phenobarbitone or
sodium valproate.
References
1. Consensus Development Conference on Febrile .Seizures. Febrile Seizures: long term management of children with fever associated seizures. Pediatrics 1910; 66: 1009 !?.
2. Nelson KB, Ellenberg JH. Predictors of epilepsy in children who have experienced, febrile .ceizures. N EngI J med 1976; 295: 1029 33.
3. Verity CM, Butler All?, Golding J. Febrile convulsions in a national cohort, followed up.from birth. 1. Prevalence and recurrence in first, five• years of life. BMJ I985; 290: 130710.
4. Forsgren G, Sidenvall R, Blomquist HK, Heijbel J. A prospective incidence of_febrile convulsions. Acta Paediatr 1990; 79: 5.50 57.
5. Nelson KB, Ellenberg JH. Prognosis in children with febrile seizures. Pediatrics 19711; 15: 720 27.
6. Knudsen FU. Febrile convulsions. In: Dam Al, Gram L eds. Comprehensive epileptology. New York: Raven Press, 1991: 133 44.
8. Annegers JF, Houser WA, .Shirts SB, Kurland LT
Factors prognostic of unprovoked seizures after
febrile convulsions. N Engl J Med 1987; 316:
493 9N.
9. Nelson KB. Ellenberg JH. Prenatal and perinatal antecedents of febrile seizures. Ann Neurol 1990; 27: l 27 31.
10. Forsgren L, Sidenvall R, Blomquist H et al. An incident case referent study of febrile convulsions in children: genetically and social aspects. Neuropediatrics 1990; 21: 153 59.
I 1. Cassano P, Koepsell T, Farwell J. Risk of febrile
seizures in childhood in relation to prenatal
maternal cigarette smoking and alcohol intake.
Am J Epidemiol 1990; 132: 462 73.
12. Forsgren L, Sidenvall R, Blomquist H et al. Pre
and perinatal factors in febrile convulsions. Acta
Paediatr .Sand 1991; 80: 218 25.
13. Hurwitz EE, gunn W, Pinsky P .Schonberger L.Risk of respiratory illness associated with day care attendance: a nationwide study. Pediatric 1991; 87: 62 69.
14. Fleming D, Sochi .S; Hightower A, Broome C.'.
Childhood upper respiratory tract infections: to
whet degree is incidence affected by day care
attendance? Pediatrics 1987; 79: 55 60.
15. El Radhi, Banajeh .S: Effect of fever on
recurrence rate of febrile convulsions. Arch Dis
Child 1989; 64: 869 70.
16. Annegers JF, Blakely .Si1, Hauser WA, Kurland
LT Recurence of febrile convulsions in a
population based cohort. Epilepsy Res 1990;5:
209 16.
17. Offringa M, Derksen Lubsen G, Bossuyt PM. 29.
Lubsen J. Seizure recurrence after a fast febrile
seizure: a multivariate approach. Dev Med Child
Neurol 1992; 34: 15 24.
18. Berg AT, .Shinnar .S; Hauser A e t al. A prospective study of recurrent febrile seizures. N Engl J ;1Ie d 1992: 317: 1122 27.
19. Annegers JF, Hauser WA, EIveback LR, Kurland LT The risk of epilepsy ,Following febrile convulsions. Neurology 1979; 29: 297 303.
20. Knudsen FU. Intermittent diazepam prophylaxis in febrile convulsions. ,Acta Neurol .Scand 1991; 83(Suppl):1 24.
21. Tsuboi T, Endo .S; Iida N. Long term opllow up of a febrile convulsions cohort. Acta Neurol .Scand 199/; 84: 369 73.
22. Wilson JT Antipyretic. management of febrile
seizures. In: Nelson KB, EIlenberg JH. Ed Febrile .Seizures. New York: Raven Press, 1981: 23/ 39.
23. Fowler PR. Aspirin, Parawtamol and non-steroidal anti inflammatory drugs. A comparative review of Side effects. Algid toxicol 1987; 2: 338-66.
24. Camfield PR, Camfield CS, Shapiro SH.
Cummings C. The first, febrile .seizure antipyretic
instruction plus either phenobarbital or placebo
to prevent recurrence. J Pediatr 1980; 97:16 21.
25. Uhair M, Rantala H, Vainlonpaa L. Kurttila R . Effect of acetaminophen and of low, intermittent doses of diazepam on prevention of recurrences of' febrile .seizures. J Pediatr 1995; 126: 99I 95.
26. Pollack MA. Continuous phenobarbital treatment after a simple febrile convulsion. Am J Dis Child 1978; 132: 87 89.
27. Verity CM, Golding J. Risk of epilepcy aver
febrile convulsions: a notional cohort .study. RAM
1991; 303: 1373 76.
28. Freeman JAI Just say no! Drugs and febrile seizures, Pediatrics 1990; 86:624.
29. Shinnar S: Febrile seizures. In: Jhonson RT ed Current therapy in neurologic disease. 3rd rd Philadelphia: B.C. Decker 1990: 29 32. 30. Knudsen FU. Optimum management of febrile seizures in childhood. Drugs 1988; 36: 111 20.
31. Hirts DG, Lee YJ, Ellenberg JH, Nelson KB.
,Survey on the management of febrile seizures. Am
J Dis Child 1986; 140: 909 14.
32. Millichap JG, Colliver JA. Management of
Febrile .Seizures ,Survey of current Practice and
Phenobarbital Usage. Pediatr Neurol 1991; 7:
243 48.
33. Lee K, Melchior JC. Sodium valproate versus
phenobarhitone in the prophylactic treatment of
febrile convulsions in childhood Eur J Pediatr
1981; 13 7: 151 53.
34. Dreifuss FE, Santilli N, Langer DH et al. Valproic and hepatic fatalities: a retrospective review Neurology 1987; 37: 379 85.
35. Knudsen FU, Vestermark ,S'. Prophylactic
diazepam or phenobarbitone in febrile
convulsions: a prospective controlled .study. Arch
Dis Child 1978; 53: 660 63.
36. Knudsen FU. Plasma diazepam in infants after
recta! administration in solution and by
suppository. Acta Paediatr ,Scand 1977; 66: .563 44.67.
37. Dulac 0, Aicardi J Rey E Olive G. Blood levels
of diazepam after single rectal administration in
infants and children. J Pediatr 1978; 93: 1039
41.
38. Autret E, Billard C, Bertrand f' et al. Double blind, randomized trial of diazepam versus placebo for prevention of recurrence of febrile .seizures. J Pediatr 1990; 117: 490-94.
39. Shirai H, Miura H, Sunaoshi HA. A clinical .study on the effectiveness of intermittent therapy with rectal diazepam suppositories for the prevenlnmu of recurrent febrile convulsions. .1 .further study. J Jpn Epil Soc 1988; 6:1 10.
40. Knudsen FU. Effective .short term diazepam
prophylaxis in febrile convuLsions. J Pesiatr
1985; 106: 487 90.
41. Knudsen FU, Paerregaard A, Andersen R.
Anderson J. Long term outcome of prophylaxis for
febrile convulsions. Arch dis Child 1996; 74: 13-18.
42. Dhillon S, Ngwane h; Richens A. Rectal
absorption of diazepam in epileptic children.
Arch Dis Child 1982; _S7: 26 t 67.
43. Banco L, Veltri D. Ability of mothers I
.subjectively assess the presence of, fever in their
children. Am J Dis ('hilt/ 1984; 1.•8: 976 78.
44. Jelling I3. Plasma and cerebrospinal fluid concentrations of phenobarbital in infants given .single doses. Dev Med Child Neurol 1974;16: 78I 93.
