Paraneoplastic NMDA encephalitis, a case report and an extensive review of available literature

Anti-N-methyl-D-aspartate receptor (NMDAr) encephalitis is a prevalent autoimmune condition marked by diverse neuropsychiatric symptoms, primarily impacting young females. The exact mechanisms underlying the development of NMDAr encephalitis have not been fully elucidated. Nonetheless, studies have demonstrated that auto-antibodies targeting the NR1-NR2 subunits of the NMDAr can trigger receptor dysfunction within the central nervous system, thus giving rise to the associated symptoms. Notably, an association exists between NMDAr encephalitis and an underlying neoplastic condition, with approximately 38% of cases exhibiting this paraneoplastic relationship with ovarian teratomas being the most commonly associated malignancy. While the association between NMDAr encephalitis and renal cell carcinoma (RCC) is exceedingly rare. This case report presents the clinical scenario of a 20-year-old female patient diagnosed with NMDAr encephalitis in conjunction with RCC discovered incidentally on a CT abdomen and pelvis performed to rule out an ovarian teratoma. The presented case underscores the importance of adopting a multidisciplinary approach in the diagnosis and treatment of NMDAr encephalitis, particularly when it is linked to an underlying malignancy. Furthermore, it emphasizes the significance of expanding our understanding of the molecular pathogenesis of NMDAr encephalitis to enhance patient care and optimize clinical outcomes. Additionally, a comprehensive review of the existing literature is included, summarizing all reported malignancies associated with NMDAr encephalitis.

The exact mechanisms underlying the development of NMDAr encephalitis have not been fully elucidated.Nonetheless, studies have demonstrated that auto-antibodies targeting the NR1-NR2 subunits of the NMDAr can trigger receptor dysfunction within the central nervous system, thus giving rise to the associated symptoms.Notably, an association exists between NMDAr encephalitis and an underlying neoplastic condition, with approximately 38% of cases exhibiting this paraneoplastic relationship with ovarian teratomas being the most commonly associated malignancy.
While the association between NMDAr encephalitis and renal cell carcinoma (RCC) is exceedingly rare.This case report presents the clinical scenario of a 20-year-old female patient diagnosed with NMDAr encephalitis in conjunction with RCC discovered incidentally on a CT abdomen and pelvis performed to rule out an ovarian teratoma.The presented case underscores the importance of adopting a multidisciplinary approach in the diagnosis and treatment of NMDAr encephalitis, particularly when it is linked to an underlying malignancy.Furthermore, it emphasizes the significance of expanding our understanding of the molecular pathogenesis of NMDAr encephalitis to enhance patient care and optimize clin-

Introduction
Anti-N-methyl-D-aspartate receptor (NMDAr) encephalitis is a rare autoimmune condition identified by a broad spectrum of neuropsychiatric symptoms, predominantly affecting young females [1] .However, its clinical diagnosis remains insufficiently recognized, contributing to the complexity of managing this condition [1] .The clinical presentation of NMDAr encephalitis encompasses psychiatric symptoms, including agitation and hyperkinetic movements, as well as autonomic dysfunction and seizures [2] .
The exact mechanisms underlying the development of NMDAr encephalitis have not been fully elucidated.Nonetheless, studies have demonstrated that auto-antibodies targeting the NR1-NR2 subunits of the NMDAr can induce receptor hypofunction or downregulation within the central nervous system, thus giving rise to the associated symptoms [3] .Notably, an association exists between NMDAr encephalitis and an underlying neoplastic condition, with approximately 38% of cases exhibiting this paraneoplastic relationship [4] .
While the association between NMDAr encephalitis and renal cell carcinoma (RCC) is exceedingly rare [5][6][7] .This case report presents the clinical scenario of a 20-year-old female patient diagnosed with NMDAr encephalitis in conjunction with RCC.The presented case underscores the importance of adopting a multidisciplinary approach in the diagnosis and treatment of NMDAr encephalitis, particularly when it is linked to an underlying malignancy.Furthermore, it emphasizes the significance of expanding our understanding of the molecular pathogenesis of NMDAr encephalitis to enhance patient care and optimize clinical outcomes.Additionally, a comprehensive review of the existing literature is included, providing insights into potential malignancies associated with or causing paraneoplastic anti-NMDA receptor encephalitis, elucidating the underlying physiological mechanisms, discussing therapeutic strategies, and shedding light on the prognosis for individuals afflicted by this complex disorder.

Case presentation
A 20-year-old African American female came to the emergency department (ED) with several symptoms that had been bothering her for several months.She had experienced paresthesia, insomnia, hyperkinetic muscle movements, and behavioral changes.She had visited other hospitals in the past month seeking help with her symptoms but had not found any relief.To manage her symptoms, she was given antiepileptic drugs and benzodiazepines, but her symptoms did not improve, and she started self-medicating with alcohol.When she came to the ED, she was exhibiting severe rhythmic movements in her extremities, a shortened attention span, and body rocking.She reported no use of illicit drugs.About a month ago, she was still able to do all her daily living activities.
Upon examination, her blood pressure was recorded as 121/67 mm Hg, heart rate as 122 beats per minute, and respiratory rate as 24 breaths per minute.She was noted to be febrile with an oral temperature of 38.5 °C.The patient's body mass index was 38.16, indicative of morbid obesity.
Upon observation, the patient was visibly distressed, exhibiting bilaterally flailing arms and legs, with repeated muscle spasms causing alternate flexion and extension of her extremities.Due to her increasing psychomotor agitation, a comprehensive neurological examination was not performed, however, the rest of the exam was unremarkable except for muscle tenderness noted throughout the patient's body.The patient was later transferred to the medical intensive care unit (ICU).Despite the administration of sedative medications, including risperidone, midazolam, diazepam, and dexmedetomidine, her symptoms persisted and worsened over the course of her admission, leading to heavy sedation and intubation for airway protection and escalating agitation.
A comprehensive evaluation of the patient's worsening mental status and choreiform kinetic movements was initiated in the emergency department and continued in the medical ICU.Upon laboratory analysis, normocytic anemia with hyperchloremia, hyperkalemia, transaminitis, and metabolic acidosis were detected.The creatine kinase level was elevated at 40,100 mIU/L, which along with the results of urinalysis were consistent with rhabdomyolysis.Further testing, including serum osmolality, thyroid and iron studies, serum ammonia levels, and toxicology screening for methanol, ethanol, salicylates, and acetaminophen, all returned normal results.Additionally, negative results were obtained from syphilis and HIV screens.Blood and urine cultures did not indicate the presence of an infectious process.Brain computed tomography and electroencephalogram results were also inconclusive in identifying the underlying cause of the patient's symptoms.
Brain magnetic resonance imaging revealed increased T2 and FLAIR hyperintensity in the bilateral amygdala and corticospinal tracts ( Fig. 1 ).To identify the cause of her worsening condition, a lumbar puncture with a thorough analysis of her cerebrospinal fluid (CSF) was conducted, including testing for arboviral and anti-N-methyl-D-aspartate (NMDA) receptor titers.The neurology team recommended testing for paraneoplastic autoantibodies using the Mayo Clinic paraneoplastic Antibody Panel (Mayo Medical Laboratories Test ID: PAVAL) as well.The patient required sedation, paralysis medication, and mechanical ventilation to manage her choreiform movements and muscle breakdown.During medical ICU admission, the test of NMDAr in serum and CSF was positive (1:640 Serum; 1:320 CSF), which raised concern for anti-NMDA receptor encephalitis of an unknown etiology.
In light of previous studies linking NMDA receptor encephalitis to ovarian teratomas, a screening CT scan of the abdomen and pelvis, as well as a transvaginal ultrasound, were performed.However, no evidence of ovarian pathology was identified by the CT scan or ultrasound examination.Instead, a left renal mass (6.1 × 5.6 × 5.4 cm) consistent with a probable renal cell carcinoma was detected ( Fig. 2 ).After 4 days of presentation, the patient was transferred to the neurological-ICU for further investigations and was maintained on deep sedation with propofol and fentanyl.
The patient was diagnosed with anti-NMDAr Encephalitis after excluding other explanations of her presentation.Despite improvement in her rhabdomyolysis through supportive care including adequate hydration, the patient continued to exhibit symptoms such as spasms, hyperkinetic movements, and an inability to protect her airway.During her 80-day admission in the neurological ICU, a multidisciplinary teambased approach was utilized with specialists from Neurology, Oncology, Urology, Hematology, and Surgical Services to guide her treatment.On hospital day 14, the patient also required a tracheostomy for prolonged mechanical ventilation.In addition, a gastrostomy tube was inserted on the same day.Additionally, the palliative team was consulted for further recommendations.
After thorough consideration and discussions with the patient's family, a total left nephrectomy was performed on the fifth hospital day (HD 5) and pathology confirmed the presence of renal cell carcinoma and incidental reno-medullary interstitial cell tumor.The patient was concurrently treated with 5 days of IV Solumedrol 1 g followed by 5 days of plasma exchange, however, due to the lack of improvement, neuroimmunology was consulted for potential immunotherapy.Subsequently, the patient was initiated on weekly rituximab 375 mg/m 2 for 4 weeks starting from hospital day (HD) 20, which showed minor improvement leading to extubation.
Despite the use of various antipsychotic and anti-epileptic medications, the patient continued to experience dysautonomia, hyperkinetic movements, clonus, and agitation.On HD 54, a 4-day cyclophosphamide protocol with pulse dose steroids was initiated for the refractory NMDAr encephalitis and soon thereafter, the patient demonstrated improvement in her activity and reduced agitation.Her alertness continued to improve, allowing communication with family and healthcare providers.By HD 60, the patient showed decreased hyperkinetic movements and improved control over her extremities.IV sedation was eventually weaned off totally and her moderate agitation and refractory movements were managed with a combination of Valproic acid, Clonazepam, Pregabalin, clonidine, propranolol, and olanzapine.
Her serum NMDAr antibody titers continued to improve, with a reading of 1:160.On HD 69, the patient was able to follow 3-step commands and had full control over her extremities with 4/5 strength bilaterally.Given the positive response to the cyclophosphamide treatment, a protracted course of 10 doses was recommended by neuroimmunology.The patient was in the hospital receiving supportive care due to ongoing agitation during stressful periods.Despite this, she continued to make progress and recover her daily functions, such as communicating effectively, self-feeding, controlling her limbs, urinating, and transferring, among others.In order to mitigate symptoms, the patient practiced alternative meditation techniques under the guidance of the nursing staff.On occasion, she required the administration of intravenous benzodiazepines and minimal respiratory support through her tracheostomy collar.On the 74th hospital day, it was observed that the patient was able to sit up, wear her glasses, and watch the TV.When questioned about her memory, she appeared disoriented and reported having no recollection of the previous days of her hospital stay.The hospital staff provided reorientation each morning to help the patient better understand her diagnosis and current state.
Finally, a joint evaluation between the neuroimmunology and oncology teams was performed to determine the next course of action for the patient, given her persistent anti-NMDAr titers at 1:120.It was suggested that a positron emission tomography-computed tomography (PET-CT) scan be conducted in an outpatient setting to assess for residual renal cell carcinoma (RCC).If there was no further improvement observed in the patient's condition, the team also discussed the possibility of performing a bilateral oophorectomy as a supplementary management step.

Causes of paraneoplastic NMRAr encephalitis
The etiology of anti-NMDAR encephalitis encompasses viral, tumor-related, and idiopathic origins, each capable of triggering the production of autoantibodies against NMDA receptors.The presence of plasma cells, IgG deposits, and reduced NM-DAR levels observed in brain biopsies and autopsies, as well as the detection of clonal plasma cells producing anti-NMDAR in the cerebrospinal fluid (CSF), provide evidence for this autoimmune response [8] .Notably, NMDAr encephalitis often manifests as a paraneoplastic syndrome, with ovarian teratoma representing the most commonly associated tumor type.
A multi-institutional observational study conducted by Titulaer et al. [4] encompassed 220 patients with tumor-associated anti-NMDAR encephalitis, wherein 94% of the tumors were ovarian teratomas, 2% were extra ovarian teratomas, and the remaining 4% comprised 2 cases each of lung cancer, breast cancer, testicular tumors, ovarian carcinoma, thymic carcinoma, and pancreatic cancer [4] .
Interestingly, anti-NMDAR receptor encephalitis has also been associated with benign and precancerous lesions.Yin et al. [10] reported 3 cases of anti-NMDA receptor encephalitis in patients without underlying tumors but with prominent melanocytic nevi.The subsequent resection of these nevi was linked to patient recovery, suggesting that melanocytes in nevi may serve as potential autoantigens, eliciting an autoimmune response leading to encephalitis.Consequently, nevi resection in these patients resulted in improved response to immunotherapy and recovery.The authors highlighted the necessity for further clinical and experimental investigations to validate the treatment approach of resecting melanocytic nevi in anti-NMDAR encephalitis patients without concurrent tumors.
In contrast, paradoxically, anti-NMDAR encephalitis has also been associated with the resection of melanocytic nevi.Yang et al. [11] reported 2 cases of anti-NMDA encephalitis following the excision of melanocytic nevi.Both patients were females in their 20s, and initial screening tests for ovarian teratoma or other tumors yielded negative results.One patient received treatment with steroids and mycophenolate mofetil, while the other patient underwent first-line immunotherapy, and both eventually achieved recovery.The authors suggested that exposure to certain antigens on nevus cells resulting from nevus excision might activate an autoimmune response leading to the development of anti-NMDAR encephalitis.They emphasized the need for further research to evaluate the validity of this hypothesis.
This review primarily focuses on paraneoplastic anti-NMDA encephalitis.A comprehensive literature search was conducted to identify the types of tumors associated with anti-NMDAR encephalitis, and a summary can be found in Table 1 .

Pathophysiology of paraneoplastic NMDAr encephalitis
NMDA receptors are heterotetrameric structures comprising essential GluN1 subunits and either GluN2 or GluN3 subunits in various combinations [ 37 ].The GluN1 subunit has 8 isoforms, while the GluN2 and GluN3 subunits have 4 and 2 isoforms, respectively [ 37,38 ].In the context of anti-NMDAr encephalitis, autoantibodies target the extracellular domain of the GluN1 subunits [2] .The binding of these autoantibodies to the subunits results in a reversible reduction in surface expression of NMDA receptors, leading to receptor hypofunction [ 38 ].This reduction occurs due to internalization of the NMDA  receptor surface protein and selective capping mediated by the autoantibodies [ 39 ].However, this mechanism does not fully explain certain excitatory neurological symptoms observed in patients with NMDAr encephalitis, including seizures, dyskinesias, and catatonia.Published data suggests that NMDA receptor antibodies can initially prolong GluN1 channel opening, followed by a subsequent decrease in receptor surface expression.Moreover, the effects of the autoantibodies on the receptors can vary depending on the specific subtype, and at times, the anti-NMDAR antibodies may act as receptor agonists rather than antagonists, contributing to the aforementioned clinical symptoms [2] .Fig. 3 provides an illustrative representation of receptor hypofunction and receptor hyperfunction, as well as the associated symptoms in patients with NM-DAr encephalitis.
In the context of RCC, we propose that anti-NMDAR encephalitis represents a rare paraneoplastic neurological syndrome associated with the tumor.Paraneoplastic neurological syndromes encompass a heterogeneous group of disorders unrelated to tumor metastasis, metabolic or nutritional deficits, coagulopathy, infections, or treatments [ 40 ].NMDA receptors are expressed not only in the central nervous system but also in certain peripheral tissues, including the kidneys [ 41,42 ].The activation of these receptors in the renal tissue is believed to play a role in tubular and glomerular function [ 42 ].In the case of RCC, we postulate that immune-related mechanisms may give rise to the production of autoantibod-ies against these receptors, leading to the manifestation of anti-NMDAR encephalitis.In the context of ovarian teratoma, it is well-documented that these tumors can contain mature and immature neuronal tissue expressing NMDA receptors.Thus, teratomas may contribute to the initiation of autoantibody synthesis, whereby these antibodies can subsequently cross-react with NMDA receptors present in the central nervous system [ 43 ].

Management
The management of paraneoplastic anti-NMDA Receptor encephalitis is complex, time-sensitive, and often requires a multidisciplinary approach.It should target the tumor and NMDA antibody levels, and provide relief for the neuropsychiatric symptoms.
The optimal line of treatment consists of tumor removal and/or chemotherapy, combined with first-line immunotherapy (steroids, intravenous immunoglobulins, and plasmapheresis) [4] .Second-line immunotherapy (rituximab, cyclophosphamide, or both) improves outcomes for patients who did not respond to first-line immunotherapy and decreases the occurrence of relapses [ 4,44 ].The elimination of tumors, frequently coupled with immunotherapy, leads to a significant decrease in NMDAR antibody levels, with optimal outcomes observed when tumors are promptly removed [ 45 ].
Removing the tumor (usually an ovarian teratoma) is often an important step in the management of anti-NMDA receptor encephalitis [ 46 ].An article describing a case of anti-NMDAr encephalitis in the setting of clear cell renal carcinoma reported that the patient markedly improved after undergoing nephron-sparing surgery for the tumor [ 47 ].Another case of a 54-year-old patient with neuropsychiatric symptoms not responding to antiviral treatment for suspected viral encephalitis who had to be sedated due to worsening of his symptoms, was found to have a clear cell renal cell carcinoma.Following tumor resection (laparoscopic partial nephrectomy) and immunotherapy, the patient improved and was later discharged [5] .
The presence of behavioral and psychotic symptoms can be a serious obstacle, as the condition is easily misdiagnosed [ 48 ]; which in turn delays the initiation of treatment.The administration of certain treatments such as plasma exchange is challenging in some patients with hyperkinesia or agitation, requiring them to be sedated.There is often a duration of a few weeks from symptom onset to laboratory confirmation of the diagnosis [ 49 ].During this time, clinicians are left to prescribe symptomatic treatments, such as providing relief for seizures, catatonia, or perceptual disturbances.The aforementioned points re-emphasize the need for a multidisciplinary approach in managing patients with autoimmune encephalitis.

Prognosis
Patient prognoses hinge on various factors, with those experiencing milder symptoms-defined as not necessitating ICU admission [ 4,25 ]-and undergoing prompt initiation of immunotherapy and tumor removal [ 4,50 ], being of younger age [ 51 ], and having lower antibody levels [ 52,53 ] generally having more favorable outcomes.
Approximately 75% of individuals with anti-NMDA receptor encephalitis experience recovery or encounter mild consequences, while the remaining 25% may exhibit severe deficits or face eventual mortality [1] .Initial immunotherapy yields improvement in 53% of patients within the first 4 weeks, with 97% showing favorable outcomes at the 24-month mark.Among the 47% who do not respond to first-line treatment, those undergoing second-line immunotherapy (ie, rituximab, cyclophosphamide, or both) demonstrate better results compared to those persisting with initial treatment or receiving no additional immunotherapy [4] .
A European study revealed that initiating treatment within 40 days of symptoms onset is associated with better outcomes [ 53 ].Individuals with delayed treatment for 3 months or more suffered permanent hippocampal damage [ 54 ].
Despite the severity of symptoms, paraneoplastic anti-NMDAr encephalitis demonstrates a more favorable prognosis compared to most other paraneoplastic encephalitides [ 60 ].

Conclusion
In conclusion, we present an exceedingly rare case of anti-NMDAr encephalitis in the setting of an incidentally discovered renal cell carcinoma in a 20-year-old female.Additionally, we performed an extensive review of existing literature on the pathophysiology, associated malignancies, management, and prognosis of paraneoplastic anti-NMDAr encephalitis.

Patient consent
Informed consent was obtained from the patient's surrogate decision-maker (Mother) for the publication of this case report, ensuring confidentiality and voluntary participation.
Written consent was not obtained at the time of acquiring patient information, the consent was obtained verbally.The patient's legal guardian is currently untraceable, but approval to publish has been given by The University of Florida ethics committee, and by local legislation given that verbal consent was obtained from the patient's legal guardian.
t r a c t Anti-N-methyl-D-aspartate receptor (NMDAr) encephalitis is a prevalent autoimmune condition marked by diverse neuropsychiatric symptoms, primarily impacting young females.

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