James A. Bourgeois, OD, MD

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).

 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.

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 

 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 

Once psychiatrists apply the general template, they may notice that the details of the case do not quite fit. Hence, 

. 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 

; 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.

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 

 (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.

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 

 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.

The growing literature on recurrence and prognosis in ANMDARE can guide the psychiatrist in management of these patients over time (

Pollak and colleagues presented an integrated approach to the identification of possible, probable, and definite 

 and outlined the options for their appropriate diagnosis and management.

 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 

 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 

 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 (

). 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.

Table 2. NEOS Score and Functional Status at 1 Year

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.

 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

 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.

 of 571 patients with ANMDARE found that that 23 patients (4%) developed isolated psychiatric episodes: 5 at disease onset and 18 during relapses (

 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.

Figure. Psychiatric Episodes in Patients With ANMDARE

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.

 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.

 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

 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.

relationship between EEG results and ANMDARE recognition

, van Sonderen et al conducted a retrospective cohort study of 35 adults and 18 children with ANMDARE.

 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

 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 

 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 

 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.

 studied the CD138 levels as well as many other biomarkers in the serum and CSF of patients with ANMDARE.

 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), 

 reviewed 44 publications representing 2823 reported patients, of which 27 studies and 1566 cases were ANMDARE.

 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.

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 

 in the treatment of the initial encephalitis episode,

 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.

 The ACS (age, disturbance of consciousness, and slow waves on EEG) score may be valuable in predicting the 

 The NEOS score may be used to predict the functional status after 1 year,

 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 (

 If the serum or CSF is positive for any onconeural antibodies, consider a 

Table 3. A Workup for Suspected Recurrent ANMDARE

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.

 Therefore, treatment decisions should be based more on 

 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 

 (serum and CSF using 2 different techniques [eg, cell-based assay, brain immunohistochemistry, IIFT, ELISA, RIA, nanoliter immunoassay]).

 between neurologists and psychiatrists is necessary to manage co-occurring neuropsychiatric symptoms.

 If the patient presents with rapidly progressive, refractory psychosis, and cognitive decline, consider

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).

 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.

 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

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.

low-dopamine receptor blocking second-generation antipsychotics

, starting at low doses and up-titrating slowly.

 Highly sedating medications such as quetiapine, chlorpromazine, valproic acid, and benzodiazepines have anecdotally been useful for psychiatric symptoms,

 for catatonia and unclear cases of psychosis or aggression.

 ECT can be helpful for immediate symptom control.

 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.

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. 

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

Anti-N-methyl-D-aspartate receptor encephalitis: a review of pathogenic mechanisms, treatment, prognosis

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

4. Balu R, McCracken L, Lancaster E, et al. 

A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis

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

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

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

8. van Sonderen A, Arends S, Tavy DLJ, et al. 

Predictive value of electroencephalography in anti-NMDA receptor encephalitis

Current progress on assessing the prognosis for anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis

10. Warren N, O’Gorman C, McKeon G, et al. 

Psychiatric management of anti-NMDAR encephalitis: a cohort analysis

Elevated serum and cerebrospinal fluid CD138 in patients with anti-N-methyl-d-aspartate receptor encephalitis

12. Broadley J, Seneviratne U, Beech P, et al. 

Prognosticating autoimmune encephalitis: a systematic review

Articles

This CME covers how CNS-related psychosis may require medical interventions beyond antipsychotic and other psychotropic medications.

Prognostic Considerations in Anti-NMDA Receptor Encephalopathy With Psychiatric Manifestations

FROM THE ACADEMY OF CONSULTATION-LIAISON PSYCHIATRY

“Ms Zorn” was a 45-year-old woman with no previous psychiatric history who presented with a 2-month period of “feeling like I am losing myself” and seeing “visually distorted faces.” Faces of people she was looking at would appear to be hideously elongated, with the facial components distorted, as if it was melting. Cars would also appear to be more round than usual.

She was admitted to an inpatient psychiatry unit for unspecified psychosis, but after 2 days she was transferred to a general medical unit for additional medical evaluation. She was started on 25-mg quetiapine bid, which was titrated to 200 mg bid. Lumbar puncture was completed to rule out central nervous system infection or autoimmune encephalopathy, with results pending at the time of transfer to an academic medical center for higher level of multispecialty care.

On interview, she said that she felt like she was “losing” herself and reported visual distortions of “faces melting.” Ms Zorn was able to recognize faces and colors. She reported photophobia. She had headaches, which were relieved with ketorolac. Her husband reported that she had new onset of episodes of shaking her arms in a circular motion. She would also walk around the room in circular patterns while saying to herself that she was “lost.”

Ms Zorn had decreased appetite, weight loss, and decreased sleep. She denied depressed mood, decreased energy, mania, trauma, or previous problems with memory. She denied auditory hallucinations and suicidal/homicidal ideation. She denied a family history of suicide and psychiatric illness. Developmental history was unremarkable. She had no history of substance abuse.

On mental status examination, she was awake, alert, oriented to person, time, place, and situation. She continued to experience visual distortions of “faces melting.” Ms Zorn’s thought process was linear and coherent. Affect was mildly anxiously perplexed, non-labile, and non-tearful. Speech was normal. Insight and judgment were marginal. Her Montreal Cognitive Assessment (MoCA) score was 10/30. Her decisional capacity was impaired, and the screening neurological examination was non-focal.

Due to the atypical presentation of psychotic disorder, the full workup included a neurology consultation; brain MRI and lumbar puncture results were normal, except for autoimmune encephalitis results that were pending. Serum HIV, syphilis, vitamin B12, lead, rapid plasma regain (RPR), anti-nuclear antibody ammonia, and thyroid stimulating hormone (TSH) levels were normal; EEG was unremarkable. Pelvic ultrasound and CT were ordered to rule out ovarian teratoma. Quetiapine regimen was changed to 100 mg in the morning and 300 mg in the evening.

Ms Zorn was seen in follow-up on hospital day 2. Neurology had started her on 1-g methylprednisolone daily for a 5-day course for presumed 

. She was placed on a continuous EEG. On exam, she reported feeling better compared with the previous day. She no longer reported any distortions of faces or objects in the room, although she did report some “blue dots” in her field of view. She had 3 hours of sleep the previous night. Her husband noted that the she had decreased episodes of her aimless pattern of waving her arms in a circular motion. Her MoCA score was 14/30. Due to the significant improvement in her hallucinations following the first dose of methylprednisolone, the scheduled quetiapine was held.

When seen on hospital day 3, Ms Zorn said that she could fall asleep, but had trouble staying asleep. She had an episode where she got up and walked around the room purposelessly. Her MoCA score was 13/30 and decisional capacity was impaired. Quetiapine 50 mg post merdien (PM) was started to address poor sleep. On hospital day 4, she reported that her visual phenomena had returned, with her seeing “pixels” (flashing punctate lights) and “faces melting.” She had had difficulty sleeping. MoCA was 12/30 with continued limited insight, judgment, and 

. Quetiapine was increased to 100 mg pm and mirtazapine 7.5 mg pm was started to improve sleep.

On hospital day 5, her husband reported that she had had continued visual phenomena of pixels and faces melting. Ms Zorn was only able to sleep for 1.5 hours after receiving quetiapine and mirtazapine. On exam, she reported the visual hallucinations and had a MoCA score of 12/30. Continuous EEG was reported as normal and abdomen CT was negative for ovarian teratoma. To address continued 

and poor sleep, quetiapine was increased to 100 mg am and 300 mg pm. Mirtazapine was increased to 15 mg pm.

Ms Zorn was seen again on hospital day 6. She reported that she had been able to sleep for 8 hours. She denied any visual “melting” of faces but stated that the “world looked pixelated at times.” MoCA score was 14/30. Subsequently, when seen on hospital day 8, she stated that she was still seeing pixels in the periphery of her visual field. MoCA score improved to 17/30. Quetiapine was consolidated to 400 mg pm.

She was next seen on hospital day 10. The cerebrospinal (CSF) encephalopathy panel came back positive for anti-NMDA receptor antibody R1, confirming a diagnosis of anti-NMDA (N-methyl-D-aspartate)-receptor encephalopathy (ANMDARE). Neurology started plasmapheresis for 7 treatments, every other day. She had no hallucinations. She reported that she was getting “deep sleep.” MoCA score was 16/30. A quetiapine 50 mg am dose was added.

Plasmapheresis started on hospital day 11. The patient denied any visual distortions. She said that she felt significantly better than the previous week; MoCA score was 16/30. When next seen on hospital day 15, Ms Zorn reported sleeping from 11:00 pm to 5:30 am. She denied visual distortions. MoCA score had improved to 21/30; however, 

continued to be impaired. On hospital day 18, she was doing well. She had declined her scheduled quetiapine the previous day “to give it a try.” She no longer saw distorted faces. She had no gait disturbance. MoCA score improved further to 25/30. Given her improved mental status, the psychiatry team decided that she had recovered her decision-making capacity. Mirtaza-pine was decreased to 7.5 mg pm and quetiapine held.

Ms Zorn was seen for the last time on day 22 of hospital admission. After her final 

treatment, she continued to be free of psychotic symptoms. She stated that she was “doing better than last week,” and that she was “80% back to normal.” She was sleeping well and was increasingly physically active during the day. She was excited to return home; MoCA score was 22/30. Decisional capacity continued to be intact. Mirtazapine 7.5 mg bedtime was continued.

As she was medically stable for discharge, she was referred for psychiatric follow-up near her home. She was advised that any future recurrence of psychosis should first be addressed as if it was a recurrence of delirium and/or ANMDARE.

ANMDARE is a relatively recently described illness that may present with psychiatric symptoms, neurologic symptoms, or both (either simultaneously or sequentially).

 While the exact mechanism remains obscure, antibodies to the NMDA receptor (on CSF and/or serum assay) is 

 Management includes empiric treatment of manifest symptoms and immunomodulation systemic therapies.

ANMDARE is important to the consultation-liaison psychiatrist for a number of reasons. First, its presentation lies in the “neuropsychiatric borderland” involving collaboration between psychiatry and neurology (as in other neuropsychiatric illnesses like Parkinson disease, Huntington disease, and multiple sclerosis). Second is its importance in the often hard-to-define syndrome of “atypical psychotic disorder.” In comparison to the classic presentation of schizophrenia, ANMDARE features a later age of onset, female predominance, visual hallucinations, relative lack of cognitive disorganization, and a lack of an extended prodromal period.

This case illustrates the atypical presentation of psychotic illness rather well. Ms Zorn was in her mid-40s, of high academic and professional achievement, adaptive social function; without a clear prodrome, she relatively promptly developed a psychotic picture with striking and disturbing visual hallucinatory phenomena. Clinical suspicion for ANMDARE was confirmed with reference laboratory (Mayo Clinic) results of + R1 antibody to NMDA receptor on CSF analysis. This was accomplished in the context of a thorough laboratory evaluation for other esoteric causes of atypical psychotic illness.

Empiric treatment of the psychiatric symptoms with mirtazapine and quetiapine, concurrent with 2 rounds of immunomodulation therapy, led to amelioration of symptoms and near complete cognitive recovery in a period of 2.5 weeks. Her cognitive status based on objective measure with the 

(MoCA) was initially in the moderate to severely impaired range.

 With comprehensive treatment, Ms Zorn’s cognitive status improved to a level of only mild impairment. Correspondingly, her decisional capacity improved from significantly impaired to largely intact over the same period.

Psychiatrists assessing and treating patients with atypical presentation of psychotic illness should actively consider a diagnosis of ANMDARE as explanatory.

 In female patients with suspicion of ANMDARE, pelvic ultrasonography and/or CT scan should be ordered to rule out commonly co-occurring ovarian teratoma.

 Patients with ANMDARE who are treated with high-dose intravenous corticosteroids should be monitored (and treated for) any corticosteroid-associated psychiatric adverse effects, which can overlap with the atypical psychotic symptoms at illness onset. Empiric treatment with psychopharmacology for psychotic and/or depressive symptoms should be pursued, although such medications may not be necessary indefinitely once definitive immunomodulation therapy is completed.

ANMDARE should be on the differential for atypical psychosis, with an expectation of a thorough search for laboratory and systemic clinical (especially neurologic) findings, empiric treatment of psychiatric symptoms, and reassessment of the patient as immunomodulation therapy is completed. Prospective study of ANMDARE illness cohorts are needed to quantify recurrence risk, need for ongoing intervention, and ultimate prognosis.

Consultation-liaison psychiatrists working in academic medical centers may be in a position to assist multispecialty teams in the identification, diagnosis, management, and ongoing follow-up of these patients. As with any illness that affects cognitive function, attention to and serial assessment of decisional capacity is a critical part of C-L psychiatry care, especially as pertains to patient consent for major immunomodulation therapies.

 is chair, Department of Psychiatry, Baylor Scott & White Health, Central Texas Division, and clinical professor for medical education, Texas A&M University Health Science Center, Temple, TX. 

is a medical student, Texas A&M University Health Science Center, Temple, TX. The authors report no conflicts of interest concerning the subject matter of this article.

1. Tuzun E, Zhou L, Baehring JM, et al. Evidence for antibody-mediated pathogenesis in anti-NMDAR encephalitis associated with ovarian teratoma. 

2. Gresa-Arribas N, Titulaer MJ, Torrents A, et al. 

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. 

4. Warren N, O’Gorman C, McKeon G, et al. Psychiatric management of anti-NMDAR encephalitis: a cohort analysis. 

5. 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. 

6. Nasreddine Z. Montreal Cognitive Assessment (MoCA) Administration and Scoring Instructions. Montreal Cognitive Assessment. Accessed July 9, 2020. 

http://www.mocatest.org/wp-content/uploads/2015/tests-instructions/MoCA-Instructions-English_2010.pdf

In comparison to the classic presentation of schizophrenia, ANMDARE features a later age of onset, female predominance, visual hallucinations, relative lack of cognitive disorganization, and a lack of an extended prodromal period.

Anti-NMDA Receptor Encephalitis With Visual Hallucinations and Cognitive Impairment

Consultation-liaison (C-L) psychiatry is a major psychiatric subspecialty that, within general medical/surgical and academic medical and increasingly in primary care settings, serves as the “tip of the spear” for psychiatry. This metaphor reflects consultation-liaison’s place as the most forward clinical psychiatry service in the wider medical world and the opportunity to lead improvements in patient care in all medical services.

Consultation-liaison psychiatrists specialize in the diagnosis and management of psychiatric disorders that are comorbid with general medical/surgical illness. Examples include the psychiatric comorbidity of neurological illnesses (eg, Parkinson disease, multiple sclerosis, cerebrovascular disease), endocrinological illness (eg, diabetes mellitus, hyper- or hypothyroidism), rheumatic illness (eg, systemic lupus erythematosus, giant cell arteritis), and cardiovascular illness (eg, heart disease, vascular disease). In addition to psychiatric comorbidity, there is a broad area of psychiatric adverse effects of systemically administered medications (eg, corticosteroids, other immunomodulators, CNS-active agents) and the often complicated systemic medical and 

 of medications used for primary psychiatric illness (eg, anticonvulsants, lithium, antipsychotics, antidepressants).

The general medical context of consultation-liaison psychiatry practice means that the psychiatric illness profile differs from that of general psychiatry practice. The most common disorders in the general medical setting include dementia, delirium, other neurocognitive disorders (eg, the sequelae of traumatic brain injury), catatonia, substance use disorders, intoxication and withdrawal states, and medical complications of psychiatric interventions (eg, neuroleptic malignant syndrome, serotonin syndrome, medication toxicity states. adverse effects) as well as depressive, anxiety, and substance use disorders. The psychiatric illnesses that constitute much of general psychiatric practice are also seen by consultation-liaison psychiatrists when they are associated with a general medical illness (eg, melancholic/psychotic depressive disorders, acute manic states, acute psychotic states) and when they result from medical illness and the trauma of treatment (eg, acute stress disorder, PTSD following major surgery or intensive care).

Consultation-liaison psychiatrists are expert at the complex task of managing psychiatric illness in the context of the general hospital and the emergency department. The responsibility of the C-L psychiatrist is first to assure that the proper medical evaluation and management are accomplished for the medical stabilization of patients before providing the necessary psychiatric treatment in collaboration with the patient’s clinical team. The C-L psychiatrist then arranges for psychiatric disposition, if and when that is clinically indicated.

Current training models for C-L psychiatry include 2 or more months of core rotation in the standard psychiatry residency program. Following residency there is an additional full academic fellowship year for psychiatrists who wish to qualify for subspecialty board eligibility and certification in consultation-liaison psychiatry.

Modern C-L psychiatry has developed as a distinct model of psychiatric practice. Unlike the care of patients with serious mental illness in long-term inpatient psychiatric facilities or the care for high functioning psychiatric outpatients with psychotherapy, the C-L model 

from placing psychiatric services in general medical hospitals, which began in the mid-20th century. This innovation led to the development of the dual partnered concepts of “consultation” and “liaison” functions in hospital-based psychiatric practice. The consultation role refers to the direct care of the medical inpatient on request from the admitting physician, with recommendations for direct care and brief, in-hospital follow-up. In contradistinction, the liaison function refers to the psychiatrist sharing their understanding and interpretation of behavioral manifestations of psychiatric illness in medical/surgical patients and direct advice to medical and nursing services to improve the care of medical/surgical patients with comorbid psychiatric conditions.

Until recently, with its inpatient medical/surgical hospital heritage, C-L psychiatry was primarily hospital-based subspecialty, with the development of one-year fellowships in C-L psychiatry that were primarily inpatient-based. However, in the past 20 years, there has been an accelerating development of outpatient C-L models. This movement involves placing psychiatrists in outpatient specialty medical settings and in primary care, where specialty physicians and primary care physicians work together with psychiatrists to care for patients.

The development of psychiatry in the general hospital led to a movement to establish C-L psychiatry as a specific and differentiated subspecialty of psychiatry. In the US, this happened in 2003 with the establishment of the subspecialty board in psychosomatic medicine (a synonym of consultation-liaison psychiatry) and with the first 

 examinations offered in 2005. The subspecialty has thrived ever since.

We are now in a period of the rapid and robust development of C-L psychiatry, driven by an increasing awareness of the need to treat the whole patient as well as by increasing amounts of evidence that indicates the clinical and financial importance of better management of psychiatric illnesses in patients under general medical care. Two major medical journals, 

, are devoted specifically to C-L psychiatry scholarship.

There are a rapidly increasing number of C-L psychiatry fellowships. The leading national and international organization, the Academy of Consultation-Liaison Psychiatry (ACLP; 

) has almost 2000 members; the most recent annual meeting in San Diego, CA, attracted more than 1200 attendees-an all-time record. The next annual meeting is in Phoenix, AZ, in November 2020 (

) and promises to be even larger. This spectacular growth largely reflects the expansion of C-L psychiatry beyond academic medical centers into community and other non-academic hospitals.

Within the broader subspecialty of C-L psychiatry, there has been further differentiation to better serve the needs of specific types of patients. Examples include HIV psychiatry, transplant psychiatry, neuro-psychiatry, psycho-oncology, and cardiovascular psychiatry. While these areas are all within the scope of practice of C-L psychiatry, there are C-L psychiatrists whose primary identification is with these sub-subspecialty areas.

Building on the pioneering work of a cadre of C-L psychiatrists such as Wayne Katon, it is increasingly common for mental health services to be embedded within primary care in innovative ways. An example of such is collaborative care, which uses standardized clinical pathways and the extension of psychiatrists’ time by care managers. Care managers deliver care and monitor outcomes under psychiatric supervision. Collaborative care allows primary care services to provide high quality evidence-based care for large number of patients who may have mild to moderate psychiatric illness.

Consultation-liaison psychiatrists have also been early adopters of innovative communication and other technology for advancing patient care. These technologies include the provision of psychiatric care by video communication (telemedicine or telepsychiatry) and the creative use of the electronic health record to enhance psychiatric care for medical patients (eg, standardized clinical pathways, incorporation of outcome and rating measures).

There are many exciting opportunities for C-L psychiatry to improve patient care. It is now clear that all sizeable hospitals must have real-time access to psychiatric consultation (whether in-person or by telemedicine). New proactive and integrated models of inpatient C-L psychiatry are increasing the field’s reach and effectiveness. The incorporation of standard clinical approaches to psychiatric illnesses (eg, dementia, delirium, catatonia, traumatic brain injury) commonly encountered in C-L practice into electronic health records is ensuring better and safer care for patients with these high-acuity psychiatric illnesses. Greater availability of psychiatric consultation for medical outpatients, with standardized pathways for patients with the common psychiatric comorbid illnesses in primary care, is extending consultation-liaison care outside the hospital setting.

Consultation-liaison psychiatrists will also continue to lead in many areas. These include emerging areas of medical genomics in psychiatry, the monitoring of drug-drug interactions, and the management of behavioral and cognitive syndromes with complicated attributable systemic illness causes. Consequently, C-L psychiatry has an important place at the forefront of clinical, academic, and administrative leadership for psychiatry.

The “tip of the spear" metaphor reflects consultation-liaison’s place as the most forward clinical psychiatry service in the wider medical world that can lead improvements in patient care.

James A. Bourgeois, OD, MD

Articles

Prognostic Considerations in Anti-NMDA Receptor Encephalopathy With Psychiatric Manifestations

Anti-NMDA Receptor Encephalitis With Visual Hallucinations and Cognitive Impairment

Consultation-Liaison Psychiatry: The Interface of Psychiatry and Other Medical Specialties

What Psychiatrists Need to Know About the Determination of Dispositional Capacity

Bioethical Challenges for Psychiatrists: Determination of Decisional Capacity

The Role of Psychiatrists in HIV Prevention