Pediatric Autoimmune Encephalitis

Abstract

Autoimmune (antibody mediated) encephalitis (AE) is emerging as a more common cause of pediatric encephalopathy than previously thought. The autoimmune process may be triggered by an infection, vaccine, or occult neoplasm. In the latter case, onconeural autoantibodies are directed against intracellular neuronal antigens, but a recent heterogeneous group of encephalitic syndromes has been found not to have underlying tumor but is associated with autoantibodies to the neuronal surface or synaptic antigens. Neuropsychiatric symptoms are very common in autoimmune encephalopathy; as a result, affected children may be initially present to psychiatrists. Neurological features are movement disorders, seizures, altered conscious level, and cognitive regression. Hypoventilation and autonomic features may be an aspect. Inflammatory findings in the cerebrospinal fluid may be present but are relatively nonspecific. Magnetic resonance imaging (MRI) may also demonstrate abnormalities that provide clues for diagnosis, particularly on fluid-attenuated inversion recovery or T2-weighted images. AE is well responsive to immune therapy, with prompt diagnosis and treatment strongly beneficial. Patients with paraneoplastic encephalitis are more refractory to treatment compared to those in whom no malignancy is identified. Herein, the authors present an update of literature data on the clinical presentation, laboratory and imaging findings, therapy, and outcomes for the most common autoimmune encephalitides.

INTRODUCTION

Autoimmune encephalitides (AE) are more frequent of individual viral etiologies, but the exact prevalence of individual disorders remains largely unknown.[1] In pediatric ages, AE usually occurs in females, as in adults, less probable with a cancer association (more common in adults), and a history of other antibody-mediated condition is frequent. Several antibodies have been demonstrated to be associated with paraneoplastic and nonparaneoplastic neurological syndromes, divided into three groups: (1) antibodies to intracellular antigens; (2) to cell-surface antigens; (3) to extracellular synaptic antigens.

PEDIATRIC AUTOIMMUNE ENCEPHALITIDES WITH ANTIBODIES TARGETING NEURONAL CELL-SURFACE ANTIGENS

Anti-N-Methyl-D-aspartic acid encephalitis

First described in 2007,[2] it is the most frequent and best characterized AE. Autoantibodies of IgG subclass G1 bind the extracellular domain of the GluN1 subunits of the N-Methyl-D-aspartic acid receptor (NMDAR), with its internalization, resulting in the surface underexpression.[3] Herpes simplex virus encephalitis (HSVE) is an important trigger for anti-NMDAR encephalitis. The so-called post-HSVE choreoathetosis in children is confirmed now as post-HSVE anti-NMDAR encephalitis.

The manifestations of anti-NDMAR encephalitis can be categorized into eight groups: abnormal behavior and cognition; memory deficit; speech disorder; seizures; abnormal movements (orofacial, limb, or trunk dyskinesias); loss of consciousness or autonomic dysfunction; central hypoventilation;[4] cerebellar ataxia or hemiparesis. Fever and headache are prodromal symptoms without specificity. In children, behavior problems, seizures, and movement disorders are most common.

Electroencephalogram (EEG) is abnormal, typically showing focal or diffuse slowing and/or epileptiform discharges. An EEG pattern known as extreme delta brush has been described in anti-NMDAR encephalitis and may support the diagnosis.[5]

Brain magnetic resonance imaging (MRI) demonstrates abnormalities in less than half of all pediatric patients,[6] including cortical and/or subcortical, basal ganglia, and infratentorial T2 hyperintensities with or without transient meningeal enhancement. Rarely, children with a demyelinating pattern have been reported.[7]

Pathogenic anti-NMDAR autoantibodies can be present both in serum and cerebrospinal fluid (CSF), with the latter a more sensitive detection. The CSF antibody titers correlate strongly with the clinical disease course and remain elevated in those who experience a relapse or do not show primary clinical improvement.[8]

Anti-NMDAR antibodies production can be stimulated by an underlying tumor and the most frequently associated is ovarian teratoma that must be removed for optimal recovery. Prompt immunotherapy improves patient outcome.[9]

The prognosis is often good in pediatric age, with 85% of full but slow recovery (up to several months) and relapse in the remaining 15%.

Encephalitides with leucine-rich glioma-inactivated 1 and contactin-associated protein-like 2 antibodies

These disorders were previously attributed to antibodies to voltage-gated potassium channels (VGKCs), but the true target antigen has been shown to be its tightly associated neuronal proteins leucine-rich gliomas-inactivated 1 (LGI1) and contactin-associated protein-like 2 (Caspr2). In these encephalitides, high titer of VGKC-complex antibodies may be present; although this finding is not relevant, in consideration that it is a not specific marker of inflammatory neurologic affections.

LGI1-AE shows a limbic syndrome (confusion, working memory deficit, mood changes, and often seizures), hyponatremia, and occasional faciobrachial dystonic seizures; in Caspr2 - AE Morvan syndrome and neuromyotonia may be present. In adult, some cases are paraneoplastic and the most common associated tumor is thymoma; however, there are currently no published reports of childhood neoplasm in these encephalitides.

CSF is often normal or only shows oligoclonal bands. MRI may demonstrate increased T2/fluid-attenuated inversion recovery (FLAIR) signal in the mesial temporal lobe as limbic encephalitis.

Immune therapy response is optimal.[10]

Anti-glycine receptor encephalitis

The activation of postsynaptic Glycine receptors (GlyRs) cause an influx of chloride ions into the cytoplasm, mediating neuronal inhibition. Autoantibodies to the α1 subunit of GlyR have been reported in only a few childhood cases as a syndrome of progressive encephalomyelitis with rigidity and myoclonus or an atypical stiff person syndrome.[11,12] Literature data show that this type of encephalitis is usually not paraneoplastic. Response to immunotherapy is variable.

Anti-gamma-aminobutyric acid type A receptor encephalitis

Gamma-aminobutyric acid type A (GABA_A) receptors are postsynaptic and mediate neuronal inhibition. A small number of pediatric patients are described in literature with clinical presentation of seizures or status epilepticus. The CSF often shows pleocytosis with increased protein. Unlike other cause of AE, in which the MRI is normal or shows abnormalities limited to the limbic system, the MRI in GABA_A receptor encephalitis often shows multifocal and widespread FLAIR and T2 signal abnormalities. The disease is rarely paraneoplastic.

Anti-gamma-aminobutyric acid type B receptor encephalitis

GABA_B are receptors linked through G-proteins to potassium channels. This type of encephalitis has been reported in a few adolescent females presenting with limbic syndrome and seizures. Half of adult cases have an associated small cell lung carcinoma. The response to immunotherapy is good. MRI FLAIR and T2 signal abnormalities are frequent as well as a lymphocytic pleocytosis in the CSF.

Anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor encephalitis

Autoantibodies targeting the glutamate receptor 1 (GluR1) or GluR2 subunits of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) result in internalization of the receptor and encephalitis. To date, 35 patients (mostly adults) with this type of encephalitis have been described, the majority of which associated with underlying neoplasm (breast, thymus, and lung). Two reported cases of pediatric anti-AMPAR encephalitis manifested with limbic syndrome.[13] A lymphocytic pleocytosis in the CSF and FLAIR signal abnormality in the medial temporal lobes is almost always present. The response to immunotherapy and neoplasm treatment is good, but relapse has been reported in adult cases.

Ophelia syndrome

Limbic encephalitis associated with antibodies against the metabotropic GluR5, which is abundantly expressed within the hippocampus, has been described in patients with Hodgkin's lymphoma. The clinical spectrum is of limbic encephalitis.[14]

Anti-dopamine D2 receptor encephalitis

The dopamine D2 receptor (D2R) modulates dopaminergic transmission. Anti-D2R antibodies have discovered in cases of pediatric basal ganglia encephalitis[15] and Sydenham's chorea. The clinical presentation included lethargy, psychiatric symptoms, and abnormal movements (dystonia, parkinsonism, chorea, or ataxia). MRIs showed T2/FLAIR hyperintensities within the basal ganglia in half of the D2R-positive cohort, but EEG was typically normal.

PEDIATRIC AUTOIMMUNE ENCEPHALITIDES WITH AUTOANTIBODIES TARGETING INTRACELLULAR ANTIGENS

In contrast to encephalitides associated with neuronal surface antigens that underline an antibody/complement-mediated immune response, encephalitides associated with intracellular antigens appear to be associated with T-cell-mediated neuronal cytotoxicity. These encephalitides typically show a poor response to immunotherapy and a poor outcome, with refractory epilepsy and/or cognitive impairment. It may be explained by the T-cell-mediated cytotoxicity, in conjunction with the intracellular antigenic location. Hence, early utilization of immunotherapeutic agents that primarily target T-cell populations is recommended.

Anti-Hu encephalitis

Antineuronal nuclear antibody type 1, also known as anti-Hu, is a marker of paraneoplastic autoimmunity associated with small cell carcinoma in adults. This autoantibody is directed to neuronal nuclei of central and peripheral nervous system. This type of encephalitis is not common in the pediatric age, in which the association with a neoplasm (most frequently a neuroblastoma) is rare. In children, the clinical presentation is of limbic encephalitis.

Anti-Ma2 encephalitis

Ma2 (also referred to as Ta) is an intracellular neuronal protein. In adult, anti-Ma2 encephalitis is associated with testicular germ cell tumor, while only few childhood cases are reported in literature. Hence, in pediatric age, the likelihood of an autoimmune, rather than paraneoplastic, origin appears to be higher. Pediatric cases presented with subacute onset of focal seizures, behavioral changes, speech disturbance, and dystonia.[16,17] MRI abnormalities are frequent in the limbic system, diencephalon, and brainstem. Inflammatory changes were typically present in the CSF.

Anti-glutamic acid decarboxylase encephalitis

Glutamic acid decarboxylase (GAD) is an intracellular enzyme responsible for the synthesis of the inhibitory neurotransmitter GABA. Anti-GAD antibodies have diverse clinical correlates, including stiff person syndrome, cerebellar degeneration, autoimmune epilepsies, limbic encephalitis, and type 1 diabetes. Pediatric patients with high titers of anti-GAD in the CSF have manifested with focal seizures (often arising from the temporal lobe), cognitive and memory decline, progressive developmental delay, and psychiatric symptoms. The CSF may appear normal or with the presence of oligoclonal bands. The MRI and EEG may show abnormalities arising from the limbic structures. Patients with anti-GAD antibodies usually do not have underlying tumors.

EVALUATION

AE should be considered in any child with acute or subacute encephalopathy.[18] Children with clinical presentation of AE will have neuroimaging, EEG, lumbar puncture, and serologic testing for appropriate biomarkers. CSF testing for IgG GluN1 (NMDA subunit) antibodies, as just said above, has been shown to be more sensitive than serologic testing. Unfortunately, antibody testing laboratories are not easily accessible in many institutions, commercial kits are not often updated to incorporate new or rare antigens, and results can take several weeks to obtain. Hence, negative results do not exclude an autoimmune disorder. A paraneoplastic cause is much less probable in children so that testing for onconeural antibodies (e.g., Hu or Ma2) can be not strictly necessary at first instance.

Traumas, central nervous system (CNS) infection, CNS vasculitis, CNS malignancies, toxic/drug ingestion, nonconvulsive status epilepticus, inborn errors of metabolism, and psychiatric conditions are differential diagnosis and must to be excluded while confirmatory autoantibody tests are being processed.

MRI findings are neither sensitive nor specific for AE. In children, FLAIR or T2 hyperintensities in medial temporal lobes, brainstem or, in some cases, subcortical regions, and cerebellum may be present. Gadolinium enhancement is variable.

An EEG should be performed to exclude nonconvulsive seizures. Not specific findings of AE are focal or generalized slowing, epileptiform activity and periodic lateralized epileptiform discharges, extreme delta brush pattern (anti-NMDAR encephalitis). A 24 h video-EEG recording may be useful.

CSF should be performed including cell count, protein, and glucose; studies to exclude viral infection and other pathogens should also be performed. In AE, CSF may be normal or abnormal, and in these cases, mild elevation of protein (<100 mg/dl) is the most common finding. A minority has a mild lymphocytic pleocytosis (<100 white blood cells/μL) or marked elevation of proteins. In children, elevated CSF neopterin can be used as an additional marker of CNS inflammation.

Evaluation for malignancy should also ensue (chest and abdomen/pelvis imaging).

Once the clinician highly suspects a diagnosis of AE or autoantibody testing is positive, immunotherapy should to be started as early as possible, after sufficiently ruling out infectious and oncologic entities; it is crucial to achieve a better outcome.

TREATMENT

Acute treatment

At present, no clinical trials have assessed the optimal treatment in AE. Accepted first-line therapy for every AE includes high-dose corticosteroids (methylprednisolone 30 mg/kg/day, up to 1 g daily, for 3–5 days), followed by or combined with IVIg (2 g/kg divided over 2–5 days). Steroids are then tapered using 1–2 mg/kg/day orally, on average for another 12 weeks, adjusting the dose according to patient tolerability or possible side effects. If no benefit is noticed, plasma exchange (PLEX), 3–5 exchanges over 10 days, should be considered.

If there is no significant clinical improvement after 10 days with these first-line therapies, second-line therapy (rituximab and/or cyclophosphamide) should be started. Rituximab (375 mg/m² every week for 4 weeks) is usually well tolerated in children and so is preferred to cyclophosphamide (750 mg/m^{2 mont} hly).

Intrathecal administration of methotrexate was reported to be effective in pediatric cases with anti-NMDAR encephalitis.[19] Thus, intrathecal immunotherapy might be a promising option for refractory cases since it may directly affect intrathecal antibody synthesis.

If an associated tumor is present, specific oncologic treatment is essential.

At seizure onset, antiepileptic therapy, with few exceptions, usually results ineffective.[20] Long-acting benzodiazepines, sedatives such as clonidine, and anticonvulsant drugs may be helpful in improving abnormal movements and mood instability. For psychiatric symptoms, sedative and sleep medications other than benzodiazepines seem to be the most effective, while antipsychotic drugs are less efficacious.

Chronic treatment

Chronic immunosuppression (e.g., mycophenolate mofetil, azathioprine) should be considered only in AE with a known risk for relapsing. To date, no formal studies have assessed the duration of adequate immunosuppression. Thus, risks versus benefits must be analyze and discuss with patients and their families.

CONCLUSION

Recognition, evaluation, and treatment of AE are growing in the last years. To facilitate early diagnosis, pediatricians need to maintain a high level of suspicion when evaluating children with new-onset seizures or encephalopathy since autoimmune encephalopathies likely remain underdiagnosed. The importance of considering autoimmune pathogenesis in the differential diagnosis of encephalitis is crucial, as early recognition and treatment may affect the outcome. Although the paraneoplastic origin is rare in childhood population, the presence of an underlying malignancy must be ruled out.

Formal, prospective, randomized controlled trials are needed to better determine the appropriate acute treatment approach to AE in pediatric age and to weigh the need for and/or benefits of long-term immunosuppression.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.