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Year : 2022  |  Volume : 20  |  Issue : 2  |  Page : 119-120

The unknown etiology of new-onset refractory status epilepticus

Medicine Department, Federal University of Santa Maria, Santa Maria, Brazil

Date of Submission14-Jan-2022
Date of Decision03-Feb-2022
Date of Acceptance06-Feb-2022
Date of Web Publication07-May-2022

Correspondence Address:
Dr. Jamir Pitton Rissardo
Av. Roraima, 1000 - Camobi, Santa Maria - RS, Brazil, 97105-900
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/cmi.cmi_5_22

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How to cite this article:
Rissardo JP, Caprara AL. The unknown etiology of new-onset refractory status epilepticus. Curr Med Issues 2022;20:119-20

How to cite this URL:
Rissardo JP, Caprara AL. The unknown etiology of new-onset refractory status epilepticus. Curr Med Issues [serial online] 2022 [cited 2022 May 21];20:119-20. Available from: https://www.cmijournal.org/text.asp?2022/20/2/119/344935

We read the manuscript entitled “Time is brain: Review of emergency management of status epilepticus in adults” on the esteemed “Current Medical Issues” with great interest. Madhiyazhagan et al. discussed the acute management of status epilepticus in the emergency department and described the choice of antiepileptic drugs and management of status epilepticus in special situations such as refractory status epilepticus and status epilepticus in pregnancy.[1]

New-onset refractory status epilepticus (NORSE) was first reported by Einar P Wilder-Smith in 2005. This term refers to individuals with super refractory status epilepticus without associated past medical history of epilepsy and with no identifiable cause despite initial evaluation.[2] About half of patients with NORSE have an unknown etiology despite an extensive workup.[3] However, a recent systematic review of the literature further “entangled” this mystery.[4]

Herein, we would to discuss the possible etiologies of NORSE. Lattanzi et al. studied 197 records with 1334 patients both pediatric and adult. We reanalyzed their spreadsheet database of [Table 1] and supplementary material to better describe the following question “What is the etiology of NORSE?”

[Figure 1] shows the etiologies reported in the most extensive review of the literature about the causes of NORSE until now [Figure 1]. The causes reported were unknown in 77.96% (1040/1334) of the individuals, nonparaneoplastic autoimmune encephalitis in 10.79% (144), infectious diseases 3.89% (52), genetic disorders 3.29% (44), paraneoplastic encephalitis 2.84% (38), endocrine disorders 0.37% (5), exogenous intoxication 0.37% (5), demyelinating diseases 0.29% (4), and rheumatic disease 0.14% (2).
Figure 1: The etiology of New-Onset Refractory Status Epilepticus (NORSE). The causes reported were unknown in 77.96% of the individuals, nonparaneoplastic autoimmune encephalitis 10.79%, infectious diseases 3.89%, genetic 3.29%, paraneoplastic encephalitis 2.84%, endocrine disorder 0.37%, exogenous intoxication 0.37%, demyelinating diseases 0.29%, and rheumatic disease 0.14%.

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The review by Lattanzi et al. was interesting because the data found supports the hypothesis that the cause of NORSE was not still discovered and that we are not on the path of finding the right answer. Previous studies revealed that the etiology was unknown in about 50% of the cases, which in the recent review by Lattanzi et al. was almost 80%. However, among the individuals reported as “unknown,” we can find interesting results such as possible new anti-basal ganglia antibodies and increased levels of inflammatory biomarkers in the cerebrospinal fluid and serum. Furthermore, impaired toll-like receptors and T-cell responses were reported.

The nonparaneoplastic autoimmune encephalitis cases included the following antibodies: N-methyl-D-aspartate receptor, leucine-rich glioma-inactivated 1, and γ-aminobutyric acid B receptor. The classic onconeural antibodies found were against collapsing response mediator protein 5, Hu, Yo, Ri, Ma2, SRY-box transcription factor 1, and amphiphysin.[5]

Herpes simplex virus, Rickettsia encephalitis, Coxsackie A9 enteroviral, Japanese encephalitis virus, severe acute respiratory syndrome coronavirus-2, Mycoplasma pneumoniae, syphilis, Toxoplasma gondii, and Epstein–Barr virus were some of the infectious-related encephalitis reported. It is worthy of mentioning that some reports are rare due to the primary disease-causing encephalitis such as rabies.

The endocrine disorders were composed of steroid-responsive encephalopathy associated with autoimmune thyroiditis. The rheumatic cases were all with systemic lupus erythematosus. The demyelinating category only had acute disseminated encephalomyelitis. Interestingly, there are cases of exogenous intoxications causing NORSE such as exposure to synthetic cannabinoids, organophosphate poisoning, and alcohol abuse.

In sum, the number of unidentified cases increased throughout the last decades. Therefore, studies aiming to search for a cause should be reported. Furthermore, it is advised in further studies to publish all the extensive workup done including some techniques already reported to increase the diagnostic accuracy of NORSE.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Madhiyazhagan M. Time is brain: Review of emergency management of status epilepticus in adults. Curr Med Issues 2021;19:269-73.  Back to cited text no. 1
Wilder-Smith EP, Lim EC, Teoh HL, Sharma VK, Tan JJ, Chan BP, et al. The NORSE (new-onset refractory status epilepticus) syndrome: Defining a disease entity. Ann Acad Med Singap 2005;34:417-20.  Back to cited text no. 2
Burd SG, Mironov MB, Moizykevich ER, Rubleva YV, Bogomazova MA, Yurchenko AV, et al. New-Onset Refractory Status Epilepticus (NORSE): Literature review and clinical case description. Epilepsy Paroxysmal Cond 2020;12:169-76.  Back to cited text no. 3
Lattanzi S, Leitinger M, Rocchi C, Salvemini S, Matricardi S, Brigo F, et al. Unraveling the enigma of new-onset refractory status epilepticus: A systematic review of aetiologies. Eur J Neurol 2022;29:626-47.  Back to cited text no. 4
Kirmani BF, Au K, Ayari L, John M, Shetty P, Delorenzo RJ. Super-refractory status epilepticus: Prognosis and recent advances in management. Aging Dis 2021;12:1097-119.  Back to cited text no. 5


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