Typically, children with AE are previously healthy and present with rapid onset of neuropsychiatric symptoms. Prodromal symptoms including fever occur in over 50% of patients. Between disease onset and initiation of therapy, symptoms typically persist over time.
Neurologic manifestations of AE include altered level of consciousness, confusion, disturbed sleep, movement disorders and seizures. Seizures are the most common feature in AE and may be the predominant manifestation. Seizures may be focal or generalized and are often multifocal. Over one third of patients with AE have abnormal movements, such as ataxia, chorea, dystonia, myoclonus, or tremor. Both seizures and movement disorders can be highly refractory to standard treatments in children with AE. Some degree of cognitive impairment is seen in the overwhelming majority of AE patients and is considered a cardinal symptom.
Memory deficits (assessing in young children may be challenging), developmental regression, language loss or speech impairments may be presenting features of pediatric AE.
Behavioral changes, such as repetitive or stereotypical behaviors, irritability, hyperactivity, hypersexuality, insomnia and anger outbursts, are common in pediatric AE. Psychiatric symptoms may range from mood swings and mild personality changes to fulminant psychosis and occur in over 50% of AE patients. New-onset psychosis in children younger than 13 years is uncommon and considered a red flag for an underlying medical, rather than primary psychiatric, condition. It is critical to assess for cognitive changes, seizures, movement abnormalities, or other neurologic symptoms in children with acute psychiatric symptoms, as these symptoms are suggestive of AE.
Children with AE are more likely to present with multifocal neuropsychiatric symptoms, rather than isolated clinical syndromes. For example, children with GAD65 antibodies may not present with the classic stiff-person syndrome or cerebellar degeneration seen in adults.
Children with anti–NMDAR-associated encephalitis are more likely to present with movement abnormalities, agitation, insomnia, seizures, speech deficits, ataxia, and/or hemiparesis, whereas memory deficits, psychiatric manifestations, and central hypoventilation are more common in adults with the same antibody. Pediatric AE is less associated with tumors compared with adults.
Pediatric acute-onset neuropsychiatric syndrome (PANS) A Differential Diagnosis and AE Mimic
Patients often experience a relapsing-remitting course with rapid progression to maximum symptom severity and rapid return to previous function over hours or days, sometimes without therapy. Normal cognition.
Differences in work-up from AE and other disease processes
CSF neopterin is a useful but not rapidly accessible biomarker that is frequently elevated in anti-NMDAR encephalitis and other encephalitides, but normal in PANS.
A normal MRI lessens suspicion for CNS vasculitis, demyelinating diseases, infections, and malignancies. In contrast, restriction on diffusion-weighted imaging reduces the likelihood of pediatric AE and should prompt consideration of other etiologies, such as infection-associated encephalopathies and vasculitis.
A normal EEG is unusual in children with AE during active disease, although prolonged EEG may be needed for improved sensitivity. Therefore, focal or generalized seizures, epileptiform discharges, and encephalopathic changes, such as diffuse or focal slowing, may help to distinguish AE from primary psychiatric disorders or PANS.
Neurocognitive testing may identify deficits in memory, attention, problem solving, language, and processing speed, particularly in younger children. A change in neurocognitive function supports a diagnosis of pediatric AE and may differentiate these patients from those with primary psychiatric disorders. However, interpretation of neurocognitive testing at diagnosis should be undertaken with caution, as there is often no premorbid testing for comparison.
Other diagnostic tests may be considered. Most children with AE do not require brain biopsy. However, a targeted brain biopsy of MRI abnormalities may be needed when the diagnosis remains uncertain after initial workup. The diagnostic yield of brain biopsy is higher in pediatric patients than in adults.
When should a diagnosis be considered?
A diagnosis of pediatric AE should be considered in previously healthy children who present with acute or subacute (less than 3 months) onset of new focal or diffuse neurologic deficits, cognitive difficulties, developmental regression, movement abnormalities, psychiatric symptoms, and/or seizures. Although children with preexisting developmental delay or chronic behavior/psychiatric abnormalities may develop AE, alternative diagnoses, such as genetic, metabolic, or neurodegenerative etiologies, should be considered in these patients.
Children with a clinical presentation suggestive of AE should have serum and CSF examined for neuronal antibodies, undergo paraclinical testing for neuroinflammation, and have disease mimics excluded. EEG is not included as paraclinical evidence of neuroinflammation because EEG cannot differentiate AE from other encephalopathies. However, EEG encephalopathic features are allowable as an alternative for clinical features of encephalopathy. If a patient fulfills criteria for possible pediatric AE (table 4) and is functionally impaired, therapy may be started while awaiting the results of antibody and other testing, given the importance of early treatment to improve outcomes. If a patient with possible AE subsequently does not have positive antibodies or paraclinical testing for neuroinflammation, a diagnosis of AE is not supported. For these children, careful further consideration of the differential diagnosis is warranted, and additional immune therapy should only be undertaken with caution.
How Pediatric AE is Diagnosed ~ Algorithm for diagnostic workup of children with suspected AE
Differential Diagnoses to Pediatric AE (Other things it could be)
The spectrum of inflammatory brain diseases in children has rapidly expanded as new diseases and new etiologies for existing conditions have been described. The underlying pathogenic mechanisms that lead to CNS inflammation may involve vessel wall inflammation, demyelination, or an immune response directed against neurons and supporting structures. Inflammation may also occur secondary to infection, malignancy, or a systemic inflammatory disease. Diagnosing pediatric AE is especially challenging because of the clinical overlap between conditions in the differential diagnosis (Table 5 below) and the clinical heterogeneity within patients having the same disease.
Specific conditions within the differential diagnosis of AE
A comprehensive evaluation is required to distinguish children with AE from those who have other inflammatory brain diseases. For example, children with large-vessel CNS vasculitis typically demonstrate a stroke phenotype, including paresis and speech deficits, and may be distinguished by the presence of ischemic changes on MRI and angiographic abnormalities, such as aneurysm and beading. In contrast, children with small-vessel CNS vasculitis present with cognitive dysfunction, seizures, vision abnormalities, and bilateral nonischemic lesions on MRI and have inflammatory vessel wall changes identified on brain biopsy.
Infection-associated encephalopathy disorders include febrile infection-related epilepsy syndrome (FIRES), acute necrotizing encephalopathy, mild encephalopathy with reversible splenium lesion, and acute encephalopathy with biphasic seizures and diffusion restriction. These syndromes have typical clinical and radiologic features, often with diffusion restriction on imaging, which may infer cytotoxicity and distinguish these patients from those with AE. For example, children with FIRES develop a nonspecific febrile illness followed by sustained refractory status and then progress to chronic, drug-resistant epilepsy with neuropsychological impairment. Neuroimaging and brain biopsy in FIRES are usually normal. The pathogenesis of these diseases is unresolved, but may include genetic vulnerability leading to an infection-triggered “cytokine storm.”
Other diagnoses within the differential are PANS and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). These conditions describe an idiopathic or postinfectious onset of obsessive-compulsive disorder, eating restriction, other emotional syndromes, tics, loss of skills, or personality change. Both clinical phenotypes lack robust biomarkers, and pathogenesis remains disputed; however, there is some evidence of immune mediation and immunotherapy responsiveness. Although patients may appear to have an acquired brain syndrome, most children with PANDAS or PANS would not fulfill the proposed pediatric AE criteria.
Also, monogenic autoinflammatory syndromes may involve the brain, such as the genetic interferonopathies, vasculopathies, and hemophagocytic lymphohistiocytosis. These disorders typically present in early childhood, result in chronic progressive disease, often involving increasing spasticity, intracranial calcifications and microcephaly, and are associated with persistent CSF immune activation. These syndromes are distinguished from AE by the presence of non-neurologic features, such as skin lesions, cytopenias, hepatosplenomegaly, and lung disease.
Finally, neuropsychiatric symptoms are common in pediatric AE and are also the hallmark of primary psychiatric disorders. Delusions, hallucinations, reduced speech, sleep disturbance, and cognitive difficulties may be seen in both disease groups. Features that distinguish patients with AE from those with psychiatric disease include autonomic instability, hyperkinesia, dyskinesia, rapid progression of psychosis despite therapy, seizures, slowing or epileptic activity on EEG, CSF pleocytosis, CSF oligoclonal bands, and MRI abnormalities.
How do the proposed pediatric AE criteria differ from the adult criteria?
First, the pediatric criteria include both acute and subacute time frames for symptom onset, reflecting the range in disease course observed in children. Adult AE criteria were developed for several well-defined syndromes (i.e., limbic encephalitis, acute disseminated encephalomyelitis [ADEM], and anti-NMDAR encephalitis) and the associated algorithm focuses on whether patients meet criteria for these syndromes. In contrast, many pediatric patients with AE do not present with a well-defined syndrome and so the pediatric criteria were devised to capture the breadth of clinical and paraclinical findings reported in children. Similarly, the pediatric AE algorithm (above figure) does not focus on syndrome identification, but is intended to guide a clinician in assessing clinical features and in paraclinical and antibody testing, so as to determine whether an AE diagnosis is appropriate. The adult AE criteria group clinical and paraclinical markers together, whereas the pediatric criteria distinguish clinical evidence of neurologic dysfunction from paraclinical evidence of neuroinflammation.
Approach to Probable antibody-negative pediatric AE
Children with a clinical phenotype of AE and paraclinical findings of neuroinflammation, but negative testing for neural antibodies, may meet criteria for probable antibody-negative pediatric AE (table 4). It is well recognized that not all neural autoantibodies have been identified. Having CSF and serum testing in a research laboratory may identify patients who have antibodies against neural cell surface antigens of yet unknown identity and who may respond to immunotherapy.
Probable antibody-negative AE is one of the most challenging clinical scenarios. It is appropriate that a child presenting with new onset encephalopathy, neuropsychiatric features, and changes in function be investigated for possible AE. However, the differential diagnosis in children is arguably broader than in adults, and so it is important to ensure that other diagnoses have been excluded before giving an AE diagnosis. Pathologic entities that often cause diagnostic difficulty are cortical dysplasias and genetic epilepsies presenting with fever-provoked symptomatic focal seizures, infection-provoked encephalopathy and PANS. In these syndromes, CSF pleocytosis or oligoclonal bands are usually absent, and MRI is either normal or demonstrates alternative pathology. Therefore, critical examination of paraclinical tests for evidence of CNS inflammation is mandatory to avoid unnecessary immune suppression. A diagnosis of probable antibody-negative pediatric AE should also be reassessed in children with atypical features.
In 2021 International consensus recommendations for the treatment of pediatric NMDAR Antibody Encephalitis were created which aimed to standardize the treatment and provide practical guidance for clinicians, rather than absolute rules.
- Corticosteroids are recommended in all children with NMDARE, with additional IV immunoglobulin or plasma exchange in severe patients.
- Prolonged first-line immunotherapy can be offered for up to 3–12 months (oral corticosteroids or monthly IV corticosteroids/immunoglobulin), dependent on disease severity.
- Second-line treatments are recommended for cases refractory to first-line therapies (rituximab preferred over cyclophosphamide) and should be considered about two weeks after the first-line initiation.
- Further immunotherapies for refractory disease 1-3 months after second-line initiation include another second-line treatment (such as cyclophosphamide) and escalation to tocilizumab.
- Maintenance immune suppression beyond six months (such as rituximab redosing or mycophenolate mofetil) is generally not required, except for patients with a more severe course or prolonged impairments and hospitalization.
- For patients with relapsing disease, second-line and prolonged maintenance therapy should be considered.
- The treatment of NMDARE following herpes simplex encephalitis should be similar to idiopathic NMDARE.
Broad guidance is provided for the total treatment duration (first line, second line, and maintenance), dictated by the severity and clinical course (i.e., median 3, 9, and 18 months in the best, average, and worst responders, respectively). Although tumors are rare in prepubertal children and boys, oncologic searches for ovarian teratoma (and neural crest tumors in children aged <5 years) are mandatory in all children with NMDARE, and should be performed early and completed in the first days-weeks after admission.
Patients with definite AE may benefit from continued or advanced immunosuppressive therapy, although specific protocols are not yet validated. Identification of an antibody associated with AE may facilitate counseling regarding expected course and outcomes. Timing of clinical responses to immunotherapy in children with AE may vary from immediate to months after starting. Therefore, using response to therapy as confirmatory support for a diagnosis of AE may be misleading. Families need to be informed of the long treatment course of many months to year(s) and the fluctuating up and down response to treatment patients experience on their journey to remission/recovery.
Cellucci et al., Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient, Neurology, Neuroimmunology & Neuroinflammation, 2020