Autoimmune Encephalitis in Children: From Suspicion to Diagnosis

There are several well-described and studied autoimmune diseases that affect different organ systems, and a limited number of these affect the central nervous system. Autoimmune encephalitis represents a disease with a wide spectrum of clinical manifestations and different levels of severity, from mild cognitive impairment to complex encephalopathy. Immune-mediated encephalitis refers to a diverse and rare group of conditions in children associated with nonspecific symptomatology, altered mental state, and recalcitrant seizures. Infectious etiology must be excluded. Immune-mediated encephalitis syndromes could be associated with paraneoplastic or primarily autoimmune mechanisms. The newest scientific advantages have concluded that autoimmune encephalitis may be further divided into different groups of diseases depending on the immune response; examples are antibodies to cell surface proteins, antibodies to intracellular synaptic proteins, T-cell response with antibodies to intracellular antigens, among others. Treatment consists of supportive therapy, ranging from supplemental oxygen, fluid restriction to mechanical circulatory support. Specific treatment includes immunoglobulin infusion, plasmapheresis, and pulse steroid treatment. Prognosis is poor if specific treatment is not timely instituted. The diagnosis of autoimmune encephalitis could be challenging to clinicians due to its diverse clinical features, which can mimic a variety of other pathologic processes. Screening for cancer and proper management that includes immune therapy are fundamental, although some patients will need immune suppression for weeks or months as autoimmune encephalitis may relapse; therefore, follow-up is always necessary.


Introduction And Background
Encephalitis is an inflammatory condition of the brain with multiple etiologies [1][2]. Autoimmune encephalitis syndromes (AESs) describe a basket of encephalitis entities associated with antibodies against the neuronal cell surface or synaptic proteins [2][3][4]. The target antigens usually play critical roles in synaptic transmission and plasticity. AES may occur in the presence or absence of malignancy, including the classic paraneoplastic encephalitis syndromes associated with antibodies against intracellular neuronal proteins (onconeuronal proteins). Beyond infections, AESs are the largest group of encephalitis in children [5][6][7][8][9].
Clinically, AESs have a wide clinical spectrum that ranges from typical limbic encephalitis to syndromes with complex neuropsychiatric symptoms such as deficits of memory, cognition, psychosis, seizures, abnormal movements, or coma. While patients are often severely affected, these disorders are highly responsive to immunomodulatory therapies. AES is often associated with significant mortality and morbidity [1,6,[10][11][12][13]. This paper provides an overview of current approaches to the diagnosis and management of autoimmune (antibody-mediated) encephalitis.

Review Classification
The exact classification of immune-mediated encephalitides is challenging. Broadly, they are classified into syndromes or according to the exact antibodies ( Table 1).
Acute to subacute onset classic antibody-mediated paraneoplastic encephalitis syndromes include anti-Hu encephalomyelitis (small cell lung cancer, SCLC), Ma2-associated encephalitis (testicular cancer), and anti-collapsin-responsive mediator protein- 5 [5,14] Antibody-mediated anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a classic example of autoimmune encephalitis [14]. Anti-NMDA receptor encephalitis is the most common autoimmune form and is accompanied by ovarian teratoma in 58% of affected women 18-45 years of age [15]. Rasmussen's encephalitis is a rare inflammatory neurological disease, characterized by frequent and severe seizures, loss of motor skills and speech, hemiparesis, encephalitis, and dementia [16]. Affection is usually limited to one hemisphere and generally occurs in children under 15 years. Limbic encephalitis refers to inflammatory disease confined to the limbic system of the brain. The clinical presentation often includes disorientation, disinhibition, memory loss, seizures, and behavioral anomalies. Magnetic resonance imaging (MRI) imaging reveals T2 hyperintensity in the structures of the medial temporal lobes and, in some cases, other limbic structures. Tumor-associated limbic encephalitis is classified according to the autoantibody that causes the disease, including anti-Hu, anti-Ma2, and anti-NMDAR. Once considered an extremely rare disorder, almost always related to cancer and refractory to treatment, limbic encephalitis is now regarded as a relatively frequent disorder, often unrelated to cancer, and with clinical-immunologic variants that respond to treatment [17].

Epidemiology
Epidemiology varies with regions. Autoimmune encephalitis is responsible for a subset of altered mental status previously considered to be idiopathic [18]. The incidence rate of autoimmune encephalitis is estimated to be 0.8/100,000 person-years [19]. The incidence and prevalence of autoimmune encephalitis are higher among African Americans than Caucasians [19]. The prevalence and incidence of autoimmune encephalitis are comparable to infectious encephalitis, and early detection is improving over time. In children, AES is less frequently associated with tumors as compared with adults. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and acute disseminated encephalomyelitis (ADEM) are the most frequently described forms of autoimmune encephalitis in children. In one study of 103 children with AES, 19 children had anti-NMDAR encephalitis and 34 children had ADEM [20].

Etiopathogenesis
ADEM, or acute demyelinating encephalomyelitis, is a rare autoimmune disease that is often triggered by a viral infection and characterized by marked inflammation of the brain and spinal cord [20]. ADEM also attacks the axons of the central nervous system and damages their myelin insulation with resultant white matter injury. Autoimmune encephalitis most common target antigens located in the limbic system [4]. The inflammatory changes produce T2 and fluid-attenuated inversion recovery (FLAIR) hyperintense signal abnormalities in the temporal lobes and limbic structures and T2-weighted hyperintense signal changes on brain MRI [4]. Paraneoplastic disorders are associated with an immune response to antigens in tumor cells and native neuronal cells, which results in an antibody-mediated attack on previously immuneprivileged neuronal structures. Paraneoplastic syndromes are most often seen in small-cell lung cancer.

Clinical manifestations
Typically, children with AES are previously healthy and present with acute or subacute onset of neuropsychiatric symptoms [21]. In contrast, the onset is almost always rapid in adults. Prodromal symptoms, such as fever and headaches, occur in over 50% of children [21]. The clinical manifestations of AES are dictated by the specific location of the underlying immune response within the nervous system, which leads to substantial variability. Autoimmune encephalitis is an important cause of new-onset altered mental status, such as memory loss, cognitive dysfunction, and behavioral changes, such as repetitive or stereotypical behaviors; the scope of which has only recently begun to be recognized in the medical literature [2,14]. Clinical manifestations depend on the underlying etiology of the AES and the specific site of involvement and include catatonia, psychosis, abnormal movements, autonomic dysregulation, dysphagia, dysarthria, nystagmus, opsoclonus, vertigo, sensorineural deafness, trigeminal sensory loss, excessive daytime sleepiness, insomnia, tremor, ataxia, dyskinesia, myoclonus, chorea, dystonia, stiffperson syndrome, stupor, confusion, seizures, and coma [4][5]14]. Affected patients may have autonomic dysfunction manifested as bradycardia, tachycardia, dysrhythmia, labile blood pressure, central hypoventilation, and hyperthermia.

Laboratory investigations and imaging
Patients with suspected paraneoplastic or autoimmune encephalitis should have brain imaging, electroencephalography (EEG), lumbar puncture, and serologic testing for appropriate biomarkers to confirm the diagnosis and exclude alternative etiologies.
A brain magnetic resonance image (MRI) is helpful to exclude a cerebrovascular event or metastatic disease. Characteristic MRI findings in patients with paraneoplastic or autoimmune encephalitis include signal hyperintensities on fluid-attenuated inversion recovery (FLAIR) or T2-weighted images in medial temporal lobes and/or brainstem; subcortical regions and the cerebellum are sometimes affected. Contrast enhancement is variable. Although MRI findings are neither sensitive nor specific for these disorders, in the appropriate clinical setting they can be highly suggestive of specific syndromes [22][23].
An EEG should be performed to exclude nonconvulsive seizures in patients with paraneoplastic and autoimmune encephalitis. Nonspecific EEG abnormalities include focal or generalized slowing, epileptiform activity, and lateralized periodic epileptiform discharges (LEDs) previously known as (PLEDs) [24]. Approximately one-third of patients with anti-NMDAR encephalitis have an EEG pattern called extreme delta brush that is considered characteristic of the disorder [24].
Patients with paraneoplastic and autoimmune encephalitis may have normal or abnormal cerebrospinal fluid (CSF) findings. Abnormalities include modest elevation of protein (<100 mg/dL), mild to moderate lymphocytic pleocytosis, elevated immunoglobulin G (IgG) index, and/or the presence of oligoclonal bands [5]. Metabolic and toxic encephalopathies should also be considered and excluded. If the patient does not have a known cancer diagnosis, evaluation for occult malignancy should ensue. Paraneoplastic and autoimmune antibody testing should be performed on both serum and cerebral spinal fluid CSF to avoid false-positive and false-negative results [25]. Broadly, two types of antibodies are involved ( Table 2). Identification of these antibodies aids diagnosis, management, and prognostication. However, their absence may not refute the diagnosis. Many more novel autoantibodies are discovered with time and advances in laboratory technologies. Not all of these antibodies or biomarkers have commercially available testing, and some antigens remain to be characterized. Thus, negative results do not exclude a paraneoplastic or autoimmune disorder [25]. The diagnosis of encephalitis is based on a decreased or altered level of consciousness, lethargy, or personality change for at least 24 hours without any other explainable cause [23]. A definitive etiologic diagnosis may not always be possible [6,13,22,26]. MRI neuroimaging is an essential aspect of evaluation [4,13]. Autoimmune encephalitis remains a diagnosis of exclusion. Recognition of the potential causes of autoimmune encephalitis by the radiologist can be the first step to optimizing clinical outcomes through ensuring that prompt and appropriate clinical workup is performed, including the use of specialized serum/cerebrospinal fluid (CSF) antibody panels, with the ultimate goal of establishing an effective treatment regimen before the onset of devastating complications. The recent consensus statement of the international encephalitis consortium serves as a practical aid to clinicians evaluating patients with suspected encephalitis [13][14]27].

Diagnosis
Criteria for diagnosing paraneoplastic disorders and a clinical approach to the diagnosis of the AES have been developed [4,17]. Diagnostic criteria for paraneoplastic limbic encephalitis included (i) short-term memory loss, seizures, or psychiatric symptoms; (ii) <4 years between symptom onset and cancer diagnosis; (iii) exclusion of metastases, infection, metabolic, or other causes; and (iv) one of the following findings: inflammatory CSF changes, electroencephalogram abnormality in the temporal lobes, or temporal lobe T2 or FLAIR hyperintensity on MRI [4,17].

Treatment
Tumor screening and treatment are essential to proper management. As autoimmune encephalitis may relapse, follow-up care is important [22]. Patients with autoimmune encephalitis are usually critically ill and managed in the intensive care unit [28]. Immunosuppressive therapy is the cornerstone of treatment. The use of immunosuppressive therapy should be prompt and should not wait for the cancer diagnosis or antibody characterization, provided an underlying infectious etiology has been excluded and there are no other contraindications [28]. The results of antibody testing can then be used to refine or alter the treatment strategy.
The neuronal damage in classical paraneoplastic encephalitis syndromes is T-cell-mediated, rapid-onset, and largely irreversible [29]. Thus, these patients often have limited neurologic recovery even with optimal treatment. The best chance for symptom stabilization or improvement appears to be the early identification and treatment of the tumor and the use of immunotherapy (such as glucocorticoids, intravenous immunoglobulin (IVIG), and plasmapheresis) [28][29]. High-dose corticosteroids are often the first line of treatment and can be given either intravenously or orally [22,30]. IVIG can be used as monotherapy but is more often used after or in combination with high-dose corticosteroid [31]. Likewise, plasma exchange has a synergistic effect when used in combination with corticosteroids [31]. A systematic review of 71 articles (n = 242) on plasma exchange in pediatric anti-NMDAR encephalitis showed a trend toward better outcomes when plasma exchange was administered early and when given in combination with corticosteroids [32]. Cyclophosphamide and rituximab are often used as second-line immunosuppressive therapy. Mycophenolate or azathioprine can be used as a steroid-sparing agent [30].
The autoimmune encephalitis syndromes are often responsive to immunomodulatory therapies, as the associated antibodies are pathogenic and reversibly affect the target antigens [2]. Thus, treatment should aim at antibody depletion and immunosuppression. Specific protocols are not yet validated. Treatment should be individualized taking into consideration the age of the patient, the severity of the disease, and whether an underlying malignancy is present. The response to treatment should be based on clinical evaluation. Seizures should be treated aggressively with antiseizure drugs. Recovery is usually slow but most patients will not require long-term antiseizure drug therapy [2,18]. Powerful immune suppression for weeks or months may be needed in difficult cases. Intensive care support should be provided if necessary.

Prognosis
Early and aggressive treatment for AES leads to better prognostic outcomes [14,18,33]. The various antibodies causing the autoimmune response can result in varying symptoms and respond widely in terms of prognosis ( Table 2). About half of patients with anti-NMDAR encephalitis show improvement within four weeks of receiving treatment and 80% of these patients eventually have partial or complete recovery. Some patients took up to 18 months to recover. While anti-NMDAR is the most studied of the antibodies, the treatment for autoimmune encephalitis is generally similar. In some cases, the damage to the brain is irreversible. A 2019 systematic review of 44 research articles (n = 2823) describing prognosis in AES showed that delay in immunotherapy contributed to a variety of worse outcomes for patients with different subsets of AES [34]. No use of immunotherapy, altered consciousness, and intensive care unit admission were variables associated with poor prognosis in anti-NMDAR [34].