Histamine in Cerebrospinal Fluid of Children with Febrile Convulsions

Summary: Febrile convulsions (FC) are frequent acute neurologic disturbances of childhood. The cellular and neurochemical mechanisms causing FC are unclear. Among other mechanisms, the CNS histamine (HA) has been suggested to participate in seizure control and thermoregulation. We evaluated the possible role of HA in regulation of FC by measuring HA and tele-methylhis- tamine (t–MH) concentrations in the cerebrospinal fluid (CSF) of children with FC. The study group consisted of 35 children treated for acute FC in the hospital. The control groups consisted of (a) feverish children without seizures ( n =23), (b) convulsive children without fever ( n =7), and (c) children with neither fever nor convulsions ( n =21). HA was assayed by high-performance liquid chromatography (HPLC) with fluorescence detection, and t-MH was measured by gas chromatography-mass spectrometry. CSF HA concentration in the group of febrile Convulsions occur rather frequently in connection with febrile children without seizures was significantly higher (0.69 ± 0.16 pmol/ml, mean k SE) than in children with FC (0.36 ± 0.07 pmol/ml, p <0.05, analysis of variance, ANOVA). HA concentration was 0.37 ± 0.18 pmoVml in the group of nonfebrile convulsive children and 0.36 k 0.08 pmol/ml in the nonfebrile nonconvulsive group. No statistical differences in t–MH were detected between groups. The increased susceptibility to seizures during fever may be connected to the lack of increase in CSF HA in the FC group. The data support the hypothesis that the central histaminergic neuron system may be involved in inhibition of seizures associated with febrile illnesses in childhood.     

Recurrent seizures in children with Shigella-associated convulsions

Fifty-five children with Shigella-associated convulsions were followed prospectively to investigate their risk of subsequent febrile or nonfebrile seizures. The duration of the follow-up period was between 6.9 and 14.1 years (9.7 +/- 3.1 years). No case of nonfebrile seizures and only 2 cases (3%) of subsequent febrile seizures were observed during this period. We conclude that although febrile and Shigella-associated convulsions share many clinical features, the natural history of these two conditions seems to be distinctly different. Shigella-related convulsions are not associated with an increased incidence of subsequent febrile or nonfebrile convulsions.     

Clinical characterization of gastroenteritis-related seizures in children: impact of fever and serum sodium levels

Gastroenteritis-related seizures have increasingly gained attention in recent years. Most cases follow a brief, benign course with very few episodes of seizure recurrence and without development of epilepsy. Published reports usually do not make a distinction between febrile and afebrile patients, and most authors include only nonfebrile convulsions in their reported series. This study evaluated the impact of fever in children presenting with seizures during a mild gastroenteritis episode and found that the presence or absence of fever did not affect seizure characteristics or duration. However, mild hyponatremia affected some seizure features, particularly seizure duration, as hyponatremic children sustained more prolonged seizures than patients with normal serum sodium levels, irrespective of body temperature.     

Clinical and immunological significance of neopterin measurement in cerebrospinal fluid in patients with febrile convulsions.

Neopterin is synthesized mainly by monocytes/macrophages and is considered to be a marker for activation of the cellular immune system. It has been reported that cerebrospinal fluid (CSF) neopterin levels are significantly higher in patients with bacterial meningitis than in those with aseptic meningitis or non-pleocytotic CSF. In this study levels of neopterin and interferon-gamma (IFN-gamma) were measured in children with non-pleocytotic CSF. The CSF neopterin levels were significantly higher in patients with typical febrile convulsions (FCs) (15.0 +/- 4.5 nmol/l) than in those with pyrexia without convulsions (6.5 +/- 2.7 nmol/l) or convulsions without pyrexia, namely, epilepsy (4.8 +/- 2.4 nmol/l). The CSF neopterin/serum neopterin ratio (C/S ratio) was also higher in patients with typical FCs (1.54 +/- 0.83) than in those with pyrexia without convulsions (0.32 +/- 0.18) or convulsions without pyrexia (0.77 +/- 0.28). Patients with prolonged FCs tended to have higher CSF neopterin levels than those with typical FCs. There was also a tendency for CSF IFN-gamma levels to be higher in patients with FCs than in those with pyrexia without convulsions or convulsions without pyrexia. The results of the present study suggest that some immune activation in the central nervous system (CNS) compartment may be related to the mechanisms of FCs.     

The Risk of Nonfebrile Seizures in Children Who Have Experienced Febrile Convulsions

Abstract: (1) The frequency of development of nonfebrile seizures in 116 children who had experienced at least one febrile convulsion and were followed for more than five to eight years was 4.3% (5 cases). Of these, three cases had prolonged generalized convulsions of the clonic or tonic-clonic type and two had brief generalized fits of the tonic-clonic type. (2) The risk factors identified as nonfebrile seizures after febrile convulsions were the preexisting neurological abnormality or developmental retardation, focal features and more than a 10-minute duration of the first febrile convulsions, and abnormal paroxysmal discharges at the initial interictal EEG recordings.     

Nonfebrile Illness Seizures: A Unique Seizure Category?

PURPOSE: To describe the clinical characteristics of children with a first-time nonfebrile seizure in the setting of mild illness and to test the hypothesis that these seizures are associated with illness characterized by diarrhea. METHODS: This retrospective cohort study was performed in a pediatric emergency department. Patients ages 6 months to 6 years who were evaluated with first-time seizures were eligible for inclusion. Subjects were divided into three groups on the basis of symptoms accompanying their seizure: febrile (temperature, >38.0 degrees C with seizure), unprovoked (no symptoms of illness), and nonfebrile illness (no fever at the time of seizure, but other symptoms of illness present). RESULTS: Of the 323 children with first-time seizures, 247 (76%) had febrile seizure, 37 (12%) had unprovoked seizures, and 39 (12%) had nonfebrile illness seizures. Children with nonfebrile illness seizures were more likely than children with febrile seizures to have diarrheal illnesses accompanying their seizure (44 vs. 16%; p=0.001). Frequency of cough, rhinorrhea, and rash did not differ significantly between children with febrile and nonfebrile illness seizures. Diagnostic testing for infectious etiologies was not performed frequently in either group. CONCLUSIONS: Nonfebrile illness seizures may represent a distinct group of seizures with unique epidemiology. Further study to define this seizure group better is warranted.     

Lipopolysaccharide-induced febrile convulsions in the rat: short-term sequelae

PURPOSE: Febrile convulsions (FCs) occur in children as a result of fever. The mechanisms involved in the genesis of FCs and their long-term consequences on brain development remain unclear. We have developed a model of FC, by using fever as a parameter, to test the hypothesis that fever can lower seizure threshold and to examine the neurologic sequelae of FCs. METHODS: Fourteen-day-old rat pups equipped with body-temperature telemetry devices exhibited approximately 1.5 degrees C fevers after lipopolysaccharide (Escherichia coli, 200 microg/kg). During such fevers, concurrently administered doses of kainic acid that are normally subconvulsant were used to induce convulsions with fever. Animals were then killed at varying times for pathological and immunohistochemical studies. RESULTS: The pairing of lipopolysaccharide and subconvulsant kainic acid resulted in convulsions in approximately 50% of febrile animals, with very low mortality. To study the neural correlates of these FCs, we used fos immunohistochemistry and found that animals with FCs had fos-positive immunoreactivity in brain regions involved in seizures. After a period of 72 h, we also examined brains for pathologic changes and found no differences among our groups. CONCLUSIONS: Our data indicate that a neuroimmune challenge and its accompanying fever reduce the seizure threshold. Furthermore, the FCs induced by fever in this model do not have short-term adverse effects on the brain. In addition, this model, by incorporating physiologic fever, may be useful for examining the role of fever and its constituent mediators in the genesis of FCs.     

Increased Concentration of Prostaglandin E-2 in Cerebrospinal Fluid of Children with Febrile Convulsions

Concentrations of prostaglandins (PGs) in the central nervous system are known to increase during and after experimentally induced seizures. In the present study, concentrations of PGE-2 were determined by radioimmunoassay in lumbar cerebrospinal fluid (CSF) of 17 children shortly after a febrile convulsion. PGE-2 data of these children were compared with those determined in afebrile children and febrile children without convulsions. Duration of storage of CSF samples at -30 degrees C prior to analysis had no influence on PGE-2 levels. Compared with afebrile patients, PGE-2 levels were significantly higher after febrile convulsions. Significantly elevated concentrations of PGE-2 were also found in febrile children without seizures, although the mean PGE-2 level in these patients was somewhat lower than that determined after a febrile convulsion. When body temperature of the patients was compared with their CSF PGE-2 levels, a significant positive correlation was determined between both variables. It is therefore not clear if the increased concentrations of PGE-2 in CSF of patients with febrile convulsions are, at least in part, to be related to increased PG synthesis and release during and after the seizure or are solely to be related to the febrile state of the children.     

Arginine vasopressin concentrations in the cerebrospinal fluid of children

Cerebrospinal fluid (CSF) arginine vasopressin (AVP) levels are reported in a group of 22 children (median age 24 months) investigated for possible bacterial meningitis and subsequently found not to be suffering from this disease. The mean CSF AVP concentration was 0.80±0.33 pg/ml. The results obtained in patients suffering from febrile convulsions (mean 0.71 pg/ml), other convulsive disorders (mean 0.80 pg/ml) and miscellaneous infectious disease (mean 0.85 pg/ml) did not differ significantly from one another. Our findings confirm the presence of AVP in the CSF of children and provide reference values for further investigations into the functions of CSF AVP in children.     

The risk of epilepsy following febrile convulsions

A cohort of 666 children who had convulsions with fever were followed to determine the risks of subsequent epilepsy. High risks were found in children with preexisting cerebral palsy or mental retardation. Other major risk factors were atypical features of the febrile convulsions (such as focal seizures) and duration of febrile seizures for 10 minuts or more. The risk of developing epilepsy by age 20 was about 6 percent for all children who had experienced febrile convulsions. However, this risk figure consisted of a combination of 2.5 percent of children without prior neurologic disorder or atypical or prolonged seizures, and 17 percent of those with such complications.     

热性惊厥持续状态复发的危险因素分析

目的 探讨儿童热性惊厥持续状态(FSE)复发的危险因素.方法 收集138例FSE患儿的临床资料,并于出院后进行2个月至8.3年的随访.根据随访结果,将患儿分为热性惊厥复发组、癫痫进展组及无惊厥复发组,分析FSE复发的相关因素.结果 根据随访结果,热性惊厥复发30例(21.7％)(热性惊厥复发组),8例(5.8％)进展为...     

gamma-Aminobutyric acid in CSF of children with febrile seizures

Previous studies have suggested that levels of cerebrospinal fluid (CSF) gamma-aminobutyric acid (GABA) may be decreased in children with febrile seizures. We used gas chromatography and mass spectrometry to measure CSF GABA levels in 14 children with febrile seizures. The results were compared with the GABA levels in six children with first-time afebrile seizures, three with recurrent febrile seizures, and 13 controls (febrile children undergoing lumbar puncture to rule out meningitis). Children with central nervous system infections or known neurologic disease were excluded. The CSF GABA levels in children with febrile seizures were not significantly different from those in controls and children with afebrile or recurrent febrile seizures. In the control group, CSF GABA levels correlated with increasing age. There was no correlation with severity of febrile response in any group. The results indicated that the CSF GABA level may not be abnormal in patients with first-time febrile convulsions.     

Low CSF GABA concentration in children with febrile convulsions,untreated epilepsy,and meningitis

In 14 children with epilepsy, 51 with febrile convulsions and 22 with meningitis gamma-aminobutyric acid (GABA) concentrations in lumbar CSF were determined. While the mean for CSF GABA concentrations for all epileptic children was unchanged [144 (range: 73-285) pmol/ml; controls: 148 (range: 90-243) pmol/ml] extraordinarily high GABA levels were found in the CSF of two children on valproate (525 and 557 pmol/ml) and remarkably low GABA concentrations in hitherto untreated epileptic children [109 (range: 67-176) pmol/ml]. Children with febrile convulsions [103 (range: 63-170) pmol/ml] and acute meningitis [105 (range: 65-171) pmol/ml] had significantly decreased CSF GABA concentrations (P less than 0.001 and P less than 0.02 compared with controls). The data indicate that valproate intake increases dramatically the GABA concentrations in the CSF of epileptic children. Furthermore, the study supports the concept that low GABAergic activity within the CNS may be one cause for an increased seizure frequency.     

Cerebrospinal fluid neurohypophysial peptides in benign intracranial hypertension.

The cerebrospinal fluid (CSF) concentrations of arginine vasopressin (AVP) and oxytocin (OT) were investigated both in patients with benign intracranial hypertension and in age and sex matched controls. Twenty eight lumbar punctures were performed on 15 patients with benign intracranial hypertension as part of their routine investigation and therapy. All patients had raised intracranial pressure (27.4, SE 1.7 cm.CSF). CSF AVP levels were significantly elevated in benign intracranial hypertension (2.1, SE 0.3 pmol/l) compared with controls (0.7, SE 0.1 pmol/l, p less than 0.001) but CSF OT concentrations were similar in both groups. CSF osmolality and plasma AVP and osmolality were identical in patients and controls. There was no correlation between CSF AVP concentration and intracranial pressure. The selective elevation of AVP in CSF may be of importance in the pathogenesis of raised intracranial pressure in benign intracranial hypertension.     

The lack of association between febrile convulsions and polymorphisms in SCN1A

Febrile convulsions (FCs) represent the majority of childhood seizures, and patients have a genetic predisposition to their development. The genetic susceptibility to FCs seems to involve multiple genes in most instances. Recent studies provided evidence that mutations in SCN1A represent the most frequent cause of generalized epilepsy with febrile seizures plus an autosomal-dominant epilepsy syndrome. SCN1A mutations alter channel inactivation, resulting in persistent inward sodium current. It is not known if polymorphisms in those genes involved in familial epilepsies also contribute to the pathogenesis of FCs. By performing an association study, we used single nucleotide polymorphisms to investigate the distribution of genotypes of SCN1A in patients with FCs. A total of 104 Taiwanese children with FCs and 83 normal control subjects were included in the study. Polymerase chain reaction was used to identify the A/G polymorphism of the SCN1A gene. The results showed that genotypes and allelic frequencies for the SCN1A gene polymorphisms in both groups were not significantly different. These data suggest that the SCN1A gene might not be one of the susceptibility factors for FCs. Pure FCs and febrile convulsions associated with idiopathic generalized epilepsy may not share a common genetic etiology.     

Prevalence and Incidence of Epilepsy in Tokyo

All children 3 years of age on January 1, 1975 in the Fuchu area of Tokyo were neurologically examined for 6 years (number examined: 17,044). The cumulative incidence of epilepsy (i.e., recurrent nonfebrile seizures) was 4.3/1,000 and that of occurrence of a single nonfebrile seizure (NS) was 4.7/1,000. Febrile convulsions (FCs) were observed in 82/1,000 in this population. The population was followed for 6-11 years after the first examination. During the follow-up (a) 4 of 80 children who had a single NS before age 3 years developed recurrence after age 3 years; (b) development of epilepsy was found in three of 1,323 randomly (10%) selected healthy children for comparison (2.3/1,000); (c) among 1,406 children with FCs, epilepsy developed in 24 (17/1,000) and a single NS occurred in 28 (20/1,000); and (d) the total cumulative incidence of epilepsy was 8.2/1,000 in the population aged 9-14 years. Age-specific annual incidence of epilepsy was highest in the age range 0-1 year (1.9/1,000), gradually falling with advancing age. The point prevalence for active epilepsy (having had a seizure within the past 5 years) was 2.8/1,000; that for inactive epilepsy was 5.4/1,000 (total 8.2/1,000). Epilepsy developed by age 14 years in (a) one-half of children with NS, (b) approximately 2% children with FCs, (c) 0.2% of healthy children with no seizure before age 3 years, and (d) an estimated 2% of potential epileptic carriers (having spike EEG abnormality by age 3; 15% of the population) who had not had a seizure by age 3 years.     

Arginine vasopressin in the pathogenesis of febrile convulsion and temporal lobe epilepsy

We aimed to investigate the possible convulsant action of arginine vasopressin (AVP) in both a febrile convulsion model in rat pups and a temporal lobe epilepsy model in adult rats and to define the receptor type which mediates this effect. In rat pups, 125 ng V2 receptor antagonist significantly prevented hyperthermic seizures, but did not affect seizure latency. In adult rats, the only effective dose and agent was 125 ng V2 receptor antagonist, which prevented pilocarpine-induced status epilepticus, extended the status epilepticus latency and improved the 24 h survival rate. These data suggest that AVP has a convulsant activity in febrile convulsions and also in seizures independent of fever, and this effect is mediated by V2 receptors.     

Clinical and genetic analysis of a new multigenerational pedigree with GEFS+ (Generalized Epilepsy with Febrile Seizures Plus)

Febrile seizures affect 2-5% of all children younger than 6 years. A small proportion of children with febrile seizures later develop epilepsy. The syndrome of generalized epilepsy with febrile seizures plus (GEFS+) is a heterogeneous disorder characterized by febrile seizures that may persist beyond age 6 years and nonfebrile seizures. Several genes have been localized for FS by linkage analysis, and three GEFS+ genes (SCN1A, SCN1B, GABRG2) have been identified. We identified a large multigenerational family with GEFS+ in France. All affected members had FSs. Among them, seven had other types of epileptic seizures including FSs after age 6 years, nonfebrile generalized seizures, or partial seizures later in life. Genetic linkage study excluded the candidate genes and loci for FS and GEFS+, thus proving the existence of a new GEFS+ genetic locus underlying the phenotype observed in this family.     

The concentrations of GABA, 5-HIAA and HVA in the cerebrospinal fluid of children with infantile spasms and the effects of ACTH treatment.

Children with infantile spasms (IS) are generally treated with ACTH although little is known of the biochemical basis of the symptoms and the mechanism of this therapy. We have measured the concentrations of gamma-aminobutyric acid (GABA), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the CSF of IS children, followed the effect of ACTH treatment on these parameters and correlated CSF GABA values with the cause of IS, cranial CT findings and antiepileptic treatment. While significant differences in GABA concentrations were found between the children with IS and those with febrile seizures or nonconvulsive symptoms, these could be accounted for by age, not the disease present. The CSF GABA level was highest in the IS children with normal CT, cryptogenic cause and no antiepileptic treatment, and lowest in those with abnormal CT, symptomatic cause and antiepileptic treatment. The basal level of CSF 5-HIAA in the IS children was higher than that in the nonconvulsive children, but HVA levels did not differ. ACTH therapy did not change the CSF levels of GABA, 5-HIAA and HVA significantly.     

Glutamic acid decarboxylase in cerebrospinal fluid in infancy and childhood Part II. Glutamic acid decarboxylase activity in cerebrospinal fluid of children with neurological diseases

Glutamic acid decarboxylase (GAD) activity in cerebrospinal fluid (CSF) was determined in 53 patients with neurological diseases as follows: Epilepsy (n:17), febrile convulsions (n:3), meningoencephalitis (n:17), encephalopathies (n:10), CNS leukemia (n:3), congenital hydrocephalus (n:2) and pseudoileus neonatorum (n:1). Compared with the mean normal value (5.2 +/- 2.5 pmol CO2 formed/hr/ml) reported in Part I, a significant increase of GAD activity in CSF was demonstrated in patients with uncontrolled epileptic seizures (11.4 +/- 3.9 pmol CO2 formed/hr/ml), febrile convulsions (13.5 +/- 8.7), viral meningitis with or without encephalitis (20.3 +/- 13.6), encephalopathies (30.0 +/- 25.9), CNS leukemia (11.1 +/- 5.0), congenital hydrocephalus (20.5 +/- 7.3) and pseudoileus neonatorum (28.6). Markedly high GAD activity was found in patients with CNS leukemia several days after intrathecal injection of methotrexate (39.8 +/- 18.0). On the other hand, significantly low GAD activity was shown in patients with bacterial meningitis or brain abscess (1.3 +/- 1.2). This suggests that some bacterial factors may be inhibitory toward GAD activity in CSF. High GAD activity in CSF may be useful as an indicator of aseptic brain dysfunction, although it was not always correlated with the severity of symptoms.