Management of Autoimmune Encephalitis in a 7-Year-Old Child With CTLA-4 Haploinsufficiency and AMPA Receptor Antibodies
Marjolijn S.W. QuaakMichiel S.J.S. BuijzeVirginie J. M. VerhoevenClementien L. VermontEmilie P. BuddinghMaud HerediaJanneke N. SamsomMaarten J. TitulaerAnnemarie M. C. van RossumSylvia KamphuisRinze F. Neuteboom
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Abstract:
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.Keywords:
Haploinsufficiency
Autoimmune encephalitis
Progress in diagnostics and immunotherapy for autoimmune encephalitis has significantly improved survival rates. However, autoimmune encephalitis remains a challenging condition, associated with a protracted recovery course and uncertain long-term outcome. Clarification of the risk factors for autoimmune encephalitis, and the development of scales to aid with prognostication, may help improve clinical management.
This month’s journal club explores three papers relating to autoimmune encephalitis. The first paper examines the frequency of and risk factors for autoimmune encephalitis following herpes simplex encephalitis. The second paper describes the development of a score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis. The third paper discusses the development of a general scale for assessing severity in diverse autoimmune encephalitis syndromes.
Autoimmune encephalitis
Neuroradiology
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Autoimmune encephalitis is emerging as an important and relatively common cause of encephalitis in the developed world. Crucially, early recognition and prompt initiation of a range of immunotherapies is likely to improve the outcomes of patients with autoimmune encephalitis, particularly for those with identifiable antibodies against neuronal cell surface proteins. There are a rapidly growing number of specific autoantibodies and associated syndromes, but many of these remain very rare. The majority of cases comprise anti-N-methyl-D-aspartate (NMDA) receptor encephalitis or anti-leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis with the remaining cases a mixture of over 10 other specific antibodies or being seronegative. The core anti-NMDA encephalitis phenotype is a distinct symptom complex involving psychiatric and neurological features and anti-LGI1 encephalitis presents with cognitive changes and distinct seizure types. Diagnosis can be delayed owing to limited access to specialised laboratory testing or in cases with atypical or limited features.
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Purpose of review Autoimmune encephalitis is increasingly recognized and must be distinguished from infectious forms of encephalitis. Moreover, physicians should be aware of infectious triggers of autoimmune encephalitis and of infectious complications associated with treatment. Recent findings Recent epidemiological studies suggest that the incidence of autoimmune encephalitis may rival that of infectious encephalitis. Although distinguishing autoimmune from infectious forms of encephalitis on clinical grounds can be challenging, recently proposed diagnostic criteria can provide some assistance. There has been an explosion in our knowledge of autoimmune encephalitis associated with antibodies to neuronal cell surface antigens, and two of the most common forms, anti-NMDA receptor encephalitis and anti-LGI1 encephalitis, are typically associated with distinctive clinical features. Although tumors have long been known to trigger autoimmune encephalitis, it has been recently recognized that herpes simplex encephalitis may trigger the generation of antineuronal autoantibodies resulting in an autoimmune neurologic relapse. Both first and second-line therapies for autoimmune encephalitis are associated with infectious complications, whereas emerging treatments, including anakinra and tocilizumab, may also result in increased susceptibility to certain infections. Summary The diagnosis and management of autoimmune encephalitis is complex, and awareness of diagnostic criteria and modalities, typical clinical syndromes, infectious triggers of disease, and infectious complications of therapies is critical in optimizing care for affected patients.
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Autoimmune encephalitis is a rare disease, which should be differentiated from aseptic encephalitis. Possessing anti-N-methyl-D-aspartate (NMDA) receptor autoantibody is the leading cause of autoimmune encephalitis. However, it may pose a diagnostic challenge to clinicians, especially to nonpsychiatric or non-neurologic specialist, resulting in a delayed initiation of treatment. Hence, we share the case of a patient with anti-NMDA receptor encephalitis who was hospitalized in the infectious diseases ward, presenting with acute febrile illness that preceded characteristic neuropsychiatric symptoms.
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Anti-NMDA Receptor Encephalitis
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Autoimmune encephalitis is a group of treatable autoimmune diseases of central nervous system.Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is one of the most common autoimmune encephalitis.Some of autoimmune encephalitis can be confirmed by specific autoantibodies, but excessive dependence on autoantibody detection usually leads to delayed treatment.This article reviews the clinical presentations of pediatric anti-NMDAR encephalitis and the antibody-negative autoimmune encephalitis so as to improve the pediatricians understanding on the diseases.
Key words:
Autoimmune encephalitis; Anti-N-methyl-D-aspartate receptor encephalitis; Antibody-negative autoimmune encephalitis
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Research on autoimmune and infectious encephalitis has made substantial progress in recent years in revealing the pathophysiology of these diseases, establishing robust diagnostic criteria, and developing promising treatment options, with a range of clinical trials currently underway. Outcome measures in studies on autoimmune and infectious encephalitis mainly relied on established and widely used tools such as the modified Rankin Scale (mRS). However, the mRS was developed to assess stroke outcome and has a strong focus on motor symptoms and the degree of dependence in daily activities. For example, approximately 80% of patients with anti-NMDA receptor encephalitis (i.e., the most common autoimmune encephalitis variant) achieve a good outcome 2 years after disease onset when evaluated using the mRS.
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Anti-NMDA Receptor Encephalitis
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Autoimmune encephalitis
Vitiligo
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About 20 years ago the group of diseases currently known as 'autoimmune encephalitis' or 'antibody-mediated encephalitis' was unknown and the entire field of 'autoimmune neurology' non-existent. Since then, 18 autoimmune encephalitis and the corresponding syndromes have been described, including 16 in which the antigens are expressed on the cell surface of neurons and two on the surface of glial cells. The characterization of these autoimmune encephalitis was facilitated by the cumulative knowledge provided by research on autoimmune disorders of the neuromuscular junction (myasthenia gravis and Lambert–Eaton myasthenic syndrome) and the paraneoplastic neurological syndromes. Up to 12.6 per 100,000 persons are affected by encephalitis annually. Of these, it has been estimated that 20–30% are caused by autoimmune mechanisms. In children the most frequent types of autoimmune encephalitis are acute disseminated encephalomyelitis (ADEM), anti-MOG, and anti-NMDAR encephalitis. In young adults, particularly women, anti-NMDAR encephalitis, and in late adulthood, anti-LGI1 encephalitis, are the most prevalent autoimmune encephalitis. The most frequently used classifications combine information related to three features: mechanisms of disease (cytotoxic T cell or antibody-mediated mechanisms), type of antigen (intracellular vs cell surface), and presence or absence of a tumour. The detection of a neoplasm frequently serves to categorize the autoimmune encephalitis as paraneoplastic.
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Acute disseminated encephalomyelitis
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Abstract Background Autoimmune encephalitis is an urgent treatable etiology that needs to be differentiated from viral encephalitis. Prompt recognition and therapy is of utmost importance. Methods We performed a retrospective cohort of encephalitis cases in 16 hospitals in Houston, Texas, between January 2005 and December 2019. Results A total of 1,310 adult (age ≥18 years) inpatient hospital admissions were identified by the presence of an encephalitis-related discharge diagnosis per the International Classification of Disease 9th edition codes. Of these, only 279 cases met the 2013 International Encephalitis Consortium criteria for probable encephalitis. A laboratory confirmed diagnosis of autoimmune encephalitis or viral encephalitis was identified in 36 (12.9%) and 88 (31.5%) cases, respectively. There were 155 cases (55.5%) that had no identifiable cause and were considered idiopathic. As compared to viral encephalitis, patients with autoimmune encephalitis were more likely to be younger (< 60 years old), have a subacute (6-30 days) or chronic ( >30 days) presentation, have seizures, and have psychiatric and/or memory complaints (P< 0.001). Furthermore, patients with autoimmune encephalitis were less likely to be febrile and to lack inflammatory cerebrospinal fluid (CSF) (defined as white blood cells < 50 per microliter or protein < 50 milligrams per deciliter) [See Table 1]. In the multivariable logistic regression model, subacute/chronic presentation, psychiatric and/or memory complaints, and lack of inflammatory CSF were significantly associated with autoimmune encephalitis. Using these 3 variables, patients were classified into 3 risk categories for autoimmune encephalitis: low risk (0-1 variables); 0%; intermediate risk (2 variables); 16%; and high risk (3 variables); 83% (P value < 0.001). Conclusion Adults with encephalitis can be accurately stratified for the risk of having autoimmune encephalitis using clinical variables available upon presentation. Disclosures Rodrigo Hasbun, MD, MPH, Biofire (Speaker's Bureau) Rodrigo Hasbun, MD, MPH, Biofire (Individual(s) Involved: Self): Consultant, Research Grant or Support
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Viral encephalitis
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CSF albumin
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The neurologic complications of COVID-19 infection are frequent in hospitalized patients; a high percentage of them present neurologic manifestations at some point during the course of their disease. Headache, muscle pain, encephalopathy and dizziness are among the most common complications. Encephalitis is an inflammatory condition with many etiologies. There are several forms of encephalitis associated with antibodies against intracellular neuronal proteins, cell surfaces or synaptic proteins, referred to as autoimmune encephalitis. Several case reports published in the literature document autoimmune encephalitis cases triggered by COVID-19 infection. Our paper first presents our experience in this issue and then systematically reviews the literature on autoimmune encephalitis that developed in the background of SARS-CoV-2 infections and also discusses the possible pathophysiological mechanisms of auto-immune-mediated damage to the nervous system. This review contributes to improve the management and prognosis of COVID-19-related autoimmune encephalitis.
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Etiology
Viral encephalitis
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