SRSE may present with contradictory clinical manifestations and EEG findings, especially in children. Different SE types and various EEG patterns may co-exist in one patient. SE may occur at any stage of the disease process during or after the withdrawal of anaesthetic therapy. All patients in this study were failed to be controlled by the AEDs and anaesthetic therapy. Therefore, it is necessary to monitor seizures by using CEEG especially for NCSE.
FIRES is a life-threatening medical emergency that affects normal children after a febrile illness, and it is a major cause of SRES in paediatric intensive care units (PICUs). SE in FIRES regularly lasts for a few weeks and may cause death or progress to drug-resistant epilepsy associated with severe intellectual disabilities. The aetiologies and pathogenetic mechanisms of FIRES remain largely unknown. CSF tests showed no signs of viral infection or autoimmunity in most cases. Recent studies showed that some gene mutations in febrile epilepsy syndrome, such as mutations of PCDH19, SCN1A and POLG, are not responsible for FIRES . Genetic testing result of six patients through gene-targeted sequencing was also negative in the present study.
MRI findings in the acute stage may be normal. Some patients may show abnormal signal in bilateral hippocampal regions, in brain gray matter and deep grey matter nuclei. A previous study also reported MRI findings of bilateral mesial temporal or general atrophy in chronic stage, and T2 hyperintensities were seen in almost half of the cases . The 10 patients with SRSE were consistent with the clinical features of FIRES. Among them, nine cases ultimately evolved into refractory epilepsy and presented with mild to severe intellectual disabilities with obvious MRI changes in the early and late stages, only one patient received favorable outcome with normal MRI. Therefore, MRI change could be used as a prognostic indicator for FIRES.
The first administration of KD may be traced back to the 1920s and was used as a treatment option for various types of refractory epilepsies in children and young adults [10,11,12,13]. Previous studies reported the successful application of KD to treat SRSE caused by FIRES or different encephalopathies, and significant clinical responses occurred within 1–19 days following the onset of KD in paediatric cases [9, 11, 14]. Five of the 10 patients in the present study recovered from SE within 6–15 days of the initiation of KD, which was consistent with previous studies. To our knowledge, standardized evaluation criteria for the efficacy of KD on SE are not established according to previous studies [11, 12, 15,16,17,18]. The results of the present study are helpful to precisely evaluate the efficacy of KD through CEEG and aEEG monitoring rather than clinical manifestations, which are difficult to differentiate and standardize.
Previous studies have reported the adverse effects of KD, including ketoacidosis, hypophosphatemia, hypokalaemia, high levels of triglycerides and pancreatitis [12,13,14,15,16]. In the present study, one subject (case 3) experienced an obvious reduction in seizure activities. KD discontinued because of ventricular fibrillation on the 27th day. He had no history of heart disease before KD treatment, and his family history was negative. Therefore, arrhythmia cannot be excluded as a side effect of KD. KD administration was significantly correlated with prolonged QT in a previous study . Therefore, continuous electrocardiogram monitoring and routine surveillance of clinical and biochemical testing are necessary during KD therapy for these patients. Renal calculi occurs in 3–7% of refractory epileptic children following KD treatment , but the incidence of urinary calculi was approximately 30% (3 out of 10 patients) in our study, which is significantly higher than that in the previous literature. The prolonged bed rest may contribute to the formation of urinary calculi in these patients.
Although KD can control SE effectively, the occurrence of chronic epilepsy cannot be prevented. KD effectively controlled SE in eight cases in the present study. However, seizures recurred 15 days to 5 months after KD treatment and inevitably progressed to refractory epilepsy in seven patients after the use of KD for 3–12 months. These results indicated that there were unknown additional mechanisms involved in epileptogenesis after FIRES, and further studies are necessary.
Notably, several previous studies denied the role of urinary ketones in evaluations of the efficacy of KD, but they affirmed the compliance of urinary ketones . In contrast to previous studies that used urinary ketone values to monitor the efficacy and adverse effects of KD, we introduced blood BHB instead of urinary ketone, as ketosis found in the urine might not be a better indicator of efficacy and fewer measurements of BHB was required to assess the extent of ketosis. Goal blood BHB levels were rapidly obtained within 1–3 days following KD onset after fasting for 3 days, and hypoglycaemia did not occur in our series. The limitations of this study can be summed up in two points: Firstly, the sample size was small. Secondly, it is lack of urinary ketone results to evaluate the relationship between blood BHB and seizure treatment outcome. Further studies should enrol more patients and measure the urine ketone results to confirm the relationship between them.