The inflammatory disorders of the central nervous system (CNS) in childhood are a heterogeneous group of conditions, manifesting most often as new-onset neurologic or psychiatric deficits in previously healthy children. These disorders can vary widely in severity, ranging from mild reversible focal neurologic abnormalities to profound encephalopathy or devastating neurologic impairment. Inflammatory disorders of the CNS can generally be divided into 3 main categories: 1) antibody-mediated CNS inflammatory disorders with an identifiable biomarker, 2) CNS inflammatory disorders without a known biomarker, and 3) systemic inflammatory disorders with secondary CNS involvement.1
This article will focus on the most common antibody-mediated CNS disorders, which can be further subdivided into antibody-mediated encephalitides and antibody-mediated demyelinating syndromes. The latter are thought to be caused by activated B cells that produce antibodies and are thought to cause up to 10% of all childhood neuroinflammatory disorders.2 Antibody-mediated demyelinating syndromes respond to immunotherapy,3,4 making it essential to recognize these conditions quickly and accurately so that treatment can be initiated quickly. In this article, we review the epidemiology, clinical presentation, diagnostic evaluation, treatment, and outcomes of the most common antibody-mediated CNS disorders.
Autoimmune encephalitis is associated with antibodies to neuronal proteins involved in synaptic transmission, plasticity, and neuronal excitability.5 Antibodies to a variety of neuronal proteins, including the N-methyl D-aspartate receptor (NMDAR), leucine-rich glioma-inactivated 1 protein (LGI1), GABA receptors, amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, glutamic acid decarboxylase 65 (GAD65), and glycine receptors have been identified as causes of autoimmune encephalitis. AntiNMDAR-mediated encephalitis was the first identified autoimmune encephalitis and the most well studied.6 Although this disorder was initially described in adults, it has become increasingly identified in children and is currently the most common form of autoimmune encephalitis in children.5 AntiNMDAR encephalitis can be difficult to diagnose because of variable heterogeneous presentations; however, early detection and initiation of treatment are crucial to limit morbidity.
AntiNMDAR encephalitis is thought to account for 40% of all cases of autoimmune encephalitis5 and is more common in both children and women than in men.7-9 In a large study characterizing 400 individuals with anti-NMDAR encephalitis, it was shown that children under age 18 were less likely to have an associated tumor compared with adults. In men, the presence of an associated testicular teratoma is rare.
Clinical Presentation and Diagnostic Evaluation
Adults with antiNMDAR encephalitis classically present with a prodromal illness often consisting of fever, headache, or viral symptoms. Following this prodrome, neuropsychiatric and behavioral symptoms can arise, including changes in level of consciousness, seizures, dyskinesias, abnormal movements, and autonomic disability over the course of days to weeks.5,10 In children, the initial symptoms commonly include seizures, dystonia, or decreased speech.9 A study of antiNMDAR encephalitis showed the most common presenting symptoms in children less than age 12 years were abnormal behavior, seizures, and movement disorders.11 Behavior changes typically include temper tantrums, agitation, aggression, and change in personality. It was also shown that more than 90% of those with antiNMDAR encephalitis develop at least 3 of the following symptoms within 1 month of disease onset: psychiatric features, memory disturbance, speech disturbance, seizures, dyskinesias, decreased level of consciousness, autonomic instability, or hypoventilation.11 The most common abnormal movements are classically oro-lingual-facial dyskinesias. The most common autonomic manifestations include hyperthermia, tachycardia, hypertension, hypotension, erectile dysfunction, and urinary incontinence, although these are more commonly seen in adults.5 Seizures often present in the early stages of the disease.9
In a study characterizing 100 children and adults with antiNMDAR encephalitis, 55% had an abnormal MRI with increased signal on MRI fluid attenuation inversion recovery (FLAIR) or T2 sequences.6 The most common abnormalities were in the cerebral cortex, meninges, basal ganglia, and temporal lobes.6,9 Those who recovered from the illness had improvement or resolution of these changes on repeat imaging.6 In children, however, MRI abnormalities are less frequent, occurring in approximately 31% of cases.12 The findings of EEG are frequently abnormal and nonspecific (eg, slowing or disorganized background) and slow continuous rhythmic delta activity (ie, a delta brush pattern) can be seen in those with a catatonic-like presentation.9,12 Findings of cerebrospinal fluid (CSF) analysis are abnormal in up to 80% of cases, with the most common findings being a lymphocytic pleocytosis, moderately increased protein, and positive CSF oligoclonal bands.9,12 The presence of antiNMDAR antibodies in CSF is diagnostic in the appropriate clinical setting.
Diagnosis of antiNMDAR encephalitis can be challenging because of the variability of presentation and sometimes nonspecific behavioral or psychiatric symptoms in young children. The diagnosis should be considered in children presenting with a rapid change of behavior or psychosis, abnormal postures or movements, seizures, and autonomic instability.9-11 Imaging, EEG, and CSF findings can also be nonspecific, as described, so the diagnosis relies heavily on the detection of antiNMDAR antibodies in the CSF in the appropriate clinical setting. Testing CSF is more sensitive than serum testing for antiNMDAR antibodies.7,9 Tumor screening, specifically for ovarian teratoma in women and girls and for testicular germ cell tumors in men and boys, is also recommended.9
With prompt and aggressive treatment early in the disease course, children generally demonstrate good recovery. In a study evaluating 360 children and adults with antiNMDAR encephalitis, approximately 75% experienced a complete or near-complete recovery following treatment. Relapses occur in 20% to 25% of both pediatric and adult patients and these relapses can be separated by months or years.5,9
Treatment of antiNMDAR encephalitis typically consists of intravenous immunoglobulin (IVIG) 2 g/kg divided over 2 to 5 days and intravenous methylprednisolone. Plasma exchange is also used in more severe or refractory cases. Most children with antiNMDAR encephalitis are now also treated with additional immunotherapy upfront, with rituximab, mycophenolate mofetil, or cyclophosphamide being the most commonly used.9,13 If a tumor is found, removal of the tumor in addition to immunotherapy is required.9 In a multi-institutional observational study, 81% of people who had antiNMDAR encephalitis had significant neurologic improvement at 24-month follow-up after receiving first- and/or second-line immunotherapy or tumor removal. This study also demonstrated that second-line therapy with rituximab, cyclophosphamide, or both led to a marked improvement in outcomes for those who did not respond to first-line therapies (eg, steroids, IVIG, and plasmapheresis) and reduced the frequency of relapses.11
Antibody-Mediated Demyelinating Syndromes
Neuromyelitis Optica Spectrum Disorder
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disorder of the CNS that predominantly affects the optic nerves and spinal cord. The aquaporin-4 (AQP4) antibody is a specific biomarker for NMOSD with some evidence suggesting pathogenicity.14 With the discovery of the aquaporin-4 antibody, the scope of the disorder has been broadened to include presentations other than optic neuritis (ON) and myelitis.
Epidemiology. The incidence and prevalence of NMOSD is not well characterized in children, although some population-based studies suggest the incidence of NMOSD ranges from 0.05 to 4 per 100,000 per year with a prevalence of 0.52 to 4.4 per 100,000.15,16 The mean age of onset for NMOSD is 32 to 45 years, occurring only rarely in childhood.16,17 Children account for up to 5% of all NMOSD cases and have a mean age of onset of 12 years with a strong female:male predominance (7:1).17,18
Classic Presentation and MRI Findings. The most common initial presentations of NMOSD in children involve ON, myelitis, and brainstem syndromes.16,19-21 Recurrent vomiting and intractable hiccups (associated with area postrema syndrome) are also 2 very common initial presentations for children with NMOSD.17,21,22 Compared with adults with NMOSD, children with NMOSD can have more disabling attacks of ON and more widespread MRI brain lesions.17
Brain and spine MRI is helpful for the diagnosis of NMOSD and to help differentiate the disease from other demyelinating syndromes such as multiple sclerosis (MS). MRI findings in patients with NMOSD can vary tremendously but classically involve longitudinally extensive lesions in the spinal cord and optic tract (Figure 1). Longitudinally extensive transverse myelitis (LETM) is the most specific MRI characteristic in NMOSD in adults but is less specific in the pediatric population because children with multiple sclerosis and myelin oligodendrocyte glycoprotein (MOG) associated demyelination can also have longitudinally extensive lesions.23 Spinal cord lesions in NMOSD can involve the central gray matter, however this can also be seen with MOG-associated demyelination and acute flaccid myelitis.23 With regard to optic nerve lesions, bilateral optic nerve enhancement, posterior optic tract involvement, and extensive optic nerve involvement are all more commonly seen in NMOSD compared with isolated ON and MS. Brain lesions have been shown to be relatively large (>2 cm) and more common in pediatric NMOSD compared with what is seen in adults with NMSOD, with the areas of high AQP4 expression being most involved (regions within the diencephalon and brainstem, infratentorial regions of midbrain, dorsal medulla/area postrema, and cerebellum).17,18,23
Figure 1. Longitudinally extensive T2 hyperintense spinal cord lesion (A) and longitudinally extensive enhancing optic nerve lesion (B) in neuromyelitis optica spectrum disorder (NMOSD).
Compared with children with MS, children with NMOSD typically have a more prominent pleocytosis, and can have a neutrophilic predominance.21,24 Also in contrast to MS, oligoclonal bands are rarely positive in NMOSD, whereas they are present in at least 85% of patients with MS.21,24
Diagnostic Criteria. The diagnostic criteria for NMOSD were revised in 2015 because of the demonstrated specificity of antiAQP4 antibodies for NMOSD and to better capture the broad spectrum of NMOSD. The current criteria are now divided into 2 large categories: 1) antiAQP4-positive NMOSD and 2) antiAQP4-negative NMOSD. To fulfill criteria of NMOSD in the presence of antiAQP4 antibodies, only 1 core clinical characteristic is required; however, to fulfill criteria of an NMOSD diagnosis in the absence of antiAQP4 antibodies, 2 core clinical characteristics are needed, with 1 of these being either ON, myelitis, or area postrema syndrome (APS). The 6 major core clinical characteristics are ON, acute myelitis, APS, diencephalic syndrome or symptomatic narcolepsy, acute brainstem syndrome, or symptomatic cerebral syndrome. There is also a requirement for the exclusion of alternate diagnoses for both antiAQP4-positive and -negative NMOSD.23 The above criteria are used for pediatric NMOSD as well. Testing for AQP4 should be done via serum cell-based assay, because serum testing has been shown to be more sensitive than CSF testing.23
Prognosis. The course of NMOSD is typically relapsing-remitting with up to 90% of patients with NMOSD having relapses.19,20,22 Compared with adults, children can take a longer time to reach disability (Expanded Disability Status Scale [EDSS] scores of 4 and 6) and may have lower mean annualized relapse rates.25
Management. For acute attacks or relapses, intravenous methylprednisolone, IVIG, or plasma exchange are the first-line treatments in NMOSD. Typically, children are treated with 3 to 5 days of high-dose intravenous methylprednisolone (30 mg/kg up to 1000 mg). If there is no significant improvement, plasma exchange or IVIG is considered depending on the severity of symptoms.17,22 All children with a diagnosis of NMOSD should be started on disease-modifying therapy. The most common disease-modifying therapies used are rituximab, azathioprine, and mycophenolate mofetil, all of which have been shown to reduce relapses and even reduce disability if initiated early.18,26,27 Certain disease-modifying therapies, including interferon β, natalizumab, and fingolimod have been shown to be ineffective and may even worsen the disease; these should be avoided in NMOSD.26,27
MOG-Antibody Associated Demyelination
Myelin oligodendrocyte glycoprotein (MOG) is a myelin glycoprotein exclusively expressed in the CNS and accounts for a minor component of the myelin sheath. Although MOG makes up less than 0.05% of all myelin proteins, its location on the outermost surface of myelin makes it accessible as a potential target of cellular and antibody-mediated immune responses.28-30 The function of MOG and its role in autoimmunity is not clear; however, some studies have suggested a role in myelin maturation, regulating interactions with the immune system, myelin integrity, and cell-surface interactions.31 Recently, with the development of a cell-based assay, antibodies to MOG have been identified in the serum of up to one-third of all children presenting with an acquired demyelinating syndrome and these patients have been found to follow a nonMS disease course. Recent cohort studies have investigated the clinical and radiographic hallmarks of these cases and research is still ongoing to provide further guidance on the diagnosis, treatment, and prognosis of this disease.
Epidemiology. Serum antiMOG antibodies are found in approximately 30% of all children presenting with an acquired demyelinating syndrome. Those with antiMOG seropositivity tend to be younger than those who are antiMOG negative.29,31-33 Multiple cohort studies have also demonstrated that MOG antibodies are much more common in children than in adults,31,34 and the disease appears to affect boys and girls equally.31-33
Presentation and Diagnostic Evaluation. The clinical presentation of MOG-associated demyelination encompasses a broad spectrum of phenotypes. The most common initial presenting phenotypes appear to be acute disseminated encephalomyelitis (ADEM), ON, and transverse myelitis (TM). Other presentations of MOG-associated disorders include encephalitis, vasculitis, and cerebellitis.29,31,35 Interestingly, multiple cohort studies have identified a correlation between age of onset and clinical phenotype at presentation, with younger children typically presenting with an ADEM-like phenotype and older children more commonly presenting with an ON phenotype.9,31-33
Children presenting with an ADEM-like phenotype have commonly demonstrated brain MRI findings consisting of large ill-defined brain lesions bilaterally with lesions in the thalamus and supratentorial white matter.29,31,32 Children presenting with ON can present with bilateral ON and rapid visual impairment, but generally have good recovery with steroid therapy. Distinct from NMO and MS, ON associated with antiMOG antibodies is often more common in the anterior portions of the optic nerves with retrobulbar involvement and more commonly demonstrates optic disc swelling.31,35 Longitudinally extensive optic nerve lesions are seen in both NMOSD and MOG-associated ON.29,31,35 In children with MOG seropositivity, TM is often longitudinally extensive, although short segment TM can also occur. Unlike the TM observed in NMOSD, the conus is more frequently involved an there is often more grey matter involvement in MOG-associated TM (Figure 2).29,31,35
The CSF generally demonstrates a pleocytosis in approximately half of all individuals with antiMOG antibody-associated demyelination.31,34,36 The CSF protein levels can also be elevated in those with MOG-antibody associated demyelination. Oligoclonal bands are rarely found.29,34,36,37
Diagnosis. Currently, there is no formal diagnostic guideline for the pediatric antiMOG antibody-associated demyelination. Thus, the diagnosis of a MOG-antibody associated disorder is currently based on serum positivity for the antiMOG antibody with a cell-based assay in children presenting with an acquired demyelinating syndrome.38
Prognosis. AntiMOG antibody-associated demyelination was originally thought to follow a monophasic course, however it has now been recognized that relapses can occur. In a large prospective study done by the Canadian Pediatric Demyelinating Disease Study (CPDDS), it was shown that more than 80% of children with seropositivity for antiMOG had a monophasic disease course.32 In this study, age correlated positively with the likelihood of having relapses. Interestingly, with relapsing disease, the most common type of relapse is ON.29,32,34,35 Persistent antiMOG antibody seropositivity was also evaluated as a potential predictor of relapse, and those who were persistently antiMOG seropositive were more likely to have relapsing disease than those who converted to seronegative status. It is important to note, however, that nearly 40% of those who were antiMOG positive experienced a relapse after their first seronegative result, suggesting that converting to antiMOG seronegativity does not guarantee that relapses will no longer occur.32 Generally, outcomes in antiMOG-associated demyelinating syndromes are good, with the majority having a full recovery. Children with a monophasic disease course are more likely to have a favorable outcome with few or no residual deficits compared with those with relapsing antiMOG disease.39 Most children with an antiMOG-associated demyelination have low EDSS scores and often low residual lesion volumes or complete resolution of lesions on MRI.32
Management. Acute management of antiMOG antibody-associated demyelination includes intravenous methylprednisolone, IVIG, and plasma exchange if needed.29,35 Because the majority of MOG-associated demyelination in children is monophasic, long-term immunomodulatory therapy at the time of initial presentation is typically deferred.32,40 This is reconsidered if relapse occurs. Precise guidelines on which disease-modifying therapies to use for relapsing disease is less well defined. In a large multinational European cohort study evaluating 102 children with relapsing antiMOG antibody-associated disease, it was shown that treatment with IVIG, rituximab, mycophenolate mofetil, or azathioprine all reduced annualized relapse rate (ARR) with scheduled IVIG having the greatest improvement in ARR and EDSS scores compared with the other therapies utilized.40 Injectable MS therapies (interferon β and glatiramer acetate) did not demonstrate a reduction in ARR during treatment or a significant improvement in EDSS, suggesting that these therapies are ineffective in the long-term treatment of antiMOG antibody-associated disorders.40 Further studies will be required to confirm these findings and to further evaluate the most optimal treatment strategies, treatment duration, and best outcome measures.
Antibody-mediated inflammatory disorders of the CNS in children represent an important group of disorders that can present with a variety of neurologic symptoms and may ultimately follow a monophasic or relapsing course. Prompt recognition of these disorders is critical because they generally respond positively to early initiation of immunomodulatory therapy. Further research into the pathogenic role of antibodies identified in these disorders will be beneficial for the development of antibody-targeted therapies. Additionally, further research into the most optimal diagnostic strategies, treatment paradigms, and outcome measures will be crucial for this expanding field of neurology.
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DIH and SN report no disclosures