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Molecularly targeted immunotherapy used to treat a novel overlap syndrome of pediatric N-methyl- d-aspartate receptor encephalitis (NMDARE) and possible neurosarcoidosis

Overlap syndromes between N-methyl-d-aspartate receptor encephalitis (NMDARE) and other neuroinflammatory conditions have been described in both pediatric and adult populations. There are few reports of overlap syndromes between NMDARE and sarcoidosis, and none previously reported in children. 

Our patient, a 9-year-old boy with new-onset seizures and worsening encephalopathy, met the criteria for definite NMDARE and possible neurosarcoidosis. Given the mixed radiographic and serologic markers in this child, cytokine levels were used to direct the choice of empiric treatment, resulting in excellent clinical response. This case suggests that targeted immunotherapy informed by cytokine testing may be helpful in cases of high-acuity pediatric neuroinflammatory disease with limited diagnostic clarity.

Clinical Characteristics and Short-Term Prognosis of Children With Antibody-Mediated Autoimmune Encephalitis: A Single-Center Cohort Study

AE is a treatable disease that can occur in children of all ages. The mortality rate is low, as most patients have a good response to immune therapy. Compared with the older children, infants and young children (≤ 3 years old) with anti-NMDAR encephalitis have a higher incidence of fever and status epilepticus, more severe condition, higher PICU admission rate and worse prognosis. AE patients with high maximum mRS scores and PICU admissions may require second-line immunotherapy.

A pediatric case of autoimmune glial fibrillary acidic protein astrocytopathy with unique brain imaging patterns and increased cytokines/chemokines

Conclusion: In cases of autoimmune encephalitis with prolonged consciousness disturbance, hyponatremia, urinary dysfunction, and MRI findings with hyperintensities in the bilateral basal ganglia, thalamus, and periventricular white matter, anti-glial fibrillary acidic protein antibodies should be examined.

Immune characteristics of children with autoimmune encephalitis and the correlation with a short-term prognosis

CONCLUSION: There is a close correlation between modified Rankin Scale (mRS) scores and the immune function index CD4/CD8 in children with autoimmune encephalitis (AE) when they are admitted to the hospital. A young age, disturbance of consciousness, limb dyskinesia, abnormal immune function in remission and anti-NMDAR encephalitis are risk factors for poor prognoses in children with autoimmune encephalitis (AE). Clinical treatment requires more attention.

Autoimmune Encephalitis and Other Neurological Syndromes With Rare Neuronal Surface Antibodies in Children: A Systematic Literature Review

Study conducted a systematic literature review on rare neuronal surface antibodies (NSAbs) in children (D2R, GABAAR, GlyR, GABABR, AMPAR, amphiphysin, mGluR5, mGluR1, DPPX, IgLON5, and neurexin-3alpha).

This review discloses antibody-specific features in children, helping clinicians suspect NSAS. We suggest examining both serum and CSF with CBA for a broad NSAbs panel in children presenting with new-onset focal or diffuse neurological deficits, cognitive difficulties, psychiatric symptoms, seizures, and/or movement disorder of unknown origin, even in the absence of definite MRI, EEG, or CSF abnormalities.

A systematic review and quantitative synthesis of the long-term psychiatric sequelae of pediatric autoimmune encephalitis

Long-term neuropsychiatric consequence of autoimmune encephalitis (AE) remain understudied, particularly in pediatric-onset AE. This study took the 29 pieces of published research & combined the data on ongoing psychiatric symptoms in pediatric-onset AE.
At long-term follow up, 52.4% of the cases with pediatric-onset AE had any persistent symptom and 36.0% had at least one psychiatric symptom. Pooled data found that 36.3% of pediatric-onset anti-NMDAR AE had ongoing psychiatric symptoms.
Conclusion: Chronic psychiatric and behavioral problems remain present in one-third of children months to years after onset of AE. Larger scaled prospective observational studies with a consistent standardized battery of testing are needed to examine impact of specific clinical features and immunotherapies on long-term mental health outcomes.

Autoimmune glial fibrillary acidic protein astrocytopathy in children: a retrospective study


The findings of pediatric patients with autoimmune GFAP astrocytopathy are different from previous reports.

Clinical Features and Outcomes in Pediatric Autoimmune Encephalitis Associated With CASPR2 Antibody

Six patients were identified. Conclusion: CASPR2 antibody-associated autoimmune encephalitis is rare in children. Our findings suggest that this type of encephalitis seems to occur more frequently in older children. Patients respond well to immunotherapy and usually demonstrate a favorable clinical outcome. Associated tumors are extremely rare.

Psychiatric Phenotypes of Pediatric Patients With Seropositive Autoimmune Encephalitis

Patients with autoimmune encephalitis (AE) often present with symptoms that are broadly characterized as psychiatric or behavioral, yet little attention is given to the precise symptomatology observed.

Psychiatric symptoms were seen in 92% of patients in our 225 patient cohort. Depressive features (72%), personality change (64%), psychosis (48%), and catatonia (32%) were the most common psychiatric symptoms exhibited. On average, patients experienced impairment in ≥4 of 7 symptom domains. No patients had isolated psychiatric symptoms. 

Conclusions: The psychiatric phenotype of AE in children is highly heterogenous. Involving psychiatry consultation services can be helpful in differentiating features of psychosis and catatonia, which may otherwise be misidentified. Patients presenting with psychiatric symptoms along with impairments in other domains should prompt a workup for AE, including testing for all known antineuronal antibodies.

Autoimmune Encephalitis in Children: From Suspicion to Diagnosis

Highly recommended overview ~

This article reviews types of AE, causes, diagnosis, differential diagnosis, treatment and prognosis.

Conclusion: Autoimmune encephalitis is an inflammatory, rapid, progressive disease that requires extensive and prompt workup. Patients should have neuroimaging, EEG, lumbar puncture, and antibody testing on serum and CSF at the same time that treatment is initiated based on a clinical diagnosis. Further investigation is necessary in search of cancer, central nervous system inflammation, infection, and other alternative etiologies. Early diagnosis and effective treatment might improve long-term outcomes.

Clinical features of paediatric and adult autoimmune encephalitis: A multicenter sample

Objective: Describe the clinical presentation, seizure type, EEG, and sleep patterns in paediatric and adult patients with AE.

Conclusion: Paediatric patients with AE were more likely to present with psychiatric symptoms, sleep disturbances, focal seizures, and/or status epilepticus compared to adults (p < 0.05). Insomnia and hypersomnia are common sleep problems associated with AE that should be screened early in the diagnostic evaluation. Further studies can be performed to explore the relationship between sleep disturbances and long-term cognitive effects and the incidence of chronic epilepsy in this subset of patients.

Bickerstaff’s brainstem encephalitis in childhood: a literature overview

This is a review on clinical presentation, diagnosis, and treatment of reported cases of Bickerstaff brain encephalitis.

CONCLUSIONS: Bickerstaff’s brainstem encephalitis is an uncommon disorder, the short-term and long-term prognoses depend on the clinical presentation of the disorder, co-morbidity, instrumental investigations, and precocity of treatment.

Immune mediated pediatric encephalitis – need for comprehensive evaluation and consensus guidelines

There is a heterogeneous presentation of autoimmune encephalitis in pediatric populations. In the absence of positive findings on testing, individuals who do not meet proposed criteria for seronegative encephalitis may be misdiagnosed, and/or may not respond adequately to treatment. In those cases, comprehensive evaluation and stringent application of consensus guidelines are necessary.

Autoimmune Encephalitis in Children: A Case Series at a Tertiary Care Center

Autoimmune encephalitis is the third most common cause of encephalitis in children. We provide a detailed account of presenting symptoms, diagnosis, and response to treatment in pediatric autoimmune encephalitis patients evaluated at University of California San Francisco within a 2.5-year period.

Autoimmune encephalitis in children and adolescents

Most neuropediatric cases of autoimmune encephalitis harbor NMDAR antibodies in CSF. Cases with other antibodies occur. The frequency of MOG antibodies in pediatric encephalitides remains to be determined; it might be higher than known today. The existing data justify the use of multiparametric testing for neural antibodies at disease onset in serum and CSF with panel diagnostic through biochips. There are no fundamental differences between autoimmune encephalitides in pediatric and adult cases and their management.

Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient

Autoimmune encephalitis (AE) is an important and treatable cause of acute encephalitis. Diagnosis of AE in a developing child is challenging because of overlap in clinical presentations with other diseases and complexity of normal behavior changes. Existing diagnostic criteria for adult AE require modification to be applied to children, who differ from adults in their clinical presentations, paraclinical findings, autoantibody profiles, treatment response, and long-term outcomes.

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Mycophenolate mofetil, azathioprine and methotrexate usage in paediatric anti-NMDAR encephalitis: A systematic literature review

NMDAR Encephalitis: A Possible Pathophysiological Model For Pediatric Neuropsychiatric Disorders

Neuroimmune disorders of the central nervous system in children in the molecular era

Anti-N-methyl-d-aspartate receptor encephalitis in children: Incidence and experience in Hong Kong

Long-term neuropsychological outcome following pediatric anti-NMDAR encephalitis

Severe GABAA receptor encephalitis without seizures: A paediatric case successfully treated with early immunomodulation

(D2 antibody) Autoimmune encephalitis in children: clinical phenomenology, therapeutics, and emerging challenges

The neuropsychological profile of children with basal ganglia encephalitis: a case series

Why Neuroimmunology Is Crucial to 21st-Century Pediatric Neuroscience

Anti-N-Methyl-D-Aspartate Receptor Encephalitis in Children and Adolescents

Acute Pediatric Encephalitis Neuroimaging: Single-Institution Series as Part of the California Encephalitis Project

Status epilepticus in paediatrics: a retrospective study and review of the literature

Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease

Paediatric AEs: clinical features: in patients w/ or w/o antibodies to known CNS autoantigens

Clinical analysis and literature review of two paediatric cases of anti-IgLON5 antibody-related encephalitis

Anti-IgLON5 antibody-related encephalitis is a rare and relatively unique form of autoimmune encephalitis. It is characterized by irreversible neurodegeneration, which contributes to the suboptimal response to immunotherapy. The disease predominantly affects middle-aged and elderly individuals, with paediatric cases being exceedingly rare. In children, anti-IgLON5 antibody-related encephalitis primarily presents with sleep disturbances and various forms of movement disorders, and there is partial effectiveness of immunotherapy. Compared to adult patients, paediatric cases tend to exhibit more pronounced psychiatric symptoms, a more acute onset of the disease, and more evident inflammatory changes in the cerebrospinal fluid. There appears to be a lesser association with HLA-DQB *05:01 and HLA-DRB *10:01 polymorphisms in children. Further research and a larger number of cases are needed to substantiate these observations.

Safety of Obinutuzumab in children with autoimmune encephalitis and early B cell repopulation on rituximab.

Key Points:

  • Obinutuzumab seems to have a longer time of B cell repopulation than rituximab.
  • All children treated with obinutuzumab for a neurological disease had a favorable evolution.
  • Obinutuzumab seems to have a good safety.

Pediatric anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis: Exploring psychosis, related risk factors, and hospital outcomes in a nationwide inpatient sample: A cross-sectional study

Adolescents, females, and Blacks with anti-NMDAR encephalitis have a higher risk of psychotic presentation leading to hospitalization. These risk factors should be considered by healthcare providers when assessing pediatric patients with anti-NMDAR encephalitis, emphasizing the need to consider the possibility of psychotic symptoms, particularly within these vulnerable groups. Moreover, the study highlights the importance of recognizing preexisting psychiatric comorbidities, such as depressive and anxiety disorders, OCD, neurodevelopmental disorders, disruptive behavior disorders, and sleep-wake disorders, as they significantly increase the risk of presenting with psychotic symptoms in anti-NMDAR encephalitis cases. Consequently, it is crucial to screen for these psychiatric conditions when managing pediatric anti-NMDAR encephalitis patients to identify individuals who are at a higher risk of developing psychotic symptoms. Identification of demographic predictors and comorbidities can aid in early recognition and intervention to optimize care and potentially reduce the healthcare burden.

Mechanisms and Emerging Therapies for Treatment of Seizures in Pediatric Autoimmune Encephalitis and Autoinflammatory/Autoimmune-Associated Epilepsy

Care should be used to distinguish seizures in the setting of autoimmune encephalitis from chronic epilepsy, as the majority respond better and faster to immunomodulation compared to anti-seizure medication. Early recognition and treatment of autoimmune encephalitis may yield improved outcomes.

Retrospective Comparison of Patients Evaluated for Pediatric Autoimmune Encephalitis with Typical and Atypical Premorbid Neuropsychiatric Development

Neurodevelopmental disorders (NDD) children with AE had a comparable number of reported clinical domains relative to TD children and a similar treatment response. NDD patients with AE had a greater number of reported clinical domains than their NDD peers without an AE diagnosis. These findings suggest that AE is a multi-domain process in both TD and NDD children.

Seizure Evolution and Outcome in Pediatric Autoimmune Encephalitis

We delineated the seizure incidence, evolution, and outcome of pediatric patients with Ab-positive and Ab-negative AE. Ab-negative status is predictive of higher seizure burden, more frequent development of postencephalitic seizures, and less favorable seizure outcome than anti-NMDAR and anti-MOG Ab-positive status.

Early and aggressive treatment may modify anti Hu associated encephalitis prognosis

Anti-Hu limbic encephalitis is a paraneoplastic syndrome in adults. In children, rare cases of anti-Hu limbic encephalitis were reported mostly without underlying tumors and clinical outcome are usually severe. Here, we describe a 4 year-old girl who developed cerebellar syndrome with abnormal behavior. The brain MRI showed several T2/FLAIR bilateral hyperintensities and auto-immune assessment showed positive anti-Hu antibodies. CT-scan revealed ganglioneuroblastoma which was surgically removed 3 months after onset. Aggressive immunotherapy including dexamethasone, rituximab and IV immunoglobulins were used and a marked neurological improvement soon after 9 months of onset was observed with a child who was able to go back to school. The short delay between diagnosis and start of aggressive immunotherapy demonstrate the paramount importance of early diagnosis and early specific therapy after onset of symptoms.

Dopamine-2 receptor antibody encephalitis presenting as pure tongue-biting in a tourette syndrome patient: a case report

Our case suggests that clinicians should discern D2R encephalitis in Tourette syndrome (TS) patients when tics are the primary symptoms. Administering immunotherapy early, according to clinical characteristics, may benefit the patient. Moreover, the features of premonitory urges could help evaluate the state of TS.

Clinical features, investigations, and outcomes of pediatric limbic encephalitis: A multicenter study

Twenty-five children fulfilling LE criteria were identified, with median age of 11 years  and median follow-up of 24 months. All children presented with seizures; 15/25 (60%) were admitted to intensive care. Neuroimaging demonstrated asymmetric mesial temporal changes in 8/25 (32%), and extra-limbic changes with claustrum involvement in 9/25 (38%). None were positive for LGI1/CASPR2 antibodies (Abs), 2/25 were positive for serum anti-NMDAR Abs, and 2/15 positive for anti-Hu Abs; one died from relapsing neuroblastoma. Two children had serum and CSF anti-GAD antibodies. Initial immune therapy included steroids in 23/25 (92%), intravenous immunoglobulin (IVIg) in 14/25 (56%), and plasma exchange in 7/25 (28%). The commonest second-line treatment was rituximab in 15/25 (60%). Median duration of hospital admission was 21 days (IQR 11, 30). At last follow-up, 13/25 (52%) had refractory seizures and 16/25 (64%) had memory impairment. Six children (24%) had modified Rankin Scale (mRS) scores ≥3. There was no significant difference in mRS, or long-term cognitive and epilepsy outcomes in those who received rituximab versus those who did not.

Usefulness of brain FDG PET/CT imaging in pediatric patients with suspected autoimmune encephalitis from a prospective study

Large lobar hypometabolism was found in 61 children, of which 54 (88.5%) children were finally diagnosed with AE. The sensitivity, specificity, and accuracy of FDG PET/CT for diagnosis of AE were 93.1%, 84.4%, and 89.3%, respectively, with a positive predictive value of 88.5% and a negative predictive value of 90.5%. The most common involved with hypometabolism was the parietal lobe, followed by occipital and frontal lobes, finally the temporal lobe on PET/CT in children with AE.

Conclusion: Brain FDG PET/CT imaging has high specificity, sensitivity, and accuracy for diagnosis of AE in clinical suspected AE children.

Autoimmune Encephalitis in Children: An Update

Conclusions: Autoimmune encephalitis is being increasingly recognized in children. Anti-NMDAR encephalitis is the most
common form. Children present with a polysymptomatic presentation including behavioral changes, psychosis, sleep
disturbances, mutism, seizures, movement disorders, memory impairment as well as other neurocognitive deficits. Diagnosis is
based on suggestive history and ancillary investigations including magnetic resonance imaging, cerebrospinal fluid analysis, and serology for autoantibodies. Treatment is based on immunomodulation of the acute episode followed by maintenance therapy, with earlier initiation being associated with better outcomes. Prognosis depends on the type of clinical syndrome.

Anti-GQ1b syndrome. A child with Miller-Fisher-Bickerstaff syndrome

Miller-Fisher syndrome and Bickerstaff brainstem encephalitis, among others, constitute the anti-GQ1b syndrome, with a common immune pathophysiologic pathway characterized by the presence of anti-GQ1b antibodies, which react against the different nervous system GQ1b sites according to their different accessibility.

Immune mediated pediatric encephalitis – need for comprehensive evaluation and consensus guidelines

Autoimmune encephalitis is characterized by neuropsychiatric symptoms associated with brain inflammation. The differential is usually broad and Psychiatry often collaborates with Neurology in diagnostic clarification and symptom management. At least 40% of neuroencephalitis cases are of unknown etiology which adds to difficulties in making the right diagnosis and deciding on the appropriate treatment

Pediatric autoimmune encephalitis Recognition and diagnosis

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

Immune mediated pediatric encephalitis - need for comprehensive evaluation and consensus guidelines

There is a heterogeneous presentation of autoimmune encephalitis in pediatric populations. In the absence of positive findings on testing, individuals who do not meet proposed criteria for seronegative encephalitis may be misdiagnosed, and/or may not respond adequately to treatment. In those cases, comprehensive evaluation and stringent application of consensus guidelines is necessary.

An evolving redefinition of autoimmune encephalitis

Childhood encephalitis: what’s new?

Encephalitis is a serious disease, which can bring grand repercussions in children’s health, such as development retardation, behavioral abnormalities and direct neurologic damage.


Mycophenolate mofetil in paediatric autoimmune or immune‐mediated diseases

In the Clinic-Autoimmune Encephalitis: Persistent Cognitive, Neuropsychological Deficits After Anti-NMDAR Encephalitis Require Therapy, Study Suggests

Initial clinical presentation of young children with N-methyl-d-aspartate receptor encephalitis

Anti-N-methyl-d-aspartate receptor encephalitis in children: Incidence and experience in Hong Kong

Anti-NMDA receptor encephalitis in Māori and Pacific Island children in New Zealand

Autoimmune encephalitis in children: clinical phenomenology, therapeutics, and emerging challenges

Anti-NMDAr Encephalitis Appearing as a New-Onset Psychosis: Disease Course in Children

anti-NMDAR survey of 151 Pediatric Neurologists: how to treat

Gait Disturbance as the Presenting Symptom in Young Children With Anti-NMDA Receptor Encephalitis

The growing spectrum of antibody-associated inflammatory brain diseases in children

Toddler's Gait Disturbance Could Signal Encephalitis

Paediatric AE clinical features, laboratory investigations & outcomes with/without anitbodies to CNS known autoantigens

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