Diagnosis and Management of Suspected Pediatric Autoimmune Encephalitis: A Comprehensive,Multidisciplinary Approach and Review of Literature

Autoimmune encephalitis is a complex and increasingly recognized disorder caused by immune-mediated central nervous system inflammation. Over the last few decades, multiple autoantibodies have been identified in patients with acute or subacute onset of noninfectious encephalitis. Additionally, there is more awareness of the potential for autoimmune etiologies in pediatric patients presenting with encephalitis. Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis, the most common cause of autoimmune encephalitis in children, is seen more frequently than any one single viral cause of encephalitis. ¹

Autoimmune encephalitis broadly comprises a variety of autoantibodies and associated clinical syndromes. These associated antibodies are typically grouped according to the location of the target antigen. Autoantibodies against intracellular antigens, including Ma, Ri, Yo, Hu, and anti-glutaric acid decarboxylase 65 (GAD65), are more likely to be associated with malignancies, commonly resulting in progressive and irreversible neurologic damage with poorer response to immunotherapy treatment.^2,3 Conversely, antibodies to cell surface antigens, such as those targeting receptors of N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), glycine, γ-amino-butyric acid (GABA), leucine-rich glioma inactivated 1 (LGI1), myelin oligodendrocyte glycoprotein (MOG), and contactin-associated protein 2 (CASPR2), more typically result in symptoms that are reversible with appropriate immunotherapies. ⁴ In pediatric patients, cell surface antigens tend to be more commonly seen, making accurate diagnosis and timely initiation of treatment imperative to reversing neurologic abnormalities in these patients.

Despite the increased recognition of pediatric autoimmune encephalitis, there is a wide variation of management approaches, with diagnosis and treatment practices often relying on information applied from the adult literature. ³ Autoimmune encephalitis is a treatable condition with favorable outcomes reported in around 80% of pediatric autoimmune encephalitis cases following appropriate immunotherapy.^5,6 Outcomes also rely on early initiation of treatment, as delays in diagnosis greater than 4 weeks from symptom onset is a poor prognostic factor at 1 year following diagnosis. ⁷

Here, we propose a multidisciplinary and comprehensive approach to the evaluation and treatment of autoimmune encephalitis in children, emphasizing the importance of early and accurate recognition, prompt empiric treatment for probable autoimmune encephalitis, early reliance on second-line immunotherapy in confirmed antibody-positive cases to prevent relapse, and well-planned transition of care to the outpatient setting.

Presentation

The presentation of autoimmune encephalitis can be variable based on the associated antibody, although there are many overlapping features. Additionally, there is also considerable heterogeneity of symptoms even within known clinical syndromes. ⁸ Pediatric patients often present differently than adult counterparts. In anti-NMDAR encephalitis, for example, children more commonly present with neurologic symptoms such as seizures or movement disorders, whereas a greater proportion of teenagers and adults have more prominent psychiatric manifestations. ⁶

It is widely recognized that autoimmune encephalitis therefore can be difficult to diagnose in a timely and accurate manner. Overlapping features with other diagnoses, heterogeneity in presentations, relatively low incidence, and nonspecific biomarkers of disease further complicate this.^8,9 Additionally, differential diagnoses may be even broader in children than adults. ¹⁰ For example, first-time seizures in pediatric patients much more commonly represent onset of childhood epilepsy, rather than a harbinger of autoimmune disease. Furthermore, genetic, metabolic, and mitochondrial conditions typically first present in childhood, making these more likely diagnostic considerations in children compared to adults. Mimics of autoimmune encephalitis include primary psychiatric disorders, infections, metabolic and genetic conditions, mitochondrial disease, toxidromes, systemic autoimmune conditions, malignancy, paraneoplastic disorders (such as opsoclonus myoclonus syndrome), demyelinating diseases, and other inflammatory neurologic disorders (such as central nervous system vasculitis, febrile illness–related epilepsy syndrome, or central nervous system hemophagocytic lymphohistiocytosis).

The pediatric population presents even more challenges to diagnosis, as cognitive deficits, psychiatric symptoms, and behavioral abnormalities may be difficult to assess in young patients. Distinct clinical syndromes associated with certain antibodies in the pediatric population are not as well-defined given their relative rarity. ¹¹ Antibodies to NMDAR, MOG, and GAD65 are the most commonly detected antibodies in pediatric patients evaluated for autoimmune encephalitis. ¹² However, there can be considerable overlap and heterogeneity in presentations of patients with these autoantibodies, especially early in the disease course.^13‐15 Practitioners should therefore be aware of general clinical features that may suggest an autoimmune process.

Typically, patients diagnosed with autoimmune encephalitis were previously healthy, although a preceding illness is common. Prodromal symptoms, reported in 48% to 70% of pediatric patients, tend to be nonspecific and can include fever, respiratory symptoms, headaches, vomiting, and diarrhea.^16‐18 The time course between prodromal illness and development of neurologic symptoms is not well established. Additionally, autoimmune encephalitis can be seen following a diagnosed infection, as demonstrated by case reports of anti-NMDAR encephalitis following herpes simplex virus encephalitis, COVID-19 infection, and tick-borne illness.^19‐22

Some degree of altered mental status or cognitive changes occurs in the majority of patients but may be difficult to identify. This can be especially challenging to discern in the youngest of patients, as anti-NMDAR encephalitis has even been reported in neonates. ²³ In infants, symptoms such as poor sleep, inconsolable crying, lethargy, and poor feeding may occur.^24,25 In toddlers or preschool-age children, symptoms of autoimmune encephalitis may manifest as behavioral abnormalities, subtle personality changes, emotional lability, worsened tantrums, or aggression that could be attributed to normal variations in behavior often seen in this age group.^17,18 Developmental regression or reduced speech have also been reported.^26,27

New-onset psychiatric symptoms are common and may include hallucinations, delusions, paranoia, catatonia, disorganized speech and behavior, mood lability, thought disorder, and anxiety.^17,28,29 Development of psychosis in elementary school–age children is especially suggestive of an underlying organic etiology. Teenage patients may present more similarly to adults with more prominent psychiatric features compared to younger children. ³⁰ Seizures occur in the majority of children with autoimmune encephalitis. ³¹ Movement disorders, included dyskinesias (notably facial or orolingual), dystonia, and choreoathetosis may also be seen. ¹⁷ Ataxia, myoclonus, tremors, or speech difficulties can also occur.^16,32 A degree of dysautonomia occurs in up to 70% of cases. ¹⁷ The majority of patients develop multiple neuropsychiatric symptoms, with monosymptomatic autoimmune encephalitis rarely occurring, especially in the pediatric population.^6,12,16

Thus, autoimmune encephalitis should be considered in any pediatric patient presenting with acute- or subacute-onset encephalopathy without another clear or more likely cause. Additionally, the presence of a prodromal viral illness or symptoms of systemic inflammation such as fevers or rash in the setting of negative infectious workup, especially with other clinical features suggestive of neurologic disease, which may include movement disorders, ataxia, changes in speech, sudden development of psychiatric symptoms, new-onset seizures, and/or dysautonomia, should increase suspicion for the diagnosis of autoimmune encephalitis.

Diagnostic Evaluation

Once a clinician suspects autoimmune encephalitis in a pediatric patient, a diagnostic workup should be initiated. As the differential diagnosis for symptoms associated with autoimmune encephalitis is broad, the initial investigation should be comprehensive to both exclude other more likely causes and to test for supportive evidence of the diagnosis. Most published diagnostic recommendations for autoimmune encephalitis suggest blood work, cerebrospinal fluid analysis, brain magnetic resonance imaging (MRI), and electroencephalography (EEG) as central components of the initial workup.^33,34 We also favor a comprehensive method to testing initially as results may take days to weeks to return (see Figure 1).

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Figure 1.

Initial diagnostic evaluation of suspected autoimmune encephalitis and differential diagnoses to consider.

Cerebrospinal fluid studies can help reassure against infection, although interpretation of results can be complicated as pleocytosis or other abnormalities such as elevated protein may be seen in both autoimmune and infectious etiologies. Autoimmune encephalitis cases tend to have lower median white blood cell (WBC) counts and protein levels compared to viral encephalitis. ¹ A cerebrospinal fluid lymphocytic pleocytosis (>5 to generally <100 leukocytes/mm³) with negative infectious workup in pediatric patients is therefore supportive of the diagnosis of autoimmune encephalitis.^12,29,35 Other cerebrospinal fluid abnormalities can be seen. In one published case series, oligoclonal bands were present in up to 58% of patients. ³¹

EEG abnormalities may be present in up to 90% of pediatric patients and may include general findings of slowing or epileptic activity, or more specific findings such as extreme delta brushing seen in anti-NMDAR encephalitis.^16,36 MRI abnormalities have been reported to be as high as 45% to 60% in larger case series.^8,16 MRI findings are often nonspecific, including cortical or subcortical T2/fluid-attenuated inversion recovery signal abnormalities, areas suggestive of demyelination, or evidence of volume loss.^6,8 Some antibodies, especially those causing limbic encephalitis, are more frequently associated with abnormal brain imaging. ¹⁶

For patients in which autoimmune encephalitis is highly suspected, antibody testing should be performed. Sensitivity and specificity of antibody detection varies by laboratory and by antibody, with some testing showing improved sensitivity in cerebrospinal fluid compared with serum, such as with antibodies to NMDAR. ⁶ IgG NMDAR antibodies are highly sensitive for anti-NMDAR encephalitis, whereas IgA and IgM NMDAR antibodies are nonspecific. ³⁷ GAD65 antibodies are less specific when found in low titer levels in the serum, but more likely pathologic at high titers and when also present in the cerebrospinal fluid. ¹² Conversely, serum is more sensitive for MOG autoantibodies, although the role of cerebrospinal fluid testing for MOG antibodies is evolving. ³⁸ Both cerebrospinal fluid and serum should therefore be sent in all cases of suspected autoimmune encephalitis. ³³ Although a patient may clinically have features of a specific associated antibody, given the overlapping features of different antibody-associated diseases, it is generally recommended to send a panel of testing that includes detection of multiple autoantibodies. ¹² If available panels do not include the most common causes of pediatric autoimmune encephalitis, these tests should be ordered in addition to standard panels.

Compared to adults, underlying malignancies are less likely to occur in pediatric autoimmune encephalitis. However, children with autoimmune encephalitis can have previously undetected tumors. Tumor association has been reported to be as high as 22% in pediatric anti-NMDAR encephalitis. ³⁹ Early tumor removal, even prior to initiation of immunotherapy, is associated with improved outcome. ⁴⁰ We therefore use tumor screening for patients early in the disease course once a tumor-associated antibody is confirmed or when suspicion for malignancy is high. This includes an ovarian ultrasonograph for females and testicular ultrasonograph for males, with consideration of an MRI of the chest, abdomen, and pelvis based on the specific antibody present and degree of clinical concern.

In addition to favoring a comprehensive workup to making a diagnosis of autoimmune encephalitis, our institution also uses a multidisciplinary team approach, which comprises pediatric neurologists, rheumatologist, hospitalists, psychiatrists, and intensivists. Owing to the broad differential for autoimmune encephalitis, we have found this collaborative and team-based method to be valuable in making timely diagnostic and treatment decisions.

Initiation of Treatment

Specific antibody testing generally takes days or weeks to result, and expert consensus affirms that initiation of treatment should not be delayed for confirmation of a positive antibody result given improved outcomes with earlier treatment.^12,35,41 Additionally, rates of antibody-negative autoimmune encephalitis are around 50%.^8,42 Favorable outcomes are associated with prompt initiation of immunotherapy.^39,43‐45 Delays in treatment may be associated with poor treatment response even after immunotherapy is started. ⁴⁶ It is therefore important for providers to use available clinical information to guide the decision to initiate treatment prior to identification of an antibody.

The disease course may be a helpful indicator when considering the likelihood of autoimmune encephalitis, as the lack of progression of symptoms in the absence of appropriate treatment is unusual and spontaneous resolution quite rare. Chronic symptoms, minimal functional impairment, intact cognition, and isolated psychiatric symptoms are less suggestive of the diagnosis. ¹⁵ As clinical presentations can be variable, it is important to also consider paraclinical features prior to initiation of treatment. Recent proposed criteria by Cellucci et al ¹² for probable autoimmune encephalitis include 2 or more features of neurologic dysfunction and at least 1 paraclinical test supportive of neuroinflammation (cerebrospinal fluid inflammatory changes, MRI features of encephalitis, or brain biopsy with inflammatory infiltrates), in addition to exclusion of other etiologies. In our approach, we therefore favor initiation of treatment when clinical suspicion is high, and observation without initiation of immunotherapy in patients with negative paraclinical testing and low clinical suspicion.

Treatment

Widely used and evidence-based treatment protocols do not exist for pediatric autoimmune encephalitis. Spontaneous and complete recovery of autoimmune encephalitis without treatment has only rarely been reported.^47,48 Autoimmune encephalitis is associated with significant morbidity and mortality, and prolonged hospitalizations, long-term cognitive deficits, persistent seizures, severe neurologic disability, and even death can occur in these patients.^40,49‐52 Thus, there has been growing support in the literature for early and appropriate immunotherapy in order to optimize patient outcomes.^39,53

Although providers generally favor treatment for autoimmune encephalitis, significant differences exist among centers regarding exact treatment regimens. ⁵⁴ Commonly used medications target the immune system and aim to reduce rampant inflammation. Because of the presumed role of cell surface autoantibodies in directly causing disease, pediatric patients with autoimmune encephalitis typically respond well to treatments aimed at decreasing antibody load. ⁵³ Corticosteroids, intravenous immunoglobulin (IVIg), and plasmapheresis are commonly considered to be first-line treatment options.^6,34

Corticosteroids have broad, nonspecific anti-inflammatory properties. High doses of intravenous (IV) methylprednisolone (30 mg/kg/d, maximum 1 g) are generally recommended for a duration of 3-5 days. ⁵³ However, corticosteroids alone may not adequately suppress autoantibody-driven disease, and outcomes are improved when used in conjunction with more targeted immune-modulation. ³⁹

A common approach is the use of corticosteroids and either IVIg or plasmapheresis, either simultaneously or shortly after a methylprednisolone course.^5,34 Both IVIg and plasmapheresis appear to be reasonable and safe treatment options in pediatric patients.^39,55 As there is no evidence to support the use of one of these modalities over the other, ease of administration and local standard practices often guides treatment choice.^34,53 IVIg is generally well tolerated in pediatric patients and commonly dosed at 2 g/kg administered over 1-5 days. ⁵⁵ Plasmapheresis requires the placement of a central catheter, and 5 to 7 cycles are typically used, spaced every other day. ⁵⁶ Plasmapheresis may be more difficult in young patients or those with prominent psychiatric symptoms and takes longer to complete a treatment course compared to IVIg. ⁵⁰ At our institution, we therefore favor use of IVIg in most pediatric cases and reserve plasmapheresis for severe or clinically declining cases requiring intensive care unit admission due to severe dysautonomia, altered mental status, or seizures (see Figure 2). These patients typically require sedation while in the acute setting, making it easier to keep central lines secure. A plasmapheresis course generally does not prolong hospitalization in these patients, as those with severe illness are more likely to require extended admissions well beyond the course of treatment.

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Figure 2.

Proposed guidelines for treatment of autoimmune encephalitis and transition to outpatient care.

Historically, second-line treatment has been reserved for severe or refractory cases. There is emerging support in the literature that the early use of second-line therapy leads to lower relapse rates and improved overall outcomes.^5,6,57,58 Additionally, some favor quick progression to second-line therapy or have suggested that it may be beneficial as a standard first-line medication, even in very young patients.^53,58‐61 With an increased recognition of the role of aggressive treatment to improve outcomes and prevent relapses, earlier and more consistent reliance on additional immunotherapy seems to be increasing. ⁶ Second-line immunotherapy use, however, remains quite variable and institution dependent, ranging from 25% to 72% of cases in pediatric patients with anti-NMDAR encephalitis.^5,6,16,39,62

Second-line therapy most commonly includes either rituximab or cyclophosphamide. Rituximab depletes circulating B cells, and retrospective studies have demonstrated relative efficacy in its use for autoimmune encephalitis in both pediatric and adult patients. ⁵⁸ Cyclophosphamide affects both B and T cells by inhibiting cell proliferation. Reported serious adverse events from second-line therapy appears to be fairly low in the literature, although rituximab is often favored over cyclophosphamide because of side effect profiles, notably, the risk of infertility with cyclophosphamide use.^53,59,60 Dosing regimens for second-line therapy tend to vary by institution. ⁵⁶ Studies are emerging suggesting the use of other immunotherapy options in severely refractory cases, including tocilizumab, interleukin-2, and bortezomib, although more research is needed regarding the use of these options for pediatric autoimmune encephalitis.^63‐66

Literature regarding the benefit of second-line therapy should be interpreted with caution as it consists primarily of retrospective studies. Additionally, patient age, type of autoantibody, disease severity, timing of initiation of first-line therapy, and other factors also may influence relapse rates and overall outcomes. However, given the growing body of literature suggestive of possible improved long-term outcomes with use of second-line therapy, our institution favors the use of rituximab at a dose of 750 mg/m² (maximum dose 1 g) for 2 doses administered 2 weeks apart (or 375 mg/m² for 4 doses administered weekly for the youngest patients) in antibody-confirmed cases of autoimmune encephalitis. However, this treatment course should only be pursued after discussion within a multidisciplinary team and a detailed review of risks and benefits with the family, as aggressive immunosuppression is not without risk. ⁶⁰

In cases of presumed antibody-negative autoimmune encephalitis who have been treated with initial immunotherapy while awaiting testing, the decision to use second-line therapy should be approached judiciously. Consensus opinions outlining the diagnosis of antibody-negative autoimmune encephalitis in children should also be reviewed to ensure the appropriate diagnosis has been made prior to deciding on a treatment course. ¹² Especially in patients with limited paraclinical evidence supportive of autoimmune encephalitis, atypical presentations, no response to immunotherapy, and/or monosymptomatic diseases without evolution of symptoms, providers should revisit the differential diagnosis and overall clinical picture to decide on next steps in management. In severely affected or declining patients with negative antibodies and no response to treatment, expansion of workup should also be discussed, including consideration of rapid whole exome or genome sequencing, if available.

Conversely, for patients with marked clinical response to first-line therapy, escalation of treatment may not be necessary. Functional outcomes and relapse rates in pediatric patients with antibody-negative autoimmune encephalitis are less well-defined, and the benefit of more aggressive immunotherapy for an unknown target is unclear. Decisions regarding treatment courses in patients meeting diagnostic criteria for antibody-negative autoimmune encephalitis with limited or moderate improvement can be challenging, although these patients may warrant escalation to second-line therapy if functional impairments remain. It is important to note that immunotherapy may take time to see full effects, so providers should be cautious in interpreting treatment response. ³⁵ It is unclear how much time should be given to monitor for a response to first-line therapy, although experts have suggested 2 weeks is likely a sufficient time period. ⁶⁷

In all patients with autoimmune encephalitis, treatment response can be challenging to measure. Recent expert consensus by Nosadini et al defines “best responders” as patients who make rapid functional gains in the first few months, “average responders” as those with slower functional gains during that time frame, and “poorest responders” as those with minimal functional gains after three months. ⁶⁷ We recommend ongoing discussions among involved specialties throughout inpatient stays to assess improvement and determine need for escalation of treatment.

Significant uncertainty exists regarding the need for maintenance immunosuppression in pediatric autoimmune encephalitis following the acute period. Although outcomes of autoimmune encephalitis are generally favorable, recovery times are often protracted and residual neurologic and behavioral symptoms are not uncommon. ⁶⁸ Given this, many providers use prolonged courses of oral corticosteroids, monthly IVIg, and/or intermittent rituximab dosing in the outpatient setting. ⁵³ Steroid-sparing agents, such as mycophenolate mofetil, azathioprine, and methotrexate, have also been used, mostly in patients with relapses. ⁵⁷ For relapsing disease or patients with significant residual symptoms, ongoing maintenance therapy is typically given for 1-2 years. ⁶⁷ Following the initial hospitalization and treatment period, we favor use of an oral corticosteroid taper and monthly IVIg for 6 months following the acute hospitalization period with consideration of outpatient redosing of rituximab or other maintenance therapies in certain cases, although clinical course should dictate ongoing outpatient management.

Other Symptoms Management

In addition to treatment of the underlying autoimmune process, most patients will require management of associated symptoms. Seizures may be treated with a variety of antiepileptic medications, and there is no clear evidence to support a specific medication as being more effective in treatment of autoimmune encephalitis-associated seizures. Seizure can be quite refractory, and a majority of children require multiple agents to obtain seizure freedom. ⁶⁹ Although less common in anti-NMDA receptor encephalitis, super refractory status epilepticus can occur in the acute period, and ketamine may be a beneficial adjunct treatment option in these patients. ⁷⁰ Anakinra, a selective interleukin-1 receptor antagonist often used in febrile illness–related epilepsy syndrome, has been shown to reduce seizures in animal models of anti-NMDA receptor encephalitis, and more targeted management of seizures in autoimmune encephalitis may be clarified in the future. ⁷¹

Psychiatric manifestations can be quite prominent and may require involvement of behavioral health teams as well as initiation of psychiatric medication. Additionally, patients are at high risk for sleep disturbances and delirium. Sleep aids, such as melatonin, trazadone, or clonidine may be used.^72,73 Antidepressants or antipsychotics are also sometimes started, although some have suggested that patients with anti-NMDAR encephalitis may be more prone to neuroleptic intolerance, so lower-potency antipsychotics are often favored if needed. ⁷⁴ High-dose benzodiazepines, and more rarely electroconvulsive therapy, have been utilized in pediatric patients with prominent catatonia.^75,76

Autonomic dysfunction may also occur, which can include tachycardia and bradycardia, blood pressure variability, bowel or bladder dysfunction, hypothermia or hyperthermia, and hypoventilation. ⁷³ These symptoms may be quite prominent and require intensive care unit–level management. Management of autoimmune encephalitis requires collaboration of multiple specialists and support staff, which may include intensivists, psychiatrists, cardiologists, physical and occupational therapists, social workers, speech pathologists, child life experts, neurologists, rheumatologists, neuropsychologists, and rehabilitation physicians.

Transition to Outpatient Care

As children near discharge, it is beneficial to have dedicated discussions regarding outpatient planning for these patients, as they typically require continued therapies, treatments, and subspecialty involvement once they leave the hospital. Primary care providers should also be updated on potential complications or other considerations related to the disease process and treatment of it, as general outpatient pediatricians may only very rarely encounter patients with autoimmune encephalitides.

Providers should especially plan for close follow-up to monitor for continued improvement and the need for weaning or escalating therapy for both the underlying autoimmunity and associated symptoms. It is not uncommon for patients to have some degree of residual symptoms following discharge, and it is important to have all involved specialties communicating should there be concerns for flares or relapses. ¹⁵ Relapses often manifest with similar symptoms to the initial attack, but can be milder in presentation. ⁵⁹ Reported relapse rates are quite variable but may be as high as 25%, with relapses occurring months to years following the initial episode.^6,43,50

Behavioral and psychiatric symptoms often persist following hospitalization, and establishing a clear behavioral health plan for the outpatient setting is also critical for successful management following discharge. Families should also be provided with resources to enable them to work with schools so that children can return to classes and stay on track to advance academically. If functional impairments remain, inpatient rehabilitation stays should be considered. Continued physical, occupational, and speech therapies are generally required in the outpatient setting. Neuropsychiatric testing outside of the acute period is helpful to identify areas of residual difficulty and formulate an effective learning plan as cognitive deficits often persist.

Additionally, tumor screening should continue in the outpatient setting. Autoimmune encephalitis may pre-date the detection of a tumor, even by years, and ongoing surveillance should be used, especially in cases with poor treatment response or relapse.^44,50 Although regular tumor screening should be part of the outpatient management of autoimmune encephalitis, there are no clear guidelines regarding how frequently or how long this should occur. At our institution, when tumor-associated antibodies are detected, we favor annual screening for 4 years with the same imaging modalities used for initial screening as outlined above. Some associated antibodies have a higher risk of comorbid malignancy and may require more aggressive imaging techniques such as positron emission tomography or longer follow-up depending on the patient's age and course, but this is typically not required for surveillance. Tumor screening may be indicated in cases of refractory or relapsing antibody-negative autoimmune encephalitis, although clinical presentation and degree of concern for malignancy should guide this decision.

Conclusion

Autoimmune encephalitis is an entity that affects children, although presentations often differ from adults and may be difficult to diagnose. The differential diagnosis for common symptoms of autoimmune encephalitis is quite broad, creating further diagnostic dilemmas in some patients. Despite these challenges, early and accurate recognition of the disorder is crucial as favorable outcomes are associated with rapid initiation of treatment. Even after a diagnosis is made, there remains uncertainty regarding the exact regimen and duration of treatment patients should be given.

Our institution uses a comprehensive guideline to manage suspected autoimmune encephalitis, with the purpose of earlier recognition of the condition, consistency in treatment, and a multidisciplinary approach to both inpatient management and preparation for transition to outpatient care. We favor early immunotherapy in cases of probable autoimmune encephalitis, with a strong consideration of treatment with rituximab in confirmed cases to prevent relapses.

We acknowledge that there remains significant uncertainty regarding treatment courses for pediatric autoimmune encephalitis. Although aggressive immunosuppressive therapy is not without risk, autoimmune encephalitis can have significant associated morbidity and even mortality. Future studies in pediatric patients are needed to further evaluate this. Additionally, as we learn more about the mechanisms that drive diseases associated with specific autoantibodies, more targeted treatment options may emerge. Future work is also needed to understand the utility of guidelines for autoimmune encephalitis, including evaluation of whether our approach impacts time to diagnosis and treatment, duration of hospital and intensive care unit stays, diagnostic accuracy, and both short- and long-term outcomes.