Febrile infection-related epilepsy syndrome treated with anakinra

Abstract

Febrile infection-related epilepsy syndrome (FIRES) is a devastating epileptic encephalopathy with limited treatment options and an unclear etiology. Anakinra is a recombinant version of the human interleukin-1 receptor antagonist used to treat autoinflammatory disorders. This is the first report of anakinra for treatment of a child with super-refractory status epilepticus secondary to FIRES. Anakinra was well tolerated and effective. Cerebral spinal fluid analysis revealed elevated levels of proinflammatory cytokines before treatment that normalized on anakinra, suggesting a potential pathogenic role for neuroinflammation in FIRES. Further studies are required to assess anakinra efficacy and dosing, and to further delineate disease etiology. Ann Neurol 2016;80:939-945.

Figure 1

Daily EEG seizure burden and treatment regimen (days 1-65 of pediatric ICU admission). Antiseizure medications were uptitrated rapidly to the following maximum daily doses: phenobarbital (20 mg/kg bolus, then 5 mg/kg/d); lacosamide (15 mg/kg/d); methylprednisolone (mp) (30 mg/kg/d); topiramate (15 mg/kg/d); propofol (60 mcg/kg/min); felbamate (83 mg/kg/d); and ketamine (3 mg/kg/h). The ketogenic diet was rapidly escalated to a 4:1 ratio (sustained ketosis was not achieved until day 47) and successfully weaned on day 98 (not shown). A midazolam infusion commenced on day 1 (daily infusion rate ranged from 0.01 mg/kg/h to 3 mg/kg/h), with a slow wean beginning on day 59 until it was discontinued on day 88 (not shown). Medications not shown include brief unsuccessful trials of levetiracetam (days 1-5) (max 63 mg/kg/d), fosphenytoin (days 1-2) (max 20 mg/kg/d), and ketamine (day 25) (1 mg/kg/h). Propofol was used briefly to break clusters of seizures (days 2, 4, 8). Clonazepam was added day 59 to help wean midazolam. DRESS = drug reaction with eosinophilia and systemic symptoms. cEEG = continuous electroencephalogram.

Figure 2

Refractory subclinical status epilepticus depicted on a quantitative EEG trends panel displaying a 4 hour epoch of continuous video-EEG monitoring and 2 raw EEG epochs. Numerous multifocal (mainly subclinical) seizures migrating independently over the right and left hemispheres (A). Left (1) and right (2) rhythmicity spectrograms; left (3) and right (4) FFT power spectrograms, asymmetry spectrogram (5) (red = right hemisphere, blue = left hemisphere), amplitude integrated EEG (6) (red=right hemisphere, blue=left hemisphere). Electrodes were applied according to the international 10-20 system (software XLTEK and Persyst 12). The red vertical line on the trends panel corresponds to a focal right posterior (max P4/O2) subclinical seizure (B). The blue vertical line on the trends panel corresponds to a focal left posterior (max P7/O1) subclinical seizure (C). Raw EEG (10 second epochs) displayed on a longitudinal bipolar montage (10μV, LFF 0.16, HFF 70 Hz, 60 Hz notch) (B & C). Throughout her ICU course, EEG background activity featured mainly reactive, diffuse polymorphic delta activity, without the need for prolonged burst suppression pattern.

Figure 3

Neuroimaging highlights MRI T2 FLAIR coronal sections performed on day 3 (A) and day 228 (B) of admission. MRI MPRage coronal sections performed on day 3 (C) and day 228 (D) of admission. While the initial acute imaging was normal (A&C), marked atrophy affecting both grey and white matter evolved to include the hippocampi, external capsules, corticospinal tracts, and corpus callosum (B&D). A F-18 FDG PET/CT scan performed on day 251 of admission (E). Images were obtained 30 minutes after injection with CT fusion imaging. Marked hypometabolism in the bilateral temporal lobes, insular cortex, and hippocampi are seen.