Focal Seizures Induced by Paraneoplastic Syndrome Leading to a Diagnosis of Small Cell Lung Carcinoma.

Paraneoplastic neurological disorders are a rare complication of multiple neoplasms, such as lung, testis, and breast, and can be associated with positive antibody anti-Hu (anti-neuronal nuclear antibody type 1 or ANNA-1), anti-Ta, anti-Ma, and uncharacterized antibody, or be antibody-negative. Early treatment of the underlying tumor is the most likely modality that will lead to regression of the paraneoplastic neurological symptoms. Here, we present a case of a 73-year-old female with new-onset seizure activity from ANNA-1 encephalitis found to have undiagnosed small cell lung cancer to highlight the need for further workup for malignancy.

Testicular Cancer and Paraneoplastic Encephalitis: A Review of the Current Literature.

INTRODUCTION: Paraneoplastic encephalitis (PE) represents a rare but significant complication in patients with testicular cancer (TC). Given the paucity of comprehensive literature on this topic, our review seeks to consolidate current knowledge and provide evidence-based recommendations for the diagnosis, prognosis, and management of PE in the context of TC. MATERIALS AND METHODS: In adherence to PRISMA guidelines, a systematic literature review was conducted from 1950 to April 2024 using PubMed. The search focused on articles where TC was identified as the primary etiology of PE. The Mixed Methods Appraisal Tool and the Oxford Centre for Evidence-Based Medicine's levels of evidence tool were employed for assessing study quality, and a thematic analysis was conducted to identify trends and patterns. RESULTS: Out of 91 articles identified, 29 met the inclusion criteria, encompassing 5 retrospective chart reviews, 3 case series, and 22 case reports. Findings indicate that PE symptoms can manifest at any stage of TC-before tumor detection, during treatment, or even years posttreatment. A notable observation was the frequent oversight of microscopic testicular tumors in ultrasound imaging, leading to diagnostic delays. The outcomes of PE in the context of TC were diverse, reflecting the heterogeneity of the studies included. CONCLUSION: PE, although rare, is a critical consideration in patients with TC presenting with neuropsychiatric symptoms. Early recognition and appropriate diagnostic workup, including consideration for microscopic neoplasms, are essential for timely intervention and improved patient outcomes.

Overview of Paraneoplastic Autoantibody-Mediated Cognitive Impairment and Behavioral Changes: A Narrative Review.

Cognitive dysfunction and behavioral change can be some of the manifestations of cancer, occurring as a part of paraneoplastic neurological syndrome, most commonly in small cell lung cancer. Paraneoplastic limbic encephalitis is the leading cause of cognitive disturbance and abnormal behavior in paraneoplastic syndromes, which is usually autoantibody-mediated. Autoantibodies are the main contributors to the development of cognitive dysfunction and behavioral change in cancer patients, with studies suggesting a higher liability for antibody-positive cancer patients to be affected. Anti-NMDAR and anti-AMPAR are antibodies targeted against surface antigens, manifesting predominantly as memory disturbance, abnormal behavior, psychiatric symptoms, and seizures. Other surface antigen-targeted antibodies include anti-GABA, anti-CASPR2, and anti-LGI1, which were shown to have cognitive function impairment and abnormal behavior as some of the main presentations, predominantly affecting memory. Cognitive deterioration and changes in behavior were also relatively common with some of the intracellular antigen-targeted antibodies, including anti-Hu, anti-SOX1, anti-PCA2, and anti-Zic2. Affected behavior and cognition, however, were reported less commonly in other paraneoplastic antibodies against intracellular antigens (anti-Yo, anti-GAD, anti-Ma2, anti-Ri, anti-CV2, and anti-KLHL11). Our article will provide a comprehensive review of the clinical manifestations of cognitive impairment and behavioral changes among cancer patients who develop paraneoplastic syndrome. Additionally, this review will discuss the role of specific paraneoplastic autoantibodies and the clinical spectrum linked to each separately.

Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults.

Autoimmune encephalitis is increasingly recognized as a neurologic cause of acute mental status changes with similar prevalence to infectious encephalitis. Despite rising awareness, approaches to diagnosis remain inconsistent and evidence for optimal treatment is limited. The following Canadian guidelines represent a consensus and evidence (where available) based approach to both the diagnosis and treatment of adult patients with autoimmune encephalitis. The guidelines were developed using a modified RAND process and included input from specialists in autoimmune neurology, neuropsychiatry and infectious diseases. These guidelines are targeted at front line clinicians and were created to provide a pragmatic and practical approach to managing such patients in the acute setting.

Primary mediastinal seminoma presenting with paraneoplastic anti-Hu encephalitis: a case report and literature review.

Primary mediastinal seminomas are exceedingly rare tumors, often localized to the anterior mediastinum. They may present with numerous complications, including superior vena cava syndrome, chylothorax, and pericardial effusions. Less commonly, they may present with paraneoplastic encephalitis. In this report we describe a case of a 19-year-old male with no significant past medical history who presented with bilateral hearing loss, progressive neuropathy, and ataxia. Subsequently the patient was found to have mediastinal mass with a high-titer anti-Hu antibody. To our knowledge, only one other case of mediastinal seminoma presenting with anti-Hu antibodies has been described in the literature. In this report, we describe a rare case of mediastinal seminoma, describe treatment options, and discuss additional known cases presenting with paraneoplastic encephalitis.

Identification of SKOR2 IgG as a novel biomarker of paraneoplastic neurologic syndrome.

Introduction: The development of new autoantigen discovery techniques, like programmable phage immunoprecipitation sequencing (PhIP-Seq), has accelerated the discovery of neural-specific autoantibodies. Herein, we report the identification of a novel biomarker for paraneoplastic neurologic syndrome (PNS), Sloan-Kettering-Virus-Family-Transcriptional-Corepressor-2 (SKOR2)-IgG, utilizing PhIP-Seq. We have also performed a thorough clinical validation using normal, healthy, and disease/cancer control samples. Methods: Stored samples with unclassified staining at the junction of the Purkinje cell and the granule cell layers were analyzed by PhIP-Seq for putative autoantigen identification. The autoantigen was confirmed by recombinant antigen-expressing cell-based assay (CBA), Western blotting, and tissue immunofluorescence assay colocalization. Results: PhIP-Seq data revealed SKOR2 as the candidate autoantigen. The target antigen was confirmed by a recombinant SKOR-2-expressing, and cell lysate Western blot. Furthermore, IgG from both patient samples colocalized with a commercial SKOR2-specific IgG on cryosections of the mouse brain. Both SKOR2 IgG-positive patients had central nervous system involvement, one presenting with encephalitis and seizures (Patient 1) and the other with cognitive dysfunction, spastic ataxia, dysarthria, dysphagia, and pseudobulbar affect (Patient 2). They had a refractory progressive course and were diagnosed with adenocarcinoma (Patient 1: lung, Patient 2: gallbladder). Sera from adenocarcinoma patients without PNS (n=30) tested for SKOR2-IgG were negative. Discussion: SKOR2 IgG represents a novel biomarker for PNS associated with adenocarcinoma. Identification of additional SKOR2 IgG-positive cases will help categorize the associated neurological phenotype and the risk of underlying malignancy.

Paraneoplastic-Like Syndrome in a Breast Cancer Patient With a Negative Paraneoplastic Panel: A Case Report.

Breast cancer is a leading cause of cancer death in the United States, with an increasing incidence in recent years. Paraneoplastic syndromes are uncommon but increasingly recognized complications of many types of cancer, including breast cancer. Here, we describe a case of a patient presenting with confounding symptoms, who was diagnosed with breast cancer and believed to have a paraneoplastic syndrome despite a negative paraneoplastic panel. This case underscores the need for more standardized diagnostic modalities and prompt recognition and treatment of these rare but serious syndromes.

Anti-CV2/Collapsin Response Mediator Protein 5 (CRMP5) Paraneoplastic Encephalitis Induced by Small Cell Lung Cancer.

Paraneoplastic neurological syndrome (PNS) associated with anti-CV2/CRMP5 antibodies is a rare entity that can present in various clinical manifestations, from encephalitis to chorea, depending on the brain region involved. We report a case of an elderly person with small cell lung cancer who presented with PNS encephalitis associated with anti-CV2/CRMP5 antibodies which were confirmed on immunological analysis.

A Rare Presentation of a Complex Mixed Autoimmune Encephalitis Diagnosis: A Case Report and Literature Review.

This case report presents a unique case of a difficult differential diagnosis of autoimmune encephalitis (AE) in the setting of Mycoplasma pneumoniae. A 40-year-old female with a history of Hashimoto thyroiditis, polycystic ovarian syndrome, and a lower respiratory infection presented to the emergency department with new-onset progressive neurological symptoms. These included generalized tonic-clonic seizure and worsening respiratory status that required intubation and tracheostomy. Blood cultures returned positive for M. pneumoniae. We concluded this to be a mixed diagnosis case of anti-glutamic acid decarboxylase 65 (anti-GAD65), Bickerstaff's brainstem encephalitis (BBE), Hashimoto's encephalopathy (HE), and Miller Fisher Syndrome (MFS) concurrently in the setting of M. pneumoniae. Initial treatment with intravenous immunoglobulin showed minimal improvement; however, subsequent treatment with plasmapheresis proved to be beneficial for the patient. Over the course of the plasma exchange therapy (PLEX), the patient slowly became more alert, attentive, and verbal. She was able to answer simple questions and follow commands. Common trends of age, gender, presenting symptoms, associated antibodies, and sessions of PLEX in different AE diseases were identified through a literature review. Only 69.7% of the cases implemented PLEX or plasmapheresis. Currently, there is no standard protocol for the treatment of AE. Our case report aims to present a clinically complicated example of AE and to provide further evidence to support PLEX as an important therapeutic option.

Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with small cell lung cancer and cytotoxic T-cell-mediated pathology: Case report.

Anti-N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is caused by a reversible inhibition of ion channel actions by autoantibodies and is associated with a relatively good prognosis. Pathological findings of NMDAR encephalitis usually do not show neurophagorous nodules, but rare or mild inflammatory infiltration. We report a patient of small cell lung cancer (SCLC)-related paraneoplastic encephalitis with NMDAR antibodies, a cytotoxic T-cell-mediated pathology of the brain, and a rapid clinical course. This case highlights that the neuropathological diversity of NMDAR encephalitis may be even broader than previously thought and that NMDAR antibodies may also be found in various pathological conditions with a vigorous immune response.

Inpatient Management of Encephalopathy.

Unexplained encephalopathy is a common occurrence in tertiary care centers and neurologic disorders should be considered after ruling out the infectious, toxic and metabolic etiologies. Neuroimaging combined with a thorough history and examination is often helpful in ruling out stroke and fulminant demyelinating encephalopathies. Autoimmune encephalopathy should be suspected in any patient with unexplained acute or subacute onset encephalopathy or rapidly progressing dementia. Anti-N-methyl-D-aspartate receptor (NMDA-R) encephalitis is the most studied form and Hashimoto encephalitis is the most controversial form of autoimmune encephalopathies. Obtaining a combined serum and Cerebrospinal fluid (CSF) autoantibody testing will increase the diagnostic yield of autoimmune and paraneoplastic encephalitis. When diagnosing NMDA receptor antibodies CSF is always more sensitive than serum and in contrast, voltage-gated potassium channel (VGKC) complex antibodies are more readily detectable in serum than in CSF. Neural-specific antibody tests frequently result after several weeks and treatment should be administered without a significant delay to prevent brain damage. Autoimmune encephalitis is often treatment responsive when immunotherapy (glucocorticoids, intravenous immune globulin, plasma exchange) is used in various combinations. The absence of inflammatory markers and autoantibodies in the serum or CSF may not rule out the possibility of paraneoplastic encephalopathies.

Diagnostic Approach and Treatment Regimens in Adult Patients Suffering from Antibody- mediated or Paraneoplastic Encephalitis.

Identification of patients with antibody-mediated encephalitis poses a diagnostic challenge, and any delay in that aspect will increase the interval until the initiation of immunotherapy and may negatively affect the patient´s clinical outcome. Within this review, we focus on therapeutic strategies in antibody-mediated encephalitis and propose how to proceed with patients who are suspected of having encephalitis of unknown origin. We further briefly outline differences in the treatment of paraneoplastic and antibody-mediated encephalitis according to its pathomechanisms.

Neurosyphilis: The Great Imitator.

Syphilis is a sexually transmitted disease caused by spirochete Treponema pallidum, with a growing incidence documented in recent years. Its clinical course is divided into three phases - primary, secondary, and tertiary syphilis - and virtually any organ can be affected, resulting in diverse clinical manifestations, making the diagnosis challenging. Neurosyphilis is a progressive, destructive disease of the central nervous system (CNS) that can develop at any stage of the infection, leading to meningeal involvement, meningovascular disease, or parenchymal syphilis (including tabes dorsalis and general paresis). Its clinical manifestations are heterogeneous and vary from focal neurologic signs to neuropsychiatric manifestations. The diagnosis is based mainly on the clinical picture and study of cerebrospinal fluid. Neuroimaging is helpful and sometimes essential, with magnetic resonance imaging being the most sensitive radiologic method, although there are no pathognomonic radiologic signs. Treatment of all forms of neurosyphilis is based on parenteral penicillin. We present a case of neurosyphilis in a patient presenting with a subacute confusional state and initial imaging findings suggestive of metastatic CNS lesions.

Clinical characteristics and prognosis of anti-alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic acid receptor encephalitis.

BACKGROUND: Encephalitis associated with antibodies against alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is an extremely rare type of antibody-mediated encephalitis. This research aims to investigate the clinical characteristics and prognosis of anti-AMPAR encephalitis. METHODS: This retrospective study enrolled nine patients with anti-AMPAR encephalitis. Demographic information, clinical manifestations, laboratory and radiological findings, treatment and response were collected and analyzed. These patients were followed up with an average period of 72 weeks to gather prognostic information. RESULTS: Nine patients (7 females and 2 males) were enrolled with a mean age at disease onset of 59 years old. Three clinical pictures, including limbic encephalitis (n = 7; 78%), pure amnesia (n = 1; 11%) and fulminant encephalitis (n = 1; 11%) were identified. New symptoms of dysphagia and deafness were identified in the clinical spectrum of anti-AMPAR encephalitis. All patients had positive blood AMPAR antibodies, and six of them (67%) had paired positive antibodies in cerebrospinal fluid (CSF). Brain magnetic resonance imaging (MRI) was abnormal in 75% of the patients with no specific patterns recognized. Six patients (67%) had tumors, including lung cancers and thymomas. After immunotherapy and oncotherapy, partial improvement of neurological symptoms was observed among all 6 patients with available records during their hospitalization. After a mean follow-up of 72 weeks, 3 patients had marked decrease of modified Rankin Scale (mRS) score, 1 patient had unchanged mRS score, 4 patients died and the other one was lost. CONCLUSIONS: Anti-AMPAR encephalitis mainly presents as limbic encephalitis, and is paraneoplastic in 67% of cases. Thus, intensive screening for tumors is recommended for all anti-AMPAR patients. Although patients showed a good short-term therapeutic response, the overall prognosis was not satisfactory.

Lung cancer masquerading as a paraneoplastic neurologic syndrome without a primary lung mass: Case report and review of literature.

Paraneoplastic and autoimmune encephalitis (AIE) syndromes describe a range of inflammatory disorders of the brain. "Classic" paraneoplastic encephalitis syndromes occur due to a remote neoplasm and are associated with antibodies that target intracellular neuronal proteins while the more recently described AIE syndromes are not always paraneoplastic and occur in association with antibodies that target cell-surface neuronal receptors (e.g., anti-NMDA receptor, anti-LGI1, anti-GABAB receptor).[1] Diagnosis can be difficult and delayed due to nonspecific clinical, imaging, and laboratory findings, and in those syndromes associated with a neoplasm, the neurologic syndromes often precede the cancer diagnosis. We present a case of a 64-year-old patient diagnosed with anti-GABAB receptor encephalitis that subsequently revealed an underlying small cell lung cancer without a primary lung tumor. This case highlights the clinical challenge in diagnosing immune-mediated encephalitis, its methodical work up, and subsequent management.

Paraneoplastic and autoimmune encephalitis: Alterations of mood and emotion.

Autoimmune encephalitis often produces signs and symptoms that appear to be at the interface between neurology and psychiatry. Since psychiatric symptoms are often prominent, patients are often first seen in a psychiatric setting. Therefore it is important that psychiatrists, as well as neurologists, be able to recognize autoimmune encephalitis, a task that is often difficult. Early diagnosis of autoimmune encephalitis is crucial as this will usually result in a better outcome for the patient. This chapter provides an introduction to various autoimmune encephalitides and describes their pathophysiology and the possible associated neuropsychiatric, neuropsychological (cognitive), and neurological (sensory-motor) signs and symptoms. This chapter also reviews the possible treatments of these associated signs and symptoms.

N-Methyl-D-Aspartate Receptor-Negative Autoimmune Encephalitis in a Patient With an Ovarian Teratoma and an Associated Novel Cerebrospinal Fluid Autoantibody.

Autoimmune encephalitis is most commonly caused by autoantibodies against N-methyl-D-aspartate (NMDA) receptors, and the malignancy most often associated with anti-NMDA receptor autoimmune encephalitis is an ovarian teratoma. Here, we describe a case of autoimmune encephalitis caused by a newly discovered cerebrospinal fluid autoantibody that has not been previously described and is not anti-NMDA receptor-mediated, which has been associated with an ovarian teratoma. It was successfully treated with high-dose corticosteroids and plasmapheresis followed by rituximab and chemotherapy (paclitaxel, ifosfamide, and cisplatin) for her teratoma.

Capgras syndrome and confabulation unfurling anti NMDAR encephalitis with classical papillary thyroid carcinoma: First reported case.

Anti NMDA Receptor encephalitis (ANMDARE) is an immune mediated disease of the central nervous system, caused by circulating antibodies against the NMDA receptor present on neuronal surface. It is known to cause a spectrum of disease ranging from mild behavioral and psychiatric manifestations to full blown seizures, dyskinesias and altered sensorium. It can also be paraneoplastic presentation of a hidden tumor, most commonly ovarian teratoma. Here we present a case of ANMDARE with intriguing presentation of Capgras syndrome and confabulations, who was found to have a malignant papillary thyroid carcinoma, which has been rarely reported.

Autoimmune Encephalitis in Children: From Suspicion to Diagnosis.

There are several well-described and studied autoimmune diseases that affect different organ systems, and a limited number of these affect the central nervous system. Autoimmune encephalitis represents a disease with a wide spectrum of clinical manifestations and different levels of severity, from mild cognitive impairment to complex encephalopathy. Immune-mediated encephalitis refers to a diverse and rare group of conditions in children associated with nonspecific symptomatology, altered mental state, and recalcitrant seizures. Infectious etiology must be excluded. Immune-mediated encephalitis syndromes could be associated with paraneoplastic or primarily autoimmune mechanisms. The newest scientific advantages have concluded that autoimmune encephalitis may be further divided into different groups of diseases depending on the immune response; examples are antibodies to cell surface proteins, antibodies to intracellular synaptic proteins, T-cell response with antibodies to intracellular antigens, among others. Treatment consists of supportive therapy, ranging from supplemental oxygen, fluid restriction to mechanical circulatory support. Specific treatment includes immunoglobulin infusion, plasmapheresis, and pulse steroid treatment. Prognosis is poor if specific treatment is not timely instituted. The diagnosis of autoimmune encephalitis could be challenging to clinicians due to its diverse clinical features, which can mimic a variety of other pathologic processes. Screening for cancer and proper management that includes immune therapy are fundamental, although some patients will need immune suppression for weeks or months as autoimmune encephalitis may relapse; therefore, follow-up is always necessary.