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"Lilly” lived as well as she did, as long as she did, because the sun does not shine in SoHo. In New York City’s SoHo district, cast-iron constructions more than a century old cast long, dark shadows, like the black shadows in 

 comic books. Narrow alleyways separate back-to-back buildings, leaving almost no room for shafts of sunlight to seep in. Film noir–style shadows are abundant in that part of town, as they are in 

 fictional Gotham City, inspired by Manhattan’s cast shadows.

SoHo began as a manufacturing zone, where floor-through factories did not demand sunny cityscape views. Yet today’s SoHo is a fashionable area with little trace of its past. It housed my psychiatry practice for the last decade. When manufacturing left New York City, those large SoHo spaces turned into artists’ lofts, which then gave way to art galleries. Gradually, pricey designer boutiques replaced many galleries, and fashionably dressed shoppers and shop salespeople displaced artists.

Lilly was unlike other SoHo shop salespeople who wore unaffordable dress samples that turned them into breathing billboards. She was an apprentice jewelry designer at an established shop on Prince Street, a few blocks from my office. Even though she was only an intern and still a student, she had already amassed an impressive portfolio. 

She was wearing one of her creations when she arrived at my office for her first appointment—a little late, because passers-by had stopped her on the street to ask where she sold her unique brooches. Such was life in SoHo.

Lilly was referred by Fashion Institute of Technology (FIT) Student Health Services to resume attention-deficit/hyperactivity disorder (

) treatment that had begun in grade school. FIT Student Health Services addressed acute symptoms only and referred students with long-standing conditions to private psychiatrists like me. 

Records documenting treatment that started when Lilly was young had arrived in advance, making it easy enough to refill her prescription for amphetamine salts. It was equally easy to add a selective serotonin reuptake inhibitor (SSRI)—and supportive therapy—when her social 

 surged in this city of strangers, and when she felt overwhelmed by the stereotypically assertive New Yorkers who surrounded her.

Previously, Lilly was treated at a federally funded clinic. This rural area grappled with physician shortages. Her stimulants did not relieve the dyslexia that caused her more distress than inattention—but there were no local resources for cognitive remediation to help with reading and spelling. Luckily, Lilly preferred an arts-related career that sidestepped academic studies.

As her social anxiety subsided, she shared details about her early life in small-town Phoenicia, which was a few hours from Manhattan, geographically speaking, but light-years away on a cultural level. Lilly was forthcoming about her struggles in school and the fact that most of her family members lacked so much as a high school diploma, much less advanced degrees. 

Still, despite her dyslexia—or maybe because of it—Lilly created clever necklaces from cans that she scavenged near the Esopus Creek, where shabby trailer camps contrasted with picturesque waterfalls that attracted tourists.

Phoenicia was a simple place, known for camping and tubing and long stretches of tall, fragrant pine trees. There, Lilly’s mother tended garden at a vacation home owned by a well-to-do Brooklyn couple. Her father functioned as a live-in caretaker, allowing the family to live rent-free. Their basement apartment was drafty and cold in the winter, when the owners were away and the heat was off, but it was still better than the trailers that lined the riverbanks, according to Lilly.

Her family lived underground—no taxes, no voting—until Lilly applied for a state scholarship. But every weekend, her father packed his pick-up truck with a fresh supply of repotted hostas, selling them to second-home owners. Lilly joked about weekenders’ willingness to pay outsize prices for minimal efforts needed to propagate common plants that grew in their shade garden.

Eventually, Lilly’s father added her found-material brooches and bracelets to his hosta display. This caught the eye of an elderly tourist, who suggested that she create a portfolio and apply for a scholarship to FIT so she could hone her skills and prepare for a “real world” career. Lilly had never heard the word “portfolio” before, but she was impressed when she heard that both husband and wife were college professors. 

So, she followed their advice. She won a scholarship, thanks to this chance encounter. Her creations also impressed a jeweler in SoHo, who offered her an internship at his shop, with a chance to make jewelry from “real” metals, not just discarded metal cans.

At each appointment, Lilly shared more details of her day-to-day life. She made her way to work early each morning, exiting the tenement apartment she shared with an elderly aunt on Mulberry Street, located a short, shaded block from my office. She scheduled the earliest appointment available and then darted between the shadows, crossing narrow cobblestone streets that paved those deep caverns created by cast-iron towers. 

To commute to FIT, she jumped on the N train at the Prince Street subway stop, half a block away. To travel to her job at the jewelry store—which offered course credit toward her jewelry-making certificate—she sped down Prince Street in the opposite direction. 

Sometimes, she said, she headed for a hidden alley near Houston Street, where she studied at a library that was sheltered from public view but gave her a great angle from which to watch discreetly staged fashion shoots at the far end of the alley.

Lilly did not resent her limited itinerary, for she found the New York City crowds too overwhelming, and she appreciated the predictability of a set schedule. And Lilly’s life was indeed predictable until something changed in late winter.

For Presidents’ Day weekend, a classmate invited her on a ski trip at an upstate resort—and that was when things started to shift. Embarrassed to admit that she could not afford a lift ticket, much less skis, Lilly sat on the sidelines for hours, near the snow-covered and sun-drenched trails. Upon return, she complained that her hands hurt, and that her fingers turned blue.

Lilly was describing Raynaud syndrome, which could worsen with vasoconstricting stimulants. Still, it seemed odd that such an adverse effect (AE) started so suddenly, after so many years on the same medication. Besides, she lived further north, where winters were far worse, yet she never previously had such symptoms in the cold. Then the clues started to fall into place. She also began experiencing fatigue once she sat outside on the slopes, which was equally strange, considering that stimulants are energizing and are sometimes used (illicitly) to combat fatigue.

I was unwilling to write these symptoms off to AEs, but I was also unwilling to continue a stimulant that could conceivably worsen Raynaud, especially since the medication offered minimal benefit for Lilly’s major dyslexia symptoms. So, we tapered her off the ADHD medication, but the pain in her fingers persisted—even though she was on SSRIs, which can relieve Raynaud. 

It was time to see the primary care physician (PCP) to find other explanations for concomitant fatigue, Raynaud, and joint pain in a 20-year-old woman. I ordered basic labs and added an antinuclear antibody (ANA) test. Her PCP referred her to a rheumatologist when the ANA read a telling 1:360.

Lilly was still waiting for a specialist appointment when college graduation came around. By then, she had a solid job offer from the jewelry boutique that had hired her as an intern. Her family was ecstatic. To celebrate this unanticipated success, they scheduled a surprise family vacation, with plans to drive their battered old pick-up truck south and stay with relatives in Key West, Florida.

Sadly, the trip was not the celebration that had been intended, but it did start to explain her symptoms. While walking outside in the intense Florida sun, Lilly developed a raised, red rash on her nose, which sounded like the butterfly rash of lupus. Her joints hurt so much that she sidestepped the subspecialist and accepted the soonest appointment available, with a nurse practitioner (NP).

Without reviewing her history—or noting that symptoms worsened with strong sunlight (or from reflected sunlight on snowy ski slopes)—the NP prescribed tramadol for pain and sent her on her way. Her family objected and drove her back to SoHo to see me. I was sorry to see Lilly in such distress, but I was happy to hear that she deferred starting a potentially habituating medication before exploring safer approaches or identifying the source of her symptoms.

Luckily, Lilly’s rural health center had ties with the regional medical school. They landed her an immediate immunology appointment at the State University of New York at Albany, not far from her family’s home. The good news was that she would be near her family, and she could continue to design for her new job remotely (but without accessing expensive metals that were available onsite only). 

Her father was thrilled to restart selling her creations from his truck, and she was relieved to return to a pace that was far simpler and slower than SoHo’s. She could rest up with relatives while awaiting more targeted treatment—and simultaneously brace for possibly bad diagnostic news.

This story did not have the happy ending that we hoped for, but the ending could have been worse. I shudder to think of what might have happened, or how this syndrome could have progressed, had someone summarily dismissed her symptoms as AEs of psychotropic medication, without additional assessment. Fortunately, psychiatrists are physicians first.

is an assistant clinical professor of psychiatry and behavioral sciences at Icahn School of Medicine at Mount Sinai in New York, NY.

Psychiatrists Are Physicians First

Smell & Taste Treatment and Research Foundation 

reported an intriguing encounter of delusional hypergeusia in their poster presented at the 2022 NEI Congress.

The case involved a 62-year-old woman whose symptoms developed after exposure to a solvent. She reported to the emergency department with 

, diffuse weakness, and fatigue. She also noted hallucinated smells and tastes. For instance, she initially felt the ambient aroma was replaced by the solvent aroma. As time progressed, the symptoms intensified, with the patient reporting that it felt like “soap was blown into nostril”; cologne exposure left her feeling shortness of breath; and the taste and smell of coffee was replaced by a chemical taste and smell. She also reported panic attacks, and she said her throat and ears closed after watching food commercials.

Upon evaluation in the emergency department, the patient’s blood pressure was 189/90 and pulse was 100. The patient displayed sad mood with congruent affect; she was hyperverbal, loud, circumstantial, and irritable with pressured speech. She appeared disheveled with racing thoughts. Neuropsychiatric testing was performed with some abnormal results. The Go-No-Go Test resulted in abnormal score of 2/6, and she scored 17 (abnormal) on the Center for Neurological Studies Lability Scale. Results of the Clock Drawing Test were normal with a score of 4.

Gustatory and olfaction testing were also completed. The Alcohol Sniff Test and Odor Discrimination/Memory Test was indicative of hyposmia, while the Retronasal Smell Index showed signs of anosmia. Waterless Empirical Taste Test and Propylthiouracil Disc showed scores were considered normogeusia.

The researchers explained that perceived delusional hyperosmia and hypergeusia may be endogenous or exogenous (ie, medically or environmentally induced). “This may represent a variant of the two-factor hypothesis of delusions whereby a distorted sensory perception is then misrepresented in a delusion,” they concluded.

Although delusional and subjective hyperosmia have received increased attention as a result of the

, the researchers noted reports of delusional hypergeusia have not been previously published.

1. Kalita S, Birwatkar D, Sundar A, Hirsch AR. Too sweet to eat: delusional hypergeusia. Poster presented at: 2022 NEI Congress. November 2022; Colorado.

A conference poster shared an unusual case of hallucinations.

In Poor Taste: A Case Report

FROM THE ACADEMY OF CONSULTATION-LIAISON PSYCHIATRY

Academic medical center psychiatry departments, like many other medical specialty areas, often struggle to find contemporary opportunities to grow and consolidate services, maintain market share, and support other clinical divisions. Psychiatry departments traditionally focus on outpatient clinics, hospital-based and emergency-based services, and inpatient psychiatric units as sources of clinical productivity and revenue. Departments with appropriately trained and privileged physicians can supplement clinical revenue with electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and other neuromodulation interventions.

The development and the recent explosion of opportunities in 

 come at an opportune time. Technologically advanced telepsychiatry functionality, combined with robust electronic health record (EHR) systems, permits high-level clinical service delivery from a secure remote platform. Telepsychiatry has been accepted as an alternative to in-person care by patients and physicians and offers clear benefits in the COVID-19 pandemic environment, facilitates care without a transport burden, and affords physicians a viable opportunity for home-based employment.

Our recent experience with telepsychiatry in an academic department of psychiatry led to significant expansion of clinical services provision and increased administrative efficiency. We are now able to provide robust psychiatric support to emergency departments (EDs), hospital inpatient units, outpatient psychiatric services, and primary care clinics in a complex, geographically dispersed, integrated health system in northern and central Texas (from Dallas to Austin).

Baylor Scott & White Health–Temple Department of Psychiatry

Baylor Scott & White Health (BSWH) is the largest not-for-profit health care system in Texas and one of the largest in the United States. Baylor Scott & White Medical Center–Temple is a comprehensive 636-bed academic medical center and level 1 trauma center and is a main clinical education site for the Texas A&M University College of Medicine Health Science Center. Baylor Scott & White Medical Center–Temple is a 2020 and 2021 Fortune/IBM Watson Health Top 100 Hospital and Top 15 Major Teaching Hospital in the US (No. 2 in 2021). The BSWH system includes 2 academic medical centers, 25 community and specialty hospitals, and 175 primary care clinics, all integrated into a network with a common EHR account.

The Department of Psychiatry at Baylor Scott & White Medical Center–Temple is the only academic psychiatry department in the BSWH system. Personnel include 40 faculty physicians and other clinicians, 20 psychiatry residents, and 6 child and adolescent psychiatry fellows. The Department of Psychiatry is backed by the academic partnership among Texas A&M University Health Science Center, College of Medicine, BSWH, and the Central Texas Veterans Health Care System (CTVHCS). Departmental hospital operations at Baylor Scott & White Medical Center–Temple have included a 23-bed inpatient psychiatry unit with 1275 inpatient discharges per year, more than 2000 annual consultation-liaison encounters, and 24-hour coverage of the emergency psychiatry service.

Departmental outpatient operations include the Alcohol and Drug Dependence Treatment Program, Harker Heights behavioral health clinic, McLane Children’s Hospital behavioral health clinic, embedded psychiatric services in primary care clinics, collaborative care support to BSWH primary care clinics, a comprehensive neuromodulation (ECT, rTMS, ketamine) program, and a BSWH systemwide hospital telepsychiatry consultation service, with more than 42,000 total outpatient encounters per year. The department participates in a strategic partnership between BSWH and a 102-bed freestanding psychiatric inpatient facility. The department is a member of the Neurosciences Institute.

In 2019, we initiated a hospital telepsychiatry service to cover 26 BSWH hospitals that had sparse in-person emergency psychiatric services coverage. This service was previously managed by a third-party telepsychiatry vendor but was excessively costly to the system. There was limited communication between consultants and hospital staff. The services were provided by many telepsychiatry psychiatrists; thus, the ED and hospitalists did not have ongoing collegial relationships with the telepsychiatry group for informal advice such as “curbsiding.”

Mindful of these concerns, we started a 7-physician telepsychiatry service. Seven telepsychiatry faculty positions were developed at the Department of Psychiatry and a faculty member was chosen as service director with a 10% leadership stipend. All telepsychiatry physicians recruited had significant experience in telepsychiatry at other institutions; 1 has a geriatric subspecialty, and 2 have a child and adolescent psychiatry (CAP) subspecialty. A project manager with extensive medical administrative experience was appointed to take charge of this telepsychiatry initiative. All telepsychiatry physicians were credentialed at all facilities served, and all were hired as faculty members in the BSWH Department of Psychiatry. Most coverage shifts have 2 or 3 psychiatrists on duty.

Coverage hours are 8 AM to 10 PM weekdays and 8 AM to 8 PM weekends and holidays. Hospitals were brought on board gradually, with all 26 facilities phased in over a 12-month period. Education of local nursing and administrative staffs was a crucial part of this go-live process. Consultation requests are entered within the EHR. The on-duty administrators organize incoming requests and schedule appointments with the physicians on duty. After examining the patient, the physician charts immediately in the EHR. The consultant communicates with the attending physician in real time by EHR secure messaging and provides input for treating the patient.

This service has had a significant impact on ED length of stay and sitter hours. Each week, various metrics are monitored and feedback is provided to the team. Volume grew steadily and the service has been well accepted by all the facilities served across BSWH.

Beginning in 2020, BSWH made the policy commitment to roll out the collaborative care/TEAMcare model (originated at the University of Washington) to all 175 primary care clinics in the system. Clinic physicians in the Department of Psychiatry devote time weekly in 2-hour increments to interface and support the collaborative care manager and primary care providers (PCPs) in the primary care clinics in their standardized treatment of mild/moderate depressive and anxiety disorders according to protocolized treatment algorithms and regular structured outcomes measures.

Patients whose psychiatric illnesses are too severe/complicated for collaborative care management can be seen for a 1-time telepsychiatry-based consultation by the consulting psychiatrist for diagnostic clarity and treatment planning. Often, the single telepsychiatry consultation by the psychiatrist leads to an enhanced clinical care intervention plan that can then be effectuated by the PCP without ongoing local psychiatric care. More severe or complex patients may be disenrolled from the collaborative care model and referred for local ongoing outpatient psychiatric treatment. Currently, 4 department physicians participate in this model.

In response to the pandemic, in 2020 the department pivoted to 100% telepsychiatry for outpatient psychiatric services within a period of 10 days. With subsequent easing of social distancing requirements, we continued to offer the option of telepsychiatry services. Since that time, a persistent fraction of 30% to 35% of outpatients continue to have their care provided exclusively by telepsychiatry. Since offering telepsychiatry outpatient services have been offered, patient satisfaction has significantly increased and outpatient no-show rates, which had never been less than below 10% despite numerous administrative initiatives, have decreased to near zero.

Inpatient Service Staffing by Telepsychiatry

Our department has recently established a partnership for exclusive physician staffing of a freestanding 102-bed inpatient psychiatry unit, operated by a private company, as our inpatient unit. We were able to bring 2 full-time CAP psychiatrists to take care of the inpatient needs of the 28-bed adolescent unit, exclusively via telepsychiatry. This stabilizes the staffing of this unit, which is also a training site for residents and CAP fellows, liberating the rest of the CAP faculty to serve the clinic and children’s hospital. Overnight and weekend on-call/rounding on inpatient units can also be accomplished by telepsychiatry.

Since the beginning of these initiatives, the department has been able to effectively add 12 physician positions that are exclusively telepsychiatry service based. This creates new employment opportunities for physicians skilled at working in this medium, establishes the department as one with substantial expertise in telepsychiatry, and facilitates hands-on experience in telepsychiatry to psychiatry residents who need to master this skill as part of their clinical repertoire. These additional physicians do not require physical office space at the medical campus and need only minimal administrative support. This enables significant departmental growth (at this point, over 33% of our physicians work exclusively via telepsychiatry) and identifies our psychiatry group as a progressive, modern department.

An additional benefit to promoting telepsychiatry-based clinical services is the indirect but significant impact on physician quality of life and burnout prevention. Robust telepsychiatry opportunities can enable many physicians to continue working from home while taking maternity/paternity leave, recovering from an acute illness or injury, or dealing with a chronic illness (such as immunocompromised states) that makes it unsafe to be in a common public setting like a clinic or hospital. Home-based telepsychiatry physicians can avoid the time and expense of commuting, gaining more free time.

Academic psychiatry departments should embrace the opportunity for telepsychiatry as permitting increased size of the faculty cohort, supporting other medical departments needing psychiatry consultation, and providing enhanced work-life balance for faculty members. Embracing modern technology should be seen as an option-generating opportunity to develop, grow, and optimize department functions.

 is medical director of the Baylor Scott & White Medical Center – Temple Hospital Telepsychiatry Service . 

is director of collaborative care for Baylor Scott & White Health and member of the Baylor Scott & White Medical Center–Temple Department of Psychiatry. 

 is an administrator within the Baylor Scott & White Health Department of Psychiatry and manager of the Hospital Telepsychiatry Service. 

 is chair, Department of Psychiatry, Baylor Scott & White Health Medical Center–Temple, Texas.

1. Abrams J, Sossong S, Schwamm LH, et al. 

Practical issues in delivery of clinician-to-patient telemental health in an academic medical center

Telepsychiatry by a public, academic medical center for inpatient consults at an unaffiliated, community hospital

Telepsychiatry consultation for medical and surgical inpatient units

4. DeVido J, Glezer A, Branagan L, et al. 

Telepsychiatry for inpatient consultations at a separate campus of an academic medical center

Emergency management guidelines for telepsychiatry

6. Patel SY, Huskamp HA, Barnett ML, et al. 

Association between telepsychiatry capability and treatment of patients with mental illness in the emergency department

7. Shayevitz C, Breitinger S, Lerario MP, et al. 

Implementation of a centralized telepsychiatry consult service in a multi-hospital metropolitan health care system: challenges and opportunities

8. Mishkin AD, Cheung S, Capote J, et al. 

Survey of clinician experiences of telepsychiatry and tele-consultation-liaison psychiatry

States leverage telepsychiatry solutions to ease ED crowding, accelerate care

Telepsychiatry in integrated care settings

11. Calderone J, Lopez A, Schwenk S, et al. 

Telepsychiatry and integrated primary care: setting expectations and creating an effective process for success

12. Hilty DM, Rabinowitz T, McCarron RM, et al. 

An update on telepsychiatry and how it can leverage collaborative, stepped, and integrated services to primary care

COVID-19 and telepsychiatry: early outpatient experiences and implications for the future

14. Gude J, Subhedar RV, Zhang MH, et al. 

Emerging needs and viability of telepsychiatry during and post COVID-19 era: a literature review

Lessons learned or forgotten? impacts of COVID-19 on the future direction of global (e-)mental health care

16. Kinoshita S, Cortright K, Crawford A, et al. 

Changes in telepsychiatry regulations during the COVID-19 pandemic: 17 countries and regions’ approaches to an evolving healthcare landscape

. 2020;1-8. Published online November 27, 2020.

Telepsychiatry adoption across hospitals in the United States: a cross-sectional study

18. Gardner JS, Plaven BE, Yellowlees P, Shore JH. 

Remote telepsychiatry workforce: a solution to psychiatry’s workforce issues

How can telehealth help academic psychiatry departments improve administrative efficiency and expand their clinical services?

Telepsychiatry Initiatives in Psychiatry Departments: Enabling Sustainable Growth

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

The goal of this activity is to review the pathophysiology of anti-N-methyl-D-aspartate (NMDA) receptor encephalitis (ANMDARE).

1. Understand the pathophysiology of ANMDARE to the cellular level.

2. Recognize the various tools used to diagnose ANMDARE as well as the specific findings seen.

This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals seeking to improve the care of patients with mental health disorders.

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Physicians’ Education Resource®, LLC, designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis (ANMDARE) is an autoimmune condition caused by reversible internalization of the NMDA receptor as the result of autoantibodies produced via an immunologic trigger.

 The condition was first described in the literature in 2005 by Vitaliani and colleagues,

 with a description of the autoantibodies coming just 2 years later by Dalmau et al.

 Since its discovery, it has become the most common autoimmune encephalitis.

Epidemiologically, a vast age range (2 months to 85 years) of affected patients has been documented, with a mean age of onset of around 21 years. There is an increased prevalence among younger women than men (4:1); this sex discrepancy appears to even out after age 45 years.

 It is frequently described as a paraneoplastic condition due to its popular association with ovarian teratomas; however, this is not always the case, as viral causes have been documented, as well as undetermined causes. This article reviews the most up-to-date literature regarding the pathophysiology of 

 and provides a brief overview of the clinical features, diagnostic imaging findings, and treatments.

The first described cases of ANMDARE involved 4 women diagnosed with comorbid ovarian teratomas and identified a distinguishable pattern of symptoms. The clinical features of ANMDARE can therefore be described as progressive through 3 stages (

This first stage presents with flu-like symptoms, such as headache, fatigue, and low-grade fever.

The prominent positive and negative symptoms indistinguishable from those seen in schizophrenia (eg, hallucinations, delusions, disorganized behavior, and paranoia) are associated with the second stage.

 In this third stage, there are more neurological symptoms, such as focal or generalized seizures, dyskinesias, and autonomic instability. Other neuropsychiatric symptoms include agitation, irritability, catatonia, 

 Some patients experience residual neurologic sequelae posttreatment that may last months to years.

These stages represent the most common progression, but other variations are seen. Below are cases discussed in the literature that exemplify this variety, followed by the pathophysiology as we understand it today and a brief overview of laboratory findings, imaging, and treatment.

A 27-year-old woman with no significant psychiatric or systemic medical history presents to the emergency department with a 15-day history of disorganized thoughts, hypochondriacal delusions, auditory hallucinations, insomnia, and short-term memory loss. History of present illness does not reveal headache, fever, seizures, dyskinesia, or autonomic instability. Mental status examination exhibits disorientation to time, abstract thinking deficits, poor attention, speech latency, verbal perseveration, and auditory hallucinations. Initial laboratory studies and imaging are normal; she is admitted to an inpatient psychiatric unit for management of 

While on the psychiatric unit, the patient displays food refusal, decreased speech, and alternating periods of hypo- and hyperkinetic movement. The initial medication regimen consists of aripiprazole, titrated to 30 mg/day and lorazepam 3 mg/day. Although she shows improvement in her psychotic and behavioral symptoms, her short-term memory symptoms worsen, leading to further neurological work-up.

Brain MRI shows diffuse sulcal enlargement of the cerebellar vermis. Electroencephalography (EEG) shows independent bilateral temporal slow activity without an extreme delta brush pattern. Complete blood analysis is unremarkable. Urine toxicology is negative.

Given the atypical presentation, anti-NMDA receptor antibodies are checked in serum and cerebrospinal fluid (CSF); results of both analyses are positive. All other autoimmune antibodies are negative. CSF also shows mild lymphocytic pleocytosis with lymphocyte predominance. Endovaginal ultrasound shows a mass in her right ovary, which is subsequently diagnosed as an ovarian teratoma.

Further treatment consists of intravenous (IV) immunoglobulin 0.4 mg/kg/d and methylprednisolone 1 g/d for 5 days, which are successful in improving her episodic and visual memory, verbal fluency, and attention as well as in decreasing her psychotic symptoms. Repeated brain MRI and EEG show no specific findings. She is discharged on aripiprazole 30 mg/d, prednisolone 60 mg/d, and monthly IV immunoglobulin 0.4 mg/kg/d for 5 days. Both psychiatric and neurological follow-up reveal marked improvement in all symptoms.

A 23-year-old woman with no psychiatric or general medical history experiences a seizure at home lasting approximately 10 minutes, followed by several minor focal seizures with mouth twitching. She then develops mood instability, increased irritability, and periods of unprovoked and inappropriate laughing and crying. She is admitted to an inpatient psychiatric unit for management. Brain MRI shows T2 and diffusion-weighted imaging–hyperintense (DWI-hyperintense) lesions of the right temporal lobe. The initial treatment regimen consists of valproic acid 500 mg twice daily and 

During her admission, she develops a fever of 37.8 °C and a tonic-clonic seizure despite treatment with 

. At the time of the seizure, vital signs are stable, and she is responsive; however, she is disoriented to time and place. Neurological examination reveals decreased muscle tone in her upper and lower limbs with normal strength. She is transferred to a general hospital for further management. Lumbar puncture is performed, showing herpes simplex virus-1 (HSV-1) polymerase chain reaction immunoglobulin M (IgM) and IgG positivity. Anti-NMDA receptor antibody IgG testing is positive in both serum and CSF. Glutamic acid decarboxylase (GAD) antibodies are positive in serum. Contrast enhanced MRI reveals T2, fluid-attenuated inversion recovery (FLAIR) imaging, and DWI-hyperintense lesions in the right temporal lobe. EEG shows diffuse slow waves in the right temporal lobe. Pelvic ultrasound is negative.

Treatment consists of acyclovir 10 mg/kg IV every 8 hours, methylprednisolone 1000 mg/d IV, and valproic acid 500 mg every 8 hours. Symptoms remain uncontrolled after 7 days, so IV immunoglobulin 0.4 mg/kg/d is added to her regimen. After a second round of IV immunoglobulin therapy, her physical and cognitive symptoms sufficiently improve and she is discharged. Follow-up MRI shows resolution of hyperintense lesions.

NMDA-glutamate receptors are ionotropic receptors that regulate multiple neuropsychiatric functions, including learning, memory, and neuroplasticity.

 They are complexes made up of 4 subunits—2 GluN1 subunits and 2 GluN2 subunits—each with similar structures. These subunits serve as the target for the autoantibodies produced in ANMDARE (

The NMDA receptor is an ionotropic glutamate receptor that regulates multiple neurologic functions. It is a heterodimer consisting of 2 NR1 subunits that bind to glycine and 2 NR2 subunits that bind to glutamate.

 These subunits serve as the target for anti-NMDA receptor antibodies. Binding of each subunit’s respective ligand activates the receptor and opens the ion channel, which is highly permeable to calcium, and allows the receptor to exert its effects.

ANMDARE is ultimately caused by autoantibodies that stimulate reversible internalization of the NMDA receptor. This internalization creates a state of NMDA hypofunctionality, which is described in the NMDA hypothesis of psychosis.

 It also is the likely cause of the prominent positive and negative psychotic symptoms. It is most widely accepted that the specific site of autoantibody action is at the GluN1 subunit. These autoantibodies cause crosslinking of the NMDA receptors, altering their ability to interact appropriately, which leads to their internalization and trafficking through endosomes and lysosomes.

Production of these autoantibodies can largely be divided into 3 categories: paraneoplastic processes, viral infections, and unknown. The most common paraneoplastic trigger is ovarian teratomas.

 It is hypothesized that neuronal tissue expressing the NMDA receptor is contained within some teratomas. These tumor cells undergo apoptosis and release antigen to antigen-presenting cells (APCs), which engulf free antigen and present it to regional lymph nodes. Because antigens are typically intracellular in tumor cells and cannot be easily accessed by APCs, it is suspected the cytotoxic T cells play a role. Herpes simplex virus (HSV) is the most common viral trigger.

 It is thought that the inflammatory process of the encephalitis causes neuronal degeneration and formation of inflammatory infiltrates, leading to antigen uptake by APCs or direct delivery to local lymph nodes.

Regardless of the initial immunologic trigger, the downstream effect is the production of memory B cells, activation of naïve B cells via CD4-positive cells, and anti-NMDA receptor antibody-producing plasma cells, which pave the way for NMDA receptor disruption, destabilization, and internalization.

 Once naïve B cells are produced and activated, they enter the central nervous system (CNS) and undergo restimulation due to the high prevalence of NMDA receptors in the brain. This results in the production of plasma cells specific to the NMDA receptor.

Research suggests that it is primarily these antibodies produced by plasma cells already in the CNS that contribute most to development of disease compared with systemic antibodies.

 The site of recognition for the autoantibodies is on the GluN1 subunit of the receptor. The autoantibodies disrupt the stability of the receptor, particularly by interfering with the interaction between the NMDA receptor and EphB2, a protein that functions in a supportive and stabilization role to the NMDA receptor. It is specifically the disrupted interaction between EphB2 and NMDA that leads to displacement and internalization.

 Further characterization regarding the mechanism of internalization has not yet been clearly described. Recent studies have begun to explore the possible role of scaffolding and stabilizing proteins in this process, the most notable of which is PDS-95 due to its role in anchoring the NMDA receptor to the cell membrane.

Regarding the progressive stages of ANMDARE, what is known of the current pathophysiology can be correlated to the progression of clinical presentation. The prodromal phase of flu-like illness may be attributed to increased proinflammatory cytokines seen in patients with ANMDARE, such as increased serum IL-2 levels and increased CSF IL-6 and CXCL13 levels.

 The psychotic symptoms seen in the second stage appear to be most likely related to NMDA hypofunctionality resulting from growing numbers of anti-NMDA antibodies and internalization of the synaptic NMDA receptors.

In later stages of ANMDARE, neurologic symptoms, such as 

, are the hallmark. Research suggests that during the molecular stages before NMDA receptor internalization, anti-NMDA receptor antibodies act briefly as agonists to NMDA receptors, which lowers the seizure threshold.

 This is an important detail regarding pathophysiology, because it reveals that NMDA hypofunctionality does not completely explain the core symptoms. Other NMDA hyperfunctional symptoms include 

 and dystonia; the same mechanism of brief NMDA receptor agonist activity is theorized to be responsible for these symptoms.

 Finally, many patients with ANMDARE suffer severe cognitive symptoms, which—like the psychotic symptoms—can be explained by NMDA hypofunctionality.

 Decreased NMDA receptor function leads to decreased neuronal activity in the dorsolateral prefrontal cortex, which is required for working memory, cognitive flexibility, and executive planning.

ANMDARE can be diagnosed with the use of laboratory tests (both serum and CSF antibodies), imaging (ie, MRI and 18-fluorodeoxyglucose–positron emission testing (FDG-PET), EEG, and the following ancillary tests.

 The most common autoantibody detected and implicated in the diagnosis of ANMDARE is anti-NMDA receptor. Antibody studies should include CSF analysis.

 Serum analysis for antibodies can be performed, but they are not completely reliable on their own due to false-negative or false-positive diagnosis. Studies have shown that serum analysis is less consistent and has even shown positive results in patients without ANMDARE.

 Specifically in cases of ANMDARE caused by HSV encephalitis, other antibodies have been seen alongside NMDA receptor antibodies, such as GABA

 receptor and dopamine 2 receptor antibodies.

 CSF findings are abnormal in most patients with ANMDARE (80%), mostly in those with late-phase disease. Findings include lymphocytic pleocytosis, normal or mildly increased protein levels, and CSF-specific oligoclonal bands. Depending on the course of treatment, antibodies may be seen only in CSF. The CSF titers may be predictive of prognosis and response to treatment.

 MRI findings are normal in 50% of patients with ANMDARE (

 When findings are present, they are mostly seen on T2 or FLAIR and show signal hyperintensity in the cerebellar or cerebral cortex, hippocampi, basal ganglia, brainstem, frontobasal and insular regions, and sometimes the spinal cord.

 These findings are mostly mild/transient and occasionally show contrast enhancement.

18F-FDG-PET/CT scan could be helpful in the diagnosis of ANMDARE in patients with normal MRI findings (

 In a small (n=5) series of cases published by Solnes et al, patients with ANMDARE who demonstrated normal MRI results were all noted to have abnormal 18F-FDG-PET/CT scan results (

 Findings included lobar hypometabolism in a wedge-shaped pattern mostly found in the parietal lobe, followed by the occipital and temporal lobes.

 One study found frontotemporal hypoperfusion and brain atrophy.

 Other imaging modalities, such as MR spectroscopy and 9mTc-d,l-hexamethyl-propyleneamine oxime (HMPAO) single photon emission computed tomography (SPECT) show transient cortical and subcortical changes.

 EEG findings are usually abnormal. The most common finding is nonspecific, slow, disorganized activity, sometimes with electrographic seizures.

 When patients present with catatonia, they show slow, continuous rhythmic activity in the delta-theta range.

 Nonepileptiform seizures may occur and, hence, video EEG may become increasingly important.

 ANMDARE often occurs as a paraneoplastic syndrome, most commonly in the presence of an ovarian teratoma. Very rarely, patients may be diagnosed with a different tumor type, such as Hodgkin lymphoma or neuroblastoma.

Important tests for ovarian teratomas include pelvic CT scans, MRI, and pelvic and transvaginal ultrasound. Tumor markers include β-human chorionic gonadotropin, AFP, CA-125, and testosterone. If an oophorectomy is performed, the resected ovaries can show presence of NMDA receptors.16

Other etiologies (aside from tumors) can include infections. Studies have shown positive mycoplasma antibodies, herpes zoster infection, diphtheria, pertussis, tetanus vaccination, and H1N1 vaccination.

 Some patients had associated microdeletion of the short arm of chromosome 6 (which included the HLA cluster) antithyroid peroxidase and antinuclear antibodies.

Despite the amount of research into ANMDARE, a definitive pathophysiologic mechanism has yet to be determined. Most studies investigating the mechanism have pinpointed the most likely pathway as NMDA receptor internalization as the result of autoantibodies, but further details regarding the process of internalization remain unclear. ANMDARE should always be kept in the differential when considering a first episode of psychosis or exploring specific anatomic causes of psychiatric symptoms. Significantly, ANMDARE provides a concrete clinical example of a pathophysiological mechanism first described only 17 years ago that is responsible for the onset of sudden psychotic symptoms.

When correctly diagnosed and treated with immunoglobulin and corticosteroids, ANMDARE resolves and these patients generally rapidly improve. As we continue to understand the complexities of the brain, and as further research reveals more information, it is likely that additional unique pathophysiology will be discovered as etiologic for psychosis, mania, and other psychiatric symptoms. These potential findings may provide pathways for the development of novel treatments to reduce, or even eliminate, these symptoms.

 The authors wish to acknowledge James A. Bourgeois, OD, MD, for offering suggestions and editing this paper.

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

2. Vitaliani R, Mason W, Ances B, et al. 

Paraneoplastic encephalitis, psychiatric symptoms and hypoventilation in ovarian teratoma.

Limbic encephalitis: the new cell membrane antigens and proposal of clinical-immunological classification with therapeutic implications.

Anti-N-methyl d-aspartate receptor encephalitis and electroconvulsive therapy: literature review and future directions.

5. Dalmau J, Armangué T, Planagumà J, et al. 

In this CME, review the pathophysiology of anti-N-methyl-D-aspartate receptor encephalitis. 

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