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Anti-N-Methyl-D-Aspartate Encephalitis as Paraneoplastic Manifestation of Germ-Cells Tumours: A Cases Report and Literature Review

Anti-N-Methyl-D-Aspartate Encephalitis as Paraneoplastic Manifestation of Germ-Cells Tumours: A... Hindawi Case Reports in Immunology Volume 2019, Article ID 4762937, 6 pages https://doi.org/10.1155/2019/4762937 Case Series Anti-N-Methyl-D-Aspartate Encephalitis as Paraneoplastic Manifestation of Germ-Cells Tumours: A Cases Report and Literature Review 1 1 2 Claudia Geraldine Rita , Israel Nieto Gañan, Adriano Jimenez Escrig, and Ángela Carrasco Sayalero Department of Immunology. Hospital Universitario Ramo´n y Cajal, Ctra. Colmenar Km 9,1, 28034 Madrid, Spain Department of Neurology. Hospital Universitario Ramo´n y Cajal, Ctra. Colmenar Km 9,1, 28034 Madrid, Spain Correspondence should be addressed to Claudia Geraldine Rita; claudiaritag@gmail.com Received 24 November 2018; Revised 18 February 2019; Accepted 19 February 2019; Published 10 March 2019 Academic Editor: Christian Drouet Copyright © 2019 Claudia Geraldine Rita et al. is Th is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is the most common form of autoimmune encephalitis, caused by the interaction between an antibody and its target, located on glutamate receptor type N-methyl-D-aspartate (NMDA) of neuronal surface. There is a wide spectrum of clinical features starting by a viral-like prodrome, followed by symptoms such as psychosis, aggressive behaviour, memory loss, seizures, movement disorders, and autonomic instability. Up to 50% of the aeff cted young female patients have germ-cells tumours as ovarian teratoma, making it essential to establish an early diagnosis through detection of specific antibodies in serum and cerebrospinal uid fl (CSF). is Th retrospective observational study was performed in patients whom positive anti-NMDA receptor antibodies have been tested, associated with clinical manifestations that suggest autoimmune encephalitis and a germ-cell tumour confirmed by pathology. Six patients have tested positive for anti-NMDA receptor antibodies associated with a germ-cell tumour and clinical manifestations of autoimmune encephalitis. Management includes aggressive immunosuppression and surgical removal. 1. Introduction against the GluN1 subunit are those that result in specific and recognizable syndromes, while those directed against Autoimmune encephalitis constitutes a group of neu- the GluN2 subunits are not associated with any specific roinflammatory pathologies, characterized by psychiatric syndrome and, in most cases, its clinical and pathogenic value and neurological manifestations caused by the interaction is uncertain [3]. Physiologically, the activation of NMDA between an antibody (Ab) and its target that can be intracel- receptor facilitates the intracellular increase of ions, initiating lular or in the cell surface [1, 2]. Anti-N-methyl-D-aspartate a cascade of cell events, which play a crucial role in the process (NMDA) antibodies are directed against the NMDA receptor of synaptic plasticity, involved in learning and memory [2]. located on neuronal surface, being a heterotetramer com- Anti-NMDA receptor encephalitis is the most common posed by two subunits of glutamate ionotropic receptor 1 form of autoimmune encephalitis, reaching 1% of all admis- (GluN1) and two subunits of glutamate ionotropic receptor sions of young adults to an intensive care unit. Up to 50% of 2 (GluN2) that acts as a postsynaptic excitatory ionotropic the affected young female patients have germ-cells tumours receptor. The GluN1 subunit is mandatory, while the GluN2 as ovarian teratoma [1]. There is a wide spectrum of clinical subunits (A, B, C, and D) vary depending on the brain features starting by a viral-like prodrome, followed by symp- region, synaptic or extrasynaptic localization, and brain toms such as psychosis, aggressive behaviour, altered mood, development. An important aspect of encephalitis mediated insomnia, memory loss, seizures, movement disorders, and by anti-NMDA receptor antibodies is that those directed pronounced autonomic instability. In addition, respiratory 2 Case Reports in Immunology Table 1: Clinical and immunological features of patients with Anti-NMDAR encephalitis. Tumor Sex, Age (y/o) CSF Anti- NMDAR Autoimmunity ID Clinical features 1st brain MRI pathology Cell: 13 ANA 1/160 Anterograde amnesia Mature P1 F, 29 Normal (+) CSF and serum ovarian Prot: 0.48 ENAS (-) Myoclonias cystic teratoma Auditory hallucinations OB: Negative Cell: 15 ANA 1/640 Immature Anterograde amnesia F, 27 (+) CSF and serum P2 Normal Teratoma Prot: 0.03 ENAS (+) Tonic-clonic seizure Stage IA OB: Negative Anti Ro (+) Anterograde amnesia Cell: 159 Cortical Mature Prot: 1.16 hyperintensity Dyskinesia F, 33 (+) CSF and serum Negative P3 ovarian in uncus and OB: mirror pattern Sialorrhea and tachycardia cystic teratoma hippocampus Tonic seizure Cell: 158 Anterograde amnesia Mature F, 27 (+) CSF and serum Negative P4 Normal ovarian Prot: 1.03 Tonic seizure cystic teratoma OB: Negative Delusions Cell: 11 Anterograde amnesia Mature P5 F, 24 Normal (+) CSF and serum Negative ovarian Prot: 0.42 Lability of blood pressure teratoma Complex partial seizures OB: Negative Bilateral Cell: 17 Anterograde amnesia mature P6 F, 17 Normal (+) CSF and serum Negative Prot: 0.21 Dystonias ovarian cystic OB: Negative teratoma Cell: cells/mm ;Prot: g/L. abnormalities sometimes require mechanical ventilation and in CSF was demonstrated in all cases (range 11-158 cells/mm ; admission to an intensive care unit [4]. Because of clinical median 60.5 cells/mm ) and increased protein levels in severity, early tumour removal and aggressive immunother- CSF were observed in two of them (range 0.03-1.16 g/L; apy are the mainstay of treatment; so it is essential to establish median 0.5 g/L); a mirror pattern in oligoclonal bands (OB) an early diagnosis through detection of specific antibodies was identified in one patient of six. In one case, magnetic in serum and CSF [2, 4]. This study reports six cases of resonance imaging (MRI) showed cortical hyperintensity on anti-NMDA receptor encephalitis associated with a germ-cell uncus and right hippocampus suggestive of limbic encephali- tumour. tis (Figure 1). There was evidence of generalized slowing in the electroencephalogram (EEG) profile in all of them. Anti- NMDA receptor antibodies were determined by indirect 2. Cases Presentation immunou fl orescence (IIF) in Hek293 transfected cells and rat We describe cases of six patients with clinical manifesta- tissues of cerebellum and hippocampus fixed with acetone in plates, included in the IIFT Glutamate Receptor Mosaic 3 kit tions of autoimmune encephalitis, mediated by anti-NMDA of Euroimmun. CSF and serum samples were analyzed with- receptor antibodies and a germ-cell tumour conrfi med by pathology; the average age of the reported cases was 26-year- out dilution and with a 1:10 dilution, respectively (Figure 2). In two cases detection was performed twice to confirm the old (range 17-33 years), all of them women. Two of the six results. All patients had extensive serum and CSF diagnostic patients showed dizziness symptom between 1 and 3 months tests with negative or normal results for viral or bacterial prior to the diagnosis of encephalitis and one had a history of infections; autoimmunity screening was performed in six epilepsy during childhood without treatment at current time. patients with positive ANA in two cases (Table 1). One patient had history of cocaine and marijuana abuse, not Computed tomography or ultrasound demonstrated an being referred toxic habits in the rest of the patients. ovarian mass in all patients. Complete tumour resection was About clinical features, all patients had anterograde amnesia; four had seizures at any time during the disease; two done in all cases and pathological studies showed mature ovarian cystic teratoma in five of them and one case had stage showed psychiatric symptoms and two patients developed dysautonomy that included one or more of the following: sial- IA immature teratoma. Tumour was unilateral in vfi e cases orrhea, tachycardia, and lability of blood pressure. Those with and bilateral in one; CA 125 was measured in all patients, being above reference range in all of them, with a maximum movement disorders presented with myoclonus, dyskinesia, and dystonia (Table 1). of 44 IU/ml in the patient who presented immature teratoma. Patients were treated with immunomodulatory therapy The diagnostic approach included blood and CSF tests, radiological images, and electroencephalogram. Pleocytosis according to the severity of their case. Overall, all of Case Reports in Immunology 3 behaviour, and cognition that are hallmarks of anti-NMDA receptor encephalitis [6]. Currently it is a very common cause of encephalitis reaching 1% of all admissions of young adults to an intensive care unit [1]. According to clinical description, patients with NMDA receptor encephalitis show a recognizable syndrome, start- ing with a rapidly progressive viral-like symptoms such as headache and hyperthermia, which progresses in days to more complex clinical features including psychosis, delu- sions, hallucinations, agitation, aggression, catatonia, insom- nia, speech dysfunction follow due to dyskinesias, memory deficits, autonomic instability, seizures, and even decreased level ofconsciousness [3,4,7,8]. These unspecicfi clinical features are often mistaken as viral encephalitis, primary psychiatric disorders, drug abuse, or neuroleptic malignant syndrome, which could delay diagnosis and treatment [3]. Clinical features observed in present study were similar to previous reports [1, 4, 5, 7, 8]. Memory deficit is commonly described in this disorder; however, it might be undervalued because of difficulties to assess it in young patients or patients with psychiatric manifestations [4]; in the present study 100% of cases had anterograde amnesia before other encephalitis Figure 1: Brain MRI of patient with positive Anti-NMDAR encephali- symptoms appeared. According to Gresa-Arribas et al., one tis. Arrow shows cortical hyperintensity in uncus right and hip- of the rfi st neurological symptoms observed in young patients pocampus with T2-FLAIR technique. with anti-NMDA receptor encephalitis are generalized (72%) and focal seizure (42%) [9]; in our series up to 50% of cases presented with seizures at any time during course of the disease; two debuted with generalized tonic-clonic seizures them received corticosteroid therapy, four with boluses of and one case presented with complex partial crisis. Kaneko methylprednisolone, 1 g intravenous during 5 days and two et al. described movement disorder in all patients studied cases received methylprednisolone according their weight [10]; in present study there was one case of dystonia, one by 1mg/kg also during 5 days; up to 50% needed a cycle case of myoclonus, and one case of dyskinesia. Autonomic of intravenous immunoglobulins (IVIG) at immunomodula- dysfunction has been previously reported in anti-NMDA tory doses (400-800mg/kg/day) during 5 or 6 days and one of receptor encephalitis [1,3,4,7,11].In a series of 100 them needed a second cycle of IVIG; four patients received patients with anti-NMDA receptor encephalitis, 37 patients rituximab according to their body surface area with a 375 presented with cardiac arrhythmias [7] and there are at least mg/m IV infusion every two weeks for 2 cycles; four patients 2 reported cases who required a permanent pacemaker to needed plasma exchange and three cyclophosphamide 750 control cardiac arrhythmia [11]. It has been hypothesized that mg/m IV; one case received 2 cycles with 6 weeks between autonomic instability might be associated with seizure activ- each one and two patients received 4 cycles every three weeks. ity or induced by sympathetic and parasympathetic stimuli In the case of immature teratoma it was necessary to add [11]. In our series, 2 patients presented with dysautonomy; four cycles of chemotherapy repeated every 21 days with one of them had lability of blood pressure, and the other bleomycin (30 IU IV every week, for three doses), etoposide one tachycardia and sialorrhea who received local botulinum (100mg/m2 IV daily for 5 days), and cisplatin (20mg/m2 IV toxin injections in two occasions to be controlled. Teenagers daily for 5 days) (Figure 3). After treatment, patients showed and young adults usually showed abnormal behaviour (psy- gradual improvement in their symptoms over months. chosis, delusions, hallucinations, agitation, aggression, or catatonia) [4, 7, 8]. This review found two patients with psychiatric symptoms, such as auditory hallucinations and 3. Discussion delusion, requiring antipsychotics. The diagnosis of anti-NMDA receptor encephalitis is N-methyl-D-aspartate receptor channel is a tetramer com- posed by two subunits of GluN1 and two subunits of GluN2; confirmed by the detection of serum or CSF antibodies in 2007 Dalmau et al. described for the first time the against the GluN1 subunit of the NMDA receptor [1–3]. A significant aspect of encephalitis mediated by anti-NMDA anti-NMDA receptor antibody associated with 12 cases of encephalitis [5]. This antibody is against the GluN1 subunit receptor antibodies is that those directed against the GluN1 subunit are those that result in specific and recognizable and it is present in neuronal surface of the hippocampus, cerebral cortex, basal ganglia, and thalamus [2, 6]. Hughes et syndromes, while those directed against the GluN2 subunits al. suggested that GluN1 antibodies from patients with anti- are not associated with any specicfi syndrome [3]. Dalmau et al. considered that serum testing is less reliable, with false NMDA receptor encephalitis decrease glutamatergic synap- tic function, which may underlie the deficits of memory, negative resultsin up to 14% of cases[1]; on the other hand 4 Case Reports in Immunology (a) (b) Figure 2: Anti-NMDAR antibodies detected by indirect immunofluorescence . (a) Hek293 transfected cells; (b) granular layer of cerebellum in tissue of rat. [1]. In a study of 100 patients with anti-NMDA-receptor encephalitis only 55% of patients had increased T2-FLAIR signal in one or several brain regions, without significant correlation with patients’ symptoms [7]. In present series only one case shows cortical hyperintensity on uncus of right hippocampus (Figure 1). EEG prole fi was abnormal in most patients, usually showing nonspecific, slow, and disorganized activity. All cases reported in this study had a generalized slow tracing in EEG. Another analysis of CSF P1 P2 P3 P4 P5 P6 usually shows moderate lymphocytic pleocytosis with normal Chemotherapy Rituximab or mildly increased protein concentration [5, 7]; all cases in this study had pleocytosis in CSF. There was evidence that Plasmapheresis Intravenous Ig more than 50% of patients showed specific oligoclonal bands Cyclophosphamide Methylprednisolone [7]; nevertheless in present series it was one case of mirror pattern on OB; mirror OB have been reported in patients with Figure 3: Treatment grouped by patient. P1, P3, P4, and P5 received methylprednisolone (1 g IV daily) during 5 days; P2 and P6 received autoantibody-associated disorders, such as NMDA receptor methylprednisolone according their weight (1mg/kg) also during 5 encephalitis and VGKC encephalopathy. This pattern implies days. IVIG was administered in vfi e cases at immunomodulatory the presence of clonal IgG in both CSF and serum and it doses (400-800mg/kg/day). P2 and P3 needed cyclophosphamide means that the production of autoantibody might be rfi st (750 mg/m IV) every three weeks during 4 cycles; P4 received triggered in the periphery, rather than in the CNS so they may cyclophosphamide (750 mg/m IV) 2 cycles with 6 weeks between be an important biomarker in inflammatory central nervous each one. Rituximab was administered every two weeks (375 mg/m system disorders [13, 14]. IV) for 2 cycles in P1, P2, P3, and P4. In P2 it was necessary to add In this study 17 percent of the patients with a positive four cycles of chemotherapy for immature teratoma repeated every NMDA receptor antibody had an ovarian teratoma, which is 21 days with bleomycin (30 IU IV every week), etoposide (100mg/m2 significantly lower than in other published series; some epi- IV daily for 5 days), and cisplatin (20mg/m2 IV daily for 5 days). demiological studies suggested that this association depends on demographic features of the population analyzed [15]. Case reports and observational studies have estimated that Guasp et al. suggested that there is an increasing number 36%-50% of patients with anti-NMDA receptor encephali- of patients mistakenly diagnosed due to false positive serum tis have an ovarian teratoma [16, 17]. Gresa-Arribas et al. results recommending conrfi mation by CSF examination [3]. reported more frequently NMDA receptor antibodies in By contrast Irani et al. reported that serum levels of anti- patients who had an underlying teratoma than in those who NMDA receptor antibodies were similar or higher to those did not have a tumour [9]. A mature cystic ovarian teratoma was identified in 5 patients in this study and one patient of CSF [12]. In this study determinations of anti-NMDA receptor were performed by IIF in serum and CSF and were had an immature teratoma conrfi med by pathology; in a concordant in 100% of them (Figure 2). cohort of 252 patients an immature ovarian teratoma was diagnosed in 11% of them [18]. One case of bilateral teratoma Diagnosis approach also included MRI and EEG; in some cases MRI scan was normal or showed unilateral changes was observed in this study with similar outcome compared Case Reports in Immunology 5 to other patients with unilateral tumour; Lee et al. reported a Conflicts of Interest case of fulminant course in a patient with bilateral teratoma The authors declare that there are no conflicts of interest suggesting that it might be related to higher antibody titers regarding the publication of this article. [19]. The optimal management of anti-NMDA receptor en- cephalitis includes immunotherapy and removal of the Acknowledgments immunological trigger, such as teratoma or another tumour [1, 5]. First-line immunosuppressive therapy includes methyl- The present investigation has not received any specific grant prednisolone 1 g per day for 5 days and concomitant from agencies of the public, commercial, or nonprofit sectors. intravenous immunoglobulins (0.4 g/kg per day for 5 days) or plasma exchange. Second-line therapy consists of rit- References uximab (375 mg m 1 week for 4 weeks) combined with [1] J. Dalmau and F. Graus, “Antibody-mediated encephalitis,” The cyclophosphamide (750 mg m ) given with the rfi st dose of New England Journal of Medicine, vol.378,no. 9,pp.840–851, rituximab, followed by monthly cycles of cyclophosphamide [15]. In present study 2 patients showed improvement of [2] A. Carrasco, I. Alarco´n,C.Gonzalez ´ , and F. Graus, “Identi- the neurological outcome aer ft tumour resection and first- ficaci´on y utilidad cl´ınica de los anticuerpos antineuronales,” line therapy, alone or combined, while 4 patients need a Inmunologıa,vol. 33, no.4, pp. 128–136, 2014. second-line immunotherapy (Figure 3). In a study of 577 [3] M. Guasp and J. Dalmau, “Encefalitis por anticuerpos contra el patients the combination of first-line immunotherapy more receptor de NMDA,” Medicina Cl´ınica, vol. 151,no. 2,pp.71–79, frequently used was steroids and IVIG [8], similar to com- bination observed in present series. Dalmau et al. reported [4] F. Graus,M.J.Titulaer,and R. Balu, “A clinical approach to that 80% of patients with a tumour (mostly teratomas) had diagnosis of autoimmune encephalitis,” The Lancet Neurology , substantial improvement aer ft tumour removal and rfi st- vol.15,no. 4,pp. 391–404,2016. line immunotherapy [15]. These observations and the possi- [5] J. Dalmau, E. Tuz ¨ un, ¨ H.-Y. Wu et al., “Paraneoplastic anti- ble rapid neurological improvement after tumour resection N-methyl-D-aspartate receptor encephalitis associated with suggest that a peripheral immune response against tumour ovarian teratoma,” Annals of Neurology, vol. 61, no.1,pp. 25–36, autoantigens could be involved in the production of anti- NMDA receptor autoantibodies [18]. [6] E.G.Hughes, X.Peng,A.J. Gleichman et al.,“Cellular and Recovery from this disorder is typically slow, and symp- synaptic mechanisms of anti-NMDA receptor encephalitis,” The toms may relapse, especially in patients with undetected or Journal of Neuroscience, vol. 30, no. 17, pp. 5866–5875, 2010. recurrent tumours [7]. In accordance with Titularer et al. [7] J. Dalmau, A. J. Gleichman, and E. G. Hughes, “Anti-NMDA- 53% of patients had clinical improvement within 4 weeks, receptor encephalitis: case series and analysis of the eeff cts of and 81% had substantial recovery (i.e., mild or no residual antibodies,” The Lancet Neurology , vol.7,no. 12,pp. 1091–1098, symptoms) at 24 months [8]. Patients analyzed in this study had no relapses reported. [8] M.J.Titulaer,L.McCracken,I.Gabilondoetal.,“Treatmentand prognostic factors for long-term outcome in patients with anti- NMDA receptor encephalitis: an observational cohort study,” 4. Conclusion The Lancet Neurology , vol. 12, no. 2, pp. 157–165, 2013. [9] N. Gresa-Arribas, M. J. Titulaer, A. Torrents et al., “Antibody Anti-NMDA receptor encephalitis is a multifaceted disease titres at diagnosis and during follow-up of anti-NMDA receptor associated with serious complications, which may require an encephalitis: a retrospective study,” The Lancet Neurology ,vol. early diagnosis and extensive studies to establish the presence 13,no. 2,pp.167–177, 2014. of an underlying germ-cell tumour to perform a prompt [10] A. Kaneko, J. Kaneko, N. Tominaga et al., “Pitfalls in clinical surgery and aggressive immunotherapy. diagnosis of anti-NMDA receptor encephalitis,” Journal of Neurology, vol.265,no. 3,pp.586–596, 2018. [11] N. Salehi, A. K. Yuan, G. Stevens, R. Koshy, and W. F. Klein, Abbreviations “A case of severe anti-N-methyl D-aspartate (Anti-NMDA) ANA: Antinuclear antibodies receptor encephalitis with refractory autonomic instability CSF: Cerebrospinal uid fl and elevated intracranial pressure,” American Journal of Case EEG: Electroencephalogram Reports,vol.19, pp.1216–1221, 2018. GluN1: Glutamate ionotropic receptor subunit 1 [12] S. R. Irani and A. Vincent, “NMDA receptor antibody GluN2: Glutamate ionotropic receptor subunit 2 encephalitis,” Current Neurology and Neuroscience Reports,vol. IIF: Indirect immunouo fl rescence 11, no. 3, pp. 298–304, 2011. IVIG: Intravenous immunoglobulins [13] A. J. Sinclair, L. Wienholt, E. Tantsis, F. Brilot, and R. C. Dale, MRI: Magnetic resonance imaging “Clinical association of intrathecal and mirrored oligoclonal NMDA: Anti-N-methyl-D-aspartate bands in paediatric neurology,” Developmental Medicine & Child Neurology, vol. 55, no. 1, pp. 71–75, 2013. OB: Oligoclonal bands T2-FLAIR: T2-weighted-Fluid-Attenuated Inversion [14] A. Vincent, C. G. Bien, S. R. Irani, and P. Waters, “Autoantibod- ies associated with diseases of the CNS: new developments and Recovery. 6 Case Reports in Immunology future challenges,” The Lancet Neurology ,vol. 10,no.8, pp. 759– 772, 2011. [15] J. Dalmau, E. Lancaster, E. Martinez-Hernandez, M. R. Rosen- feld, and R. Balice-Gordon, “Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis,” The Lancet Neurology, vol.10,no.1,pp.63–74,2011. [16] A. L. Martin, E.Jollieff ,and S. P. Hertweck,“Ovarianter- atoma associated with coexisting Anti-N-Methyl-D-Aspartate receptor and glial fibrillary acidic protein autoimmune menin- goencephalitis in an adolescent girl: a case report,” Journal of Pediatric & Adolescent Gynecology,vol.31, no.3,pp. 321–324, [17] C. A. Cundiff, N.Elawabdeh, M.M.Naguibetal.,“Does MAP2 have a role in predicting the development of anti-NMDAR encephalitis associated with benign ovarian teratoma? A report of six new pediatric cases,” Pediatric and Developmental Pathol- ogy,vol.18, no. 2,pp.122–126, 2015. [18] C. Bost,E.Chanson, G.Picard et al., “Malignant tumors in autoimmune encephalitis with anti-NMDA receptor antibod- ies,” Journal of Neurology, vol. 265, no. 10, pp. 2190–2200, 2018. [19] K. W. Lee and L. M. Liou, “Fulminant course in a patient with anti-N-methyl-D-aspartate receptor encephalitis with bilateral ovarian teratomas: a case report and literature review,” Medicine (Baltimore),vol.97, no. 15,p. e0339, 2018. 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Anti-N-Methyl-D-Aspartate Encephalitis as Paraneoplastic Manifestation of Germ-Cells Tumours: A Cases Report and Literature Review

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Abstract

Hindawi Case Reports in Immunology Volume 2019, Article ID 4762937, 6 pages https://doi.org/10.1155/2019/4762937 Case Series Anti-N-Methyl-D-Aspartate Encephalitis as Paraneoplastic Manifestation of Germ-Cells Tumours: A Cases Report and Literature Review 1 1 2 Claudia Geraldine Rita , Israel Nieto Gañan, Adriano Jimenez Escrig, and Ángela Carrasco Sayalero Department of Immunology. Hospital Universitario Ramo´n y Cajal, Ctra. Colmenar Km 9,1, 28034 Madrid, Spain Department of Neurology. Hospital Universitario Ramo´n y Cajal, Ctra. Colmenar Km 9,1, 28034 Madrid, Spain Correspondence should be addressed to Claudia Geraldine Rita; claudiaritag@gmail.com Received 24 November 2018; Revised 18 February 2019; Accepted 19 February 2019; Published 10 March 2019 Academic Editor: Christian Drouet Copyright © 2019 Claudia Geraldine Rita et al. is Th is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is the most common form of autoimmune encephalitis, caused by the interaction between an antibody and its target, located on glutamate receptor type N-methyl-D-aspartate (NMDA) of neuronal surface. There is a wide spectrum of clinical features starting by a viral-like prodrome, followed by symptoms such as psychosis, aggressive behaviour, memory loss, seizures, movement disorders, and autonomic instability. Up to 50% of the aeff cted young female patients have germ-cells tumours as ovarian teratoma, making it essential to establish an early diagnosis through detection of specific antibodies in serum and cerebrospinal uid fl (CSF). is Th retrospective observational study was performed in patients whom positive anti-NMDA receptor antibodies have been tested, associated with clinical manifestations that suggest autoimmune encephalitis and a germ-cell tumour confirmed by pathology. Six patients have tested positive for anti-NMDA receptor antibodies associated with a germ-cell tumour and clinical manifestations of autoimmune encephalitis. Management includes aggressive immunosuppression and surgical removal. 1. Introduction against the GluN1 subunit are those that result in specific and recognizable syndromes, while those directed against Autoimmune encephalitis constitutes a group of neu- the GluN2 subunits are not associated with any specific roinflammatory pathologies, characterized by psychiatric syndrome and, in most cases, its clinical and pathogenic value and neurological manifestations caused by the interaction is uncertain [3]. Physiologically, the activation of NMDA between an antibody (Ab) and its target that can be intracel- receptor facilitates the intracellular increase of ions, initiating lular or in the cell surface [1, 2]. Anti-N-methyl-D-aspartate a cascade of cell events, which play a crucial role in the process (NMDA) antibodies are directed against the NMDA receptor of synaptic plasticity, involved in learning and memory [2]. located on neuronal surface, being a heterotetramer com- Anti-NMDA receptor encephalitis is the most common posed by two subunits of glutamate ionotropic receptor 1 form of autoimmune encephalitis, reaching 1% of all admis- (GluN1) and two subunits of glutamate ionotropic receptor sions of young adults to an intensive care unit. Up to 50% of 2 (GluN2) that acts as a postsynaptic excitatory ionotropic the affected young female patients have germ-cells tumours receptor. The GluN1 subunit is mandatory, while the GluN2 as ovarian teratoma [1]. There is a wide spectrum of clinical subunits (A, B, C, and D) vary depending on the brain features starting by a viral-like prodrome, followed by symp- region, synaptic or extrasynaptic localization, and brain toms such as psychosis, aggressive behaviour, altered mood, development. An important aspect of encephalitis mediated insomnia, memory loss, seizures, movement disorders, and by anti-NMDA receptor antibodies is that those directed pronounced autonomic instability. In addition, respiratory 2 Case Reports in Immunology Table 1: Clinical and immunological features of patients with Anti-NMDAR encephalitis. Tumor Sex, Age (y/o) CSF Anti- NMDAR Autoimmunity ID Clinical features 1st brain MRI pathology Cell: 13 ANA 1/160 Anterograde amnesia Mature P1 F, 29 Normal (+) CSF and serum ovarian Prot: 0.48 ENAS (-) Myoclonias cystic teratoma Auditory hallucinations OB: Negative Cell: 15 ANA 1/640 Immature Anterograde amnesia F, 27 (+) CSF and serum P2 Normal Teratoma Prot: 0.03 ENAS (+) Tonic-clonic seizure Stage IA OB: Negative Anti Ro (+) Anterograde amnesia Cell: 159 Cortical Mature Prot: 1.16 hyperintensity Dyskinesia F, 33 (+) CSF and serum Negative P3 ovarian in uncus and OB: mirror pattern Sialorrhea and tachycardia cystic teratoma hippocampus Tonic seizure Cell: 158 Anterograde amnesia Mature F, 27 (+) CSF and serum Negative P4 Normal ovarian Prot: 1.03 Tonic seizure cystic teratoma OB: Negative Delusions Cell: 11 Anterograde amnesia Mature P5 F, 24 Normal (+) CSF and serum Negative ovarian Prot: 0.42 Lability of blood pressure teratoma Complex partial seizures OB: Negative Bilateral Cell: 17 Anterograde amnesia mature P6 F, 17 Normal (+) CSF and serum Negative Prot: 0.21 Dystonias ovarian cystic OB: Negative teratoma Cell: cells/mm ;Prot: g/L. abnormalities sometimes require mechanical ventilation and in CSF was demonstrated in all cases (range 11-158 cells/mm ; admission to an intensive care unit [4]. Because of clinical median 60.5 cells/mm ) and increased protein levels in severity, early tumour removal and aggressive immunother- CSF were observed in two of them (range 0.03-1.16 g/L; apy are the mainstay of treatment; so it is essential to establish median 0.5 g/L); a mirror pattern in oligoclonal bands (OB) an early diagnosis through detection of specific antibodies was identified in one patient of six. In one case, magnetic in serum and CSF [2, 4]. This study reports six cases of resonance imaging (MRI) showed cortical hyperintensity on anti-NMDA receptor encephalitis associated with a germ-cell uncus and right hippocampus suggestive of limbic encephali- tumour. tis (Figure 1). There was evidence of generalized slowing in the electroencephalogram (EEG) profile in all of them. Anti- NMDA receptor antibodies were determined by indirect 2. Cases Presentation immunou fl orescence (IIF) in Hek293 transfected cells and rat We describe cases of six patients with clinical manifesta- tissues of cerebellum and hippocampus fixed with acetone in plates, included in the IIFT Glutamate Receptor Mosaic 3 kit tions of autoimmune encephalitis, mediated by anti-NMDA of Euroimmun. CSF and serum samples were analyzed with- receptor antibodies and a germ-cell tumour conrfi med by pathology; the average age of the reported cases was 26-year- out dilution and with a 1:10 dilution, respectively (Figure 2). In two cases detection was performed twice to confirm the old (range 17-33 years), all of them women. Two of the six results. All patients had extensive serum and CSF diagnostic patients showed dizziness symptom between 1 and 3 months tests with negative or normal results for viral or bacterial prior to the diagnosis of encephalitis and one had a history of infections; autoimmunity screening was performed in six epilepsy during childhood without treatment at current time. patients with positive ANA in two cases (Table 1). One patient had history of cocaine and marijuana abuse, not Computed tomography or ultrasound demonstrated an being referred toxic habits in the rest of the patients. ovarian mass in all patients. Complete tumour resection was About clinical features, all patients had anterograde amnesia; four had seizures at any time during the disease; two done in all cases and pathological studies showed mature ovarian cystic teratoma in five of them and one case had stage showed psychiatric symptoms and two patients developed dysautonomy that included one or more of the following: sial- IA immature teratoma. Tumour was unilateral in vfi e cases orrhea, tachycardia, and lability of blood pressure. Those with and bilateral in one; CA 125 was measured in all patients, being above reference range in all of them, with a maximum movement disorders presented with myoclonus, dyskinesia, and dystonia (Table 1). of 44 IU/ml in the patient who presented immature teratoma. Patients were treated with immunomodulatory therapy The diagnostic approach included blood and CSF tests, radiological images, and electroencephalogram. Pleocytosis according to the severity of their case. Overall, all of Case Reports in Immunology 3 behaviour, and cognition that are hallmarks of anti-NMDA receptor encephalitis [6]. Currently it is a very common cause of encephalitis reaching 1% of all admissions of young adults to an intensive care unit [1]. According to clinical description, patients with NMDA receptor encephalitis show a recognizable syndrome, start- ing with a rapidly progressive viral-like symptoms such as headache and hyperthermia, which progresses in days to more complex clinical features including psychosis, delu- sions, hallucinations, agitation, aggression, catatonia, insom- nia, speech dysfunction follow due to dyskinesias, memory deficits, autonomic instability, seizures, and even decreased level ofconsciousness [3,4,7,8]. These unspecicfi clinical features are often mistaken as viral encephalitis, primary psychiatric disorders, drug abuse, or neuroleptic malignant syndrome, which could delay diagnosis and treatment [3]. Clinical features observed in present study were similar to previous reports [1, 4, 5, 7, 8]. Memory deficit is commonly described in this disorder; however, it might be undervalued because of difficulties to assess it in young patients or patients with psychiatric manifestations [4]; in the present study 100% of cases had anterograde amnesia before other encephalitis Figure 1: Brain MRI of patient with positive Anti-NMDAR encephali- symptoms appeared. According to Gresa-Arribas et al., one tis. Arrow shows cortical hyperintensity in uncus right and hip- of the rfi st neurological symptoms observed in young patients pocampus with T2-FLAIR technique. with anti-NMDA receptor encephalitis are generalized (72%) and focal seizure (42%) [9]; in our series up to 50% of cases presented with seizures at any time during course of the disease; two debuted with generalized tonic-clonic seizures them received corticosteroid therapy, four with boluses of and one case presented with complex partial crisis. Kaneko methylprednisolone, 1 g intravenous during 5 days and two et al. described movement disorder in all patients studied cases received methylprednisolone according their weight [10]; in present study there was one case of dystonia, one by 1mg/kg also during 5 days; up to 50% needed a cycle case of myoclonus, and one case of dyskinesia. Autonomic of intravenous immunoglobulins (IVIG) at immunomodula- dysfunction has been previously reported in anti-NMDA tory doses (400-800mg/kg/day) during 5 or 6 days and one of receptor encephalitis [1,3,4,7,11].In a series of 100 them needed a second cycle of IVIG; four patients received patients with anti-NMDA receptor encephalitis, 37 patients rituximab according to their body surface area with a 375 presented with cardiac arrhythmias [7] and there are at least mg/m IV infusion every two weeks for 2 cycles; four patients 2 reported cases who required a permanent pacemaker to needed plasma exchange and three cyclophosphamide 750 control cardiac arrhythmia [11]. It has been hypothesized that mg/m IV; one case received 2 cycles with 6 weeks between autonomic instability might be associated with seizure activ- each one and two patients received 4 cycles every three weeks. ity or induced by sympathetic and parasympathetic stimuli In the case of immature teratoma it was necessary to add [11]. In our series, 2 patients presented with dysautonomy; four cycles of chemotherapy repeated every 21 days with one of them had lability of blood pressure, and the other bleomycin (30 IU IV every week, for three doses), etoposide one tachycardia and sialorrhea who received local botulinum (100mg/m2 IV daily for 5 days), and cisplatin (20mg/m2 IV toxin injections in two occasions to be controlled. Teenagers daily for 5 days) (Figure 3). After treatment, patients showed and young adults usually showed abnormal behaviour (psy- gradual improvement in their symptoms over months. chosis, delusions, hallucinations, agitation, aggression, or catatonia) [4, 7, 8]. This review found two patients with psychiatric symptoms, such as auditory hallucinations and 3. Discussion delusion, requiring antipsychotics. The diagnosis of anti-NMDA receptor encephalitis is N-methyl-D-aspartate receptor channel is a tetramer com- posed by two subunits of GluN1 and two subunits of GluN2; confirmed by the detection of serum or CSF antibodies in 2007 Dalmau et al. described for the first time the against the GluN1 subunit of the NMDA receptor [1–3]. A significant aspect of encephalitis mediated by anti-NMDA anti-NMDA receptor antibody associated with 12 cases of encephalitis [5]. This antibody is against the GluN1 subunit receptor antibodies is that those directed against the GluN1 subunit are those that result in specific and recognizable and it is present in neuronal surface of the hippocampus, cerebral cortex, basal ganglia, and thalamus [2, 6]. Hughes et syndromes, while those directed against the GluN2 subunits al. suggested that GluN1 antibodies from patients with anti- are not associated with any specicfi syndrome [3]. Dalmau et al. considered that serum testing is less reliable, with false NMDA receptor encephalitis decrease glutamatergic synap- tic function, which may underlie the deficits of memory, negative resultsin up to 14% of cases[1]; on the other hand 4 Case Reports in Immunology (a) (b) Figure 2: Anti-NMDAR antibodies detected by indirect immunofluorescence . (a) Hek293 transfected cells; (b) granular layer of cerebellum in tissue of rat. [1]. In a study of 100 patients with anti-NMDA-receptor encephalitis only 55% of patients had increased T2-FLAIR signal in one or several brain regions, without significant correlation with patients’ symptoms [7]. In present series only one case shows cortical hyperintensity on uncus of right hippocampus (Figure 1). EEG prole fi was abnormal in most patients, usually showing nonspecific, slow, and disorganized activity. All cases reported in this study had a generalized slow tracing in EEG. Another analysis of CSF P1 P2 P3 P4 P5 P6 usually shows moderate lymphocytic pleocytosis with normal Chemotherapy Rituximab or mildly increased protein concentration [5, 7]; all cases in this study had pleocytosis in CSF. There was evidence that Plasmapheresis Intravenous Ig more than 50% of patients showed specific oligoclonal bands Cyclophosphamide Methylprednisolone [7]; nevertheless in present series it was one case of mirror pattern on OB; mirror OB have been reported in patients with Figure 3: Treatment grouped by patient. P1, P3, P4, and P5 received methylprednisolone (1 g IV daily) during 5 days; P2 and P6 received autoantibody-associated disorders, such as NMDA receptor methylprednisolone according their weight (1mg/kg) also during 5 encephalitis and VGKC encephalopathy. This pattern implies days. IVIG was administered in vfi e cases at immunomodulatory the presence of clonal IgG in both CSF and serum and it doses (400-800mg/kg/day). P2 and P3 needed cyclophosphamide means that the production of autoantibody might be rfi st (750 mg/m IV) every three weeks during 4 cycles; P4 received triggered in the periphery, rather than in the CNS so they may cyclophosphamide (750 mg/m IV) 2 cycles with 6 weeks between be an important biomarker in inflammatory central nervous each one. Rituximab was administered every two weeks (375 mg/m system disorders [13, 14]. IV) for 2 cycles in P1, P2, P3, and P4. In P2 it was necessary to add In this study 17 percent of the patients with a positive four cycles of chemotherapy for immature teratoma repeated every NMDA receptor antibody had an ovarian teratoma, which is 21 days with bleomycin (30 IU IV every week), etoposide (100mg/m2 significantly lower than in other published series; some epi- IV daily for 5 days), and cisplatin (20mg/m2 IV daily for 5 days). demiological studies suggested that this association depends on demographic features of the population analyzed [15]. Case reports and observational studies have estimated that Guasp et al. suggested that there is an increasing number 36%-50% of patients with anti-NMDA receptor encephali- of patients mistakenly diagnosed due to false positive serum tis have an ovarian teratoma [16, 17]. Gresa-Arribas et al. results recommending conrfi mation by CSF examination [3]. reported more frequently NMDA receptor antibodies in By contrast Irani et al. reported that serum levels of anti- patients who had an underlying teratoma than in those who NMDA receptor antibodies were similar or higher to those did not have a tumour [9]. A mature cystic ovarian teratoma was identified in 5 patients in this study and one patient of CSF [12]. In this study determinations of anti-NMDA receptor were performed by IIF in serum and CSF and were had an immature teratoma conrfi med by pathology; in a concordant in 100% of them (Figure 2). cohort of 252 patients an immature ovarian teratoma was diagnosed in 11% of them [18]. One case of bilateral teratoma Diagnosis approach also included MRI and EEG; in some cases MRI scan was normal or showed unilateral changes was observed in this study with similar outcome compared Case Reports in Immunology 5 to other patients with unilateral tumour; Lee et al. reported a Conflicts of Interest case of fulminant course in a patient with bilateral teratoma The authors declare that there are no conflicts of interest suggesting that it might be related to higher antibody titers regarding the publication of this article. [19]. The optimal management of anti-NMDA receptor en- cephalitis includes immunotherapy and removal of the Acknowledgments immunological trigger, such as teratoma or another tumour [1, 5]. First-line immunosuppressive therapy includes methyl- The present investigation has not received any specific grant prednisolone 1 g per day for 5 days and concomitant from agencies of the public, commercial, or nonprofit sectors. intravenous immunoglobulins (0.4 g/kg per day for 5 days) or plasma exchange. Second-line therapy consists of rit- References uximab (375 mg m 1 week for 4 weeks) combined with [1] J. Dalmau and F. Graus, “Antibody-mediated encephalitis,” The cyclophosphamide (750 mg m ) given with the rfi st dose of New England Journal of Medicine, vol.378,no. 9,pp.840–851, rituximab, followed by monthly cycles of cyclophosphamide [15]. In present study 2 patients showed improvement of [2] A. Carrasco, I. Alarco´n,C.Gonzalez ´ , and F. Graus, “Identi- the neurological outcome aer ft tumour resection and first- ficaci´on y utilidad cl´ınica de los anticuerpos antineuronales,” line therapy, alone or combined, while 4 patients need a Inmunologıa,vol. 33, no.4, pp. 128–136, 2014. second-line immunotherapy (Figure 3). In a study of 577 [3] M. Guasp and J. Dalmau, “Encefalitis por anticuerpos contra el patients the combination of first-line immunotherapy more receptor de NMDA,” Medicina Cl´ınica, vol. 151,no. 2,pp.71–79, frequently used was steroids and IVIG [8], similar to com- bination observed in present series. Dalmau et al. reported [4] F. Graus,M.J.Titulaer,and R. Balu, “A clinical approach to that 80% of patients with a tumour (mostly teratomas) had diagnosis of autoimmune encephalitis,” The Lancet Neurology , substantial improvement aer ft tumour removal and rfi st- vol.15,no. 4,pp. 391–404,2016. line immunotherapy [15]. These observations and the possi- [5] J. Dalmau, E. Tuz ¨ un, ¨ H.-Y. Wu et al., “Paraneoplastic anti- ble rapid neurological improvement after tumour resection N-methyl-D-aspartate receptor encephalitis associated with suggest that a peripheral immune response against tumour ovarian teratoma,” Annals of Neurology, vol. 61, no.1,pp. 25–36, autoantigens could be involved in the production of anti- NMDA receptor autoantibodies [18]. [6] E.G.Hughes, X.Peng,A.J. Gleichman et al.,“Cellular and Recovery from this disorder is typically slow, and symp- synaptic mechanisms of anti-NMDA receptor encephalitis,” The toms may relapse, especially in patients with undetected or Journal of Neuroscience, vol. 30, no. 17, pp. 5866–5875, 2010. recurrent tumours [7]. In accordance with Titularer et al. [7] J. Dalmau, A. J. Gleichman, and E. G. Hughes, “Anti-NMDA- 53% of patients had clinical improvement within 4 weeks, receptor encephalitis: case series and analysis of the eeff cts of and 81% had substantial recovery (i.e., mild or no residual antibodies,” The Lancet Neurology , vol.7,no. 12,pp. 1091–1098, symptoms) at 24 months [8]. Patients analyzed in this study had no relapses reported. [8] M.J.Titulaer,L.McCracken,I.Gabilondoetal.,“Treatmentand prognostic factors for long-term outcome in patients with anti- NMDA receptor encephalitis: an observational cohort study,” 4. Conclusion The Lancet Neurology , vol. 12, no. 2, pp. 157–165, 2013. [9] N. Gresa-Arribas, M. J. Titulaer, A. Torrents et al., “Antibody Anti-NMDA receptor encephalitis is a multifaceted disease titres at diagnosis and during follow-up of anti-NMDA receptor associated with serious complications, which may require an encephalitis: a retrospective study,” The Lancet Neurology ,vol. early diagnosis and extensive studies to establish the presence 13,no. 2,pp.167–177, 2014. of an underlying germ-cell tumour to perform a prompt [10] A. Kaneko, J. Kaneko, N. Tominaga et al., “Pitfalls in clinical surgery and aggressive immunotherapy. diagnosis of anti-NMDA receptor encephalitis,” Journal of Neurology, vol.265,no. 3,pp.586–596, 2018. [11] N. Salehi, A. K. Yuan, G. Stevens, R. Koshy, and W. F. Klein, Abbreviations “A case of severe anti-N-methyl D-aspartate (Anti-NMDA) ANA: Antinuclear antibodies receptor encephalitis with refractory autonomic instability CSF: Cerebrospinal uid fl and elevated intracranial pressure,” American Journal of Case EEG: Electroencephalogram Reports,vol.19, pp.1216–1221, 2018. GluN1: Glutamate ionotropic receptor subunit 1 [12] S. R. Irani and A. Vincent, “NMDA receptor antibody GluN2: Glutamate ionotropic receptor subunit 2 encephalitis,” Current Neurology and Neuroscience Reports,vol. IIF: Indirect immunouo fl rescence 11, no. 3, pp. 298–304, 2011. IVIG: Intravenous immunoglobulins [13] A. J. Sinclair, L. Wienholt, E. Tantsis, F. Brilot, and R. C. Dale, MRI: Magnetic resonance imaging “Clinical association of intrathecal and mirrored oligoclonal NMDA: Anti-N-methyl-D-aspartate bands in paediatric neurology,” Developmental Medicine & Child Neurology, vol. 55, no. 1, pp. 71–75, 2013. OB: Oligoclonal bands T2-FLAIR: T2-weighted-Fluid-Attenuated Inversion [14] A. Vincent, C. G. Bien, S. R. Irani, and P. Waters, “Autoantibod- ies associated with diseases of the CNS: new developments and Recovery. 6 Case Reports in Immunology future challenges,” The Lancet Neurology ,vol. 10,no.8, pp. 759– 772, 2011. [15] J. Dalmau, E. Lancaster, E. Martinez-Hernandez, M. R. Rosen- feld, and R. Balice-Gordon, “Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis,” The Lancet Neurology, vol.10,no.1,pp.63–74,2011. [16] A. L. Martin, E.Jollieff ,and S. P. Hertweck,“Ovarianter- atoma associated with coexisting Anti-N-Methyl-D-Aspartate receptor and glial fibrillary acidic protein autoimmune menin- goencephalitis in an adolescent girl: a case report,” Journal of Pediatric & Adolescent Gynecology,vol.31, no.3,pp. 321–324, [17] C. A. Cundiff, N.Elawabdeh, M.M.Naguibetal.,“Does MAP2 have a role in predicting the development of anti-NMDAR encephalitis associated with benign ovarian teratoma? A report of six new pediatric cases,” Pediatric and Developmental Pathol- ogy,vol.18, no. 2,pp.122–126, 2015. [18] C. Bost,E.Chanson, G.Picard et al., “Malignant tumors in autoimmune encephalitis with anti-NMDA receptor antibod- ies,” Journal of Neurology, vol. 265, no. 10, pp. 2190–2200, 2018. [19] K. W. Lee and L. M. Liou, “Fulminant course in a patient with anti-N-methyl-D-aspartate receptor encephalitis with bilateral ovarian teratomas: a case report and literature review,” Medicine (Baltimore),vol.97, no. 15,p. e0339, 2018. 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