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Unique indirect immunofluorescence assay on mouse brain with antihuman IgG staining. Key: ANNA-1, anti-neuronal nuclear antibody type-1 (anti-Hu); CRMP5, collapsin response-mediator protein-5; GM, gastric mucosa; KLHL11, Kelch-like Protein 11; MP, myentric plexus; WM, white matter.
Source publication
We provide an overview of the varied presentations of paraneoplastic neurological syndromes. We also review the onconeural antibodies and their particular oncological and neurological associations. Recognition of these syndromes and their oncological associations is crucial, as early diagnosis and management has been associated with better patient...
Citations
... Despite this advance, robust prospective randomized control studies looking at treatment efficacy for PNS remain scarce. In fact, the general approach to management has remained fundamentally the same and entails a combination of immunotherapy and tumor treatment [3,[7][8][9]. Additionally, the multi-disciplinary team treating cancer patients is facing new challenges in the era of immune checkpoint inhibitors (ICI). Specifically, there is growing evidence that patients on ICI are developing PNS or have worsening pre-existing PNS [10-12, 13 ••]. ...
Opinion statement
Our understanding of paraneoplastic neurologic syndromes (PNS) has blossomed over the past few decades. Clinicians have access to more robust diagnostic criteria and have a heightened index of suspicion for these disorders. Nonetheless, treatment, which typically includes immunosuppression, and response to treatment, varies. Due to persistent difficulty in making a definitive diagnosis, we favor empiric treatment when a possible diagnosis of PNS is suspected, and other alternative causes have substantially been excluded (e.g., infections, toxic-metabolic derangements, metastasis, or leptomeningeal disease). Treatment of the underlying cancer, if identified, is the first therapeutic step and can prevent disease worsening and in rare cases, can reverse neurologic symptoms. In addition to anti-cancer treatment, first line immunotherapies, which include corticosteroids, intravenous immunoglobulins (IVIG), or plasma exchange (PLEX) are typically used. If partial or no benefit is seen, second line immunotherapeutic agents such as rituximab are considered. Additionally, the severity of the initial presentation and possible risk for relapse influences the use of the latter agents. Symptomatic management is also an important component in our practice and will depend on the syndrome being treated. One of the more novel entities we are facing currently is the management of immune checkpoint (ICI)-induced PNS. In those cases, current American Society of Clinical Oncology (ASCO) guidelines are followed.
... Antibodies directed against intracellular proteins are thought to cause the disease through T-cell-mediated cytotoxicity. Whereas antibodies against surface proteins or receptors are thought to have antibody-mediated pathogenesis [14]. ...
... Individuals may present with hypokinesis, limb rigidity, vertical gaze palsy, and orofacial and jaw dystonia. Sleep abnormalities can manifest as cataplexy, narcolepsy, excessive daytime sleepiness, and rapid eye movement sleep disorders [10,14]. ...
... Also known as the collapsin response-mediator protein-5 (CRMP5) antibody, it is an IgG that has been described in association with paraneoplastic peripheral neuropathy, cranial neuropathy, gastroparesis, encephalitis, cerebellar ataxia, myelopathy, and chorea [14]. ...
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.
... Table S1 in Supplementary Materials section lists the included diseases. For the group of AIND, we included multiple sclerosis (MS; n = 73; 61 with relapsing-remitting type, 6 with the secondary progressive type, and 6 with the primary progressive type according to the 2017 revised criteria of McDonald [77]), clinically isolated syndrome (CIS; n = 3), isolated optic neuritis (ON; n = 18), neuromyelitis optic spectrum disease (NMOSD; n = 4), autoimmune (limbic) encephalitis with antibody detection [78,79] (n = 14), paraneoplastic syndrome other than limbic encephalitis [78,80] (n = 11), chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) (n = 1), a neurological manifestation of Sjögren's syndrome (n = 1), CNS-vasculitis (n = 8), Neuro-Behçet's disease [81,82] (NBD; n = 3), and neurosarcoidosis (n = 10). Of the 73 MS patients, 65 were not receiving immunomodulatory or immunosuppressive treatment at the time of lumbar puncture, as well as two CIS and two NMOSD patients. ...
... Table S1 in Supplementary Materials section lists the included diseases. For the group of AIND, we included multiple sclerosis (MS; n = 73; 61 with relapsing-remitting type, 6 with the secondary progressive type, and 6 with the primary progressive type according to the 2017 revised criteria of McDonald [77]), clinically isolated syndrome (CIS; n = 3), isolated optic neuritis (ON; n = 18), neuromyelitis optic spectrum disease (NMOSD; n = 4), autoimmune (limbic) encephalitis with antibody detection [78,79] (n = 14), paraneoplastic syndrome other than limbic encephalitis [78,80] (n = 11), chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) (n = 1), a neurological manifestation of Sjögren's syndrome (n = 1), CNS-vasculitis (n = 8), Neuro-Behçet's disease [81,82] (NBD; n = 3), and neurosarcoidosis (n = 10). Of the 73 MS patients, 65 were not receiving immunomodulatory or immunosuppressive treatment at the time of lumbar puncture, as well as two CIS and two NMOSD patients. ...
C-X-C-motif chemokine ligand 13 (CXCL13) in cerebrospinal fluid (CSF) is increasingly used in clinical routines, although its diagnostic specificity and divergent cut-off values have been defined so far mainly for neuroborreliosis. Our aim was to evaluate the value of CSF-CXCL13 as a diagnostic and treatment response marker and its role as an activity marker in a larger disease spectrum, including neuroborreliosis and other neuroinflammatory and malignant CNS-disorders. Patients who received a diagnostic lumbar puncture (LP) (n = 1234) between July 2009 and January 2023 were included in our retrospective cross-sectional study. The diagnostic performance of CSF-CXCL13 for acute neuroborreliosis was highest at a cut-off of 428.92 pg/mL (sensitivity: 92.1%; specificity: 96.5%). In addition, CXCL13 levels in CSF were significantly elevated in multiple sclerosis with clinical (p = 0.001) and radiographic disease activity (p < 0.001). The clinical utility of CSF-CXCL13 appears to be multifaceted. CSF-CXCL13 is significantly elevated in patients with neuroborreliosis and shows a rapid and sharp decline with antibiotic therapy, but it is not specific for this disease and is also highly elevated in less common subacute neuroinfectious diseases, such as neurosyphilis and cryptococcal meningitis or in primary/secondary B-cell lymphoma.
... adrenocorticotropic hormone). SRY-Box Transcription Factor 1) (7,(9)(10)(11). Primer PNS na živčno mišičnem stiku je Lambert-Eatonov miastenični sindrom (LAMS). Klinična slika spominja na miastenijo gravis. ...
... stiff person), nevromiotonija, optična nevropatija, paraneoplastična miastenia gravis, avtonomna, motorična ali senzorična nevropatija in drugi. V tabeli 3 so predstavljeni nekateri najpogostejši nevrološki PNS (7,9,11). ...
Paraneoplastični sindromi so redki klinični sindromi, ki nastanejo kot posledica sistemskih učinkov tumorjev. Nastanejo po dveh glavnih mehanizmih: neimunološki in imunološki mehanizmi. Neimunološki mehanizmi so povezani s tumorskim izločanjem hormonov, funkcionalno aktivnih peptidov ali citokinov, imunološki mehanizmi pa so posledica navzkrižnih reakcij protiteles med tumorskimi in normalnimi tkivi. Prizadeti so lahko različni organi in organski sistemi. Skladno s tem je različna klinična slika. Najpogostejši paraneoplastični sindromi so: nevrološki, endokrinološki, dermatološki in revmatološki. Drobnocelični pljučni rak je najpogosteje pridružena maligna bolezen, sledijo limfoproliferativne bolezni, ginekološki raki in rak dojk. Paraneoplastični sindromi so lahko prva manifestacija maligne bolezni in zato pogosto predstavljajo diagnostični in terapevtski izziv. Izid zdravljenja bolnikov s paraneoplastičnimi sindromi je odvisen predvsem od učinkovitosti zdravljenja osnovne maligne bolezni.
... Among patients with negative CT scan, FDG PET/CT can improve detection rates by approximately 20%. [39] Our study showed that FDG PET/CT enabled the detection of underlying primary tumor in nine patients, which earlier been not detected with previous CT imaging. By its virtue of combining a whole-body structural and metabolic imaging in a single examination session, FDG PET/CT can enable the detection of primary tumor in a significant number of otherwise negative CT studies. ...
Background: Paraneoplastic neurological syndromes (PNS) result from an underlying malignant tumor. However, in a significant number of patients, underlying primary tumor may remain undetected as conventional computed tomography (CT) imaging and onconeural antibodies have a low sensitivity to detect the occult tumor. Objectives: To evaluate the diagnostic performance of FDG PET/CT for detecting underlying tumor in patients with suspected neurological PNS. Materials and Methods: Retrospective analysis of findings from fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scans of 143 patients from two PET/CT centers in north India was done and compared to findings of CT scans and onconeural antibody panel of these patients. Results: Overall, 39 (27%) patients had positive PET/CT findings. Of these, 24 (17%) patients were proven to have underlying malignant tumor. Among 104 FDG PET/CT negative patients, six (5%) patients were subsequently found to have an underlying malignant tumor on subsequent follow-up and workup. Therefore, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of FDG PET/CT for detecting underlying tumor were 80%, 86.7%, 61.5%, 94.2%, and 85.3%compared to sensitivity, specificity, PPV, NPV, and accuracy of 60%, 89.8%, 61%, 89.4%, and 83.5% for CT and 43.3%, 97.3%, 81.2%, 86.6%, and 86% for onconeural antibodies, respectively. Conclusions: FDG PET/CT should be preferred as an initial investigation for the detection of underlying malignancy in patients with suspected neurological paraneoplastic syndromes. It can help in the early detection of underlying malignancy in a significant number of patients with negative onconeural antibody and conventional CT results. However, a negative FDG PET/CT scan does not always rule out the possibility of an underlying malignancy, and a follow-up is indicated in such clinically suspected PNS cases.
... Paraneoplastic neurological syndrome (PNS) is an immunemediated neurological disorder caused by antibodies against intracellular, neuronal surface or synaptic proteins expressed by cancer cells. The detection of these antibodies is useful for PNS diagnosis and recent studies report the presence of a variety of onconeural antibodies (1). ...
Amphiphysin (AMPH) autoimmunity is associated with a variety of neurological complications, including encephalitis, peripheral neuropathy, myelopathy, and cerebellar syndrome. Its diagnosis is based on clinical neurological deficits and the presence of serum anti-AMPH antibodies. Active immunotherapy, such as intravenous immunoglobulins, steroids, and other immunosuppressive therapies, has been reported to be effective in most patients. However, the extent of recovery varies depending on the case. Herein, we report the case of a 75-year-old woman with semi-rapidly progressive systemic tremors, visual hallucinations, and irritability. Upon hospitalization, she developed a mild fever and cognitive impairment. Brain magnetic resonance imaging (MRI) showed semi-rapidly progressive diffuse cerebral atrophy (DCA) over 3 months, while no clear abnormal intensities were observed. The nerve conduction study revealed sensory and motor neuropathy in the limbs. The fixed tissue-based assay (TBA) failed to detect antineuronal antibodies; however, based on commercial immunoblots, the presence of anti-AMPH antibodies was suspected. Therefore, serum immunoprecipitation was performed, which confirmed the presence of anti-AMPH antibodies. The patient also had gastric adenocarcinoma. High-dose methylprednisolone, and intravenous immunoglobulin were administered and tumor resection was performed, resulting in resolution of the cognitive impairment and improvement in the DCA on the post-treatment MRI. After immunotherapy and tumor resection, the patient's serum was analyzed using immunoprecipitation, which showed a decrease in the level of anti-AMPH antibodies. This case is noteworthy because the DCA showed improvement after immunotherapy and tumor resection. Additionally, this case demonstrates that negative TBA with positive commercial immunoblots do not necessarily indicate false positive results.
... The presence of a high-risk antibody accompanied by classical phenotypes and cancer for ANNA-2/ anti-Ri consolidated the definite PNS diagnosis according to the 2021 Updated Diagnostic Criteria for PNS. 5 The principles of management of PNS are early treatment of underlying cancer and immunotherapy. 6 An oncologist, a general surgeon, and a radiation oncologist were consulted for the treatment of breast cancer. For immunotherapy, she received IV methylprednisolone for 5 days with minimal improvement and continued on 60 mg/d of oral prednisone. ...
... Cyclophosphamide is a cytotoxic agent more often considered in those with antibodies to intracellular targets, in whom a CD8 T-cell-mediated process is suspected, particularly with fulminant presentations. 6 However, T cells and B cells work in tandem, and thus, these treatments may sometimes be used in combination, as in this case. ...
Jaw dystonia and laryngospasm in the context of subacute brainstem dysfunction have been described in a small number of diseases, including antineuronal nuclear antibody type 2 (ANNA-2, also known as anti-Ri) paraneoplastic neurologic syndrome. Severe episodes of laryngospasms causing cyanosis are potentially fatal. Jaw dystonia can also cause eating difficulty, resulting in severe weight loss and malnutrition. In this report, we highlight the multidisciplinary management of this syndrome associated with ANNA-2/anti-Ri paraneoplastic neurologic syndrome and discuss its pathogenesis.
... IVMP and IVIg are typically continued weekly for 6-12 weeks to sustain response. Second-line treatments include rituximab and intravenous cyclophosphamide [218]. Depending on the disease mechanism, rituximab, IVIg, and PLEX are preferred for antibodies to neuronal surface antigen, while cyclophosphamide is preferred for antibodies to intracellular antigens, which are considered surrogate biomarkers for T-cell-mediated cytotoxicity [9]. ...
Introduction:
Acute transverse myelitis (ATM) is a term that encompasses a wide range of etiologies from immune-mediated to infectious. Management and prognosis differ for each specific etiology, and thus determining the disease-specific diagnosis of ATM is crucial.
Areas covered:
The distinguishing clinical, radiologic, serologic, and cerebrospinal fluid features for common etiologies of ATM, such as multiple sclerosis, aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and spinal cord sarcoidosis, are covered. Acute flaccid myelitis variant of ATM is also explored. Red flags suggesting ATM mimics are briefly reviewed. Management of ATM in this review mainly focuses on treatment for immune-mediated causes and is divided into acute treatment, preventive treatment for certain etiologies, and supportive management. Although maintenance attack-prevention treatment for immune-mediated ATM is mainly guided by observational studies and expert opinion, clinical trials have been completed in AQP4+NMOSD and are underway in MOGAD to help provide solid evidence for treatment efficacy.
Expert opinion:
The term ATM should be replaced by a disease-specific diagnosis to direct management. Discovery of disease-associated antibodies has changed the landscape of ATM diagnosis and allowed research on disease mechanisms. Translating our knowledge on pathophysiology into targeted therapy with monoclonal antibodies has provided new treatment options for patients.
... Neurological manifestations with grade 3 or 4, including autoimmune encephalitis, were reported with an incidence of 1.5% after ICI treatment [21]. Melanomas are very rare among the tumors usually associated with PNS [22]. However, ICI could induce such complications also in patients with tumors not commonly associated with paraneoplastic neurological syndromes [23,24]. ...
Background
Septins are cytoskeletal proteins with filament forming capabilities, which have multiple roles during cell division, cellular polarization, morphogenesis, and membrane trafficking. Autoantibodies against septin-5 are associated with non-paraneoplastic cerebellar ataxia, and autoantibodies against septin-7 with encephalopathy with prominent neuropsychiatric features. Here, we report on newly identified autoantibodies against septin-3 in patients with paraneoplastic cerebellar ataxia. We also propose a strategy for anti-septin autoantibody determination.
Methods
Sera from three patients producing similar immunofluorescence staining patterns on cerebellar and hippocampal sections were subjected to immunoprecipitation followed by mass spectrometry. The identified candidate antigens, all of which were septins, were expressed recombinantly in HEK293 cells either individually, as complexes, or combinations missing individual septins, for use in recombinant cell-based indirect immunofluorescence assays (RC-IIFA). Specificity for septin-3 was further confirmed by tissue IIFA neutralization experiments. Finally, tumor tissue sections were analyzed immunohistochemically for septin-3 expression.
Results
Immunoprecipitation with rat cerebellum lysate revealed septin-3, -5, -6, -7, and -11 as candidate target antigens. Sera of all three patients reacted with recombinant cells co-expressing septin-3/5/6/7/11, while none of 149 healthy control sera was similarly reactive. In RC-IIFAs the patient sera recognized only cells expressing septin-3, individually and in complexes. Incubation of patient sera with five different septin combinations, each missing one of the five septins, confirmed the autoantibodies’ specificity for septin-3. The tissue IIFA reactivity of patient serum was abolished by pre-incubation with HEK293 cell lysates overexpressing the septin-3/5/6/7/11 complex or septin-3 alone, but not with HEK293 cell lysates overexpressing septin-5 as control. All three patients had cancers (2 × melanoma, 1 × small cell lung cancer), presented with progressive cerebellar syndromes, and responded poorly to immunotherapy. Expression of septin-3 was demonstrated in resected tumor tissue available from one patient.
Conclusions
Septin-3 is a novel autoantibody target in patients with paraneoplastic cerebellar syndromes. Based on our findings, RC-IIFA with HEK293 cells expressing the septin-3/5/6/7/11 complex may serve as a screening tool to investigate anti-septin autoantibodies in serological samples with a characteristic staining pattern on neuronal tissue sections. Autoantibodies against individual septins can then be confirmed by RC-IIFA expressing single septins.
... SOX1 abs have been considered well-characterized ONAs in association with PNSs and SCLC, especially Lambert-Eaton myasthenic syndrome (LEMS) [2,5]. They do not appear to have a strong association with a particular neurological phenotype, but seem to be cancer-specific serological biomarkers [20]. In a recent review, Sun et al [21] identified PNSs in 67.3% of the patients with anti-SOX1 abs and other coexisting ONAs, and in 21.2% of those with anti-SOX1 abs alone. ...
... Adult cancers associated with OMS include SCLC with NSCLC and gynecologic tumors less frequently identified [15]. CASPR2-IgG can manifest as Morvan's syndrome, peripheral nerve hyperexcitability, LE, cerebellar dysfunction, painful small-fiber neuropathies associated with neuropathic pain, or epilepsy [1,5,20]. CASPR2-IgG is associated with thymomas in about 20% of cases [1,15], though other tumors have been reported rarely (melanomas, NSCLC, prostatic cancer, endometrial carcinoma, and pancreatic adenocarcinoma) [20,25]. ...
... CASPR2-IgG can manifest as Morvan's syndrome, peripheral nerve hyperexcitability, LE, cerebellar dysfunction, painful small-fiber neuropathies associated with neuropathic pain, or epilepsy [1,5,20]. CASPR2-IgG is associated with thymomas in about 20% of cases [1,15], though other tumors have been reported rarely (melanomas, NSCLC, prostatic cancer, endometrial carcinoma, and pancreatic adenocarcinoma) [20,25]. Recently, Rosenow et al. proposed a novel association between Caspr2 abs in a patient with mixed NSCLC-SCLC [23]. ...
Background:
Paraneoplastic neurological syndromes (PNSs) are nonmetastatic complications of malignancy, defined by the presence of onconeural antibodies (ONAs). ONAs may be found in 60% of patients with central nervous system (CNS) involvement, and they are directed against intraneuronal antigens or channels, receptors or associated proteins located at the synaptic or extra-synaptic neuronal cell membrane. Given its rare incidence, there are few epidemiological case series on CNS-PNS. We aim to discuss the variability of CNS-PNSs etiology, clinical features, management and outcome, highlighting the importance of early recognition and appropriate treatment, leading to significant reduction of mortality and morbidity.
Methods:
We retrospectively reviewed our 7-years single-center experience, and specifically discussed the underlying etiology, parenchymal CNS involvement, and the acute treatment response. Only cases fulfilling PNS Euronetwork criteria for definitive PNS were included.
Results:
A total of 26 probable PNSs cases involving CNS were identified. We reported medical records of eleven (42.3%) illustrative cases, meeting the criteria of definite PNS and presenting variable clinical spectrum and different radiological appearances. Our series has a relative paucity of the most common syndromes and larger portion of clinical diagnosis with ONAs. Well-characterized ONAs had been detected in CSF of six patients.
Conclusions:
Our case series supports the utmost importance of early recognition of CNS-PNSs. Screening for occult malignancies should not be limited to patients with classical CNS syndrome. Empiric immunomodulatory therapy may be considered before the diagnostic evaluation is completed, in order to prevent unfavorable outcome. Late presentations should not discourage initiation of treatment.
