Use and Safety of Immunotherapeutic Management of N-Methyl-d-Aspartate Receptor Antibody Encephalitis: A Meta-analysis.

Importance: Overall, immunotherapy has been shown to improve outcomes and reduce relapses in individuals with N-methyl-d-aspartate receptor (NMDAR) antibody encephalitis (NMDARE); however, the superiority of specific treatments and combinations remains unclear. Objective: To map the use and safety of immunotherapies in individuals with NMDARE, identify early predictors of poor functional outcome and relapse, evaluate changes in immunotherapy use and disease outcome over the 14 years since first reports of NMDARE, and assess the Anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score. Data Sources: Systematic search in PubMed from inception to January 1, 2019. Study Selection: Published articles including patients with NMDARE with positive NMDAR antibodies and available individual immunotherapy data. Data Extraction and Synthesis: Individual patient data on immunotherapies, clinical characteristics at presentation, disease course, and final functional outcome (modified Rankin Scale [mRS] score) were entered into multivariable logistic regression models. Main Outcomes and Measures: The planned study outcomes were functional outcome at 12 months from disease onset (good, mRS score of 0 to 2; poor, mRS score greater than 2) and monophasic course (absence of relapse at 24 months or later from onset). Results: Data from 1550 patients from 652 articles were evaluated. Of these, 1105 of 1508 (73.3%) were female and 707 of 1526 (46.3%) were 18 years or younger at disease onset. Factors at first event that were significantly associated with good functional outcome included adolescent age and first-line treatment with therapeutic apheresis, corticosteroids plus intravenous immunoglobulin (IVIG), or corticosteroids plus IVIG plus therapeutic apheresis. Factors significantly associated with poor functional outcome were age younger than 2 years or age of 65 years or older at onset, intensive care unit admission, extreme delta brush pattern on electroencephalography, lack of immunotherapy within the first 30 days of onset, and maintenance IVIG use for 6 months or more. Factors significantly associated with nonrelapsing disease were rituximab use or maintenance IVIG use for 6 months or more. Adolescent age at onset was significantly associated with relapsing disease. Rituximab use increased from 13.5% (52 of 384; 2007 to 2013) to 28.3% (311 of 1100; 2013 to 2019) (P < .001), concurrent with a falling relapse rate over the same period (22% [12 of 55] in 2008 and earlier; 10.9% [35 of 322] in 2017 and later; P = .006). Modified NEOS score (including 4 of 5 original NEOS items) was associated with probability of poor functional status at 1 year (20.1% [40 of 199] for a score of 0 to 1 points; 43.8% [77 of 176] for a score of 3 to 4 points; P = .05). Conclusions and Relevance: Factors influencing functional outcomes and relapse are different and need to be considered independently in development of evidence-based optimal management guidelines of patients with NMDARE.

International Consensus Recommendations for the Treatment of Pediatric NMDAR Antibody Encephalitis.

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.

Acquired demyelinating disorders of childhood in the Western Cape, South Africa.

In a retrospective review of patients with acquired demyelinating disorders of the central nervous system, 19 children (0.6%) were identified from the Paediatric Neurology database of 3159 patients; 7 had acute disseminated encephalomyelitis, 1 had Schilder's disease, 5 had multiple sclerosis, and 6 had acute transverse myelitis. The median age of presentation was 83 months, with increased incidence during the summer and winter months. The commonest presentation was hemiparesis. The commonest regions of magnetic resonance imaging (MRI) abnormalities were the deep white matter (68%) and cerebellum (48%).The patients with multiple sclerosis had more monosymptomatic presentations (P < .02), raised cerebrospinal fluid protein (P = .022), and contrast enhancement of lesions (P = .05) compared with the acute disseminated encephalomyelitis group. Neuroepidemiological published surveillances of African children provide no data about these disorders. The prevalence of acquired demyelinating disorders in resource-poor settings is under-estimated because of the large burden of infections and limited access to neuroimaging.

Clinical phenotype of South African children with neurofibromatosis 1.

Forty-eight children with neurofibromatosis 1 presenting between 2000 and 2004 were reviewed for their clinical phenotype, and data were compared with published reports. The median age at presentation was 4 years (range 10 days to 12 years). The male to female ratio was similar (22 male:26 female). There were frequencies of café au lait spots, axillary freckling, Lisch nodules, and new mutations comparable to those cited in the literature. Fewer patients had neurofibromas (4%), but more patients had plexiform neurofibromas of the head and neck (16%). Three patients of the 22 who had neuroimaging had optic gliomas (14%). The most consistent disability, with maximum impact, related to the patient's cognitive level of functioning. School problems, defined as learning and behavioral problems observed in the classroom, were reported in 70% of school-aged children (n = 21), compared with international figures of 29.8% to 45%. This high prevalence has reinforced the clinic service policy of formal neuropsychology assessments in all children with reported school problems. In addition, earlier referral of children to the service (preschool n = 18) has enabled formal developmental assessments and planning of specific educational placement to optimize learning. This is the first description of the neurofibromatosis 1 phenotype from the African continent. The multidisciplinary approach to management has proved beneficial in the South African context. The combined clinic has resulted in a holistic approach to patient care, early detection of pathology, consistent therapies across the specialties, and better patient attendance and compliance. (J Child Neurol 2006;21:63-70).

Progressive multifocal leukoencephalopathy after initiation of highly active antiretroviral therapy in a child with advanced human immunodeficiency virus infection: a case of immune reconstitution inflammatory syndrome.

Five weeks after commencing highly active antiretroviral therapy, a 12-year-old boy with advanced human immunodeficiency virus infection presented with acute cerebellar dysfunction and hemiparesis. Progressive multifocal leukoencephalopathy was diagnosed by cerebrospinal fluid polymerase chain reaction for JC virus and magnetic resonance imaging of the brain. Rapid and sustained improvement followed a prolonged course of glucocorticosteroid therapy while continuing antiretrovirals.

Hydatid disease of the spine in South African children.

We present three patients with neurologic complications of the spine from hydatid disease. The first was a 6-year-old girl with lower limb paralysis evolving over 2 weeks. Neuroimaging revealed a cystic mass compressing the spinal cord at the level of T8 and extending from the vertebral body. She underwent surgical decompression. Histopathologic examination confirmed hydatid disease. At 6-month follow-up, functional improvement had occurred with full ambulation. She continues on long-term albendazole therapy. Two other patients are described, one with primary spinal disease and the other with cerebral disease and secondary seeding to the spine. Spinal hydatid disease is a rarity, even more so in children. Although secondary disease, primarily affecting bone, carries a poorer long-term outlook, the first patient made a dramatic recovery and has raised therapeutic dilemmas as to the total duration of continuing albendazole therapy. The literature documents some 37 reports, mostly in adults. Considering the frequency of hydatid disease in South Africa, the incidence in our population could be under-recorded. Unless the clinician includes spinal hydatid disease, in endemic areas, as part of the differential list for paralysis and considers performing neuroimaging, this potentially treatable diagnosis will be missed.