- Email: [email protected]
The Child Who Convulses with Fever
Symposium on Recent Clinical Advances
The Child Who Convulses with Fever
Eileen M. Ouellette, M.D.*
It has been well known since ancient times that seizures frequently accompany fever in young children. Hippocrates noted that "convulsions occur to children if acute fever be present ... most readily up to their seventh year. Older children and adults are not equally liable to be seized with convulsions in fevers, unless some of the strongest and worst symptoms precede". 26 At the present time, febrile convulsions remain one of the most common pediatric problems. It is estimated that one-half million children in the United States have had such seizures, which comprises 3 per cent of the population under the age of 5 years and accounts for half of all seizures in this age group. 7. 36, 48, 49, 6t, 68, 69 Despite their ubiquity, febrile convulsions remain one of the most controversial topics in pediatrics with disagreement about definition, prognosis, and advisability of continued anticonvulsant therapy. An enormous amount of data has been published on this subject. In spite of this, meaningful comparisons of studies are virtually impossible to make. Patient selection is variable. Previously neurologically abnormal children are grouped with apparently normal children and the quality, duration, and frequency of their seizures are not differentiated. Several recent studies have provided additional information on some of these points which may be helpful to the pediatrician faced with a patient who has had a convulsion with fever. This information may help him or her to make an intelligent decision on how to proceed and what to tell the family.
DEFINITION Two distinct definitions are currently advocated with regard to a seizure which occurs with fever in a young child between the ages of 6 months and 6 years. Seizures which occur with fever whose source derives from illness within the central nervous system are excluded from the category of febrile convulsions. 1. The first definition is that a febrile convulsion is an epileptic event occurring in the context of a febrile illness, regardless of type of seizure, *Assistant Professor of Pediatrics and Neurology, Boston University School of Medicine; Associate Director of Pediatric Neurology, Boston City Hospital, Boston, Massachusetts 02118
Pediatric Clinics of North America- Vol. 21, No. 2, May 1974
467
468
EILEEN OUELLETTE
duration, or previous state of the patient with regard to central nervous system abnormalities. 11-14, a6, 42, 48, 5t-5a, 66 2. The second is that all such seizures are not alike, either etiologically or with regard to prognosis, but fall into two categories. 6 • 20 • 37• 38 Simple febrile convulsions occur in previously normal children, are brief, are generalized, and have a benign prognosis. Seizures with fever are prolonged and/or focal or occur in previously abnormal children. These are considered to be epileptic seizures precipitated by fever, and to carry a graver prognosis. In this article, febrile convulsion will refer to any seizure with fever, simple febrile convulsions to those which are brief and generalized, and seizures with fever to those which are focal and/or prolonged.
CHARACTERISTICS OF FEBRILE CONVULSIONS Type of Seizure. The vast majority of febrile convulsions are generalized. About 80 to 85 per cent are clonic, 14 per cent tonic, and 6 per cent atonic. Approximately 15 per cent are focal. 17• 48 • 67 Age. Almost all first febrile convulsions occur between the ages of 6 months and 6 years, and are infrequent after the age of 3 years. 19 • 30 • 36-38 , 48 • 68 One to 2 per cent occur below 6 months and 1 to 6 per cent after 5 years. 35 • 49 The vast majority of first febrile convulsions occur during the first 3 years. 20 • 32 • 35 • 44 • 67 For males the decline in incidence with age is smooth over the first 4 years, but in females the decline is sharp and sudden, occurring inainly during the second year. 65 • 66 The strong relationship between age and incidence of febrile convulsions is of great interest but is imperfectly understood. The relative lack of myelinization in the immature brain, its changing chemical composition, differences in water and electrolyte balance, increased oxygen consumption, diininished dendritic connections, and electrophysiologic differences from the adult brain have all been implicated as possible reasons for the remarkable correlation betwen febrile convulsions and a restricted age group. 27 • 36• 47 • 48 • 55 It has been postulated that more rapid cerebral maturation in girls accounts for the rapid rate of decline of febrile convulsions after the second year. 65 • 66 Sex. In almost all series, febrile convulsions and simple febrile convulsions have occurred more frequently in males, with a male to female ratio ranging from 1.1 to 1 to 4 to 1.32 • 48 • 54• 67 It has been postulated that the excess of males was due to an overrepresentation in males from exclusively male sibships. There is no satisfactory explanation of this overrepresentati9n among patients with febrile convulsions. 36 Although females appear to have a lower incidence of febrile convulsions, they appear to have a higher incidence of seizures with fever and an increased risk of sequelae. 32 • 36• 66 Duration of Seizure. Most febrile convulsions are brief. About 40 per cent last less than 5 minutes, 75 per cent are over by 20 minutes, and only 2 per cent last more than 1 hour. 48 Livingston has included only those seizures whose duration was less than "a few minutes" in his definition of simple convulsions. He considers the prolonged febrile convulsion to be representative of an underlying seizure disorder. 37• 38
THE CHILD WHO CONVULSES WITH FEVER
469
Role of Fever. By definition, fever is always present with these seizures. The temperature is almost always high, over 102°F. rectally,38• 67 and the risk of febrile convulsions increases with increasing temperature. 20 • 30 The duration of the fever prior to the convulsion ranges from minutes to 2 days. 54 LiVingston found simple febrile convulsions to begin from 2 to 6 hours after the onset of fever and has never seen one beginning later than 24 hours. 38 The influence of the rapidity of rise of the temperature still remains the subject of some debate. Wegman 72 induced seizures in young kittens by a rapid rise in body temperature 4 or 5°F. above normal through exposure to external heat and postulated that rate of rise was the most important factor. In similar experiments, both the height of fever and rapidity of rise were considered equally important by some,34 while others believed the height of the fever alone was significant. 46 Clinically, a "slow rate of temperature elevation" has been observed in 65 per cent of 100 patients with febrile convulsions. 36 Electroencephalogram. It is well known that fever or convulsions alone will result in slowing of the electroencephalogram. 33 • 36- 38 With febrile convulsions marked slowing is usually noted, especially posteriorly, and is often focal. 18 In a recent study, 88 per cent of patients with febrile convulsions had abnormal electroencephalograms on the day following the seizure, and 33 per cent were still abnormal 3 and 7 days after the seizure, a duration longer than is generally seen after fever or seizure alone. 18 Only 1.4 per cent of patients with febrile convulsions had paroxysmal electroencephalograms acutely, but 20 per cent subsequently developed this pattern. 18 Among those factors correlating with extreme and focal slowing were duration and height of fever, past history of brain injury, and duration or focality of the seizure. 36 Livingston found the slowing on the electroencephalogram to be reversible in cases of simple febrile convulsions by 10 days following the seizure, but found persistent slowing in cases of seizures with fever. 37 • 38
FACTORS AFFECTING OCCURRENCE OF FEBRILE CONVULSIONS Associated Illness The majority of febrile convulsions occur with intercurrent viral illness, primarily tonsillitis, pharyngitis, and otitis. 48 • 71 Some other illnesses have been associated with a particularly high incidence of febrile convulsions. From 4.8 to 45 per cent of patients with Shigella gastroenteritis have had associated febrile seizures8 • 15 • 30 as compared to gastroenteritis from other causes where the incidence of febrile convulsions is about 1 per cent. 15 • 48 Roseola infantum has also been associated with a high frequency of febrile convulsions. 36 Of interest is the low incidence of febrile convulsions with the common cold. 36 A possible explanation for this is the generally low tempera-
470
EILEEN OUELLETTE
ture associated with these illnesses compared to other more systemic infections. Pyuria has also .seldom been stressed as being associated with febrile convulsions. Kastrup, however, noted that in 50 patients with fever and pyuria under 5 years of age there was a 15 per cent incidence of febrile convulsions. 29 He concluded that pyuria was as likely to be associated with febrile convulsions as other infections but that its low association was due to the great preponderance of other infections in the susceptible age group.
Antecedent Brain Injury The presence or absence of antecedent central nervous system damage is vital in attempting to assess the implications of a febrile convulsion in a child. Livingston has defined a simple febrile convulsion as occurring only in normal children. 37· 38 Seizures in children with known central nervous system abnormalities have thus been termed seizures with fever. Others, however, have included all children, including those with previous afebrile seizures, birth injury, and other central nervous system abnormalities in the group with febrile convulsions and have made no distinction between these and previously normal children when discussing seizure types or prognosisP· 2o, 25, 36, 48, 68, 69, n In some series the incidence of patients with central nervous system abnormalities has been low,20 · 25 · 36 but in others 15 to 23 per cent of children have had an obvious neurologic abnormality prior to the time of the first febrile convulsion 17· 48 · 70 and one reported 7.3 per cent with "severe congenital anomalies." 68 Perinatal difficulties, when mentioned, have been present in from 3 to 61 per cent of patients with febrile convulsions.48 Unfortunately, qualitative descriptions of the seizures in these two groups have not been given and it is not possible to determine whether their seizures differed in any way from those of normal children. The wide variation in percentage of abnormal children in these series has made other comparisons also impossible. Role of Inheritance A high incidence of febrile seizures has been found in families of patients with febrile convulsions. Although some have postulated an autosomal recessive inheritance, more recent studies have suggested a simple autosomal dominant inheritance with incomplete penetrance.t9, a6. sa One study noted a positive history of seizures in 13 per cent offamilies of children with febrile convulsions, versus 1 per cent in families of children with similar illnesses and fever who did not convulse. 30 Another recent study of 208 children with febrile convulsions disclosed a 50 per cent incidence of seizures in their relatives. 19 The relatives of 40 per cent of these patients had febrile convulsions while there were recurrent afebrile convulsions in the families of 20 per cent. In 10 per cent of families both were seen. Among the relatives with febrile convulsions, 95 per cent were first degree relatives, while 50 per cent of the relatives with recurrent afebrile convulsions were distant. The incidence of epilepsy in near relatives of these 208 children was not above the prevalence in the population at large, while the incidence of febrile seizures in parents and
THE CHILD WHO CONVULSES WITH FEVER
471
siblings was 9 per cent, three times the prevalence in the population at large. This is consistent with an autosomal dominant inheritance and with previously reported data. 35 A high association of mental retardation in siblings of patients with febrile convul!tions has been reported, 61 but this has not been substantiated by subsequent series. 19· 36 Twin studies have been carried out to investigate further the role of genetic influence, but results at present are conflicting. One study reported that although dizygotic twins did not differ from non-twin siblings, there was an 80 per cent concordance for febrile convulsions in monozygotic tWins and 100 per cent concordance for recurrent afebrile convulsions. 36 Another recent series showed no difference between dizygotic and monozygotic twins. 59· 60 Attempts have been made to utilize genetic information to substantiate or negate the validity of the division of febrile convulsions into the two groups, simple febrile convulsions and seizures with fever. Livingston reported a 58 per cent incidence of simple febrile convulsions in families of 201 patients with simple febrile convulsions, versus 3 per cent in families of 355 children with seizures with fever. The incidence of recurrent afebrile convulsions in these two groups of families was not reported. 38
DIFFERENTIAL DIAGNOSIS OF FEBRILE CONVULSIONS Of maximum importance is the exclusion of acute disease affecting the central nervous system. Among these, bacterial and viral meningitis, encephalitis, acute toxic encephalopathy, 4 Reye's syndrome,57 intracranial hemorrhage, and acute hemiplegia of infancy63 are all examples of diseases in which both seizures and fever may be present at the onset. In the past, the persistence of hemiplegia has been thought to be secondary to the febrile convulsions, but in recent years, as more of these patients have been studied with angiography, a vascular etiology has been found in many.21, 63 Other, more chronic diseases of the central nervous system, such as the effects of neonatal hypoxi:l, toxoplasmosis, cytomegalic inclusion disease, chronic subdural effusions, tuberous sclerosis, vascular malformations, porencephaly, and other developmental defects of brain, may first become apparent with a febrile convulsion as well as an afebrile seizure. Other illnesses outside the central nervous system must be ruled out. Hypocalcemia resulting from rickets is rare but still occurs among the underprivileged. Hypoglycemia, renal disease, and electrolyte disturbances, especially hyponatremia, should be excluded.
EVALUATION OF A FEBRILE CONVULSION It is of vital importance to delineate the cause of any seizure as precisely as possible in order to be able to discuss its implications and
472
EILEEN OUELLETTE
prognosis with the parents. It must be stressed that witnessing a seizure is very frightening to parents and counselling them may be as important as other evaluation and treatment. A careful history with special reference to the quality and duration of the seizure, the presence of a focal component, and possible family history of seizures, both febrile and afebrile, should be taken. The physical examination should include special attention to the state of alertness of the patient, fullness of the fontanel, and funduscopic examination, abnormalities in which may indicate increased intracranial pressure. The presence of nuchal rigidity is consistent with meningitis or intracranial hemorrhage. Examination of the skin for the hypopigmented macules seen in tuberous sclerosis should be made. 16 • 22 Cranial auscultation should be done. Loud bruits suggest the presence of a vascular malformation. Transillumination of the skull56 is also important. In chronic subdural effusions, porencephaly, and other major malformations of brain this will be increased. Cerebrospinal fluid examination should be carried out on: (1) all children with a first febrile convulsion; (2) all children with a febrile convulsion under 2 years of age, regardless of the presence of signs of infection at other sites of the body. Nuchal rigidity is seldom present in this age group and meningitis may be present with few or no localizing signs; (3) on older children with recurrent febrile convulsions whenever a central nervous system infection is suspected. A careful measurement of cerebrospinal fluid pressure should be made, the number and type of cells recorded, bacterial cultures obtained, and protein and sugar determinations made. At the time of the first seizure skull films should be obtained. If intracranial calcifications are seen, the diagnosis of febrile convulsions should be suspect and the patient should be evaluated for congenital infections, tuberous sclerosis, and parathyroid abnormalities. Blood sugar, calcium, and electrolytes should be determined. Abnormalities suggest a diagnosis other than febrile convulsions. A complete blood count and urinalysis should be done. Appropriate cultures of nasopharynx, urine, and blood should be carried out when indicated. A Wood's lamp examination of the skin should be performed to exclude the presence of hypopigmented macules which may be inapparent to routine examination in fairskinned children. Tuberous sclerosis usually presents as seizures in the susceptible age group. It is of autosomal dominant inheritance and early detection is advisable if genetic counselling is to be carried out. Patients who show abnormal cerebrospinal fluid examinations, intracranial calcifications on x-ray, abnormal transillumination, or persistent hemiplegia should not be considered as having febrile convulsions and additional investigations may be warranted. These may include brain scans, subdural taps, pneumoencephalography, and angiography which are not indicated in febrile convulsions.
ACUTE TREATMENT OF FEBRILE CONVULSIONS In all cases, the cause of the fever should be determined and treated appropriately. Of primary importance is the prompt reduction of the tern-
THE CHILD WHO CONVULSES WITH FEVER
473
perature with brisk tepid water sponging and antipyretics. Aspirin or acetaminophen (Tylenol), 60 mg. per year of age by mouth, or 120 mg. per year of age by rectum, should be given every 4 hours for a temperature above 101.0°F. If a seizure is observed, the child should be placed in a semiprone position to minimize the danger of aspiration and adequate oxygenation maintained. Intravenous diazepam (Valium), 0.3 mg. per kg., may be given slowly at a rate of 1 mg. per min. until the seizure stops. Alternatively, phenobarbital, 3 to 6 mg. per kg., may be given slowly intravenously. Phenobarbital has an antipyretic as well as an anticonvulsant effect and acts by inhibiting heat production. 48 Lennox-Buchthal, however, does not recommend phenobarbital to stop seizures acutely, and states that "even when given intravenously or intramuscularly, the delay until the level has built up in the brain is so long that it has no value in an emergency." 3 • 36 After a loading dose of phenobarbital, 5 mg. per kg. intravenously or intramuscularly, has been given, oral phenobarbital in a dosage range of 3 to 6 mg. per kg. per 24 hr. may be given until the child is afebrile. Oral phenobarbital without a loading dose is useless as it takes days to weeks to achieve therapeutic blood levels by this route alone. 3 • 36 • 64
Febrile Status Epilepticus A continuous grand mal seizure lasting more than 30 minutes should be considered status epilepticus and treated accordingly as a medical emergency, regardless of the presence or absence of fever. Even today, the mortality remains at least 15 per cent, 5 much of which is attributable to overmedication with resultant respiratory arrest. Prolonged hypoxia is another danger and adequate oxygenation must be assured. Intravenous diazepam as described above is now considered the treatment of choice by many5 • 36 • 40 • 43 • 62 in status epilepticus and is equally effective in febrile status epilepticus. If the above dose is ineffective, it may be repeated cautiously in a similar amount and manner in 30 minutes. 5 Caution should be taken not to employ intravenous phenobarbital with this regimen as deaths from respiratory arrests have been reported when both drugs have been used together. 2 Severe hypotension in association with the simultaneous use of intravenous diazepam, paraldehyde, and intramuscular phenobarbital has also been reported! If diazepam is ineffective in controlling the status epilepticus, paraldehyde, 1 ml. per year of age, mixed with an equal amount of mineral oil, can be given rectally.
PROGNOSIS OF FEBRILE CONVULSIONS To a great extent, the prognosis with regard to recurrent febrile convulsions, incidence of subsequent recurrent afebrile convulsions, and risk of subsequent brain damage depends on the definition of febrile convulsions put forth and the selection of case material, especially with regard to previous neurological impairment and birth injury. As few series are entirely comparable, there is a wide variation in reported outcome.
474
EILEEN OUELLETTE
Recurrent Febrile Convulsions Few series comment on the chance of seizure recurrence during a single febrile episode, but Millichap puts the figure of recurrent febrile convulsions during one febrile episode at 1 in 3. 48 Repeated febrile convulsions and simple febrile convulsions with subsequent febrile illnesses are known to be common,l 8· 20 · 24 · 35 ~ 38 · 48 ranging from 12.320 to 54 per cent.48 Lennox, in his series of 407 patients, found 41.8 per cent with one subsequent febrile convulsion, 13.3 per cent with two, and 12 per cent with more than four. 35 The rate of recurrence clearly appears to be dependent on age at time of first seizure. A recent prospective study of 138 children found a 25 per cent recurrence rate of febrile convulsions. Of those children less than 13 months old at the time of the first febrile convulsion, the chance of recurrence was 2:1, compared to 1:5 when the first febrile convulsion occurred between 14 and 32 months. 18 Thirty per cent of these recurrences took place within 6 months of the first seizure, half within 13 months, and all within 30 months. Other factors in addition to age may also be important. Another recent study showed that girls are more likely to have a recurrent febrile convulsion. Those children with a positive family history of febrile convulsions also have a greater risk of recurrent febrile convulsions.a6 The risk of subsequent seizures with fever has recently been studied in patients with febrile convulsions. The proportion of seizures with fever increased with the number of febrile convulsions, reaching 35 per cent with the third febrile convulsion and increasing to 50 per cent by the fifth.:l 6 Seizures with fever were nearly twice as frequent in the first year of life. 33 · 36 No sex difference was noted.au Nearly all episodes of febrile status epilepticus occurred below 18 months of age' and the female to male proportion was 3:2. It must be noted, however, that the percentage of patients in these studies who were neurologically abnormal at the time of the first febrile convulsion or had abnormal birth histories was not supplied. It is unclear to what degree they were represented in these groups. It is therefore premature to apply these data to children who are apparently normal at the time of the first febrile convulsion.
Recurrent Afebrile Convulsions Differing beliefs regarding the risk of recurrent afebrile convulsions in the previously normal child with a simple febrile convulsion account for the varied recommendations for the management of such patients.4· 11 ~ 14 · 23 · 31 · 37 · 38 · 44 · 65 • 66 Depending on the series, the risk is said to vary between almost no to almost all patients. Several-important factors underlie these differences. SELECTION OF CASE MATERIAL. Groups whose series are composed of adults with seizure disorders, especially temporal lobe epilepsy, have found a very high incidence of previous febrile convulsions, almost always with seizures with fever or febrile status epilepticus.''- 14 · 42 • 65 · 66 They postulate that seizures with fever or febrile status epilepticus are associated to a large degree with hypoxia, resulting in neuronal death in
THE CHILD WHO CONVULSES WITH FEVER
475
the cerebellum, thalamus, and mesial temporal area. Mesial temporal sclerosis then resqlts. This is highly epileptogenic and temporal lobe epilepsy ensues. These groups believe all febrile convulsions are epileptic phenomena of potentially dangerous significance. Others, whose series consist of children, have emphasized that the majority of febrile convulsions in childhood have a good prognosis. Several studies report less than a 3 per cent incidence of recurrent afebrile convulsions following all febrile convulsions. 19 • 20 • 24 • Gs. 69 LENGTH OF FoLLOw-UP. Most recurrent afebrile convulsions occurred within 10 years of the first febrile convulsion and 4 7 per cent occurred within 1 year. 35 Recurrent afebrile convulsions following simple febrile convulsions generally developed before the age of 5 yearsY 7• 38 DURATION OF FEBRILE CONVULSION. Many agree with those above that seizures with fever carry a greater risk of recurrent afebrile convulsions. Livingston 37 • 38 reported that of 622 patients with febrile convulsions, 58 per cent developed recurrent afebrile convulsions. Of the 256 patients with simple febrile convulsions, only 2.9 per cent subsequently developed recurrent afebrile convulsions. Ninety-seven per cent of the 366 patients with seizures with fever went on to develop recurrent afebrile convulsions. Others who disagree with the appropriateness of dividing febrile convulsions into simple febrile convulsions and seizures with fever, considering all to be epileptic phenomena, have also found that the incidence of recurrent afebrile convulsions correlates with seizures with fever and repeated seizures. 32 • 36 • 48 The low incidence of recurrent afebrile convulsions in one series (1.4 per cent)1 9 may be due to prompt cessation of the seizures. AGE AND SEx. It appears that the risk of recurrent afebrile convulsions correlates with both age and sex. An age of onset in the first year of life was followed by recurrent afebrile convulsions in 39 per cent. 36 Girls are more likely to develop recurrent afebrile convulsions. 36 • 53 • 65 • 66 This may be related to the fact that they often have febrile convulsions at a younger age than boys. 65 • 66 It is also postulated that as more males die with febrile status epilepticus than females, there are more females left with serious sequelae. 65 • 66 ANTECEDENT BRAIN INJURY. Antecedent injury has been reported to be from 2 to 4 times as frequent in those who develop recurrent afebrile convulsions following febrile convulsions. 36 It is unclear whether the occurrence of febrile convulsions in this group in any way influences the development of recurrent afebrile convulsions. 36 The inclusion of these patients with obvious neurologic injury in most series, comprising 15 to 61 per cent of some series,1 7 • 48 • 70 is unfortunate. The failure to indicate whether their seizures constitute the majority of those in the greater risk categories has made it impossible to tell what the subsequent risk of recurrent afebrile convulsions is in previously normal children with simple febrile convulsions. The data concerning normal children are presented separately only by Livingston. 37 • 38 These children are said to have a benign prognosis. It appears inappropriate to ascribe the development of recurrent afebrile convulsions in the previously abnormal group to the febrile convulsions, as has been done by many.
476
EILEEN OUELLETTE
ELECTROENCEPHALOGRAMS. Most children With febrile convulsions and simple febrile convulsions have temporary slowing of the electroencephalogram acutely following the seizure and it is of no prognostic significance.19 The presence of moderate or severe slowing on the electroencephalogram 1 week following an initial febrile convulsion has been associated with a 50 per cent risk of recurrent afebrile convulsions and a paroxysmal electroencephalogram with a 25 per cent risk,:l:l In children with simple febrile convulsions, the electroencephalogram slowing has reverted to normal by 10 days, and persistence beyond that time has been considered to be a poorer prognostic sign.'37 • 38 A recent study also disclosed that moderate to severe slowing of the electroencephalogram within 7 days of the initial febrile convulsion in children less than 2.5 years old at least doubled the chance that the child would subsequently develop a spike focus. 19
Subsequent Intelligence and Behavior At the present time, the role of febrile convulsions or simple febrile convulsions in the production of intellectual or behavioral changes is not definitely known. Because of the inclusion of children with neurological abnormalities at the time of the first febrile convulsion in many series, it has been difficult to evaluate claims that febrile convulsions are associated with a higher subsequent incidence of mental retardation. Others have proposed that hyperactivity is more common in children who have had febrile convulsions, but no substantiating data have yet been reported. 2s, 4s Two recent reports have attempted to assess the relationship of febrile convulsions to subsequent intellectual performance and behavior. Nelson, reporting on the data obtained from the Collaborative Perinatal Project, NINDS, 50 identified all children in the group of 4 7,222 children who developed a febrile convulsion within the first year of life. 5° Those children with a simple febrile convulsion had normal IQ levels at age 4 years and these correlated with those of their sibs who had not experienced a febrile convulsion. Those with several febrile convulsions also had normal IQ's at age 4 years, but these were significantly lower than those of their siblings. The children with the worst prognosis were those with more than 1 febrile convulsion on the first day of an illness. These children were reported to have a 70 per cent chance of subsequent mental retardation. The percentage of children with neurologic abnormalities at the time of the first febrile convulsion was not given. Another investigation has recently been carried out to determine intellectual and behavioral function in 4 7 twin pairs, one of whom had had a febrile convulsion and the other had not. 60 Psychological testing of 14 monozygous twin pairs produced small and questionably significant poorer results in the febrile convulsions group compared with controls. There appeared to be no correlation between birth history and cerebral dysfunction. The authors themselves are not yet willing to ascribe these minor differences entirely to febrile convulsions.
THE CHILD WHO CONVULSES WITH FEVER
477
INDICATIONS FOR PROLONGED PROPHYLACTIC ANTICONVULSANT TREATMENT There is no disagreement that children who have seizures with fever or febrile status epilepticus should be treated with anticonvulsants on a long-term basis. Phenobarbital, 3 to 6 mg. per kg. per 24 hr. given orally in 2 divided doses, is recommended at least until the child is free of seizures for 3 years. At issue is whether previously normal children with a single simple febrile convulsion are at risk for subsequent seizures with fever or febrile status epilepticus, with their graver prognostic implications, and should also be placed on maintenance anticonvulsant therapy. There are numerous difficulties in attempting to assess data as presented. As should be clear from material previously discussed, most series do not present data in a way which makes meaningful comparisons possible. Different terminology is employed and patient groups are not comparable. In some series, a large percentage of the patients have had evidence of neurologic impairment at the time of the first seizure and the characteristics of their seizures have not been separately described. It does not appear appropriate to implicate febrile convulsions or simple febrile convulsions alone as a cause of subsequent difficulties in these patients. Others report data of previous febrile convulsions, seizures with fever, and febrile status epilepticus in retrospective studies of adults with epilepsy and attempt to make correlations and predictions of the dangerous implications of all febrile convulsions and simple febrile convulsions in all children. These conclusions also do not appear warranted. Recent data suggesting that onset of febrile convulsions in the first year of life carries a greater risk of recurrent febrile convulsions and recurrent afebrile convulsions are important, especially in view of the fact that other studies suggest an increasing incidence of seizures with fever and febrile status epilepticus with each recurrent febrile convulsion. Here, too, unfortunately, information concerning the presence or absence of previous neurologic impairment in these children is lacking. Recurrent febrile convulsions and simple febrile convulsions have also been stressed as being associated with an increased risk of recurrent afebrile convulsions. 38 • 48 Data concerning intellectual and behavioral outcome in patients with febrile convulsions has been reported only recently and is also incomplete. One hopes that further information will be presented in such a way that subgroups of children with regard to age, sex, duration and type of seizure, and presence of previous neurologic impairment can be identified and comparisons made. Despite an enormous amount of data, one is left with making empirical decisions with incomplete information. Livingston's data are clinically useful. On the basis of this i.t does not appear warranted to place previously normal children with a single simple febrile convulsion on long-term anticonvulsant medication at the present time. The treatment of these children itself is not without risk. Not only do drug reactions occur, but sudden withdrawal of medication carries a risk of seizures, often status epilepticus. Compliance may be poor. In two series in which
478
EILEEN OuELLETTE
long-term anticonvulsant medication was shown to have no effect in preventing febrile convulsions and simple febrile convulsions, serum drug level determinations were not carried out. 37 • 38 • 48 A more recent study by Faero, 10 in which blood phenobarbital levels were obtained, indicated that 26 of 52 patients had levels habitually below the therapeutic range. Intermittent therapy with phenobarbital with fever, although advocated by some48 • 69 does not appear to be of value. Not only does the occurrence of the febrile convulsions often herald the presence of a febrile illness, but it has been recently demonstrated that it takes 2 days t"o achieve a therapeutic serum phenobarbital concentration on double doses given orally 10 and several weeks on ordinary doses. 64 Maintenance anticonvulsant therapy in cases of repeated febrile convulsions or simple febrile convulsions in young children may be indicated. The ineffectiveness of diphenylhydantoin in the prevention of recurrent febrile convulsions in 23 children under the age of 3 years with adequate blood levels has recently been demonstrated. 44 The successful prophylaxis of febrile convulsions with phenobarbital in 26 children whose mean serum concentration remained within 16 to 30 mg. per liter has recently been reported. 9 • 10 While these data are of. interest, 25 per cent of the group had had a seizure with fever and no information concerning the incidence of birth injury or previous central nervous system impairment was given. 9 • 10 The advisability of long-term anticonvulsant medication in normal patients with simple febrile convulsions will no doubt continue to remain a controversy. Those who choose to treat such patients are urged to employ phenobarbital in the doses given above and to obtain serum drug determinations at frequent intervals in order to check compliance and assure that levels remain in the therapeutic range. In all cases of seizures with fever and febrile status epilepticus, prompt attempts to bring the seizure under control are urged. Careful attention must be given to the maintenance of adequate oxygenation and the prevention of aspiration, and overmedication must be guarded against. Shortened duration of seizure may subsequently prove to be as important as any regimen of treatment in the prevention of serious sequelae.
SUMMARY From the data presented above, it can be seen that controversy still exists concerning the definition, prognosis and management of febrile convulsions. Certain facts, however, are apparent. Febrile seizures by definition are always associated with fever whose source lies outside the central nervous system. They occur primarily in children between the ages of 6 months and 6 years. The maximum incidence of febrile seizures occurs during the second year of life and falls off rapidly after the third year. The vast majority are generalized and brief. They are more frequent in males. The risk of febrile convulsions
THE CHILD WHO CONVULSES WITH FEVER
479
increases with increasing fever. Febrile seizures appear to be inherited as an autosomal dominant with incomplete penetrance. Those seizures which are prolonged and/or focal are associated with a greater risk of development of subsequent afebrile seizures. Infants in the first year of life and girls are more at risk for these types of seizures. The younger the child, the greater is the risk of recurrent febrile convulsions. Those children with neurologic abnormality prior to the time of the first febrile convulsion have a greater risk of developing subsequent afebrile seizures and/or intellectual impairment. It is not clear what role, if any, a febrile convulsion plays in this risk. The electroencephalogram demonstrates slowing in almost all patients within the first week after a febrile convulsion and thus obtaining the electroencephalogram should be delayed beyond this time. There remains at issue whether a single brief febrile seizure in a previously normal child carries a greater risk for future afebrile seizures or intellectual impairment. It is hoped that further studies on febrile convulsions will distinguish patient populations, type and duration of seizures and report data in such a way that the question of the prognosis of febrile seizures and need for prolonged treatment can soon be established without doubt.
REFERENCES 1. Aicardi, J., and Chevrie, J. J.: Convulsive status epilepticus in infants and children. Epilepsia, 11:187-197, 1970. 2. Bell, D. S.: Dangers of treatment of status epilepticus with diazepam. Brit. Med. ]., 1:159161, 1969. 3. Buchthal, F., and Lennox-Buchthal, M.A.: Phenobarbital. Relation of serum concentration to control of seizures. In Woodbury, D. M., ed.: Antiepileptic Drugs. N.Y., Raven Press,1972,pp.335-343. 4. Carter, S.: Diagnosis and treatment: Management of the child who has had one convulsion. Pediatrics, 33:431-434, 1964. 5. Carter, S., and Gold, A. P.: The critically ill child: Management of status epilepticus. Pediatrics, 44:732-733, 1969. 6. Cary, W.: Febrile convulsions in infancy and childhood. Med. J. Australia, 43:254-256, 1956. 7. Costeff, H.: Convulsions in childhood. Their natural history and indications for treatment. New Eng.]. Med., 273:1410-1413, 1965. 8. Donald, W. D., Winkler, C. H., and Bargeron, L. M.: The occurrence of convulsions in children with shigella gastroenteritis. J. Pediat., 48:323-327, 1956. 9. Faero, 0., Kastrup, K. W., Melchior, J. C., et al.: Phenobarbital as prophylaxis for febrile convulsions. Epilepsia, 12:109-112, 1971. 10. Faero, 0., Kastrup, K. W., Nielsen, E. L., et al.: Successful prophylaxis of febrile convulsions with phenobarbital. Epilepsia, 13:279-285, 1972. 11. Falconer, M. A.: Genetic and related aetiological factors in temporal lobe epilepsy. Epilepsia, 12:13-31, 1971. 12. Falconer, M.A.: Febrile convulsions in early childhood. Brit. Med. ]., 2:292, 1972. 13. Falconer, M.A., Serafetinides, E. A., and Corsellis, J. A. N.: Etiology and pathogenesis of temporal lobe epilepsy. Arch. Neural., 10:233-248, 1964. 14. Falconer, M. A., and Taylor, D. C.: Surgical treatment of drug-resistant epilepsy due to mesial temporal sclerosis. Arch. Neural., 19:353-361, 1966. 15. Fischler, E.: Convulsions as a complication of shigellosis in children. Helvet. Paediat. Acta, 17:389-394, 1962. 16. Fitzpatrick, T. B., Szabo, G., Yoshiaki, H., et al.: White leaf-shaped macules. Arch. Derm., 98:106,1968. 17. Fogelson, M. H., and Shelburne, S. A.: Febrile convulsions, how should they be treated? Clin. Pediat., 10:27-29, 1971.
480
EILEEN OUELLETTE
18. Frantzen, E., Lennox-Buchthal, M., and Nygaard, A.: Longitudinal EEG and clinical study of children with febrile convulsions. EEG Clin. Neurophysiol., 24:197-212, 1968. 19. Frantzen, E., Lennox-Buchthal, M., Nygaard, A., eta!.: A genetic study of febrile convulsions. Neurol., 20:909-917, 1970. 20. Friderichsen, C., and Melchior, J.: Febrile convulsions in children, their frequency and prognosis. Acta Paediat. Scand., Suppl., 100:307-317, 1954. 21. Gas taut, H., Poirier, F., Payan, H., et al.: H. H. E. syndrome, Hemiconvulsions, hemiplegia, epilepsy. Epilepsia, 1:418-447, 1960. 22. Gold, A. P., and Freeman, J.: Depigmented nevi: the earliest sign of tuberous sclerosis. Pediatrics, 35:1003-1005, 1965. 23. Hammill, J. H., and Carter, S.: Febrile convulsions. New Eng. J. Med., 274:563-565, 1966. 24. Hauser, W. A., Kurland, L. T., Gomez, M. R., eta!.: Prognosis of patients with febrile convulsions in Rochester, Minnesota, 1945-1967. Trans. Amer. Neurol. Assoc., 95:257-259, 1970. 25. Herlitz, G.: Studien uber die sogenann ten initialen Fieber kframpfe bei kindern. Acta. Paediat. Scand., 29(Suppl.):142, 1941. 26. Hippocrates, (F. Adams transiation): The Genuine Works of Hippocrates, Vol. 2, London, The Sydenham Society, 1849, p. 212. 27. Huttenlocher, P., and Rawson, M.D.: Neuronal activity and adenosine triphosphatase in immature cerebral cortex. Exper. Neurol., 22:118-129, 1968. 28. Ingram, T. T. S.: The treatment of febrile convulsions in childhood. Devel. Med. Child Neurol., 15:531-533, 1973. 29. Kastrup, K. W.: Round table discussion on febrile convulsions. Epilepsia, 12:191-194, 1971. 30. Kowlesser, M., and Forbes, G. B.: The febrile convulsion in shigellosis. New Eng. J. Med., 258:520-526, 1958. 31. Lagos, J. C.: Febrile seizures: to treat or not to treat. Post grad. Med., 47:180-193, 1970. 32. Lennox, M.: Febrile convulsions in childhood: their relationship to adult-epilepsy. J. Pediat., 35:427-435, 1949. 33. Lennox, M.: Febrile convulsions in childhood, a clinical and electroencephalographic study. Amer. J. Dis. Child., 78:868-882, 1949. 34. Lennox, M., Sibley, W., and Zimmerman, H. M.: Fever and febrile convulsions in kittens. J. Pediatrics, 45:179-190, 1954. 35. Lennox, W.: Significance of febrile convulsions. Pediatrics, 11:341-357, 1953. 36. Lennox-Buchthal, M.: Febrile convulsions, a reappraisal. EEG Clin. Neurophysiol., Suppl. 32, 138 pp., 1973. 37. Livingston, S.: Infantile febrile convulsions. Devel. Med. Child Neurol., 10:374-376, 1968. 38. Livingston, S.: Febrile convulsions. Comprehensive Management of Epilepsy in Infancy, Childhood and Adolescence. Charles C Thomas, Springfield, Illlinois, 1972, pp. 16-33. 39. Livingston, S., Bridge, E. M., and Kajdi, L.: Febrile convulsions: A clinical study with special reference to heredity and prognosis. J. Pediat., 31:509-512, 1947. 40. Lombroso, C.: Treatment of status epilepticus with diazepam. Neurol., 16:629-634, 1966. 41. Lyon, G., Dodge, P.R., and Adams, R. D.: The acute encephalopathies of obscure origin in infants and children. Brain, 84:680-708, 1961. 42. Margerison, J, H., and Corsellis, J. A. N.: Epilepsy and the temporal lobes. Brain, 89:499530, 1966. . 43. McMorris, S., and McWilliam, P. K. A.: Status epilepticus in infants and young children treated with parenteral diazepam. Arch. Dis. Childh., 44:606-611, 1969. 44. Melchior, J. C., Buchthal, F., and Lennox-Buchthal, M.: The ineffectiveness of diphenylhydantoin in preventing febrile convulsions in the age of greatest risk, under three years. Epilepsia, 12:55-62, 1971. 45. Meloff, K.: Seizures and fever. Postgrad. Med., 50:107-111, 1971. 46. Millichap, J. G.: Studies in febrile seizures. I. Height of body temperature as a measure of the febrile-seizure threshhold. Pediatrics, 23:76-85, 1959. 47. Millichap, J. G.: Studies in febrile seizures: II. Febrile seizures and the balance of water and electrolytes. Neurol., 10:312-321, 1960. 48. Millichap, J. G.: Febrile Convulsions. New York, MacMillan, 1968. 49. Millichap, J. G., Aledort, L. M., and Madsen, J. A.: A critical evaluation of the therapy of febrile seizures. J. Pediat., 56:364-368, 1960. 50. Nelson, K., Rubenstein, D., and Beadle, E. L.: Seizures with fever beginning in the first · year of life. Child Neurology Society Meetings, October 5-7, 1972. 51. Ounsted, C., Lindsay, J., and Norman, R.: Biological Factors in Temporal Lobe Epilepsy. London, Hinemann Co., 1966. 52. Ounsted, C.: Temporal lobe epilepsy: the problem of aetiology and prophylaxis. J. Roy. Coli. Phys. Lond., 1 :273-284, 1967. 53. Ounsted, C.: Some aspects of seizure disorders. In Hull, D., and Gairdner, D., eds.: Recent Advances in Pediatrics. London, Churchill, 1970.
THE CHILD WHO CONVULSES WITH FEVER
481
54. Pascual, R., and McGovern, J.P.: Febrile convulsions in childhood. Clin. Proc. Hosp. D. C., 8:92-98, 1952. 55. Purpura, D. P.: Stability and seizure susceptibility of immature brain. In Jasper, H. H., Ward, A. A., and Pope, A. eds.: Basic Mechanisms of the Epilepsies. Boston, Little Brown, 1969, pp. 481-505. 56. Rabe, E. F.: Skull transillumination in infants. G. P., 36:78-87, 1967. 57. Reye, R. D. K.: Encephalopathy and fatty degeneration of the viscera, a disease entity in childhood. Lancet, 2:749-752, 1963. 58. Schiottz-Christensen, E.: Genetic factors in febrile convulsions. Acta Neurol. Scandinav., 48:538-546, 1972. 59. Schiottz-Christensen, E.: Genetic factors in febrile convulsions, a twin study. Acta Neurol. Scandinav., Suppl., 48:493-494, 1972. 60. Schiottz-Christensen, E., and Bruhn: Intelligence, behaviour and scholastic achievement subsequent to febrile convulsions: an analysis of discordant twin pairs. Devel. Med. Child. Neurol., 15:565-575, 1973. 61. Schuman, S. H., and Miller, L. J.: Febrile convulsions in families: findings in an epidemiologic survey. Clin. Pediat., 5:604-608, 1966. 62. Smith, B. T., and Masotti, R. E.: Intravenous diazepam in the treatment of prolonged seizure activity in neonates and infants. Devel. Med. Child. Neurol., 13:630-634, 1971. 63. Solomon, G., Hilal, S. K., Gold, A. P., et al.: Natural history of acute hemiplegia in childhood. Brain, 93:107-120, 1970. 64. Svensmark, 0., and Buchthal, F.: Diphenylhydantoin and phenobarbital serum levels in children. Amer. J. Dis. Childh., 108:82-87, 1964. 65. Taylor, D. C.: Differential rates of cerebral maturation between sexes and between hemispheres. Evidence from epilepsy. Lancet, 2:140-142, 1969. 66. Taylor, D. C., and Ounsted, C.: Biological mechanisms influencing the outcome of seizures in response to fever. Epilepsia, 12:33-45, 1971. 67. Thorn, 1.: Round table discussion on febrile convulsions. Epilepsia, 12:191-194, 1971. 68. van den Berg, B. J., and Yerushalmy, J.: Studies on convulsive disorders in young children. Pediat. Res., 3:298-304, 1969. 69. van den Berg, B. J., and Yerushalmy, J.: Studies on convulsive disorders in young children. J. Pediat., 79:1004-1012, 1971. 70. Wallace, S.: Aetiological aspects of febrile convulsions. Arch. Dis. Childh., 47:171-178, . 1972. 71. Wallace, S., and Zealley, H.: Neurological electroencephalographic, and virological findings in febrile children. Arch. Dis. Childh., 45:611-623, 1970. 72. Wegman, M. E.: Factors influencing the relation of convulsion and hyperthermia. J. Pediat., 14:190-202, 1939. Boston City Hospital 818 Harrison Ave Boston, Massachusetts 02118
The Child Who Convulses with Fever
Eileen M. Ouellette, M.D.*
It has been well known since ancient times that seizures frequently accompany fever in young children. Hippocrates noted that "convulsions occur to children if acute fever be present ... most readily up to their seventh year. Older children and adults are not equally liable to be seized with convulsions in fevers, unless some of the strongest and worst symptoms precede". 26 At the present time, febrile convulsions remain one of the most common pediatric problems. It is estimated that one-half million children in the United States have had such seizures, which comprises 3 per cent of the population under the age of 5 years and accounts for half of all seizures in this age group. 7. 36, 48, 49, 6t, 68, 69 Despite their ubiquity, febrile convulsions remain one of the most controversial topics in pediatrics with disagreement about definition, prognosis, and advisability of continued anticonvulsant therapy. An enormous amount of data has been published on this subject. In spite of this, meaningful comparisons of studies are virtually impossible to make. Patient selection is variable. Previously neurologically abnormal children are grouped with apparently normal children and the quality, duration, and frequency of their seizures are not differentiated. Several recent studies have provided additional information on some of these points which may be helpful to the pediatrician faced with a patient who has had a convulsion with fever. This information may help him or her to make an intelligent decision on how to proceed and what to tell the family.
DEFINITION Two distinct definitions are currently advocated with regard to a seizure which occurs with fever in a young child between the ages of 6 months and 6 years. Seizures which occur with fever whose source derives from illness within the central nervous system are excluded from the category of febrile convulsions. 1. The first definition is that a febrile convulsion is an epileptic event occurring in the context of a febrile illness, regardless of type of seizure, *Assistant Professor of Pediatrics and Neurology, Boston University School of Medicine; Associate Director of Pediatric Neurology, Boston City Hospital, Boston, Massachusetts 02118
Pediatric Clinics of North America- Vol. 21, No. 2, May 1974
467
468
EILEEN OUELLETTE
duration, or previous state of the patient with regard to central nervous system abnormalities. 11-14, a6, 42, 48, 5t-5a, 66 2. The second is that all such seizures are not alike, either etiologically or with regard to prognosis, but fall into two categories. 6 • 20 • 37• 38 Simple febrile convulsions occur in previously normal children, are brief, are generalized, and have a benign prognosis. Seizures with fever are prolonged and/or focal or occur in previously abnormal children. These are considered to be epileptic seizures precipitated by fever, and to carry a graver prognosis. In this article, febrile convulsion will refer to any seizure with fever, simple febrile convulsions to those which are brief and generalized, and seizures with fever to those which are focal and/or prolonged.
CHARACTERISTICS OF FEBRILE CONVULSIONS Type of Seizure. The vast majority of febrile convulsions are generalized. About 80 to 85 per cent are clonic, 14 per cent tonic, and 6 per cent atonic. Approximately 15 per cent are focal. 17• 48 • 67 Age. Almost all first febrile convulsions occur between the ages of 6 months and 6 years, and are infrequent after the age of 3 years. 19 • 30 • 36-38 , 48 • 68 One to 2 per cent occur below 6 months and 1 to 6 per cent after 5 years. 35 • 49 The vast majority of first febrile convulsions occur during the first 3 years. 20 • 32 • 35 • 44 • 67 For males the decline in incidence with age is smooth over the first 4 years, but in females the decline is sharp and sudden, occurring inainly during the second year. 65 • 66 The strong relationship between age and incidence of febrile convulsions is of great interest but is imperfectly understood. The relative lack of myelinization in the immature brain, its changing chemical composition, differences in water and electrolyte balance, increased oxygen consumption, diininished dendritic connections, and electrophysiologic differences from the adult brain have all been implicated as possible reasons for the remarkable correlation betwen febrile convulsions and a restricted age group. 27 • 36• 47 • 48 • 55 It has been postulated that more rapid cerebral maturation in girls accounts for the rapid rate of decline of febrile convulsions after the second year. 65 • 66 Sex. In almost all series, febrile convulsions and simple febrile convulsions have occurred more frequently in males, with a male to female ratio ranging from 1.1 to 1 to 4 to 1.32 • 48 • 54• 67 It has been postulated that the excess of males was due to an overrepresentation in males from exclusively male sibships. There is no satisfactory explanation of this overrepresentati9n among patients with febrile convulsions. 36 Although females appear to have a lower incidence of febrile convulsions, they appear to have a higher incidence of seizures with fever and an increased risk of sequelae. 32 • 36• 66 Duration of Seizure. Most febrile convulsions are brief. About 40 per cent last less than 5 minutes, 75 per cent are over by 20 minutes, and only 2 per cent last more than 1 hour. 48 Livingston has included only those seizures whose duration was less than "a few minutes" in his definition of simple convulsions. He considers the prolonged febrile convulsion to be representative of an underlying seizure disorder. 37• 38
THE CHILD WHO CONVULSES WITH FEVER
469
Role of Fever. By definition, fever is always present with these seizures. The temperature is almost always high, over 102°F. rectally,38• 67 and the risk of febrile convulsions increases with increasing temperature. 20 • 30 The duration of the fever prior to the convulsion ranges from minutes to 2 days. 54 LiVingston found simple febrile convulsions to begin from 2 to 6 hours after the onset of fever and has never seen one beginning later than 24 hours. 38 The influence of the rapidity of rise of the temperature still remains the subject of some debate. Wegman 72 induced seizures in young kittens by a rapid rise in body temperature 4 or 5°F. above normal through exposure to external heat and postulated that rate of rise was the most important factor. In similar experiments, both the height of fever and rapidity of rise were considered equally important by some,34 while others believed the height of the fever alone was significant. 46 Clinically, a "slow rate of temperature elevation" has been observed in 65 per cent of 100 patients with febrile convulsions. 36 Electroencephalogram. It is well known that fever or convulsions alone will result in slowing of the electroencephalogram. 33 • 36- 38 With febrile convulsions marked slowing is usually noted, especially posteriorly, and is often focal. 18 In a recent study, 88 per cent of patients with febrile convulsions had abnormal electroencephalograms on the day following the seizure, and 33 per cent were still abnormal 3 and 7 days after the seizure, a duration longer than is generally seen after fever or seizure alone. 18 Only 1.4 per cent of patients with febrile convulsions had paroxysmal electroencephalograms acutely, but 20 per cent subsequently developed this pattern. 18 Among those factors correlating with extreme and focal slowing were duration and height of fever, past history of brain injury, and duration or focality of the seizure. 36 Livingston found the slowing on the electroencephalogram to be reversible in cases of simple febrile convulsions by 10 days following the seizure, but found persistent slowing in cases of seizures with fever. 37 • 38
FACTORS AFFECTING OCCURRENCE OF FEBRILE CONVULSIONS Associated Illness The majority of febrile convulsions occur with intercurrent viral illness, primarily tonsillitis, pharyngitis, and otitis. 48 • 71 Some other illnesses have been associated with a particularly high incidence of febrile convulsions. From 4.8 to 45 per cent of patients with Shigella gastroenteritis have had associated febrile seizures8 • 15 • 30 as compared to gastroenteritis from other causes where the incidence of febrile convulsions is about 1 per cent. 15 • 48 Roseola infantum has also been associated with a high frequency of febrile convulsions. 36 Of interest is the low incidence of febrile convulsions with the common cold. 36 A possible explanation for this is the generally low tempera-
470
EILEEN OUELLETTE
ture associated with these illnesses compared to other more systemic infections. Pyuria has also .seldom been stressed as being associated with febrile convulsions. Kastrup, however, noted that in 50 patients with fever and pyuria under 5 years of age there was a 15 per cent incidence of febrile convulsions. 29 He concluded that pyuria was as likely to be associated with febrile convulsions as other infections but that its low association was due to the great preponderance of other infections in the susceptible age group.
Antecedent Brain Injury The presence or absence of antecedent central nervous system damage is vital in attempting to assess the implications of a febrile convulsion in a child. Livingston has defined a simple febrile convulsion as occurring only in normal children. 37· 38 Seizures in children with known central nervous system abnormalities have thus been termed seizures with fever. Others, however, have included all children, including those with previous afebrile seizures, birth injury, and other central nervous system abnormalities in the group with febrile convulsions and have made no distinction between these and previously normal children when discussing seizure types or prognosisP· 2o, 25, 36, 48, 68, 69, n In some series the incidence of patients with central nervous system abnormalities has been low,20 · 25 · 36 but in others 15 to 23 per cent of children have had an obvious neurologic abnormality prior to the time of the first febrile convulsion 17· 48 · 70 and one reported 7.3 per cent with "severe congenital anomalies." 68 Perinatal difficulties, when mentioned, have been present in from 3 to 61 per cent of patients with febrile convulsions.48 Unfortunately, qualitative descriptions of the seizures in these two groups have not been given and it is not possible to determine whether their seizures differed in any way from those of normal children. The wide variation in percentage of abnormal children in these series has made other comparisons also impossible. Role of Inheritance A high incidence of febrile seizures has been found in families of patients with febrile convulsions. Although some have postulated an autosomal recessive inheritance, more recent studies have suggested a simple autosomal dominant inheritance with incomplete penetrance.t9, a6. sa One study noted a positive history of seizures in 13 per cent offamilies of children with febrile convulsions, versus 1 per cent in families of children with similar illnesses and fever who did not convulse. 30 Another recent study of 208 children with febrile convulsions disclosed a 50 per cent incidence of seizures in their relatives. 19 The relatives of 40 per cent of these patients had febrile convulsions while there were recurrent afebrile convulsions in the families of 20 per cent. In 10 per cent of families both were seen. Among the relatives with febrile convulsions, 95 per cent were first degree relatives, while 50 per cent of the relatives with recurrent afebrile convulsions were distant. The incidence of epilepsy in near relatives of these 208 children was not above the prevalence in the population at large, while the incidence of febrile seizures in parents and
THE CHILD WHO CONVULSES WITH FEVER
471
siblings was 9 per cent, three times the prevalence in the population at large. This is consistent with an autosomal dominant inheritance and with previously reported data. 35 A high association of mental retardation in siblings of patients with febrile convul!tions has been reported, 61 but this has not been substantiated by subsequent series. 19· 36 Twin studies have been carried out to investigate further the role of genetic influence, but results at present are conflicting. One study reported that although dizygotic twins did not differ from non-twin siblings, there was an 80 per cent concordance for febrile convulsions in monozygotic tWins and 100 per cent concordance for recurrent afebrile convulsions. 36 Another recent series showed no difference between dizygotic and monozygotic twins. 59· 60 Attempts have been made to utilize genetic information to substantiate or negate the validity of the division of febrile convulsions into the two groups, simple febrile convulsions and seizures with fever. Livingston reported a 58 per cent incidence of simple febrile convulsions in families of 201 patients with simple febrile convulsions, versus 3 per cent in families of 355 children with seizures with fever. The incidence of recurrent afebrile convulsions in these two groups of families was not reported. 38
DIFFERENTIAL DIAGNOSIS OF FEBRILE CONVULSIONS Of maximum importance is the exclusion of acute disease affecting the central nervous system. Among these, bacterial and viral meningitis, encephalitis, acute toxic encephalopathy, 4 Reye's syndrome,57 intracranial hemorrhage, and acute hemiplegia of infancy63 are all examples of diseases in which both seizures and fever may be present at the onset. In the past, the persistence of hemiplegia has been thought to be secondary to the febrile convulsions, but in recent years, as more of these patients have been studied with angiography, a vascular etiology has been found in many.21, 63 Other, more chronic diseases of the central nervous system, such as the effects of neonatal hypoxi:l, toxoplasmosis, cytomegalic inclusion disease, chronic subdural effusions, tuberous sclerosis, vascular malformations, porencephaly, and other developmental defects of brain, may first become apparent with a febrile convulsion as well as an afebrile seizure. Other illnesses outside the central nervous system must be ruled out. Hypocalcemia resulting from rickets is rare but still occurs among the underprivileged. Hypoglycemia, renal disease, and electrolyte disturbances, especially hyponatremia, should be excluded.
EVALUATION OF A FEBRILE CONVULSION It is of vital importance to delineate the cause of any seizure as precisely as possible in order to be able to discuss its implications and
472
EILEEN OUELLETTE
prognosis with the parents. It must be stressed that witnessing a seizure is very frightening to parents and counselling them may be as important as other evaluation and treatment. A careful history with special reference to the quality and duration of the seizure, the presence of a focal component, and possible family history of seizures, both febrile and afebrile, should be taken. The physical examination should include special attention to the state of alertness of the patient, fullness of the fontanel, and funduscopic examination, abnormalities in which may indicate increased intracranial pressure. The presence of nuchal rigidity is consistent with meningitis or intracranial hemorrhage. Examination of the skin for the hypopigmented macules seen in tuberous sclerosis should be made. 16 • 22 Cranial auscultation should be done. Loud bruits suggest the presence of a vascular malformation. Transillumination of the skull56 is also important. In chronic subdural effusions, porencephaly, and other major malformations of brain this will be increased. Cerebrospinal fluid examination should be carried out on: (1) all children with a first febrile convulsion; (2) all children with a febrile convulsion under 2 years of age, regardless of the presence of signs of infection at other sites of the body. Nuchal rigidity is seldom present in this age group and meningitis may be present with few or no localizing signs; (3) on older children with recurrent febrile convulsions whenever a central nervous system infection is suspected. A careful measurement of cerebrospinal fluid pressure should be made, the number and type of cells recorded, bacterial cultures obtained, and protein and sugar determinations made. At the time of the first seizure skull films should be obtained. If intracranial calcifications are seen, the diagnosis of febrile convulsions should be suspect and the patient should be evaluated for congenital infections, tuberous sclerosis, and parathyroid abnormalities. Blood sugar, calcium, and electrolytes should be determined. Abnormalities suggest a diagnosis other than febrile convulsions. A complete blood count and urinalysis should be done. Appropriate cultures of nasopharynx, urine, and blood should be carried out when indicated. A Wood's lamp examination of the skin should be performed to exclude the presence of hypopigmented macules which may be inapparent to routine examination in fairskinned children. Tuberous sclerosis usually presents as seizures in the susceptible age group. It is of autosomal dominant inheritance and early detection is advisable if genetic counselling is to be carried out. Patients who show abnormal cerebrospinal fluid examinations, intracranial calcifications on x-ray, abnormal transillumination, or persistent hemiplegia should not be considered as having febrile convulsions and additional investigations may be warranted. These may include brain scans, subdural taps, pneumoencephalography, and angiography which are not indicated in febrile convulsions.
ACUTE TREATMENT OF FEBRILE CONVULSIONS In all cases, the cause of the fever should be determined and treated appropriately. Of primary importance is the prompt reduction of the tern-
THE CHILD WHO CONVULSES WITH FEVER
473
perature with brisk tepid water sponging and antipyretics. Aspirin or acetaminophen (Tylenol), 60 mg. per year of age by mouth, or 120 mg. per year of age by rectum, should be given every 4 hours for a temperature above 101.0°F. If a seizure is observed, the child should be placed in a semiprone position to minimize the danger of aspiration and adequate oxygenation maintained. Intravenous diazepam (Valium), 0.3 mg. per kg., may be given slowly at a rate of 1 mg. per min. until the seizure stops. Alternatively, phenobarbital, 3 to 6 mg. per kg., may be given slowly intravenously. Phenobarbital has an antipyretic as well as an anticonvulsant effect and acts by inhibiting heat production. 48 Lennox-Buchthal, however, does not recommend phenobarbital to stop seizures acutely, and states that "even when given intravenously or intramuscularly, the delay until the level has built up in the brain is so long that it has no value in an emergency." 3 • 36 After a loading dose of phenobarbital, 5 mg. per kg. intravenously or intramuscularly, has been given, oral phenobarbital in a dosage range of 3 to 6 mg. per kg. per 24 hr. may be given until the child is afebrile. Oral phenobarbital without a loading dose is useless as it takes days to weeks to achieve therapeutic blood levels by this route alone. 3 • 36 • 64
Febrile Status Epilepticus A continuous grand mal seizure lasting more than 30 minutes should be considered status epilepticus and treated accordingly as a medical emergency, regardless of the presence or absence of fever. Even today, the mortality remains at least 15 per cent, 5 much of which is attributable to overmedication with resultant respiratory arrest. Prolonged hypoxia is another danger and adequate oxygenation must be assured. Intravenous diazepam as described above is now considered the treatment of choice by many5 • 36 • 40 • 43 • 62 in status epilepticus and is equally effective in febrile status epilepticus. If the above dose is ineffective, it may be repeated cautiously in a similar amount and manner in 30 minutes. 5 Caution should be taken not to employ intravenous phenobarbital with this regimen as deaths from respiratory arrests have been reported when both drugs have been used together. 2 Severe hypotension in association with the simultaneous use of intravenous diazepam, paraldehyde, and intramuscular phenobarbital has also been reported! If diazepam is ineffective in controlling the status epilepticus, paraldehyde, 1 ml. per year of age, mixed with an equal amount of mineral oil, can be given rectally.
PROGNOSIS OF FEBRILE CONVULSIONS To a great extent, the prognosis with regard to recurrent febrile convulsions, incidence of subsequent recurrent afebrile convulsions, and risk of subsequent brain damage depends on the definition of febrile convulsions put forth and the selection of case material, especially with regard to previous neurological impairment and birth injury. As few series are entirely comparable, there is a wide variation in reported outcome.
474
EILEEN OUELLETTE
Recurrent Febrile Convulsions Few series comment on the chance of seizure recurrence during a single febrile episode, but Millichap puts the figure of recurrent febrile convulsions during one febrile episode at 1 in 3. 48 Repeated febrile convulsions and simple febrile convulsions with subsequent febrile illnesses are known to be common,l 8· 20 · 24 · 35 ~ 38 · 48 ranging from 12.320 to 54 per cent.48 Lennox, in his series of 407 patients, found 41.8 per cent with one subsequent febrile convulsion, 13.3 per cent with two, and 12 per cent with more than four. 35 The rate of recurrence clearly appears to be dependent on age at time of first seizure. A recent prospective study of 138 children found a 25 per cent recurrence rate of febrile convulsions. Of those children less than 13 months old at the time of the first febrile convulsion, the chance of recurrence was 2:1, compared to 1:5 when the first febrile convulsion occurred between 14 and 32 months. 18 Thirty per cent of these recurrences took place within 6 months of the first seizure, half within 13 months, and all within 30 months. Other factors in addition to age may also be important. Another recent study showed that girls are more likely to have a recurrent febrile convulsion. Those children with a positive family history of febrile convulsions also have a greater risk of recurrent febrile convulsions.a6 The risk of subsequent seizures with fever has recently been studied in patients with febrile convulsions. The proportion of seizures with fever increased with the number of febrile convulsions, reaching 35 per cent with the third febrile convulsion and increasing to 50 per cent by the fifth.:l 6 Seizures with fever were nearly twice as frequent in the first year of life. 33 · 36 No sex difference was noted.au Nearly all episodes of febrile status epilepticus occurred below 18 months of age' and the female to male proportion was 3:2. It must be noted, however, that the percentage of patients in these studies who were neurologically abnormal at the time of the first febrile convulsion or had abnormal birth histories was not supplied. It is unclear to what degree they were represented in these groups. It is therefore premature to apply these data to children who are apparently normal at the time of the first febrile convulsion.
Recurrent Afebrile Convulsions Differing beliefs regarding the risk of recurrent afebrile convulsions in the previously normal child with a simple febrile convulsion account for the varied recommendations for the management of such patients.4· 11 ~ 14 · 23 · 31 · 37 · 38 · 44 · 65 • 66 Depending on the series, the risk is said to vary between almost no to almost all patients. Several-important factors underlie these differences. SELECTION OF CASE MATERIAL. Groups whose series are composed of adults with seizure disorders, especially temporal lobe epilepsy, have found a very high incidence of previous febrile convulsions, almost always with seizures with fever or febrile status epilepticus.''- 14 · 42 • 65 · 66 They postulate that seizures with fever or febrile status epilepticus are associated to a large degree with hypoxia, resulting in neuronal death in
THE CHILD WHO CONVULSES WITH FEVER
475
the cerebellum, thalamus, and mesial temporal area. Mesial temporal sclerosis then resqlts. This is highly epileptogenic and temporal lobe epilepsy ensues. These groups believe all febrile convulsions are epileptic phenomena of potentially dangerous significance. Others, whose series consist of children, have emphasized that the majority of febrile convulsions in childhood have a good prognosis. Several studies report less than a 3 per cent incidence of recurrent afebrile convulsions following all febrile convulsions. 19 • 20 • 24 • Gs. 69 LENGTH OF FoLLOw-UP. Most recurrent afebrile convulsions occurred within 10 years of the first febrile convulsion and 4 7 per cent occurred within 1 year. 35 Recurrent afebrile convulsions following simple febrile convulsions generally developed before the age of 5 yearsY 7• 38 DURATION OF FEBRILE CONVULSION. Many agree with those above that seizures with fever carry a greater risk of recurrent afebrile convulsions. Livingston 37 • 38 reported that of 622 patients with febrile convulsions, 58 per cent developed recurrent afebrile convulsions. Of the 256 patients with simple febrile convulsions, only 2.9 per cent subsequently developed recurrent afebrile convulsions. Ninety-seven per cent of the 366 patients with seizures with fever went on to develop recurrent afebrile convulsions. Others who disagree with the appropriateness of dividing febrile convulsions into simple febrile convulsions and seizures with fever, considering all to be epileptic phenomena, have also found that the incidence of recurrent afebrile convulsions correlates with seizures with fever and repeated seizures. 32 • 36 • 48 The low incidence of recurrent afebrile convulsions in one series (1.4 per cent)1 9 may be due to prompt cessation of the seizures. AGE AND SEx. It appears that the risk of recurrent afebrile convulsions correlates with both age and sex. An age of onset in the first year of life was followed by recurrent afebrile convulsions in 39 per cent. 36 Girls are more likely to develop recurrent afebrile convulsions. 36 • 53 • 65 • 66 This may be related to the fact that they often have febrile convulsions at a younger age than boys. 65 • 66 It is also postulated that as more males die with febrile status epilepticus than females, there are more females left with serious sequelae. 65 • 66 ANTECEDENT BRAIN INJURY. Antecedent injury has been reported to be from 2 to 4 times as frequent in those who develop recurrent afebrile convulsions following febrile convulsions. 36 It is unclear whether the occurrence of febrile convulsions in this group in any way influences the development of recurrent afebrile convulsions. 36 The inclusion of these patients with obvious neurologic injury in most series, comprising 15 to 61 per cent of some series,1 7 • 48 • 70 is unfortunate. The failure to indicate whether their seizures constitute the majority of those in the greater risk categories has made it impossible to tell what the subsequent risk of recurrent afebrile convulsions is in previously normal children with simple febrile convulsions. The data concerning normal children are presented separately only by Livingston. 37 • 38 These children are said to have a benign prognosis. It appears inappropriate to ascribe the development of recurrent afebrile convulsions in the previously abnormal group to the febrile convulsions, as has been done by many.
476
EILEEN OUELLETTE
ELECTROENCEPHALOGRAMS. Most children With febrile convulsions and simple febrile convulsions have temporary slowing of the electroencephalogram acutely following the seizure and it is of no prognostic significance.19 The presence of moderate or severe slowing on the electroencephalogram 1 week following an initial febrile convulsion has been associated with a 50 per cent risk of recurrent afebrile convulsions and a paroxysmal electroencephalogram with a 25 per cent risk,:l:l In children with simple febrile convulsions, the electroencephalogram slowing has reverted to normal by 10 days, and persistence beyond that time has been considered to be a poorer prognostic sign.'37 • 38 A recent study also disclosed that moderate to severe slowing of the electroencephalogram within 7 days of the initial febrile convulsion in children less than 2.5 years old at least doubled the chance that the child would subsequently develop a spike focus. 19
Subsequent Intelligence and Behavior At the present time, the role of febrile convulsions or simple febrile convulsions in the production of intellectual or behavioral changes is not definitely known. Because of the inclusion of children with neurological abnormalities at the time of the first febrile convulsion in many series, it has been difficult to evaluate claims that febrile convulsions are associated with a higher subsequent incidence of mental retardation. Others have proposed that hyperactivity is more common in children who have had febrile convulsions, but no substantiating data have yet been reported. 2s, 4s Two recent reports have attempted to assess the relationship of febrile convulsions to subsequent intellectual performance and behavior. Nelson, reporting on the data obtained from the Collaborative Perinatal Project, NINDS, 50 identified all children in the group of 4 7,222 children who developed a febrile convulsion within the first year of life. 5° Those children with a simple febrile convulsion had normal IQ levels at age 4 years and these correlated with those of their sibs who had not experienced a febrile convulsion. Those with several febrile convulsions also had normal IQ's at age 4 years, but these were significantly lower than those of their siblings. The children with the worst prognosis were those with more than 1 febrile convulsion on the first day of an illness. These children were reported to have a 70 per cent chance of subsequent mental retardation. The percentage of children with neurologic abnormalities at the time of the first febrile convulsion was not given. Another investigation has recently been carried out to determine intellectual and behavioral function in 4 7 twin pairs, one of whom had had a febrile convulsion and the other had not. 60 Psychological testing of 14 monozygous twin pairs produced small and questionably significant poorer results in the febrile convulsions group compared with controls. There appeared to be no correlation between birth history and cerebral dysfunction. The authors themselves are not yet willing to ascribe these minor differences entirely to febrile convulsions.
THE CHILD WHO CONVULSES WITH FEVER
477
INDICATIONS FOR PROLONGED PROPHYLACTIC ANTICONVULSANT TREATMENT There is no disagreement that children who have seizures with fever or febrile status epilepticus should be treated with anticonvulsants on a long-term basis. Phenobarbital, 3 to 6 mg. per kg. per 24 hr. given orally in 2 divided doses, is recommended at least until the child is free of seizures for 3 years. At issue is whether previously normal children with a single simple febrile convulsion are at risk for subsequent seizures with fever or febrile status epilepticus, with their graver prognostic implications, and should also be placed on maintenance anticonvulsant therapy. There are numerous difficulties in attempting to assess data as presented. As should be clear from material previously discussed, most series do not present data in a way which makes meaningful comparisons possible. Different terminology is employed and patient groups are not comparable. In some series, a large percentage of the patients have had evidence of neurologic impairment at the time of the first seizure and the characteristics of their seizures have not been separately described. It does not appear appropriate to implicate febrile convulsions or simple febrile convulsions alone as a cause of subsequent difficulties in these patients. Others report data of previous febrile convulsions, seizures with fever, and febrile status epilepticus in retrospective studies of adults with epilepsy and attempt to make correlations and predictions of the dangerous implications of all febrile convulsions and simple febrile convulsions in all children. These conclusions also do not appear warranted. Recent data suggesting that onset of febrile convulsions in the first year of life carries a greater risk of recurrent febrile convulsions and recurrent afebrile convulsions are important, especially in view of the fact that other studies suggest an increasing incidence of seizures with fever and febrile status epilepticus with each recurrent febrile convulsion. Here, too, unfortunately, information concerning the presence or absence of previous neurologic impairment in these children is lacking. Recurrent febrile convulsions and simple febrile convulsions have also been stressed as being associated with an increased risk of recurrent afebrile convulsions. 38 • 48 Data concerning intellectual and behavioral outcome in patients with febrile convulsions has been reported only recently and is also incomplete. One hopes that further information will be presented in such a way that subgroups of children with regard to age, sex, duration and type of seizure, and presence of previous neurologic impairment can be identified and comparisons made. Despite an enormous amount of data, one is left with making empirical decisions with incomplete information. Livingston's data are clinically useful. On the basis of this i.t does not appear warranted to place previously normal children with a single simple febrile convulsion on long-term anticonvulsant medication at the present time. The treatment of these children itself is not without risk. Not only do drug reactions occur, but sudden withdrawal of medication carries a risk of seizures, often status epilepticus. Compliance may be poor. In two series in which
478
EILEEN OuELLETTE
long-term anticonvulsant medication was shown to have no effect in preventing febrile convulsions and simple febrile convulsions, serum drug level determinations were not carried out. 37 • 38 • 48 A more recent study by Faero, 10 in which blood phenobarbital levels were obtained, indicated that 26 of 52 patients had levels habitually below the therapeutic range. Intermittent therapy with phenobarbital with fever, although advocated by some48 • 69 does not appear to be of value. Not only does the occurrence of the febrile convulsions often herald the presence of a febrile illness, but it has been recently demonstrated that it takes 2 days t"o achieve a therapeutic serum phenobarbital concentration on double doses given orally 10 and several weeks on ordinary doses. 64 Maintenance anticonvulsant therapy in cases of repeated febrile convulsions or simple febrile convulsions in young children may be indicated. The ineffectiveness of diphenylhydantoin in the prevention of recurrent febrile convulsions in 23 children under the age of 3 years with adequate blood levels has recently been demonstrated. 44 The successful prophylaxis of febrile convulsions with phenobarbital in 26 children whose mean serum concentration remained within 16 to 30 mg. per liter has recently been reported. 9 • 10 While these data are of. interest, 25 per cent of the group had had a seizure with fever and no information concerning the incidence of birth injury or previous central nervous system impairment was given. 9 • 10 The advisability of long-term anticonvulsant medication in normal patients with simple febrile convulsions will no doubt continue to remain a controversy. Those who choose to treat such patients are urged to employ phenobarbital in the doses given above and to obtain serum drug determinations at frequent intervals in order to check compliance and assure that levels remain in the therapeutic range. In all cases of seizures with fever and febrile status epilepticus, prompt attempts to bring the seizure under control are urged. Careful attention must be given to the maintenance of adequate oxygenation and the prevention of aspiration, and overmedication must be guarded against. Shortened duration of seizure may subsequently prove to be as important as any regimen of treatment in the prevention of serious sequelae.
SUMMARY From the data presented above, it can be seen that controversy still exists concerning the definition, prognosis and management of febrile convulsions. Certain facts, however, are apparent. Febrile seizures by definition are always associated with fever whose source lies outside the central nervous system. They occur primarily in children between the ages of 6 months and 6 years. The maximum incidence of febrile seizures occurs during the second year of life and falls off rapidly after the third year. The vast majority are generalized and brief. They are more frequent in males. The risk of febrile convulsions
THE CHILD WHO CONVULSES WITH FEVER
479
increases with increasing fever. Febrile seizures appear to be inherited as an autosomal dominant with incomplete penetrance. Those seizures which are prolonged and/or focal are associated with a greater risk of development of subsequent afebrile seizures. Infants in the first year of life and girls are more at risk for these types of seizures. The younger the child, the greater is the risk of recurrent febrile convulsions. Those children with neurologic abnormality prior to the time of the first febrile convulsion have a greater risk of developing subsequent afebrile seizures and/or intellectual impairment. It is not clear what role, if any, a febrile convulsion plays in this risk. The electroencephalogram demonstrates slowing in almost all patients within the first week after a febrile convulsion and thus obtaining the electroencephalogram should be delayed beyond this time. There remains at issue whether a single brief febrile seizure in a previously normal child carries a greater risk for future afebrile seizures or intellectual impairment. It is hoped that further studies on febrile convulsions will distinguish patient populations, type and duration of seizures and report data in such a way that the question of the prognosis of febrile seizures and need for prolonged treatment can soon be established without doubt.
REFERENCES 1. Aicardi, J., and Chevrie, J. J.: Convulsive status epilepticus in infants and children. Epilepsia, 11:187-197, 1970. 2. Bell, D. S.: Dangers of treatment of status epilepticus with diazepam. Brit. Med. ]., 1:159161, 1969. 3. Buchthal, F., and Lennox-Buchthal, M.A.: Phenobarbital. Relation of serum concentration to control of seizures. In Woodbury, D. M., ed.: Antiepileptic Drugs. N.Y., Raven Press,1972,pp.335-343. 4. Carter, S.: Diagnosis and treatment: Management of the child who has had one convulsion. Pediatrics, 33:431-434, 1964. 5. Carter, S., and Gold, A. P.: The critically ill child: Management of status epilepticus. Pediatrics, 44:732-733, 1969. 6. Cary, W.: Febrile convulsions in infancy and childhood. Med. J. Australia, 43:254-256, 1956. 7. Costeff, H.: Convulsions in childhood. Their natural history and indications for treatment. New Eng.]. Med., 273:1410-1413, 1965. 8. Donald, W. D., Winkler, C. H., and Bargeron, L. M.: The occurrence of convulsions in children with shigella gastroenteritis. J. Pediat., 48:323-327, 1956. 9. Faero, 0., Kastrup, K. W., Melchior, J. C., et al.: Phenobarbital as prophylaxis for febrile convulsions. Epilepsia, 12:109-112, 1971. 10. Faero, 0., Kastrup, K. W., Nielsen, E. L., et al.: Successful prophylaxis of febrile convulsions with phenobarbital. Epilepsia, 13:279-285, 1972. 11. Falconer, M. A.: Genetic and related aetiological factors in temporal lobe epilepsy. Epilepsia, 12:13-31, 1971. 12. Falconer, M.A.: Febrile convulsions in early childhood. Brit. Med. ]., 2:292, 1972. 13. Falconer, M.A., Serafetinides, E. A., and Corsellis, J. A. N.: Etiology and pathogenesis of temporal lobe epilepsy. Arch. Neural., 10:233-248, 1964. 14. Falconer, M. A., and Taylor, D. C.: Surgical treatment of drug-resistant epilepsy due to mesial temporal sclerosis. Arch. Neural., 19:353-361, 1966. 15. Fischler, E.: Convulsions as a complication of shigellosis in children. Helvet. Paediat. Acta, 17:389-394, 1962. 16. Fitzpatrick, T. B., Szabo, G., Yoshiaki, H., et al.: White leaf-shaped macules. Arch. Derm., 98:106,1968. 17. Fogelson, M. H., and Shelburne, S. A.: Febrile convulsions, how should they be treated? Clin. Pediat., 10:27-29, 1971.
480
EILEEN OUELLETTE
18. Frantzen, E., Lennox-Buchthal, M., and Nygaard, A.: Longitudinal EEG and clinical study of children with febrile convulsions. EEG Clin. Neurophysiol., 24:197-212, 1968. 19. Frantzen, E., Lennox-Buchthal, M., Nygaard, A., eta!.: A genetic study of febrile convulsions. Neurol., 20:909-917, 1970. 20. Friderichsen, C., and Melchior, J.: Febrile convulsions in children, their frequency and prognosis. Acta Paediat. Scand., Suppl., 100:307-317, 1954. 21. Gas taut, H., Poirier, F., Payan, H., et al.: H. H. E. syndrome, Hemiconvulsions, hemiplegia, epilepsy. Epilepsia, 1:418-447, 1960. 22. Gold, A. P., and Freeman, J.: Depigmented nevi: the earliest sign of tuberous sclerosis. Pediatrics, 35:1003-1005, 1965. 23. Hammill, J. H., and Carter, S.: Febrile convulsions. New Eng. J. Med., 274:563-565, 1966. 24. Hauser, W. A., Kurland, L. T., Gomez, M. R., eta!.: Prognosis of patients with febrile convulsions in Rochester, Minnesota, 1945-1967. Trans. Amer. Neurol. Assoc., 95:257-259, 1970. 25. Herlitz, G.: Studien uber die sogenann ten initialen Fieber kframpfe bei kindern. Acta. Paediat. Scand., 29(Suppl.):142, 1941. 26. Hippocrates, (F. Adams transiation): The Genuine Works of Hippocrates, Vol. 2, London, The Sydenham Society, 1849, p. 212. 27. Huttenlocher, P., and Rawson, M.D.: Neuronal activity and adenosine triphosphatase in immature cerebral cortex. Exper. Neurol., 22:118-129, 1968. 28. Ingram, T. T. S.: The treatment of febrile convulsions in childhood. Devel. Med. Child Neurol., 15:531-533, 1973. 29. Kastrup, K. W.: Round table discussion on febrile convulsions. Epilepsia, 12:191-194, 1971. 30. Kowlesser, M., and Forbes, G. B.: The febrile convulsion in shigellosis. New Eng. J. Med., 258:520-526, 1958. 31. Lagos, J. C.: Febrile seizures: to treat or not to treat. Post grad. Med., 47:180-193, 1970. 32. Lennox, M.: Febrile convulsions in childhood: their relationship to adult-epilepsy. J. Pediat., 35:427-435, 1949. 33. Lennox, M.: Febrile convulsions in childhood, a clinical and electroencephalographic study. Amer. J. Dis. Child., 78:868-882, 1949. 34. Lennox, M., Sibley, W., and Zimmerman, H. M.: Fever and febrile convulsions in kittens. J. Pediatrics, 45:179-190, 1954. 35. Lennox, W.: Significance of febrile convulsions. Pediatrics, 11:341-357, 1953. 36. Lennox-Buchthal, M.: Febrile convulsions, a reappraisal. EEG Clin. Neurophysiol., Suppl. 32, 138 pp., 1973. 37. Livingston, S.: Infantile febrile convulsions. Devel. Med. Child Neurol., 10:374-376, 1968. 38. Livingston, S.: Febrile convulsions. Comprehensive Management of Epilepsy in Infancy, Childhood and Adolescence. Charles C Thomas, Springfield, Illlinois, 1972, pp. 16-33. 39. Livingston, S., Bridge, E. M., and Kajdi, L.: Febrile convulsions: A clinical study with special reference to heredity and prognosis. J. Pediat., 31:509-512, 1947. 40. Lombroso, C.: Treatment of status epilepticus with diazepam. Neurol., 16:629-634, 1966. 41. Lyon, G., Dodge, P.R., and Adams, R. D.: The acute encephalopathies of obscure origin in infants and children. Brain, 84:680-708, 1961. 42. Margerison, J, H., and Corsellis, J. A. N.: Epilepsy and the temporal lobes. Brain, 89:499530, 1966. . 43. McMorris, S., and McWilliam, P. K. A.: Status epilepticus in infants and young children treated with parenteral diazepam. Arch. Dis. Childh., 44:606-611, 1969. 44. Melchior, J. C., Buchthal, F., and Lennox-Buchthal, M.: The ineffectiveness of diphenylhydantoin in preventing febrile convulsions in the age of greatest risk, under three years. Epilepsia, 12:55-62, 1971. 45. Meloff, K.: Seizures and fever. Postgrad. Med., 50:107-111, 1971. 46. Millichap, J. G.: Studies in febrile seizures. I. Height of body temperature as a measure of the febrile-seizure threshhold. Pediatrics, 23:76-85, 1959. 47. Millichap, J. G.: Studies in febrile seizures: II. Febrile seizures and the balance of water and electrolytes. Neurol., 10:312-321, 1960. 48. Millichap, J. G.: Febrile Convulsions. New York, MacMillan, 1968. 49. Millichap, J. G., Aledort, L. M., and Madsen, J. A.: A critical evaluation of the therapy of febrile seizures. J. Pediat., 56:364-368, 1960. 50. Nelson, K., Rubenstein, D., and Beadle, E. L.: Seizures with fever beginning in the first · year of life. Child Neurology Society Meetings, October 5-7, 1972. 51. Ounsted, C., Lindsay, J., and Norman, R.: Biological Factors in Temporal Lobe Epilepsy. London, Hinemann Co., 1966. 52. Ounsted, C.: Temporal lobe epilepsy: the problem of aetiology and prophylaxis. J. Roy. Coli. Phys. Lond., 1 :273-284, 1967. 53. Ounsted, C.: Some aspects of seizure disorders. In Hull, D., and Gairdner, D., eds.: Recent Advances in Pediatrics. London, Churchill, 1970.
THE CHILD WHO CONVULSES WITH FEVER
481
54. Pascual, R., and McGovern, J.P.: Febrile convulsions in childhood. Clin. Proc. Hosp. D. C., 8:92-98, 1952. 55. Purpura, D. P.: Stability and seizure susceptibility of immature brain. In Jasper, H. H., Ward, A. A., and Pope, A. eds.: Basic Mechanisms of the Epilepsies. Boston, Little Brown, 1969, pp. 481-505. 56. Rabe, E. F.: Skull transillumination in infants. G. P., 36:78-87, 1967. 57. Reye, R. D. K.: Encephalopathy and fatty degeneration of the viscera, a disease entity in childhood. Lancet, 2:749-752, 1963. 58. Schiottz-Christensen, E.: Genetic factors in febrile convulsions. Acta Neurol. Scandinav., 48:538-546, 1972. 59. Schiottz-Christensen, E.: Genetic factors in febrile convulsions, a twin study. Acta Neurol. Scandinav., Suppl., 48:493-494, 1972. 60. Schiottz-Christensen, E., and Bruhn: Intelligence, behaviour and scholastic achievement subsequent to febrile convulsions: an analysis of discordant twin pairs. Devel. Med. Child. Neurol., 15:565-575, 1973. 61. Schuman, S. H., and Miller, L. J.: Febrile convulsions in families: findings in an epidemiologic survey. Clin. Pediat., 5:604-608, 1966. 62. Smith, B. T., and Masotti, R. E.: Intravenous diazepam in the treatment of prolonged seizure activity in neonates and infants. Devel. Med. Child. Neurol., 13:630-634, 1971. 63. Solomon, G., Hilal, S. K., Gold, A. P., et al.: Natural history of acute hemiplegia in childhood. Brain, 93:107-120, 1970. 64. Svensmark, 0., and Buchthal, F.: Diphenylhydantoin and phenobarbital serum levels in children. Amer. J. Dis. Childh., 108:82-87, 1964. 65. Taylor, D. C.: Differential rates of cerebral maturation between sexes and between hemispheres. Evidence from epilepsy. Lancet, 2:140-142, 1969. 66. Taylor, D. C., and Ounsted, C.: Biological mechanisms influencing the outcome of seizures in response to fever. Epilepsia, 12:33-45, 1971. 67. Thorn, 1.: Round table discussion on febrile convulsions. Epilepsia, 12:191-194, 1971. 68. van den Berg, B. J., and Yerushalmy, J.: Studies on convulsive disorders in young children. Pediat. Res., 3:298-304, 1969. 69. van den Berg, B. J., and Yerushalmy, J.: Studies on convulsive disorders in young children. J. Pediat., 79:1004-1012, 1971. 70. Wallace, S.: Aetiological aspects of febrile convulsions. Arch. Dis. Childh., 47:171-178, . 1972. 71. Wallace, S., and Zealley, H.: Neurological electroencephalographic, and virological findings in febrile children. Arch. Dis. Childh., 45:611-623, 1970. 72. Wegman, M. E.: Factors influencing the relation of convulsion and hyperthermia. J. Pediat., 14:190-202, 1939. Boston City Hospital 818 Harrison Ave Boston, Massachusetts 02118