Anti-NMDAR Encephalitis: CPCP Review

We had a Clinical Problems in Consult Psychiatry (CPCP) conference recently that made us scratch our heads about the role of psychiatric consultants. It was about the psychiatric manifestations of anti-NMDA receptor encephalitis, a syndrome which has been increasingly recognized since 2007. Depending on which journal you read, you get a slightly different perspective on what to do about the protean psychiatric symptoms, which often are the first features to appear. This is why they may first present to psychiatrists.

The most succinct summary of what the condition is comes from a practical journal of psychiatry I recently mentioned in a previous post, The Journal of Psychiatric Practice (“We Need a Journal of Practical Psychiatry”, He said… – The Practical Psychosomaticist [1]:

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a newly described form of encephalitis associated with prominent psychiatric symptoms at onset. Recognition of the symptom complex is the key to diagnosis. Most patients with anti-NMDAR encephalitis develop a multistage illness that progresses from initial psychiatric symptoms to memory disturbance, seizures, dyskinesia, and catatonia. Psychiatric manifestations include anxiety, mania, social withdrawal, and psychosis (i.e., delusions, hallucinations, disorganized behavior). The disorder is more common in females (80%), in approximately half of whom it is associated with an underlying ovarian teratoma. Treatment involves immunosuppression, with steroids and intravenous immunoglobulin considered first line. The disorder is particularly relevant to psychiatrists, because most patients are initially seen by psychiatric services. Psychiatrists should consider anti-NMDAR encephalitis in patients presenting with psychosis as well as dyskinesia, seizures, and/or catatonia, especially if there is no history of a psychiatric disorder.

However, the article we chose for our review was published in 2011 by Chapman and colleagues in the American Journal of Psychiatry [2]. The upshot was that most psychiatric treatments were inconsistently effective and secondary and that the focus should be on treating the underlying disease with immunotherapy.

Other authors thought that psychiatric treatments should not be ignored, especially for the catatonia, for which electroconvulsive therapy can be helpful [3]. This is a both/and approach, combining psychiatric and medical expertise, treating the syndromes clinicians see:

A few case reports suggest ECT either alone or in conjunction with other medical interventions may be effective in this population. Braakman et al. described a previously healthy 47-year-old man who was initially diagnosed with encephalitis lethargica (and was only later diagnosed with anti-NMDAR encephalitis), who failed to show clinical improvement with high-dose steroid pulse therapy and lorazepam. He only achieved clinical remission following treatment with ECT. A large case series reported only one response to ECT. In one case report, ECT was reported to be useful in ameliorating symptoms of catatonia; full recovery was limited until the underlying tumor was removed. The complexity of the treatments reported in the literature suggests that an integrated symptom-based treatment should be considered in anti-NMDAR encephalitis.

Our patient only improved significantly after receiving immunotherapy and tumor removal as well as ECT and high-dose benzodiazepines. Our rationale was to use immunotherapy to address the primary immune-mediated encephalitis combined with ECT and high-dose benzodiazepines to manage the symptoms of malignant catatonia. C.R.’s symptoms of malignant catatonia did not resolve until pharmacotherapy was combined with ECT. The pattern of response in our patient raises the hypothesis that treatment of anti-NMDAR encephalitis requires both management of the effect of the antibody on the brain and prevention of the antibody production through a combination of surgical removal of the stimulating tumor when present and immunotherapy. The immunotherapy is thought to target both B cells and antibody production via rituximab and steroid treatment. ECT and benzodiazepines potentially target the effects of the antibodies on the brain, providing management of symptoms until immunotherapy is effective. In animal models, ECT has been shown to upregulate NMDARs in the brain, potentially providing one explanation as to why ECT is effective in this population. This case illustrates that symptom management with ECT is necessary in severe cases when benzodiazepines are not sufficient. ECT targets the effect of the antibodies on the brain, providing protection until immunotherapy and tumor removal successfully stop antibody production. We propose that the risk of catatonic symptoms remains until there is decay of antibodies in the system. If this hypothesis is correct, then treatment of anti-NMDAR encephalitis presenting with malignant catatonia should include a combination of immunotherapy with benzodiazepines or ECT or both.

The perspective of Wilson and colleagues above is understandable. They are consulting psychiatrists and Psychosomatics is the practical journal for Psychosomatic Medicine specialists.

And then there was the perspective of neurologists gathered from an important study of 571 patients [4]. The abstract suggests immunotherapy is effective for the physical as well as the psychiatric symptoms, similar to the conclusion by psychiatrists as reported by Chapman and colleagues in the American Journal of Psychiatry:

Findings from this study have several practical implications. For patients with a history of anti-NMDAR encephalitis, any behavioral change might represent relapse. In these patients, serum and CSF antibody testing should be obtained if possible, and they should be treated aggressively with immunotherapy and symptomatic management of psychiatric symptoms. No specific guidelines exist for treatment of psychiatric symptoms in this setting, but clinical experience and anecdotal evidence suggest use of highly sedating medications such as quetiapine, chlorpromazine, valproic acid, and benzodiazepines; high-potency antipsychotics like haloperidol have been observed to exacerbate motor symptoms in patients with anti-NMDAR encephalitis. In this series, most patients received steroids, but generally for a short period. Most importantly, an interdisciplinary approach to management is needed. Given that relapses may represent the presence of a previously unidentified or recurrent tumor, patients should have tumor screening, mainly focusing on a teratoma of the ovary. In patients presenting to a psychiatrist with new-onset psychosis or mania, history of illness and other clinical data should serve as a guide as to whether CSF and serum analysis is necessary (keeping in mind that in 15% of patients, antibodies are detected only in CSF). History of encephalitis or encephalopathy of unclear etiology, mild neurological abnormalities such as transient facial twitching, and abnormal but nonspecific findings on EEG or MRI are all examples of findings that might prompt antibody studies.

Note that Kayser and colleagues mention that an “interdisciplinary approach to management is needed”. It’s also worth pointing out that Wilson and colleagues (the Psychosomatic Medicine specialists promoting ECT and high dose benzodiazepines in this population) acknowledge that “A large case series reported only one response to ECT”.

This is anything but an exhaustive review and comments are welcome. It seems to me that the positions advanced in these papers seem to depend to some degree on the subspecialty in which they practice, which could mean we need to pay more attention to a collaborative approach to helping these patients recover. As always, more research is needed.

References:

1. Ryan, S. A., D. J. Costello, et al. (2013). “Anti-NMDA receptor encephalitis: a cause of acute psychosis and catatonia.” J Psychiatr Pract 19(2): 157-161.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a newly described form of encephalitis associated with prominent psychiatric symptoms at onset. Recognition of the symptom complex is the key to diagnosis. Most patients with anti-NMDAR encephalitis develop a multistage illness that progresses from initial psychiatric symptoms to memory disturbance, seizures, dyskinesia, and catatonia. Psychiatric manifestations include anxiety, mania, social withdrawal, and psychosis (i.e., delusions, hallucinations, disorganized behavior). The disorder is more common in females (80%), in approximately half of whom it is associated with an underlying ovarian teratoma. Treatment involves immunosuppression, with steroids and intravenous immunoglobulin considered first line. The disorder is particularly relevant to psychiatrists, because most patients are initially seen by psychiatric services. Psychiatrists should consider anti-NMDAR encephalitis in patients presenting with psychosis as well as dyskinesia, seizures, and/or catatonia, especially if there is no history of a psychiatric disorder. We present the case of a 37-year-old woman who demonstrated many of the key clinical features of this potentially treatable disorder.

2. Chapman, M. R. and H. E. Vause (2011). “Anti-NMDA receptor encephalitis: diagnosis, psychiatric presentation, and treatment.” Am J Psychiatry 168(3): 245-251.

A growing literature describes the clinical presentation, diagnosis, and pathophysiology of anti-NMDA (N-methyl-d-aspartic acid) receptor encephalitis. Once conceptualized as a condition primarily affecting adult women and frequently associated with tumors, anti-NMDA receptor encephalitis is increasingly recognized in males, in children, and in the absence of tumors. Despite the expanding knowledge base, much remains to be understood about effective treatments. The little available information on management focuses primarily on tumor management and immunotherapy to control the antibody response. Limited information is available on the management of psychiatric symptoms in these complex, often critically ill patients. Here we describe, through an illustrative case example, the clinical characteristics of anti-NMDA receptor encephalitis in an adolescent male. We also outline other disease processes to be considered in the differential diagnosis and describe currently used interventions, including psychotropic medications.

3. Wilson, J. E., J. Shuster, et al. “Anti-NMDA Receptor Encephalitis in a 14-Year-Old Female Presenting as Malignant Catatonia: Medical and Psychiatric Approach to Treatment.” Psychosomatics(0).

4. Kayser, M. S., M. J. Titulaer, et al. (2013). “Frequency and characteristics of isolated psychiatric episodes in anti–n-methyl-d-aspartate receptor encephalitis.” JAMA Neurology: -.

Importance  Patients with anti–N-methyl-d-aspartate receptor (NMDAR) encephalitis often develop prominent psychiatric manifestations. The frequency and type of isolated psychiatric episodes (pure psychiatric symptoms without neurological involvement) either as initial presentation of the disease or as relapse are unknown.Objective  To determine the frequency, symptoms, and outcome of isolated psychiatric episodes in a cohort of patients with anti-NMDAR encephalitis.Design, Setting, and Participants  Observational cohort of patients diagnosed during a 5-year period (median follow-up, 2 years). A total of 571 patients with IgG antibodies against the NR1 subunit of the NMDAR were included in the study. Antibody studies were performed at the University of Pennsylvania and the University of Barcelona, and clinical information was obtained by us or referring physicians.Main Outcomes and Measures  Frequency, type of symptoms, and outcome of patients with anti-NMDAR encephalitis and isolated psychiatric manifestations.Results  Of 571 patients, 23 (4%) developed isolated psychiatric episodes, 5 at disease onset and 18 during relapse. For all 23 patients, age (median, 20 years), sex (91% female), and tumor association (43%; ovarian teratoma in all cases) were similar to the population at large. Predominant symptoms included delusional thinking (74%), mood disturbances (70%, usually manic), and aggression (57%). Brain magnetic resonance imaging findings were abnormal in 10 of 22 patients (45%) and cerebrospinal fluid analysis showed pleocytosis in 17 of 22 patients (77%). Eighty-three percent of the patients had full or substantial recovery after immunotherapy and tumor resection when appropriate. After relapse, 17 of 18 patients (94%) returned to a similar or better prerelapse functional level.Conclusions and Relevance  Isolated psychiatric episodes are rare but can occur as initial onset or relapse of anti-NMDAR encephalitis. Recognition of these episodes is important because they respond to immunotherapy. In patients with new-onset psychosis, having a history of encephalitis, subtle neurological symptoms, and/or abnormal results on ancillary tests should prompt screening for NMDAR antibodies.

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