Cerebrospinal Fluid Purine Metabolites and Pyrimidine Bases After Brief Febrile Convulsions

Summary: Adenosine monophosphate, inosine monophosphate, inosine, adenosine, guanosine, adenine, guanine, hypoxanthine, xanthine, uric acid, and pyrimidines bases were determined in cerebrospinal fluid (CSF) of 52 children after simple febrile seizures and in a control group of 63 children. There was no statistically significant difference between the two groups for any of these metabolites, suggesting that simple febrile seizures (SFS) neither significantly disturb the metabolism of nucleotides, nucleosides, or bases nor significantly deplete neuron adenosine ATP levels. Therefore, they do not appear to constitute a threat of neuronal damage.     

Cerebrospinal fluid purine metabolite and neuron-specific enolase concentrations after febrile seizures

If febrile seizures cause significant compromise of neuronal metabolism (whether permanent or reversible), this should be reflected in an increase in the cerebrospinal fluid concentrations of neuron-specific enolase (NSE) and/or adenosine triphosphate (ATP) breakdown products. In the present study, AMP, IMP, inosine, adenosine, guanosine, adenine, guanine, hypoxanthine, xanthine, uric acid and NSE concentrations were determined in the cerebrospinal fluid of 90 children 1 h after febrile seizure (73 simple febrile seizures (SFS); 17 complex febrile seizures (CFS)), and in a control group of 160 children. There was no statistically significant difference between the SFS group and the control group for any of the substances determined, suggesting that SFS neither significantly depletes neuronal ATP concentration, nor significantly increases NSE concentration; thus, SFS do not appear to constitute a threat to neuronal integrity. However, patients with CFS showed significantly lower IMP concentrations and significantly higher adenine concentrations than controls, and significantly higher AMP concentrations than SFS patients; these results suggest that CFS may affect energy metabolism in the brain. However, NSE concentrations were normal in the cerebrospinal fluid of both SFS and CFS patients, suggesting that neither type of seizure causes significant neuronal damage, at least early after the seizure.     

PURINE METABOLITES AND PYRIMIDINE BASES IN CEREBROSPINAL FLUID OF CHILDREN WITH SIMPLE FEBRILE SEIZURES

Adenosine monophosphate, inosine monophosphate, inosine, adenosine, guanosine, adenine, guanine, hypoxanthine, xanthine, uric acid and pyrimidine bases were determined in the CSF of 18 children after simple febrile seizures and in a control group. There was no statistically significant difference between the two groups for any of these metabolites. This suggests that simple febrile seizures neither significantly disturb the metabolism of nucleotides, nucleosides or bases, nor significantly deplete neuron adenosine triphosphate ATP levels.     

Differences in iron deficiency anemia and mean platelet volume between children with simple and complex febrile seizures

ObjectiveThe relationship between iron deficiency anemia and febrile seizures (FSs) were examined in several studies before. The aim of our study is to find out the differences regarding iron deficiency anemia, demographic characteristics and mean platelet volume (MPV) which is an inflammatory marker between simple and complex febrile seizure groups.MethodsIn this study, the authors investigated the recordings of 493 children with a diagnosis of simple and complex febrile seizure, aged between 6 months and 6 years, followed between 2002 and 2010 retrospectively.ResultsMean age and male/female ratio were similar in two groups. There was no significant difference regarding with age, gender and family history of FS between two groups. We found significant difference statistically with respect to gestational age, consanguinity, family history of epilepsy and birth weight between two groups. The mean levels of Hb, Htc, MCV were lower and Plt and RDW levels were higher in children with CFS than SFS group, the differences were statistically significant (p: 0.001).A higher proportion of children with CFS (16.2%) had iron deficiency anemia compared to SFS group (12.1%). Mean platelet volume (MPV) of CFS (7.99 ± 0.96 fL) were significantly lower than that of SFS group (8.77 ± 0.75) (p < 0.001).ConclusionsThe results of this study suggests that iron deficiency anemia is more frequently seen among the patients with CFS than the patients with SFS. The lower levels of MPV as an inflammatory marker, supports the idea that CFS is a brain inflammatory disease and the consequence of this inflammatory mechanism is the development of the epilepsy. Further studies are necessary to highlight the relationship between iron metabolism, inflammation and seizures.     

Concentrations of nucleotides, nucleosides, purine bases, oxypurines, uric acid, and neuron-specific enolase in the cerebrospinal fluid of children with sepsis

To determine the effects of sepsis on cerebral energy metabolism, the cerebrospinal fluid adenosine monophosphate, inosine monophosphate, inosine, adenosine, guanosine, hypoxanthine, xanthine, and urate concentrations were determined by high-performance liquid chromatography and the neuron-specific enolase levels by means of an enzyme immunoassay method in 32 children with sepsis, without meningitis, aged between 2 months and 13 years, and in 160 age-matched controls. The septic group had significantly higher cerebrospinal fluid concentrations of inosine, adenosine, xanthine, and urate than controls. These results suggest that sepsis could provoke some degree of neuronal hypoxia and significant alterations of cerebral energy metabolism homeostasis.     

Roles of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases 1 in acute encephalopathy following prolonged febrile seizures

Prolonged febrile seizures may be followed by acute encephalopathy with neurological sequelae. To investigate the function of the blood-brain-barrier (BBB) in acute encephalopathy following prolonged febrile seizures with neurological sequelae (AEPFS), the concentrations of serum matrix metalloproteinase-9 (MMP-9) and tissue inhibitors of metalloproteinases 1 (TIMP-1) were measured by ELISA in 10 children with AEPFS, 16 with prolonged febrile seizures without encephalopathy (PFS), 20 with simple febrile seizures (SFS), 23 with convulsive status epilepticus (CSE), and 18 with West syndrome. Serum MMP-9 levels in AEPFS and PFS patients were significantly higher than those in SPS and West syndrome patients and in controls, and those in CSE patients were significantly higher than in controls. Serum TIMP-1 levels in AEPFS patients were significantly lower than those in PFS, SFS, CSE and West syndrome patients and in controls. Serum MMP-9 levels and MMP-9/TIMP-1 ratios in AEPFS patients with motor paralysis were significantly higher than for those without motor paralysis. Our results suggest that prolonged seizures are related to high serum MMP-9 levels, and that an increased MMP-9/TIMP-1 ratio in AEPFS might induce dysfunction of the BBB. Furthermore, an imbalance of serum MMP-9 and TIMP-1 levels in patients with AEPFS may be associated with severe neurological sequelae.     

Do clinical variables predict an abnormal EEG in patients with complex febrile seizures?

PURPOSE: Febrile seizures are the commonest convulsive event in children younger than 5 years of age (incidence of 2-5%). Electroencephalography (EEG) is not indicated in the work up of simple febrile seizures. Information about its role in the assessment of complex febrile seizures (CFSs) is unclear and EEGs are frequently ordered. This study was designed to assess utility of clinical variables at presentation in predicting the likelihood of an abnormal EEG. METHODS: EEG requisitions, EEG reports, clinic charts and medical records over an 11-year period (1990--2001) were retrospectively reviewed. The relationship between clinical variables like age, timing of the EEG since CFS, family history of seizures, neurological assessment and EEG abnormalities was statistically analyzed. RESULTS: One hundred and seventy-five children were included in the study. Of these 39.43% had EEG abnormalities. Children with a normal EEG were younger than those with an abnormal EEG (mean age 15.72 months versus 19.75 months, p<0.05). Using multivariate analysis, factors predictive of abnormal EEGs in children with CFS were; age >3 years (p=0.010; 95% CI: 1.5--18.8), EEGs performed within 7 days (p=0.00; 95% CI: 1.78--7.12) and an abnormal neurological exam (p=0.053; 95% CI: 0.98--16.9). A family history of febrile seizures was more likely to be associated with a normal EEG (p=0.01; 95% CI: 0.04--0.60). CONCLUSIONS: Clinical variables at presentation can be used to screen children with CFS for whom an EEG is considered. This may lead to better use of resources. Whether abnormal EEG translates to future recurrences or epilepsy needs a prospective study.     

Total cerebral volume is reduced in patients with localization-related epilepsy and a history of complex febrile seizures

CONTEXT: Febrile seizures may lead to later epilepsy. They have been associated with hippocampal atrophy but their effect on total cerebral volume is unknown. OBJECTIVE: To compare total cerebral volume in patients with mesial temporal lobe epilepsy with and without a history of complex febrile seizures (CFS). DESIGN: Survey. SETTING: Epilepsy monitoring center. SUBJECTS: Forty patients with localization-related epilepsy and temporal lobe onset determined by video electroencephalogram and 20 controls. INTERVENTION: Magnetic resonance imaging measurement of cerebral volume. MAIN OUTCOME MEASURE: Total cerebral volume. RESULTS: Patients with a history of CFS had significantly reduced total cerebral volume compared with patients without CFS. In addition, male patients with CFS had significantly lower total cerebral volume than male normal controls. There was no significant difference between patients without CFS, or all patients, and controls. CONCLUSION: Complex febrile seizures may have a global effect on brain development.     

Neuron-specific enolase,nucleotides, nucleosides,purine bases,oxypurines and uric acid concentrations in cerebrospinal fluid of children with meningitis

To determine the effects of meningitis on cerebral energy metabolism, cerebrospinal fluid concentrations of adenosine monophosphate, inosine monophosphate, inosine, adenosine, guanosine, adenine, guanine, hypoxanthine, xanthine and urate were determined by high-performance liquid chromatography, and neuron-specific enolase by an enzyme immunoassay method, in 100 children with meningitis (45 bacterial, 46 viral and nine tuberculous), aged between 1 month and 13 years, and in 160 age-matched controls. Compared with controls, patients with bacterial meningitis showed high concentrations of hypoxanthine, xanthine and urate; patients with viral meningitis showed high concentrations of inosine, guanosine, xanthine, urate and neuron-specific enolase; and patients with tuberculous meningitis showed very high concentrations of inosine, xanthine and urate. Xanthine and urate concentrations were significantly higher in patients with tuberculous meningitis than in patients with viral or bacterial meningitis. These results suggest that in the acute stage of bacterial, viral and tuberculous meningitis, neuronal energy metabolism may be altered. The measurement of cerebrospinal xanthine and uric acid concentrations may be useful for the early diagnosis of a tuberculous origin.     

Hippocampal volumetry in children 6 years or younger: assessment of children with and without complex febrile seizures

PURPOSE: To study the relationship of complex febrile seizures (CFS) in the evolution of mesial temporal sclerosis. METHODS: We studied five children 22-68 (mean 44) months old with MRI volumetry 2 days-46 months after their first CFS, and compared total hippocampal volumes and right to left hippocampal volume ratios to those of 11 controls, 15-83 (mean 55) months old, who had MRI for complaints which turned out to be neurologically insignificant. RESULTS: In control children, total hippocampal volumes increased linearly with age, while right to left hippocampal volume ratios tended to decrease with age. In children with CFS total hippocampal volumes tended to be smaller than in controls. Right to left ratios were greater than 1 in all five children with CFS compared to seven of 11 controls. Hippocampal asymmetry was noted in only one child, with the right to left volume ratio exceeding two standard deviations from the control mean. The MRI of this child also demonstrated a subarachnoid cyst in the left frontocentral region, ipsilateral to the smaller hippocampus. Visual inspection of the remaining patients revealed no definite structural cortical abnormalities. None of the children developed subsequent afebrile seizures during the brief follow-up period. CONCLUSIONS: Hippocampal volumetry in controls revealed a linear increase in total hippocampal volumes and a statistically nonsignificant trend toward reduced right larger than left hippocampal ratios between 17 and 83 months old. The tendency for smaller total hippocampal volumes and larger right to left hippocampal volume ratios in children with CFS compared to controls could suggest a developmental abnormality, injury during CFS, or be age-related. The significant hippocampal asymmetry in a single child with CFS suggests that age may not be a factor in every case. Further studies are needed to collect control data in young children as well as prospectively follow children with CFS with serial imaging to better understand the relationship between CFS and the evolution of hippocampal atrophy.     

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.     

Influenza A and febrile seizures in childhood

The aims of the present study are to identify predisposing factors of febrile seizures in influenza A infection and to clarify the special characteristics of febrile seizures in children with influenza A infection. Between January and July 2005, children hospitalized because of febrile seizures and subsequently confirmed influenza A infection were enrolled as subjects. Age-matched control subjects were those admitted as a result of influenza A infection but no febrile seizures (control 1) and children who developed febrile seizures with negative viral studies (control 2). Significant factors for the development of febrile seizures include: history of febrile seizures, family history of seizure disorders, and coexisting gastroenteritis. Independent risk factor for febrile seizures was history of febrile seizures (odds ratio 7.58, 95% confidence interval CI 1.48 to 38.84, P = 0.015). When compared with children who developed febrile seizures with negative virus studies, children who developed febrile seizures in influenza A infection had a significantly higher maximum body temperature, shorter duration of fever before seizure onset, and more frequent occurrence of partial seizures. Current episode represented first seizure in 26.5% of children infected with influenza A as compared with 50% of children whose virus studies were negative (P = 0.04). The findings suggest that effective vaccination may prevent development of febrile seizures, especially in those patients with past history of febrile seizures. Rapid diagnostic testing for influenza infection in the management of complex febrile seizures, especially during influenza season, is cost-effective.     

Repetitive febrile seizures in rat pups cause long-lasting deficits in synaptic plasticity and NR2A tyrosine phosphorylation

Adult rats with early-life frequently repetitive febrile seizures (FRFS), but not single febrile seizure (SFS), exhibited impaired performance in inhibitory avoidance tasks but without significant hippocampal neuronal loss. The mechanisms of long-term memory impairment in the hippocampus of adult rats with early-life FRFS remain unknown. Using a heated-air febrile seizures (FS) paradigm, male rat pups were subjected to single or nine episodes of brief FS at days 10 to 12 postpartum. We found that early-life FRFS led to long-term bidirectional modulation in hippocampal synaptic plasticity, i.e., impaired long-term potentiation and facilitated long-term depression. Three hours after inhibitory avoidance training, phosphorylation of hippocampal extracellular signal-regulated kinase (ERK) 1/2 was significantly less in the FRFS group than in controls. Furthermore, there was a selective alteration in NMDA receptor-mediated ERK1/2 phosphorylation in the hippocampus of the FRFS group. Although the expression levels of NMDA receptor subunits and interaction of NMDA receptor and postsynaptic density 95 did not alter quantitatively, there was a specific alteration in NR2A, but not NR2B, subunit tyrosine phosphorylation after NMDA stimulation in the FRFS group. These data offer a potential molecular explanation for the hippocampus-dependent memory deficits observed in the rats with early-life FRFS.     

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.     

Seizures with Fever After Unprovoked Seizures: An Analysis in Children Followed from the Time of a First Febrile Seizure

Summary: Purpose: To determine how the onset of unprovoked seizures influences recurrence of seizures with fever in children followed from the time of a first febrile seizure.
Methods: In a prospective cohort of children (n = 428) identified at the time of a first febrile seizure, predictors of a second seizure with fever were identified. The occurrence of a first unprovoked seizure was treated as a time-dependent covariate in a Cox regression model rather than as a censoring point as it traditionally has been in the past.
Results: One hundred forty-three (33.4%) children had further seizures. Seven had further seizures with fever only after onset of unprovoked seizures. After adjustment was made for the four previously described predictors of recurrent febrile seizures (age at onset, family history, height of fever, and duration of fever), the onset of unprovoked seizures was associated with a rate ratio of 3.47 (p = 0.0015), indicating a large increase in the risk of further seizures with fever after onset of unprovoked seizures.
Conclusions: Young children who develop unprovoked seizures after a febrile seizure are at substantial risk for further seizures with fever. This may represent part of the spectrum of benign febrile seizures or it may represent the so-called "epilepsy triggered by fever" spectrum. It affects only a small proportion of children with febrile seizures; however, in some children, it may be useful information to consider when making treatment decisions.     

Increased IL-1beta production from dsRNA-stimulated leukocytes in febrile seizures

This study examined the possibility that children with and without a history of febrile seizures might mount different immune responses to double-stranded ribonucleic acid, which is a common viral factor that induces host cell immune responses, and is recognized by Toll-like receptor 3. The production of interleukin-1beta and interferon-alpha from double-stranded ribonucleic acid-stimulated leukocytes was examined in 27 children (age 3.6+/-0.3 years) with a history of febrile seizures and in 18 children (age 3.4+/-0.2 years) without a history of febrile seizures. Significantly (P=0.0007) increased interleukin-1beta production was observed in children with a history of febrile seizures, compared with control subjects. When patients with a single prior episode of febrile seizures (n=9) and those with multiple prior episodes of febrile seizures (n=18) were compared, a significant difference in interleukin-1beta production was not observed. Genotyping of interleukin-1beta(-511), Toll-like receptor 3, Toll-IL-1 receptor domain-containing adapter inducing interferon-beta, and interleukin-1 receptor antagonist polymorphisms revealed no significant differences in allelic distribution among febrile seizure patients and control subjects. Interleukin-1beta production was not significantly influenced by genotype. Viral infection results in increased interleukin-1beta production in febrile seizure patients, and this may play a role in febrile seizures.     

The value of early postictal EEG in children with complex febrile seizures

PURPOSE: To assess the usefulness of an early postictal EEG in neurologically normal children with complex febrile seizures. METHODS: We conducted a retrospective chart review of all neurologically normal children who were hospitalized over a period of 2.5 years after complex febrile seizures, and had an EEG up to 1 week after the seizure. RESULTS: Thirty-three patients (mean age, 17.8 months) qualified for inclusion into the study. Twenty-four patients were qualified as complex cases based on one factor (prolonged in 9, repetitive in 13, and focal in 2). Nine other patients had two complex factors: in six patients, the seizures were long and repetitive; in two patients, the seizures were focal and repetitive; and in one patient, the seizures were long, focal, and repetitive. Thirteen (39%) patients experienced prior febrile seizures. All 33 patients had a normal postictal sleep EEG. Our results indicate with a 95% probability that the true rate of abnormalities in an early postictal EEG performed on otherwise normal children with complex febrile seizures is 8.6% or less. CONCLUSIONS: The yield of abnormalities of an early postictal EEG in this population is low and similar to the reported rate of abnormalities in children with simple febrile seizures. The routine practice of obtaining an early EEG in neurologically normal children with complex febrile seizures is not justified.     

High incidence of status epilepticus and ongoing seizures on arrival to the hospital due to high prevalence of febrile seizures in Izumo,Japan: A questionnaire-based study

ObjectivesTo determine the incidence of prolonged febrile seizures and status epilepticus in the first three years of life.MethodsA questionnaire was sent to 1560 families between April 2016 and March 2017 before their child attended a routine health check at three years of age in Izumo, Shimane prefecture, Japan. The questionnaire included an overview of febrile seizures, including the age at which febrile seizures occurred, the duration, and how the condition was managed.ResultsWe received 1089 (69.8%) responses and these showed that 134 (12.3%) children had a history of febrile seizures. Fourteen children with febrile seizures (10.4%) had prolonged seizures lasting 10–30 min and six children (4.5%) had status epilepticus. Ongoing febrile seizures that did not terminate on arrival to the hospital were observed in 11 children (8.2%) with febrile seizures. The incidence rates of status epilepticus, prolonged febrile seizures including status epilepticus and ongoing febrile seizures were 184, 612 and 337 per 100,000 children aged 36 months or less, respectively.ConclusionsThere was a greater incidence of status epilepticus than previously thought, possibly due to the high prevalence of febrile seizures in Japan. Eight percent of children with febrile seizures were seizing on arrival to the hospital. These ongoing seizures requiring emergency interventions were almost twice more than status epilepticus. Thus, it is necessary to develop an early intervention for the termination of prolonged febrile seizures.     

Febrile convulsions after 5 years of age: long-term follow-up

In order to examine the natural history of febrile convulsions occurring after 5 years of age, we studied 44 children in whom febrile convulsions persisted after 5 years of age (group 1) and compared their development of unprovoked seizures with a group of 195 children in whom febrile convulsions occurred before 5 years of age (group 2). All subjects of group 1 were re-evaluated at the mean age of 13.4+/-1.7 years. The children in group 2 were followed up until they reached the same mean age as children in group 1 (13.1+/-2.3 years). In group 1, we found a higher percentage of unprovoked seizures than in children with febrile convulsions with onset before 5 years of age (18.1% vs 7.4%, P < .05). Our data suggest that children with febrile convulsions after 5 years of age probably must be considered as a group of patients at risk of developing unprovoked seizures.     

Childhood-onset epilepsy with and without preceding febrile seizures

OBJECTIVE: To identify characteristics in children with epilepsy that differ between those who did versus did not have a history of preceding febrile seizures. BACKGROUND: Febrile seizures precede epilepsy in 10 to 15% of children. Little is known about the specific types of epilepsy associated with febrile seizures. METHODS: In a community-based, prospectively identified cohort of children, the association between prior febrile seizures and characteristics of the children's epilepsy (seizure type, epilepsy syndrome, age at onset, underlying etiology, family history) were examined for 524 of the children who were aged > or =1 year at onset of epilepsy. RESULTS: Seventy-three (13.9%) had febrile seizures. Children with febrile seizures were more likely to have a first-degree or a second-higher-degree relative with febrile seizures and less likely to have childhood absence epilepsy and absence seizures compared with children without febrile seizures. This was especially true for simple febrile seizures. There was no specific association with localization-related forms of epilepsy. Complex, but not simple, febrile seizures were associated with younger age at onset of epilepsy. There was no evidence that focal or prolonged febrile seizures were associated with localization-related epilepsy or temporal lobe epilepsy per se. Of the three children whose initial MRIs demonstrated hippocampal atrophy, none had a history of febrile seizures. CONCLUSIONS: At the time of diagnosis, febrile seizures are not specifically related to temporal lobe epilepsy or localization-related epilepsy in general. A genetic component for febrile seizures is suggested by its positive associations with family history, especially for simple febrile seizures. Complex febrile seizures represent an underlying age-dependent susceptibility.