Neurobiology of autoimmune encephalitis with anti-N-methyl-D-aspartate receptor (NMDAR) antibodies in children

Neurobiology and biochemistry of anti-N-methyl-D-aspartate receptors, encephalitis-related

The N-methyl-D-aspartate (NMDA) receptor is an ionotropic glutamate receptor that mediates excitatory neurotransmission in the mammalian brain. These receptors localize to the postsynaptic terminal and allow for the influx of sodium and calcium, which are essential for the synaptic transmission of neuronal activity. The anti-N-methyl-D-aspartate receptor (anti-NMDAR) antibody is present on the surface of hippocampal neurons and their processes⁽¹⁾. It specifically reacts with the NR1 subunit of the NMDA receptor. The antibody is present at a relatively higher titer in the cerebrospinal fluid (CSF) than in serum, suggesting intrathecal synthesis, and there appears to be an interrelationship between the CSF titer and the severity of neurologic symptomatology⁽²⁾. The NMDA receptor is one of three ion channel glutamate receptors at the post-synaptic excitatory synapse. The other two NMDA receptors are the AMPA receptor (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) and the kainite receptor⁽³⁾. However, the only biomarker widely used in clinical practice in anti-NMDAR encephalitis is the identification of IgG antibodies against the GluN1 subunit of the NMDAR in the cerebrospinal fluid, which are indispensable to attain a definite diagnosis⁽⁴⁾. Excitatory synaptic transmission in the central nervous system (CNS) is mediated by the release of glutamate from presynaptic terminals onto postsynaptic channels gated by N-methyl-D-aspartate (NMDA) and non-NMDA (AMPA and KA) receptors. Extracellular signals control diverse neuronal functions and are responsible for mediating activity-dependent changes in synaptic strength and neuronal survival. The influx of extracellular calcium ([Ca2+]e) through the NMDA receptor is required for neuronal activity to change the strength of many synapses. At the molecular level, the NMDAR interacts with signaling modules which, like the mitogen-activated protein kinase (MAPK) superfamily, transduce excitatory signals across neurons⁽⁵⁾.

Supposed disease mechanisms

The NMDA receptor (NMDAR) is a ligand-gated cation channel highly involved in synaptic transmission. NMDAR is structured into two heteromers, NR1 and NR2. NR1 primarily binds glycine, while NR2 binds glutamate. The synthesis of these heteromers leads to a receptor with complex functions, the overactivity of which leads to epilepsy, strokes and dementia, while the underactivity is presumed to cause schizophrenia⁽⁶⁾. As NMDA receptors are widely distributed across the brain, their blockade produces myriad effects. Anti-NMDA receptor antibodies mainly block the GABAergic neurons, indicating a disinhibition of the excitatory pathways and increased extracellular glutamate. The resulting frontostriatal syndrome is characterized by psychosis, catatonia, mutism and dystonia. The brainstem central pattern generator, which is normally inhibited by the GABAergic systems, is disinhibited, leading to orofacial dyskinesias and the involuntary movements of the limbs and trunk. The ubiquitous presence of NMDAR in the dopaminergic, cholinergic and noradrenergic systems and the resultant hypofunction may explain the dysautonomia. Finally, a direct effect of the antibodies on the nucleus of Kölliker-Fuse or the pontomedullary respiratory network could explain the respiratory dysfunction⁽⁷⁾.

Epidemiology

Recent data provided insights into the likely burden of “encephalitic illness”. Of 203 patients with an encephalitic illness, 42% had an infectious cause (including 19% with herpes simplex encephalitis, 5% with varicella encephalitis, and 5% with Mycobacterium tuberculosis), 37% were of “unexplained encephalitis”, and 21% had immune-mediated encephalitis (IME). Of the last category, 11% were diagnosed with acute disseminated encephalomyelitis (ADEM), while 9% had other autoimmune causes. Among this subgroup, 1% of the patients were diagnosed with anti-NMDAR encephalitis⁽⁸⁾.
 

Diagnosis and clinical presentation

The clinical aspect of autoimmune encephalitis (AE) is heterogeneous and depends on the damaged brain area. More areas may be affected at the same time, responsible for different combinations of symptoms, some of which can be grouped into clinically recognizable syndromes⁽⁹⁾. The onset of symptoms can be subacute (less than three months), and may occur after events like infections, fever or traumas⁽¹⁰⁾.

The diagnosis of AE in children can be difficult because of the diversity of the presenting characteristics and extensive differential diagnosis⁽¹¹⁾. A multidisciplinary approach is imperative, including consultations between neurologists, rheumatologists, psychiatrists and infectious disease specialists. In children, the differential diagnosis consists of infection, vascular etiologies, demyelinating disorders, metabolic and/or mitochondrial disorders, malignancies, drug intoxications, neurorheumatologic disorders, genetic leukoencephalopathies, and psychiatric disturbances. Infection should be specifically controlled promptly, as immunotherapies used in autoimmune encephalitis could worsen an infectious process. For children with a high clinical suspicion of autoimmune encephalitis (children presenting with all three of the major cli­nical features of AE), a full workup, including serologic, cerebrospinal fluid, neuroimaging, and elec­tro­encephalography (EEG if indicated) evaluation, is recommended. EEG may be considered clinically indicated in patients with profound encephalopathy, abnormal movements, or paroxysmal events or behaviors suggestive of seizure activity.

Major presentation characteristics:

1. Seizures
2. Movement disorder
3. Behavioral change/psychosis.

Minor presenting characteristics:

1. Dysautonomia
2. Speech changes or focal neurologic deficit
3. Memory disruptions
4. Decreased level of consciousness.

Possible signs of neuroinflammation:

1. MRI with cortical T2 hyperintense lesions suggestive of encephalitis
2. Abnormal EEG
3. CSF pleocytosis.

The diagnostic approach requires the following four criteria be met: (1) rapid progression (over less than three months) of alteration in mental status, psychiatric symptoms, or memory loss; (2) exclusion of well-defined AE syndromes (ex.: Bickerstaff encephalitis, ADEM)⁽¹²⁾; (3) absence of well-known autoantibodies in the serum and CSF, and at least two of the following: (a) MRI findings suggestive of AE, (b) CSF with pleocytosis or oligoclonal bands, (c) brain biopsy showing CNS inflammation; and (4) exclusion of alternate diagnostics⁽¹³⁾.

Immunoserological and cerebrospinal fluid analysis

Systemic infection, neuroinflammatory and neurorheumatologic conditions, metabolic and mitochondrial conditions, and drug ingestion/toxic risks are susceptible, mimicking autoimmune encephalitis, and should be detected with specific laboratory testing. Particularly, serum MOG (myelin oligodendrocyte protein) and AQP-4 (aquaporin 4) antibody testing should be performed, as these antibodies can coincide with NMDAR antibodies. This pre-clinical laboratory testing panel should be controlled as well during the evolution of the disease and adapted/readapted specifically to the patient. For a decisive diagnosis, both serum and CSF AE antibody panels should be performed. CSF testing is more sensitive than serum testing, except in the case of MOG and LGI-1 (leucine-rich glioma-inactivated 1) antibodies, where serum detection is more sensitive. CSF laboratory investigation shows pleocytosis and high protein amount, frequently with a lymphocytic predominance; however, normal CSF does not exclude a diagnosis of autoimmune encephalitis⁽¹⁰⁾.

Imagistic and electrophysiological investigations

Neuroimaging is often normal in autoimmune encephalitis, but if abnormalities are detected, they reveal a generally nonspecific pattern. More than 50% of children with autoimmune encephalitis will have normal magnetic resonance imaging (MRI)⁽¹⁴⁾. Neuroimaging is usually advantageous to rule out AE mimics such as vasculitis, demyelinating syndromes, stroke, or malignancy. Electroencephalography (EEG) is sufficient for an electrophysiological investigation. EEG traces in pediatric autoimmune encephalitis are often abnormal, although nonspecific. EEG findings are more expected to be generalized, and relatively focal in children than adults. In children with AE, extreme delta brush, characterized by rhythmic delta-asynchrony activity with overriding fast modulation of beta frequencies, can be seen in up to half of children with NMDAR encephalitis⁽¹⁵⁾.

Therapeutic principles in autoimmune NMDAR encephalitis in children

Although autoimmune encephalitis can present with dramatic, life-threatening neuropsychiatric deficits, the potential for recovery with efficient treatment is notable. First- and second-line therapies for AE brings a clinical improvement in most patients, including full recoveries in many.

First-line therapy is represented by corticosteroids, methylprednisolone or dexamethasone, intravenous immunoglobulin, plasmapheresis, or plasma exchange.

Second-line therapy is represented by rituximab and cyclophosphamide, though one anti-metabolite agent – mycophenolate mofetil and azathioprine. Second-line therapy can be started in hospitalized patients, if there are no signs of clinical improvement within 10-14 days of first-line therapy.

Adjuvant therapy: auxiliary to immunotherapy, continuing symptomatic treatment with anti-epileptic drugs, and psychiatric medications are essential to maximize functionality and minimize suffering. Benzodiazepines, often at high doses, are frequently used early in the course of disease for agitation, seizures and catatonia. Catatonia is a prominent characteristic in many children with autoimmune encephalitis, and differentiating it from psychosis and avoiding antipsychotic medications in those cases can avoid precipitating the neuroleptic malignant syndrome^(16,17).

Conclusions

Understanding the global molecular mechanisms of a disease leads to a better deepening and approach, from the point of view of investigations and therapeutic conduct. The principles of treatment have been briefly listed, not being the main purpose of this article. The multidisciplinary problem raised by the approach to this neurological disease in children requires the consultation of other specialists from related fields. Anti-NMDR autoimmune encephalitis remains a challenge both for established researchers in the field and for clinicians who mainly deal with this group of autoimmune diseases with neurological impact.  

Autor corespondent: Bogdan-Marius Istrate E-mail: istratem.bogdan@yahoo.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.