Objective To create an international consensus treatment recommendation for pediatric NMDA receptor antibody encephalitis (NMDARE). Methods After selection of a panel of 27 experts with representation from all continents, a 2-step Delphi method was adopted to develop consensus on relevant treatment regimens and statements, along with key definitions in pediatric NMDARE (disease severity, failure to improve, and relapse). Finally, an online face-to-face meeting was held to reach consensus (defined as ≥75% agreement). Results Corticosteroids are recommended in all children with NMDARE (pulsed IV preferred), with additional IV immunoglobulin or plasma exchange in severe patients. Prolonged first-line immunotherapy can be offered for up to 3–12 months (oral corticosteroids or monthly IV corticosteroids/immunoglobulin), dependent on disease severity. Second-line treatments are recommended for cases refractory to first-line therapies (rituximab preferred over cyclophosphamide) and should be considered about 2 weeks after first-line initiation. Further immunotherapies for refractory disease 1-3 months after second-line initiation include another second-line treatment (such as cyclophosphamide) and escalation to tocilizumab. Maintenance immune suppression beyond 6 months (such as rituximab redosing or mycophenolate mofetil) is generally not required, except for patients with a more severe course or prolonged impairments and hospitalization. For patients with relapsing disease, second-line and prolonged maintenance therapy should be considered. The treatment of NMDARE following herpes simplex encephalitis should be similar to idiopathic NMDARE. Broad guidance is provided for the total treatment duration (first line, second line, and maintenance), which is dictated by the severity and clinical course (i.e., median 3, 9 and 18 months in the best, average, and worst responders, respectively). Recommendations on the timing of oncologic searches are provided. Conclusion These international consensus recommendations for the management of pediatric NMDARE aim to standardize the treatment and provide practical guidance for clinicians, rather than absolute rules. A similar recommendation could be applicable to adult patients.

We characterize clinical and neuroimaging features of SARS-CoV-2-related acute necrotizing encephalopathy (ANE). Systematic review of English language publications in PubMed and reference lists between January 1, 2020, and June 30, 2023, in accordance with PRISMA guidelines. Patients with SARS-CoV-2 infection who fulfilled diagnostic criteria for sporadic and genetic ANE were included. From 899 articles, 20 cases (17 single case reports and 3 additional cases) were curated for review (50% female; 8 were children). Associated COVID-19 illnesses were febrile upper respiratory tract infections in children while adults had pneumonia (45.6%) and myocarditis (8.2%). Children had early neurologic deterioration (median day 2 in children vs day 4 in adults), seizures (5 (62.5%) children vs 3 of 9 (33.3%) adults), and motor abnormalities (6 of 7 (85.7%) children vs 3 of 7 (42.9%) adults). Eight of 12 (66.7%) adults and 4 (50.0%) children had high-risk ANE scores. Five (62.5%) children and 12 (66.7%) adults had brain lesions bilaterally and symmetrically in the putamina, external capsules, insula cortex, or medial temporal lobes, in addition to typical thalamic lesions of ANE. Hypotension was only seen in adults (30%). Hematologic derangements were common: lymphopenia (66.7%), coagulopathy (60.0%), or elevated D-dimers (100%), C-reactive protein (91.7%), and ferritin (62.5%). A pathogenic heterozygous c/.1754 C>T variant in RANBP2 was present in 2 children: one known to have this before SARS-CoV-2 infection, and a patient tested because the SARS-CoV-2 infection was the second encephalopathic illness. Three other children with no prior encephalopathy or family history of encephalopathy were negative for this variant. Fifteen (75%) received immunotherapy (with IV methylprednisolone, immunoglobulins, tocilizumab, or plasma exchange): 6 (40.0%) with monotherapy and 9 (60.0%) had combination therapy. Deaths were in 8 of 17 with data (47.1%): a 2-month-old male infant and 7 adults (87.5%) of median age 56 years (33-70 years), 4 of whom did not receive immunotherapy. Children and adults with SARS-CoV-2 ANE have similar clinical features and neuroimaging characteristics. Mortality is high, predominantly in patients not receiving immunotherapy and at the extremes of age.

Bilateral hemorrhagic thalamic lesions in dengue encephalitis resemble lesions seen in acute necrotizing encephalopathy (ANE). We investigate whether dengue-associated ANE (DANE) should be considered an ANE variant or a mimic. Systematic review of dengue encephalitis literature from PubMed and SCOPUS (inception to December 31, 2022). Diagnostic criteria for ANE, acute encephalitis (AE), acute disseminated encephalomyelitis (ADEM), and infection-triggered encephalopathy syndromes were applied. Data on 162 patients (median age 20 [0.4 to 79] years; 69 [42.3%] female; 72 [44.4%] aged ≤18 years) from 103 articles were analyzed. DANE (62, 38.3%) was the commonest, followed by AE (56, 34.6%) and ADEM (27, 16.7%). The main clinical features were fever (100%), thrombocytopenia (79.0%), headache (57.8%), and seizures (43.7%). Patients with DANE had earlier neurological deterioration (3.5 [1 to 8] vs 5 [1 to 14] days in other encephalitis syndromes, P = 0.0127), seizures (54.2% vs 37.4%, P = 0.0471), higher cerebrospinal fluid (CSF) protein (0.92 [0.18 to 4.8] vs 0.73 [1 to 16] g/L, P = 0.0469), thalamic (100% vs 8.0%) and hemorrhagic brain lesions (73.3% vs 7.5%, P < 0.0001). CSF pleocytosis and positive CSF dengue IgM/viral polymerase chain reaction were reported in 66.7% and 78.6% with DANE. Mortality was 16.1% in DANE, and 40.6% of survivors had disability. High-risk ANE severity scores predicted poor outcomes (positive predictive value 64.3% [95% confidence interval 38.8% to 83.7%]). DANE differs from other dengue encephalitis syndromes and is clinicoradiologically indistinguishable from sporadic ANE with sufficient evidence to be considered an ANE variant.

Objective To test the utility and diagnostic yield of a medical-exome gene panel for identifying pathogenic variants in Mendelian disorders. Methods Next-generation sequencing was performed with the TruSight One gene panel (targeting 4813 genes) followed by MiSeq sequencing on 216 patients who presented with suspected genetic disorders as assessed by their attending physicians. Results There were 56 pathogenic and 36 likely pathogenic variants across 57 genes identified in 87 patients. Causal mutations were more likely to be truncating and from patients with a prior clinical diagnosis. Another 18 promising variants need further evaluation for more evidence to meet the requirement for potential upgrade to pathogenic. Forty-five of the 92 clinically significant variants were novel. Conclusion The 40.3% positive yield compares favourably with similar studies using either this panel or whole exome sequencing, demonstrating that large gene panels could be a good alternative to whole exome sequencing for quick genetic confirmation of Mendelian disorders.