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 REVIEW ARTICLE

Anti-N-methyl-d-aspartate receptor encephalitis: A targeted review of clinical presentation, diagnosis, and approaches to psychopharmacologic management

Jennifer L. Kruse, MD*

Department of Psychiatry and Biobehavioral Sciences, The David Geffen School of Medicine at UCLA, Los Angeles, California, USA, Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota, USA

Jessica K. Jeffrey, MD, MPH, MBA*

Department of Psychiatry and Biobehavioral Sciences, The David Geffen School of Medicine at UCLA, Los Angeles, California, USA

Michael C. Davis, MD, PhD

VA Greater Los Angeles, Los Angeles, California, USA, Department of Psychiatry and Biobehavioral Sciences, The David Geffen School of Medicine at UCLA, Los Angeles, California, USA

Joanna Dearlove, MD, MPH

Department of Neurology, The David Geffen School of Medicine at UCLA, Los Angeles, California, USA

Waguih William IsHak, MD, FAPA

Department of Psychiatry and Behavioral Neurosciences, Cedars-Sinai Medical Center, Department of Psychiatry and Biobehavioral Sciences, The David Geffen School of Medicine at UCLA, Los Angeles, California, USA

John O. Brooks III, PhD, MD

Department of Psychiatry and Biobehavioral Sciences, The David Geffen School of Medicine at UCLA, Los Angeles, California, USA

*These authors contributed equally

BACKGROUND: Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis was formally described in 2007 and includes a range of psychiatric and neurologic symptoms. Most patients with anti-NMDAR encephalitis initially present to psychiatrists for diagnosis and treatment. However, there is limited literature summarizing treatment strategies for psychiatric symptoms. In an effort to improve identification and treatment, this review article provides an overview of anti-NMDAR encephalitis, with a focus on psychopharmacologic treatment strategies. Two case reports provide a clinical context for the literature review.

METHODS: The authors conducted a PubMed search.

RESULTS: Prominent psychiatric symptoms of anti-NMDAR encephalitis include psychosis, agitation, insomnia, and catatonia. Neuroleptics may be helpful for managing psychosis and agitation, but may exacerbate movement abnormalities. Diphenhydramine and benzodiazepines are helpful for agitation and insomnia. In addition, the anticholinergic affinity of diphenhydramine can improve dystonia or rigidity attributable to anti-NMDAR encephalitis, while benzodiazepines and electroconvulsive therapy have been used for catatonia associated with this condition.

CONCLUSIONS: Psychiatrists play an important role in the diagnosis and treatment of anti-NMDAR encephalitis. Recognizing the typical clinical progression and closely monitoring for accompanying neurologic symptoms will facilitate diagnosis and timely treatment. Careful selection of psychopharmacological interventions may reduce suffering.

KEYWORDS: N-methyl-d-aspartate receptor, limbic encephalitis, behavioral symptoms, benzodiazepines, antipsychotic agents

ANNALS OF CLINICAL PSYCHIATRY 2014;26(2):111-119

  INTRODUCTION

Encephalitis is defined as inflammation of the brain parenchyma. The condition is life threatening and requires prompt diagnosis and treatment. Etiologies comprise a range of inflammatory conditions including those of paraneoplastic, autoimmune, and infectious origin (TABLE 11,2). Encephalitis presents with a variety of symptoms, which may vary depending on the etiology of the encephalitis or the particular regions of the brain that are affected. Across the range of etiologies, common symptoms of encephalitis may include headache, confusion, altered level of consciousness, memory disturbances, seizures, and hallucinations. Particular symptom clusters may lead the clinician to consider one etiology over another.


TABLE 1

Selected causes of encephalitis1,2

Infectious
Viral HSV, enteroviruses, arboviruses, mumps, measles, varicella zoster, rubella, influenza, HIV, rabies virus
Bacterial Tropheryma whipplei, Mycoplasma pneumonia, Bartonella henselae, Listeria monocytogenes, Borrelia burgdorferi, Treponema pallidum
Parasitic Toxoplasma gondii, malaria, primary amoebic meningoencephalitis
Fungal Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides
Immune-mediated
Acute disseminated encephalomyelitis (ADEM) Classically associated with post-immunization or following a systemic viral infection
Antibody-associated Anti-NMDA receptor encephalitis (sometimes paraneoplastic)
Anti-VGKC encephalitis (sometimes paraneoplastic)
Other paraneoplastic etiologies include antibodies to Hu, Ma2, CRMP5, AMPA, GABA (B), among others
AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CRMP: collapsin response mediator protein; GABA: γ-aminobutyric acid; HIV: human immunodeficiency virus; HSV: herpes simplex virus; NMDA: N-methyl-d-aspartate; VGKC: voltage-gated potassium channel.

Recently, a previously unknown autoimmune cause of encephalitis has been identified, which presents with prominent psychiatric symptoms. When the presenting signs of encephalitis are primarily psychiatric in nature, patients may be diagnosed mistakenly with a primary psychiatric disorder, and definitive diagnosis and treatment for encephalitis is delayed. Psychiatrists must be aware of medical or neurologic disorders that present with psychiatric symptoms to rule out organic etiologies, such as anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis.

This article presents 2 cases illustrating dramatic psychiatric presentations of autoimmune encephalitis, and includes an overview of the clinical presentation, diagnosis, and management of this condition.

Case 1

Ms. A, a 16-year-old, previously healthy adolescent, presented with fatigue, headache, and diarrhea followed 1 week later by insomnia, mood lability, auditory and visual hallucinations, and agitation. She began to have difficulty recognizing her parents and misidentified them as intruders, even making a 911 call when panicked that “intruders” (her parents) had entered the home. During a 6-day psychiatric hospitalization she was treated with risperidone, aripiprazole, chlorpromazine, and lorazepam for agitation.

Ms. A developed ataxia and had a generalized tonic-clonic seizure, prompting transfer to a medical facility. At time of transfer, she was disoriented and began to exhibit echolalia, prolonged staring episodes, and difficulty following simple commands. Magnetic resonance imaging (MRI) findings were unremarkable, and results of a lumbar puncture were within normal limits except for mild pleocytosis. An electroencephalogram (EEG) demonstrated diffuse slowing of background activity, more prominent in the right temporal region. All infectious studies were negative.

Because of the patient’s demographics (young female) and prominent psychiatric symptoms, anti-NMDAR encephalitis was suspected and confirmed via detection of serum antibodies to the NMDA receptor. Plasmapheresis and high-dose IV methylprednisolone were initiated. The patient was evaluated for ovarian teratoma, which is frequently associated with this condition; pelvic ultrasound and a positron emission tomography–computed tomography (PET-CT) scan were negative. Psychopharmacologic treatment in the general medical hospital included olanzapine as needed for agitation.

The patient continued to exhibit echolalia, waxing and waning mental status, intermittent agitation, catatonia, and auditory and visual hallucinations. Olanzapine was ineffective at reducing psychotic symptoms and impractical to administer orally during acute periods of agitation; therefore, it was discontinued. IV lorazepam was effective in reducing agitation, and because of its theoretical benefits for catatonia, this agent was administered on a scheduled basis. Diphenhydramine also was used as needed for milder agitation, with good effect. After 5 treatments with plasmapheresis, Ms. A’s mental status improved markedly. She continued to have difficulty with short-term memory, but no longer displayed motor or behavioral abnormalities. She was discharged for outpatient rehabilitation after 3 weeks in the general medical hospital.

  Discussion

Ms. A suffered from anti-NMDAR encephalitis, which is an autoimmune encephalitis first described in 2007 as a paraneoplastic syndrome associated with ovarian teratomas.3 However, analysis of the increasing number of cases of anti-NMDAR encephalitis reveals that only 38% of patients have an underlying neoplasm. To date there have been >570 reported cases of anti-NMDAR encephalitis, with those affected ranging in age from 8 months to 85 years. Patients who were age ≤18, such as Ms. A, accounted for 37% of cases; 19% of total cases were in children age ≤13.4

Etiology of anti-NMDAR encephalitis. The NMDAR is an ionotropic glutamate receptor that plays an important role in memory and learning; it has been studied in brain disorders ranging from Alzheimer’s disease to schizophrenia. Some NMDAR antagonists, such as ketamine and phencyclidine, cause psychotic and dissociative symptoms.5 In the case of Ms. A and many patients with anti-NMDAR encephalitis, symptoms are first mistaken for a psychiatric disorder.

Three possible mechanisms for the development of NMDAR autoimmunity have been suggested.6 Because of the frequent association with ovarian teratoma, there is likely a mechanism by which expression of NMDAR in the teratoma leads to a downstream autoimmune response. Pathologic examination of 25 ovarian teratomas from patients with anti-NMDAR encephalitis revealed the presence of NMDAR in all cases.7 In cases where no tumor is identified, Peery et al6 suggest 2 alternate mechanisms for development of autoimmunity, both of which remain unproven:

1. Infectious agents may lead to development of autoantibodies, perhaps by epitope similarity between a pathogen and the NMDAR. However, no consistent infectious agents have been identified.

2. Tissues outside the CNS that normally express NMDAR may become infected or damaged, leading to immune activation and eventual loss of self-tolerance to the receptor.

Incidence of anti-NMDAR encephalitis. Because of the recent identification of anti-NMDAR encephalitis, incidence estimates are not available. However, this syndrome may represent a relatively common cause of encephalitis. In the California Encephalitis Project (CEP), established to study the epidemiology and etiologies of encephalitis, anti-NMDAR encephalitis was the most frequently identified etiology for encephalitis in patients age ≤30, between September 2007 and February 2011. The CEP cohort is biased toward diagnostically challenging cases; therefore, anti-NMDAR encephalitis may be over-represented in this cohort compared with encephalitides that are more routinely included in a diagnostic evaluation.8 It should be noted that encephalitis is a rare disorder, and anti-NMDAR encephalitis represents a small proportion of cases of an already rare clinical disorder. As awareness of anti-NMDAR encephalitis becomes more widespread and screening becomes more routine in the assessment of encephalitis, incidence estimates may become available.

Presentation of anti-NMDAR encephalitis. In Case 1, we met Ms. A, an otherwise healthy adolescent girl who presented with classic symptoms of anti-NMDAR encephalitis. She experienced a typical prodrome, including fatigue, headache, nausea, and diarrhea, followed days later by onset of psychiatric symptoms, including hallucinations, agitation, insomnia, mood lability, and delusional thought content.

A variety of psychiatric symptoms are associated with anti-NMDAR encephalitis, including anxiety, sleep disturbances, mood disturbances including depression or mania, mood lability, psychosis, agitation, and catatonia. Behavioral abnormalities are the rule rather than the exception in anti-NMDAR encephalitis, developing early in the progression of this syndrome, as seen with Ms. A. Psychiatrists often are the first clinicians to have contact with an affected patient and must keep a healthy degree of suspicion regarding the possibility that a patient’s psychiatric symptoms may be secondary to anti-NMDAR encephalitis. In 1 series, 77% of adult and adolescent patients were evaluated by a psychiatrist before diagnosis of anti-NMDAR encephalitis.9 This was true for Ms. A, who was admitted to a psychiatric facility before consideration of encephalitis as the etiology of her symptoms.

The course of Ms. A’s illness progressed fairly stereotypically from prodrome to psychiatric symptoms to neurologic symptoms to autonomic instability. See TABLE 27,9-12 for a summary of typical clinical manifestations and progression of anti-NMDAR encephalitis, noting the differences in presentation between adults and children. Although Ms. A was only age 16, her symptoms and presentation were consistent with those commonly seen in adult patients. In children, psychiatric symptoms may be less dramatic, though temper tantrums, hyperactivity, and irritability are common. Autonomic instability and central hypoventilation may be less severe in children compared with adults.13 Although Ms. A had hypotension and tachycardia, her autonomic instability was not severe, she did not develop central hypoventilation, and did not require intubation.


TABLE 2

Clinical manifestations of anti-NMDAR encephalitis in adults and children

  Adults Children
Prodrome (0 to 2 weeks) Seen in 70% of cases; may include headache, fever, nausea, vomiting, diarrhea, upper respiratory symptoms7 As per adults
Initial presentation In a series of 100 patients, 77 were first seen by a psychiatrist, with symptoms including anxiety, agitation, bizarre behavior, delusions, paranoia, and auditory or visual hallucinations9 Behavioral symptoms such as temper tantrums, hyperactivity, and irritability are common7
Initial presentation is more likely to be non-psychiatric than in adults, with symptoms including seizures and motor abnormalities11
Progression Most develop seizures, decreased level of consciousness, and alternating periods of agitation and catatonia
Dyskinesias, choreoathetoid movements, dystonic posturing, and abnormal ocular movements are common
Sleep disturbances (sleep inversion, insomnia, hypersomnia) are frequent9
As per adults, but possibly decreased occurrence of catatonia12
70% develop mutism12
Tend to experience insomnia more commonly than hypersomnia10
Autonomic instability In a series of 100 patients, 69% had autonomic instability, including tachycardia, bradycardia, central hypoventilation, hypotension, and hyperthermia9 Autonomic instability and central hypoventilation are reported to be less severe than in adults, possibly related to developmental differences in autonomic function11
NMDAR: N-methyl-d-aspartate receptor.
Case 2

Ms. B, a previously healthy 19-year-old woman, had a generalized tonic-clonic seizure followed by several days of intermittent psychiatric symptoms, including paranoia, auditory hallucinations, and disorganized behavior. Initial emergency department (ED) workup, including head CT, urine toxicology, urinalysis, and thyroid studies, were negative. She was discharged, but symptoms continued and progressed; family reported that she appeared fearful, was not acting like herself, and was unable to carry on a conversation. Approximately 1 week after initial presentation to the ED, Ms. B’s mother found her with eyes closed, gurgling, with hands clenched and pulled up against her chest while her upper body was shaking. She was transported by ambulance back to the community hospital, where she received phenytoin for the presumed seizure, and was admitted to the psychiatric unit for treatment of recent-onset paranoia and auditory hallucinations.

Over several days, Ms. B became mute and required feeding assistance. She exhibited increasingly disorganized behavior and confusion, wandering into patient rooms, banging on doors, and demanding to leave the hospital. She had persecutory delusions and auditory hallucinations, and became increasingly aggressive. She was managed with haloperidol and lorazepam for episodes of aggression.

Ms. B became incontinent of urine, developed mandibular stiffness, copious oral secretions, and myoclonus involving her upper body and face. Status epilepticus was suspected, and she was transferred from the psychiatric unit to the intensive care unit and intubated. Neuroleptic malignant syndrome (NMS) was considered, after altered mental status and muscle stiffness occurred following treatment with haloperidol; antipsychotics were discontinued. Cerebrospinal fluid (CSF) examination was remarkable only for mild pleocytosis. Extensive infectious work-up was negative. Multiple head CTs, brain MRIs, lumbar punctures, and ultrasound studies were unrevealing. Ms. B further deteriorated clinically, developing autonomic instability and intractable myoclonus. After over 40 days at a community hospital without a diagnosis or improvement in her condition, Ms. B was transferred to a tertiary care center.

Her exam on arrival to the neurological ICU at the tertiary care center was significant for bilateral choreoathetoid movements, rigidity in the bilateral lower extremities, and occasional left-gaze nystagmus. An MRI of the brain demonstrated subtle fluid-attenuated inversion recovery (FLAIR) abnormalities in the bilateral hippocampi. CSF was sent for additional studies and was positive for NMDAR antibodies. Plasmapheresis and methylprednisolone were started for treatment of anti-NMDAR encephalitis, but there was no improvement in her condition. Second-line treatment (rituximab) was initiated. Extensive work-up for an underlying malignancy was pursued and was negative. After 4 weeks on rituximab with no significant improvement, the decision was made with Ms. B’s family to perform bilateral salpingo-oophorectomy, given association of anti-NMDAR encephalitis with ovarian teratoma. Pathological specimens from the fallopian tubes and ovaries were unremarkable.

With no clinical improvement 1 week following bilateral salpingo-oophorectomy, Ms. B was started on weekly cyclophosphamide IV for additional immunotherapy. After approximately 3 months at the tertiary care center, Ms. B had not regained the ability to follow commands, was not visually tracking consistently, and did not demonstrate purposeful movement. She was transferred to a skilled nursing facility >4 months after her symptoms began. Her hospital course had been complicated by Acinetobacter pneumonia, enterococcus percutaneous endoscopic gastrostomy site infection, syndrome of inappropriate antidiuretic hormone secretion, acute renal insufficiency due to early treatment with acyclovir, hemorrhagic cystitis and neutropenia due to cyclophosphamide, unexplained vaginal bleeding, and refractory seizures requiring a multi-drug anticonvulsant regimen.

  DISCUSSION

Ms. A and Ms. B had psychotic symptoms that were initially misconstrued as evidence of a primary psychiatric disorder, leading to admission to inpatient psychiatric facilities. Diagnosis of anti-NMDAR encephalitis was delayed for over a month in the case of Ms. B, although her first symptoms were neurologic (generalized tonic-clonic seizure). Ms. B’s long and complex hospital course demonstrates the severity and high morbidity of anti-NMDAR encephalitis.

Diagnosis of anti-NMDAR encephalitis. Detection of NMDAR antibodies in the patient’s serum or CSF is considered the gold standard diagnostic test for anti-NMDAR encephalitis. If this condition is suspected based on clinical characteristics and compatible laboratory, EEG, and imaging studies, evaluation for antibodies to the NMDAR should be pursued. Most laboratories do not perform the assay for this antibody; therefore, most institutions send specimens to outside laboratories to complete the assays for anti-NMDAR, which can take several days. Detection of antibodies in the CSF is more sensitive than detection in serum. In 250 patients diagnosed with anti-NMDAR encephalitis, 100% had anti-NMDAR detected in the CSF, but only 85% had anti-NMDAR detected in serum.4 Most patients have intrathecal synthesis of NMDAR antibodies.7

CSF may reveal other abnormalities, most commonly lymphocytic pleocytosis. Protein concentration often is normal or mildly increased.7 Ms. A and Ms. B both had mild CSF pleocytosis.

MRI of the brain is abnormal in 33% of cases. When findings are present, they are present on T2 or FLAIR sequences, with hyperintensity in a variety of regions.7 Neither Ms. A nor Ms. B had neuroimaging abnormalities early in the course of their illness. However, later in the course of Ms. B’s illness, once she had been transferred to a tertiary care facility (after >40 days), subtle hyperintensities were noted on FLAIR, in the bilateral hippocampi. Given non-specific and often absent findings on imaging studies, imaging is not particularly helpful in diagnosing anti-NMDAR encephalitis, except to rule out other etiologies.

EEG. EEG studies are not particularly helpful in making a specific diagnosis of anti-NMDAR encephalitis. However, EEG is helpful in differentiating between psychiatric and encephalitic etiologies of psychiatric and behavioral disturbances, because most patients with encephalitis will have EEG abnormalities. In anti-NMDAR encephalitis, EEG is abnormal in 90% of patients.4 EEG may reveal seizure activity if the patient is having seizures, and otherwise may reveal slow disorganized activity.7

In case 1 (Ms. A), an EEG demonstrated diffuse slowing of background activity and mild asymmetry, with more prominent slowing in the right temporal region. In case 2 (Ms. B), non-convulsive status epilepticus was diagnosed on EEG. In both cases, the EEG indicated abnormal brain function, but did not provide a specific diagnosis. In tandem with a diagnostic work up for anti-NMDAR encephalitis, other potential etiologies for presenting symptoms should be evaluated. This would include completing an evaluation for infectious etiologies and other immune-mediated etiologies. If a patient is found to have NMDAR antibodies, one must evaluate for an ovarian teratoma or other occult malignancy (TABLE 34).


TABLE 3

Tumors among 577 patients reviewed by Titulaer et al4

Patients with tumor 38%
Female patients with tumor 46%
Male patients with tumor 6%
Among patients with tumor, % ovarian teratoma 94%
Other tumors identified Extra-ovarian teratomas (4): breast, lung, testicular (2 each); ovarian, thymic, and pancreatic carcinomas (1 each)

In both cases presentations, investigations for ovarian teratoma or other underlying malignancies were negative. For Ms. B, in the context of severe and recalcitrant symptoms, bilateral salpingo-oophorectomy was pursued, with the goal of potentially removing a microscopic teratoma unidentifiable via imaging studies. Pathologic examination of the ovaries and fallopian tubes did not reveal teratoma or other gynecologic malignancy. In some cases, teratoma not previously identified on imaging has been identified microscopically after removal of the ovaries.14 See the FIGURE7 for a summary of diagnostic work up.

FIGURE: Overview of evaluation and treatment of anti-NMDAR encephalitis7
CSF: cerebrospinal fluid; ECT: electroconvulsive therapy; EEG: electroencephalogram; EPS: extrapyramidal symptoms; FLAIR: fluid-attenuated inversion recovery; IVIG: intravenous immunoglobulin; LP: lumbar puncture; MRI: magnetic resonance imaging; NMDAR: N-methyl-d-aspartate receptor.

Treatment of anti-NMDAR encephalitis

The treatment of anti-NMDAR encephalitis is complex, multi-disciplinary, prolonged, and has been reviewed extensively elsewhere.7 See the FIGURE for a summary of management principles proposed by Dalmau et al.7 Ms. A had a good response to first-line treatment with IV glucocorticoids and plasmapheresis. Unfortunately, Ms. B’s diagnosis of anti-NMDAR encephalitis was delayed for more than a month, and she did not have an underlying tumor that could be removed; prompt initiation of immunotherapy and tumor removal, if applicable, are positive predictors of treatment response. Ms. B did not respond to first-line treatment with IV glucocorticoids and plasmapheresis; she required advancement to second-line treatments, including rituximab and cyclophosphamide, to which she also did not demonstrate clinical response.

The 2 cases presented demonstrate the discrepancy in clinical outcome between 2 young women with anti-NMDAR encephalitis. Both demonstrated dramatic behavioral changes and psychosis, and were initially admitted to inpatient psychiatric units before consideration of encephalitis in the differential diagnosis. These cases outline the importance of rapid recognition of this disorder, and draw attention to the important role that psychiatrists can play if they consider this syndrome early in the course of illness.

Management of psychiatric symptoms

We have thus far discussed the diagnosis of anti-NMDAR encephalitis and the treatment of the underlying autoimmune process. Now we will focus on the management of psychiatric symptoms, given their ubiquity in the illness and the important role psychiatrists play in management. TABLE 410,15,16,21-23 provides a summary of target symptoms and effective reported drug dosages. Of note, positive response to psychotropic medications may depend on when these agents are administered in the course of overall treatment, with generally improved responses if given in combination with aggressive immunotherapy.


TABLE 4

Summary of treatments for selected symptoms of anti-NMDAR encephalitis

Target Symptom Treatment Dose range (total daily)
Psychosis Risperidone
Aripiprazole
Olanzapine
1 to 2 mg15
30 mg22
5 mg22
Agitation Lorazepam
Diazepam
Midazolam
Risperidone
Olanzapine
Aripiprazole
Amisulpride
Haloperidol
Diphenhydramine
2 to 4 mg23,15
5 to 7 mg16
0.1 mg/kg IV16
1 to 4 mg16,10
5 mg23
30 mg22
100 mg22
5 mg22
25 to 100 mg10
Dystonia Benztropine
Trihexyphenidyl
Biperiden
Levodopa/carbidopa
1.5 mg15
8 mg15
2 to 4 mg16
20 mg/200 mg10
Insomnia Trazodone
Diphenhydramine
75 to 100 mg15,10,22
25 to 100 mg10
Catatonia Electroconvulsive therapy
Lorazepam
7 sessions10,19,21
8 to 30 mg10,21

Psychosis. Case reports have illustrated use of both typical and atypical antipsychotics for psychosis in patients with encephalitis. Chapman et al15 described successive trials of aripiprazole, 2.5 mg/d, and haloperidol, 4 mg/d, which were associated with worsening motor symptoms (increased facial masking, bradykinesia, drooling, and decreased blink rate) in a 16-year-old male. The patient later tolerated and responded well to risperidone, 2 mg/d, as evidenced by decreased response to internal stimuli.15 A general caution in the use of antipsychotics is the potential for worsening of abnormal movements associated with anti-NMDAR encephalitis itself, thus complicating the clinical picture. Close observation following antipsychotic administration, and selection of pharmacologic agents with decreased propensity toward extrapyramidal side effects (EPS), is recommended. In the case of Ms. B, NMS was considered in the differential diagnosis after her mental status worsened and she developed muscle rigidity following treatment with haloperidol. No further antipsychotics were used during her inpatient treatment.

Agitation. Benzodiazepines have been used successfully to manage agitation and also may treat insomnia, which often is associated with anti-NMDAR encephalitis.15 With severe agitation, parenteral benzodiazepines may be required.16 With Ms. A, lorazepam was favored over antipsychotics for the treatment of agitation, as it provided more rapid and effective sedation and could be administered via IV route. Diphenhydramine also has been described as effective for treating both agitation and insomnia,10 which is consistent with our clinical experience with Ms. A. The anticholinergic effect of diphenhydramine also may reduce rigidity or dystonias associated with anti-NMDAR encephalitis. Both typical and atypical antipsychotics have been used for agitation, with mild to moderate benefit, but they may worsen motor symptoms.15

Dystonia/rigidity. Dystonic symptoms and muscle rigidity frequently occur in the course of anti-NMDAR encephalitis, as a consequence of the illness itself, and may be exacerbated by antipsychotic use. Anticholinergic medications are the most commonly used medications to treat dystonia in anti-NMDAR encephalitis, and are used in the same general dosage range as in the treatment of antipsychotic-induced EPS. Chapman et al15 reported decreased jaw dystonia and rigidity with the use of benztropine, 0.5 mg 3 times daily, but noted that they later transitioned the patient to trihexyphenidyl liquid, 4 mg twice daily, when he could no longer swallow capsules or tablets. In 1 case report, the use of carbidopa-levodopa was described as a treatment for muscle rigidity.10

Insomnia. In addition to benzodiazepines and diphenhydramine, trazodone has been described as a useful treatment for insomnia. In 1 case report, trazodone, 100 mg/d, was continued even after other psychotropics were no longer needed, due to continued sleep difficulties in the course of rehabilitation.15

Catatonia. General recommendations for managing catatonia associated with psychiatric illness suggest the liberal use of benzodiazepines, progressing to electroconvulsive therapy (ECT) for resistant or malignant catatonia.17 These guidelines have been used for catatonia in patients with anti-NMDAR encephalitis. Consoli et al18 reported the case of a 17-year-old female with anti-NMDAR encephalitis who developed malignant catatonia. The symptoms did not improve until immunotherapy (prednisone and cyclophosphamide) was initiated, despite use of lorazepam, 15 mg/d. Mann et al10 described dramatic, but temporary, improvement in an anti-NMDAR encephalitis patient with catatonia upon treatment with lorazepam, 2 mg IV every 6 hours; this patient soon required emergent ECT and showed marked improvement with a course of 7 ECT sessions scheduled every other day. ECT also was reported to dramatically improve catatonia, as well as other clinical symptoms of anti-NMDAR encephalitis, in a case report by Braakman et al.19 The authors hypothesized that ECT may upregulate expression of NMDA receptors, as has been shown in animal studies.20 Wilson et al21 described improvement in malignant catatonia upon combining benzodiazepines and ECT with immunotherapy. See TABLE 410,15,16,21-23 for a summary of psychiatric treatments for select symptoms of anti-NMDAR encephalitis.

  CONCLUSIONS

Anti-NMDAR encephalitis, initially described in 2007, presents with psychiatric symptoms accompanied by other encephalitic symptoms including memory problems, seizures, and/or abnormal movements. The majority of patients are seen by a psychiatrist before definitive diagnosis. Thus, psychiatrists have a crucial role in the recognition of anti-NMDAR encephalitis and must be vigilant in their assessment of patients presenting with new-onset psychosis or behavioral changes.

If a patient without a history of psychiatric illness presents with rapid onset of psychiatric symptoms and/or behavioral change, this should prompt the psychiatrist to include a thorough evaluation of neurological signs and symptoms, as part of the diagnostic evaluation. The psychiatrist should be alert for common accompanying neurologic signs and symptoms of anti-NMDAR encephalitis, including memory problems, seizure, and abnormal movements. Presence of such neurologic symptoms should prompt referral for further diagnostic evaluation.

Prognosis of anti-NMDAR encephalitis is improved if the diagnosis is made early, facilitating rapid initiation of treatment. Our 2 cases anecdotally demonstrate the discrepancy in clinical outcome between 2 young women with anti-NMDAR encephalitis.

Psychiatrists also play an important role as consultants in recommending appropriate pharmacological treatments for behavioral symptoms of anti-NMDAR encephalitis. One must pay particular attention to selecting agents that are likely to reduce agitation and suffering, while avoiding those that may exacerbate or confound symptoms of anti-NMDAR encephalitis.

DISCLOSURES: Dr. Brooks has received a research grant from Pfizer, and is a speaker for Sunovion. Drs. Kruse, Jeffrey, Davis, Dearlove, and IsHak report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

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CORRESPONDENCE: John O. Brooks III, PhD, MD, UCLA Semel Institute, 760 Westwood Plaza, B3-267, Los Angeles, CA 90024-1759 USA E-MAIL: john.brooks@ucla.edu