Paraneoplastic Neurological Syndromes Research Articles

Utility of the 2021 paraneoplastic neurologic syndromes diagnostic criteria

Utility of the 2021 paraneoplastic neurologic syndromes diagnostic criteria

Epidemiological analysis of paraneoplastic neurological syndromes and autoimmune encephalitides in Vilnius County, Lithuania

Epidemiological analysis of paraneoplastic neurological syndromes and autoimmune encephalitides in Vilnius County, Lithuania

NCMP-21. AQP4-MOG DOUBLE-POSITIVE PARANEOPLASTIC NEUROLOGICAL SYNDROME IN A PATIENT WITH TRIPLE NEGATIVE BREAST CANCER

Abstract We report a rare case of paraneoplastic neurological syndrome (PNS) with dual seropositivity of anti-aquaporin-4 (AQP-4) and myelin oligodendrocyte glycoprotein (MOG) antibodies in a 40 year-old lady with metastatic triple negative breast cancer with involvement of mediastinal, right axillary, and supraclavicular lymph nodes. She received multiple lines of anti-neoplastic treatment including immunotherapy with pembrolizumab as well as chemotherapy with taxol, carboplatin, gemcitabine, capecitabine, cytoxan, sacituzumab and nevalbine. Paraneoplastic meningoencephalomyelitis developed 2 years after diagnosis of breast cancer and 1 year after discontinuation of immunotherapy with pembrolizumab. She first developed longitudinally extending transverse myelitis extending from T11-12 that symptomatically improved with high dose intravenous methylprednisolone. One month later she developed left optic neuritis and meningoencephalitis with new enhancing lesions in the brain and spinal leptomeninges. Cerebrospinal fluid (CSF) analysis during both episodes revealed normal glucose, protein, elevated white blood cell count. Cytology was negative for malignancy. CSF was positive for neuromyelitis optica (NMO) IgG antibody APQ-4 and autoimmune myelopathy panel was positive for MOG antibody. Patient had significant clinical and radiographic improvement after completion of plasmapheresis and intravenous immunoglobulin. There was resolution of pleocytosis on repeat CSF testing. She did not have recurrence of paraneoplastic syndrome with maintenance rituximab every six months and daily low dose prednisone. She succumbed to progressive systemic metastatic disease 4.5 years after her breast cancer diagnosis. This case demonstrates that these antibodies can occur concurrently and cause clinical features like both neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) in a patient with a singular type of cancer. We highlight the importance of testing for paraneoplastic etiology in cancer patients with radiographic menigoencephalomyelitis or meningitis with atypical symptoms of meningeal carcinomatosis and/or CSF profile negative for leptomeningeal carcinomatosis.

Быстропрогрессирующий мозжечковый синдром как проявление паранеопластического поражения головного мозга. Клиническое наблюдение

Introduction. Rapidly progressive cerebellar syndrome (RPCS), previously referred to as “subacute cerebellar degeneration” or “paraneoplastic cerebellar degeneration”, is an autoimmune disorder, wich in the most cases is associated with a malignancy located outside the nervous system. RPCS is classified as one of the the paraneoplastic neurological syndromes and manifests in the early, often preclinical stages of oncopathology. Its diagnosis is difficult, but is necessary, since it can become a starting point for further screening for cancer. The article provides a clinical description of a 40-year-old patient with subacute development of hemiataxia and subsequent rapid progression of bilateral cerebellar deficiency associated with brainstem signs. The example of this case shows how difficult the diagnostic path is, since only the use of positron emission tomography and subsequent examination of a biopsy of the lesion in this patient made it possible to identify metastasis of poorly differentiated breast carcinoma in the axillary lymph node. The tumor itself was not found in the mammary gland. Since paraneoplastic antibodies were not detected in the patient’s blood and cerebrospinal fluid, a diagnosis of “probable” (not “definite”) RPCS was diagnosed in accordance with the diagnostic criteria proposed by the panel of experts in 2021. The treatment of cancer stopped progression of neurological deficit in the patient, but she remained severely disabled. Discussion. The approaches to the examination of patients with RPCS are discussed. Clinical assessment, neuronal antibodies testing and a targeted screening for cancer should be performed. Brief information is provided on the use of the PNS-Care scale in the diagnosis of paraneoplastic neurological syndromes. Conclusion. The presented case demonstrates the difficulties of diagnosing the RPCS and the associated cancer. The “definite” diagnosis of rapidly progressive cerebellar syndrome requires the presence of high or moderate risk antibodies and cancer that is consistent with the syndrome’s phenotype.

Aquaporin-4-IgG positive neuromyelitis optica spectrum disorder in a paraneoplastic context

ObjectiveThe association between aquaporin-4-immunoglobulin-G-positive neuromyelitis optica spectrum disorder (AQP4-IgG-NMOSD) and cancer via a plausible immunological response has been reported. Here, we investigated the frequency of cancer in a large cohort of patients with AQP4-IgG-NMOSD. MethodsBetween May 2005 and January 2023, patients with AQP4-IgG-NMOSD and a history of cancer were included by searching for diagnostic codes of both NMOSD and cancer in the electronic medical records and/or reviewing the database of the National Cancer Center registry of inflammatory diseases of the central nervous system. Probable paraneoplastic AQP4-IgG-NMOSD was defined according to the 2021 Criteria for Paraneoplastic Neurological Syndrome. ResultsOf 371 patients with AQP4-IgG-NMOSD, 23 (6.2%) had a history of cancer and four (1.1%) experienced NMOSD in a paraneoplastic context. Among the four patients with probable paraneoplastic AQP4-IgG-NMOSD, the types of cancer were lung (1 adenocarcinoma, 1 squamous cell carcinoma) and colorectal (2 adenocarcinomas). In three patients, the first NMOSD symptoms developed after a cancer diagnosis (median, 8 months [range, 4–23]), and one patient's symptoms preceded the cancer diagnosis (6 months). Compared to the 367 non-paraneoplastic patients, those in the paraneoplastic context had an older age at onset (median: 59.5 vs. 37 years, p = 0.012) and a higher proportion of longitudinally extensive transverse myelitis (LETM) as an initial manifestation (4/4[100%] vs. 130/367[35.4%], p = 0.017). ConclusionsIn a large cohort of patients with AQP4-IgG-NMOSD, the frequency of cancer was low. Older age, LETM features at onset, and adenocarcinoma as the histological type were usually observed in patients with AQP4-IgG-NMOSD in a paraneoplastic context.

Anti-Ma2 Antibody-Mediated Paraneoplastic Cerebellar Degeneration and Myeloneuropathy Secondary to Lymphoma.

A 61-year-old woman with a history of untreated low-grade B-cell lymphoma presented with blurry vision, unsteadiness, and worsening pain on touching skin of the upper trunk was enrolled. Blurry vision was attributed to oscillopsia from downbeat nystagmus, which later evolved into macrosaccadic oscillations. MRI brain and spine showed mild, longitudinally extensive T2 hyperintensity in the central gray matter of the spinal cord extending from the medulla to T11 level. Serum paraneoplastic panel was negative; however, she had very high titers of anti-Ma2 antibodies in cerebrospinal fluid. The diagnosis of paraneoplastic neurological syndrome was made. Empiric treatment with high dose of intravenous steroids followed by intravenous immunoglobulin infusions did not improve her symptoms. An extensive search for an underlying tumor commenced and was initially unrevealing. However, two-month follow-up positron emission tomography scan showed increased uptake in a right pulmonary nodule, which when biopsied confirmed diagnosis of extranodal marginal zone lymphoma. The final diagnosis was anti-Ma2 antibody-mediated paraneoplastic cerebellar degeneration and myeloneuropathy secondary to lymphoma.

When we Fight a Winnable Battle in an Unwinnable War? The Story of a Cancer - A Case Report

Introduction: Breast cancer is the most frequent malignancy in women and is curable in ~70-80% of patients with early-stage detection and without complication. Paraneoplastic neurologic syndrome of breast cancer is one such complication which is often hard to diagnose, severely debilitating, and also challenging to treat. Materials and Methods: A 57-year- old woman with no known co-morbidity presented with sudden onset altered sensorium. She was in status epilepticus when brought to emergency and progressed to super refractory status epilepticus in-spite of our efforts. MRI of the brain with contrast done revealed hyper intense signal in bilateral frontal, parietal, occipital, bilateral thalami, periaqueductal region and dorsal midbrain. Cerebrospinal fluid (CSF) study revealed only increased protein. The comprehensive infective panel of CSF was negative. The vasculitis marker, anti NMO and anti MOG antibody were absent. So, we suspected a possibility of autoimmune aetiology and started methylprednisolone along with intravenous immunoglobulin. Results: Her epileptic discharges settled in an electroencephalogram, and we weaned her off ventilation. We detected a right breast mass on clinical examination. The PET CT scan revealed metastasis in the liver, bones, right axillary lymph nodes, and bone marrow. Conclusion: Our patient, who had the first-time presentation, was diagnosed to have paraneoplastic encephalopathy in the background of breast cancer. The importance of proper clinical examination and whole-body PET CT scan, followed by a trial of immunomodulator therapy, is necessary in all patients with non-infective encephalitis.

828P Clinical features and outcomes of neurologic paraneoplastic syndromes in Hodgkin lymphoma

828P Clinical features and outcomes of neurologic paraneoplastic syndromes in Hodgkin lymphoma

B-076 Comparison of Three Methods for the Detection of Antibodies Against Muscle-Specific Kinase

Abstract Background Myasthenia gravis (MG) is a neuromuscular disease characterized by skeletal muscle weakness and fatigue. These symptoms are due to a reduction in synaptic signal transduction caused by autoantibodies against post-synaptic proteins in the neuromuscular junction. Approximately 85% of patients with MG have autoantibodies against acetylcholine receptors (AChR); however, autoantibodies against muscle specific kinase (MuSK) and low-density lipoprotein receptor-related protein 4 (LRP4) may also be found in patients with MG. Detection and identification of these antibodies is important in the diagnosis and treatment of patients under evaluation for MG. MuSK, a transmembrane protein expressed on skeletal muscles, is essential to the formation and maintenance of the neuromuscular junction. Approximately 6% of MG patients have MuSK autoantibodies. Traditionally, radioimmunoprecipitation assays (RIA) have been used to detect MuSK antibodies in patient sera. However, RIA has several limitations, including safety and regulatory concerns associated with using radioactive materials and the short half-life of reagents. Alternatives to RIA, such as enzyme-linked immunosorbent assays (ELISA) and cell-based assays (CBA), do not have the same challenges. Recent studies outside of the USA suggest that cell-based assays may have equal or superior sensitivity than RIA; particularly in the detection of MuSK antibodies in patients previously diagnosed with seronegative MG (MG patients without detectable AChR or MuSK antibodies by RIA). The objective of this study was to compare the performance of two commercially available ELISA and fixed cell-based assay (f-CBA) kits to RIA for the detection of MuSK antibodies. Methods A total of 237 sera were evaluated by RIA, ELISA and/or f-CBA. These sera include 47 MuSK RIA positive sera, 55 MuSK RIA negative sera, 70 self-reported healthy control sera, and 65 sera positive for other neural antibodies associated with MG, Lambert-Eaton Myasthenic Syndrome, paraneoplastic neurologic syndromes, or autoimmune encephalitis. Results Both f-CBA and ELISA demonstrated 100% specificity for MuSK antibodies in sera from self-reported healthy controls and sera from patients positive for other antibodies. Forty-seven sera tested positive for anti-MuSK antibodies by RIA; of those 47 sera, 7 sera tested negative by ELISA and 5 tested negative by f-CBA kits while the remaining 40 were concordant between ELISA, f-CBA and RIA. The discrepancy between RIA and the commercial kits for ELISA and f-CBA was only observed in low positive sera (0.04–0.21 nmol/L ARUP RIA). Clinical information was not available for discrepant specimens. However, a review of MuSK RIA results for University of Utah patients shows that of 7 patients with an ARUP RIA result of 0.04–0.21 nmol/L, only 1 had symptoms that may possibly be consistent with MG. The remaining 6 low positive patients did not have symptoms consistent with a diagnosis of MG. This may suggest an issue with RIA specificity rather than ELISA and f-CBA sensitivity. However, further studies are needed to confirm this. Conclusion Commercially available ELISA and f-CBA kits offer viable alternatives to traditional RIA for detection of MuSK antibodies.

Different Genetic Signatures of Small-Cell Lung Cancer Characterize Anti-GABAB R and Anti-Hu Paraneoplastic Neurological Syndromes.

Small-cell lung cancer (SCLC) is the malignancy most frequently associated with paraneoplastic neurological syndromes (PNS) and can trigger different antibody responses against intracellular (Hu) or neuronal surface (GABAB R) antigens. Our aim was to clarify whether the genomic and transcriptomic features of SCLC are different in patients with anti-GABAB R or anti-Hu PNS compared with SCLC without PNS. A total of 76 SCLC tumor samples were collected: 34 anti-Hu, 14 anti-GABAB R, and 28 SCLC without PNS. The study consisted of 4 steps: (1) pathological confirmation; (2) next generation sequencing using a panel of 98 genes, including those encoding the autoantibodies targets ELAVL1-4, GABBR1-2, and KCTD16; (3) genome-wide copy number variation (CNV); and (4) whole-transcriptome RNA sequencing. CNV analysis revealed that patients with anti-GABAB R PNS commonly have a gain in chromosome 5q, which contains KCTD16, whereas anti-Hu and control patients often harbor a loss. No significantly different number of mutations regarding any onconeural genes was observed. Conversely, the transcriptomic profile of SCLC was different, and the differentially expressed genes allowed effective clustering of the samples into 3 groups, reflecting the antibody-based classification, with an overexpression of KCTD16 specific to anti-GABAB R PNS. Pathway analysis revealed that tumors of patients with anti-GABAB R encephalitis were enriched in B-cell signatures, as opposed to those of patients with anti-Hu, in which T-cell- and interferon-γ-related signatures were overexpressed. SCLC genetic and transcriptomic features differentiate anti-GABAB R, anti-Hu, and non-PNS tumors. The role of KCTD16 appears to be pivotal in the tumor immune tolerance breakdown of anti-GABAB R PNS. ANN NEUROL 2023;94:1102-1115.

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

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. 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. 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. 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.

Anti-aquaporin-4 immunoglobulin G/anti-myelin oligodendrocyte glycoprotein immunoglobulin G double-positive paraneoplastic neurological syndrome in a patient with triple-negative breast cancer.

We report a rare case of paraneoplastic neurological syndrome with dual seropositivity of anti-aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies in a 40 year-old woman with metastatic triple-negative breast cancer. She received multiple lines of anti-neoplastic treatment, including immunotherapy with pembrolizumab, as well as cytotoxic chemotherapy. Paraneoplastic meningoencephalomyelitis developed 2 years after diagnosis of breast cancer and 1 year after discontinuation of immunotherapy with pembrolizumab. She first developed longitudinally extending transverse myelitis followed by left optic neuritis and meningoencephalitis with new enhancing lesions in the brain and spinal leptomeninges. Cerebrospinal fluid analysis during both episodes showed normal glucose and protein, and elevated white blood cell count. Cytology was negative for malignancy. Cerebrospinal fluid was positive for neuromyelitis optica immunoglobulin G antibody anti-aquaporin-4, and autoimmune myelopathy panel was positive for myelin oligodendrocyte glycoprotein antibody. The patient had significant clinical and radiographic improvement after completion of five cycles of plasmapheresis followed by intravenous immunoglobulin. She did not have recurrence of paraneoplastic syndrome with maintenance rituximab every 6 months and daily low-dose prednisone. She succumbed to progressive systemic metastatic disease 4.5 years after her breast cancer diagnosis. This case shows that these antibodies can occur concurrently and cause clinical features, such as both neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody disease, in a patient with a singular type of cancer. We highlight the importance of testing for paraneoplastic etiology in cancer patients with radiographic menigoencephalomyelitis or meningitis with atypical symptoms of meningeal carcinomatosis and/or cerebrospinal fluid profile negative for leptomeningeal carcinomatosis.

Revisiting anti-Hu paraneoplastic autoimmunity: phenotypic characterization and cancer diagnosis.

Anti-Hu are the most frequent antibodies in paraneoplastic neurological syndromes, mainly associated with an often limited stage small cell lung cancer. The clinical presentation is pleomorphic, frequently multifocal. Although the predominant phenotypes are well characterized, how different neurological syndromes associate is unclear. Likewise, no specific study assessed the performance of new-generation CT and PET scanners for cancer screening in these patients. Herein, we aimed to describe the clinical pattern and cancer screening in a retrospective cohort of 466 patients with anti-Hu autoimmunity from the French Reference Centre on Paraneoplastic Neurological Syndromes registry. Clinical presentation, cancer screening and diagnosis were analysed. Among the 466 patients, 220 (54%) had multifocal neurological involvement. A hierarchical cluster analysis grouped the patients into (i) mainly limbic encephalitis, (ii) predominantly peripheral neuropathy and (iii) broad involvement of the nervous system (mixed group). Compared with limbic encephalitis and mixed groups, patients in the neuropathy group more frequently had a chronic onset of symptoms (29 versus 13 and 17%), elevated CSF proteins (83 versus 47 and 67%) and died from cancer progression (67 versus 15 and 28%; all P < 0.05). No significant difference in overall survival was observed between groups. Dysautonomia and brainstem signs were associated with a higher risk of death from the neurological cause; cancer diagnosis was the main predictor of all-cause death, especially when diagnosed within 2 years from clinical onset (all P < 0.05). Three hundred and forty-nine (75%) patients had cancer: in 295 (84%) neurological symptoms preceded tumour diagnosis, being lung cancer in 262 (89%), thereof small cell lung cancer in 227 (87%). First CT scan revealed lung cancer in 205/241 (85%), and PET scan shortened the interval to diagnosis when the initial CT scan was negative [7 months (1-66) in 27 patients versus 14 months (2-45) in 6; P < 0.001]. Although cancer diagnosis mostly occurred within 2 years from clinical onset, 13/295 (4%) patients exceeded that threshold. Conversely, 33 patients (7%) were 'cancer-free' after 2 years of follow-up. However, 13/33 (39%) had initial suspicious imaging findings that spontaneously regressed. In conclusion, although anti-Hu autoimmunity clinical presentation is mostly multifocal, we observed patients with a predominant limbic syndrome or isolated sensory neuropathy. Early implementation of PET scan shortens the interval to cancer diagnosis, which was the strongest predictor of death, especially if diagnosed ≤2 years from clinical onset. As cancer was diagnosed >2 years after clinical onset in few patients, screening should be extended up to 5 years. In addition, tumour regression was suspected in a substantial proportion of 'cancer-free' patients.

Paraneoplastic Neurologic Syndrome in Small Cell Lung Carcinoma

A 54-year-old male smoker, previously in good health, was admitted to the hospital due to a tingling sensation in his upper and lower extremities. He reported difficulty walking due to a loss of balance and numbness, leading to an initial diagnosis of chronic inflammatory demyelinating polyneuropathy. Brain and spine magnetic resonance imaging, along with needle electromyography, yielded inconclusive findings. However, a nerve conduction study indicated a length-dependent pattern of sensory-dominant polyneuropathy. A cerebrospinal fluid study did not reveal any specific findings in terms of cell numbers, proteins, or immune tests. Following hospitalization, the patient reported progressive dizziness upon standing, leading to a preliminary diagnosis of orthostatic hypotension. However, a positive anti-Hu autoantibody test, along with chest computed tomography and positron emission tomography scans, revealed a mass in the left interlobar lymph node, suggestive of lung cancer. An endoscopic biopsy confirmed the presence of small cell lung cancer (SCLC). The patient underwent chemo-radiation treatment for the SCLC and immunoglobulin therapy for sensory ganglionopathy. As a result, a definitive diagnosis of paraneoplastic neurologic syndrome was made. Although such cases are rare, our observations suggest that symptoms of dysautonomia and sensory ganglionopathy may be associated with the production of anti-Hu antibodies.

A case of severe paraneoplastic glutamic acid decarboxylase antibody‐spectrum disorder with improvement through prior immunotherapy before surgical intervention

AbstractBackgroundInitially associated with stiff‐person syndrome, antibodies to glutamic acid decarboxylase (GAD) antibodies are now recognized as indicators of GAD antibody‐spectrum disorders (GAD‐SD), which encompass cerebellar ataxia, autoimmune epilepsy and limbic encephalitis. Paraneoplastic neurological syndromes associated with GAD‐SD are rare, and optimal timing of surgical intervention and impact on neurological symptoms remain poorly understood.Case PresentationWe present the case of a 65‐year‐old woman who developed overlapping symptoms of cerebellar ataxia and stiff‐person syndrome detected through high‐titer GAD antibodies in both serum and cerebrospinal fluid, alongside the presence of a thymoma. Due to severe dysphagia and gait ataxia that rendered her bedridden on admission, surgical intervention was initially deferred. Instead, she received immunotherapies including intravenous methylprednisolone and intravenous immunoglobulin, which remarkably improved neurological symptoms. However, a decline in symptoms occurred on tapering oral prednisolone. Subsequently, a thoracoscopic thymectomy was carried out 27 months after symptom onset, leading to further neurological improvement and successful reduction of prednisolone.ConclusionIn paraneoplastic GAD‐SD cases with severe symptoms at presentation, prioritizing immunotherapy and considering surgical intervention once the symptoms have stabilized might be advantageous.

Paraneoplastic Syndromes Associated with Gynecologic Neoplasms: Experience from a Tertiary Care Center in South India.

Surabhi SudhakaranParaneoplastic syndromes associated with gynecologic neoplasms are rare and can involve various organ systems including the central nervous system, hematopoietic system, musculoskeletal, dermal and endocrine systems. They can result from cancer-associated immune reactions or the production of ectopic substances by the tumor tissue. This study retrospectively reviews the clinical presentations, management and outcome of patients who presented with paraneoplastic syndromes associated with gynecologic malignancies. Retrospective data were collected from medical records of patients who exhibited paraneoplastic symptoms associated with gynecologic neoplasms and were managed by department of gynecologic oncology at a tertiary care hospital in South India between 2014 and 2021. Medical case records of all eligible patients were reviewed, identifying eight women with gynecological neoplasms who presented with associated paraneoplastic symptoms. Among them, two cases pesented with paraneoplastic neurologic syndromes, four cases with paraneoplastic dermatologic syndromes, including three cases of dermatomyositis and one case with multicentric reticulohistiocytosis, and two cases with hypercalcemia. Paraneoplastic syndromes are rare manifestations that can precede or develop following the diagnosis of a malignancy. They require integrated management by a multidisciplinary team including physicians and oncologists. Early recognition of these symptoms and prompt evaluation have the potential to improve the prognosis and quality of life, at least in a small fraction of patients.

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.

Immune checkpoint inhibitors induced side effects of the peripheral nervous system.

This review highlights recent knowledge on the diagnosis and treatment of immune checkpoint inhibitor-induced neurological side effects (irNAE) focussing on the neuromuscular system. irNAEs mainly resemble sporadic neuromuscular autoimmune diseases and paraneoplastic neurological syndromes. However, neurological symptoms may be unspecific (muscle weakness, fatigue) in the oncological setting and carry the risk of misdiagnosis and delayed therapeutic intervention. The role of disease-specific neuromuscular autoantibodies in the diagnosis is controversial as preexisting autoantibodies may otherwise be present before immune checkpoint inhibitor (ICI) treatment without clinical symptoms and may not develop in case of irNAE manifestation. A new necrotising form of myositis (irMyositis) has been described presenting with facial weakness and ptosis mimicking myasthenia gravis. It comes along with a high rate of severe myocarditis accounting for a triad overlap syndrome (myasthenia/myositis/myocarditis). The role of modern biologicals in the treatment of irNAEs has to be determined. irNAEs are rare but carry the risk of permanent morbidity and mortality. Early suspicion and diagnosis are key to prevent neurological sequelae. Beyond interruption of ICI administration, treatment corresponds to sporadic autoimmune diseases. The myasthenia/myositis/myocarditis overlap syndrome deserves special attention as it carries the highest risk of mortality. The role of neurotoxic pretreatment regimens, preexisting subclinical neurological autoimmune diseases and the risk of ICI-re-challenge after irNAEs has to be further investigated.

Neuroendocrine carcinoma of the small intestine diagnosed as a result of paraneoplastic neurological syndrome.

Paraneoplastic neurological syndromes, a diverse group of neurological syndromes, are associated with small cell lung, testicular, ovarian, and breast cancers; however, their association with neuroendocrine carcinoma of the small intestine remains unreported. In this report, we present the case of a 78-year-old man diagnosed with neuroendocrine carcinoma of the small intestine and experienced symptoms such as subacute progressive numbness of the extremities and impaired gait. These symptoms were diagnosed as tumor-associated neurological syndrome. The patient had also undergone pyloric gastrectomy for early-stage gastric cancer several years prior to the appearance of the neurological symptoms. Therefore, we could not determine whether the tumor-related neurologic syndrome was owing to gastric cancer or neuroendocrine carcinoma of the small intestine; however, one of these conditions was the cause of the neuropathy. The gait disturbance and numbness relatively improved after surgery for the neuroendocrine carcinoma of the small intestine, suggesting that the neuroendocrine carcinoma of the small intestine likely caused the paraneoplastic neurological syndrome. Collectively, we present a unique report highlighting the putative relationship between small bowel neuroendocrine carcinoma and tumor-associated neurologic syndromes.

Seizure characteristics and outcomes in patients with neurological conditions related to high-risk paraneoplastic antibodies.

Seizures are a common manifestation of paraneoplastic neurologic syndromes. The objective of this study was to describe the seizure characteristics and outcomes in patients with high-risk paraneoplastic autoantibodies (>70% cancer association) and to determine factors associated with ongoing seizures. Patients from 2000 to 2020 with seizures and high-risk paraneoplastic autoantibodies were retrospectively identified. Factors associated with ongoing seizures at last follow-up were evaluated. Sixty patients were identified (34 males, median age at presentation = 52 years). ANNA1-IgG (Hu; n = 24, 39%), Ma2-IgG (n = 14, 23%), and CRMP5-IgG (CV2; n = 11, 18%) were the most common underlying antibodies. Seizures were the initial presenting symptom in 26 (43%), and malignancy was present in 38 (63%). Seizures persisted for >1 month in 83%, and 60% had ongoing seizures, with almost all patients (55/60, 92%) still being on antiseizure medications at last follow-up a median of 25 months after seizure onset. Ongoing seizures at last follow-up were associated with Ma2-IgG or ANNA1-IgG compared to other antibodies (p = .04), highest seizure frequency being at least daily (p = .0002), seizures on electroencephalogram (EEG; p = .03), and imaging evidence of limbic encephalitis (LE; p = .03). Death occurred in 48% throughout the course of follow-up, with a higher mortality in patients with LE than in those without LE (p = .04). Of 31 surviving patients at last follow-up, 55% continued to have intermittent seizures. Seizures in the setting of high-risk paraneoplastic antibodies are frequently resistant to treatment. Ongoing seizures are associated with ANNA1-IgG and Ma2-IgG, high seizure frequency, and EEG and imaging abnormalities. Although a subset of patients may respond to immunotherapy and achieve seizure freedom, poor outcomes are frequently encountered. Death was more common among patients with LE.