PIRSE: Philosophical Investigations in Refractory Status Epilepticus.

98 www.pccmjournal. org January 2020 • Volume 21 • Number 1 Philosophy of language enthusiasts will be familiar with Gottlieb Frege’s famous example, “Hesperus is the same planet as Phosphorus” encapsulating the question of how names can have meaning and how language, mathematics, and even moral philosophy can be said to be true, false, or meaningful (1). Indeed, the International League Against Epilepsy position is that classification of an epilepsy syndrome is fundamental to understanding of mechanism, treatment, and prognosis (2). The issues of meaning and reference Frege illuminated in the 19th century for the philosophy of language have also hampered progress in the treatment and mitigation of morbidities associated with status epilepticus (SE). SE is a neurologic emergency which comes in many forms, refractory (RSE), super-refractory (SRSE), new-onset refractory (NORSE) de novo cryptogenic, and febrile illness-related (FIRES), to name a partial list. The definitions of RSE and SRSE are relatively recent, with SRSE now defined as SE persisting for at least 24 hours after initiation of anesthesia despite appropriate treatment or recurring during anesthesia withdrawal (3). These new definitions acknowledge the fact that for reasons which we do not understand some patients do not respond immediately to anti-seizure medications (ASMs) and represent an important cohort who have an even higher risk for mortality of up to 40% and significant morbidity in survivors (4, 5). Early and adequate dosing with an ASM is a key tenet of neuroprotection for the treatment of SE (6). Effective neuroprotection also requires identification and treatment of the proximate cause of SE. Accordingly, healthy patients who present with newonset RSE (NORSE) are clearly an important subgroup in the spectrum of Rand SRSE, requiring both emergent treatment and rapid identification of the etiology of SE. Advances in treatment of this spectrum of SE in children and adults have been hampered by the proliferation of overlapping descriptive terms and definitions including idiopathic catastrophic epileptic encephalopathy, acute encephalitis with refractory repetitive partial seizures (AERRPS), and devastating epilepsy in school-age children (DESC), now unified under the acronym FIRES (7). In this issue of Pediatric Critical Care Medicine, Husari et al (8) used the recently established consensus criteria for the definition of NORSE to analyze the etiologies, diagnostic studies, treatment approaches and neurologic outcomes of 40 children with NORSE (among a total of 674 patients presenting with SE) at their center over a 13.5-year period. Importantly, the consensus criteria specify that FIRES is a subcategory of NORSE which applies to all ages and requires the presence of a febrile illness 1 to 14 days before the onset of RSE (9). Thus, these investigators have brought together in a single cohort, children who previously may have been studied under the acronyms FIRES, AERRPS, or DESC. In doing so, they provide a valuable insight into the outcomes from this disorder and guidance for standardizing diagnostic studies and acute treatments. All the patients (median age 6.6 yr) were developmentally normal and the majority (58%) had no identified etiology for NORSE. Of the 17 with an identified cause, 14 (82%) had a form of neuroinflammatory process (viral or autoimmune encephalitis or acute disseminated encephalomyelitis). The timing and types of diagnostic evaluations were not standardized in this retrospective study, and some etiologies may have been missing. Brain imaging (MRI) did not appear always to be helpful and was normal in 13 cases (32%). Notably, only seven patients underwent genetic testing and in three of these cases a pathologic mutation was identified. Nevertheless, the results highlight the neuroinflammation as an important mechanism in this syndrome. For their analysis, the authors did not separate patients with FIRES out from the larger cohort but their fever occurred in 30 (75%) of the study cohort, including those with autoimmune or genetic etiologies. The frequency of fever and indirect evidence for neuroinflammation offer some clues about mechanisms and future therapies, including focused immunomodulation. Multiple lines of evidence identify neuroinflammation and oxidative stress as mechanisms of SE and epileptogenesis (10, 11). In the long-term, the implications of these findings for NORSE and its ilk are that biomarkers may help identify these patients earlier and treatment combinations may extend beyond ASMs to incorporate focused suppression of astrocyte or microglial activation and restoration of mitochondrial function. The authors provide follow-up data on 31 patients with a median interval of 3.8 years after hospital discharge, another strength of the article. Consistent with other studies, morbidity was high with five deaths (13%) before discharge and 18 of the survivors (58%) left with neurocognitive deficits detected at the last clinic visit. Half the patients developed SRSE and all the deaths occurred in this group. Of the survivors, 20 (65%) developed epilepsy, including the majority of the SRSE group, in which 12 (86%) were intractable. There are important caveats to these findings. The treatment of RSE and SRSE over the study period was not standardized, and we cannot therefore know how to generalize the conditions under *See also p. 59.