Antibody-mediated diseases of the central nervous system are a relatively new and challenging field in autoimmune neurologic disease and of major clinical importance in children and adults. The antibodies bind to cell-surface epitopes on neuronal or glial proteins, and the patients demonstrate either focal or more generalized clinical signs depending on the extent of brain regions targeted by the antibodies. The presence of seizures, movement disorders, autonomic dysfunction and sleep disorders, alongside neuroimaging and electrophysiological features may indicate a specific antibody-mediated disorder. However, phenotypic variation may be observed in children with the same antibody. Regardless, many patients benefit from immunotherapy with substantial improvement.
Key points
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There are several antibody-mediated central nervous system diseases that need to be recognized in children.
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These diseases are identified by the clinical features, paraclinical findings, and presence of serum/cerebrospinal fluid antibodies to cell-surface proteins, such as the N-methyl d -aspartate receptor.
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Early recognition and institution of treatment can optimize outcomes in some but not all patients with autoimmune encephalopathy.
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Despite some very characteristic and easily recognizable features of certain antibody-mediated syndromes, significant phenotypic overlap exists between children with different antibodies.
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The lack of detection of an established cell-surface antibody should not dissuade clinicians from early initiation of immune therapy.
Introduction
The immune response within the brain depends on interactions between the immune and nervous systems, complicated by the blood-brain barrier. Neuroinflammation, involving the innate (glial cells) and/or components of the adaptive (lymphocytes) immune system infiltrating the central nervous system (CNS), is observed in a range of neurologic disorders and may represent the primary pathology in an autoimmune condition like multiple sclerosis but can also represent a secondary response to biological processes, such as neurodegeneration.
Over the last few years, a more specific form of CNS autoimmunity has been recognized, identified mainly by the presence of antibodies binding to neuronal synaptic receptors and ion channel–related proteins, and found in both adults and children. These cell-surface antigens are important for cellular function or neurotransmission and are generally expressed at different levels throughout the CNS, with patients demonstrating either focal or more generalized clinical signs, probably depending on the extent of brain regions targeted. Some of these disorders are associated with tumors and are, therefore, paraneoplastic; but the frequency of malignancies differs depending on the identity of the antigen and the age of the patients. By contrast to classic paraneoplastic syndromes that are associated with antibodies against intracellular antigens, these conditions frequently respond to immunotherapy; although some have a monophasic illness, both a protracted period for recovery and/or a relapsing course can occur in adults and children.
In a large multicenter UK encephalitis study of acute or subacute encephalitis presenting to general hospitals, 21% patients without a detected infection were found retrospectively to have a specific antibody to N-methyl d -aspartate receptor (NMDAR) or to the voltage-gated potassium channel (VGKC) complex, a frequency that surpassed that of any single virus identified. This finding was mirrored in the California Encephalitis project, whereby the frequency of NMDAR antibody encephalitis surpassed that of any of the individual viral encephalitides. The discovery that several forms of encephalitis result from neuronal antibodies, and are immunotherapy responsive, has led to a paradigm shift in the diagnostic and management approach to all forms of encephalitis. Here, the authors review the important developments in characterizing the autoimmune encephalopathies in children, particularly when antibodies targeting neuronal cell-surface antigens have been implicated, with a focus on how to recognize and treat these conditions early.
Introduction
The immune response within the brain depends on interactions between the immune and nervous systems, complicated by the blood-brain barrier. Neuroinflammation, involving the innate (glial cells) and/or components of the adaptive (lymphocytes) immune system infiltrating the central nervous system (CNS), is observed in a range of neurologic disorders and may represent the primary pathology in an autoimmune condition like multiple sclerosis but can also represent a secondary response to biological processes, such as neurodegeneration.
Over the last few years, a more specific form of CNS autoimmunity has been recognized, identified mainly by the presence of antibodies binding to neuronal synaptic receptors and ion channel–related proteins, and found in both adults and children. These cell-surface antigens are important for cellular function or neurotransmission and are generally expressed at different levels throughout the CNS, with patients demonstrating either focal or more generalized clinical signs, probably depending on the extent of brain regions targeted. Some of these disorders are associated with tumors and are, therefore, paraneoplastic; but the frequency of malignancies differs depending on the identity of the antigen and the age of the patients. By contrast to classic paraneoplastic syndromes that are associated with antibodies against intracellular antigens, these conditions frequently respond to immunotherapy; although some have a monophasic illness, both a protracted period for recovery and/or a relapsing course can occur in adults and children.
In a large multicenter UK encephalitis study of acute or subacute encephalitis presenting to general hospitals, 21% patients without a detected infection were found retrospectively to have a specific antibody to N-methyl d -aspartate receptor (NMDAR) or to the voltage-gated potassium channel (VGKC) complex, a frequency that surpassed that of any single virus identified. This finding was mirrored in the California Encephalitis project, whereby the frequency of NMDAR antibody encephalitis surpassed that of any of the individual viral encephalitides. The discovery that several forms of encephalitis result from neuronal antibodies, and are immunotherapy responsive, has led to a paradigm shift in the diagnostic and management approach to all forms of encephalitis. Here, the authors review the important developments in characterizing the autoimmune encephalopathies in children, particularly when antibodies targeting neuronal cell-surface antigens have been implicated, with a focus on how to recognize and treat these conditions early.
Clinical and paraclinical features of autoimmune encephalopathies
The key clinical feature is that children and adolescents present with encephalopathy, a clinical description of an altered mental state that can manifest as confusion, disorientation, behavioral changes, or other cognitive impairments ( Box 1 ). This condition is often preceded by a less specific prodrome composed of a viral illness with headaches and fever. However, at the early stage of illness, an autoimmune cause cannot be distinguished from the many conditions that cause encephalopathy, such as infections, parainfectious, metabolic, genetic, traumatic, malignant, or toxic disorders. The clinical features of these disorders overlap; in many cases, the cause will not be apparent from the initial history and examination. Rigorous clinical observations and extensive investigations, with empirical treatments for multiple, potentially life-threatening causes, are often started simultaneously in patients presenting with encephalopathy.
Encephalopathy
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Behavioral change (eg, confusion, excessive irritability)
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Or alteration in consciousness (eg, lethargy, coma)
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Encephalitis
Encephalopathy was present with 2 or more of the following:
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Fever or history of fever (≥38°C)
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Seizures and/or focal neurologic findings (with evidence of brain parenchyma involvement)
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Cerebrospinal fluid pleocytosis (>4 white blood cells per microliter)
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Electroencephalogram findings indicating encephalitis
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Neuroimaging in keeping with encephalitis (computed tomography or MRI)
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Seizures occur in most autoimmune encephalopathies, indicating an encephalitic process; but the clinical evidence of inflammation of brain parenchyma may not always be accompanied by radiological or biological evidence of inflammation, such as a reactive cerebrospinal fluid (CSF), as reviewed in the adult and pediatric literature. Hence, autoimmune encephalopathy is the more accurate term to describe these disorders but is often used interchangeably with autoimmune encephalitis (see Box 1 ; Granerod and colleagues, 2010).
The presence of seizures, movement disorders, autonomic dysfunction, and sleep disorders, alongside more specific neuroimaging and electrophysiological features, may indicate a specific antibody-mediated disorder (see Table 1 ) as described in more detail later. However, despite the recognizable features of some antibody-mediated diseases, there are emerging phenotypic overlaps between children with different antibodies and conversely phenotypic differences in children with the same detected antibody.
Antibody detection methods
Methods such as immunohistochemistry on brain tissue are useful to demonstrate regional-specific binding but often identify intracellular proteins (eg, paraneoplastic antigens) that may not be disease causative. The denaturation of proteins for immunoblotting often destroys the conformationally dependent antigenic targets and is seldom helpful for the antibodies discussed here. Radioimmunoprecipitation assays are highly sensitive but not suitable for most of the CNS antigens and can detect antibodies to intracellular as well as extracellular epitopes on the precipitated proteins. These techniques may be of help, but the specific and most appropriate tests are currently the cell-based assays (CBAs). These assays allow optimal detection of antibodies binding extracellular epitopes of the neuronal surface antigens in a manner that would occur when antigen is exposed to circulating antibodies (in tissue fluids). Each CBA relies on introducing, by transfection, the DNA for the specific antigen into a suitable human cell line. Many clinical laboratories use a commercial mosaic of fixed cells expressing different antigens. Although this allows greater accessibility to testing, the fixation of the cells, required for transportation may obscure some epitopes and reduce sensitivities. Alternatively, live cell assays can be developed in-house but are much more time consuming.
These assays can be designed for use with either serum or CSF. The CSF, usually tested at a high concentration, can be surprisingly strongly positive (given the normal ratio of serum to CSF immunoglobulin G [IgG] levels of around 400), which indicates intrathecal synthesis of the specific antibody. Some laboratories prefer CSF because the results can be easier to assess than using serum with its greater stickiness even after dilution. An additional test of binding of antibody to the surface of live neurons in culture, usually from the hippocampus, can be undertaken to confirm the relevance of the antibody detected but is not yet available commercially. An understanding of the assays used, and communication with the clinical laboratory, can be very helpful to the clinician in assessing the results of these tests.
Specific antibody-mediated syndromes
N-Methyl d -Aspartate Receptor Antibody Encephalitis
NMDAR antibody encephalitis was first characterized in young girls presenting with severe encephalopathy, psychiatric features, movement disorder, and autonomic dysfunction associated with an ovarian teratoma. Historical cases of sudden catastrophic encephalopathy in children with relatively good outcomes likely represent the same condition. Patients are found to have antibodies in serum and CSF targeting the extracellular epitopes of the NR1 subunit of the NMDAR. In children, the presence of an underlying tumor is uncommon, but 30% of girls younger than 18 years and 9% of girls younger than 14 years are reported to have an associated ovarian teratoma. The characteristic clinical syndrome of a poly-symptomatic encephalopathy affects both adults and children, with around 40% of the patients presenting at less than 18 years of age.
Most patients develop at least 3 of the following groups of symptoms within 1 month of disease onset: psychiatric features, memory disturbance, speech disorder, seizures, dyskinesias, decreased level of consciousness, autonomic instability, or hypoventilation. There may be seasonal variability in non–tumor-related pediatric NMDAR antibody encephalitis, with 78% presenting in the warmer months of April to September.
The behavioral changes are age dependent; younger children develop new-onset temper tantrums, whereas agitation, aggression, and changes in mood or personality predominate in older children. Many parents also report changes in speech, including reduced speech, mutism, echolalia, or perseveration. On occasions, the cognitive regression may be accompanied by a loss of social and communication skills, mimicking an autistic spectrum disorder. Infants and young children may present with more neurologic (eg, seizures, movement disorder) than psychiatric symptoms, but psychiatric symptoms may go under recognized in the young. Autonomic features and hypoventilation are less frequently reported in children.
Despite the severity of the encephalopathy, with 69% of the patients being admitted to intensive care, the neuroimaging is normal in most patients. When abnormal, MRI usually reveals discrete lesions in white and/or gray matter that are predominantly subtle (see Fig. 1 ), nonenhancing, and often reverse spontaneously. Similarly, the CSF analysis reveals only moderate lymphocytic pleocytosis, with normal protein concentration, but can be normal. Intrathecal oligoclonal bands are present in up to 60% of patients but not necessarily at the onset of the disease.
The electroencephalogram (EEG) is encephalopathic in the majority, with generalized rhythmic delta activity with or without epileptic discharges. Extreme delta brush is a continuous EEG pattern that may be unique to some patients with NMDAR antibody encephalitis and, when found, can be a clue to the diagnosis. Early electro-clinical features may also correlate with severity; persistence of normal physiologic background activity in at least one hemisphere is suggestive of moderate severity and better outcomes, whereas diffuse abnormalities, with lack of physiologic background activity, indicate severe neurologic impairment and poor prognosis.
Despite the widely reported initial excellent response to immunotherapy, children are often left with residual deficits. Of the 211 children reported in a comprehensive mainly retrospective multicenter study of 577 patients with NMDAR antibody encephalitis, only 60% made a full recovery at the 2-year follow-up. In that study, concomitant and early use of intravenous steroids and intravenous immunoglobulins and/or plasmapheresis (deemed first-line therapy) was effective in achieving control of symptoms and remission, with additional benefits of second-line therapy, such as rituximab and cyclophosphamide, when first-line therapy failed or was partially effective. Additionally, in a recent international study on the utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease, the prompt use of second-line therapy (rituximab) within 4 weeks of diagnosis was found to be beneficial in NMDAR antibody encephalitis. Relapses were noted in 12% to 25% of patients, with risk factors including lack of immunotherapy at the first episode and absence of a tumor diagnosis. Predictors of a good outcome included early administration of therapy and avoidance of an intensive care admission. Thus, it seems that early diagnosis and immunotherapy at first presentation reduces the chance of relapses and improves neurologic outcomes.
N-methyl d -aspartate receptor antibody mediates neurologic relapse following herpes simplex encephalitis
Neurologic relapse in the weeks or months following primary herpes simplex encephalitis (HSVE) is well described in children and adults as reviewed by Hacohen and colleagues. In a subset of children presenting with biphasic illness, the second stage was characterized by predominant movement disorder but negative CSF herpes simplex virus polymerase chain reaction and stable brain MRI findings. The clinical characteristics of these relapses resembled the acute stages of NMDAR antibody encephalitis and were associated with NMDAR antibodies and, less commonly, dopamine-2 receptor and other unidentified neuronal surface targets. Importantly, in the handful of previous cases of relapsing HSVE, when the immunotherapy used was of adequate intensity and duration, a benefit was reported. However, the eventual outcomes are likely to be confounded by the sequelae of the initial infective encephalitis. Intriguingly, the immune response to NMDAR may preexist or begin very early in the HSVE; variable classes (IgG, IgA, and IgM) and levels of NMDAR antibodies were reported in 13 out of 44 (30%) adults with HSVE.
Limbic Encephalitis
Voltage-gated potassium channel–complex antibody-mediated encephalopathy
VGKC-complex antibody-associated CNS diseases, as measured by antibodies that immunoprecipitate 125I-α-dendrotoxin-labeled VGKC extracted from mammalian brain tissue, have been detected in patients with limbic encephalitis (LE), Morvan syndrome, neuromyotonia, and cases of adult-onset epilepsy. Associated neoplasms have been found in less than 10% (most often thymomas); patients respond well to immunotherapy, with substantial and sometimes complete recovery. However, it is now clear that the VGKC-complex antibodies in LE are mainly directed at neuronal proteins that are complexed with the VGKCs in situ. These proteins include the secreted synaptic protein leucine-rich glioma inactivated 1 (LGI1) and the transmembrane axonal protein contactin-associated protein 2 (CASPR2). Antibodies to LGI1 (LGI1-Abs) are frequent in adult limbic encephalitis, and CASPR2-antibodies (CASPR2-Abs) are more common in patients with peripheral nerve hyperexcitability, including the rare Morvan syndrome.
In adults the most commonly associated phenotype is LE, presenting with seizures, amnesia, limbic changes on MRI imaging ( Fig. 1 ), and frequently low sodium levels. Children with VGKC-complex antibodies can present with limbic encephalitis but much less frequently than adults. The clinical phenotypes associated with VGKC-complex antibodies in children are very broad and includes both epilepsies (summarized in Hacohen and colleagues, 2013; see also Table 1 ) and some children with acute demyelination syndromes. In most pediatric cases, the antibodies to the recognized VGKC-complex proteins are not found (Hacohen, Lim, and Vincent, submitted for publication, 2015), suggesting that most of the sera bind to novel autoreactive targets within the VGKC-complex. These targets could include intracellular epitopes on the VGKC subunits or other components of the complexes, and may sometimes be secondary to other disease mechanisms. For instance, in a study of 39 children with a range of different presentations, high levels of VGKC-complex antibodies were only found in children with neuroinflammatory diseases, suggesting that they may occur secondary to other inflammatory CNS mechanisms (Hacohen, Lim, and Vincent, submitted for publication, 2015).
Other antibody-mediated limbic encephalitides
Three other neuronal cell-surface antibodies have been associated with limbic encephalitis. Antibodies to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), γ-aminobutyric acid B receptor (GABAbR) or GABAaR, and metabotropic glutamate receptors (mGluR), are briefly described focusing on the pediatric aspect of presentation ( Table 1 ). Antibodies against intracellular antigen, such as thyroid peroxidase (TPO) and the intracellular synaptic proteins glutamic acid decarboxylase (GAD65) and amphyphysin, have also been reported in patients with LE; but the pathogenic potential of the antibodies is not established, and most adult patients with these antibodies do not show good immunotherapy responses. There are occasional case reports of children with GAD65 antibodies who benefit from immunotherapies. These forms of LE are also briefly outlined in Table 1 .
| Antibody | Clinical Presentations | Specific Features | Disease Course |
|---|---|---|---|
| NMDAR |
|
|
|
|
|
| |
|
|
| |
| AQP4 |
|
|
|
| MOG |
|
|
|
| VGKC- complex |
|
|
|
| LGI1 |
|
|
|
| CASPR2 |
|
|
|
| Contactin- 2 |
|
|
|
| D2R |
|
|
|
| GlyR |
|
|
|
| GABAbR |
|
|
|
| GABAaR |
|
|
|
| DPPX |
|
|
|
| mGluR1 |
|
| |
| mGluR5 |
|
|
|
| AMPAR |
|
|
|
| GAD65 |
|
|
|
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