Currently, the diagnostic criteria for SFSs state a cut-off of 15 min to define the benignity, the seizure should be self-limiting, tonic-clonic generalized, with normal EEG, neuroimaging, and lab results. In our study, we found that most FSs end within minutes, typically less than 5 mins. Therefore, we decided to study those seizures lasting more than 5 minutes, evaluating what happens from the 6th minutes of seizure, by the study of EEG alterations at 6 and 12 months, and the neurological clinical signs during follow-up.
This hypothesis refers to the specific pathogenesis described in the model suggested by Riazi et al. (13). The Authors performed an in vivo study on animal models demonstrating how peripheral inflammation can alter hippocampal neuronal excitability. These authors induced colitis in mouse models by injecting 2,4,6-trinitrobenzene sulfonic acid (TNBS) and they showed that TNBS could induce a Th1cell-mediated inflammation of the mice bowel (13–17). After 2,4,6-TNBS colitis-induction, the authors found an increase in serum Tumor Necrosis Factor-alpha (TNF-a), which was responsible for mice’ blood-brain barrier disruption and acted as a trigger for seizures (13). They, therefore, identified a model of microglial-dependent, TNF-mediated neuronal excitability that might represent a potential link between peripheral and central inflammation. This pathogenic model explains how peripheral inflammation, phenotypically expressed by the onset of fever, can trigger seizures, and typically fever-induced seizures. These last are brief, strictly linked to the ongoing inflammatory process, with a rare occurrence, without post-ictal consequences or further evolution to epilepsy.
Other Author suggests the correlation between plasma interleukin-6 (IL-6) levels and the onset of febrile seizures (FS). Previous studies showed significantly higher serum IL-6 levels in FS patients than in controls. However, the mechanism underlying this association remains unclear (18). Chen et al provided knowledge regarding the association of IL-6 polymorphisms with susceptibility to FS (18).
The current classification of SFS considers a duration as long as 15 min for a fever associated seizure, that corresponds to prolonged inflammatory status altering neuronal susceptibility and hyperactivity. Studies have found that prolonged FSs are associated with an increased risk of subsequent epilepsy compared to a complex FS that was less prolonged (19–22). In regards, studies on animal models showed that prolonged seizures lead to brain injury in paralyzed and mechanically ventilated baboons (20).
In our study, we decided to identify the optimal cut-off to determine the benignity of simple febrile seizures, and based on our statistical analysis (Youden index) we found this cut-off at 6 mins. After 6 mins of duration, we found a higher probability of presenting EEG alterations and abnormal neurological objectivity, such as psychomotor retardation. After 6 mins, the risk of recurrence of FSs during the following year is higher. Moreover, literature data showed that the occurrence of multiple FSs is also associated with a slight but statistically significant increase in the risk of subsequent epilepsy (17–22).
In our study, only 2% of the studied children developed epilepsy, in particular, children who had a seizure with a duration greater than 6 mins. These were the only children who developed epilepsy.
Limits of the study
The EEG study was performed outside the two Hospital centres. It was not prescribed by our neuropediatricians, but it was requested by the General Medical Doctor after specific request of parents. In fact, the most of parents coming to our observation with their children for FSs faced this disease as a dramatic event, feeling the need to further diagnose eventual neurologic problems by EEG study.
Unfortunately, in the south of Italy, there is a lack of concern on the benignity of febrile seizures, and parents often face the disease with fear and preoccupation.
For this reason, EEG was prescribed by their Medical Doctor to exclude potential brain damage.