Anti-NMDAR Encephalitis: Multidisciplinary Development of a Clinical Practice Guideline

Knowledge about the diagnosis of autoimmune encephalitis (AE) is rapidly expanding. In the last 15 years, multiple new antibodies have been described. Anti-N-methyl-D-aspartate receptor (NMDAR)–antibody-mediated encephalitis, in particular, has been found to be common among teenagers and young adults1 and accounts for up to 86% of AE in patients aged <18 years.2 Other antibodies associated with AE (leucine-rich glioma-inactivated 1, contactin-associated protein-like 2, glutamic acid decarboxylase 65-kilodalton isoform, γ-aminobutyric acid A, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) are reported in children as case reports or series and with less clear typical clinical syndromes.3–9The presentation and clinical course of anti-NMDAR encephalitis has been extensively described in the literature.10,11 The NMDAR is located on neuronal cell surfaces with high concentration in the limbic system, hypothalamus, and forebrain. When pathogenic antibodies to the ionotropic glutamate receptors subunit of the receptor are present in the cerebrospinal fluid (CSF), they bind and cause internalization of the receptors as well as disruption of the synaptic proteins and plasticity leading to synaptic dysfunction.12,13 The role of the NMDAR in complex neurologic and psychiatric processes accounts for the symptoms and clinical presentation. Initial symptoms at presentation vary on the basis of age of the patient. Large cohort studies have revealed that those aged >18 years present with behavioral, psychiatric, and/or memory issues ∼75% of the time. In the pediatric population of those aged <12 years, neurologic symptoms, including seizures and movement disorders (dyskinesia, chorea, dystonia) account for initial symptoms in 50% to 60% of patients.11,14 Specifically, in regards to movement disorders, orofacial dyskinesias are common in all ages, but children initially present with higher prevalence of chorea and other dyskinesias, whereas the majority of adults ultimately develop bradykinesia and catatonic symptoms (orofacial dyskinesia, echolalia, mutism, staring, and stereotypy) throughout the course of their illness.10,15 Both children and adults may develop autonomic instability, but central hypoventilation and cardiac dysrhythmias have higher prevalence in the adult population.11,16There is a lack of large scale cohort studies or clinical trials16 regarding management leading to a wide variation in treatment approaches.17 As awareness of this diagnosis has increased, early diagnosis and treatment are more likely and there are increasing efforts to define a multidisciplinary algorithm to guide assessment and diagnosis of pediatric AE.6 The critical importance of assessment and management of the psychiatric symptoms is underrepresented in the available literature.18 There is no clear consensus among providers on the time line for antibody testing or empirical immunotherapy19,20 with a need for evidence-based guidelines. Treatments typically target antibody production by removal of tumor if present and immunomodulatory therapy to mitigate the effect of the antibodies on the brain.16 Aggressive, early immunomodulatory treatment can improve outcomes in NMDAR encephalopathy11,21; however, care must be taken to exclude other disease processes, particularly treatable diseases or ones that could be made worse by immunosuppressive treatment. Response to first-line (corticosteroids, plasma exchange, and intravenous immunoglobulins) and second-line immunotherapy (rituximab, cyclophosphamide, or both) may be slow, and, at times, incomplete for sustained control of the immune process.10Supportive treatment is also critical during this time period before biochemical effects at the synaptic level. This includes monitoring and addressing autonomic instability, seizures, movement disorders, agitation, catatonia, other psychiatric manifestations, nutritional needs, and risk for aspiration. Note that catatonia is a syndrome that can occur with severe medical or psychiatric illness. Patients present with psychomotor changes ranging from increased, abnormal, or decreased motor activity and are evaluated through observation, interview, and physical examination.22 Despite the reported benefit of antiepileptic drugs for seizure management or benzodiazepines and electroconvulsive therapy (ECT) for catatonia management, their use is inconsistent among providers.19,23 A recent review by Forrester et al17 highlights the lack of consistency in approach to assessment and treatment of anti-NMDAR encephalitis and the need for a multidisciplinary approach. The authors note the report by Dalmau et al10 of 100 patients, of whom 77 presented first to psychiatric services, emphasizing the importance of a standardized approach to collaborative care. Multidisciplinary team involvement and collaboration is critical because each team has expertise to address these issues.24We present a clinical practice guideline (CPG) developed by a multidisciplinary team at a 267-bed acute care children’s teaching hospital in the southern United States to facilitate communication and effective application of collaborative care. The CPG provides a standardized approach to assessment and treatment of anti-NMDAR encephalitis at our institution, providing a framework for education regarding rationale for targeting antibody production through use of immunotherapy, management of neurologic symptoms, and targeting the psychiatric symptoms resulting from the effects of the antibody on the brain. A key aspect of the CPG is that pediatric neurology, rheumatology, and psychiatry are all consulted simultaneously. This ensures dialogue among the specialties and coordination of care.Representatives from pediatric critical care, emergency medicine, neurology, psychiatry, rheumatology, and hospital medicine identified the need for a CPG to ensure simultaneous involvement of consultants from the various specialties. An additional goal was to ensure effective communication through use of standardized clinical assessment tools. Mental status changes and catatonic symptoms in NMDAR encephalitis can be especially complicated to assess and manage; this can be even more challenging when patients develop autonomic instability seen with malignant catatonia. ECT may be a lifesaving treatment of those with malignant catatonia.25 Access to ECT varies by state,26 and understanding of ECT is inconsistent among various disciplines, including child and adolescent psychiatrists. The process described here focuses on the input from neurology, psychiatry, and rheumatology to ensure effective multidisciplinary care using a common language for assessment and treatment of patients presenting with possible NMDAR encephalitis.The CPG was developed from a multidisciplinary collaboration between providers and other clinical personnel at our hospital with guidance from the Evidence Enhanced Medicine (EEM) Committee, which oversees the development of evidence-supported best medical practices based on literature review and internal data. After CPG approval, the EEM committee works with hospital administration, physicians, nursing, and ancillary staff as well to disseminate the information and ensure implementation of the CPG throughout the hospital. A multidisciplinary team, including representatives from neurology, rheumatology, psychiatry, pediatric hospital medicine, pediatric critical care, and pediatric emergency medicine, as well as pharmacy and nursing leadership, was involved in the creation of the CPG through multidisciplinary meetings, evaluation of institutional data, and literature review. Patients were identified with possible AE over a 4-year period. Information for length of hospital admission, ICU admission, time to consultant evaluations, time to initiation of workup, and time to treatment were collected and deidentified (Table 1). The pre-CPG data will be used as a baseline for review of improvement in recognition, evaluation, and early intervention of patients with anti-NMDAR encephalitis.To determine inclusion in the CPG, one of the authors (E.H.) retrospectively reviewed 30 charts to identify the number of symptoms at presentation, referencing the 6 symptoms as defined by Graus et al.27 The number of symptoms in those with anti-NMDAR encephalitis (9 charts) versus those ultimately found to have other diagnoses (21 charts) are revealed in Table 2. On the basis of this review, we defined a minimum of 3 (of 6) symptoms developing within 12 weeks of symptom onset27 as our requirement for initial entry into the CPG pathway (Fig 1). The CPG describes clear workup parameters to guide emergency rooms, general pediatricians, and other specialties. The known pathophysiology of internalization of NMDARs, leading to a progression of symptoms from the acute to subacute state, highlights the importance of simultaneous consultation with pediatric services for neurology, rheumatology, and psychiatry as well as the importance of serial examinations to recognize and treat complications in the initial disease process.The CPG dictates that CSF samples should be sent for the NMDAR antibody because of the pathophysiology of the disease, emphasizing the predominance of NMDAR antibodies among AE in children and need for CSF antibody identification for diagnosis. Results of serum studies are negative in up to 15% of patients with CSF-positive antibodies,11,28,29 whereas up to 10% of healthy controls have been revealed to be seropositive, necessitating presence of CSF antibodies for appropriate diagnosis and treatment.30 Because of the low prevalence of other antibodies in the pediatric population, the CPG requires a saved sample of CSF but avoids AE antibody panel testing in the initial workup, which takes up to 9 days longer for results to return and can thus delay treatment; the saved CSF sample is sent as a second-tier test if suspicion remains high with no other diagnosis identified. If there is clinical suspicion of another antibody-associated AE, then the full panel should be sent at time of initial workup. It is important to note that clinical decisions often need to be made before confirmation of diagnosis because laboratory results are often delayed because of the send-out nature of the testing. CSF should be obtained before initiation of immunomodulatory treatment to minimize risk of false-positive (intravenous immunoglobulin [IVIG]) or false-negative (other immunomodulatory treatment) results. The CPG includes a subset of ancillary studies, with faster result times that can help guide differential diagnosis and treatment decisions pending diagnosis while also ruling out other diagnoses. Although nonspecific, EEG is abnormal in 85% to 96% of patients with NMDAR encephalitis. CSF pleocytosis and/or oligoclonal bands are seen in 80% to 85% of patients with AE.11,28,31,32 Note that the Graus criteria were initially developed for adults and later revealed to have high sensitivity and specificity in pediatric patients in a retrospective cohort.33 On the basis of this information, our retrospective patient review, and literature review in children,11,27,33 the CPG recommends that patients meeting at least 4 (of 6) clinical criteria with at least 1 supplementary criterion (EEG abnormalities, CSF, pleocytosis) warrant the next step of empirical immunomodulatory treatment while awaiting confirmatory antibody results. Seronegative autoimmune encephalopathy should be considered in all cases that are evaluated in this protocol. The diagnosis of seronegative autoimmune encephalopathy is largely considered on the basis of CSF (pleocytosis, elevated protein) as well as findings on EEG and MRI that suggest an inflammatory or autoimmune encephalopathy. Brain biopsy can also be considered. Careful exclusion of other causes is especially required in seronegative cases. Empirical immunomodulatory treatment can be given to these patients but requires significant clinical judgment.6Prompt involvement of the psychiatry team facilitates identification of catatonia and other psychiatric symptoms. Autonomic instability, at times presenting as malignant catatonia, is a significant source of morbidity often overlooked until late in the course, resulting in increased ICU admissions and prolongation of hospital stay. As part of the development of the CPG, the Child and Adolescent Psychiatry Consultation Liaison team defined a protocol for assessment of catatonia using the Bush Francis Catatonia Rating Scale (BFCRS).34 The BFCRS provides a checklist of 14 items for screening and an additional 9 items for assessment of severity of catatonia symptoms. Serial evaluations with the BFCRS provide a visual guide to assessment and response to treatment; treatment considerations include pharmacologic management and possible ECT (Fig 2). Early ECT therapy for catatonia not responsive to pharmacology has been revealed to decrease length of hospital stays and speed recovery.35Rheumatology involvement is necessary for guidance on the early treatment and long-term management of immunomodulatory therapies to treat the underlying disease (Fig 2). Early immunomodulatory treatment improves the degree of disability and long-term outcomes.11 Treatment typically includes corticosteroids and IVIG with consideration of plasma exchange in the early phases and rituximab and/or cyclophosphamide as second line.11 However, significant heterogeneity exists in both the choice of immunomodulatory treatment and timing of escalation of therapy.20 Our CPG used the SickKids protocol from The Hospital for Sick Children, Toronto, Ontario, Canada.36 Because the disease mechanism is felt to involve dysfunction of the glutamatergic synapse, improvement from treatment with immune modulation may take weeks to months. Therefore, significant improvement before 3 weeks of immunomodulatory therapy alone is rare in severe cases.29,37Initial symptoms are largely neurologic and psychiatric; early involvement of both consultation services is important to evaluate and treat as appropriate, often including bedside testing with the BFCRS, EEG monitoring, and MRI, as noted in the CPG. Neurologic symptoms include movement disorders, seizures, and sleep disturbance; neurology colleagues provide EEG interpretation, management of seizures and movement disorders, and coordination of CSF results. Seizures can be difficult to control, and status epilepticus has been revealed as an indicator of poor long-term prognosis.2 Aggressive treatment of symptomatic epilepsy is especially important, impacting clinical course.2 There is also the larger bucket of neuropsychiatric symptoms that often get collectively labeled as altered mental status; this can include both altered cognition and memory. Clinical manifestations that present psychiatrically can include insomnia, mania, anxiety, and psychosis38; decisions regarding pharmacologic management of these symptoms should be considered in the context of presence or absence of catatonia. The diversity of symptoms on presentation highlights the importance of communication and collaboration between the psychiatry and neurology teams, recognizing the many components of mental status, including level of consciousness and cognition, but also affect, thought process, and thought content. A useful tool for thought process and content is the Dimensions of Psychosis Symptom Severity.39 Some psychiatric symptoms can be categorized as catatonia, including agitation, restlessness, mutism, staring, stereotypy, posturing, perseveration, negativism, grimacing, rigidity, echopraxia and echolalia, and decreased oral intake. Catatonic symptoms may limit assessment of cognition. Thus, cognition should be considered in combination with the results of the BFCRS to facilitate recognition of altered mental status due to catatonic symptoms. In more severe cases, paroxysmal sympathetic hyperactivity, which may be categorized under malignant catatonia, can be life-threatening, with resultant ICU stay predicting poor outcome.11 Because of a lack of a standard of care for symptomatic treatment, coordinated management of the myriad of symptoms (management that includes the ICU team, who were involved in creation of this CPG) is vital.Malignant catatonia is a fulminant and systemically devastating type of catatonia that presents with an acute onset of intense excitement, delirium, catalepsy, mutism, rigidity, stereotypy, posturing, and refusal to eat or drink, along with autonomic instability (fever, tachycardia, tachypnea, and hypertension) and a high fatality rate.40 Because of the potential dangers of malignant catatonia, rapid treatment with benzodiazepines, in addition to immunotherapy, is generally recommended.25 For catatonia, benzodiazepines such as lorazepam can be helpful by increasing γ-aminobutyric acid A inhibitory tone.41 benzodiazepines have potential limitations, especially the risk of sedation and potential for hypoventilation via respiratory depression24 as well as the possibility of exacerbation of comorbid delirium. In addition to the potential risks of significant use of benzodiazepines, occasionally this treatment is not always fully adequate in managing the symptoms of catatonia associated with AE. Despite prompt initiation of benzodiazepines and immunomodulatory treatments (corticosteroids, plasmapheresis, IVIG, etc) patients can still have manifestations of malignant catatonia. For these cases, use of ECT may be of significant benefit.25ECT has been revealed to be effective in adults with malignant catatonia42 with multiple case reports suggesting benefit in children and adolescents,43 some of whom had not responded to immunomodulatory therapies and benzodiazepines. Case reports suggest that the initial course of ECT in anti-NMDAR encephalitis is similar to ECT for other psychiatric illnesses.43,44 For example, ECT for suicidality in major depressive disorder often includes an index course of between 8 and 12 treatments.45 Likewise, in the pediatric NMDAR encephalitis cases reviewed, one teenager displayed significant positive response after 8 ECT treatments, 1 after 9, and one after 7 treatments.41,43 In literature not specific to adolescents and children, efficacy rates for ECT in the treatment of malignant catatonia range from 80% to 100%.46 Stigma and resistance to use,44 in addition to significant variation in state regulations,47 often contributes to ECT being less frequently implemented. The mechanism of action (MOA) of ECT is poorly understood, potentially limiting use as a treatment modality. One proposed MOA includes various pathways, including NMDAR-mediated signaling, activation of brain-derived neurotrophic factor and vascular endothelial growth factor, coming together by increased production and release of tissue plasminogen activator, which may have an effect on neurogenesis and improved synaptic transmission and plasticity.48An additional limitation is the fact that there are no randomized controlled trials for ECT in anti-NMDAR encephalitis, and current evidence is from review of case reports.35,43 Although immunomodulatory therapy and, if possible, tumor removal, are the definitive treatments of anti-NMDAR encephalitis, ECT should be considered as an earlier treatment option for children and adolescents who do not respond to or cannot tolerate benzodiazepines because of safety and efficacy in catatonia.49 It has been suggested that, given the severity of illness with catatonic symptoms, ECT should even be considered as a potential first-line treatment rather than a last resort treatment modality.47,48 The American Academy of Child and Adolescent Psychiatry set forth practice guidelines in 2004, including ECT as a safe and effective first-line treatment of catatonia when severe and persistent symptoms significantly interfere with function and if there is risk of death with delay of ECT.50 Timing of treatment with ECT can vary on the basis of course of immunotherapy; it is important to recognize the use of ECT when catatonia is present and benzodiazepines are inadequate even before confirmation of diagnosis of anti-NMDAR encephalitis.43 Further analysis of specifics of ECT treatment (such as electrode placement, parameters of machine settings, anesthetics used, seizure duration and quality, and concomitant medications) may be useful for eventual development of more standardized guidelines in treatment of anti-NMDAR encephalitis.We present the development of a CPG for anti-NMDAR antibody-mediated AE as a protocol to ensure standardized workup and management of effective multidisciplinary communication. Our multidisciplinary team identified inconsistent workup and management of patients with anti-NMDAR AE causing challenges in collaboration and implementation of recommendations. We recognized the importance of a protocol for effective patient care. Since the development of this CPG, Celluci et al6 have published an algorithm for assessment of AE in children. Our CPG is focused specifically on NMDAR AB and expands the multidisciplinary team to include assessment and management of psychiatric morbidity. The CPG provides a protocol for communication, education among disciplines, and inclusion of each discipline simultaneously on day 1 of consultation for AE with a specific focus on NMDAR. This approach requires collaborative understanding of the importance of managing the direct effects of the antibody targeting the receptor(s) in the brain (rheumatology), managing the behavioral effects of the antibody against the brain (Child and Adolescent Psychiatry), and managing the physiologic and neurologic consequences of the antibody against the brain (neurology and PICU).As the CPG was developed, it was identified that ECT is inconsistently recognized as a potential treatment in severe cases of AE. ECT has been identified as a safe and effective adjuvant treatment to immunomodulatory treatment.32 Although the exact mechanism of ECT is unknown, it has been hypothesized it helps with protecting the brain against the effect of the NMDAR antibodies.51 Inclusion of ECT as a component of the structured guidelines helps standardize its use and improve the current inconsistencies in use.23 The use of a standardized tool (BFCRS) to measure change in clinical symptoms, including behavioral changes reflecting catatonia, increases consistency with resultant increased quality of care. The BFCRS has also been revealed to be useful for monitoring treatment response to ECT.43The provision of a flowchart (Figs 1 and 2) for treatment decisions facilitates effective collaboration as well as ensuring timely involvement of all teams involved. As the understanding of anti-NMDAR AE evolves, it will be important to have multidisciplinary discussions to provide education and to revise the clinical approach to care.