Anti-NMDA-Receptor Encephalitis: From Bench to Clinic - ACS

Review pubs.acs.org/chemneuro

Anti-NMDA-Receptor Encephalitis: From Bench to Clinic Arun Venkatesan* and Krishma Adatia Johns Hopkins Encephalitis Center, Division of Neuroimmunology and Neuroinfectious Diseases, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States

ABSTRACT: NMDAR encephalitis is a common cause of autoimmune encephalitis, predominantly affecting young adults. Current data supports the idea that autoantibodies targeting NMDARs are responsible for disease pathogenesis. While these autoantibodies occur in the setting of underlying malignancy in approximately half of all patients, initiating factors for the autoimmune response in the remainder of patients are unclear. While there is increasing evidence supporting viral triggers such as herpes simplex encephalitis, this association and the mechanism of action have not yet been fully described. Although the majority of patients achieve good outcomes, those without an underlying tumor consistently show worse outcomes, prolonged recovery, and more frequent relapses. The cloning of patient-specific autoantibodies from affected individuals has raised important questions as to disease pathophysiology and clinical heterogeneity. Further advances in our understanding of this disease and underlying triggers are necessary to develop treatments which improve outcomes in patients presenting in the absence of tumors. KEYWORDS: NMDA, autoimmune encephalitis, plasma cells, receptor internalization, immunotherapy

■

INTRODUCTION

■

EPIDEMIOLOGY

but cases have been reported across a wide age range, from 2 months16 to the ninth decade of life.7,13,16−21 The traditional association of NMDAR encephalitis with an underlying tumor has been shown to be less common than first thought. In various reports, 20−59%7,8,14,22 of cases are seen in the presence of an underlying tumor, occurring less frequently in younger and male patients.7,8,10,22,23 While coexisting tumors were seen in 52% of females, this was only found to be the case in 6% of children and male patients.23 NMDAR encephalitis additionally not only appears to be more prevalent among nonCaucasians, but also shows a greater association with teratomas in African Americans compared to any other ethnic group.7,14,15,18,24,25 Ovarian teratoma is the tumor most commonly implicated with NMDAR encephalitis;7,8,22 a large series demonstrated that of all cases associated with an underlying malignancy, 98% were due to ovarian teratomas.7 Other malignancies seen in NMDAR encephalitis include mediastinal teratomas, sex cord stromal tumors, small cell lung cancer, testicular teratomas,

Encephalitis is a neurological disorder caused by inflammation of the brain parenchyma.1 Its incidence is approximated at 5− 10 per 100 000 people per year, though this is likely an underestimation.2,3 Although encephalitis is most commonly attributed to underlying viral infection, autoimmune conditions have become increasingly appreciated as causes of encephalitis.4 Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis was first described by Dalmau et al. in 2007 as a disease in which antibodies to the NMDAR are associated with ovarian teratomas in young women.5 In the time since this initial description, our understanding of the mechanisms and clinical features associated with this disorder has greatly increased.

Initially described as a disease of young females with ovarian teratomas,5,6 NMDAR encephalitis has since been identified in males, children, and in the absence of tumors.7−13 There remains a female predominance, however, with approximately 80% of cases occurring in women,7 though this percentage is lower in patients younger than 12 and older than 45. Young adults in their third decade of life are primarily affected,5,8,14,15 © 2017 American Chemical Society

Received: August 21, 2017 Accepted: October 27, 2017 Published: October 27, 2017 2586

DOI: 10.1021/acschemneuro.7b00319 ACS Chem. Neurosci. 2017, 8, 2586−2595

Review

ACS Chemical Neuroscience

Figure 1. Model of receptor internationalization following binding of NMDAR antibody. (A) NMDARs (dark blue) are associated with EphB2Rs (purple) in the extrasynaptic region. Glycine and glutamate binding to the GluN1 and GluN2 subunits, respectively, leads to receptor activation and Na+ and Ca2+ entry, causing depolarization. (B) In patients with NMDAR encephalitis, antibody attachment, capping, and cross-linking occur on the GluN1 subunit. This disrupts the interaction between NMDAR and EphB2R, reducing NMDAR stability and clustering. (C) Receptor internalization occurs, resulting in reduced NMDAR density and decreased currents.

psychiatric presentations, such as anxiety, paranoia, and hallucinations, seen in adults.8,15,23 Additional differences include a greater incidence of atypical symptoms, such as cerebellar ataxia or hemiparesis in children, and a greater incidence of memory deficits and autonomic instability in adults; 66% of adult cases suffer from central hypoventilation in contrast to only 23% of pediatric cases.8,22,38,40 Although initial presentations differ between children and adults, in most cases the clinical picture for all age groups converges at 3−4 weeks following symptom onset; behavioral symptoms, for example, occur in 90% of patients at 1 month regardless of age group.23

breast cancer, lung cancer, thymic carcinoma, pancreatic cancer, neuroblastoma, and Hodgkin’s lymphoma.7,8,18,23,26

■

CLINICAL PICTURE The presentation of NMDAR encephalitis has been welldefined in adults, with disease progression consisting of four distinct stages: the prodromal phase, psychotic phase, unresponsive phase, and hyperkinetic phase.7,15,27 A viral prodrome is experienced by up to 86% of patients;7 the remaining phases are more variable in presentation, severity, and sequence in which they occur.28 During the prodromal phase, patients typically experience a flulike illness for 1−21 days, consisting of low grade fever, malaise, headache, upper respiratory tract symptoms, fatigue, nausea, vomiting, and diarrhea.10,17,20,29 Delusions, auditory and visual hallucinations, depression, paranoia, agitation, and insomnia occur with progression to the psychotic phase.28 Most patients present to medical attention at this stage, with numbers quoted in the range of 72−84%.8,10,29,30 Approximately 40−42% are initially misdiagnosed as having a psychiatric disorder.29,31−35 Further progression may lead to seizures (commonly generalized tonicclonic), dyskinesias (predominantly perioral such as lipsmacking and grimacing), catatonia, impaired attention, and episodic memory loss.7,20,27,28 Seizures are a common manifestation of this disease, and are experienced by 76−82% of patients.8,10 Although they may occur at any time throughout the course of illness, males tend to present with seizures earlier.9 Mutism or akinesia is typically seen in the unresponsive phase, but athetosis may also occur.8,27 Autonomic instability is a hallmark of the hyperkinetic phase, and may manifest as hypotension, hypertension, cardiac arrhythmias, hypoventilation and hypo- or hyperthermia. Hypoventilation is a significant feature of the illness and patients who progress often require ventilatory support.5,8,10,12,22,23 In children, seizures often mark the onset of the disease, with behavioral problems such as inattention, aggression, temper tantrums, hyperactivity, or irritability occurring subsequently.8,22 These behavioral symptoms play a more significant role compared to adults, and may make diagnosis more difficult.7,36 The typical presentation of seizures or abnormal movements15,37−39 are in contrast to the predominance of

■

PATHOPHYSIOLOGY NMDARs are heterotetrameric ionotropic receptors 41,42 composed of two GluN1 subunits and combinations of two GluN2 or GluN3 subunits.43 The subunit composition of the receptor depends upon brain location and drives receptor function; GluN2A and GluN2B subunits, for example, are commonly seen in the forebrain, compared to GluN2C in the cerebellum.44 NMDARs are predominantly found in the forebrain and limbic system, most notably the hippocampus,8,15,45 and play a significant role in learning, memory, cognition and behavior.41,46−48 The available data suggests that IgG antibodies that target the GluN1 subunit of the NMDAR are responsible for disease pathogenesis.49 Three mechanisms for the resulting symptoms have been proposed in the literature: (i) receptor internalization, (ii) antibody blockade of ion entry, and (iii) complement mediated cell lysis.41 Receptor internalization is the mechanism most supported by current literature. Here, antibody attachment, capping and cross-linking of NMDARs induces their endocytosis and lysosomal degradation22,40,50,51 (Figure 1). Internalization of NMDARs is also facilitated by antibody-mediated disruption of NMDAR and ephrin B2 receptor (EphB2R) interactions; EphB2Rs normally aid stabilization of NMDARs at the membrane.51 Receptor internalization similarly occurs for both excitatory and inhibitory NMDARs.40 Electrophysiological studies have demonstrated reduced NMDAR-mediated currents due to decreased receptor density, the magnitude of which is related to antibody titers.40,41,50,52 By 2587


Review

ACS Chemical Neuroscience

Figure 2. Cloning of patient-specific autoantibodies from individuals with NMDAR encephalitis. Individual antibody secreting cells are isolated by flow cytometry from the CSF, followed by cloning and expression of patient-specific antibodies. These antibodies were found to bind multiple cell types in the CNS.

Figure 3. Model of antibody cross-reactivity in the setting of tumor. (1) NMDARs are expressed by ovarian teratomas. Where apoptosis occurs, these are released and taken up by antigen presenting cells, predominantly dendritic cells. (2) These dendritic cells migrate to regional lymph nodes, where activation of B, CD4+, and CD8+ cells occurs. (3) Immune cells migrate back to the ovary, where they target NMDARs. (4) In the presence of impaired blood brain barrier permeability, these cells are also able to enter the brain and cross-react with NMDARs found on neurons.

analysis of brain tissue demonstrates binding of human IgG to NMDARs, predominantly in the hippocampus.8,53 Brain tissue samples also show a notable absence of complement.8 Reduction of NMDAR density to similar extents following administration of either heat inactivated CSF or nonheat inactivated CSF provides further evidence that pathogenesis is not complement-mediated.40,41,50 Moreover, Kreye et al. have demonstrated NMDAR downregulation in vitro in the presence of the GluN1 antibody alone.52 More recently, patient-specific antibodies have been cloned from individual antibody-secreting cells in the CSF of affected patients. Notably, these antibodies were observed to bind to additional epitopes in the brain, such as endothelium, glial cells and Purkinje neurons, the significance of which remains to be determined52 (Figure 2).

the time internalization of receptors becomes microscopically visible at 2 h after exposure in vitro, receptor density has already fallen by 19%,51 continuing to fall until a nadir at 12 h, after which a plateau is seen that persists for the duration of antibody exposure.40 Total loss of NMDAR density in vitro may be greater than 45%.52 Importantly, this process is reversible with removal of antibodies; return to baseline NMDAR density occurs within 4 days in in vitro models.50 Animal studies have supported the concept that antibodies can drive disease pathogenesis; mice develop symptoms of depression, anhedonia, and memory deficits following the intrathecal injection or infusion of CSF from affected humans.8,53 Symptoms in mice show increasing severity with infusion time, and resolve upon stopping the infusion, demonstrating similar titer-dependence and reversal as seen in electrophysiological studies.53 Subsequent histopathological 2588


Review

ACS Chemical Neuroscience Triggers. Malignancies and infections have been proposed as triggers for NMDAR encephalitis. Ectopic expression of NMDARs in ovarian teratomas, for example, is thought to trigger the immune response in NMDAR encephalitis8,54 (Figure 3). A likely oversimplified model is as follows: antigens are released by these tumor cells when undergoing apoptosis, and are taken up by antigen-presenting cells which travel to regional lymph nodes. Here, plasma cells produce antibodies which later cross-react with NMDARs in the brain following impaired blood-brain barrier (BBB) permeability.49 While ovarian teratomas are the most widely recognized tumor associated with NMDAR encephalitis, other tumors and tumor cell lines have been shown to express the NMDAR, potentially explaining the association of such tumors with NMDAR encephalitis albeit at lower frequencies.55−58 In up to 80% of cases, no underlying tumor is found.22 Recent evidence has suggested the presence of NMDARs on a variety of peripheral blood cells, including red blood cells and immune cells,59,60 which could potentially play a triggering role in NMDAR encephalitis were self-tolerance to these antigens broken. The viral prodrome seen with this disease may support the idea of an infectious trigger. However, it is unclear whether this prodrome is merely a consequence of the early immune response or due to an infection which then facilitates antibody passage across the BBB.8 Herpes simplex has been the virus most commonly implicated in the development of NMDAR encephalitis.14,61−71 Up to 20−30% of patients with herpes simplex encephalitis (HSE) have been reported to develop NMDAR antibodies,61,66,69 occurring in the CSF before serum.62 These antibodies are not usually present at the onset of HSE, instead developing over the course of infection, suggesting that HSE triggers B cell and plasma cell generation. Development of antibodies, however, does not always lead to progression to NMDAR encephalitis.69 In those who do go on to develop NMDAR encephalitis, this may be seen as behavioral change and choreoathetosis in children,61,66 or psychiatric and cognitive abnormalities in adults.62 Identifying post-HSE NMDAR encephalitis may have significant prognostic implications, as these patients do not appear to be as responsive to treatment as those with other triggers such as teratoma.61 Although post-HSE NMDAR encephalitis has been the most widely reported, there have been a few reported cases where NMDAR encephalitis has occurred following mycoplasma, Epstein−Barr, varicella zoster, or influenza infections.14,72−74 Molecular mimicry, altered self-antigens, and dysregulation of immunoregulatory pathways are some of the mechanisms proposed for the link between infections and induction of CNS autoimmunity.75 In molecular mimicry, antibody crossreactivity with self-antigens occurs when there is sufficient structural similarity between epitopes on foreign and selfproteins. Self-antigens may also induce immune activation themselves, through alterations via expression level changes, or post-translational modification, thereby contributing to breaking of immune tolerance. Notably, the immune response resulting from an altered antigen may potentially be persistent even in the absence of further altered antigens, thus resulting in chronic neuroinflammation.75

presence of antibodies in patients without NMDAR encephalitis.9,77−82 When compared with CSF testing, serum testing also demonstrates a lower sensitivity than CSF testing (approximately 85%).23,83,84 Although testing of CSF titers alone is generally considered to be sufficient for the diagnosis of NMDAR encephalitis, some propose testing both CSF and serum to reduce the risk of false positive and false negative results.7,76,84 Antibody titers show temporal increase with disease progression, and appear to correlate with clinical symptoms; patients with more severe symptoms and associated malignancies have been reported to have higher titers.8,50 Other CSF abnormalities seen include lymphocytic pleocytosis (in 89− 90%), increased protein levels (33%), and oligoclonal bands (60%).5,8,14,23,85 Again, temporal changes in these abnormalities are seen throughout the course of the disease; lymphocytic pleocytosis has been reported to be present in early CSF samples while oligoclonal bands are typically not, and the reverse is more often observed later in the disease.10 Routine imaging techniques are not typically useful in aiding diagnosis, as CT very rarely reveals abnormalities14 and normal MRIs are seen in 50−70% of cases.5,7,8,10,11,14,86 When MRI abnormalities are present, changes are seen in the hippocampi, cerebellar or cerebral cortex, frontobasal and insular regions, basal ganglia, brainstem, or spinal cord.5 These findings may be transient, can be nonspecific, and do not correlate with symptom severity.8 Whether follow up MRIs demonstrate any abnormalities is not agreed upon. Dalmau et al. reported normal or minimal changes regardless of symptom severity and duration,7 while Gable et al. reported changes in 40% of follow up MRIs, though these changes were inconsistent between patients.14 Some abnormalities that have been reported on serial imaging include periventricular white matter demyelination, temporal lobe hyperintensity, and frontotemporal or medial temporal lobe atrophy.5,14 Thus, due to the large variability in findings between patients, currently utilized routine imaging techniques show little usefulness as diagnostic tools in NMDAR encephalitis. Recent work has suggested that fluorodeoxyglucose positron emission tomography scanning (FDG-PET) may serve a role in the assessment of patients with autoimmune encephalitis, as abnormalities are observed more frequently than in MRI.87,88 Interestingly, a pattern of occipital lobe hypometabolism has emerged as a biomarker that appears to distinguish NMDAR encephalitis from other autoimmune encephalitides.87 EEG monitoring is abnormal in 90% of patients with NMDAR encephalitis, where nonspecific slowing of brain activity is typically seen.8,14,15,22,23 Focal electrographic seizures may also be seen in 10%14 and extreme delta brush (EDB) pattern in 16−33%.89−91 EDB is manifested as delta waves (1− 3 Hz) upon which beta waves (20−30 Hz) are superimposed, and is named such due to the resemblance to the “delta brush” EEG pattern seen in premature infants. EDB is distinct from this neonatal pattern as it is typically synchronous and does not vary with sleep--wake cycles or level of arousal, and is thus a relatively unique feature of NMDAR encephalitis.90 It is typically seen as a continuous pattern, unrelated to symptoms such as dystonia, choreoathetosis or orofacial dyskinesias.90,92 Whether the presence of EDB reflects greater disease severity90,92−94 and worse outcomes90,93,94 remains controversial.91 Importantly, EDB is an early finding which may guide investigations and facilitate diagnosis of NMDAR encephalitis.94

■

DIAGNOSIS Identification of NMDAR antibodies in CSF or serum is the mainstay of diagnosis.8,11,76 Some studies have suggested lower specificity of serum testing, which occasionally demonstrates 2589


Review

ACS Chemical Neuroscience An overview of diagnostic findings in patients is given in Figure 4.

who also show inadequate response to rituximab, tocilizumab (monoclonal antibody against the interleukin-6 receptor) and bortezomib (a proteasome inhibitor) may have some additional benefit.98,99 In a recent nonrandomized study, tocilizumab resulted in better long-term outcomes compared to those given further rituximab or no subsequent treatment.98 Bortezomib therapy in refractory anti-NMDAR encephalitis patients demonstrated a fall in CSF antibody levels, with corresponding clinical improvement.99 Of note, while there have been few reported cases of recovery occurring in the absence of any targeted therapy, the natural history of NMDAR encephalitis remains to be defined.15,100 Symptom specific pharmacological management has been reported in few studies, though this has not been investigated in great detail.32 Catatonia is frequently managed with benzodiazepines. In some patients, sufficient control is only achieved with up to 20−30 mg of lorazepam per day.101−104 In such cases, electroconvulsive therapy (ECT) may be beneficial, though current literature provides inconsistent reports on its efficacy;42,101−104 it has been quoted in the range of 80−96% compared to lorazepam at 80−100%.101 Some case reports have demonstrated full recovery after ECT in patients with disease refractory to first and second line therapies.32,102−105 The mechanism by which ECT is able to exert symptomatic benefits in NMDA encephalitis is still unclear, but it has been proposed that it is able to increase the number of GluN2A and GluN2B subunits.106

Figure 4. Frequency of common diagnostic findings in patients with NMDAR encephalitis. Findings from 577 patients with NMDAR encephalitis are depicted. N, normal; A, abnormal; U, unknown.

It is also necessary to screen for underlying malignancies if NMDAR encephalitis is suspected. MRI, CT, and pelvic and transvaginal ultrasound are useful for identifying tumor presence. Serological tumor markers, on the other hand, tend to be negative in most patients.7

■

TREATMENT In patients with underlying malignancies, removal of the tumor improves symptoms in 75% of cases;7,8,24,95,96 this rises to 80% with the addition of immunotherapy.23 Where tumors are not present, first line treatment comprises corticosteroids, intravenous immunoglobulins, and/or plasma exchange.7,11,23,41,96,97 Good responses are usually seen following these treatments,5,8,22 but in patients who are unresponsive to or relapse after first line therapy, rituximab or cyclophosphamide are useful as second line treatments.7,11,23,41,96,97 Patients without tumors are usually less responsive to first line therapy, and thus more often require these second line therapies.7 In patients

■

PROGNOSIS

NMDAR encephalitis tends to show a better prognosis compared to most other causes of encephalitis;11 over 75% recover to at or near baseline neurological functioning,7,9,23,29,97,107 and only 25% suffer significant morbidity or mortality.7,23,34,107 Although there has yet to be a randomized controlled trial of therapies in NMDAR encephalitis, large retrospective studies suggest that good prognosis, including fewer relapses, is associated with early diagnosis and treatment,23 milder symptoms, and removal of tumor when

Figure 5. Outcomes following NMDAR encephalitis. 2590


Review

ACS Chemical Neuroscience present.5,8,15,22,108−110 Presence of tumor itself, however, is not a prognostic indicator; final outcomes are similar between patients with and without tumor (Figure 5).7,10 Long-term outcome is associated with treatment responsiveness: 97% of patients responsive to first line therapy show good outcome at 2 year follow up (modified Rankin Score 0−2).23 In patients who do not respond to first line therapy, subsequent treatment with second line therapies confers better long-term outcome compared to patients who have no further treatment.7,23,107 Improvements in symptoms begin within a few weeks after initiating treatment,24 but return to baseline functioning may only be achieved up to 3 years later.4,8,22,37,95 Patients without tumors typically show a slower course of recovery and some patients do not ever recover fully.8,111 Serum and CSF antibody titers can be measured to demonstrate control of the immune response. Although serum levels tend to show a faster rate of decline than CSF titers,8 CSF antibody titers show better correlation with longterm clinical outcome and relapses.8,10,76,108,112 Lower initial CSF titer and early decline in antibody levels are associated with better outcome; however, patients may have persistent positive titers even in the setting of recovery.8,10,76,108,112 Despite achieving medical recovery, rehabilitation is required in around 85% of patients upon discharge; deficits in attention, memory, and executive functions may persist for many years.8,10,107 Persisting amnesia of the entire duration of illness, in particular, is a characteristic feature.29 Memory deficits seen following NMDAR encephalitis have recently been demonstrated to correlate with degree of hippocampal atrophy, which in turn are associated with symptom duration and severity.113 Diffuse cerebral atrophy (DCA) and progressive cerebellar atrophy (PCA) have also been reported in patients with NMDAR encephalitis. Where DCA occurs, although full recovery may take a number of years, follow up MRIs may demonstrate some reversal of brain atrophy.111 In patients with PCA, however, only partial clinical improvement is seen, with persisting atrophy.114 Residual visual impairments following NMDAR encephalitis have also been reported.115 Here, deficits in both high and low contrast acuity are reported, with extent of high contrast deficit associated with disease severity.115 NMDARs can be found in the retina, so such visual dysfunction may originate here. With use of optical coherence tomography, Brandt et al. failed to find any structural retinal damage in patients with NMDAR encephalitis, suggesting that cortical deficits may be responsible.115 Relapses have been reported in approximately 10−29% of cases,7,10,23 being more common in patients without tumors.7,23 Death has been reported in 4−10% of patients;8,14 this is usually seen within months following disease onset.7,13

of disease pathogenesis and may shed light on some of the clinical heterogeneity of the disease. In addition, such studies may contribute to the development of new targeted therapies for individuals afflicted by this condition.

■

AUTHOR INFORMATION

Corresponding Author

*Mailing address: Johns Hopkins Hospital, 600 N. Wolfe St., Meyer 6-113, Baltimore, MD 21287, USA. E-mail: avenkat2@ jhmi.edu. ORCID

Arun Venkatesan: 0000-0002-9335-7361 Funding

This work was supported by the National Institutes of Health (NINDS R21 NS098229 to A.V.). Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS

■

REFERENCES

Figures 4 and 5 represent new figures created from data presented by J. Dalmau and colleagues in prior publications.

(1) Venkatesan, A., Tunkel, A., Bloch, K. C., Lauring, A. S., Sejvar, J., Bitnun, A., Stahl, J. P., Mailles, A., Drebot, M., Rupprecht, C. E., Yoder, J., Cope, J. R., Wilson, M. R., Whitley, R. J., Sullivan, J., Granerod, J., Jones, C., Eastwood, K., Ward, K. N., Durrheim, D. N., Solbrig, M. V., Guo-Dong, L., Glaser, C. A., et al. (2013) Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin. Infect. Dis. 57, 1114−1128. (2) Jmor, F., Emsley, H., Fischer, M., Solomon, T., and Lewthwaite, P. (2008) The incidence of acute encephalitis syndrome in Western industrialised and tropical countries. Virol. J. 5, 134. (3) Vora, N. M., Holman, R., Mehal, J., Steiner, C., Blanton, J., and Sejvar, J. (2014) Burden of encephalitis-associated hospitalizations in the United States, 1998−2010. Neurology 82, 443−451. (4) Leypoldt, F., Armangue, T., and Dalmau, J. (2015) Autoimmune encephalopathies. Ann. N. Y. Acad. Sci. 1338, 94−114. (5) Dalmau, J., Tuzun, E., Wu, H., Masjuan, J., Rossi, J., Voloschin, A., Baehring, J., Shimazaki, H., Koide, R., King, D., Mason, W., Sansing, L., Dichter, M., Rosenfeld, M., and Lynch, D. R. (2007) Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann. Neurol. 61, 25−36. (6) Vitaliani, R., Mason, W., Ances, B., Zwerdling, T., Jiang, Z., and Dalmau, J. (2005) Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma. Ann. Neurol. 58, 594−604. (7) Dalmau, J., Lancaster, E., Martinez-Hernandez, E., Rosenfeld, M., and Balice-Gordon, R. (2011) Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 10, 63−74. (8) Dalmau, J., Gleichman, A. J., Hughes, E. G., Rossi, J. E., Peng, X., Lai, M., Dessain, S. K., Rosenfeld, M. R., Balice-Gordon, R., and Lynch, D. R. (2008) Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 7, 1091−1098. (9) Viaccoz, A., Desestret, V., Ducray, F., Picard, G., Cavillon, G., Rogemond, V., Antoine, J., Delattre, J., and Honnorat, J. (2014) Clinical specificities of adult male patients with NMDA receptor antibodies encephalitis. Neurology 82, 556−563. (10) Irani, S. R., Bera, K., Waters, P., Zuliani, L., Maxwell, S., Zandi, M. S., Friese, M. A., Galea, I., Kullmann, D. M., Beeson, D., Lang, B., Bien, C. G., and Vincent, A. (2010) N-methyl-d-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain 133, 1655−1667.

■

CONCLUSIONS Over the past 10 years, it has become well-established that NMDAR encephalitis is a common cause of autoimmune encephalitis. The available data from in vitro and in vivo studies demonstrate that autoantibodies targeting NMDARs can result in receptor internalization, perturbation of NMDAR currents, and behavioral alterations. While both malignancy and infections can trigger NMDAR encephalitis, the mechanisms by which infections in particular may do so remain to be explored. The recent cloning of patient-specific autoantibodies from patients with NMDAR encephalitis may facilitate studies 2591


Review

ACS Chemical Neuroscience (11) Maneta, E., and Garcia, G. (2014) Psychiatric manifestations of anti-NMDA receptor encephalitis: neurobiological underpinnings and differential diagnostic implications. Psychosomatics 55, 37−44. (12) Sansing, L. H., Tuzun, E., Ko, M., Baccon, J., Lynch, D., and Dalmau, J. (2007) A patient with encephalitis associated with NMDA receptor antibodies. Nat. Clin. Pract. Neurol. 3, 291−296. (13) van de Riet, E. H., and Schieveld, J. N. (2013) First-onset psychosis, anti-NMDAR encephalitis, schizophrenia and ConsultationLiaison psychiatry. Gen Hosp Psychiatry 35, 442−443. (14) Gable, M. S., Gavali, S., Radner, A., Tilley, D. H., Lee, B., Dyner, L., Collins, A., Dengel, A., Dalmau, J., and Glaser, C. A. (2009) AntiNMDA receptor encephalitis: report of ten cases and comparison with viral encephalitis. Eur. J. Clin. Microbiol. Infect. Dis. 28, 1421−1429. (15) Iizuka, T., Sakai, F., Ide, T., Monzen, T., Yoshii, S., Iigaya, M., Suzuki, K., Lynch, D. R., Suzuki, N., Hata, T., and Dalmau, J. (2008) Anti-NMDA receptor encephalitis in Japan: Long-term outcome without tumor removal. Neurology 70, 504−511. (16) Armangue, T., Titulaer, M. J., Málaga, I., Bataller, L., Gabilondo, I., Graus, F., and Dalmau, J. (2013) Pediatric Anti-N-methyl-DAspartate Receptor EncephalitisClinical Analysis and Novel Findings in a Series of 20 Patients. J. Pediatr. 162, 850−856. (17) Day, G. S., High, S., Cot, B., and Tang-Wai, D. F. (2011) AntiNMDA-receptor encephalitis: case report and literature review of an under-recognized condition. J. Gen Intern Med. 26, 811−816. (18) Titulaer, M. J., McCracken, L., Gabilondo, I., Iizuka, T., Kawachi, I., Bataller, L., Torrents, A., Rosenfeld, M., Balice-Gordon, R., Graus, F., and Dalmau, J. (2013) Late-onset anti-NMDA receptor encephalitis. Neurology 81, 1058−1063. (19) Dalmau, J., Lancaster, E., Martinez-Hernandez, E., Rosenfeld, M. R., and Balice-Gordon, R. (2011) Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 10, 63−74. (20) Luca, N., Daengsuwan, T., Dalmau, J., Jones, K., deVeber, G., Kobayashi, J., Laxer, R. M., and Benseler, S. M. (2011) Anti-N-MethylD-Aspartate Receptor Encephalitis: A Newly Recognized Inflammatory Brain Disease in Children. Arthritis Rheum. 63, 2516−2522. (21) Zekeridou, A., Karantoni, E., Viaccoz, A., Ducray, F., Gitiaux, C., Villega, F., Deiva, K., Rogemond, V., Mathias, E., Picard, G., Tardieu, M., Antoine, J., Delattre, J., and Honnorat, J. (2015) Treatment and outcome of children and adolescents with N-methyl-D-aspartate receptor encephalitis. J. Neurol. 262, 1859−1866. (22) Florance, N. R., Davis, R., Lam, C., Szperka, C., Zhou, L., Ahmad, S., Campen, C., Moss, H., Peter, N., Gleichman, A., Glaser, C., Lynch, D., Rosenfeld, M., and Dalmau, J. (2009) Anti-N-methyl-Daspartate receptor (NMDAR) encephalitis in children and adolescents. Ann. Neurol. 66, 11−18. (23) Titulaer, M. J., McCracken, L., Gabilondo, I., Armangué, T., Glaser, C., Iizuka, T., Honig, L. S., Benseler, S. M., Kawachi, I., Martinez-Hernandez, E., Aguilar, E., Gresa-Arribas, N., Ryan-Florance, N., Torrents, A., Saiz, A., Rosenfeld, M. R., Balice-Gordon, R., Graus, F., and Dalmau, J. (2013) Treatment and prognostic factors for longterm outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 12, 157−165. (24) Lesher, A. P., Myers, T. J., Tecklenburg, F., and Streck, C. J. (2010) Anti−N-methyl-d-aspartate receptor encephalitis associated with an ovarian teratoma in an adolescent female. Journal of Pediatric Surgery 45, 1550−1553. (25) Parratt, K. L., Allan, M., Lewis, S., Dalmau, J., Halmagyi, G., and Spies, J. M. (2009) Acute psychiatric illness in a young woman: an unusual form of encephalitis. Med. J. Aust 191, 284−286. (26) Eker, A., Saka, E., Dalmau, J., Kurne, A., Bilen, C., Ozen, H., Ertoy, D., Oguz, K. K., and Elibol, B. (2008) Testicular teratoma and anti-N-methyl-D-aspartate receptor-associated encephalitis. J. Neurol., Neurosurg. Psychiatry 79, 1082−1083. (27) Peery, H. E., Day, G., Dunn, S., Fritzler, M., Pruss, H., De Souza, C., Doja, A., Mossman, K., Resch, L., Xia, C., Sakic, B., Belbeck, L., and Foster, W. G. (2012) Anti-NMDA receptor encephalitis. The disorder, the diagnosis and the immunobiology. Autoimmun. Rev. 11, 863−872.

(28) Loughan, A. R., Allen, A., Perna, R., and Malkin, M. G. (2016) Anti-N-Methyl-D-Aspartate Receptor Encephalitis: A Review and Neuropsychological Case Study. Clinical Neuropsychologist 30, 150− 163. (29) Wandinger, K. P., Saschenbrecker, S., Stoecker, W., and Dalmau, J. (2011) Anti-NMDA-receptor encephalitis: a severe, multistage, treatable disorder presenting with psychosis. J. Neuroimmunol. 231, 86−91. (30) Maat, P., de Graaff, E., van Beveren, N. M., Hulsenboom, E., Verdijk, R. M., Koorengevel, K., van Duijn, M., Hooijkaas, H., Hoogenraad, C., and Sillevis Smitt, P. A. (2013) Psychiatric phenomena as initial manifestation of encephalitis by anti-NMDAR antibodies. Acta Neuropsychiatr 25, 128−136. (31) Lejuste, F., Thomas, L., Picard, G., Desestret, V., Ducray, F., Rogemond, V., Psimaras, D., Antoine, J.-C., Delattre, J.-Y., Groc, L., Leboyer, M., and Honnorat, J. (2016) Neuroleptic intolerance in patients with anti-NMDAR encephalitis. Neurology - Neuroimmunology Neuroinflammation 3, e280. (32) Chapman, M. R., and Vause, H. E. (2011) Anti-NMDA Receptor Encephalitis: Diagnosis, Psychiatric Presentation, and Treatment. Am. J. Psychiatry 168, 245−251. (33) Kruse, J. L., Jeffrey, J., Davis, M., Dearlove, J., IsHak, W., and Brooks, J. O. (2014) Anti-N-methyl-D-aspartate receptor encephalitis: a targeted review of clinical presentation, diagnosis, and approaches to psychopharmacologic management. Ann. Clin. Psychiatry 26, 111−119. (34) van de Riet, E. H., Esseveld, M., Cuypers, L., and Schieveld, J. N. (2013) Anti-NMDAR encephalitis: a new, severe and challenging enduring entity. Eur. Child Adolesc Psychiatry 22, 319−323. (35) Kayser, M., Titulaer, M., Gresa-Arribas, N., and Dalmau, J. (2013) Frequency and characteristics of isolated psychiatric episodes in anti-N-methyl-d-aspartate receptor encephalitis. JAMA Neurol 70, 1133−1139. (36) Leypoldt, F., Gelderblom, M., Schottle, D., Hoffmann, S., and Wandinger, K. P. (2013) Recovery from severe frontotemporal dysfunction at 3 years after N-methyl-d-aspartic acid (NMDA) receptor antibody encephalitis. J. Clin. Neurosci. 20, 611−613. (37) Poloni, C., Korff, C., Ricotti, V., King, M., Perez, E., MayorDubois, C., Haenggeli, C., and Deonna, T. (2010) Severe childhood encephalopathy with dyskinesia and prolonged cognitive disturbances: evidence for anti-N-methyl-D-aspartate receptor encephalitis. Dev Med. Child Neurol. 52, 78−82. (38) Biancheri, R., Pessagno, A., Baglietto, M., Irani, S., Rossi, A., Giribaldi, G., Badenier, M., Vincent, A., and Veneselli, E. (2010) AntiN-methyl-D-aspartate-receptor encephalitis in a four-year-old girl. J. Pediatr. 156, 332−334. (39) Lebas, A., Husson, B., Didelot, A., Honnorat, J., and Tardieu, M. (2010) Expanding spectrum of encephalitis with NMDA receptor antibodies in young children. J. Child Neurol 25, 742−745. (40) Moscato, E. H., Peng, X., Jain, A., Parsons, T. D., Dalmau, J., and Balice-Gordon, R. J. (2014) Acute mechanisms underlying antibody effects in anti−N-methyl-D-aspartate receptor encephalitis. Ann. Neurol. 76, 108−119. (41) Dowben, J. S., Kowalski, P. C., and Keltner, N. L. (2015) Biological Perspectives. Perspectives in Psychiatric Care 51, 236−240. (42) Mann, A. P., Grebenciucova, E., and Lukas, R. V. (2014) AntiN-methyl-D-aspartate-receptor encephalitis: diagnosis, optimal management, and challenges. Ther. Clin. Risk Manage. 10, 517−525. (43) Masdeu, J. C., Dalmau, J., and Berman, K. F. (2016) NMDA Receptor Internalization by Autoantibodies: A Reversible Mechanism Underlying Psychosis? Trends Neurosci. 39, 300−310. (44) Wyllie, D. J. A., Livesey, M. R., and Hardingham, G. E. (2013) Influence of GluN2 subunit identity on NMDA receptor function. Neuropharmacology 74, 4−17. (45) Tüzün, E., Zhou, L., Baehring, J. M., Bannykh, S., Rosenfeld, M. R., and Dalmau, J. (2009) Evidence for antibody-mediated pathogenesis in anti-NMDAR encephalitis associated with ovarian teratoma. Acta Neuropathol. 118, 737−743. 2592


Review

ACS Chemical Neuroscience (46) Javitt, D. C., and Freedman, R. (2015) Sensory processing dysfunction in the personal experience and neuronal machinery of schizophrenia. Am. J. Psychiatry 172, 17−31. (47) Lau, C. G., and Zukin, R. S. (2007) NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nat. Rev. Neurosci. 8, 413−426. (48) Traynelis, S. F., Wollmuth, L., McBain, C., Menniti, F., Vance, K., Ogden, K., Hansen, K., Yuan, H., Myers, S., and Dingledine, R. (2010) Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev. 62, 405−496. (49) Martinez-Hernandez, E., Horvath, J., Shiloh-Malawsky, Y., Sangha, N., Martinez-Lage, M., and Dalmau, J. (2011) Analysis of complement and plasma cells in the brain of patients with antiNMDAR encephalitis. Neurology 77, 589−593. (50) Hughes, E. G., Peng, X., Gleichman, A. J., Lai, M., Zhou, L., Tsou, R., Parsons, T. D., Lynch, D. R., Dalmau, J., and Balice-Gordon, R. J. (2010) Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J. Neurosci. 30, 5866−5875. (51) Mikasova, L., De Rossi, P., Bouchet, D., Georges, F., Rogemond, V., Didelot, A., Meissirel, C., Honnorat, J., and Groc, L. (2012) Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis. Brain 135, 1606−1621. (52) Kreye, J., Wenke, N. K., Chayka, M., Leubner, J., Murugan, R., Maier, N., Jurek, B., Ly, L. T., Brandl, D., Rost, B. R., Stumpf, A., Schulz, P., Radbruch, H., Hauser, A. E., Pache, F., Meisel, A., Harms, L., Paul, F., Dirnagl, U., Garner, C., Schmitz, D., Wardemann, H., and Pruss, H. (2016) Human cerebrospinal fluid monoclonal N-methyl-Daspartate receptor autoantibodies are sufficient for encephalitis pathogenesis. Brain 139, 2641−2652. (53) Planaguma, J., Leypoldt, F., Mannara, F., Gutierrez-Cuesta, J., Martin-Garcia, E., Aguilar, E., Titulaer, M. J., Petit-Pedrol, M., Jain, A., Balice-Gordon, R., Lakadamyali, M., Graus, F., Maldonado, R., and Dalmau, J. (2015) Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice. Brain 138, 94−109. (54) Day, G. S., Laiq, S., Tang-Wai, D. F., and Munoz, D. G. (2014) Abnormal neurons in teratomas in NMDAR encephalitis. JAMA Neurol 71, 717−724. (55) Takano, T., Lin, J. H., Arcuino, G., Gao, Q., Yang, J., and Nedergaard, M. (2001) Glutamate release promotes growth of malignant gliomas. Nat. Med. 7, 1010−1015. (56) Seidlitz, E. P., Sharma, M. K., Saikali, Z., Ghert, M., and Singh, G. (2009) Cancer cell lines release glutamate into the extracellular environment. Clin. Exp. Metastasis 26, 781−787. (57) Li, L., and Hanahan, D. (2013) Hijacking the neuronal NMDAR signaling circuit to promote tumor growth and invasion. Cell 153, 86− 100. (58) Titulaer, M. J., McCracken, L., Gabilondo, I., Armangué, T., Glaser, C., Iizuka, T., Honig, L. S., Benseler, S. M., Kawachi, I., Martinez-Hernandez, E., Aguilar, E., Gresa-Arribas, N., Ryan-Florance, N., Torrents, A., Saiz, A., Rosenfeld, M. R., Balice-Gordon, R., Graus, F., and Dalmau, J. (2013) Treatment and prognostic factors for longterm outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 12, 157−165. (59) Makhro, A., Hänggi, P., Goede, J. S., Wang, J., Brüggemann, A., Gassmann, M., Schmugge, M., Kaestner, L., Speer, O., and Bogdanova, A. (2013) N-methyl-D-aspartate receptors in human erythroid precursor cells and in circulating red blood cells contribute to the intracellular calcium regulation. Am. J. Physiol Cell Physiol 305, C1123−1138. (60) Boldyrev, A. A., Bryushkova, E. A., and Vladychenskaya, E. A. (2012) NMDA receptors in immune competent cells. Biochemistry (Moscow) 77, 128−134. (61) Armangue, T., Leypoldt, F., Málaga, I., Raspall-Chaure, M., Marti, I., Nichter, C., Pugh, J., Vicente-Rasoamalala, M., LafuenteHidalgo, M., Macaya, A., Ke, M., Titulaer, M. J., Höftberger, R., Sheriff, H., Glaser, C., and Dalmau, J. (2014) Herpes simplex virus encephalitis is a trigger of brain autoimmunity. Ann. Neurol. 75, 317−323. (62) Armangue, T., Moris, G., Cantarín-Extremera, V., Conde, C. E., Rostasy, K., Erro, M. E., Portilla-Cuenca, J. C., Turón-Viñas, E.,

Málaga, I., Muñoz-Cabello, B., Torres-Torres, C., Llufriu, S., GonzálezGutiérrez-Solana, L., González, G., Casado-Naranjo, I., Rosenfeld, M., Graus, F., and Dalmau, J. (2015) Autoimmune post−herpes simplex encephalitis of adults and teenagers. Neurology 85, 1736−1743. (63) Bektaş, Ö ., Tanyel, T., Kocabaş, B. A., Fitöz, S., Iṅ ce, E., and Deda, G. (2014) Anti-N-Methyl-d-Aspartate Receptor Encephalitis that Developed after Herpes Encephalitis: A Case Report and Literature Review. Neuropediatrics 45, 396−401. (64) Desena, A., Graves, D., Warnack, W., and Greenberg, B. M. (2014) Herpes simplex encephalitis as a potential cause of anti-Nmethyl-D-aspartate receptor antibody encephalitis: report of 2 cases. JAMA Neurol 71, 344−346. (65) Granerod, J., Ambrose, H., Davies, N., Clewley, J., Walsh, A., Morgan, D., Cunningham, R., Zuckerman, M., Mutton, K., Solomon, T., Ward, K., Lunn, M., Irani, S., Vincent, A., Brown, D., and Crowcroft, N. S. (2010) Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect. Dis. 10, 835−844. (66) Hacohen, Y., Deiva, K., Pettingill, P., Waters, P., Siddiqui, A., Chretien, P., Menson, E., Lin, J., Tardieu, M., Vincent, A., and Lim, M. J. (2014) N-methyl-D-aspartate receptor antibodies in post-herpes simplex virus encephalitis neurological relapse. Mov. Disord. 29, 90−96. (67) Leypoldt, F., Titulaer, M., Aguilar, E., Walther, J., Bonstrup, M., Havemeister, S., Teegen, B., Lutgehetmann, M., Rosenkranz, M., Magnus, T., and Dalmau, J. (2013) Herpes simplex virus-1 encephalitis can trigger anti-NMDA receptor encephalitis: case report. Neurology 81, 1637−1639. (68) Mohammad, S. S., Sinclair, K., Pillai, S., Merheb, V., Aumann, T. D., Gill, D., Dale, R. C., and Brilot, F. (2014) Herpes simplex encephalitis relapse with chorea is associated with autoantibodies to NMethyl-D-aspartate receptor or dopamine-2 receptor. Mov. Disord. 29, 117−122. (69) Pruss, H., Finke, C., Holtje, M., Hofmann, J., Klingbeil, C., Probst, C., Borowski, K., Ahnert-Hilger, G., Harms, L., Schwab, J., Ploner, C., Komorowski, L., Stoecker, W., Dalmau, J., and Wandinger, K. P. (2012) N-methyl-D-aspartate receptor antibodies in herpes simplex encephalitis. Ann. Neurol. 72, 902−911. (70) Venkatesan, A., and Benavides, D. R. (2015) Autoimmune encephalitis and its relation to infection. Curr. Neurol. Neurosci. Rep. 15, 3. (71) Wickstrom, R., Fowler, A., Cooray, G., Karlsson-Parra, A., and Grillner, P. (2014) Viral triggering of anti-NMDA receptor encephalitis in a child - an important cause for disease relapse. Eur. J. Paediatr Neurol 18, 543−546. (72) Baltagi, S. A., Shoykhet, M., Felmet, K., Kochanek, P., and Bell, M. J. (2010) Neurological sequelae of 2009 influenza A (H1N1) in children: a case series observed during a pandemic. Pediatric Critical Care Medicine 11, 179−184. (73) Xu, C. L., Liu, L., Zhao, W., Li, J., Wang, R., Wang, S., Wang, D., Liu, M., Qiao, S., and Wang, J. W. (2011) Anti-N-methyl-D-aspartate receptor encephalitis with serum anti-thyroid antibodies and IgM antibodies against Epstein-Barr virus viral capsid antigen: a case report and one year follow-up. BMC Neurol. 11, 149. (74) Solis, N., Salazar, L., and Hasbun, R. (2016) Anti-NMDA Receptor antibody encephalitis with concomitant detection of Varicella zoster virus. J. Clin. Virol. 83, 26−28. (75) Atassi, M. Z., and Casali, P. (2008) Molecular mechanisms of autoimmunity. Autoimmunity 41, 123−132. (76) Gresa-Arribas, N., Titulaer, M. J., Torrents, A., Aguilar, E., McCracken, L., Leypoldt, F., Gleichman, A. J., Balice-Gordon, R., Rosenfeld, M. R., Lynch, D., Graus, F., and Dalmau, J. (2014) Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol. 13, 167− 177. (77) Deakin, J., Lennox, B. R., and Zandi, M. S. (2014) Antibodies to the N-methyl-D-aspartate receptor and other synaptic proteins in psychosis. Biol. Psychiatry 75, 284−291. 2593


Review

ACS Chemical Neuroscience (78) Hammer, M. S., Larsen, M., and Stack, C. V. (1995) Outcome of children with opsoclonus-myoclonus regardless of etiology. Pediatr Neurol 13, 21−24. (79) Mackay, G., Ahmad, K., Stone, J., Sudlow, C., Summers, D., Knight, R., Will, R., Irani, S., Vincent, A., and Maddison, P. (2012) NMDA receptor autoantibodies in sporadic Creutzfeldt-Jakob disease. J. Neurol. 259, 1979−1981. (80) Zandi, M., Irani, S., Lang, B., Waters, P., Jones, P., McKenna, P., Coles, A., Vincent, A., and Lennox, B. R. (2011) Disease-relevant autoantibodies in first episode schizophrenia. J. Neurol. 258, 686−688. (81) Zandi, M. S., Paterson, R. W., Ellul, M. A., Jacobson, L., AlDiwani, A., Jones, J. L., Cox, A. L., Lennox, B., Stamelou, M., Bhatia, K. P., Schott, J. M., Coles, A. J., Kullmann, D. M., and Vincent, A. (2015) Clinical relevance of serum antibodies to extracellular N-methyl-Daspartate receptor epitopes. J. Neurol., Neurosurg. Psychiatry 86, 708− 713. (82) Wang, R., Guan, H. Z., Ren, H. T., Wang, W., Hong, Z., and Zhou, D. (2015) CSF findings in patients with anti-N-methyl-Daspartate receptor-encephalitis. Seizure 29, 137−142. (83) Pruss, H., Dalmau, J., Harms, L., Holtje, M., Ahnert-Hilger, G., Borowski, K., Stoecker, W., and Wandinger, K. P. (2010) Retrospective analysis of NMDA receptor antibodies in encephalitis of unknown origin. Neurology 75, 1735−1739. (84) Suh-Lailam, B. B., Haven, T., Copple, S., Knapp, D., Jaskowski, T., and Tebo, A. E. (2013) Anti-NMDA-receptor antibody encephalitis: performance evaluation and laboratory experience with the anti-NMDA-receptor IgG assay. Clin. Chim. Acta 421, 1−6. (85) Barry, H., Hardiman, O., Healy, D., Keogan, M., Moroney, J., Molnar, P., Cotter, D., and Murphy, K. C. (2011) Anti-NMDA receptor encephalitis: an important differential diagnosis in psychosis. Br. J. Psychiatry 199, 508−509. (86) Barry, H., Byrne, S., Barrett, E., Murphy, K. C., and Cotter, D. R. (2015) Anti-N-methyl-d-aspartate receptor encephalitis: review of clinical presentation, diagnosis and treatment. BJPsych Bulletin 39, 19− 23. (87) Probasco, J. C., Solnes, L., Nalluri, A., Cohen, J., Jones, K. M., Zan, E., Javadi, M. S., and Venkatesan, A. (2017) Abnormal brain metabolism on FDG-PET/CT is a common early finding in autoimmune encephalitis. Neurol Neuroimmunol. Neuroinflamm. 4, e352. (88) Solnes, L. B., Jones, K. M., Rowe, S. P., Pattanayak, P., Nalluri, A., Venkatesan, A., Probasco, J. C., and Javadi, M. S. (2017) Diagnostic Value of (18)F-FDG PET/CT Versus MRI in the Setting of AntibodySpecific Autoimmune Encephalitis. J. Nucl. Med. 58, 1307−1313. (89) Veciana, M., Becerra, J. L., Fossas, P., Muriana, D., Sansa, G., Santamarina, E., Gaig, C., Carreno, M., Molins, A., Escofet, C., Ley, M., Vivanco, R., Pedro, J., Miro, J., and Falip, M. (2015) EEG extreme delta brush: An ictal pattern in patients with anti-NMDA receptor encephalitis. Epilepsy Behav 49, 280−285. (90) Schmitt, S. E., Pargeon, K., Frechette, E., Hirsch, L., Dalmau, J., and Friedman, D. (2012) Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology 79, 1094− 1100. (91) Zhang, Y., Liu, G., Jiang, M. D., Li, L. P., and Su, Y. Y. (2017) Analysis of electroencephalogram characteristics of anti-NMDA receptor encephalitis patients in China. Clin. Neurophysiol. 128, 1227−1233. (92) Shi, Y. (2017) Serial EEG Monitoring in a Patient With AntiNMDA Receptor Encephalitis. Clin EEG Neurosci 48, 301−303. (93) da Silva-Junior, F. P., Castro, L. H., Andrade, J. Q., Bastos, C. G., Moreira, C. H., Valerio, R. M., Jorge, C. L., Marchiori, P. E., Nitrini, R., and Garzon, E. (2014) Serial and prolonged EEG monitoring in antiN-Methyl-d-Aspartate receptor encephalitis. Clin. Neurophysiol. 125, 1541−1544. (94) VanHaerents, S., Stillman, A., Inoa, V., Searls, D. E., and Herman, S. T. (2014) Early and persistent ‘extreme delta brush’ in a patient with anti-NMDA receptor encephalitis(). Epilepsy & Behavior Case Reports 2, 67−70.

(95) Platt, M. P., Agalliu, D., and Cutforth, T. (2017) Hello from the Other Side: How Autoantibodies Circumvent the Blood−Brain Barrier in Autoimmune Encephalitis. Front. Immunol. 8, 442. (96) Graus, F., Titulaer, M. J., Balu, R., Benseler, S., Bien, C. G., Cellucci, T., Cortese, I., Dale, R. C., Gelfand, J. M., Geschwind, M., Glaser, C. A., Honnorat, J., Höftberger, R., Iizuka, T., Irani, S. R., Lancaster, E., Leypoldt, F., Prüss, H., Rae-Grant, A., Reindl, M., Rosenfeld, M. R., Rostásy, K., Saiz, A., Venkatesan, A., Vincent, A., Wandinger, K.-P., Waters, P., and Dalmau, J. (2016) A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 15, 391−404. (97) Kuppuswamy, P. S., Takala, C. R., and Sola, C. L. (2014) Management of psychiatric symptoms in anti-NMDAR encephalitis: a case series, literature review and future directions. Gen Hosp Psychiatry 36, 388−391. (98) Lee, W.-J., Lee, S.-T., Moon, J., Sunwoo, J.-S., Byun, J.-I., Lim, J.A., Kim, T.-J., Shin, Y.-W., Lee, K.-J., Jun, J.-S., Lee, H. S., Kim, S., Park, K.-I., Jung, K.-H., Jung, K.-Y., Kim, M., Lee, S. K., and Chu, K. (2016) Tocilizumab in Autoimmune Encephalitis Refractory to Rituximab: An Institutional Cohort Study. Neurotherapeutics 13, 824−832. (99) Scheibe, F., Prüss, H., Mengel, A. M., Kohler, S., Nümann, A., Köhnlein, M., Ruprecht, K., Alexander, T., Hiepe, F., and Meisel, A. (2017) Bortezomib for treatment of therapy-refractory anti-NMDA receptor encephalitis. Neurology 88, 366−370. (100) Niehusmann, P., Dalmau, J., Rudlowski, C., Vincent, A., Elger, C., Rossi, J., and Bien, C. G. (2009) Diagnostic value of N-methyl-Daspartate receptor antibodies in women with new-onset epilepsy. Arch. Neurol. 66, 458−464. (101) Fink, M., and Taylor, M. (2009) The catatonia syndrome: Forgotten but not gone. Arch. Gen. Psychiatry 66, 1173−1177. (102) Braakman, H. M., Moers-Hornikx, V., Arts, B., Hupperts, R., and Nicolai, J. (2010) Pearls & Oy-sters: electroconvulsive therapy in anti-NMDA receptor encephalitis. Neurology 75, 44−46. (103) Lee, A., Glick, D., and Dinwiddie, S. H. (2006) Electroconvulsive therapy in a pediatric patient with malignant catatonia and paraneoplastic limbic encephalitis. J. ECT 22, 267−270. (104) Dhossche, D. M., and Wachtel, L. E. (2010) Catatonia is Hidden in Plain Sight Among Different Pediatric Disorders: A Review Article. Pediatric Neurology 43, 307−315. (105) Matsumoto, T., Matsumoto, K., Kobayashi, T., and Kato, S. (2012) Electroconvulsive therapy can improve psychotic symptoms in anti-NMDA-receptor encephalitis. Psychiatry Clin. Neurosci. 66, 242− 243. (106) Watkins, C. J., Pei, Q., and Newberry, N. R. (1998) Differential effects of electroconvulsive shock on the glutamate receptor mRNAs for NR2A, NR2B and mGluR5b. Mol. Brain Res. 61, 108−113. (107) Finke, C., Kopp, U., Pruss, H., Dalmau, J., Wandinger, K., and Ploner, C. J. (2012) Cognitive deficits following anti-NMDA receptor encephalitis. J. Neurol., Neurosurg. Psychiatry 83, 195−198. (108) Seki, M., Suzuki, S., Iizuka, T., Shimizu, T., Nihei, Y., Suzuki, N., and Dalmau, J. (2008) Neurological response to early removal of ovarian teratoma in anti-NMDAR encephalitis. J. Neurol., Neurosurg. Psychiatry 79, 324−326. (109) Breese, E. H., Dalmau, J., Lennon, V. A., Apiwattanakul, M., and Sokol, D. K. (2010) Anti-N-Methyl-d-Aspartate Receptor Encephalitis: Early Treatment is Beneficial. Pediatric Neurology 42, 213−214. (110) Wong-Kisiel, L. C., Ji, T., Renaud, D. L., Kotagal, S., Patterson, M. C., Dalmau, J., and Mack, K. J. (2010) Response to immunotherapy in a 20-month-old boy with anti-NMDA receptor encephalitis. Neurology 74, 1550−1551. (111) Iizuka, T., Yoshii, S., Kan, S., Hamada, J., Dalmau, J., Sakai, F., and Mochizuki, H. (2010) Reversible brain atrophy in anti-NMDA receptor encephalitis: a long-term observational study. J. Neurol. 257, 1686−1691. (112) Vincent, A., and Bien, C. G. (2008) Anti-NMDA-receptor encephalitis: a cause of psychiatric, seizure, and movement disorders in young adults. Lancet Neurol. 7, 1074−1075. 2594


Review

ACS Chemical Neuroscience (113) Finke, C., Kopp, U. A., Pajkert, A., Behrens, J. R., Leypoldt, F., Wuerfel, J. T., Ploner, C. J., Pruss, H., and Paul, F. (2016) Structural Hippocampal Damage Following Anti-N-Methyl-D-Aspartate Receptor Encephalitis. Biol. Psychiatry 79, 727−734. (114) Iizuka, T., Kaneko, J., Tominaga, N., et al. (2016) Association of progressive cerebellar atrophy with long-term outcome in patients with anti-n-methyl-d-aspartate receptor encephalitis. JAMA Neurology 73, 706−713. (115) Brandt, A. U., Oberwahrenbrock, T., Mikolajczak, J., Zimmermann, H., Prüss, H., Paul, F., and Finke, C. (2016) Visual dysfunction, but not retinal thinning, following anti-NMDA receptor encephalitis. Neurol. Neuroimmunol. Neuroinflamm. 3, e198.

2595


Anti-NMDA-Receptor Encephalitis: From Bench to Clinic - ACS

Recommend Documents