An autoimmune-based, paraneoplastic neurologic syndrome following checkpoint inhibition and concurrent radiotherapy for merkel cell carcinoma: case report.

PURPOSE: Merkel cell carcinoma is highly sensitive to both radiation and immunotherapy. Moreover, concurrent radioimmunotherapy may capitalize on anti-tumor immune activity and improve Merkel cell treatment response, although an enhanced immune system may cross-react with native tissues and lead to significant sequelae. METHODS: Here we present a case study of a patient with metastatic Merkel cell carcinoma treated with radiotherapy concurrent with pembrolizumab. RESULTS: After radioimmunotherapy, the patient developed sensory neuropathy, visual hallucinations, and mixed motor neuron findings. Neurologic dysfunction progressed to profound gastrointestinal dysmotility necessitating parenteral nutrition and intubation with eventual expiration. CONCLUSION: This case represents a unique autoimmune paraneoplastic neurologic syndrome, likely specific to neuroendocrine tumors and motivated by concurrent radioimmunotherapy. Recognition of the potential role of radioimmunotherapy may provide an advantage in anticipating these severe sequelae.

Neuropsychiatric Disorders Due to Limbic Encephalitis: Immunologic Aspect.

Limbic encephalitis (LE) is a rare cause of encephalitis presenting as an acute and subacute onset of neuropsychiatric manifestations, particularly with memory deficits and confusion as core features, along with seizure occurrence, movement disorders, or autonomic dysfunctions. LE is caused by neuronal antibodies targeting the cellular surface, synaptic, and intracellular antigens, which alter the synaptic transmission, especially in the limbic area. Immunologic mechanisms involve antibodies, complements, or T-cell-mediated immune responses in different degree according to different autoantibodies. Sensitive cerebrospinal fluid markers of LE are unavailable, and radiographic findings may not reveal a typical mesiotemporal involvement at neurologic presentations; therefore, a high clinical index of suspicions is pivotal, and a neuronal antibody testing is necessary to make early diagnosis. Some patients have concomitant tumors, causing paraneoplastic LE; therefore, tumor survey and treatment are required in addition to immunotherapy. In this study, a review on the molecular and immunologic aspects of LE was conducted to gain awareness of its peculiarity, which we found quite different from our knowledge on traditional psychiatric illness.

Case of anti-Hu antibody-mediated encephalopathy associated with ovarian cancer.

The present report describes a case of anti-Hu antibody-mediated encephalopathy associated with ovarian cancer. The patient developed paraneoplastic neurologic syndromes (PNS) during the course of ovarian cancer and showed a symptom of jargon aphasia; diagnosis of PNS was made on the basis of serological and cerebrospinal examination, electroencephalogram (EEG), and magnetic resonance images. EEG initially indicated a condition of non-convulsive status epilepticus; however, levetiracetam administration facilitated complete recovery of this condition. Furthermore, immunotherapy and steroid therapy were very effective and significant improvement was achieved. PNS usually occur before the cancer is identified; however, the possibility of PNS should be considered when neurologic symptoms are noted during the course of oncologic diseases, including ovarian cancer.

Paraneoplastic neurologic syndrome as a presentation of underlying breast malignancy.

While breast cancer most commonly presents as a screen-detected mammographic finding or a breast symptom, in very rare instances it may first present as a paraneoplastic neurologic syndrome (PNS; Surg Case Rep, 2015;1:59; Ann Neurol 2004;56:715). Fewer than 1% of breast cancer patients have PNS, and an even smaller percentage initially present with neurologic symptoms (J Neurol Neurosurg Psychiatry, 2004;75:ii43). We report a case series of three patients who presented with neurological disorders suspicious for PNS, and were subsequently found to have underlying breast cancer. We follow this with a discussion of key clinical features of management considerations in paraneoplastic syndromes secondary to breast malignancy.

Extra-Limbic Seronegative Encephalitis Preceding Recurrent Hodgkin's Lymphoma and Gastric Diffuse Large B-Cell Lymphoma: A Case Report.

We describe a patient with extra-limbic seronegative encephalitis with relapsing progressive course as the harbinger of sequential Hodgkin's lymphoma and Diffuse Large B-Cell lymphoma. Diagnosis of probable paraneoplastic neurologic syndrome (PNS) was arrived at by exhaustive elimination of alternative causes and supportive tissue diagnosis. This case highlights the phenotypic variety of paraneoplastic neurologic syndromes associated with hematologic malignancies and the challenges in their recognition, diagnosis, and treatment. We discuss and apply the updated consensus diagnostic criteria for paraneoplastic syndromes to our case as a means of bolstering probability in cases of diagnostic uncertainty.

Complexities in the Diagnosis and Management of Anti-Hu Antibody-Associated Paraneoplastic Syndrome.

Anti-Hu is the most commonly associated antibody in paraneoplastic syndromes (PNS) - mainly secondary to small cell lung cancer (SCLC), breast cancer, thymoma, and lymphoma. This case is about a 65-year-old female patient presenting with slurred speech, headache, and loss of balance for one day. On examination, she was found to have downbeat and bilateral gaze-evoked nystagmus, dysarthria, and bilateral intention tremors. The rest of the neurological examination was unremarkable. Upon investigation, a CT scan showed a pre-sacral mass and a PET scan showed a lobulated soft tissue mesenteric mass at L5/S1, thought to possibly be a gastrointestinal stromal tumour, and mediastinal lymph nodes including right lower pre-tracheal, subcarinal and right hilar lymph nodes. Additionally, paraneoplastic antibody testing was positive for anti-Hu antibodies. She was given a five-day course of intravenous immunoglobulin without significant clinical improvement. The patient was discharged on a fast-track pathway and did not undergo chemotherapy, radiotherapy or surgical resection as the primary tumour could not be diagnosed.  Paraneoplastic antibodies are a family of autoantibodies occurring as a result of malignancy that act to recognize antigens in the brain, resulting in a variety of neurological manifestations. Despite well-known literature on this entity, PNS is notoriously difficult to diagnose and manage. The first step in the management of PNS is to treat the underlying malignancy. Beyond this, the other key component of PNS treatment is immune modulation which may involve immunosuppression with high-dose corticosteroids, IV immunoglobulins, plasma exchange or plasmapheresis. It is therefore important for PNS to be diagnosed early and to adopt a comprehensive multidisciplinary approach to improve the outcomes of those presenting with PNS.

Case report: PCA-2-associated encephalitis with different clinical phenotypes: a two-case series and literature review.

Purkinje cell cytoplasmic antibody type 2 (PCA-2), identified in 2000, targets the widely distributed microtubule-associated protein 1B in the central and peripheral nervous systems, leading to diverse clinical phenotypes of neurological disorders. We report two cases of PCA-2-associated encephalitis, each presenting with distinct onset forms and clinical manifestations, thereby illustrating the phenotypic variability of PCA-2-related diseases. The first patient was diagnosed with PCA-2-associated autoimmune cerebellitis and undifferentiated small cell carcinoma with metastasis in mediastinal lymph nodes of unknown primary origin. The second patient was diagnosed with PCA-2-associated limbic encephalitis. Our findings underscore the superior sensitivity of positron emission tomography-computed tomography over brain magnetic resonance imaging in the early detection of PCA-2-associated encephalitis. Given the high risk of relapse and suboptimal response to traditional immunotherapy in PCA-2-related neurological disorders, this study highlights the need for a deeper understanding of their pathogenesis to develop more effective treatments to control symptoms and improve patient prognosis.

Clinical and serological insights into paraneoplastic brachial amyotrophic diplegia.

BACKGROUND: Brachial amyotrophic diplegia (BAD) is typically linked to a neurodegenerative etiology such as amyotrophic lateral sclerosis (ALS). Clinical and serological characterizations of paraneoplastic neurologic syndromes resembling BAD are limited. METHODS: A retrospective chart review of patients with BAD-like presentations was conducted. Clinical/paraclinical features of paraneoplastic BAD and neurodegenerative BAD cases were compared. RESULTS: Between 2017 and 2023, 13 cases of BAD were identified, of these 10 were neurodegenerative BAD (ALS variant), and 3 cases associated with paraneoplastic autoimmunity. An additional paraneoplastic BAD case diagnosed in 2005 was included. LUZP4-IgG was detected in all four paraneoplastic cases, with coexisting KLHL11-IgG in three cases and ANNA1 (anti-Hu)-IgG in one case. Out of the four paraneoplastic cases, two patients had seminoma, while the remaining two had limited cancer investigation. Three patients exhibited bi-brachial weakness as the initial symptom before the onset of brainstem symptoms or seizures. Compared to BAD patients with a neurodegenerative etiology, a higher proportion of paraneoplastic cases had ataxia (75% vs 0%, p = 0.011). Other clinical features only detected in the paraneoplastic BAD group were vertigo (n = 2), hearing loss (n = 2) and ophthalmoplegia (n = 2). Electrodiagnostic studies in these patients revealed cervical myotome involvement, supportive of motor neuronopathy. All paraneoplastic cases but none of the neurodegenerative BAD cases exhibited inflammatory cerebrospinal fluid (CSF) findings (lymphocytic pleocytosis and/or supernumerary oligoclonal bands; p = 0.067). Despite the administration of immunotherapy and/or cancer treatment, none of the paraneoplastic patients reported clinical improvement. DISCUSSION: BAD or bi-brachial neurogenic weakness is a rare phenotypic presentation associated with paraneoplastic autoimmunity. Co-existing features of brainstem dysfunction or cerebellar ataxia should prompt further paraneoplastic evaluation. Common serological and cancer associations among these cases include LUZP4-IgG and KLHL11-IgG, along with testicular germ cell tumors, respectively.

Diagnosis and Treatment of Paraneoplastic Neurologic Syndromes.

Paraneoplastic antibody syndromes result from the anti-tumor antibody response against normal antigens ectopically expressed by tumor cells. Although this antibody response plays an important role in helping clear a nascent or established tumor, the engagement of antigens expressed in healthy tissues can lead to complex clinical syndromes with challenging diagnosis and management. The majority of known paraneoplastic antibody syndromes have been found to affect the central and peripheral nervous system. The present review provides an update on the pathophysiology of paraneoplastic neurologic syndromes, as well as recommendations for their diagnosis and treatment.

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.

A Case of Primary Lung Adenocarcinoma With Two Uncommon Presentations: Neurological Paraneoplastic Syndrome and Pericardial Effusion.

Lung cancer is the second most common cancer worldwide and remains the first cause of cancer death. The diagnosis of lung cancer is mostly made following evaluation for respiratory signs and symptoms but sometimes the first presentation may be atypical. Some symptoms may be related to the invasion of adjacent structures and others caused by an autoimmune-mediated process when cross-reactivity between tumor antigens and normal nervous tissues is responsible for paraneoplastic syndromes. We present a case of a young woman with a smoking history who first manifested with two uncommon presentations of lung cancer: a paraneoplastic neurological syndrome and a hemorrhagic pericardial effusion with cardiac tamponade.

Clinical Impact of Pre-Existing Autoantibodies in Patients With SCLC Treated With Immune Checkpoint Inhibitor: A Multicenter Prospective Observational Study.

Introduction: Although pretreatment autoantibodies have been associated with immune-related adverse events (irAEs) and immune checkpoint inhibitor treatment efficacy in some types of cancer, their importance has not been evaluated in patients with SCLC. Methods: A multicenter prospective observational study was conducted on a total of 52 patients with extensive-disease SCLC who received immune checkpoint inhibitors in combination with chemotherapy as the first-line treatment at either of the six participating centers in Japan. Pretreatment serum samples were collected and analyzed for autoantibodies (rheumatoid factor, antinuclear antibodies, and antithyroid). Moreover, 12 antineuronal antibodies (AMPH, CV2, PNMA2, Ri, Yo, Hu, Recoverin, SOX1, Titin, Zic4, GAD65, and Tr) were analyzed using immunoblot assays. The primary end point was the incidence of irAEs with or without autoantibodies. The secondary end points were progression-free survival (PFS) and overall survival (OS) on the basis of the presence or absence of autoantibodies. Results: PFS and OS were 4.4 and 25.3 months, respectively. Autoantibodies (rheumatoid factor, antinuclear antibodies, and antithyroid antibodies) were detected in 29 patients (56%). In total, irAEs were observed in 18 patients (35%); irAE incidence was 48% in the autoantibody-positive group and 17% in the autoantibody-negative group (p = 0.039). There was no difference in PFS or OS between patients with and without autoantibodies (4.4 mo versus 4.6 mo, p = 0.36; 15.3 mo versus 18.2 mo, p = 0.36). Antineuronal antibodies were detected in 16 patients (31%). However, the development of neurologic irAEs was not observed in both groups. Conclusions: Vigilance is required against the development of irAEs in pretreatment antibody-positive patients.

A not so incidental 'incidentaloma' - pediatric ganglioneuroma-associated cerebellar degeneration and super-refractory status epilepticus: case report and literature review.

Paraneoplastic neurological disorders are rare in children, with paraneoplastic cerebellar degeneration (PCD) considered highly atypical. We describe a 13-year-old girl with progressive neurobehavioral regression, cerebellar ataxia, and intractable epilepsy presenting in super-refractory status epilepticus. After an extensive evaluation, her clinical picture was suggestive of probable autoimmune encephalitis (AE). Further diagnostic testing revealed a molecularly undefined neural-restricted autoantibody in both serum and CSF, raising suspicion over an adrenal mass previously considered incidental. Surgical resection led to a robust clinical improvement, and pathology revealed a benign ganglioneuroma. This report widens the spectrum of paraneoplastic manifestations of ganglioneuroma, reviews the diagnostic approach to antibody-negative pediatric AE, and raises important clinical considerations regarding benign and incidentally found tumors in the setting of a suspected paraneoplastic neurologic syndrome.

Successful Treatment of Paraneoplastic Neuropathy and Pruritis With Scrambler Therapy: A Case Report.

Paraneoplastic neuropathy, including pruritis, remains a vexing problem as it often does not resolve even with successful treatment of cancer. Scrambler Therapy is a superficial form of neuromodulation that replaces the pain signal with "non-pain information" that is approved for chronic and neuropathic pain, with few side effects. We report here two cases of paraneoplastic neuropathy, one with additional pruritis, that both responded satisfactorily to Scrambler Therapy with no side effects.

Evaluation of the Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes in China.

Background: Recently, the paraneoplastic neurologic syndrome (PNS) diagnostic criteria have received a major update with a new score system over the past 16 years. We aimed to evaluate the diagnostic performance and clinical utility in China. Methods: An eligible cohort of 113 Chinese patients diagnosed with PNSs from the Second Affiliated Hospital School of Medicine Zhejiang University and published data were enrolled retrospectively. Data including clinical phenotype, antibody type, the presence of cancer, and duration of follow-up were reviewed and re-evaluated to classify the diagnostic levels for the 2004 and 2021 PNS criteria. The performances of these 2 criteria were compared. The critical parameters of antibody and cancer for the updated criteria were further explored. Results: The cohort consisted of 69 males and 44 females with a median age of 60 years. Limbic encephalitis (23, 20.4%), anti-Hu antibody (32, 28.3%), and small-cell lung cancer (32, 28.3%) were the most common clinical phenotype, detected antibody, and concomitant cancer, respectively. A total of 97 (85.8%) patients were diagnosed with definite PNS according to the 2004 criteria: only 42.3% (41/97) fulfilled the 2021 criteria, while the remaining 40, 14, and 2 re-diagnosed with probable PNS, possible PNS, and non-PNS. The requirement of cancers consistent with antibody and phenotype increased the specificity and thus greatly enhanced the accuracy of the 2021 criteria. Conclusion: The updated criteria for PNS emphasized the consistency between cancer phenotype and antibody and showed a better diagnostic value. A better diagnostic yield could benefit disease management.

A Case of a Splitting Headache: Paraneoplastic Rhombencephalitis.

Paraneoplastic neurologic syndromes are a set of rare neurological conditions with a wide variety of presentations, ranging from headache to gait imbalance. These conditions are often underreported and underdiagnosed. Paraneoplastic rhombencephalitis is a subtype that involves inflammation of the hindbrain. This case involves a 67-year-old female with metastatic small-cell lung cancer who acutely developed neurological symptoms with magnetic resonance imaging findings consistent with rhombencephalitis. Our case discusses the updated diagnostic criteria for paraneoplastic neurologic syndrome released in July 2021 compared with the prior criteria in 2004. In addition, it illustrates the importance of increasing awareness of this condition for early diagnosis and prompt treatment, which can potentially influence morbidity outcomes.

CV2/CRMP5-antibody-related Paraneoplastic Neurologic Syndrome Associated with Gastrointestinal Stromal Tumor.

Paraneoplastic neurological syndrome (PNS) is a heterogeneous group of neurological disorders caused by immune-mediated inflammatory mechanisms. We herein report a 77-year-old man with CV2/CRMP5-antibody-related PNS associated with a gastrointestinal stromal tumor (GIST). He was admitted for forgetfulness and delusional behavior. His neurological symptoms were subacute, and a whole-body examination revealed a gastric GIST. Serology showed CV2/collapsin response mediator protein (CRMP)-5 antibodies. Partial gastrectomy was performed for the GIST, and the neurological symptoms and serum CV2/CRMP5 antibodies disappeared. No relapse has occurred since the surgery. PNS should be considered in patients with subacute neurological disorders.

Anti-Ri-Associated Paraneoplastic Neurological Syndrome Revealing Breast Cancer: A Case Report.

Neurological paraneoplastic syndromes are a rare entity that affects patients with cancer. Anti-Ri antibodies affect the brain stem and produce a heterogeneous rapidly progressive subacute syndrome depending on the involvement of the different regions concerned. The most common clinical presentation is opsoclonus-myoclonus syndrome and paraneoplastic cerebellar degeneration. Here we report a case of a 60-year-old woman with a subacute static-kinetic cerebellar syndrome, cervical dystonia, and multiple cranial nerve palsies revealing a mammary adenocarcinoma. Anti-Ri antibodies were positive in her blood. Our observation underscored the importance of the identification of the tumor for early treatment management to avoid irreversible neurological manifestations.