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New-onset refractory status epilepticus (NORSE) is defined as a clinical presentation, in a patient without active epilepsy or another preexisting relevant neurological disorder, of refractory status epilepticus (SE) without an acute or active structural, toxic, or metabolic cause. This uncommon condition has a poor prognosis, with 16-27% mortality in adults, long-term disability, and drug-resistant epilepsy, and the etiology remains unknown in up to 50% of cases.[
An immune mechanism, mediated by pro-convulsive cytokines, has been proposed. Better outcomes have been obtained with immunotherapies than with traditional anti-seizure drugs (ASDs).[
] and cases of febrile infection-related epilepsy syndrome (FIRES) - a subcategory of NORSE - have been shown to respond positively to anakinra, which is a recombinant analog of the human endogenous IL-1 receptor antagonist (IL-1RA).[
] We describe a case of NORSE of unknown cause with remarkable clinical and EEG responses to anakinra.
2. Case report
A 23-year-old male, with a paternal cousin with developmental and epileptic encephalopathy of presumed genetic origin and no relevant medical history, presented with focal clonic to bilateral tonic-clonic seizures progressing to refractory SE after one week of fever and headache. The patient required non-barbiturate sedation and admission to the intensive care unit (ICU) due to the lack of response to intravenous ASDs. A 1.5-Tesla cranial MRI did not reveal any alterations, and toxicological and blood tests were unremarkable aside from elevated concentrations of IL-1β, IL-6, IL-8, IL-10, and TNF-α. Two initial RT-PCRs for SARS-CoV-2 from nasopharyngeal swabs were negative. Cerebrospinal fluid (CSF) analysis revealed 7 leucocytes/µl (78% lymphocytes), protein levels of 46mg/dl, an increased IgM index, and concentrations of IL-1β and IL-6 of 6.7pg/ml (reference range:<5pg/ml) and 21.7pg/ml (reference range:<4.3pg/ml), respectively. The microbiological assessment and determinations of anti-neuronal and anti-neuropil antibodies in serum and CSF were negative. A full-body CT scan and testicular ultrasound ruled out neoplasms.
The most common pattern exhibited in video-EEGs, during withdrawal of sedation, was a diffuse slow background in delta band around 1.5Hz (Fig. 1-A). Left fronto-temporal focal seizures were recorded, which presented clinically with right clonic facial movements and electrically originated from a recruiting rhythm in F7/T3 (Fig. 1-B).
Fig. 1Progression of the video-EEG findings prior to anakinra initiation: A) 48 hours after the first epileptic seizure (during withdrawal of sedation): diffuse slow delta activity (at 1-2.5 Hz) and no epileptiform activity. B) 7 days after NORSE onset: left frontal-temporal focal seizure originated from a recruiting rhythm in F7/T3 C) 14 days after NORSE onset (on barbituric sedation): burst-suppression pattern. D) 48 hours before initiation of anakinra: persistent rhythmic delta activity associated with left temporal (F7-T3, T3-T5) spikes and sharp waves at 2 Hz suggestive of left temporal status epilepticus.
Genomic DNA from peripheral blood was analyzed by targeted enrichment next-generation sequencing (NGS) (Appendix 1). No pathogenic or likely-pathogenic variants were found (including IL-1RN and SCN genes).
After a week in the ICU, a nosocomial SARS-CoV-2 infection was diagnosed based on a positive RT-PCR in a bronchoalveolar lavage fluid sample. The patient exhibited a torpid evolution with recurrence of seizures, despite several ASDs and switch to barbiturate sedation. Successive video-EEGs revealed a burst-suppression pattern during barbiturate sedation (Fig. 1-C) and multifocal seizures with left temporal predominance and progression to a practically continuous acute rhythmic activity at 2Hz in this region, interpreted as a focal SE, when the sedation was reduced. (Fig. 1-D).
Methylprednisolone 1g/day, IV-Ig 0.4g/kg/day, tocilizumab 8mg/kg/day, and plasma exchange were successively administered at days 14, 17, 20 and 23, respectively, without response. Additionally, the patient was on brivaracetam 400mg/day, lacosamide 500mg/day, perampanel 12mg/day, phenobarbital 800mg/day, phenytoin 800mg/day, clonazepam 3mg/day, and barbiturate sedation, persisting 1-2 seizures every day, with worsening of frequency when sedation was interrupted.
At day 28, anakinra at 5mg/kg every 12 hours was started, which resulted in notable clinical and EEG improvements, without SE recurrence after withdrawal of sedation. The EEGs after anakinra initiation showed background activity with higher frequency rhythms reaching 7Hz, which improved clearly in subsequent registers (Fig. 2-A and B). However, 2-3 focal clonic and focal to bilateral tonic-clonic seizures persisted every day. Subsequent adjustments of the ASDs, such as increasing perampanel dose to 20mg/day, initiation of zonisamide 200mg/day and valproic acid 1500mg/day and discontinuation of phenobarbital and phenytoin, added to the introduction of ketogenic diet and cannabidiol slightly reduced the seizure frequency. Anakinra was discontinued after four weeks due to neutropenia.
Fig. 2Video-EEG findings after anakinra initiation: A) 24 hours after initiation of anakinra: notable improvement in the pattern with diffuse slow theta-delta activity and occasional sharp waves in the left temporal region. B) 72 hours after anakinra initiation: background activity with higher frequency rhythms reaching 7Hz and delta activity at 2-3Hz intermixed.
After three months in the ICU, the patient was transferred to the hospitalization area. A second cranial MRI revealed mild diffuse cerebral atrophy. At discharge, almost daily seizures persisted on valproic acid 3400mg/day, brivaracetam 400mg/day, zonisamide 500mg/day, perampanel 12mg/day, ketogenic diet, and cannabidiol 10mg/day. The cognitive assessment revealed mild behavioral disturbances and semantic memory deficits. One month later, seizures occurred every 3-4 days, albeit with a lower intensity, and treatment tolerability was good.
3. Discussion
We present the case of a previously healthy young adult with a super-refractory SE without identified cause after an extensive work-up. The clinical, electroencephalography, and neuroimaging features are consistent with a NORSE of unknown cause.[
Our patient did not respond to multiple ASDs or various types of immunotherapies, including tocilizumab, which was initiated prior to anakinra due to the marked elevation of IL-6 levels in CSF. However, the addition of anakinra, 28 days after the SE onset, lead to an immediate cessation of the SE.
Anakinra inhibits IL-1β, which is a pro-convulsive cytokine.[
] Clarkson et al. studied seven patients with FIRES, and they provided data regarding the role of IL-1 in the pathogenesis of FIRES. The authors found elevated endogenous IL-1RA and IL-1β in the patients’ serum and CSF, reduced expression of intracellular IL-1RA isoforms, a functional deficit in the inhibition of IL-1RA signaling, and multiple noncoding polymorphisms and a silent exonic mutation of unknown significance in the IL-1RN gene.[
] However, there is limited information available about its clinical efficacy in NORSE. There are reports of children with FIRES with clinical response to anakinra in the acute and chronic phases of the disease (Appendix 2-1). Additionally, a 21-year-old adult with FIRES and improvement of seizures when anakinra was started has been described.[
Our patient presented headache and fever in the week before the SE onset. These prodromal symptoms precede seizures onset by 1-14 days in up to 90% of NORSE cases.[
] The serum and CSF concentrations of IL-1β and IL-6 were elevated, but the NGS did not reveal any pathogenic variants in the IL-1RN gene, although deep intronic variants cannot be excluded. The prodrome and laboratory findings, could be compatible with an underlying neuroinflammatory condition, which is concordant with the response to immunotherapy. We consider that, probably, a functional deficit in IL-1 pathway or a non-detected mutation could explain the marked improvement after anakinra initiation in our patient, and the difference of response with respect to tocilizumab despite the higher concentrations of IL-6 in CSF compared to IL-1β.
Although the temporal relationship between anakinra initiation and the clinical improvement in our patient, we cannot exclude the contribution of a late effect of tocilizumab to this response. Jun et al. have reported improvement with tocilizumab in six of seven adults with NORSE, with a median of 3 days after the administration; however, a delayed response, with an interval of 6-10 days from the initiation, was described in two cases.[
Neutropenia, a common side effect of anakinra, forced us to discontinue this drug after one month of treatment, and this did not lead to a worsening of the epilepsy.
Ketogenic diet and cannabidiol have been reported to have anti-seizure efficacy in children and adults with FIRES.[
] Both of these treatments appeared to contribute to the reduction of seizures frequency and intensity in our patient.
Two cases of NORSE related to SARS-CoV-2 autoimmune encephalitis have been recently reported (Appendix 2-2). A nosocomial origin of the SARS-CoV-2 infection was assumed in our patient based on the initial negative RT-PCR tests. Consequently, a causative role of SARS-CoV-2 in the NORSE appears to be unlikely. However, the SARS-CoV-2 infection could have contributed to an increase in the inflammatory mediators and persistence of the SE in our patient.
In conclusion, anakinra appears to be a suitable option for the treatment of NORSE of unknown cause that should be considered in the early stages of SE. The clinical and EEG responses reported here provide additional support for the role of IL-1 in NORSE and the efficacy of anakinra.
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