This CME covers how CNS-related psychosis may require medical interventions beyond antipsychotic and other psychotropic medications.
Premiere Date: July 20, 2021
Expiration Date: January 20, 2023
The goal of this activity is to help psychiatrists recognize and treat autoimmune encephalitis, despite the fact that it will often initially present as psychosis.
After participating in this activity, you should be better prepared to:
1. Describe the prognostic factors for anti-NMDA [N-methyl-D-aspartate] receptor encephalitis (ANMDARE).
2. Conduct a clinical workup and treatment plan for recurrent ANMDARE episodes.
This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.
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In recent years, a growing body of literature has described autoimmune encephalitis as an important, if infrequently seen, cause of subacute onset of psychotic illness in patients. One of the important syndromes in this group is anti-NMDA (N-methyl-D-aspartate) receptor encephalitis (ANMDARE).1-3 As patients experiencing ANMDARE may experience exclusively psychiatric symptoms (eg, psychosis, depressive symptoms), they will likely initially present to psychiatrists. The psychiatrist therefore must consider various components of the presentation in clinical evaluation and management.
Psychotic and depressive illnesses are common in the population, compared with ANMDARE. Consequently, psychiatrists must decide which patients warrant consideration of ANMDARE and the associated diagnostic studies, which are quite detailed and not part of a typical workup for psychotic and depressive disorders. Three broad areas can guide the physician: atypicality of presentation, comorbid neurologic symptoms and signs, and other systemic medical comorbidity commonly reported in ANMDARE. Ultimately, clinical intervention, treatment approaches, and surveillance for recurrence and prognosis will need to be considered.
Presentation and Diagnosis
Atypicality of presentation is an inherently imprecise construct, in that it refers to how a given case presents differently from other more common presentations of the same illness. Herein lies the conceptual challenge. Understanding the construct of atypicality requires the clinician to apply an initial classification template to the overall gestalt of a case. For psychotic illness, the physician starts with an observation of the primacy of disordered reality testing (eg, delusions, hallucinations) and thought process (eg, looseness of associations, thought blocking, disorganization) in patient presentation. The primacy of the psychotic symptoms must outweigh other psychiatric findings (eg, depressive, anxiety, cognitive symptoms) so as to define the case as psychotic disorder.
Once psychiatrists apply the general template, they may notice that the details of the case do not quite fit. Hence, atypicality. Atypicality may include epidemiologic features (eg, psychotic symptoms occurring at a later-than-typical age of onset; psychotic illness in a patient with no similar family history), course of presentation (eg, a patient with abrupt onset of psychosis that develops rapidly to impair function without a prodromal state), and social context (eg, onset of psychotic illness without notable social stressors temporally associated with illness onset).
Comorbid neurologic symptoms and signs should be routinely considered in any psychiatric evaluation; after all, psychiatric illnesses are, by definition, brain diseases. Specific consideration of motor signs, sensory symptoms, seizures, and disorders of arousal and attention should be considered. The more coincident neurologic comorbidities that are present, the greater the likelihood of ANMDARE and other neuropsychiatric illnesses will be as a central explanatory hypothesis.
Finally, it is important to consider comorbid systemic (ie, non-central nervous system) illness. Psychotic illness occurring in the presence of rheumatologic illness with the use of immunomodulators, endocrinologic illness (eg, hypothyroidism), and/or with concurrent neoplasms raises the odds that the psychotic presentation may be directly attributable to systemic factors being etiologically associated with an illness with an apparent primary psychotic psychiatric presentation.
Prognosis and Treatment
To make an ANMDARE diagnosis, it is important to consult with a neurologist to obtain a lumbar puncture for cerebrospinal fluid (CSF) studies, magnetic resonance imaging (MRI) (unless the psychiatrist has already obtained it), and electroencephalography (EEG). Once the diagnosis is rendered, clinical intervention needs to be coordinated with other physicians. Clinicians should use antipsychotic and antidepressant medication to address manifest symptoms, but there is a likelihood that systemic immunomodulation therapies (eg, corticosteroids, intravenous immunoglobulin [IVIG], plasma exchange) may ameliorate the psychotic symptoms, such that long-term maintenance with antipsychotic or antidepressant medication may not be indicated. Similarly, resection of an ovarian teratoma may lead to improvement in symptoms.1-3
The prognosis for recurrence of atypical psychiatric illness due to ANMDARE is likely different from recurrence in more common psychiatric illness. In known ANMDARE, vigilance for recurrence should be permanent and lifelong. Recurrence of any clinically significant psychiatric illness should prompt reevaluation of neurologic and systemic medical status via a coordinated effort by the various physician specialties, while empirically treating the presenting symptoms. This is analogous to a patient with a known history of thyroid disease, wherein a recurrence of psychiatric symptoms mandates a prompt reevaluation of thyroid status and consideration of a change in endocrinologic treatment in addition to empiric use of psychotropic medications.1-3
Lessons From the Literature
The growing literature on recurrence and prognosis in ANMDARE can guide the psychiatrist in management of these patients over time (Table 1).
Pollak and colleagues presented an integrated approach to the identification of possible, probable, and definite autoimmune psychoses and outlined the options for their appropriate diagnosis and management.1 Psychiatric symptoms consistent with possible autoimmune encephalitis include abrupt onset of psychosis (with rapid progression within 3 months); movement disorder (eg, catatonia, dyskinesia); adverse response to antipsychotics, raising suspicion of neuroleptic malignant syndrome; disproportionate cognitive dysfunction; as well as decreased level of consciousness.
A diagnosis of probable or definite autoimmune encephalitis would further require confirmatory CSF, MRI, and/or EEG studies. Comorbid, nonpsychiatric red flags (eg, infectious prodrome, severe headache, focal neurologic signs, dysautonomia, tumor, hyponatremia, and other autoimmune disorders) should arouse suspicion of autoimmune encephalitis.1 The preferred treatment of psychosis in the acute phase is with second-generation antipsychotics, starting at low doses and titrating slowly. Benzodiazepines are indicated in the management of catatonia and in unclear cases of psychosis or aggression. Electroconvulsive therapy (ECT) has shown to be helpful in some cases for rapid symptom control.
If neuronal autoantibody seropositivity is the only abnormality, treatment with immunotherapy may be dangerous and is therefore not recommended. Treatment should be considered on a case-by-case basis following evaluation by a team of neurologists and psychiatrists. Circulating antibodies should be removed via tumor removal, plasma exchange, immunoadsorption, or IVIGs, followed by immunosuppression (with either steroids or steroid-sparing immunomodulating agents such as azathioprine, methotrexate, or mycophenolate mofetil).
Utilizing a study of 382 patients with ANMDARE, Balu and colleagues constructed a grading score for predicting a patient’s neurologic function 1 year after diagnosis of ANMDARE.4 The study results indicated that intensive care unit (ICU) admission, treatment delay > 4 weeks, lack of clinical improvement within 4 weeks, abnormal brain MRI suggestive of encephalitis, and CSF white blood cell count >20cells/µL were independent predictors for outcome. Poor functional status was defined as a modified Rankin Scale (mRS) score ≥ 3, and good functional status was defined as mRS score ≤ 2. Each of the 5 variables were equally weighted at 1 point each to construct a 5-point anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score. The NEOS score was strongly associated with the probability of poor functional status at 1 year (Table 2). These findings suggest that the NEOS score accurately predicts 1-year functional status and should be used to estimate the velocity of clinical improvement, not the ultimate clinical outcome.
A retrospective case-control study looked at the sensitivity and specificity of serum and CSF antibody testing in patients with ANMDARE as well as the correlation among titers, relapses, and eventual outcome.5 The study included 250 patients with ANMDARE and 100 control participants. All 250 patients had NMDAR antibodies in CSF, but only 86% of patients had antibodies in the serum. CSF and serum titers were higher in patients with poor outcome as well as in those with teratoma. Over time, there was a decrease of antibody titers regardless of outcome. Relapse correlated better with titer change in CSF than that in serum. The findings suggest that NMDAR antibody testing is more sensitive using CSF than using serum. Antibody titers in CSF and serum are higher in patients with poor outcome or teratoma.
Huang et al conducted a literature review examining the prognostic factors and treatment of ANMDARE.2 They found that the proportion of patients with deficits during long-term follow-up ranged from 27% to 85% and the recurrence rate ranged from 12% to 29%, with a median interval of 2 years. Most patients responded well to first-line treatment and tumor removal. When first-line immunotherapy fails, second-line immunotherapy can improve outcome. Immunomodulators and tumor removal are effective for pregnant patients. Benzodiazepines are preferred for patients with catatonia, and ECT may be used when pharmacological treatment fails.
Further, Huang and colleagues found that older age and ICU admission were poor prognostic factors. They also found that antibody titers may not be early or sensitive biomarkers, as most patients will still have anti-NMDAR antibodies in the CSF and serum for months to years after treatment. Instead, early prognostic biomarkers included cell-free mitochondrial DNA, interleukin-17, YKL-40 (chitinase 3-like 1), neuron-specific enolase, and S100 calcium-binding protein B; the presence of any of these means a poor response to immunotherapy is more likely. The literature also indicated that those who did not receive adequate immunotherapy to treat the first episode were more likely to relapse. First-line immunotherapy treatments include IVIG, plasma exchange, and high-dose corticosteroids. Second-line treatments should include rituximab and cyclophosphamide. Third-line therapy includes tocilizumab, methotrexate, bortezomib, azathioprine, and mycophenolate mofetil, many of which have not been systemically verified in large cohorts.
A retrospective cohort study of 571 patients with ANMDARE found that that 23 patients (4%) developed isolated psychiatric episodes: 5 at disease onset and 18 during relapses (Figure).3 Brain MRI was abnormal in 45% of these patients, and CSF showed pleocytosis in 77%. Furthermore, 83% had substantial recovery after immunotherapy and tumor resection when appropriate. After relapse, 94% of patients improved or returned to a similar or better prerelapse functional level. These findings suggest that isolated psychiatric episodes are rare, but they can occur as initial onset or relapse of ANMDARE. Patients with new-onset psychosis, history of encephalitis, subtle neurological symptoms, and/or abnormal ancillary tests should be screened for NMDAR antibodies.
In another retrospective cohort study that included 60 patients with ANMDARE, results showed that age ≥ 25 years, disturbance of consciousness at admission (defined as Glasgow Coma Scale < 5), and ≥ 50% slow waves (4-8 Hz theta waves or 0.5-4 Hz delta waves) on EEG were significantly associated with poor patient outcome.6 These 3 factors make up the 5-point age, consciousness, and slow waves (ACS) composite score, which are scored with 1, 1, and 2 points, respectively. An ACS > / = 3 meant a poor prognosis, defined as mRS score ≥ 3, whereas an ACS < 3 meant a good prognosis, defined as mRS score ≤ 2. The ACS score was determined to have a sensitivity of 84% and specificity of 74%. The study found 38% of patients had good prognoses. These results suggest that the ACS score may be used to predict the early-stage prognosis of patients with ANMDARE.
Titulaer and colleagues conducted a retrospective study of 501 patients with ANMDARE; 81% of which were female, 38% had an underlying neoplasm, and 97% of those with a neoplasm were female.7 Of note, 65% of adults presented with behavioral problems, and 50% of children younger than 12 years presented with seizures or movement disorders. Regarding intervention, 94% underwent first-line immunotherapy or tumor removal, resulting in improvement within 4 weeks in 53% of those patients. For the remaining participants who failed first-line therapy, 57% received second-line immunotherapy, which led to better outcomes than in those who did not receive second-line immunotherapy. During the first 24 months, 79% achieved a good outcome while 6% died. At the 24-month follow-up, 81% had a good outcome, and 9.5% had died. Outcomes continued to improve for up to 18 months after symptom onset.
Early treatment and lack of ICU admission predicted good outcome in another study.7 During the 24-month follow up, 45 patients had relapses; for 15 patients, multiple relapses occurred. Relapses were milder than previous episodes in 67% of the cases, monosymptomatic in 35%, and resulted in fewer admissions to the ICU in 17% of the cases. In cases with relapses, the severity of symptoms was comparable with that of the initial episode in 23% of the cases and worse in 10%. The use of immunotherapy in the initial episode of encephalitis was associated with a lower frequency of relapses. A relapse-decreasing effect of second-line immunotherapy was observed in patients without tumor. The introduction of second-line immunotherapy during relapses decreased the frequency of subsequent relapses. The findings suggest that second-line immunotherapy is usually effective when first-line therapies fail. Recovery can take more than 18 months.
To determine the relationship between EEG results and ANMDARE recognition, van Sonderen et al conducted a retrospective cohort study of 35 adults and 18 children with ANMDARE.8 Control EEGs were added to the data set for blinding. The median time from disease onset to the first EEG recording was 19 days for adults and 8 days for children. The results showed that in the majority of patients (71%), first EEGs showed normal posterior rhythm, which was associated with a shorter hospital stay and better clinical outcome, measured by the mRS at follow-up at least 6 months after disease onset. EEGs commonly showed focal (73%) or diffuse slowing (67%). First EEGs containing severely abnormal readings (ie, lack of normal posterior rhythm with severe slowing, periodic discharges, or status epilepticus) were associated with a longer hospital stay. However, 57% of patients who had severely abnormal EEGs still had a good clinical outcome. Extreme delta brushes (EDBs) were present in only severely affected patients with mRS score ≥ 4. An abnormal EEG result has a 96% sensitivity for ANMDARE, but a normal EEG did not exclude the disease. The findings suggest that the first EEGs commonly show normal posterior rhythm, which is associated with a better clinical outcome at least 6 months after disease onset. Additionally, diffuse and focal slowing are common EEG findings; EDBs are present only in severely affected patients; and abnormal EEGs can still result in good clinical outcome.
In regard to EEGs, a literature review found that patients with a normal EEG background, epileptic discharge, polymorphic delta rhythm, and diffuse β activity have a good long-term prognosis, but abnormal EEG readings (eg, EDB) have no clear correlation with the final clinical outcome.9 Imaging findings show poor specificity and have limited prognostic value. Fluorodeoxyglucose-positron emission tomography (FDG-PET) has a high sensitivity for the most severe forms of ANMDARE. Although antibody titers increase at the onset of the disease, the improvement of symptoms after treatment was not found to be associated with a decline in antibody titers. Like the findings noted in Huang et al,2 the titers remained positive for a while even after recovery. The relationship among CSF antibody titer, prognosis, and relapse still requires further research. Treatment includes early initiation of immunotherapy and tumor removal, both of which expedite recovery and decrease ANMDARE recurrence risk. Wang et al found that those who required ICU support had a poorer prognosis.
Warren and colleagues conducted a retrospective cohort study to better understand the effectiveness and adverse effects (AEs) of the treatment options.10 The study included 30 patients who tested CSF positive for ANMDARE; results showed that a majority of patients (83%) had early psychiatric symptoms, including agitation and psychosis within the first week of admission and 3 cases of catatonia within the second week. These patients were treated with antipsychotics (67%), with an average daily olanzapine equivalence dose of 11.5 mg, prior to immunomodulation therapy. Although there was an 88% reduction in cases with aggression, antipsychotics alone provided little improvement in psychosis, affective symptoms, or catatonia.
Warren et al found no significant difference in the rate of occurrence of neurological and autonomic symptoms (ie, extrapyramidal symptoms [EPS] and neuroleptic malignant syndrome [NMS]) between those who received antipsychotics (20 patients) vs those who did not receive them (5 patients). Four patients experienced a possible recurrence of encephalitis: 1 who had seizures and 3 others with cognitive deterioration, mild movement disturbance, and recurrence of psychosis despite being continued on antipsychotic medications. All 4 cases resolved with immunomodulation therapy.
These findings suggest a need for psychiatric care for those with ANMDARE in both acute and chronic phases. Antipsychotic medications should be considered an adjunct to immunomodulation therapy. Suspected NMS and EPS cannot be differentiated easily from clinical progression of ANMDARE. Clinical reevaluation, careful withdrawal of potential causative agent, and immunomodulation therapy should be considered. Psychiatric management and psychotropic medication choice must be flexible, with dosing modifications depending on the most pressing psychiatric symptom, stage of illness, neurological symptoms, and risks of adverse effects.
In a prospective case-control study, Zhu and colleagues studied the CD138 levels as well as many other biomarkers in the serum and CSF of patients with ANMDARE.11 CD138 is a component of the endothelial cell glycocalyx. The study included 27 patients with ANMDARE, 11 with viral meningoencephalitis, and 22 control participants, and the results showed that serum and CSF levels of CD138 were significantly increased in patients with ANMDARE. After 3 to 6 months, their CSF CD138 levels were significantly decreased. Decreases in CD138 levels were associated with an improvement in the clinical outcome measured by the mRS. The findings suggest that a high level of CSF CD138 is associated with inflammation and poor prognosis.
In a recent major review of autoimmune encephalitis (comprising multiple mechanisms, including ANMDARE), Broadley and colleagues reviewed 44 publications representing 2823 reported patients, of which 27 studies and 1566 cases were ANMDARE.12 Specifically pertaining to prognosis for ANMDARE, and mindful of the emerging and somewhat varied research methodology in this area, the authors concluded that ANMDARE prognosis was worse with delay in initiation of or lack of immunotherapy, altered level of consciousness at clinical presentation, and admission to ICU. Other clinical variables, such as older age, sex, status epilepticus at clinical presentation, and abnormal CSF and MRI studies, did not have significant prognostic value, while the impact of antibody titers, dysautonomia, and comorbid malignancy was uncertain.
Discussion and Concluding Thoughts
The literature illuminates some key points about clinical presentation, risk factors, prognostic factors, clinical workup, and treatment recommendations for recurrent ANMDARE. Although ANMDARE usually presents initially as an abrupt onset of psychosis with comorbid neurologic symptoms and/or systemic symptoms, recurrent episodes may present, in rare cases, as an isolated change in mood or behavior (eg, delusional thinking, mood disturbances, aggression).
Risk factors for ANMDARE recurrence include presence of a tumor,9 lack of immunotherapy in the treatment of the initial encephalitis episode,7 and an increased CSF antibody titer compared with baseline.5 Poor prognostic factors include later initiation of treatment (more than 4 weeks after initial onset of symptoms) and ICU admission.
Many possible prognostic biomarkers are still under study, but some are at least partially understood. A normal EEG background, epileptic discharge, polymorphic delta rhythm, and diffuse beta activity are associated with a shorter hospital stay and good long-term prognosis, but abnormal EEG readings (eg, EDBs) have no clear correlation with the final clinical outcome.8,9 The ACS (age, disturbance of consciousness, and slow waves on EEG) score may be valuable in predicting the early-stage prognosis.6 The NEOS score may be used to predict the functional status after 1 year,4 but not the ultimate clinical outcome. Recovery can take more than 18 months.7 Patients experiencing recurrent episodes should undergo proper clinical workup to minimize the risk of further recurrence and improve prognosis.
For recurrent cases of ANMDARE, a detailed workup should be completed (Table 3).1,3,5 If the serum or CSF is positive for any onconeural antibodies, consider a full body PET scan to search for occult malignancy.1
Antibody titers should be interpreted with caution, as they may not be early or sensitive biomarkers. The improvement of symptoms has not been found to be associated with a decline in antibody titers.2,9 Therefore, treatment decisions should be based more on clinical evaluations, rather than on antibody titers.9 For those who present with atypical clinical findings, such as the presence of a characteristic syndrome with negative serum antibodies or a discrepancy between serum and CSF antibodies, obtain comprehensive antibody testing (serum and CSF using 2 different techniques [eg, cell-based assay, brain immunohistochemistry, IIFT, ELISA, RIA, nanoliter immunoassay]).5 Collaboration between neurologists and psychiatrists is necessary to manage co-occurring neuropsychiatric symptoms.1 If the patient presents with rapidly progressive, refractory psychosis, and cognitive decline, consider brain biopsy.1
Treatment of first-episode and recurrent ANMDARE cases are similar. Both involve removal of circulating antibodies via tumor removal as well as plasma exchange, immunoadsorption, IVIGs, and/or immunosuppressors (eg, corticosteroids, azathioprine, methotrexate, mycophenolate mofetil).1 For unconfirmed cases of ANMDARE (eg, serum-only NMDAR antibody positivity without any other clinical abnormality), treatment with immunotherapy is not recommended and should be reviewed on a case-by-case basis by a team of neurologists and psychiatrists.1 For those who do not respond to first-line therapy with IVIG, plasma exchange, or high-dose corticosteroids, second-line immunotherapy with rituximab, cyclophosphamide, or both can significantly improve the outcome and decrease the frequency of relapses.7
In addition to immunomodulation, psychotic symptoms should be specifically managed. For the treatment of agitation, avoid high-potency antipsychotics (eg, haloperidol, risperidone) as they can worsen motor symptoms.3 Instead, use low-dopamine receptor blocking second-generation antipsychotics, starting at low doses and up-titrating slowly.1 Highly sedating medications such as quetiapine, chlorpromazine, valproic acid, and benzodiazepines have anecdotally been useful for psychiatric symptoms,3 particularly benzodiazepines for catatonia and unclear cases of psychosis or aggression.1 ECT can be helpful for immediate symptom control.1 After the patient’s recovery from the ANMDARE episode, obtain their baseline serum and CSF titers to monitor for possible relapses; of the 2, the CSF titer is a more reliable indicator of new-onset relapse. Nevertheless, clinicians should base their treatment decisions more on clinical evaluation, rather than antibody titers, as the relationship among CSF antibody titer, prognosis, and relapse is still being studied.
Monitoring for recurrence is lifelong, as ANMDARE episodes can reoccur months to years after initial onset. Further randomized controlled trials are needed for a universal consensus on management of ANMDARE.
Dr Li is a recent graduate of Texas A&M College of Medicine and has recently joined the Texas A&M Psychiatry Residency Program in Bryan, Texas. Dr Bourgeois is chair, Department of Psychiatry, Baylor Scott & White Health, Central Texas Division, and clinical professor of medical education, College of Medicine, Texas A&M University Health Science Center, Temple, Texas.
1. Pollak TA, Lennox BR, Müller S, et al. Autoimmune psychosis: an international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin. Lancet Psychiatry. 2020;7(1):93-108.
2. Huang Q, Xie Y, Hu Z, Tang X. Anti-N-methyl-D-aspartate receptor encephalitis: a review of pathogenic mechanisms, treatment, prognosis. Brain Res. 2020;1727:146549.
3. Kayser MS, Titulaer MJ, Gresa-Arribas N, Dalmau J. Frequency and characteristics of isolated psychiatric episodes in anti-N-methyl-d-aspartate receptor encephalitis. JAMA Neurol. 2013;70(9):1133-1139.
4. Balu R, McCracken L, Lancaster E, et al. A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis. Neurology. 2019;92(3):e244-e252.
5. Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol. 2014;13(2):167-177.
6. Mo Y, Wang L, Zhu L, et al. Analysis of risk factors for a poor prognosis in patients with anti-N-methyl-D-aspartate receptor encephalitis and construction of a prognostic composite score. J Clin Neurol. 2020;16(3):438-447.
7. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12(2):157-165.
8. van Sonderen A, Arends S, Tavy DLJ, et al. Predictive value of electroencephalography in anti-NMDA receptor encephalitis. J Neurol Neurosurg Psychiatry. 2018;89(10):1101-1106.
9. Wang H, Xiao Z. Current progress on assessing the prognosis for anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Biomed Res Int. 2020;2020:7506590.
10. Warren N, O’Gorman C, McKeon G, et al. Psychiatric management of anti-NMDAR encephalitis: a cohort analysis. Psychol Med. 2019;51(3):435-440.
11. Zhu J, Li Y, Zheng D, et al. Elevated serum and cerebrospinal fluid CD138 in patients with anti-N-methyl-d-aspartate receptor encephalitis. Front Mol Neurosci. 2019;12:116.
12. Broadley J, Seneviratne U, Beech P, et al. Prognosticating autoimmune encephalitis: a systematic review. J Autoimmun. 2019;96:24-34. ❒