Journal of Neurology & Neurophysiology

IVIG Treatment in FIRES: Report of 3 cases from Southeastern Anatolia and a Brief Review of the Literature

Ipek Polat^{* *}Correspondence: Ipek Polat, Department of Pediatric Neurology, Mardin State Hospital, Mardin, Turkey, Tel: +90 482 212 10 48, Email:

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Introduction

The diagnosis of Febrile infection-related epilepsy syndrome (FIRES) is made clinically in healthy children with the onset of treatment-resistant seizures that develop 4 days (1-12 days) on average after a febrile disease with the absence of an infectious agent, and with the progression to chronic refractory epilepsy, with cognitive sequelae [1-4]. Super-refractory status epilepticus (SRSE) is a treatment-resistant condition that persists for more than 24 hours despite intravenous (i.v.) anesthetics and antiepileptics (AED) [5-7]. Version, tonic posturing, lateralized face jerking, focal motor limb movements with autonomic feature are frequently observed [8]. Clustered seizures are observed every 2-4 weeks on average, sometimes accompanied by status epilepticus (SE) during chronic phase [1,4]. Cranial magnetic resonance imaging (MRI) is usually normal on admission [9]. Then cerebral edema, leptomeningeal involvement, signal abnormalities in the hypothalamus, thalamus, frontotemporal regions are reported [9-12]. Global brain atrophy mostly occurs within a few weeks [3,9]. Electroencephalography (EEG) reveals diffuse background slowing and interictal discharges at the frontotemporal regions [3,4,11]. Although burst-suppression coma is induced with i.v. anesthetics, SE repeats during weaning in the acute phase [4]. Studies about immunotherapies such as corticosteroids, intravenous immunoglobulin (IVIG), and plasma exchange (PE) are very limited. Here, we aimed to share our experience in the treatment of SRSE that progressed on the basis of FIRES and to discuss the effects of immunotherapy in the acute and chronic periods by reviewing the literature.

Cases

Case 1: A previously healthy 4-year-old male was hospitalized with SE 4 days later his first complex febrile seizure. The seizures were observed to start in the form of the clonic spasm of the right arm, twitching of mouth, lip smacking, cyanosis, and become generalized. Laboratory investigations (including blood cell count, biochemical investigations, metabolic and infectious analyzes) were normal. Cerebrospinal fluid (CSF) analysis showed mildly increased protein. Cranial MRI revealed hyperintensity on T2 and FLAIR sequences in the left medial temporal lobe. Seizure activity continued despite treatments with diazepam, phenytoin, levetiracetam, midazolam infusion, valproic acid, oxcarbazepine, thiopental infusion, and ketamine infusion. IVIG was administered on the fourth day, followed by pulse steroid. The frequency of seizures decreased slightly one week after immunotherapy. In the second week, the patient’s seizures became constant. He benefited from topiramate loading. On the 32nd day, febrile SE was observed again. IVIG was administered again. Seizure control was partially achieved on the 36th day. SE developed on the 64th day again. IVIG was administered for the third time. Seizure control was partially achieved within two days, and IVIG was continued to be administered every 28 days. The patient was discharged in the fourth month with topiramate, phenytoin, gabapentin, and clobazam. In cranial MRI, there was parenchymal loss and mesial temporal atrophy in the left hemisphere. In the follow-up, seizures, of which frequency increased with fever were observed. He did not experience SRSE during the IVIG period. After the monthly IVIG treatment was discontinued, there were recurrent hospitalizations because of seizures lasting for 20-30 minutes during infection periods. He benefited from phenytoin loading treatment in all of them. At the end of 1 year, short-term focal seizures are observed a few times a month in Table 1.

Table 1: Summary of Clinical Features of our Patients

Case 2: A previously healthy 5-year-old male patient was admitted with spasm of the left hand. It was learned that five days ago, he had started on antibiotics due to a febrile respiratory infection. His physical examination and laboratory investigations were normal. CSF analysis revealed mild pleocytosis. Within hours, his seizures were observed to start in the left arm and leg and to turn into secondarily generalized convulsions. Cranial MRI was normal. Seizure activity continued despite treatments with diazepam, phenytoin, levetiracetam, valproate, topiramate, phenobarbital, oxcarbazepine, midazolam, propofol, ketamine and thiopental. IVIG and steroid were administered on the third day. At the end of the first month, the SRSE developed again with high fever. The frequency of seizures regressed after the second dose of IVIG. Brain edema, and T2/FLAIR hyperintense lesions in the bilateral parietooccipital regions were observed on second MRI. However, one week later, despite multiple AEDs, he continued to have seizures 4-6 times a day. In table 1 he died in the second month of his hospitalization due to sepsis and multiple organ failure.

Case 3: A previously healthy 5-year-old female patient, applied with asymmetry in the right half of her face. It was learned that she had been started on oral antibiotics due to a febrile respiratory infection three days ago. During the follow-up, twitching in the right half of her face, the clonic spasm of the arm, and seizure displaying generalization were observed. It stormwas thought that facial palsy could be a postictal finding. Within hours, her seizures became frequent and generalized with SRSE. Cranial MRI revealed an increase in leptomeningeal contrast in bilateral frontotemporal areas. CSF analysis was normal. Her seizures continued despite diazepam, phenytoin, levetiracetam, midazolam infusion, valproic acid, and thiopental infusion. IVIG was administered on the second day. The frequency of seizures began to decrease after IVIG. However, at the end of the first month, mild fever and an increase in seizure frequency were observed again. IVIG was administered for the second time. Cranial MRI was normal. At the end of the second month, table 1 indicates she was discharged with partially provided seizure control.

Discussion

The disease course and outcomes of our patients who received similar treatments at a similar time and benefited from IVIG were different from each other. We cannot differentiate whether the treatment responses we observed based on the cases were the natural course of the disease or the IVIG effect. However, we think that the frequency of seizures, which increased with fever in the acute phase and the transition to the chronic phase, could be controlled by IVIG to some extent, and even we were able to prevent the patients from reentering the SRSE picture. The FIRES diagnosis of our cases, who did not have any previous disease and were aged between 4-5 years, was made with their clinical picture which started with focal seizures 3-5 days after their upper respiratory tract infection and progressed rapidly to SRSE and continued with chronic refractory epilepsy. These seizures were characterized by autonomic findings, orofacial and extremity motor jerks with secondary generalization, and in which consciousness is affected as reported in the literature [3,4,8,13]. Similarly to the previous cases, we observed slowing in the diffuse ground rhythm and/or epileptiform discharges in the frontotemporal and/or frontocentral regions in EEG [3,4,11]. Similarly to the recently identified MRI findings, the MRI of one case was normal at the admission, and hippocampal, temporal signal changes and leptomeningeal contrasting were detected in the others as indicated in Table 1 and Table 2 [1,3,9,14]. The underlying mechanisms that cause FIRES have not been clearly explained. Although there had been a history of a previous febrile infection, due to the inability to detect an infectious agent, the non-infectious immune-mediated process was considered [3,12,13,15]. Thus, immunotherapies such as corticosteroids, IVIG, PE and rituximab have been tried. Although there are studies in which they were found to be ineffective in the acute phase, Alparslan et al. Table 3 shows presented that they received a response to IVIG within two days [1,16]. Table 1 stipulates we could not receive a response in one case, and in the other two patients, we observed a slight decrease in the frequency of seizures between 2-7 days . Table 1 specifies in some publications, IVIG was continued for a long time with better outcomes [3,11,17,18]. In our first case, we observed seizure clusters triggered by fever and the recurrence of SE during the clinical course. Furthermore, we realized that these periods coincided with 24-30 days which is the half-life of IVIG [19,20]. We observed that the frequency of seizures which increased during the exacerbation period decreased 2-4 days after regular IVIG and he was not hospitalized due to SE after IVIG courses. As denoted in Table 1 in the other case, we received a partial response to the first dose of IVIG within seven days and second IVIG dose prevented exacerbation of fever induced SE. In our first case who benefited regular IVIG, there was a mild protein increase in CSF. Thus FIRES cases with CSF protein increase may be a subgroup benefiting from immunotherapy [1,3,4,12,18]. The literature presented that ketogenic diet (KD), high-dose phenobarbital, plasma exchange, ketamine, lidocaine, and MgSO4 were partially effective in the acute phase [3,6,11,14,21-24]. With their anti-inflammatory effects and cytokine storm inhibiting effects, cannabidiol, anakinra, and hypothermia were presented as other options [9, 25-28]. The literature on the use of immunotherapies in the chronic phase is limited, and positive effects have been reported on a case basis [3,11,17]. Table 3 signifies although one study reported the IVIG first dose time, administration schedule, and time of effect, these details were not included in other studies [17]. While Van Baalen et al. recommended empirical immunotherapy in the acute phase, Kramer et al. suggested that long-term treatment could be continued if the effect of immunotherapy was observed [1,3] We also agree with these opinions. These cases may benefit from regular IVIG treatment. However, there is a need for prospective studies on this issue, which include the time of administration of agents and their duration of action and which use standard definitions required to say that they are effective [29- 32].

Table 2: Summary of Clinical Features of Cases Published in the Literature.

Table 3: Summary of Treatment Options and Treatment Responses of Cases Published in the Literature.

Conclusion

Despite various difficulties in management of such critically ill patients, it is observed and evaluated these patients progression and experienced IVIG therapy in chronic phase of the disease. Although all cases received similar treatments at similar times, different outcomes from each other developed. There is no treatment scheme with a positive response yet. Although IVIG treatment alone does not appear to be effective in the acute phase, It is observed that regular IVIG treatment may prevent recurrent exacerbations. In this study, it is aimed to present the summary of literature in terms of our experience in FIRES and super-refractory status epilepticus management in a secondary care hospital in the Southeastern Anatolia region, immunotherapy outcomes, and other treatment options.

Conflict of Interest

The authors declare no conflict of interest

Acknowledgements

We want to thank to our patients parents that they accept to be a participiant in this study.

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