Diagnosis of FIRES, in the first phase of the disorder, is not feasible as currently no specific test are available [
28]. On the second stage of the disorder with the acute onset of afebrile seizures some diagnostic indication can arise analyzing the clinical and laboratory results of the subject with previous negative personal history of seizures and with no specific hematological and liquor laboratory anomalies. The rapid evolution of the seizures to RSE are the critical points for a correct diagnosis of FIRES according to the results of the clinical examination, hematologic test, serial electroencephalogram recording, and not specific anomalies at brain MRI, and at the liquor examination. Neurologic examination between the seizures shows signs of confusional state and poor reaction, whereas cranial nerves are not involved and meningeal signs are absent. The remaining of clinical examination is normal including levels of spleen and liver. Blood tests are unrevealing. As reported by Caraballo et al. [
29] the seizures, in the acute phase are focal with possible secondary generalization, in association sometime to autonomic manifestations such as pallor, apnea, and cyanosis. These authors [
29] in 12 patients with FIRES at interictal EEG recordings report on a diffuse delta-theta background slowing and at the initial EEG recordings a temporal seizure onset in four children, fronto-temporal in four, frontal in two, and fronto-parietal in two, respectively. All the 12 patients rapidly developed multifocal and independent seizures [
29]. In FIRES, Rachfalska et al. [
30] refer that seizures are usually focal or secondarily generalized without regaining consciousness between them. Multifocal seizures are present in most of the patients and in some of them, the foci may migrate indicating a compromision of both the hemispheres. The EEG initially shows high-voltage slow background activity with subsequent development of interictal epileptiform discharges with variable spatial distribution. Ictal recording are most commonly located in temporal, fronto-temporal and frontal regions including perisylvian area [
30]. Wu et al. [
31] collected 92 patients with NORSE among which 90% were affected by FIRES. Interictal EEG recording showed slow wave, suppression, burst suppression, and multifocal or focal discharges. In 72 patients, focal interictal discharges were found in 36.1% of cases, extensive or multifocal discharges in 61.1% and in 2.8% periodic discharges were registered. In the remaining 20 patients, no discharges were reported at the interictal period. During the ictal period, a rhythmic theta or beta wave; focal sharp or spike and slow wave; or generalized discharge were reported. Either sustained or intermittent, were present in the background. During the SE phase or after the SE interruption, epileptic EEG signs were noted in 48 patients. To note, in this series 21 patients had nonconvulsive status epilepticus presentation (NCSE) [
31]. Farias-Moeller et al. [
32], in a retrospective single-center study of seven children with FIRES, report the EEG recordings and distinguished the results obtained in two phases: the initial, with 12 h of recording and the subsequent with 12 h of recording performed prior to initiation of the medically induced burst suppression (BS). The EEG background for all the patients showed extreme delta brush (EDB) with paroxysmal beta-delta complex consisting of 15–18 Hz beta activity superimposed over 1–3 Hz delta in the frontal and central regions. On the subsequent EEG recording, the typical seizure burden was found higher at 1–5 seizures/h. A specific seizure pattern was reported in six out the seven patients consisting of focal activity > 10 Hz of small to moderate amplitude evolving to well-formed rhythmic spike and spike-wave complexes. In four of the patients, ictal activity shifted from one hemisphere to the contralateral. Most seizures in the first 12 h of recording came from frontal, central, and temporal areas on either hemisphere; whereas in the subsequent EEG recording the seizures were found to come from occipital and parietal areas [
32]. Together with EEG recording, brain MRI is a relevant diagnostic exam and it should be promptly required to exclude structural abnormalities and to proceed in further assessments including the CSF examination. Culleton et al. [
33] collected a total of 129 MRI brain scans reports from the literature carried up during the acute phase of FIRES. The authors report than in the initial phase of the disorder in most of the patients the MRI is inconclusive for FIRES diagnosis. They refer that at initial presentation the most common finding was a normal brain MRI in 79/129 (61,2%).Temporal lobe (including the mesial temporal lobe structures and hippocampi), signal abnormalities unilateral and bilateral were reported in 33 out 129 cases (25.5%); basal ganglia changes in 9 out 129 (6.9%); insular and periinsular changes in 7 out 129 (5.4%) as well as cortical edema either focal and diffuse was reported in 6/129 (4.6%). Signal abnormalities in the thalamus and in brainstem were reported in 2/129 cases (1.5%), respectively, and less frequently multifocal subcortical infarcts and cerebellar edema and hemorrhage. The same authors [
33] report results of brain MRI imaging in children with FIRES during the chronic phase of the disease: the available data were 97/131 (74%). Among these, normal brain imaging was reported in 18/97 (18.5%). The most frequent abnormalities were a generalized brain atrophy including ventriculomegaly reported in 48 out of 97 (49.4%), cerebellar atrophy was specifically noted in 3 out 78 (3.1%), mesial temporal lobe hyperintense signal changes and/or atrophy in 24 out 97 (18.5%), ventricular white matter hyperintensities in 9 out 97 (9.2%) or deep or subcortical white matter changes in 2 out 97 (2.1%). Moreover, Insular and periinsular hyperintensities were reported in 3 out 97 (3.1%), deep grey matter and thalamic hyperintensities signal changes in 5 out 97 (5.3%) and cortical hyperintensities in 2 out 97 (2.1%). In general, brain MRI performed at distant is reported to show bilateral temporal atrophy and T2 hypersignal in almost half of cases [
33]. Lee and Chi [
34] collected 29 patients affected by FIRES: abnormal brain MRI findings, were reported in the initial phase of the disorder in 38% of the patients and in 87% at the follow up. Serial magnetic resonance imaging were carried out during the course of FIRES in 7 children aged 3 months to 9 years and performed from the initial presentation through 18 years of follow up. Results showed progressive evolution from normal imaging to severe cerebral atrophy. After six to twelve months, most of the children showed moderate to severe cerebral atrophy and by 1 year, also cerebellar atrophy was noted [
35]. Laboratory analysis are usually normal. Spinal liquor may express an increased number of leucocytes observed in over 50% of patients [
30,
35] as well levels of proinflammatory cytokines and chemokines [
22].
In our probands the initial seizures were focal, recurrent and of short duration with subsequent develop of RSE happened after 4 days and 5 days, respectively. Initial EEG showed spike and waves in the fronto-temporal region in case 1 and multifocal spike and waves more evident in fronto-temporal regions in case 2. In the initial phase, in both Brain MRI was normal as well all the laboratory analysis including cerebrospinal fluid.