James S. Brown, Jr, MD, MPH, MS

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

To identify the psychiatric and neurological implications of anti-NMDA receptor encephalitis.

At the end of this CE activity, participants should be able to:

• Recognize when a patient may be presenting with anti-NMDA receptor encephalitis

• Describe the progression of anti-NMDA receptor encephalitis symptoms

• Identify psychiatric and neurological signs and symptoms

• Describe the differential diagnosis for anti-NMDA receptor encephalitis symptoms

This continuing medical education 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.

CME Credit (Physicians): This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of CME Outfitters, LLC, and Psychiatric Times. CME Outfitters, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

CME Outfitters designates this enduring material for a maximum of 1.5 

™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Note to Nurse Practitioners and Physician Assistants: AANPCP and AAPA accept certificates of participation for educational activities certified for 

It is the policy of CME Outfitters, LLC, to ensure independence, balance, objectivity, and scientific rigor and integrity in all of their CME/CE activities. Faculty must disclose to the participants any relationships with commercial companies whose products or devices may be mentioned in faculty presentations, or with the commercial supporter of this CME/CE activity. CME Outfitters, LLC, has evaluated, identified, and attempted to resolve any potential conflicts of interest through a rigorous content validation procedure, use of evidence-based data/research, and a multidisciplinary peer-review process.

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James S. Brown Jr, MD, MPH, MS, has no disclosures to report.

Josep Dalmau, MD, PhD, (peer/content reviewer) reports that he has received a grant from the NIH; he receives royalties for NMDAR antibody testing and other autoimmune encephalitic testing products from Euroimmun.

 staff and CME Outfitters staff have no disclosures to report.

Faculty of this CME/CE activity may include discussion of products or devices that are not currently labeled for use by the FDA. The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational uses (any uses not approved by the FDA) of products or devices. CME Outfitters, LLC, and the faculty do not endorse the use of any product outside of the FDA-labeled indications. Medical professionals should not utilize the procedures, products, or diagnosis techniques discussed during this activity without evaluation of their patient for contraindications or dangers of use.

-methyl-D-aspartate receptor (NMDAR) encephalitis was first reported in 2005 but not identified as a diagnostic entity until 2007.

 At that time, 12 female patients were identified; they ranged in age from 14 to 44 years. All presented with various psychiatric and neurological symptoms, including personality and behavioral changes, paranoia, agitation, confusion, catatonia, autonomic instability, dyskinetic movements, seizures, hypoventilation requiring mechanical ventilation, hyperthermia (less often hypothermia), and coma.

All 12 patients had serum/cerebrospinal fluid (CSF) antibodies to the NR1 subunit of the NMDAR. Moreover, 11 had ovarian teratomas, of which 5 were examined and found to have nervous tissue expressing NR2 subunits that reacted with patient antibodies. The teratoma was removed in 8 patients, followed by immunotherapy that resulted in improvement of symptoms or full recovery. Two of three patients who did not have the tumor resected died.

Anti-NMDAR encephalitis is recognized as an autoimmune disorder in which IgG autoantibodies are directed against the NR1 subunit of the NMDAR. Binding of the antibodies to NMDARs induces internalization of the receptors in synapses, which is a mechanism that agrees with the glutamate hypothesis of schizophrenia in which NMDAR antagonists cause psychotic symptoms. The condition can present as a paraneoplastic syndrome that is often but not always associated with ovarian teratoma. However, in many patients no tumor can be found. A general definition of “paraneoplastic syndrome” is one that is caused by cancer but not by direct invasion so that most are the result of hormones, cytokines, and immune responses from or as a result of the tumor.

Hundreds of cases of anti-NMDAR encephalitis have been reported, and many patients -possibly up to 40% -are initially hospitalized on psychiatric units.

 Some patients may present with psychiatric symptoms without neurological involvement, and there may not be any differences in demographics, psychiatric symptoms, or outcomes compared with patients who have neurological symptoms. In Dalmau’s original case series, 77% of cases were initially seen by psychiatrists and 23% by neurologists.

 Because of the significant morbidity and mortality associated with NMDAR encephalitis, it is essential that psychiatrists in all settings but especially in inpatient, emergency, and consultation-liaison roles be acquainted with the presentation and diagnosis of the condition.

Most cases of anti-NMDAR encephalitis occur in young women, although ages range from 2 months to 85 years. Prodromal symptoms are common (more than 75% of patients) and usually appear as a viral syndrome with headache, fever, and respiratory and gastrointestinal symptoms. The initial psychiatric symptoms may include prominent visual and auditory hallucinations, paranoia, delusions, agitation, memory loss, depression, and eating disorders (

The condition usually progresses to include serious neurological symptoms such as seizures, abnormal movements, autonomic instability, and hypoventilation. Seizures may include any type but especially generalized tonic-clonic or partial complex. Dyskinesias may be of any type but include orofacial, complex extremity, abdominal and pelvic movements, abnormal postures, and rigidity. A frequent pattern seen in case reports is admission to a psychiatric unit followed by transfer to an ICU after the onset of serious neurological symptoms. At this point, treatment usually requires a multidisciplinary approach.

Similar symptoms may be observed in children, although the youngest may have less apparent psychiatric symptoms and more prominent abnormalities of sleep, speech, and/or gait that progress to motor abnormalities, dyskinesias, and seizures. Tumors are found less often in pediatric cases. In older patients (older than 45 years), behavioral changes, seizures, and cognitive problems are frequent; males represent a greater proportion of cases than in younger groups; and fewer have an identifiable tumor compared with younger patients. Tumors, especially in older patients, can include not only ovarian tumors but also carcinomas and tumors of the breast, lung, and thymus as well as melanocytic nevi. In male cases, fewer tumors are found but have included schwannoma and mediastinal and testicular teratomas.

Psychiatric misdiagnosis can occur before the onset of neurological symptoms. Early diagnoses have included schizophrenia, schizoaffective disorder, bipolar disorder, depression, conversion disorder, and anorexia nervosa (

). However, most cases of schizophrenia, new-onset psychosis, and depression do not involve anti-NMDAR antibodies. Although most patients with anti-NMDAR encephalitis have no prior psychiatric histories, some do -including schizophrenia and autism, or positive family histories of mental illness. In cases of anti-NMDAR encephalitis in adults with preexisting autism or intellectual disability, initial presentations may be mistaken for new-onset primary psychosis or medication effects.

One case report describes a young woman with a 7-year history of schizophrenia who received a diagnosis of anti-NMDAR encephalitis, although the relationship of her prior schizophrenia to the newly diagnosed encephalitis could not be discerned.

 In another case report, a young woman with a 14-year history of neuropsychiatric symptoms presented as an outpatient with symptoms of word-finding difficulties, later diagnosed as anti-NMDAR encephalitis.

Anti-NMDAR encephalitis can occur during pregnancy and can resemble postpartum depression and neuroleptic malignant syndrome (NMS). Many symptoms of NMS (rigidity, hyperthermia, elevated serum creatine kinase, rhabdomyolysis) may also occur in anti-NMDAR encephalitis. Testing for anti-NMDAR antibodies should therefore be considered in any patient with acute-onset psychiatric symptoms who has neurological or autonomic abnormalities, including rigidity and altered consciousness. (See Sansing and colleagues

 for an in-depth discussion of differential diagnoses for anti-NMDAR encephalitis, NMS, and serotonin syndromes.)

Psychiatrically and neurologically, the differential diagnosis is quite broad (

). A key factor for recognizing this disorder is that it often follows a pattern of syndrome development. In about 70% of cases, prodromal symptoms develop, including headache, fever, and gastrointestinal and upper respiratory tract symptoms. Usually within 2 weeks, psychiatric symptoms emerge, which often leads to psychiatric assessment. These symptoms may include anxiety, insomnia, delusions, mania and paranoia, possibly social withdrawal, and stereotypical behaviors. Short-term memory loss occurs as does disrupted language.

The condition progresses to decreased responsiveness with agitation, catatonia, abnormal movements, and autonomic instability and “storms,” as well as hypoventilation that may require ventilation. Seizures including status epilepticus can occur at any stage, can overlap with abnormal movements, and can decrease over the course of the illness.

The diagnosis is often made on the presence of neurological impairment, including abnormal movements, speech problems, rigidity, and altered consciousness as indications of something other than primary psychiatric disorders, although these are not universal. Drug screening and medication history may help rule out intoxication. Encephalitis from other causes including infections and autoimmune responses can be assessed with basic laboratory screenings, metabolic testing, immunological testing, MRI findings, and response to treatments such as thiamine and corticosteroids. Once anti- NMDAR encephalitis is diagnosed, care of the patient usually involves psychiatric consultation on ICU, surgery, medical, and/or neurological units.

Very small and even microscopic tumors can cause anti-NMDAR encephalitis, and the condition can occur as a complication of herpes simplex encephalitis. Initial laboratory studies can be normal, electroencephalograms (EEGs) can show non-specific slowing, and CSF analysis may show only lymphocytic pleocytosis. Confirmation of the diagnosis is based on positivity of the serum or, more importantly, the CSF for antibodies to the GluN1 NMDA receptor subunit. Serum testing alone may result in false positive or negative results.

Following tumor resection, if a tumor is found, treatment often begins with first-line immunotherapy (corticosteroids, plasma exchange, intravenous immunoglobulin). Second-line immunotherapy (rituximab, cyclophosphamide) may become necessary and increases the likelihood of better outcome.

Psychiatric management includes psychotropic medications, although the response can be poor especially before a precise diagnosis is made. Irritability toward caregivers and family is often reported, and suicidal ideation with severe agitation and aggression can occur. ECT has been used successfully in some cases of catatonia but is not well studied and not always successful. Some treatment recommendations include atypical antipsychotics for behavioral symptoms, valproic acid for mood dysregulation, and benzodiazepines for catatonia. Medically induced comas have sometimes been required in the most psychiatrically severe cases.

Recovery depends on many factors, but Dalmau’s original case series remains a general guide: 75% of patients recovered, although some still had mild residual deficits, and 25% had poor outcomes with severe residual deficits or died. Because anti-NMDAR encephalitis is potentially curable, early diagnosis and treatment including tumor removal and immunotherapy are key to best outcomes. Antipsychotic medications can help control psychotic symptoms; however, be aware that, especially before diagnosis, rigidity and autonomic instability from anti-NMDAR encephalitis can be mistaken for NMS, and antipsychotic medications can cause NMS in these patients.

Improvement of psychiatric and neurological symptoms during treatment can be observed within days -in some cases hours -after tumor resection, but full recovery may be a slow process, perhaps taking several months, with possible relapses. Most neurological symptoms may improve, but executive functions and severe psychiatric symptoms, including suicidality and aggression, can persist for many months, possibly requiring inpatient psychiatric treatment. Lengthy outpatient psychiatric treatment with antipsychotic medication may be necessary. Recurrences caused by recurring tumors have also been reported.

Much remains to be learned about the various presentations of anti- NMDAR encephalitis. A case report, for example, described an adolescent who presented to an outpatient service and received a diagnosis of atypical anorexia nervosa without secondary amenorrhea.

 She was treated as an outpatient until 3 weeks later when she was admitted with a seizure. On day 23 of hospitalization, hallucinations developed that did not respond to antipsychotic medications. They were initially diagnosed as dissociative because the neurological workup was mostly non-specific. The diagnosis of anti- NMDAR encephalitis was confirmed 36 days after admission.

No tumor was found, but near-baseline functioning was achieved with immunotherapy after 10 months. The case is atypical because most patients with anti-NMDAR encephalitis do not have an identifiable eating disorder.

Future research on anti-NMDAR encephalitis will contribute to our knowledge of psychosis, autoimmunity, and glutamatergic function; although the extent to which the condition applies to specific conditions such as schizophrenia remains unknown. However, the recognition of anti-NMDAR encephalitis has already led to further research that contributed to the discovery of other autoimmune synaptic encephalitides. And, the elucidation of anti-NMDAR encephalitis has led to new approaches to the diagnosis of catatonia, movement abnormalities, memory problems, seizures, and limbic encephalitis.

Jenny, a 23-year-old white graduate student with no psychiatric history, has had a flu-like condition with headache and nausea for about 10 days, and she has been having problems in school because of unusual memory loss. At home, she seems lethargic during the day but is unable to sleep at night. Her family reports that Jenny has become irritable, which is out of character for her. They brought her to the ED after she was found wandering confused in the yard.

An uncle has bipolar disorder, and the family is concerned she may have the same condition. She has a temperature of 100ºF, but baseline blood work and physical and neurological examination results are normal. A brain CT scan is unremarkable. Psychiatric assessment finds symptoms consistent with mild depression, but she is alert and oriented. There are no findings that support admission. Antibiotics are prescribed, and the patient is discharged.

A few days later she returns to the ED after becoming agitated and paranoid and experiencing auditory hallucinations. She is admitted to the psychiatric unit, where she exhibits bizarre behavior including giggling, echolalia, and posturing. She has frequent cycling leg movements and believes that staff members are plotting against her and that her food is poisoned. She is hyperkinetic, screaming, hallucinating, and sexually disinhibited. Antipsychotic medications do not seem effective, and prominent orofacial dyskinetic movements develop.

She experiences altered mental status followed by a generalized tonic-clonic seizure, although she has no history of seizures. An EEG shows nonspecific slowing, and leukocytosis is noted in the CSF. She does not return to her previous level of consciousness, autonomic instability develops, and she is transferred to the ICU.

In the ICU she requires sedation and mechanical ventilation. Subsequent EEGs reveal only nonspecific slowing, and a brain MRI scan shows non-specific small hyperintensities. During an extensive work-up, anti-NMDA receptor antibodies are found in her CSF. CT scanning of the chest, abdomen, and pelvis reveals a small right ovarian mass. The tumor is surgically resected and diagnosed as a teratoma.

Three days after the operation, she starts to improve significantly and is extubated. She receives first-line immunotherapy before discharge to a rehabilitation unit. Several months later, her neurological and psychiatric examinations are normal and she returns to academic study.

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Assistant Clinical (Adjunct) Professor of Psychiatry, VCU [Virginia Commonwealth University] School of Medicine, Department of Psychiatry, Richmond, VA

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-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. 

. Oxford, UK: Oxford University Press; 2011.

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 Sansing LH, Tuzun E, Ko MW, et al. A patient with encephalitis associated with NMDA receptor antibodies. 

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-methyl-D-aspartate receptor encephalitis: review of clinical presentation, diagnosis, and treatment. 

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-methyl-D-aspartate receptor encephalitis: a new challenging entity for consultation-liaison psychiatrists. 

Articles

This articles focuses on the psychiatric and neurological implications of anti-NMDA receptor encephalitis. 

Anti-NMDA Receptor Encephalitis: Diagnostic Issues for Psychiatrists

To view the information in PDF format, click here.

Slideshows

A growing body of scientific literature associates psychiatric symptoms with man-made toxic substances and environmental exposure. Practical implications for psychiatrists are discussed in this Special Report collection.

Psychiatric Fallout From Toxic Exposure

Psychiatric effects of environmental and chemical toxins were described in the medical literature as early as 1850 and were compiled in a monograph in 2002, with updates in 2007 and 2013.

In the 21st century there has been, sadly, no shortage of victims of environmental disasters to assess and treat according to guidelines presented in this Special Report.

Understanding the Link Between Lead Toxicity and ADHD

, discusses assessment of lead toxicity in children. He points out that levels above 5 µg/dL require clinical interventions and that levels lower than 1 µg/dL have been associated with behavioral problems.

The importance of this finding is reflected by the recent Flint, Michigan, drinking water crisis in which 99,000 residents were potentially exposed to lead-contaminated water between 2014 and 2015. Two studies have since confirmed that the incidence of elevated lead levels in children younger than 6 years has nearly doubled since the contamination.

 Research trends highlight the possible role of prenatal lead exposure in adult-onset schizophrenia; the association of adult lead levels with mental disorders; and the cause of mental disturbances by unexpected lead sources, including so-called “moonshine.”

Illicit drugs continue to pose severe risks for behavioral changes from neurotoxicity as described in “

Neurobiology and Clinical Manifestations of Methamphetamine Neurotoxicity

” by Anna Moszczynska, PhD. Illicit drugs such as “ecstasy” are often adulterated with methamphetamine. Solvent abuse that results in altered mental status and potentially lethal physical abnormalities remains a frequent presentation in the emergency setting. Occupational exposure to various solvents also results in neuropsychiatric injury, often referred to as “chronic solvent encephalopathy.” Contaminants including thallium or infectious agents such as anthrax can be consumed with illicit drugs. Methamphetamines are also considered an “emerging contaminant” of water, a term that describes the growing numbers of toxins that enter the human environment-especially surface water.

As Dan Rossignol, MD, and Richard Frye, MD, PhD, point out in “

Environmental Toxicants and Autism Spectrum Disorder

,” a growing body of scientific literature associates symptoms of autism spectrum disorder (ASD) with environmental toxin exposure, including exposures from contaminants in herbal remedies. Indeed, the most recent reports confirm that exposure to heavy metals (especially during fetal growth), polychlorinated biphenyls, bisphenol A, and organophosphate pesticides is associated with increased risk not only of ASD but also ADHD.

The case vignette in the article describes ASD symptoms from the use of Ayurvedic herbs, which emphasizes the importance of asking patients about herbal use. Herbal supplements, both pure and adulterated, continue to appear in conjunction with cases of psychosis and mania, anxiety, and depression.

Food additives, as described by Katie Holton, PhD, MPH, and coauthors in the article “

,” continue to receive attention regarding their role in ADHD, especially in susceptible individuals. Although there has been concern over a possible link between autism and early exposure to mercury in thimerosal-containing vaccines, there is no evidence to support this.

Major environmental toxic exposures continue to occur-even weather events such as hurricanes are now known to expose individuals to chemical toxins through redistributed sediments in water and soil. After the earthquake in Japan in March 2011, a nuclear accident occurred at the Fukushima Daiichi Nuclear Power Plant. This incident, like the Chernobyl and Three Mile Island nuclear accidents before it, highlighted the increased incidence of anxiety and depressive disorders following such disasters.

Radiation disasters may cause psychiatric symptoms not only through the psychological trauma of the experience but also from the effect of radiation exposure. In addition to radiation events, large-scale neurotoxic exposure events can include chemical accidents, terrorism, and warfare. Terrorism and warfare events such as the use of the chemical warfare nerve agent sarin in Syria remain a major threat.

Clinicians should remain cognizant of the co-occurrence of psychological casualty with neurotoxic reactions in both the emergency and aftermath settings. As described by Mike Caudle, PhD, in his article, “

On the Mark: Translating Biomarker Technology to Clinical Neurotoxicity

,” biomarker technology for the assessment of clinical neurotoxicity is advancing. Hopefully, such approaches will eventually contribute to focused treatments of specific neurotoxic injuries.

Dr. Brown is Assistant Clinical Professor of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA. He reports no conflicts of interest concerning the subject matter of this Special Report.

Environmental and Chemical Toxins and Psychiatric Illness

. Washington, DC: American Psychiatric Publishing; 2002.

 Brown JS Jr. Psychiatric issues in toxic exposures. 

 Brown JS Jr. Psychiatric effects of organic chemical exposure. In: Carpenter DO, ed. 

Effects of Persistent and Bioactive Organic Pollutants on Human Health

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 Hanna-Attisha M, LaChance J, Sadler RC, Champney Schnepp A. Elevated blood lead levels in children associated with the Flint drinking water crisis: a spatial analysis of risk and public health response. 

 Abazyan B, Dziedzic J, Hua K, et al. Chronic exposure of mutant DISC1 mice to lead produces sex-dependent abnormalities consistent with schizophrenia and related mental disorders: a gene-environment interaction study. 

 Yoon JH, Ahn YS. The association between blood lead level and clinical mental disorders in fifty thousand lead-exposed male workers. 

 Arnold J, Morgan B. Management of lead encephalopathy with DMSA after exposure to lead-contaminated moonshine. 

 Fujiwara T, Morisaki N, Honda Y, et al. Chemicals, nutrition, and autism spectrum disorder: a mini-review. 

 Vrijheid M, Casas M, Gascon M, et al. Environmental pollutants and child health: a review of recent concerns. 

 Kondolot M, Ozmert EN, Axci A, et al. Plasma phthalate and bisphenol A levels and oxidant-antioxidant status in autistic children. 

A report on the psychiatric effects of environmental and chemical toxins.

James S. Brown, Jr, MD, MPH, MS

Articles

Anti-NMDA Receptor Encephalitis: Diagnostic Issues for Psychiatrists

Psychiatric Fallout From Toxic Exposure

Introduction: An Update on Psychiatric Effects of Toxic Exposures