Appendix e-1
This appendix includes additional clinical information, and figure legends for Figures e-1, e-2, and e-3.
Clinical information of 136 patients with clinically-suspected autoimmune encephalitis
NSA-antibodies were identified in 39 of 136 patients (29%).These seropositive patients were finally diagnosed with anti-NMDAR encephalitis (n=32: paraneoplastic [n=14], and non-paraneoplastic [n=18]; one with antibodies to NMDAR, AMPAR, and GABAbR), autoimmune post-herpes simplex encephalitis1 (n=2: with NMDAR antibodies [n=1], and antibodies to unknown antigens [n=1]), ALE (n=4: with LGI1 antibodies [n=2], AMPAR antibodies [n=1], and antibodies to unknown antigens [n=1]), and overlapping encephalitis and stiff-person spectrum syndrome with antibodies to AMPAR, GABAaR, and CV2 associated with thymoma (n=1).
The final diagnoses of the remaining seronegative 97 patients were as follows:encephalitis of unknown etiologies (n=21), autoantibodies-negative but probable autoimmune encephalitis2 (n=14), C-NORSE (n=11), primary psychiatric disorder (n=12), seronegative ALE (n=8), ADEM (n=5), neuropsychiatric lupus (n=4), idiopathic opsoclonus-myoclonus/ocular flutter syndrome (n=4), NMOSD associated with AQP4 antibodies (n=2), viral encephalitis (n=2: HHV6 [n=1], and VZV [n=1]), CJD (n=1), neuro-Bechet's disease (n=1), multiple sclerosis (n=1), AERRPS3 (n=1: 5 years old boy), intravascular lymphoma (n=1), primary CNS lymphoma (n=1), and others (n=8).
ADEM: acute disseminated encephalomyelitis; AERRPS: acute encephalitis with refractory, repetitive partial seizures; ALE: autoimmune limbic encephalitis; AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; AQP4: aquaporin 4; C-NORSE: cryptogenic new-onset refractory status epilepticus; CJD: Creutzfeldt–Jakob disease; GABAaR: γ-aminobutyric acid-A receptor; GABAbR: γ-aminobutyric acid-B receptor; HHV6: human herpesvirus 6; LGI1: leucine-rich glioma inactivated-1; NMDAR: n-methyl-d-aspartate receptor; NMOSD: neuromyelitis optica spectrum disorder; NORSE: new-onset refractory status epilepticus; NSA-antibodies: antibodies to neuronal cell surface antigens or synaptic proteins; VZV: varicella zoster virus
References
- Armangue T, Moris G, Cantarín-Extremera V, et al. Autoimmune post-herpes simplex encephalitis of adults and teenagers. Neurology2015;85:1736-1743.
- Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol2016;15:391-404.
- Sakuma H, Awaya Y, Shiomi M, et al. Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis. Acta Neurol Scand 2010;121:251-256.
Reasonable exclusion of alternative causes in patients with C-NORSE
Excluded alternative causes include acute brain injury, bacterial meningitis or abscess, virus encephalitis, metabolic or alcohol-related encephalopathy, mitochondrial encephalopathy, Hashimoto encephalopathy, CJD, intravascular lymphoma, primary psychiatric disorder, previously known seizure disorder, multiple sclerosis/ADEM, neuropsychiatric lupus, encephalitis with rheumatoid arteritis, Sjögren's syndrome, neuro-Behçet's disease, or paraneoplastic or autoimmune encephalitis with anti-neuronal antibodies.
Comparison of clinical features and C-NORSE score between C-NORSE and other groups
NSA antibody-negative cases (n=97) / NSA antibody-positive cases (n=39)C-NORSE
(n=11) / Miscellaneous disorders (n=86)1 / NMDARE (n=32) / Other seropositive AE(n=7)1
Sex: female / 7 (64%) / 54 (63%) / 24 (75%) / 5 (71%)
Median age at onset, y / 27 (range, 17-59) / 37 (range, 5-91) / 27 (range, 12-47) / 37 (19-66)
Prodromal fever / 10 (91%) / 36/84 (43%)** / 12 (38%)** / 3 (43%)*
Seizure / 11 (100%) / 34 (40%)** / 28 (88%) / 3 (43%)*
SE / 11 (100%) / 13 (15%)** / 6 (19%)** / 1(14%)2**
Refractory SE / 11 (100%) / 1 (1%)** / 6 (19%)** / 0 (0%)**
Median C-NORSE score / 6 (range, 5-6)3 / 0 (range, 0-6)4** / 0 (range, 0-4)3** / 0 (range, 0-0)**
*: P.05, **: P.01
1See the clinical information of appendix e-1.2Generalized convulsive SE was seen in a case of AE associated with antibodies to unknown antigens but paroxysmal discharges were not confirmed by EEG recording. 3In patients with C-NORSE, C-NORSE score was 5 (n=4) and 6 (n=7), while it was 0 (n=26), 2 (n=1), 3 (n=3), and 4 (n=2) in those with NMDARE (see Figure e-3). 4Seronegative patients with miscellaneous disorders were all scored 0 except one who was scored 6. This patient, a 5-year-old boy, presented with the symptoms mimicking NORSE but he was diagnosed with AERRPS, which is often used in pediatric cases for similar syndrome but probably identical to C-NORSE. This patient is not included in a group of C-NORSE because of a pediatric case under the age of 17 years (see definition criteria of C-NORSE in the text).The Fisher exact test was performed for comparison of categorical variables, and the Mann-Whitney test was used for continuous variables. The statistical significance was set at P<.05.
AE: autoimmune encephalitis; AERRPS: acute encephalitis with refractory repetitive partial seizures; C-NORSE: cryptogenic new-onset refractory status epilepticus; NMDARE: anti-NMDA receptor encephalitis; NSA: neuronal cell surface antigens or synaptic proteins; SE: status epilepticus
Figure e-1: Progressive brain atrophy and multifocal lesions (Patient 4)
Brain MRIs show multiple FLAIR hyperintensities (light blue arrows) in the bilateral medial temporal lobes, left medial occipital lobe, bilateral posterior thalamus, and basal ganglia on day 15, and left insula on day 23 and day 68. The patient was initially treated with conventional AEDs and IVMP started on day 3 for possible diagnosis of NMDARE; however, the patient becamea state of unresponsive wakefulness with diffuse brain atrophy. Five months after transfer to our hospital, the patient was treated with IVMP, IVIg, PLEX, and IVCPA. Augmented gadolinium enhancement into the sulci of the brain, Sylvian fissure, and left occipital lesion (at 5 months, light green allows) resolved after these immunotherapies (at 9 months); however, the patient remained persistent vegetative state with frequent repetitive partial seizures, and died 35 months after symptoms onset. Note progressive brain atrophy (at 5, 9 months). Note progressive brain atrophy and ventricular dilatation (*). MRI obtained at 5 and 9 months were obtained after intravenous administration of gadolinium (see Table e-1, and e-2).
AED: anti-epileptic drugs; IVCPA: intravenous cyclophosphamide; IVIg: intravenous immunoglobulin; IVMP: intravenous high-dose methylprednisolone; NMDARE: anti-NMDAR encephalitis; PLEX: plasma exchange.
Figure e-2: EEG obtained on day 3 (Patient 3)
This EEG was recorded on day 3 of the onset of refractory status epilepticus. Panel A recorded during inter-ictal state shows periodic paroxysmal discharges in the O1, F7 and T3. Panel B shows recruiting rhythm developing from the O2, F8 and T4. Panel C and D show continuous spread of seizure activity evolving generalized convulsive status epilepticus.EEG was recorded with 60 Hz low-pass and 1.5 Hz high-pass filters.
Figure e-3:Comparison of C-NORSE score between C-NORSE and other groups
Median C-NORSE score is higher in patients with C-NORSE than those with miscellaneous disorders (P<.0001), NMDARE (P<.0001), or other seropositive AE (P=.0002). Data are shown as mean ± SD. * Indicates significant difference between groups.
The cut-off value was set as C-NORSE score 5. This scoring system provides clinical clue when the C-NORSE score is high (5 or 6), the patient is more likely seronegative (suggesting C-NORSE); however, it is important to note when the score is low (0-4), antibody status remains uncertain, the etiology should be extensively investigated including NSA antibodies, and low C-NORSE scoredoes not preclude either positive or negative antibody-testing-results. C-NORSE score should be usedcautiously in patients who developed SE especially RSE, but not in those without SE for screening possible AE. The Mann-Whitney test was used, and the statistical significance was set at P<.05.
AE: autoimmune encephalitis; C-NORSE: cryptogenic new-onset refractory status epilepticus; NMDARE: anti-NMDA receptor encephalitis; NSA-antibodies: antibodies to neuronal cell surface antigens or synaptic proteins; RSE: refractory SE; SE: status epilepticus