Management of Autoimmune Encephalitis in a 7-Year-Old Child With CTLA-4 Haploinsufficiency and AMPA Receptor Antibodies: A Case Report.

OBJECTIVES: We report on the therapeutic management of early-onset severe neurologic symptoms in cytotoxic T lymphocyte antigen-4 haploinsufficiency (CTLA-4h) and the presence of antibodies to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) as an important finding. METHODS: This is a case report from a Dutch academic hospital. Repeated clinical examinations, repeated brain MRI and extended diagnostics on serum and CSF were performed. We used the CARE checklist. RESULTS: A 7-year-old boy was diagnosed with CTLA-4h based on family screening. On diagnosis, he had mild chronic diarrhea and autism spectrum disorder, but no abnormalities in extensive laboratory screening. Six months later, he presented with sudden-onset autoimmune encephalitis. Repeated brain MRI revealed no abnormalities, but immunohistochemistry analysis on serum and CSF showed the presence of AMPAR antibodies. Treatment was initially focused on immunomodulation and targeted CTLA-4 replacement therapy. Because of the persistent fluctuating cerebellar and neuropsychiatric symptoms and the potential clinical significance of the AMPAR antibodies, treatment was intensified with repetition of first-line immunomodulation and rituximab. This combined therapy resulted in sustained clinical improvement and served as a bridge to curative hematopoietic stem cell transplantation. DISCUSSION: This case illustrates the rare early onset of autoimmune encephalitis and presence of AMPAR antibodies in CTLA-4h. Targeted CTLA-4 replacement therapy resulted in a partial response. However, awaiting its optimal therapeutic effect, refractory CNS symptoms required intensification of immunomodulation. The identification of AMPAR antibodies guided our treatment decisions. CLASSIFICATION OF EVIDENCE: This provides Class IV evidence. It is a single observational study without controls.

Mimics of Autoimmune Encephalitis: Validation of the 2016 Clinical Autoimmune Encephalitis Criteria.

BACKGROUND AND OBJECTIVES: The clinical criteria for autoimmune encephalitis (AE) were proposed by Graus et al. in 2016. In this study, the AE criteria were validated in the real world, and common AE mimics were described. In addition, criteria for probable anti-LGI1 encephalitis were proposed and validated. METHODS: In this retrospective cohort study, patients referred to our national referral center with suspicion of AE and specific neuroinflammatory disorders with similar clinical presentations were included from July 2016 to December 2019. Exclusion criteria were pure cerebellar or peripheral nerve system disorders. All patients were evaluated according to the AE criteria. RESULTS: In total, 239 patients were included (56% female; median age 42 years, range 1-85). AE was diagnosed in 104 patients (44%) and AE mimics in 109 patients (46%). The most common AE mimics and misdiagnoses were neuroinflammatory CNS disorders (26%), psychiatric disorders (19%), epilepsy with a noninflammatory cause (13%), CNS infections (7%), neurodegenerative diseases (7%), and CNS neoplasms (6%). Common confounding factors were mesiotemporal lesions on brain MRI (17%) and false-positive antibodies in serum (12%). Additional mesiotemporal features (involvement extralimbic structures, enhancement, diffusion restriction) were observed more frequently in AE mimics compared with AE (61% vs 24%; p = 0.005). AE criteria showed the following sensitivity and specificity: possible AE, 83% (95% CI 74-89) and 27% (95% CI 20-36); definite autoimmune limbic encephalitis (LE), 10% (95% CI 5-17) and 98% (95% CI 94-100); and probable anti-NMDAR encephalitis, 50% (95% CI 26-74) and 96% (95% CI 92-98), respectively. Specificity of the criteria for probable seronegative AE was 99% (95% CI 96-100). The newly proposed criteria for probable anti-LGI1 encephalitis showed a sensitivity of 66% (95% CI 47-81) and specificity of 96% (95% CI 93-98). DISCUSSION: AE mimics occur frequently. Common pitfalls in AE misdiagnosis are mesiotemporal lesions (predominantly with atypical features) and false-positive serum antibodies. As expected, the specificity of the criteria for possible AE is low because these criteria represent the minimal requirements for entry in the diagnostic algorithm for AE. Criteria for probable AE (-LGI1, -NMDAR, seronegative) and definite autoimmune LE are applicable for decisions on immunotherapy in early disease stage, as specificity is high.

Comparison of acute flaccid myelitis and transverse myelitis in children and evaluation of diagnostic criteria.

BACKGROUND AND PURPOSE: Acute flaccid myelitis (AFM) and transverse myelitis (TM) are serious conditions that may be difficult to differentiate, especially at onset of disease. In this study, we compared clinical features of pediatric AFM and TM and evaluated current diagnostic criteria, aiming to improve early and accurate diagnosis. METHODS: Two cohorts of children with enterovirus D68-associated AFM and clinically diagnosed TM were compared regarding presenting clinical features, additional investigations, and outcome. Current diagnostic criteria for AFM and TM were applied to evaluate their specificity. RESULTS: Children with AFM (n = 21) compared to those with TM (n = 36) were younger (median 3 vs. 10 years), more often had a prodromal illness (100% vs. 39%), predominant proximal weakness (69% vs. 17%), and hyporeflexia (100% vs. 44%), and less often had sensory deficits (0% vs. 81%), bowel and/or bladder dysfunction (12% vs. 69%), and hyperreflexia (0% vs. 44%). On magnetic resonance imaging, brainstem involvement was more common in AFM (74% vs. 21%), whereas supratentorial abnormalities were only seen in TM (0% vs. 40%). When omitting the criterion of a sensory level, 11 of 15 (73%) children with AFM fulfilled the diagnostic criteria for TM. Of children with TM, four of 33 (12%) fulfilled the diagnostic criteria for probable/definite AFM. CONCLUSIONS: Although there is considerable overlap between AFM and TM in children, we found important early differentiating clinical and diagnostic features. Meeting diagnostic criteria for AFM in children with TM and vice versa underlines the importance of thorough clinical examination and early and accurate diagnostic studies.

Predictive Value of Serum Neurofilament Light Chain Levels in Anti-NMDA Receptor Encephalitis.

BACKGROUND AND OBJECTIVES: Determinants of disease activity and prognosis are limited in anti-NMDA receptor (NMDAR) encephalitis. Neurofilament light chains (NfL) are markers of axonal damage and have been identified as valuable biomarkers for neurodegenerative and other neuroinflammatory disorders. We aimed to investigate serum NfL levels in patients with anti-NMDAR encephalitis as a biomarker for disease severity and outcome. METHODS: In this retrospective study, NfL values were measured in all available pretreatment serum and paired CSF samples of the nationwide anti-NMDAR encephalitis cohort. The values were analyzed in duplicate using single-molecule array and compared with measurements in healthy references. Follow-up sera were tested to analyze longitudinal responsiveness, if at least available from 2 time points after diagnosis. Serum NfL levels were compared with data on disease activity (seizures, MRI, and CSF findings), severity (modified Rankin Scale [mRS] score, admission days, and intensive care unit admission), and outcome (mRS score and relapses), using regression analysis. RESULTS: We have included 71 patients (75% female; mean age 31.4 years, range 0-85 years) of whom pretreatment serum samples were analyzed. Paired CSF samples were available of 33 patients, follow-up serum samples of 20 patients. Serum NfL levels at diagnosis were higher in patients (mean 19.5 pg/mL, 95% CI 13.7-27.7) than in references (mean 6.4 pg/mL, 95% CI 5.8-7.2, p < 0.0001). We observed a good correlation between serum and CSF NfL values (R = 0.84, p < 0.0001). Serum NfL levels and age correlated in patients (Pearson R = 0.57, p < 0.0001) and references (R = 0.62, p < 0.0001). Increased NfL values were detected in patients post-herpes simplex virus 1 encephalitis (mean 248.8 vs 14.1 pg/mL, p < 0.0001) and in patients with brain MRI lesions (mean 27.3 vs 11.1 pg/mL, p = 0.019). NfL levels did relate to the long-term follow-up (mRS score at 12 months; ßNfL = 0.55, p = 0.013), although largely explained by the effect of age on NfL levels and prognosis. In serial samples, NfL values did roughly follow clinical disease activity, albeit with delay. DISCUSSION: Increased serum NfL levels reflect neuroaxonal damage in anti-NMDAR encephalitis. No relationship was identified with disease severity, whereas the association with outcome was confounded by age. The implied role of sampling timing on NfL levels also limits the applicability of NfL as a prognostic marker.

Pediatric acute flaccid myelitis: Evaluation of diagnostic criteria and differentiation from other causes of acute flaccid paralysis.

BACKGROUND: Acute flaccid paralysis (AFP) is characterized by rapidly progressive limb weakness with low muscle tone. It has a broad differential diagnosis, which includes acute flaccid myelitis (AFM), a rare polio-like condition that mainly affects young children. Differentiation between AFM and other causes of AFP may be difficult, particularly at onset of disease. Here, we evaluate the diagnostic criteria for AFM and compare AFM to other causes of acute weakness in children, aiming to identify differentiating clinical and diagnostic features. METHODS: The diagnostic criteria for AFM were applied to a cohort of children with acute onset of limb weakness. An initial classification based on positive diagnostic criteria was compared to the final classification, based on application of features suggestive for an alternative diagnosis and discussion with expert neurologists. Cases classified as definite, probable, or possible AFM or uncertain, were compared to cases with an alternative diagnosis. RESULTS: Of 141 patients, seven out of nine patients initially classified as definite AFM, retained this label after further classification. For probable AFM, this was 3/11, for possible AFM 3/14 and for uncertain 11/43. Patients initially classified as probable or possible AFM were most commonly diagnosed with transverse myelitis (16/25). If the initial classification was uncertain, Guillain-Barré syndrome was the most common diagnosis (31/43). Clinical and diagnostic features not included in the diagnostic criteria, were often used for the final classification. CONCLUSION: The current diagnostic criteria for AFM usually perform well, but additional features are sometimes required to distinguish AFM from other conditions.

Multiple sclerosis risk variants influence the peripheral B-cell compartment early in life in the general population.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is associated with abnormal B-cell function, and MS genetic risk alleles affect multiple genes that are expressed in B cells. However, how these genetic variants impact the B-cell compartment in early childhood is unclear. In the current study, we aim to assess whether polygenic risk scores (PRSs) for MS are associated with changes in the blood B-cell compartment in children from the general population. METHODS: Six-year-old children from the population-based Generation R Study were included. Genotype data were used to calculate MS-PRSs and B-cell subset-enriched MS-PRSs, established by designating risk loci based on expression and function. Analyses of variance were performed to examine the effect of MS-PRSs on total B-cell numbers (n = 1261) as well as naive and memory subsets (n = 675). RESULTS: After correction for multiple testing, no significant associations were observed between MS-PRSs and total B-cell numbers and frequencies of subsets therein. A naive B-cell-MS-PRS (n = 26 variants) was significantly associated with lower relative, but not absolute, naive B-cell numbers (p = 1.03 × 10-4 and p = 0.82, respectively), and higher frequencies and absolute numbers of CD27+ memory B cells (p = 8.83 × 10-4 and p = 4.89 × 10-3 , respectively). These associations remained significant after adjustment for Epstein-Barr virus seropositivity and the HLA-DRB1*15:01 genotype. CONCLUSIONS: The composition of the blood B-cell compartment is associated with specific naive B-cell-associated MS risk variants during childhood, possibly contributing to MS pathophysiology later in life. Cell subset-specific PRSs may offer a more sensitive tool to define the impact of genetic risk on the immune system in diseases such as MS.

De Novo ATP1A1 Variants in an Early-Onset Complex Neurodevelopmental Syndrome.

ATP1A1 encodes the α1 subunit of the sodium-potassium ATPase, an electrogenic cation pump highly expressed in the nervous system. Pathogenic variants in other subunits of the same ATPase, encoded by ATP1A2 or ATP1A3, are associated with syndromes such as hemiplegic migraine, dystonia, or cerebellar ataxia. Worldwide, only 16 families have been reported carrying pathogenic ATP1A1 variants to date. Associated phenotypes are axonal neuropathies, spastic paraplegia, and hypomagnesemia with seizures and intellectual disability. By whole exome or genome sequencing, we identified 5 heterozygous ATP1A1 variants, c.674A>G;p.Gln225Arg, c.1003G>T;p.Gly335Cys, c.1526G>A;p.Gly509Asp, c.2152G>A;p.Gly718Ser, and c.2768T>A;p.Phe923Tyr, in 5 unrelated children with intellectual disability, spasticity, and peripheral, motor predominant neuropathy. Additional features were sensory loss, sleep disturbances, and seizures. All variants occurred de novo and are absent from control populations (MAF GnomAD = 0). Affecting conserved amino acid residues and constrained regions, all variants have high pathogenicity in silico prediction scores. In HEK cells transfected with ouabain-insensitive ATP1A1 constructs, cell viability was significantly decreased in mutants after 72h treatment with the ATPase inhibitor ouabain, demonstrating loss of ATPase function. Replicating the haploinsufficiency mechanism of disease with a gene-specific assay provides pathogenicity information and increases certainty in variant interpretation. This study further expands the genotype-phenotype spectrum of ATP1A1.

Anti-NMDAR Encephalitis in the Netherlands, Focusing on Late-Onset Patients and Antibody Test Accuracy.

BACKGROUND AND OBJECTIVES: To describe the clinical features of anti-NMDAR encephalitis, emphasizing on late-onset patients and antibody test characteristics in serum and CSF. METHODS: Nationwide observational Dutch cohort study, in patients diagnosed with anti-NMDAR encephalitis between 2007 and 2019. RESULTS: One hundred twenty-six patients with anti-NMDAR encephalitis were included with a median age of 24 years (range 1-86 years). The mean annual incidence was 1.00/million (95% CI 0.62-1.59). Patients ≥45 years of age at onset (19%) had fewer seizures (46% vs 71%, p = 0.021), fewer symptoms during disease course (3 vs 6 symptoms, p = 0.020), and more often undetectable serum antibodies compared with younger patients (p = 0.031). In the late-onset group, outcome was worse, and all tumors were carcinomas (both p < 0.0001). CSF was more accurate than serum to detect anti-NMDAR encephalitis (sensitivity 99% vs 68%, p < 0.0001). Using cell-based assay (CBA), CSF provided an unconfirmed positive test result in 11/2,600 patients (0.4%); 6/11 had a neuroinflammatory disease (other than anti-NMDAR encephalitis). Patients with anti-NMDAR encephalitis, who tested positive in CSF only, had lower CSF antibody titers (p = 0.003), but appeared to have an equally severe disease course. DISCUSSION: Anti-NMDAR encephalitis occurs at all ages and is less rare in the elderly patients than initially anticipated. In older patients, the clinical phenotype is less outspoken, has different tumor association, and a less favorable recovery. Detection of antibodies in CSF is the gold standard, and although the CBA has very good validity, it is not perfect. The clinical phenotype should be leading, and confirmation in a research laboratory is recommended, when in doubt.

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.

Prognostic factors for relapse and outcome in pediatric acute transverse myelitis.

OBJECTIVE: It may be difficult for clinicians to estimate the prognosis of pediatric acute transverse myelitis (ATM). The aim of this study was to define prognostic factors for relapsing disease and poor outcome in pediatric ATM. METHODS: This prospective cohort study included 49 children, 18 boys and 31 girls (median age 13.1 years, IQR 6.5-16.2) with a first episode of ATM. Factors associated with relapsing disease and poor outcome (Expanded Disability Status Scale (EDSS) ≥ 4) were assessed during a median follow-up of 37 months (IQR 18-75). RESULTS: In total, 14 patients (29%) experienced ≥ 1 relapse(s) and nine patients (18%) had a poor outcome. Factors at onset associated with relapsing disease included higher age (16.1 vs. 11.6 years, p = 0.002), longer time to maximum severity of symptoms (5.5 vs. 3 days, p = 0.01), lower maximum EDSS score (4.0 vs. 6.5, p = 0.003), short lesion on spinal MRI (64 vs. 21%, p = 0.006), abnormalities on brain MRI (93 vs. 44%, p = 0.002) and presence of oligoclonal bands in cerebrospinal fluid (67 vs. 14%, p = 0.004). The only factor associated with poor outcome was presence of a spinal cord lesion on MRI without cervical involvement (56 vs. 14%, p = 0.02). CONCLUSION: Pediatric ATM patients presenting with clinical, radiological and laboratory features associated with multiple sclerosis (MS) are at risk for relapsing disease. In absence of these known MS risk factors at onset of disease these patients are at low risk for relapses. Only a minority of pediatric ATM patients in this cohort have a poor outcome.

Atypical neuroimaging characteristics of hemophagocytic lymphohistiocytosis in infants: a case series of hemorrhagic brain lesions in the deep grey matter.

Hemophagocytic lymphohistiocytosis (HLH) is a rare multisystem condition associated with uncontrolled overproduction and infiltration of lymphocytes and histiocytes predominantly in liver, lymph nodes, spleen, and central nervous system. Neuroimaging findings on MRI are fairly nonspecific and classically include periventricular white matter signal abnormalities and diffuse atrophy. Focal parenchymal lesions may demonstrate post contrast ring or nodular enhancement and calcification. However, the MR imaging characteristics can be highly variable. Here, we present two cases of HLH in infants with multiple hemorrhagic lesions mostly depicted in both thalami and basal ganglia regions. Thalamic, basal ganglia, and brain stem involvement with hemorrhagic changes in HLH are rarely described in literature. Early diagnosis of HLH may be lifesaving. Awareness of the disease is necessary to investigate its characteristic findings and avoiding a delay in diagnosis.

Neurologic syndromes related to anti-GAD65: Clinical and serologic response to treatment.

OBJECTIVE: Antibodies against glutamic acid decarboxylase 65 (anti-GAD65) are associated with a number of neurologic syndromes. However, their pathogenic role is controversial. Our objective was to describe clinical and paraclinical characteristics of anti-GAD65 patients and analyze their response to immunotherapy. METHODS: Retrospectively, we studied patients (n = 56) with positive anti-GAD65 and any neurologic symptom. We tested serum and CSF with ELISA, immunohistochemistry, and cell-based assay. Accordingly, we set a cutoff value of 10,000 IU/mL in serum by ELISA to group patients into high-concentration (n = 36) and low-concentration (n = 20) groups. We compared clinical and immunologic features and analyzed response to immunotherapy. RESULTS: Classical anti-GAD65-associated syndromes were seen in 34/36 patients with high concentration (94%): stiff-person syndrome (7), cerebellar ataxia (3), chronic epilepsy (9), limbic encephalitis (9), or an overlap of 2 or more of the former (6). Patients with low concentrations had a broad, heterogeneous symptom spectrum. Immunotherapy was effective in 19/27 treated patients (70%), although none of them completely recovered. Antibody concentration reduction occurred in 15/17 patients with available pre- and post-treatment samples (median reduction 69%; range 27%-99%), of which 14 improved clinically. The 2 patients with unchanged concentrations showed no clinical improvement. No differences in treatment responses were observed between specific syndromes. CONCLUSION: Most patients with high anti-GAD65 concentrations (>10,000 IU/mL) showed some improvement after immunotherapy, unfortunately without complete recovery. Serum antibody concentrations' course might be useful to monitor response. In patients with low anti-GAD65 concentrations, especially in those without typical clinical phenotypes, diagnostic alternatives are more likely.

Pediatric autoimmune encephalitis: Recognition and diagnosis.

OBJECTIVE: The aims of this study were (1) to describe the incidence of autoimmune encephalitis (AIE) and acute disseminated encephalomyelitis (ADEM) in children, (2) to validate the currently used clinical criteria to diagnose AIE, and (3) to describe pitfalls in the diagnosis of pediatric autoimmune (AI) and inflammatory neurologic disorders. METHODS: This study cohort consists of 3 patient categories: (1) children with antibody-mediated AIE (n = 21), (2) children with ADEM (n = 32), and (3) children with suspicion of an AI etiology of their neurologic symptoms (n = 60). Baseline and follow-up clinical data were used to validate the current guideline to diagnose AIE. In addition, patient files and final diagnoses were reviewed. RESULTS: One-hundred three of the 113 included patients fulfilled the criteria of possible AIE. Twenty-one children had antibody-mediated AIE, of whom 19 had anti-N-methyl-D-aspartate receptor (NMDAR), 1 had anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, and 1 had anti-leucine-rich glioma-inactivated protein 1 encephalitis. Finally, 34 children had ADEM, and 2 children had Hashimoto encephalopathy. Mean incidence rates were 1.54 children/million (95% CI 0.95-2.35) for antibody-mediated AIE and 2.49 children/million (95% CI 1.73-3.48) for ADEM. Of the other 48 children, treating physicians' diagnoses were reviewed. In 22% (n = 6) of children initially diagnosed as having an AI/inflammatory etiology (n = 27), no support for AI/inflammation was found. CONCLUSION: Besides anti-NMDAR encephalitis and ADEM, other AIEs are rare in children. The current guideline to diagnose AIE is also useful in children. However, in children with nonspecific symptoms, it is important to review data critically, to perform complete workup, and to consult specialized neuroinflammatory centers.

Acute flaccid myelitis and enterovirus D68: lessons from the past and present.

Acute flaccid myelitis is characterized by the combination of acute flaccid paralysis and a spinal cord lesion largely restricted to the gray matter on magnetic resonance imaging. The term acute flaccid myelitis was introduced in 2014 after the upsurge of pediatric cases in the USA with enterovirus D68 infection. Since then, an increasing number of cases have been reported worldwide. Whereas the terminology is new, the clinical syndrome has been recognized in the past in association with several other neurotropic viruses such as poliovirus.Conclusion: This review presents the current knowledge on acute flaccid myelitis with respect to the clinical presentation and its differential diagnosis with Guillain-Barré syndrome and acute transverse myelitis. We also discuss the association with enterovirus D68 and the presumed pathophysiological mechanism of this infection causing anterior horn cell damage. Sharing clinical knowledge and insights from basic research is needed to make progress in diagnosis, treatment, and prevention of this new polio-like disease. What is Known: • Acute flaccid myelitis (AFM) is a polio-like condition characterized by rapid progressive asymmetric weakness, together with specific findings on MRI • AFM has been related to different viral agents, but recent outbreaks are predominantly associated with enterovirus D68. What is New: • Improving knowledge on AFM must increase early recognition and adequate diagnostic procedures by clinicians. • The increasing incidence of AFM urges cooperation between pediatricians, neurologists, and microbiologists for the development of treatment and preventive options.

Ketogenic diet treatment as adjuvant to standard treatment of glioblastoma multiforme: a feasibility and safety study.

BACKGROUND: High-grade glioma cells consume mainly glucose and cannot compensate for glucose restriction. Apoptosis may potentially occur under carbohydrate restriction by a ketogenic diet (KD). We explored the feasibility and safety of KD during standard treatment of chemoradiation in patients with glioblastoma multiforme. METHODS: A full liquid KD induced ketosis within 2 weeks before start of chemoradiation. After 6 weeks, the KD was modified with solid foods and medium-chain-triglyceride emulsions and used for an additional 6 weeks while maintaining ketosis. During the total study period (14 weeks), feasibility, safety, coping (both patient and partner), quality of life (QoL), neurological functioning and impairment were measured. Overall survival was analyzed with actuarial estimates. RESULTS: Eleven patients started the study protocol, nine reached ketosis and six (67%) completed the study. Severe adverse effects did not occur. The majority of coping scores ranged from 3 to 6 on a 10-point scale at all timepoints; QoL, neurological functioning, and impairment did not essentially change over time; overall survival ranged between 9.8 and 19.0 months. CONCLUSION: KD was feasible and safe as an adjuvant to standard chemoradiation treatment of glioblastoma multiforme. A supportive partner and intensive counseling were essential for coping. Future research should identify possible beneficial effects on overall survival. CLINICAL TRIAL REGISTRATION: Netherlands Trial Registry: NTR5167 (registration date 29-01-2015), http://www.trialregister.nl/trialreg/index.asp.

Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis.

OBJECTIVE: This nationwide cohort study evaluates seizure responses to immunotherapy and antiepileptic drugs (AEDs) in patients with anti-leucine-rich glioma-inactivated 1 (LGI1), anti-NMDA receptor (NMDAR), and anti-gamma-aminobutyric-acid B receptor (GABABR) encephalitis. METHODS: Anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis patients with new-onset seizures were included. Medical information about disease course, AEDs and immunotherapies used, effects, and side effects were collected. Outcome measures were (1) seizure freedom while using AEDs or immunotherapy, (2) days to seizure freedom from start of AEDs or immunotherapy, and (3) side effects. RESULTS: Of 153 patients with autoimmune encephalitis (AIE) (53 LGI1, 75 NMDAR, 25 GABABR), 72% (n = 110) had epileptic seizures, and 89% reached seizure freedom. At least 53% achieved seizure freedom shortly after immunotherapy, and 14% achieved seizure freedom while using only AEDs (p < 0.0001). This effect was similar in all types (p = 0.0001; p = 0.0005; p = 0.013, respectively). Median time to seizure freedom from AEDs start was 59 days (interquartile range [IQR] 27-160), and 28 days from start of immunotherapy (IQR 9-71, p < 0.0001). Side effects were psychotic behavior and suicidal thoughts by the use of levetiracetam, and rash by the use of carbamazepine. Carbamazepine was more effective than levetiracetam in reducing seizures in anti-LGI1 encephalitis (p = 0.031). Only 1 patient, of 86 surviving patients, developed epilepsy after resolved encephalitis. CONCLUSION: Epilepsy after resolved encephalitis was rare in our cohort of patients with AIE treated with immunotherapy. In addition, seizure freedom is achieved faster and more frequently after immunotherapy. Therefore, AEDs should be considered as add-on treatment, and similar to treatment of other encephalitis symptoms, immunotherapy is crucial.

A framework for measurement and harmonization of pediatric multiple sclerosis etiologic research studies: The Pediatric MS Tool-Kit.

BACKGROUND: While studying the etiology of multiple sclerosis (MS) in children has several methodological advantages over studying etiology in adults, studies are limited by small sample sizes. OBJECTIVE: Using a rigorous methodological process, we developed the Pediatric MS Tool-Kit, a measurement framework that includes a minimal set of core variables to assess etiological risk factors. METHODS: We solicited input from the International Pediatric MS Study Group to select three risk factors: environmental tobacco smoke (ETS) exposure, sun exposure, and vitamin D intake. To develop the Tool-Kit, we used a Delphi study involving a working group of epidemiologists, neurologists, and content experts from North America and Europe. RESULTS: The Tool-Kit includes six core variables to measure ETS, six to measure sun exposure, and six to measure vitamin D intake. The Tool-Kit can be accessed online ( www.maelstrom-research.org/mica/network/tool-kit ). CONCLUSION: The goals of the Tool-Kit are to enhance exposure measurement in newly designed pediatric MS studies and comparability of results across studies, and in the longer term to facilitate harmonization of studies, a methodological approach that can be used to circumvent issues of small sample sizes. We believe the Tool-Kit will prove to be a valuable resource to guide pediatric MS researchers in developing study-specific questionnaire.

Ketogenic diet treatment in recurrent diffuse intrinsic pontine glioma in children: A safety and feasibility study.

BACKGROUND: The mean overall survival rate of children with diffuse intrinsic pontine glioma (DIPG) is 9-11 months, with current standard treatment with fractionated radiotherapy and adjuvant chemotherapy. So far, novel therapeutic strategies have not yet resulted in significantly better survival. The main source of energy for glioblastoma cells is glucose. Therefore, metabolic alterations induced by the use of the extremely carbohydrate-restricted ketogenic diet (KD) as adjuvant therapy are subject of interest in cancer research. PROCEDURE: This study explores the safety and feasibility of the KD in children with recurrent DIPG and no remaining treatment options. Safety was defined as the number of adverse effects. Feasibility was defined as the number of patients who were able to use the KD for three months. Coping of patients and parents was measured with questionnaires. RESULTS: Three of 14 children referred to our hospital between 2010 and 2015 were included. Two patients completed the study, and one died before the end of the study. Hospitalizations were needed for placing a nasogastric tube (n = 1) and epileptic seizures (n = 1). Adverse effects related to the diet were mild and transient. Parents were highly motivated during the study. CONCLUSION: Use of KD is safe and feasible, but the effect on survival has to be proven in a larger cohort of children who start the KD earlier after diagnosis, preferably as adjuvant therapy to fractionated radiotherapy.

T-cell activation marker sCD27 is associated with clinically definite multiple sclerosis in childhood-acquired demyelinating syndromes.

BACKGROUND: Cerebrospinal fluid (CSF) levels of T-cell activation marker soluble CD27 (sCD27) are associated with subsequent disease activity after a first attack of suspected MS in adults. The predictive value for disease course in children with acquired demyelinating syndromes (ADS) is unknown. OBJECTIVES: To assess the predictive value of sCD27 levels for clinically definite multiple sclerosis (CDMS) diagnosis in childhood ADS. METHODS: Children <18 years with a first demyelinating event were prospectively included and followed. Soluble CD27 was determined in CSF using an enzyme-linked immunosorbent assay (ELISA). Cox regression analyses were used to calculate hazard ratios (HRs) for CDMS. RESULTS: A total of 94 ADS children were included (ADS with encephalopathy (ADS+) n = 33 and ADS without encephalopathy (ADS-) n = 61). Of the 61 ADS- children, 21 (48%) were diagnosed with CDMS during follow-up. At baseline, sCD27 levels were higher in patients with a future CDMS diagnosis ( n = 29) than in monophasic ADS+ ( n = 30), monophasic ADS- ( n = 28) and relapsing non-MS patients ( n = 7; p < 0.001). In ADS- patients, sCD27 was associated with CDMS (HR = 1.8 per 100 U/mL increase in sCD27 levels, p = 0.031), after adjustments for age, oligoclonal bands and the presence of dissemination in space on baseline magnetic resonance imaging (MRI). CONCLUSION: CSF sCD27 levels at first attack of demyelination were associated with CDMS diagnosis in children. This makes sCD27 a potential clinically relevant quantitative marker when performing routine CSF diagnostics.