Continuous phenobarbital treatment after a 'simple febril convulsion'

In only a small proportion of young children with brief, generalized, febrile convulsions do afebrile seizures develop, but this fraction is several times the prevalence of epilepsy in an unselected population. The risk of another febrile convulsion is approximately 30%. Febrile status epilepticus during a subsequent infection is a potential source of serious morbidity and mortality. Intermittent phenobarbital administration during subsequent, febrile illnesses confers little protection against recurrent, febrile convulsions. Continuous phenobarbital administration during the preschool years is indicated for most children who have had a simple febrile convulsion.     

Epilepsy and mental retardation following febrile seizures in childhood

In an unselected group of children who were seen following an initial febrile convulsion, the frequency of subsequent afebrile seizures was 3.5% and of mental retardation 1%. The most common afebrile seizure type was generalized major (86%). About 3/4 of the children who developed afebrile seizures did so by three years and all by five years following the initial febrile seizure. The children with afebrile seizures differed from those without afebrile seizures in the frequency of neonatal abnormality, family history of mental retardation, focal initial febrile convulsions, and delay in psychomotor milestones before the initial febrile seizure. Only about 1/3 of the children who developed afebrile seizures ever had a recurrent febrile convulsion and none had complex recurrent febrile seizures. Half the children with mental retardation had histories of delay in psychomotor milestones prior to the initial febrile seizure, and no child with mental retardation had any seizure longer than five minutes. The administration of daily phenobarbital did not reduce the frequency of epilepsy, in spite of a significant reduction in the incidence of recurrent febrile seizures. There remains no evidence that the prevention of recurrent febrile convulsions significantly decreases the frequency of afebrile seizures or mental retardation.     

Epilepsy and Mental Retardation Following Febrile Seizures In Childhood

ABSTRACT. In an unselected group of children who were seen following an initial febrile convulsion, the frequency of subsequent afebrile seizures was 3.5% and of mental retardation 1%. The most common afebrile seizure type was generalized major (86%). About 3/4 of the children who developed afebrile seizures did so by three years and all by five years following the initial febrile seizure. The children with afebrile seizures differed from those without afebrile seizures in the frequency of neonatal abnormality, family history of mental retardation, focal initial febrile convulsions, and delay in psychomotor milestones before the initial febrile seizure. Only about 1/3 of the children who developed afebrile seizures ever had a recurrent febrile convulsion and none had complex recurrent febrile seizures. Half the children with mental retardation had histories of delay in psychomotor milestones prior to the initial febrile seizure, and no child with mental retardation had any seizure longer than five minutes. The administration of daily phenobarbital did not reduce the frequency of epilepsy, in spite of a significant reduction in the incidence of recurrent febrile seizures. There remains no evidence that the prevention of recurrent febrile convulsions significantly decreases the frequency of afebrile seizures or mental retardation.     

PROPHYLAXIS AGAINST FEBRILE CONVULSIONS WITH PHENOBARBITAL

Abstract. Pilgaard, S., Hansen, F. J. and Paerregaard, P. (Department of Paediatrics, Sundby Hospital, Copenhagen, Denmark). Prophylaxis against febrile convulsions with phenobarbital. Acta Paediatr Scand, 70:67, 1981. An unselected patient material of 182 children admitted consecutively with febrile convulsions during a period of two years was classified into five risk-groups. Continuous phenobarbital therapy for two years was recommended for 113 children (Groups I-IV). These children were followed-up as outpatients for at least one year after admission. In children receiving phenobarbital therapy, serum concentrations were controlled every third month. A total of 59 children completed the treatment according to the directives given and seven of these (12%) developed renewed febrile convulsions despite serum phenobarbital concentrations within the therapeutic range (70–120 µmol/l). No particular characteristics for these children could be established on the basis of the parameters registered. The therapeutic model established was found to be suitable for distinguishing between children with massive risk for renewed convulsions (Groups I-IV) compared with children for whom treatment was not recommended (Group V).     

左乙拉西坦、丙戊酸钠、苯巴比妥预防大鼠反复热性惊厥疗效观察

目的：比较左乙拉西坦、丙戊酸钠、苯巴比妥对大鼠反复热性惊厥的预防作用的差异,指导临床选药。方法：60只Wistar大鼠,随机分为4组,分别每日灌服左乙拉西坦（200 mg/kg）、丙戊酸钠（250 mg/kg）、苯巴比妥（30 mg/kg）及生理盐水（8 mL/kg）。连续灌服5 d后,用热水浴（45℃）诱导热性惊厥,观察其热性惊厥潜伏期、惊厥持续时间、惊厥严重程度改变情况。结果：大鼠用药后,3个药物干预组惊厥潜伏期延长、惊厥持续时间缩短,惊厥严重程度也明显减轻,与对照组比较差异有统计学意义（P＜0.05或0.01）,其中苯巴比妥组惊厥持续时间最短,惊厥严重程度最轻;左乙拉西坦组与丙戊酸钠组差异无统计学意义。结论：左乙拉西坦与丙戊酸钠、苯巴比妥比较均能有效预防大鼠反复热性惊厥,其中苯巴比妥疗效较好,左乙拉西坦与丙戊酸钠疗效无差异。［中国当代儿科杂志,2010,12（7）：573-575］     

Changes in serum lipids and lipoproteins in epileptic children treated with anticonvulsants

Objective: To assess the effect of long-term treatment of phenobarbital, carbamazepine and sodium valproate on serum lipids and lipoproteins in epileptic children.
Methodology: One hundred and fourteen (55 male, 59 female) children and adolescents suffering from various types of epilepsy who received different antiepileptic drugs were studied. The patients were subdivided into three groups according to their therapy: (i) carbamazepine (35 patients); (ii) phenobarbital (34 patients); and (iii) sodium valproate (45 patients). One-hundred healthy sex- and age-matched children served as controls. Lipids and lipoprotein profile were evaluated before the beginning of the anticonvulsant therapy and after at least 2.5 years. In the patients receiving phenobarbital, we re-evaluated 12 children (seven male, five female) at the end of therapy.
Results: The children receiving phenobarbital showed high levels of serum total cholesterol and low-density lipoprotein (LDL) cholesterol and low levels of triglycerides, while children treated with carbamazepine had high levels of total cholesterol, triglycerides, LDL and high-density lipoprotein (HDL) cholesterol. Children treated with valproate had low triglycerides and LDL cholesterol levels with high levels of HDL cholesterol. The patients treated with phenobarbital showed a normalization of all parameters after the end of therapy.
Conclusions: Anticonvulsant drugs significantly modify serum lipids and lipoproteins in epileptic children. The changes due to phenobarbital seem to be transient.     

Reduction of serum carnitine concentrations during anticonvulsant therapy with phenobarbital, valproic acid, phenytoin, and carbamazepine in children

We determined four carnitine constituents (total and free carnitine and short- and long-chain fatty acid carnitine esters) in serum from 471 patients treated for convulsions with phenobarbital, valproic acid, phenytoin, and/or carbamazepine. The 471 patients were in eight treatment groups; four were treated with monotherapy and four with polytherapy. The means of all four carnitine constituents were significantly reduced in all treatment groups (except for free carnitine in four groups). Total carnitine was reduced by 23% to 48%, free carnitine by 9% to 45%, short-chain fatty acid carnitine by 46% to 64%, and long-chain fatty acid carnitine by 6% to 29%. Patient frequency of reduction for total carnitine was 20% of all patients (10% for free carnitine), 23% of patients receiving valproate (9% for free carnitine), 36% of those receiving phenobarbital (21% for free carnitine), 12% of those receiving phenytoin (8% for free carnitine), and 8% of those receiving carbamazepine (1% for free carnitine). Only for phenobarbital was there an inverse correlation between the serum concentration of the drug and that of carnitine concentration. One patient receiving carbamazepine had a 59% reduction in the total and a 65% reduction in the free carnitine concentration and a fivefold increase in long-chain fatty acid carnitine, values similar to those seen in neonatal lethal carnitine palmitoyl transferase II deficiency. It remains to be determined whether a reduction in serum carnitine values in patients receiving anticonvulsant therapy is of clinical consequence, whether the reduction is present in some patients before the start of therapy, when and by what mechanism carnitine levels may become reduced during therapy, and whether the reduction exists in the solid tissues of these patients.     

Lower degree of fever at the initial febrile convulsion is associated with increased risk of subsequent convulsions.

We studied 132 children admitted consecutively with their first febrile convulsion to assess whether the degree of fever at the onset of the convulsion can predict the risk of subsequent convulsions. The children studied were reviewed at least 2 years after the initial febrile convulsion to determine the number of children who had recurrences of febrile convulsions and/or afebrile convulsions. Children with body temperatures below 39 degrees C at the onset of their initial febrile convulsion (Group 1) were two and half times more likely to experience multiple convulsions within the same illness than those with body temperatures above 39 degrees C (Group 2). This occurred when the body temperature rose above that which had triggered the initial febrile convulsion. Children in Group 1 were also over three times more likely to experience recurrent febrile convulsion in subsequent illnesses than those in Group 2. As for subsequent development of afebrile convulsion or epilepsy, although the risk was low, it only occurred in Group 1. It is suggested that the known association between multiple convulsions, recurrent febrile convulsions and epilepsy may be due to the single predisposing factor of a low degree of fever at the onset of febrile convulsion. Each child with febrile convulsion may have his own threshold for eliciting a convulsion with fever; the lower this threshold is, the more likely are subsequent convulsions.     

The prognosis of convulsions during childhood shigellosis

We examined the long-term outcome in 111 children who had convulsions during shigellosis and were followed for 3–18 years after the incident. No deaths or persistent motor deficits occurred as sequellae. Poor coordination of fine hand movements were noted in 3.3% of the 92 children who had no pre-existing neurological abnormality. Only 1 child developed epilepsy by the age of 8 years. Of the children 15.7% had recurrent febrile seizures. The only risk factor identified for febrile seizures following convulsions in shigellosis was a previous history (P<0.01). These observations suggest that convulsions in shigellosis have a favourable prognosis, and do not necessitate long-term follow up.     

Febrile status epilepticus

As part of a study of status epilepticus in children (Maytal J, Shinnar S, Moshe SL, Alvarez LA. Pediatrics. 1989; 83:323-331); 44 children with febrile convulsions lasting more than 30 minutes were followed for a mean of 28 months (range 4 to 72). Thirty children were followed prospectively. Children with prior afebrile seizures or evidence of acute central nervous system infection were excluded. Nine (20%) children had prior neurological deficits. The duration of the febrile seizure was 0.5 to 1 hour in 41 cases (85%), 1 to 2 hours in 5 (10%), and greater than 2 hours in 2 children (5%). No child died or developed new neurological deficits following the seizures. The risk of recurrent seizures was increased, but only in the group with prior neurological abnormality. Six (66%) of these children had subsequent febrile seizures compared with 12 (34%) of the normal children (P = .08). Three (33%) had recurrent febrile status epilepticus compared with only 1 (3%) normal child (P = .023). The 2 children in the prospective arm of the study with recurrent febrile status epilepticus were both neurologically abnormal (P = .035). All 3 of the children who subsequently had afebrile seizures (2 prospective) were neurologically abnormal (P = .006 overall, P = .035 for prospective only). It is concluded that the occurrence of febrile status epilepticus in a neurologically impaired child is a risk factor for subsequent febrile as well as afebrile seizures. The occurrence of febrile status epilepticus in an otherwise normal child does not significantly increase the risk for subsequent febrile (brief or prolonged) or afebrile seizures in the first few years following the episode.     

Retrospective study of 160 children with febrile convulsions]

In a retrospective study of 411 children with cerebral convulsions over a period of 4 years, 160 patients with febrile seizures were found. This group consisted of 94 boys and 66 girls. The main purpose of this study was to establish the age of the first convulsive fit in each child. Febrile convulsions started in the first half year, increased in the second half year and culminated in the second year of life. This age dependent appearance was explained with passive immunization by maternal antibodies so that febrile convulsions appear when these antibodies decrease. The first occurrence of febrile convulsions appeared on an average of 22.9 months, in children with recurrent febrile convulsions a little earlier with 18.2 months. The most interesting fact was that children with a family history of febrile seizures showed an even earlier occurrence of the first seizure with 14.5 months. This tendency of early incidence of febrile convulsion in the group with family history and in the group of recurrent febrile convulsions could be shown as statistically significant respectively nearly significant in comparing with the group of retarded patients. A peculiar tendency for febrile convulsions seems to be documented by recurrent seizures in the patient himself, but also by a history of febrile convulsions in other family members. Both facts may lead to a very early incidence of febrile convulsions.     

Convulsions in childhood shigellosis. Clinical and laboratory features in 153 children

We studied 153 children who experienced convulsions associated with shigellosis. The male-female ratio was 1.2:1.0. Thirty-six children had a previous history of febrile convulsions, and 31 children had a family history of convulsive disorder. Most of the children were 0.5 to 3 years of age, although 49 (32%) were older than 3 years of age and 20 (13.1%) were older than 5 years of age. All children were febrile; in 75% of the children, the temperature was over 39 degrees C. The majority of the children had generalized, self-limited convulsions, which lasted less than ten minutes. In 30 children the seizures were categorized as complex; ten of them had recurrent episodes, although none had any residual neurologic deficit. The total leukocyte count was usually within normal limits, but the differential count characteristically showed a marked increase in the number of band forms. Hypocalcemia (blood calcium level, less than 9.01 mg/dL [less than 2.25 mmol/L]) was observed in four patients; hyponatremia (blood sodium level, 130 mEq/L [130 mmol/L]), in 11 patients; and hypernatremia (blood sodium level, 157 mEq/L [157 mmol/L]), in one patient. Electroencephalographic (EEG) studies were performed in ten children, and lumbar punctures were performed in 34 children; both procedures usually yielded normal results. Shigella sonnei was isolated from 69% of the children; Shigella flexneri from 25%; Shigella boydii from 5%; and Shigella dysenteriae from 1%. Due to the benign and self-limited nature of most of the convulsions, neither diagnostic procedures, nor drug therapy, are usually necessary. These measures should, however, be considered in complicated cases characterized by focal or prolonged seizures.     

Sodium valproate versus phenobarbital in the prophylactic treatment of febrile convulsions in childhood

Phenobarbital has been shown to offer effective prophylaxis against childhood febrile convulsions. However, a high percentage of children do not tolerate phenobarbital, mainly due to behavioral changes. Valproate, due to its low toxicity, appears to be an attractive alternative to phenobarbital treatment. Ninety children admitted with their first febrile convulsion were offered prophylactic treatment with either phenobarbital 3–5 mg/kg/day or valproate 20–30 mg /kg/day. Twenty-five children whose parents refused prophylactic treatment make up an untreated control group. Serum levels of the appropriate drug were measured at each follow-up visit. The three groups appear to be comparable. Twenty-one per cent of the phenobarbital treated children required discontinuation of the drug due to side effects. All the children tolerated valproate therapy.Twelve out of 25 untreated children suffered recurrences. Eight out of 33 children treated with phenobarbital suffered recurrences. Four out of 32 children on valproate therapy had recurrences. The difference between valproate treatment and no therapy at all is highly significant (P<0.0001). Phenobarbital did not reduce the risk of recurrence. We now recommend prophylactic treatment with valproate to children with febrile seizures.     

New aspects in prevention of febrile convulsions]

In general, febrile convulsions have a good prognosis. The risk of death or neurologic and mental handicap is low. Though the risk of epilepsy is increased, there is no evidence that anticonvulsant treatment can prevent occurrence of later epilepsy. The aim of anticonvulsive prophylaxis is reduction of the rate of recurrences of febrile convulsions. Recent results point against the assumption that these can be prevented by long-term anticonvulsive treatment with phenobarbital or valproate. An alternative for longterm prophylaxis is intermittent short-term rectal application of diazepam suggested for children with a hightened risk of recurrences. Long-term prophylaxis with phenobarbital should only be considered in a small number of selective children.     

Thalassemia major may decrease the frequency of febrile convulsions in children

Aim: We aimed to determine the relative frequency of febrile convulsion in children with major thalassemia to theorize that higher serum iron levels could reduce the incidence of febrile convulsion. Background: Febrile convulsion is the most common type of seizure in childhood that its causes are not fully understood. However, some risk factors have been cited such as the serum iron level. Materials and methods: Three hundred and fifty-nine children aged more than 5 years with major thalassemia who were receiving blood were enrolled as the case group. The control group consisted of 357 children without thalassemia aged 4–7 years (151 boys, 206 girls) who were referred to healthcare centers for routine health monitoring. Included data were the history of febrile convulsion, age of onset and type and the frequency of convulsions. Results: Children in control group significantly experienced more febrile convulsions than thalassemic children [4/359 (1.1%) in the thalassemic children and 14/357 (3.9%) in the control group had experienced febrile convulsions (P = 0.017)]. Conclusion: The frequency of febrile convulsion in children with major thalassemia is less than that of normal children. Children with thalassemia major may have higher serum levels of iron and such high serum iron levels might have a protective role in the children who have a vulnerability for febrile convulsions.     

Recurrence risk after first febrile seizure and effect of short term diazepam prophylaxis.

In a prospective randomised study, 289 children admitted consecutively to hospital with their first febrile seizure were allocated, by date of admission, to short term diazepam prophylaxis (n = 152) or to no prophylaxis (n = 137) and followed for 18 months. In untreated children, five major risk factors for recurrent febrile convulsions were identified: age 15 months or less at the time of the first febrile seizure, epilepsy in first degree relatives, febrile convulsions in first degree relatives, a first complex febrile seizure, and day nursery care. The 18 month recurrence rate was 80 to 100% if three to five risk factors were present, 50% if two factors were identified, 25% where one factor was found, and 12% if there were no predictors. During prophylaxis the recurrence rate was uniformly low (mean 12%) in all risk groups. In high (three or more factors) and intermediate (two factors) risk children prophylaxis provided effective seizure control and reduced the recurrence rate from 80%, or more, to 12% and 50% to 12%, respectively. In children with one risk factor 50% of all recurrences were prevented (25% to 12%). Prophylaxis was ineffective in very low risk children (12% to 12%).     

Viral infections and recurrences of febrile convulsions

To determine whether complicated febrile seizures occur more often in children with a proven viral infection, we performed viral examinations on 144 children with febrile convulsions, of whom 112 had simple and 32 had complicated seizures. A diagnosis of virus infection was verified in 46% of the former patients and 53% of the latter. Three adenoviruses, one parainfluenza virus type 2 and one type 3, one respiratory syncytial virus, one echovirus type 11, one herpes simplex virus type 2, and one influenza B virus were isolated from the cerebrospinal fluid. A simple febrile convulsion occurred in seven children with a positive cerebrospinal fluid viral isolation, and two had a complex febrile seizure. In a follow-up of 2 to 4 years (mean 3.3 years), 21 of the 107 children with simple seizures (19.6%) and 3 of the 32 children with complicated seizures (9.4%) had recurrent febrile seizures. The children with positive evidence for a viral infection, even with a virus isolated from the cerebrospinal fluid, had no more recurrences than those without any proven viral infection. We conclude that children with a proven viral infection have no worse prognosis than those without.     

Reduced carnitine and antiepileptic drugs: cause relationship or co-existence?

Serum carnitine was measured longitudinally before and after therapy in 15 patients receiving valproic acid, 14 patients receiving carbamazepine and 8 patients receiving phenobarbital. The patients who received valproic acid showed a significant reduction in free (and total) serum carnitine (mean (SE) 37.6 (6.2)/umol/l without valproic acid, 29.1 (1.6)/xmol/l with valproic acid (p < 0.001)). Such an effect was not found in patients receiving carbamazepine or phenobarbital.     

Spontaneous fits after convulsions with fever.

112 of an original sample of 134 children with febrile convulsions were reviewed between 8 years and 9 years 10 months after their initial attack. 17% of those followed up had had at least one spontaneous fit. A significant correlation was found with perinatal abnormalities. 12% had continuing recurrent fits. Persisting grand mal occurred most commonly in lower social class children who had had perinatal abnormalities and continued to have long-term neurological disorders. Psychomotor epilepsy correlated significantly with a prolonged or repeated initial convulsion with unilateral features. It is suggested that the development of grand mal and temporal lobe epilepsies after convulsions with fever are determined by different mechanisms.     

Serum thyroid hormones and pituitary response to thyrotropin-releasing hormone in epileptic children receiving anti-epileptic medication

Thyroid hormones and pituitary function were assessed in 49 children with epilepsy who were receiving either a single medication of carbamazepine, phenobarbital and valproate or a combination of carbamazepine with phenobarbital or valproate. All therapeutic regimens except valproate monotherapy were associated with low levels of circulating thyroxine, free tri-iodothyronine and free thyroxine. Carbamazepine with valproate was associated with the lowest serum concentration of thyroid hormones. It seems probable that accelerated hormone metabolism is responsible for these hormonal changes. However, all drug regimens also had effects on the function of the hypothalamic pituitary axis. Because of these findings, thyroid hormones should be checked frequently during anti-epileptic drug treatment, although clinical hypothyroidism was not seen in our patients.