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IVIG Treatment in FIRES: Report of 3 cases from Southeastern Anat

Journal of Neurology & Neurophysiology

ISSN - 2155-9562

Case Report - (2020) Volume 11, Issue 4

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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Abstract

Background: Febrile infection-related epilepsy syndrome (FIRES) is a severe epileptic encephalopathy with acute onset following a febrile disease in previously healthy children. Its etiology has not been elucidated yet. There is no treatment algorithm with a positive response. Here, we aimed to present the summary of literature in terms of our experience in FIRES management in a secondary care hospital in the Southeastern Anatolia and immunotherapy outcomes.

Cases: We report three FIRES-associated super-refractory status epilepticus cases followed up by the Pediatric Neurology Unit at Mardin State Hospital. The cases known to be healthy were hospitalized due to focal seizures and seizures with secondary generalization which started after a febrile disease which had developed 3-5 days before. Since seizures persisted for more than 24 hours despite the effective treatment, the super-refractory status epilepticus was accepted. No infectious agent was detected. Progression to chronic refractory epilepsy with cognitive impairment was observed. Two patients received intravenous immunoglobulin (IVIG) and steroids, other received only IVIG. IVIG was continued monthly. The time of the first administration of IVIG was days 2-4. Partial response was obtained within 2-7 days. Monthly IVIG was observed to be protective against status epilepticus attacks triggered by fever. Although all cases received similar treatments at similar times, different outcomes from each other developed. One of them died, the others developed sequelae.

Conclusion: FIRES is a condition that can cause super-refractory status epilepticus. Although IVIG treatment alone does not appear to be effective in the acute phase, regular IVIG treatment may prevent recurrent exacerbations.

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.

Case Case I Case II Case III
Gender M M F
Age 4 5 5
Lag from febrile illness onset to SE 4 5 3
Lag from fever control to SE 1 2 -
Laboratory Elevated CSF protein (50mg/ dL) Mild pleocyctosis 8/mm3 UR
EEG Left frontotemporal and frontocentral epileptiform discharges Generalized slowing
Right frontotemporal epileptiform discharges
Bilateral frontotemporal epileptiform discharges
MRI A: Hypersignal left temporal lobe
FU: Brain atrophy of left hemisphere
A: Normal
FU: Brain edema, parietal-occipital hypersignal
A: Bilateral frontotemporal leptomeningeal enhancement
FU: Hypersignal periventricular region
Treatment DZP, PHT, LEV, MDZ, VPA, OXC, Thiopental, Ketamine, TPM, LTG, CLOB, GABA DZP, PHT, PHB, LEV, MDZ, PROP, VPA, TPM, Thiopental, Ketamine, OXC DZP, PHT, LEV, MDZ, VPA, Thiopental
IVIG (2gr/ kg in 2 days) (monthly IVIG) (2 gr/kg in 2 days) (2 times) (2 gr/ kg in 2 days) (2 times)
Steroid 30 gr/ kg 3 days (tapering in 2 weeks) 30 gr/ kg 3 days (tapering in 2 weeks) -
Responsive to treatment Partially responsive to IVIG and phenytoin and clobazam Nonresponsive Responsive to IVIG
IVIG initiation day / Time for effectiveness 1st course: 4th day / 7 days
2nd course: 32th day / 4 days
3rd course: 64th day / 2 days
4th course: 3th month / 2 days
5th course: 4th month / good response
6th course: 5th month / good response
7 th course: 6th month / good response
1st course: 3rd day / -
2nd course: 30th day / -
1st course: 2nd day / 7 days
2nd course: 1st month / 7 days
AED at discharge TPM, PHT, CLOB, GABA OXC, LEV, TPM, PHT LEV, VPA
  Outcome Refractory epilepsy
Loss of ambulation
Feeding via nasogastric tube
FU (1 year later): Epilepsy, ambulation with help, oral feding achieved
Exitus Mild facial palsy sequele
Epilepsy

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].

  Study n of patients M:F Age (years) Lag from febrileillness onset to SE (days) Seizure type Laboratory (n) MRI (n) EEG(n) Outcome
1 Agarwal et al. [29] 1 NA 4 3 weeks Secondary generalized UR A: Hypersignal hippocampus
FU: Hippocampal atrophy
A:Multifocal epileptiform discharges Epilepsy
Cognitive decline
2 Alpaslan et al. [16] 1 1:0 8 6 Secondary generalized UR A: Normal
FU: Normal
A:Generalized slowing
FU: Focal temporal epileptiform discharges
Epilepsy
Cognitive decline
3 Byler et al. [17] 1 1:0 5 7 Secondary generalized Leukopenia Thrombocytopenia Transaminase elevation
Pleocytosis
A: Hypersignal hippocampi
FU: Bilateral hippocampal atrophy
A: Frontal, occipital or  centrotemporal epileptiform discharges Epilepsy
4 Caputo et al. [6] 1 0:1 13 6 Focal seizures
Secondary generalized
UR A: Normal
FU: Normal
A: Diffuse slowing
Bilateral temporal focal discharges
FU: Bilateral temporal slowing
Cognitive decline Anxiety
Depression
5 Carabolla et al. [11] 12 8:4 Mean 8.5 (2-13.5) 2-10 Focal seizures
Secondary generalized
Pleocytosis(7)
Elevated CSF protein(1)
A: Normal(5) Hypersignal  hippocampi/ periinsula/ basal ganglia(7)
FU: Diffuse atrophy(5), Mesial temporal sclerosis(4)
A: Diffuse slowing(12),
Temporal(4), frontotemporal(4),
frontal(2),
frontoparietal(2) seizure onset
FU: Backround slowing(12) Frontal, temporal or frontotemporal focalspikes(12)
Epilepsy
Mental retardation
Behavioral disturbances
6 Chou et al. [30] 1 0:1 12 7 Generelized UR A: Hypersignal hippocampi, medial temporal, posteromedial thalamus, external capsules A: Diffuse slowing
Frequent ictal fast activity
FU: Normal
Impaired short term memory
7 Fen Lee et al. [10] 29 12:17 Mean 8.9 (1.2-17.8) Mean 6 (2-14) Secondary generalized(25)
Generalized(4)
Pleocytosis(9) A:Normal(18)
Leptomeningeal enhancement, Hypersignal hypocampi, temporal, thalamus(11)
FU: Diffuse brain atrophy, Temporal, preiventricular hyperintensity (20)
Focal spike(15)
Generalized polyspike(3)
Generalized spike and wave(1)
BS(4)
PLED(1)
Exitus (3 during acute phase, 3 during follow-up)
Epilepsy(20)
Learning disability(6) Vegetative state, severe mental retardation(11)
8 Fox et al. [4] 1 0:1 6 7 Secondary generalized UR Normal Left foci
Generalized periodic epileptic discharges
PLED
Epilepsy
Cognitive decline
9 Gofstheyn et al. [26] 7 5:2 Mean 7 (3-8) NA Focal seizures
Secondary generalized
Pleocytosis(6)
Elevated CSF protein(1)
A: Normal(4), restricted diffusion in the lentiform nuclei(1), bleeding along the corpus callosum(1), signal abnormality of temporalsulcus(1), volume loss, gliotic change, hippocampal sclerosis(1) Diffuse background slowing
Focal epileptifom discharges
Epilepsy
Cognitive decline
Ataxia
Exitus(1)
10 Howell et al. [8] 7 7:0 Mean 10.8 (6.7-14) 3-6 Focal seizure
Secondary generalized
Pleocytosis(2)
Elevated CSF protein(2)
A: Temporal, hippocampal, insular hyperintensity
FU: Normal (3) Diffuse cortical atrophy(2) Hippocampal atrophy±sclerosis(2)
Diffuse background slowing
Focal epileptifom discharges
BiPLED
BS
Epilepsy
Cognitive decline
Exitus(1)
11 Kenney Jung et al. [28] 1 0:1 32 months 7 Generalized UR A: Normal
FU: Diffuse cortical volume loss
Multifocal discharges Epilepsy
12 Kramer et al*[3] 77 4:3 Mean 8 (2-17) Mean 4 (1-14) Generalized (5)
Secondary generalized (19)
Opercular (9)
Focal seizure (58)
Pleocytosis(44)
OCB(4)
A:Normal(35)
Leptomeningeal enhancement(4)
Hippocampal, periinsular hyperintensity(12), diffuse atrophy(2)
FU: Diffuse brain atrophy(28) Hippocampal hyperintensity(17)
Generalized polyspike(5)
Temporal(16), frontotemporal(16),
frontal(13),
central, parietal, occipital(15) seizure onset
Exitus(9)
Epilepsy(63)
Normal(12)
Borderline cognitive decline(11)
Mild MR(10)
Moderate MR(16)
Severe MR(8)
Vegetative state(11)
13 Lin et al. [7] 2 1:1 4-10 1-6 Generalized Pleocytosis Cerebral edema
Rhombencephalitis
Bilateral temporal epileptiform discharge Cognitive decline
Motor deficit
Epilepsy
14 Nabbout et al. [21] 9 4:5 Mean 74 months (54-98 months) 1-6 Focal seizure
Generalized
Pleocytosis A: Hypersignal mesial temporal A: Diffuse delta/teta activity with spikes
FU: Perisylvian discharges
Exitus(1)
Epilepsy
15 Nozaki et al. [14] 1 1:0 7 3 Secondary generalized Pleocytosis A: Hypersignal splenium of corpus callosum
FU: Brain atrophy
A: Diffuse slowing Hyperactive behaviour
16 Patil et al. [2] 15 4:1 Mean 6.3 Mean 4 (1-12) Generalized
Opercular
Facial twitching
UR A: Normal (13) Hyperintensity in temporal, hippocampi (2)
FU: Normal(6)
Diffuse atrophy (1)
Hiperintensity in hippocampi, temporal, putaminal (3)
Dilate ventricule(1)
A: Diffuse slowing
FU: Diffuse slowing(6), Focal discharge(2), Multifocal spikes(2)
Exitus(3)
Epilepsy
Motor deficit
17 Rivas Coppola et al. [9] 7 6:1 Mean 4.7 (3 months-9 years) Mean 5.5 (1-14) Focal seizure
Secondary generalized
Pleocytosis(3)
Elevated CSF protein(3)
A:Normal(4), Cytotoxic edema in hippocampi(1)
FU: Cerebral atrophy and cerebellar volume loss(7)
A: Multifocal epileptiform discharges, Temporal lobe epileptifrom discharges Non-ambulatory and non-verbal(4)
Cognitive decline(1)
Epilpesy(7)
18 Sa et al. [25] 2 2:0 9 and 5 years respectively 4 *Secondary generalized *Generalized respectively NA A: *Abnormal signal in basal ganglia, external capsule, cortex / *Brain edema
respectively
NA 1st patient: Epilepsy
2nd patient: Epilepsy and vegetative state
19 Sakuma et al. [13] 29 19:10 Mean 6.8 (1-14) Mean 4.9 (2-109) Generalized(8)
Secondary generalized(24)
Focal seizure (26)
Pleocytosis(19)
Elevated CSF protein(5)
A:Brain edema(2)
Hippocampal, amygdaloid, periventricular, claustrum hyperintensity(12)
FU: Diffuse brain atrophy, Hippocampal, amygdaloid hyperintensity
A: high voltage slow background(7), Multiple independent foci(15) Exitus(1)
Epilepsy(29)
Cognitive decline,
Memory impairment, Autistic tendency, Hyperkinetism, Learning disability, Personality change, Emotional instability
20 Singh et al. [22] 2 1:1 7 and 10 years 7 Generalized UR A: 1st patient: Hypersignal medial temporal lobe
2nd patient:Normal
FU: 1st patient: Mesial temporal sclerosis
1st patient: Generalized periodic epileptiform discharges
2nd patient: SE arising fromleft frontal and temporal regions
Epilepsy
Cognitive decline
21 Sort et al. [23] 1 1:0 11 7 Focal seizure
Generalized
Pleocytosis A: Normal
FU: Diffuse brain atrophy
NA Epilepsy
Cognitive decline
Hemiplegia
22 Specchio et al. [32] 8 5:3 Mean 7.4 (8months-17 years) NA Focal seizure Elevated CSF protein(2)
OCB(+)(2)
A: Normal(3), lateral ventricule enlargement(1), hypersignal periinsular, mesial temporal(4) A: Diffuse slowing(7), BiPLEDs(1), frontal,central or temporal discharges Epilepsy(7)
Cognitive decline(8)
23 Tan  et al. [24] 2 2:0 2 and 16 years 5 Focal seizure
Generalized
UR A: Normal/Leptomeningeal enhancement/Hypersignal thalami
FU: Frontoparietal microinfarcts/ diffuse brain atrophy
A: Frontal and central bisysnchromous discharges Exitus(1)
Epilepsy(1)
24 Van Baalen et al. [12] 12 1:1 Mean 6 (2-12) Mean 4 weeks (2 week-4 months) NA Pleocytosis A: Basal gangliaand temporal signal changes NA NA
25 Veiga et al. [31] 1 1:0 4 7 Secondary generalized Pleocytosis A: Normal(CT)
FU: Diffuse brain atrophy
A: Multifocal epileptiform discharges
FU: Rare discharges, backroud slowing
Mental retardation
Motor deficite
Gastrostomy tube

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

  Study Acute treament(n) IVIG
(n, dose, duration, administration day)
Steroid
(n, dose, duration, administration day)
KD
(n, dose, duration, administration day)
Other AED/Treatment after discharge Effective treatments (n) Lag from SE onset to effective treatment administration Lag  to responsive of effective treatment
1 Agarwal et al. [29] LRZ
PHT
- - - - NA acute treatment   3 hours
2 Alpaslan et al. [16] MDZ
Thiopental
PHT
LEV
TPM
2gr/kg (2 days) - - - LVT IVIG 9 days 2 days
3 Byler et al. [17] LRZ
Barbiturate
PHB
PHT
VPA
LEV
2gr/kg (5 days)
Monthly IVIG for 9 months
- 4:1 lipid/nonlipid - KD
PHB
PHT
LVT
IVIG 42 days Extubation at the 56th day
4 Caputo et al. [6] MDZ
PROP
PHT
PHB
LEV
LAC
Ketamine
IVIG +
(dose NA)
Methylprednisolone (1 gr for 5 days)
10th day
- PE (5 days) Prednisone
LAC
PHB
LEV
LRZ
*ketamine + steroid infusion
*PE
*10 days (steroid)
*12 days (PE)
A few hours (ketamin and methylprednisolone)
Discahrge at 21th day (after PE)
5 Carabolla et al. [11] PHB(12)
PHT(12)
BZD(12)
LVT(12)
VPA(6)
Thiopental(6)
CZP (5)
OXC(4)
TPM(6)
Barbiturates(8)
IVIG 1.2 gr 3 times(10)
IVIG every 21 days over 4,6 and 8 months(3)
Steroid(9)
(30mg/kg/d over 5 days folowed by oral prednisolone at 1 mg/kg/day)
KD(2) PE(1)
RTX(1)
2-3 AEDs(10)
IVIG(3)
KD(2) Surgery(1)
VNS(1)
Barbiturates(5)
IVIG(2), Steroid(1),
KD(1)
NA NA
6 Chou et al. [30] PHB
LEV
VPA
MDZ
Pyridoxine Pentobarbital PROP
Thiopental Lidocaine
IVIG 1g/kg 3 times Dexamethasone 7 days KD (gastrointestinal bleeding side effect) MgSO4 (20mg/kg/h) PHB
TPM
LEV
LRZ
Pyridoxine
Lidocaine
MgSO4
27 days (lidocaine)
30 days (MgSO4)
2 days (lidocaine)
1 day (MgSO4)
7 Fen Lee et al. [10] AEDs(29) (NA)
MDZ and/or Ketamin(29)
Lidocain(3)
IVIG(4) Steroid(3) KD(7) Hypothermia(2) 3 (1-5) AEDs (NA) NA NA NA
8 Fox et al. [4] PHB
LEV
MDZ
Pentopbarbital
LRZ
PHT
Pyridoxine
Folinic acid
ZNS
CZP
VPA
IVIG Methylprednisolone KD PE
Biotin
L-carnitine
NA NA NA NA
9 Gofstheyn et al. [26] PHB(7)
VPA(7)
LEV(7)
PHT(5)
TPM(4)
LAC(4)
CRB(2)
OXC(1)
CLOB(4)
CLON(1) Felbamate(2) RUF(1)
ZNS(2) Perampanel(1) LTG(2)
MDZ(4) Isoflurane(3) Pentobarbital(3) PROP(3) Ketamine(4)
IVIG(6) Steroid(6) KD(6) PE(1) Hypothermia(3) RTX(1)
CYC(1)
VNS(2)
Cannabidiol(7)(15-25 mg/kg/d))
2.8 AEDs
KD(3)
Cannabidiol
Cannabidiol(6) NA %90.94 mean change of seizure frequency at 4th week (Cannabidiol)
10 Howe Howell et al. [8] PHB(5) Thiopental(3) PROP(2)
BZD(7)
CBZ(2) Gabapentin(1) LTG(1)
LEV(2)
PHT(7)
OXC(2)
VPA(3)
TPM(4)
IVIG(2) (2gr/kg in 2 days) Methylprednisolone(4) (15-30 mg/kg/day 5 days) - PE(1) (3 days)
RTX(1)
VNS(2)
2-3 AEDs (NA)
VNS
Oral steroid
VNS
Oral steroid
NA %30-40 reduction in seizure frequency (VNS)
11 Kenney Jung et al. [28] MDZ
PHB
LAC
TPM
PROP
Felbamate
Ketamin
CLON
Fosphenytoin
- Methylprednisolone (30mg/kg/day 3 days) KD (4:1) Anakinra (5mg/kg) Anakinra Felbamate
LEV
Anakinra 1st epoch 6 days
2nd epoch 54 days
3rd epoch 191 days
NA
12 Kramer et al* [3] MDZ
PROP
Lidocaine
Ketamine
MgSO4
Pyridoxine
Folinic acid
PHB
Thiopental
AEDs 6 (2-16)
IVIG(30) Steroid(29) KD(4) Verapamil
Biotin
Dextrametorphan
PE
Paraldehyde
Chloralhydrate
Lignocaine
NA IVIG(2) (2 gr/kg once per month for 8-9 months)
KD(1)
Barbiturate(1)
NA 2 days(KD)
13 Lin et al. [7] MDZ
LRZ
DZP
PHT
PHB
VPA
IVIG 2gr/kg (5 days) Steroid (30 mg/kg/day 3 days and 4 mg/kg/day 4 days) - Hypothermia (8days and 3 days respectively) NA Hypothermia 8 hours and 12 hours respectively Extubation at the 25th and 9th day respectively
14 Nabbout et al. [21] VPA
VGB
CZP
PHB
PHT
TPM
LEV
LTG
BZD
Thiopental
- Steroid(2) KD(9)
(4:1 lipid:nonlipid)
- NA KD(7) 4-55 days 4-6 days
15 Nozaki et al. [14] DZP
MDZ
CZP
PHB
PHT
- - - - NA High dose phenobarbital NA NA
16 Patil et al. [2] MDZ(7)
PHT(11)
PHB(11)
VPA(13)
LEV(14)
TPM(12)
CLOB(12)
CLON(9)
Barbiturate(8)
Ketamine(1)
IVIG(6) (2gr/kg in 5 days) Steroid(15) (30mg/kg/day 3 days, 2mg/kg/day and tapering in 4-6 weeks) KD(2) - Mean 5 (3-6) AEDs Poor response to immunotheraphy NA NA
17 Rivas Coppola et al. [9] MDZ(5)
LRZ(6)
DZP(1)
PHT/Fosphenytoin(6)
PHB(6)
VPA(4)
LEV(7)
TPM(2)
CLOB(3)
CLON(1)
ZNS(4)
RUF(1)
LTG(1)
OXC(2)
Felbamate(3)
LAC(5)
VGB(1)
Ketamine(1)
Pentobarbital(6)
Thiopental(1)
IVIG(5) (1-2gr/kg) Methylprednisolone(4) (20-30mg/kg) KD(4) Hypothermia(3)   Poor response to KD(4)
Transient improvement with hypothermia(1)
NA NA
18 Sa et al. [25] PHB(2)
MDZ(2)
Ketamine(2)
Thiopental(2)
- - KD(2) Cannabidiol(2)
Anakinra(2) (5-10mg/kg/d)
CMN-DBS(2)
NA CMN-DBS(1)
Anakinra(1)
(responsive for the 1st patient)
27 and 37 days (CMN-DBS)
43 and 22 days (Anakinra) respectively
51th day
(responsive for the 1st patient)
19 Sakuma et al. [13] PHB(15)
Thiopental(5)
Thyamiral(4)
DZP(5)
MDZ (25)
Lİdocaine
PHT
IVIG(13) Steroid(12)   PE(1) NA Steroid(2)
MDZ(5)
NA NA
20 Singh et al. [22] PHT/fosphenytoine(2)
PHB(2)
LEV(2)
VPA(2)
TPM(2)
MDZ(1)
LRZ(1)
Pentobarbital(2)
LAC(1)
CLOB(1)
- Methylprednisolone(2) (5 days) KD (4:1 lipid:nonlipid)
KD (6:1 lipid:nonlipid)
- 1st patient:
KD (3.25:1 lipid:nonlipid))
TPM
PHB
2nd patient:
KD (4:1 lipid:nonlipid)
PHB
TPM
CLOB
KD(2) 1st patient:
13 days
2nd patient:
3 days
1st patient:
2 days
2nd patient:
Ketosis achieved at the 20th day
21 Sort et al. [23] DZP
MDZ
VPA
PHT
PROP
VGB
TPM
LEV
Pyridoxine
Pentobarbital
- Steroid (3 days) (2 courses) KD - PHB
TPM
VGB
KD 48 days 61 days
22 Specchio et al. [32] PHT(4)
PHB(8)
CBZ(6)
OXC(1)
VPA(3)
TPM(3)
CLOB(4)
LEV(1)
MDZ(2)
IVIG(6) Steroid(8) - - Repeated IVIG(5) IVIG NA 25%-75% reduction in seizure frequency(IVIG)
23 Tan et al. [24] PHT(2)
PHB(2)
MDZ(2)
LRZ(2)
Thiopental(2)
LEV(2)
TPM(2)
VPA(2)
Pyridoxine(1)
CBZ(1)
IVIG(2) Steroid(1) KD(1) MgSO4(2) (50mg/kg loading; 10-30mg/kg/h maintenance) NA MgSO4(1) 35 days 37 days
24 Van Baalen et al. [12] NA IVIG Steroid   PE NA No clear effect of immunotheraphy NA NA
25 Veiga et al. [31] MDZ
PHT
PHB
LEV
VPA
LAC
TPM
Thiopental
Lidocaine
Ketamine
PROP
Perampanel
Pyridoxine
Desflurane
IVIG (5 days) Steroid - PE (4 times)
Hypothermia (48 hours)
ECT (Bifrontotemporal) (14 sessions over 12 days)
NA ECT NA NA

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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Author Info

Ipek Polat*
 
Department of Pediatric Neurology, Mardin State Hospital, Turkey
 

Citation: Ipek Polat. IVIG Treatment in FIRES: Report of 3 cases from Southeastern Anatolia and a Brief Review of the Literature. J Neurol Neurophysiol, 2020, 11(4), 001-009.

Received: 11-May-2020 Published: 12-Jun-2020

Copyright: 2020 Ipek Polat. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.