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Encephalitis is a complex, debilitating, and sometimes fatal neurologic condition to which children are especially prone. Mycoplasma pneumoniae, a common respiratory pathogen, has been implicated as an etiology of encephalitis. Evidence for recent or acute M. pneumoniae infection has been demonstrated in limited studies of both pediatric and adult...
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Citations
... In particular, the possibility of direct cerebral parenchymal infection by the pathogen itself and the development of encephalitis through systemic immune-mediated responses or thromboembolic manifestations triggered by the infection have been reported for Mycoplasma pneumoniae. 16,17 Similarly, the association between other systemic infections and the occurrence of encephalitis needs to be considered thoroughly. In addition to the relatively common causative agents, it is necessary to test for rare causative agents, such as arbovirus, rickettsia, and Bartonella, based on travel and medical histories. ...
Purpose
Encephalitis is a heterogeneous syndrome that occurs in childhood and is not rare. However, epidemiological studies of encephalitis based on the International Encephalitis Consortium (ICS) and expert recommendations are lacking. We investigated the aetiology and prognosis of encephalitis in Korean children.
Materials and Methods
This retrospective study included children aged <19 years hospitalised for encephalitis at Severance Children’s Hospital between 2005 and 2020. The 2013 ICS criteria were used to diagnose encephalitis, and causality was classified according to the site from which the specimen was obtained. Neurological sequelae were categorised using the modified Rankin Scale (mRS) score.
Results
In total, 551 children were included, with 7% classified as possible, 77% as probable, and 15% as proven cases. A cause was identified in 42% of the cases (n=222), with viruses being the most common (42%), followed by bacteria (38%) and autoimmune encephalitis (12%). In cases of proven/probable encephalitis (n=65), bacteria accounted for 52%, followed by viruses (25%) and autoimmune encephalitis (22%). In cases with a single pathogen, the anti-N-methyl-D-aspartate receptor autoantibody (n=14) was the most common, followed by Group B streptococcus (n=13), herpes simplex virus (n=11), enterovirus (n=4), and others. Approximately 37% of patients had severe sequelae (mRS score ≥3) at discharge, which decreased to 31% 6 months after discharge.
Conclusion
This large-scale study showed that autoimmune and infectious causes accounted for a significant proportion of encephalitis in Korean children. Further studies are needed to determine whether early targeted treatment following early diagnosis leads to a favourable prognosis in these populations.
... For instance, the hazard ratio was 1.40 for juvenile idiopathic arthritis and 1.26 for autoimmune thyroid disease. These differences may reflect variations in the prevalence and pathogenicity of different autoimmune diseases in children Moreover, our results are consistent with previous studies that have reported associations between M. pneumoniae infection and autoimmune diseases such as Guillain-Barre's syndrome (GBS) (30,31) and polyarthritis (32). However, these previous studies were limited by a cross-sectional design, which precluded causal inferences. ...
Background
Mycoplasma pneumoniae infection is common in the general population and may be followed by immune dysfunction, but links with subsequent autoimmune disease remain inconclusive.
Objective
To estimate the association of M. pneumoniae infection with the risk of subsequent autoimmune disease.
Methods
This retrospective cohort study examined the medical records of South Korean children from 01/01/2002 to 31/12/2017. The exposed cohort was identified as patients hospitalized for M. pneumoniae infection. Each exposed patient was matched with unexposed controls based on birth year and sex at a 1:10 ratio using incidence density sampling calculations. The outcome was subsequent diagnosis of autoimmune disease, and hazard ratios (HRs) were estimated with control for confounders. Further estimation was performed using hospital-based databases which were converted to a common data model (CDM) to allow comparisons of the different databases.
Results
The exposed cohort consisted of 49,937 children and the matched unexposed of 499,370 children. The median age at diagnosis of M. pneumoniae infection was 4 years (interquartile range, 2.5–6.5 years). During a mean follow-up time of 9.0 ± 3.8 years, the incidence rate of autoimmune diseases was 66.5 per 10,000 person-years (95% CI: 64.3–68.8) in the exposed cohort and 52.3 per 10,000 person-years (95% CI: 51.7–52.9) in the unexposed cohort, corresponding to an absolute rate of difference of 14.3 per 10,000 person-years (95% CI: 11.9–16.6). Children in the exposed cohort had an increased risk of autoimmune disease (HR: 1.26; 95% CI: 1.21–1.31), and this association was similar in the separate analysis of hospital databases (HR: 1.25; 95% CI 1.06–1.49).
Conclusion
M. pneumoniae infection requiring hospitalization may be associated with an increase in subsequent diagnoses of autoimmune diseases.
... ADEM is linked with infectious or autoimmune triggers, though in many cases, no etiological factor is identified (1). Our patient had a positive qualitative serologic test for Mycoplasma pneumoniae, which has a high false positive rate due to seroprevalence of the infection in this age group (10,11). ...
Acute Disseminated Encephalomyelitis (ADEM) is a monophasic demyelinating disease most often triggered by infection or immunization, though associations with malignancy and stem cell transplant have been described. We described the case of a four-year-old boy with new-onset neurological symptoms associated with ADEM, acute leukemia, and equivocal evidence of Mycoplasma pneumoniae infection. He responded to a short course of antibiotics and chemotherapy for B cell acute lymphoblastic leukemia (B-ALL) that included a prolonged course of high dose steroids with immunosuppressive therapy. This case illustrated a possible association between paraneoplastic ADEM and leukemia in pediatric patients.
... Infectious encephalitis was distributed among children aged 1-5 years old (35.71%) followed by the 11-15 years old age group (28.57%). On the other hand, immunemediated encephalitis was observed to be more common among adolescents (11)(12)(13)(14)(15) years old) at 56% with slight female preponderance (55.56%). The nutritional status of the patients was based on their body mass index (BMI) and interpreted in correlation with age. ...
... Due to the low yield of positive CSF PCR results for Mycoplasma pneumoniae, Christie, et al. defined M. pneumoniae-associated encephalitis as any patient with the presence of acute M. pneumoniae infection by a positive IgM, a significant rise in IgG titers between acute and convalescent specimens, or a positive respiratory or CSF PCR. 14 Neuroimaging can be a helpful tool in the diagnosis of pediatric encephalitis and to exclude other possible neurologic conditions. MRI is more sensitive and provides more details. ...
Introduction: The etiology of encephalitis involves an enormous range and can be classified as infectious or immune-mediated. There are several factors influencing its prognosis and has been associated with significant morbidity and mortality. This study aims to evaluate the clinico-epidemiologic characteristics and outcomes of infectious and immune-mediated encephalitis among pediatric patients. Methodology: Retrospective descriptive cross-sectional study that included patients aged 6 months to 17 years old with encephalitis in a tertiary hospital between January 2010 to December 2020. Results: A total of 23 cases were reviewed and 60.87% were infectious while that of immune-mediated was 39.13%. Among those with identified infectious cause, Mycoplasma pneumonia was the most common (28.57%). Infectious encephalitis was more common among younger males (35.71%) while immune-mediated affected female adolescents more (55.56%). The most common neurologic manifestation was altered mental status and/or behavioral changes. Treatment such as antibiotics (78.26%), anticonvulsant therapy (78.26%), and steroids (43.48%) were given. All immune-mediated cases received steroids. More than half of patients had complete recovery (56.52%). Conclusion: Pediatric encephalitis should be considered among patients with neurologic dysfunction with or without systemic involvement. Behavioral changes in an apparently well child should prompt clinicians to consider anti-NMDAR encephalitis, especially if viral studies are negative and with no other known cause. Viruses remain to be the most common etiology, but other possible causes should be highly considered such as anti-NMDAR and Mycoplasma. A normal CSF analysis, imaging and/or encephalography (EEG) may not totally exclude encephalitis. Prognosis is relatively good hence an early diagnosis and initiation of appropriate management is important.
... M.P. encephalitis is one of the most severe extra-respiratory complications, accounting for 5-30% of all reported encephalitis cases (38). The latency period between the onset of respiratory symptoms and the development of neurological abnormalities varies. ...
Background and Purpose
An increasing number of autoimmune encephalitis (AE)-associated autoantibodies have been successfully characterized. However, many cases of AE remain unexplained on account of unknown antibodies. The aim of the present study was to identify a novel antibody against collapsin response mediator protein 2 (CRMP2) in suspected AE patients.
Methods
A patient’s serum and cerebrospinal fluid samples tested negative for known AE antibodies; however, strong immunolabel signals were observed in the neuronal cytoplasm of the cortex, hippocampus, and Purkinje cells on rat brain sections. Immunoprecipitation from the rat brain protein lysate, followed by mass spectrometry analysis, was used to identify the targeting antigen. Western blotting and cell-based assay with antigen-overexpressing HEK293T cells were used for antibody specificity, epitope, IgG subtype determination, and retrospective study.
Results
An antibody against CRMP2, a synaptic protein involved in axon guidance, was identified. The immunostains of the patient’s samples on rat brain sections were eliminated by pre-absorption with HEK293T cells overexpressing CRMP2. The samples specifically immunoreacted with CRMP2, but not with CRMP1, CRMP3, CRMP4, and CRMP5. The C-terminus of CRMP2 with 536 amino acids contained the epitope for antibody binding. The subtype analysis showed that the anti-CRMP2 antibody was IgG4. Furthermore, a screening of 46 patients with neurological disoders and neuro-cytoplasm immunostainings on rat brain sections resulted in the identification of anti-CRMP2 antibodies in a case of encephalomyelitis. The two patients responded well to immunotherapies.
Conclusions
This study discovered that a novel anti-CRMP2 antibody was associated with suspected AE and thus should be included in the testing list for AE.
... 1,2 In addition, IgM antibodies vary with age; and usually become positive in acute infection but also may be negative in the course of acute infection or it`s positivity may last for months. 22 Seroconversion is defined as a 4-fold increase in titre between acute and convalescent sera, or a single high anti-M. pneumoniae complement fixation antibody titre of >1:128. 1 Cold agglutinins had been used in the past as they are produced 1-2 weeks after infection in 50% of patients and may persist for several weeks but they have poor sensitivity and specificity. ...
A case of a 4-year-old boy who developed acute disseminated encephalomyelitis (ADEM) and optic neuritis (ON) following Mycoplasma pneumoniae infection is reported. His symptoms, including excessive sleepiness, frontal headache, bilateral vision impairment, retro-auricular pain and unbalanced gait, were resolved after methylprednisolone pulse therapy, intravenous immunoglobulin (IVIG) and ciprofloxacin. Cerebrospinal fluid myelin basic protein (MBP) and Mycoplasma serology IgM were detected in our patient. This is the first report of a child with ADEM and ON associated with mastoditis caused by M. pneumoniae infection. Combined immunomodulatory therapy (pulse steroids and immunoglobulin) with anti- mycoplasma microbial therapy resulted in favorable visual recovery. Bilateral isolated optic neuritis as the first presenting feature in childhood ADEM is rare and requires proper evaluation and early therapeutic management. This case highlights the need for physician awareness of the association of mycoplasma infection with optic neuritis and ADEM.
... An exception can be made for aseptic meningitis, for which in several cases, cerebral spinal fluid (CSF) analysis led to the identification of M. pneumoniae DNA and increased interleukin (IL)-6 and IL-8 concentrations [78,79]. Unfortunately, much rare is the detection of M. pneumoniae in the CSF of patients with acute encephalitis [80,81], although M. pneumoniae has been associated with the development of this disease in 5-30% of the cases [82]. However, generally, direct extra-respiratory damage is only supposed on the basis of M. pneumoniae detection in nasopharyngeal respiratory secretions by means of molecular methods and/or serology. ...
... Molecular mimicry between some M. pneumoniae components (P1 adhesin and glycolipids) and host myelin glycolipids leads the production of antibodies against myelin components of the host that are the cause of the damage [86]. Antibodies can be produced intrathecally, as evidenced by the higher level of antibodies detected in the CSF than in the serum or reach the CNS through the inflamed blood-brain barrier [82]. However, the demonstration of a direct connection between neurologic damage and M. pneumoniae infection occurs only when antibodies are detected in the CSF as their presence in the serum can be related to a previous infection occurred in absence of nervous system involvement [87]. ...
Introduction
Despite the amount of new information, the most effective approach for the diagnosis and treatment of Mycoplasma pneumoniae infections is not established. In this narrative review the pharmacological options for macrolide-resistant (ML) M. pneumoniae infections in children are discussed.
Areas covered
Despite significant improvement in the diagnosis and in the definition of diseases potentially associated with this pathogen, not all the problems related to M. pneumoniae infection are solved. True epidemiology of M. pneumoniae diseases and the real role of this pathogen in extra-respiratory manifestations is still unestablished. This reflects on therapy. It is not known whether antibiotics are really needed in all the cases, independently of severity and localization. The choice of antibiotic therapy is debated as it is not known whether ML resistance has clinical relevance. Moreover, not precisely defined is the clinical importance of corticosteroids for improvement of severe cases, including those associated with ML-resistant strains.
Expert opinion
Improvement in M. pneumoniae identification is mandatory to reduce antibiotics overuse , especially in the presence of ML-resistant strains. Priority for future studies includes the evaluation of the true benefit of therapeutic approaches including corticosteroids in patients with severe CAP and in those with extra-respiratory M. pneumoniae diseases.
... Mycoplasma pneumoniae Mycoplasma pneumoniae-associated encephalitis is not rare in the paediatric population; however, its exact pathophysiological mechanism is still debated, largely because of inconsistent laboratory findings [72]. An 18year-old male patient from a large retrospective study by Mejia et al. developed sudden onset ataxia and simple motor tics following Mycoplasma pneumoniae infection [28]. ...
Background
Movement disorders have been described in the context of different types of encephalitis. Among hyperkinetic manifestations, tics have sporadically been reported in cases of encephalitis resulting from a range of aetiologies.
Objective
This review aimed to assess the prevalence and characteristics of tics in patients with encephalitis.
Methods
We conducted a systematic literature review of original studies on the major scientific databases, according to the standards outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
Results
In addition to the established association between tics and encephalitis lethargica, our literature search identified reports of tics in patients with immune-mediated pathologies (including autoimmune encephalitides affecting the N -methyl- d -aspartate receptor, voltage-gated potassium channels, and glycine receptors) and infective processes (ranging from relatively common viral pathogens, such as herpes simplex, to prions, as in Creutzfeldt-Jakob disease). Tics were most commonly reported in the post-encephalitic period and involvement of the basal ganglia was frequently observed.
Discussion
The association of new-onset tics and encephalitis, in the background of other neuropsychiatric abnormalities, has practical implications, potentially improving the detection of encephalitis based on clinical features. Future research should focus on the categorisation and treatment of hyperkinetic movement disorders associated with encephalitis.
... M. pneumoniae can also lead to extrapulmonary manifestations including central nervous system (CNS) complications. In a study of 1,988 patients in the California Encephalitis Project, M. pneumoniae was the most common agent implicated in encephalitis, especially in children [3]. They were diagnosed primarily by the elevation of M. pneumoniae IgM in the blood. ...
... They were diagnosed primarily by the elevation of M. pneumoniae IgM in the blood. PCR and antibodies in CSF were rarely positive [3]. Qualitative measurement of IgM has only moderate sensitivity, but serial testing in our patient revealed peak levels at hospital day 1 and then a gradual decrease which turned to negative after 8 months, strongly implying that M. pneumoniae may be responsible. ...
... ANE is often associated with significant morbidity. Although clinical usefulness of the immunomodulating therapy has not been confirmed, early IVIG and steroid pulse therapy is thought to be associated with better outcomes [3,4]. ...
... One case each of "probable" EBV encephalitis and "possible" HHV-6 encephalitis were subject to these limitations. A further important controversy surrounds the attribution of M. pneumoniae as a cause partly because of inherent limitations with available diagnostic tests [19,44,45]. Here, all cases were diagnosed serologically, did not have alternative causes, and did not have imaging consistent with ADEM as per Granerod et al. ...
Background:
We aimed to determine the contemporary causes, clinical features, and short-term outcome of encephalitis in Australian children.
Methods:
We prospectively identified children (≤14 years of age) admitted with suspected encephalitis at 5 major pediatric hospitals nationally between May 2013 and December 2016 using the Paediatric Active Enhanced Disease Surveillance (PAEDS) Network. A multidisciplinary expert panel reviewed cases and categorized them using published definitions. Confirmed encephalitis cases were categorized into etiologic subgroups.
Results:
From 526 cases of suspected encephalitis, 287 children met criteria for confirmed encephalitis: 57% (95% confidence interval [CI], 52%-63%) had infectious causes, 10% enterovirus, 10% parechovirus, 8% bacterial meningoencephalitis, 6% influenza, 6% herpes simplex virus (HSV), and 6% Mycoplasma pneumoniae; 25% (95% CI, 20%-30%) had immune-mediated encephalitis, 18% acute disseminated encephalomyelitis, and 6% anti-N-methyl-d-aspartate receptor encephalitis; and 17% (95% CI, 13%-21%) had an unknown cause. Infectious encephalitis occurred in younger children (median age, 1.7 years [interquartile range {IQR}, 0.1-6.9]) compared with immune-mediated encephalitis (median age, 7.6 years [IQR, 4.6-12.4]). Varicella zoster virus encephalitis was infrequent following high vaccination coverage since 2007. Thirteen children (5%) died: 11 with infectious causes (2 influenza; 2 human herpesvirus 6; 2 group B Streptococcus; 2 Streptococcus pneumoniae; 1 HSV; 1 parechovirus; 1 enterovirus) and 2 with no cause identified. Twenty-seven percent (95% CI, 21%-31%) of children showed moderate to severe neurological sequelae at discharge.
Conclusions:
Epidemic viral infections predominated as causes of childhood encephalitis in Australia. The leading causes include vaccine-preventable diseases. There were significant differences in age, clinical features, and outcome among leading causes. Mortality or short-term neurological morbidity occurred in one-third of cases.
