Paraneoplastic Neurological Syndromes Research Articles

Atypical presentation of anti-Ma2-associated encephalitis mimicking diencephalic demyelinating syndrome

Anti Ma 2 encephalitis is an autoimmune encephalitis, usually paraneoplastic, characterized by isolated or combined limbic, diencephalic, or brainstem dysfunction. It most commonly affects males with testicular or small cell lung cancer, though cases have been reported in females with gynecologic malignancies [1]. We describe an unusual presentation of a paraneoplastic neurologic syndrome presenting with predominant involvement of the hypothalamus and deep grey nuclei secondary to a testicular cancer associated with anti-Ma2 antibody.

Significant improvement in paraneoplastic neurological syndromes without identifiable anti-neural antibodies in patients with breast cancer after breast surgery

Significant improvement in paraneoplastic neurological syndromes without identifiable anti-neural antibodies in patients with breast cancer after breast surgery

Paraneoplastic Neurologic Syndromes Associated with Testicular Germ Cell Tumors: Clinical and Serological Characteristics (S38.005)

Paraneoplastic Neurologic Syndromes Associated with Testicular Germ Cell Tumors: Clinical and Serological Characteristics (S38.005)

Patients with Anti-Hu/ANNA1 Paraneoplastic Neurological Syndromes Develop Progressive Disability but Have Increased Survival Compared to SCLC Patients Without Paraneoplastic Syndromes (S38.008)

Patients with Anti-Hu/ANNA1 Paraneoplastic Neurological Syndromes Develop Progressive Disability but Have Increased Survival Compared to SCLC Patients Without Paraneoplastic Syndromes (S38.008)

Identification of SKOR2 IgG as a Novel Biomarker of Paraneoplastic Neurologic Syndrome (N1.001)

Identification of SKOR2 IgG as a Novel Biomarker of Paraneoplastic Neurologic Syndrome (N1.001)

A Case of MET Exon 14 Skipping Mutation: Positive Lung Adenocarcinoma Complicated by Paraneoplastic Neurological Syndrome

A Case of MET Exon 14 Skipping Mutation: Positive Lung Adenocarcinoma Complicated by Paraneoplastic Neurological Syndrome

HSR24-169: Autonomic Symptoms May Suggest Paraneoplastic Neurological Syndromes in Small Cell Lung Cancer.

HSR24-169: Autonomic Symptoms May Suggest Paraneoplastic Neurological Syndromes in Small Cell Lung Cancer.

[Neuropathology of Inflammatory and Autoimmune-Mediated Diseases].

Herein, the author summarize the basic findings on the neuropathology of inflammatory and autoimmune central nervous system (CNS) diseases. Current knowledge on infectious, demyelinating, and autoimmune diseases have also been reported. Further, I emphasize the importance of considering the neuropathology of meningitis, encephalitis, and abscesses as infectious diseases; multiple sclerosis and neuromyelitis optica as demyelinating diseases; and vasculitis, paraneoplastic neurological syndrome, and collagen diseases as autoimmune diseases.

Lung Cancer Wherein Durvalumab Induced Both Anti-CRMP-5 Antibody-related Paraneoplastic Neurological Syndromes and Neurological Adverse Events.

A 68-year-old man with small-cell lung cancer developed anti-collapsin response-mediator protein (CRMP)-5 antibody-related paraneoplastic neurological syndrome (PNS) presenting with ataxia and chorea during treatment with durvalumab. As a result of steroid therapy, anti-CRMP-5 antibodies became negative, hyperintense lesions on brain magnetic resonance imaging disappeared, and neurological symptoms improved. After resuming durvalumab, he became unable to walk due to neurological adverse events (nAEs). There have been no reported cases manifesting PNSs and nAEs as a result of the same immune checkpoint inhibitors (ICIs) administered at different times. Resuming ICIs in patients diagnosed with PNSs should be performed with prudence.

Interest of rare autoantibodies in autoimmune encephalitis and paraneoplastic neurological syndromes: the utility (or futility) of rare antibody discovery.

The increasing recognition and diagnosis of autoimmune encephalitis (AE) and paraneoplastic neurological syndromes (PNS) is partly due to neural autoantibody testing and discovery. The past two decades witnessed an exponential growth in the number of identified neural antibodies. This review aims to summarize recent rare antibody discoveries in the context of central nervous system (CNS) autoimmunity and evaluate the ongoing debate about their utility. In the last 5 years alone 15 novel neural autoantibody specificities were identified. These include rare neural antibody biomarkers of autoimmune encephalitis, cerebellar ataxia or other movement disorders, including multifocal presentations. Although the clinical applications of these rare antibody discoveries may be limited by the low number of positive cases, they still provide important diagnostic, prognostic, and therapeutic insights.

Neurological Paraneoplastic Syndromes in most Common Cancers in Poland

INTRODUCTION: Paraneoplastic Neurological Syndromes (PNS) represent a heterogeneous group of diseases associated with the presence of neoplasm. The appearance of PNS can precede cancer diagnosis. The estimated frequency amongst cancer patients is about 1%. Malignant tumors represent a serious health problem and are the second leading cause of death in Poland. The aim of this study is to collect information about PNS focusing on cancers mostly diagnosed in Polish adults. REVIEW METHODS: The analysis was conducted based on information regarding PNS gathered from PubMed and Google Scholar within the context of selected cancers. THE STATE OF KNOWLEDGE: PNS develop from an autoimmune reaction in which onconeural antibodies are produced. The recent classification divides PNS to high risk, indicating a likely paraneoplastic origin and intermediate risk, if this association is less evident. Diagnosis is difficult and usually relies on exclusion methods. The symptoms described are non-specific and the diagnostic process may require the involvement of various specialists. The main approaches include cancer treatment, especially tumor removal and immunotherapy, which in certain may prove to be effective. SUMMARY: Although PNS is relatively rare, its detectability has recently increased. Many syndromes are especially associated with lung cancer (mainly small cell carcinoma). Breast and prostate cancers have also shown associations with certain syndromes. They can present with nonspecific symptoms related to different organ systems. Awareness and understanding of this phenomenon can be helpful amongst many specialists.

Dysautonomia in anti-Hu paraneoplastic neurological syndromes.

Dysautonomia has been associated with paraneoplastic neurological syndrome (PNS)-related mortality in anti-Hu PNS, but its frequency and spectrum remain ill-defined. We describe anti-Hu patients with dysautonomia, estimate its frequency, and compare them to patients without dysautonomia. Patients with anti-Hu antibodies diagnosed in the study centre (1990-2022) were retrospectively reviewed; those with autonomic signs and symptoms were identified. Among 477 anti-Hu patients, 126 (26%) had dysautonomia (the only PNS manifestation in 7/126, 6%); gastrointestinal (82/126, 65%), cardiovascular (64/126, 51%), urogenital (24/126, 19%), pupillomotor/secretomotor (each, 11/126, 9%), and central hypoventilation (10/126, 8%). Patients with isolated CNS involvement less frequently had gastrointestinal dysautonomia than those with peripheral (alone or combined with CNS) involvement (7/23, 30% vs. 31/44, 70% vs. 37/52, 71%; P = 0.002); while more frequently central hypoventilation (7/23, 30% vs. 1/44, 2.3% vs. 2/52, 4%; P < 0.001) and/or cardiovascular alterations (18/23, 78% vs. 20/44, 45% vs. 26/52, 50%; P = 0.055). Median [95% CI] overall survival was not significantly different between patients with (37 [17; 91] months) or without dysautonomia (28 [22; 39] months; P = 0.78). Cardiovascular dysautonomia (HR: 1.57, 95% CI [1.05; 2.36]; P = 0.030) and central hypoventilation (HR: 3.51, 95% CI [1.54; 8.01]; P = 0.003) were associated with a higher risk of death, and secretomotor dysautonomia a lower risk (HR: 0.28, 95% CI [0.09; 0.89]; P = 0.032). Patients with cardiovascular dysautonomia dying ≤ 1year from clinical onset had severe CNS (21/27, 78%), frequently brainstem (13/27, 48%), involvement. Anti-Hu PNS dysautonomia is rarely isolated, frequently gastrointestinal, cardiovascular and urogenital. CNS dysfunction, particularly brainstem, associates with lethal cardiovascular alterations and central hypoventilation, while peripheral involvement preferentially associates with gastrointestinal or secretomotor dysautonomia, being the latest more indolent.

Genetic predisposition to autoimmune encephalitis and paraneoplastic neurological syndromes.

We summarize the recent discoveries on genetic predisposition to autoimmune encephalitis and paraneoplastic neurological syndromes (PNS), emphasizing clinical and pathophysiological implications. The human leukocyte antigen (HLA) is the most studied genetic factor in autoimmune encephalitis and PNS. The HLA haplotype 8.1, which is widely known to be related to systemic autoimmunity, has been only weakly associated with a few types of autoimmune encephalitis and PNS. However, the strongest and most specific associations have been reported in a subgroup of autoimmune encephalitis that comprises antileucine-rich glioma-inactivated 1 (LGI1) limbic encephalitis, associated with DRB1∗07 : 01, anticontactin-associated protein-like 2 (CASPR2) limbic encephalitis, associated with DRB1∗11 : 01, and anti-IgLON5 disease, associated with DRB1∗10 : 01∼DQA1∗01∼DQB1∗05. Non-HLA genes have been poorly investigated so far in autoimmune encephalitis, mainly in those lacking HLA associations such as anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, with only a few genome-wide association studies (GWAS) reporting equivocal results principally limited by small sample size. Genetic predisposition seems to be driven mostly by HLA in a group of autoimmune encephalitis characterized by being nonparaneoplastic and having predominantly IgG4 autoantibodies. The contribution of non-HLA genes, especially in those diseases lacking known or strong HLA associations, will require large cohorts enabling GWAS to be powerful enough to render meaningful results.

Central nervous system adverse events of immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICI) may trigger immune-related adverse events which rarely affect the central nervous system (CNS-irAEs). Over the past few years, cumulative data have led to the characterization of well defined syndromes with distinct cancer and antibody associations as well as different outcomes. The most frequent CNS-irAE is encephalitis, which includes three main groups: meningoencephalitis, a nonfocal syndrome usually responsive to corticosteroids; limbic encephalitis, associated with high-risk paraneoplastic neurological syndromes (PNS) antibodies (e.g. anti-Hu, anti-Ma2) and neuroendocrine cancers, characterized by poor treatment response and outcomes; and cerebellar ataxia, with variable outcomes (worse when high-risk PNS antibodies are detected). Additionally, a diffuse encephalopathy without inflammatory findings, with poor response to corticosteroids and high mortality has been described. The spectrum of CNS-irAEs also includes meningitis, myelitis, and rarer presentations. A subset of CNS-irAEs (i.e. limbic encephalitis and/or rapidly progressive cerebellar ataxia) is undistinguishable from ICI-naïve PNS. The clinical and outcomes diversity of CNS-irAEs suggests different pathogenic mechanisms, which need to be understood to establish more effective and specific treatment modalities. It is crucial to identify biomarkers able to predict which patients will experience severe CNS-irAEs, to anticipate their diagnosis, and to predict long-term outcomes.

Paraneoplastic neurological syndromes: upgraded approaches to diagnosis

Paraneoplastic neurological syndromes (PNNS) are neurological disorders due to autoimmune attack on the nervous system, induced by a tumor remote from these structures. The existence of relatively stable associations between the neurological syndrome, the type of antineuronal antibodies (Ab) and the nature of tumor has been proven. At the same time, there are no pathognomonic combinations of this kind: the same antibodies can be detected in diff erent types of tumors and in diff erent syndromes. In addition, level of reliability of the diagnosis of PNNS is considered, taking into account the phenotype of the neurological disorder, the presence of certain antibodies in the blood serum, the verifi cation of oncopathology and the duration of the observation for the patient.

Neurological autoimmunity in melanoma patients: a comparison between those exposed and non-exposed to immune checkpoint inhibitors.

The clinical spectrum of melanoma-associated neurological autoimmunity, whether melanoma-associated paraneoplastic neurological syndromes (PNS) or induced by immune checkpoint inhibitors (ICI), is not well characterized. We aim to describe the clinical spectrum of melanoma-associated neurological autoimmunity. A systematic review of the literature combined with patients from French databases of paraneoplastic neurological syndromes was conducted. All melanoma patients with a possible immune-mediated neurologic syndrome were included and classified according to whether they had previously been exposed to ICI (ICI-neurotoxicity) or not (ICI-naïve) at first neurological symptoms. Seventy ICI-naïve (literature: n = 61) and 241 ICI-neurotoxicity patients (literature: n = 180) were identified. Neuromuscular manifestations predominated in both groups, but peripheral neuropathies were more frequent in ICI-neurotoxicity patients (39.4% vs 21.4%, p = 0.005) whereas myositis was more frequent in ICI-naïve patients (42.9% vs 18.7%, p < 0.001). ICI-naïve patients had also more frequent central nervous system (CNS) involvement (35.7% vs 23.7%, p = 0.045), classical paraneoplastic syndrome (25.7% vs 5.8%, p < 0.001), and more frequently positive for anti-neuron antibodies (24/32, 75.0% vs 38/90, 42.2%, p = 0.001). Although more ICI-neurotoxicity patients died during the acute phase (22/202, 10.9% vs 1/51, 2.0%, p = 0.047), mostly myositis patients (14/22, 63.6%), mortality during follow-up was higher in ICI-naïve patients (58.5% vs 29.8%, p < 0.001). There was no significant difference in the frequency of life independence (mRS ≤ 2) in the surviving patients in both groups (95.5% vs 91.0%, p = 0.437). Melanoma-associated PNS appear remarkably rare. The clinical similarities observed in neurological autoimmunity between ICI-treated and ICI-naïve patients, characterized predominantly by demyelinating polyradiculoneuropathy and myositis, suggest a potential prior immunization against melanoma antigens contributing to ICI-related neurotoxicity.

Seroprevalence of neuronal antibodies in diseases mimicking autoimmune encephalitis

Detection of neuronal antibodies for autoimmune encephalitis and paraneoplastic neurological syndromes relies on commercially available cell-based assays and lineblots. However, lineblots may reveal the presence of neuronal antibodies in patients with various non-autoimmune etiologies. Herein we describe patients with non-autoimmune etiologies (cohort B) and detectable neuronal antibodies and compare them to definite cases of autoimmune encephalitis (cohort A) for differences in clinical data. All patients positive for at least one neuronal antibody were retrospectively evaluated for autoimmune encephalitis and/or paraneoplastic neurological syndrome between 2016 and 2022. 39 cases in cohort B and 23 in cohort A were identified. In cohort B, most common diagnoses were neurodegenerative disorders in 9/39 (23.1%), brain tumors in 6/39 (15.4%) while most common detected antibodies were anti–titin (N10), anti-recoverin (N11), anti-Yo (N8) and all were detected in serum only. Differential aspects between cohort A and B were CSF pleocytosis (14/23 (60.8%) vs 11/35 (31.4%), p = 0.042, respectively), MRI features suggestive of encephalitis (6/23 (26.1%) vs 0 (0%), p = 0.002, respectively) and epilepsy restricted to temporal lobes (14/23 (60.9%) vs 2/30 (6.7%), p = 0.0003, respectively). A large proportion of lineblot results were non-specific when only serum was tested and were frequently found in non-autoimmune neurological conditions.

Trismus as the Initial Presentation of Anti-Hu Paraneoplastic Neurological Syndrome

Trismus as the Initial Presentation of Anti-Hu Paraneoplastic Neurological Syndrome

New-onset seizures misdiagnosed as psychogenic non-epileptic seizures: a case of paraneoplastic limbic encephalitis with primary testicular cancer

BackgroundBehavioral psychiatric symptoms can be the only warning signs of more serious conditions such as paraneoplastic limbic encephalitis. Differentiating between primary psychiatric disorders and paraneoplastic neurological syndromes is crucial as they require distinct treatment approaches. In this case report, we provide an overview of paraneoplastic encephalitis and introduce a unique case that showcases a misdiagnosis of psychogenic non-epileptic seizures (PNES) in a male as the primary symptom of paraneoplastic encephalitis due to pure seminoma. This case highlights the underlying pathophysiology of antibody-mediated paraneoplastic encephalitis and its significance.Case presentationA 31-year-old male with no known past medical history presented due to recurrent seizures. There was no prior history of epilepsy or exposure to seizure-triggering agents. Imaging and electroencephalogram findings during his initial hospitalizations pointed to a potential diagnosis of PNES. The patient continued to experience seizures following discharge, leading to repeat hospitalizations. During the fourth hospitalization, the patient received mood-stabilizing anti-seizure medications and benzodiazepines, but he deteriorated and required intubation. It was during this time that the patient was transferred to our facility. Magnetic resonance imaging of the brain revealed multifocal areas of hyperintensity and restricted diffusion with avid enhancement. Immunotherapy was initiated with improvement of non-epileptic spells and encephalopathy. Outpatient workup uncovered malignant pure seminoma with metastases to the retroperitoneum. The authors theorize that paraneoplastic neurological disorders stemming from testicular cancer led to the neurological symptoms seen in this case.ConclusionThis report highlights a rare occurrence of paraneoplastic limbic encephalitis associated with pure testicular seminoma, clinically manifested as PNES. The diagnostic challenge posed by variability of presenting symptoms in paraneoplastic encephalitis emphasizes the importance of accurate differentiation from conditions such as autoimmune encephalitis. Current diagnostic approaches for paraneoplastic and autoimmune etiologies involve detection of known antibodies, as well as brain imaging. Notable antibodies associated with psychogenic non-epileptic seizures symptoms include anti-GAD-65, anti-Ma2, KLH11-antibodies, anti-Hu, and NMDA receptor antibodies. Recognizing paraneoplastic limbic encephalitis symptoms is challenging and often leads to misdiagnosis or overlooking of malignancies highlighting the need for awareness, comprehensive evaluation and timely treatment. Through this comprehensive case analysis, we enhance the understanding of underlying mechanisms, associated symptoms, and treatment options.

Paraneoplastic neurological syndrome associated with onconeural autoantibodies: report of two cases

Paraneoplastic neurological syndromes (PNS) are rare and often severe neurological complications of malignancies, significantly impacting patient prognosis and quality of life. They are characterized by a diverse range of onconeural autoantibodies, with further discoveries likely due to ongoing research. Among these, high-risk autoantibodies primarily target intracellular neural cell antigens. We present cases of lung cancer patients who developed limbic encephalitis and seizures at diagnosis, suggestive of PNS. Each case demonstrated distinct autoantibody profiles. Recognition of these potentially life-altering neurological sequelae, as paraneoplastic manifestations of malignancies, is crucial for physicians. PNS may precede primary cancer diagnosis and substantially affect patient presentation and overall outcome. We provide in detail the diagnostic work-up and available treatment options for these complex cases.