Well-characterized Onconeural Antibodies Research Articles

Paraneoplastic neurological syndromes of the central nervous system: a single institution 7-year case series.

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. 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. 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. 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.

Anti-Ma2 Antibody-Associated Paraneoplastic Neurological Syndromes: A Pilot Study.

Paraneoplastic neurologic syndromes (PNSs) are a heterogeneous group of disorders caused by the remote effects of cancer with immune-mediated pathogenesis. Anti-Ma2 antibody was defined as one of the well-characterized onconeural antibodies that could help establish a definite PNS diagnosis. We aimed to report and explore patients with anti-Ma2 antibody-associated paraneoplastic neurologic syndrome (Ma2-PNS) who frequently exhibit sensorimotor neuropathy (SMN) using a new method of factor analysis of mixed data (FAMD). Clinical data from a case series of eight patients with definite diagnoses were retrospectively reviewed. FAMD conducted further analyses with a comprehensive visualization in R software. Our cohort, with a predominance of females (5/8), presented more frequently with SMN (4/8), followed by limbic encephalitis (LE) (3/8). Two patients with LE were found to have a testicular germ-cell tumor and a thymoma, respectively. In addition, a patient who developed chronic SMN was diagnosed with multiple myeloma (MM) involving multiple organs. FAMD exhibited the overall features into a two-dimensional coordinate and located each individual into their corresponding position with high relevance. It provided a clue for determining their potential relationships and predictors. Our findings indicated that Ma2-PNS could frequently involve the peripheral nervous system, MM might be one of its associated cancers with a presentation of chronic SMN, and FAMD might be a clinically valuable tool.

Clinical characteristics of "classical" and "non-classical" paraneoplastic neurological syndrome

Objective: To explore the clinical features of classical and non-classical paraneoplastic neurological syndrome (PNS). Methods: From 2015 to 2020, 48 cases of definite PNS admitted to the First Affiliated Hospital of University of Science and Technology of China were retrospectively collected, and classification, clinical characteristics, onconeural antibodies and primary tumors were analyzed. The included cases were divided into classical and non-classical groups according to Graus criteria, and the differences of clinical characteristics, onconeural antibodies, combined tumors, time of diagnosis and mortality were compared between the two groups. Results: Among the 48 confirmed patients, 21 (43.8%) were positive for well-characterized onconeural antibodies. There were 28 cases (58.3%) and 20 cases (41.7%) in classic and non-classical PNS groups, respectively. No significant differences of age, sex, clinical involvement site, characteristic positive antibody type, tumor diagnosis rate and follow-up mortality were found between the two groups (all P>0.05). The time of diagnosis in the non-classical PNS group was 3.0 (2.0, 6.5) months, which was significantly longer than that in the classical PNS group 1.0(0.6, 3.0) months (P<0.05). Meanwhile, the combination rate of non-characteristic antibodies in the classical PNS group (10 cases, 35.7%) was significantly higher than that in the non-classical PNS group (1 case, 5.0%) (P=0.016). During the follow-up, 39 patients (81.3%) with tumor were confirmed, and 29 patients (60.4%) were diagnosed with PNS before the tumor was found. Conclusions: The"non-classical"PNSs are common in clinical settings. Diagnosis may be delayed due to the nonclassical symptoms of the patients. When patients have clinical symptoms related to PNS, onconeural antibodies should be detected and the relevant tumors should also be screened. Patients have positive antibodies but with no tumors should be closely followed up for more than 5 years.

Anti-Ri-associated paraneoplastic ophthalmoplegia-ataxia syndrome in a woman with breast cancer: a case report and review of the literature

BackgroundBreast cancer is the most common cancer in women. However, in the management of breast cancer, paraneoplastic neurological syndromes represent a diagnostic and therapeutic challenge. The diagnosis of paraneoplastic neurological syndromes is difficult due to the heterogeneity of symptoms, the timing of presentation, and the absence of antibodies, and it generally occurs before the diagnosis of breast cancer in 80% of patients who develop paraneoplastic neurological syndromes. We describe a 72-year-old woman with subacute ophthalmoplegia-ataxia syndrome who was subsequently diagnosed as having breast cancer and anti-Ri antibodies.Case presentationA 72-year-old post-menopausal Caucasian woman, with a positive medical history for diabetes mellitus and hypertension, presented with a 3-month onset of blurred vision, diplopia, and progressive gait disturbance. Serological tests were positive for well-characterized onconeural antibodies (anti-Ri). A whole-body computed tomography scan revealed a nodular opacity under her left nipple and axillary adenopathy. A biopsy of her left breast was performed, and histological examination showed ductal carcinoma. She underwent a superoexternal quadrantectomy with left axillary dissection. The final diagnosis showed infiltrating ductal carcinoma of the breast (T1c N1 M0, stage IIA) associated with paraneoplastic ophthalmoplegia-ataxia syndrome. At a 6-month follow-up, she showed no clinical or instrumental evidence of neoplastic recurrence with partial clinical improvement of neurological symptoms, such as ataxia and diplopia.ConclusionThe diagnosis of paraneoplastic neurological syndromes is often late, as in this patient, but treatment at an early stage may provide a good prognosis. Furthermore, this is one of several cases of an anti-Ri paraneoplastic neurological syndrome not associated with myoclonus, which reinforces the belief that opsoclonus myoclonus syndrome is not pathognomonic of the associated anti-Ri paraneoplastic neurological syndromes.

Paraneoplastic cerebellar degeneration in a patient with breast cancer associated with carbonic anhydrase–related protein VIII autoantibodies

Paraneoplastic cerebellar degeneration is a neurological syndrome resulting from immune-mediated dysfunction of Purkinje cells and commonly is associated with a tumor. In most cases, well-characterized onconeural antibodies are detected, such as anti-Yo and anti-Ri antibodies.Carbonic anhydrase-related protein VIII (CARP VIII) antibodies associated with paraneoplastic cerebellar degeneration have been previously described in only two cases. Herein, we present a 75-year-old female who developed progressive cerebellar ataxia. Anti-CARP VIII autoantibodies were found at high titres and screening for underlying malignancies revealed a breast cancer. Intravenous immunoglobulin was administered with poor results. Our report further confirms the role of CARP VIII antibodies in cerebellar degeneration.

Absent well-characterized onconeural antibodies in 283 patients with various polyneuropathies: A retrospective monocenter study

BackgroundParaneoplastic neurological syndromes (PNS) might present as polyneuropathies (PNP). Because PNS are rare and PNP are frequent, it may be difficult to decide in patients with PNP of unclear or presumably idiopathic etiology whether to test for onconeural antibodies, which are highly predictive for PNS. In this regard, this is the largest study investigating the prevalence of onconeural antibodies in patients with PNP, in order to clarify whether such testing should be standard. MethodsOf 1842 consecutive patients, 283 were suitable and had stored serum samples for screening for onconeural antibodies (anti-Hu, Yo, Ri, CV2/CRMP5, Ma2, and amphiphysin) by ELISA: 159 patients with PNP of – despite laborious work-up – unknown etiology without cancer, 67 with Guillain-Barré syndrome (GBS), 31 with chronic inflammatory demyelinating PNP (CIDP), and 26 with cancer and PNP. ResultsNone of the 283 screening samples revealed high concentrations for any of the tested antibodies. Thirteen sera (4.6%) showing positive reactivity in the screening ELISA (11 with PNP of unknown etiology without cancer, one with GBS, and one with CIDP) most likely represented increased background activity, as confirmatory assays (immunoblotting and immunohistochemistry) were negative. Furthermore, none of these 13 patients had diagnosed cancer and 10 with sufficient follow-up data did not develop cancer during follow-up. Interestingly, none of the patients with known cancer and PNP was screened positive for any antibody reactivity. ConclusionsOur data suggest that routine screening for onconeural antibodies in etiologically unclear and in presumably idiopathic (GBS and CIDP) PNP is not mandatory.

What is the significance of onconeural antibodies for psychiatric symptomatology? A systematic review

BackgroundPatients with intracellular onconeural antibodies may present with neuro-psychiatric syndromes. We aimed to evaluate the evidence for an association between well-characterized onconeural antibodies and psychiatric symptoms in patients with and without paraneoplastic central nervous system syndromes.MethodsEligible studies were selected from 1980 until February 2017 according to standardized review criteria and evaluated using Quality Assessment of Diagnostic Accuracy Studies−2 (QUADAS-2). We included studies describing the psychiatric symptomatology of onconeural antibody positive patients and the prevalence of onconeural antibodies in patients with psychiatric disorders.ResultsTwenty-seven studies met the inclusion criteria. Six studies reported on the prevalence of well-characterized onconeural antibodies in patients with different psychiatric disorders, ranging from 0% to 4.9%. Antibody prevalence in controls was available from three studies, ranging from 0% to 2.8%. Data heterogeneity precluded a meta-analysis. Two cerebrospinal fluid studies found well-characterized onconeural antibodies in 3.5% and 0% of patients with psychotic and depressive syndromes, respectively.ConclusionsThe available evidence suggests that the prevalence of well-characterized onconeural antibodies in patients with psychiatric disorders is generally low. However, the question whether onconeural antibodies are important in select patients with a purely psychiatric phenotype needs to be addressed by appropriately designed studies in the future.

PARANEOPLASTIC DAMAGE TO THE CENTRAL AND PERIPHERAL NERVOUS SYSTEM IN BREAST CANCER: A CASE REPORT

Paraneoplastic neurological syndrome involves the concurrent development of cancer and neurologicaldiseases. Breast cancer is the second most common cancer associated with paraneoplastic damage to the central and peripheral nervous system. Autoimmune genesis of the disease is characterized by the presence of highly specific onconeural antibodies, which selectively affect neurons in the brain cord, spinal cord and spinal ganglia, and cause the onset of neurological symptoms within 2 years before cancer is detected. Six well-characterized onconeural antibodies detected in the blood serum of breast cancer patients can be used for the laboratory diagnosis of paraneoplastic neurological syndrome. Of them, anti-Hu, anti-CV2 and anti-amphiphysin antibodies cause polyneuropathy most often. Anti-Yo antibody is usually associated with cerebellar degeneration. Multiple neuronal autoantibodies can be simultaneously detected in a patient. Removal of the tumor may lead to stabilization and even partial regression of the neurological symptoms in 70 % of patients. Therefore, the surgical treatment of cancer should consider not only the tumor extension, but also the severity and progression of neurological deficit. We present a case of paraneoplastic cerebellar degeneration and paraneoplastic polyneuropathy in a 50-year-old woman with the neurological symptoms appeared 5 months before breast infiltrating ductal carcinoma was detected. The current approaches to the diagnosis of paraneoplastic neurological syndrome, as well as feasibility of radical removal of the tumor due to progression of neurological deficit were discussed.

Prevalence of anti-SOX1 reactivity in various neurological disorders

ObjectivesAnti-SOX1 antibodies are associated with small cell lung cancer (SCLC) and predict a paraneoplastic etiology in Lambert-Eaton myasthenic syndrome (LEMS). In 2010, a study described these antibodies in a small cohort of putative non-paraneoplastic, immune-mediated neuropathies. In this respect, we investigated the seroprevalence and specificity of anti-SOX1 antibodies in a large cohort of neurological disorders. MethodsOverall, serum samples of 1493 consecutive patients were screened for anti-SOX1 reactivity by an ELISA: 471 with well-defined neurological disorders (multiple sclerosis, motor neuron disease, Guillain-Barré syndrome, and chronic inflammatory demyelinating polyneuropathy), 185 with polyneuropathy (PNP) of unknown origin, and 837 with neurological syndromes of suspicious paraneoplastic etiology. These were compared to eight positive controls with definite paraneoplastic neurological syndromes (PNS) and 92 healthy individuals. We also collected demographic and clinical data, including well-characterized onconeural antibodies in anti-SOX1–positive patients. ResultsFifteen patients (1.0%) showed anti-SOX1 reactivity: two with multiple sclerosis, two with PNP of unknown origin, and 11 suspicious PNS cases. Remarkably, 9/15 anti-SOX1–positive patients had a PNP. However, antibody concentrations were significantly lower compared to positive controls, and none additionally harbored well-characterized onconeural antibodies. During a follow-up of at least four years, only five patients had cancer: one thyroid, one Hodgkin lymphoma, two breast, and one patient had multiple malignancies - prostate, penis, cecum, liver, and non–small cell lung cancer. However, none had SCLC, typically associated with SOX1 antibodies. ConclusionsThe seroprevalence of anti-SOX1 antibodies in patients with various neurological disorders is low. These patients predominantly have PNPs, which might represent a group of immune-mediated diseases.

Autoimmune Encephalitis Associated with Malignant Tumors

Autoimmune encephalitis consists of limbic symptoms and signs associated with antibodies against neuronal cell-surface antigens or intracellular antigens. Some cases are known to be associated with anti-channel or anti-receptor-related molecule antibodies. Whether these cases are paraneoplastic depends on the kinds of antigens that the antibodies are produced against. Other cases due to well-characterized onco-neural antibodies are almost always paraneoplastic and are generally resistant to anti-tumor therapy and/or immunotherapy. An exception is anti-Ma2 antibody-positive encephalitis associated with a testicular tumor. Antibodies for intracellular antigens are considered not to be pathogenic. Rather, the T-cell response is thought to be responsible. These antibodies are useful markers for the diagnosis of paraneoplastic disorders and in the search for underlying cancer, as neurological symptoms often precede tumor diagnosis. There is a relationship among onco-neural antibodies, clinical features, tumor types, and response to immunotherapy. Here we describe the characteristics of autoimmune encephalitis cases with antibodies against different intracellular antigens, such as Hu, Ma2, CRMP5, or amphiphysin.

Screening for anti-titin antibodies in patients with various paraneoplastic neurological syndromes

Anti-titin antibodies indicate a paraneoplastic etiology pointing towards a thymoma in myasthenia gravis (MG), but their seroprevalence and potential diagnostic value in patients with other paraneoplastic neurological syndromes (PNS) is unknown. Therefore, we screened the sera of 44 PNS patients with well-characterized onconeural antibodies (anti-Hu, Yo, Ri, CV2/CRMP5, Ma1, Ma2/Ta, or amphiphysin) for anti-titin reactivity. Two patients (4.5%) were positive for anti-titin antibodies: both patients differed regarding the PNS (sensorimotor neuropathy and subacute cerebellar degeneration vs. chorea), well-characterized onconeural antibodies (CV2/CRMP5 vs. Ri), and malignoma (small cell lung cancer vs. breast cancer). However, retrospectively, the patients neither showed any symptoms of MG nor a thymoma on a computed tomographic (CT) scan. The results of this study indicate that anti-titin antibodies without a predictive relevance for MG or thymoma may be present in a small proportion of patients with PNS.

Prostate cancer, Hu antibodies and paraneoplastic neurological syndromes.

Prostate cancer is the most common cancer among American and European men. Nervous system affection caused by local tumor growth or osseous metastases are the main causes of neurological symptoms in prostate cancer patients. Prostate cancer is rarely reported in association with paraneoplastic neurological syndromes (PNS). We have, therefore, studied clinical and paraclinical findings of a series of patients with prostate cancer and PNS, and reviewed cases reported in the literature. Case histories of 14 patients with definite PNS from the PNS Euronetwork database and from the authors' databases were reviewed. A PubMed literature search identified 23 patients with prostate cancer and PNS. Thus, a total of 37 case histories were reviewed with respect to syndrome type, cancer evolution, paraclinical investigations, antibody status, treatment and outcome. The three most frequent isolated PNS were paraneoplastic cerebellar degeneration, paraneoplastic encephalomyelitis (PEM)/limbic encephalitis and subacute sensory neuronopathy (SSN). Onconeural antibodies were detected in 23 patients, in most cases the Hu antibody (17 patients, 74% of all antibody-positive cases). Other well-characterized onconeural antibodies (Yo, CV2/CRMP5, amphiphysin, VGCC antibodies) were found in a minority. PNS was diagnosed prior to prostate cancer diagnosis in 50% of the cases. The association of PNS with prostate cancer is quite infrequent, but clinically important. PNS often heralds prostate cancer diagnosis. Syndromes associated with Hu antibodies predominate. Another tumor more prone to associate with PNS should always be excluded.

Pathologically confirmed autoimmune encephalitis in suspected Creutzfeldt-Jakob disease.

Objective:To determine the clinical features and presence in CSF of antineuronal antibodies in patients with pathologically proven autoimmune encephalitis derived from a cohort of patients with suspected Creutzfeldt-Jakob disease (CJD).Methods:The Dutch Surveillance Centre for Prion Diseases performed 384 autopsies on patients with suspected CJD over a 14-year period (1998–2011). Clinical information was collected from treating physicians. Antineuronal antibodies were tested in CSF obtained postmortem by immunohistochemistry on fresh frozen rat brain sections, by Luminex assay for the presence of well-characterized onconeural antibodies, and by cell-based assays for antibodies against NMDAR, GABABR1/2, GABAAR GLUR1/2, LGI1, Caspr2, and DPPX.Results:In 203 patients, a diagnosis of definite CJD was made, while in 181 a variety of other conditions were diagnosed, mainly neurodegenerative. In 22 of these 181, the neuropathologist diagnosed autoimmune encephalitis. One patient was excluded because of lack of clinical information. Inflammatory infiltrates were predominantly perivascular and consisted mainly of T cells. The predominant locations were basal ganglia and thalamus (90%) and temporal lobes and hippocampus (81%). In 6 patients (29%), antineuronal antibodies were detected in postmortem CSF, directed against Hu, NMDAR, GABABR1/2, Caspr2, and an unidentified synaptic antigen in 2. The most frequent symptoms were dementia (90%), gait disturbance (86%), cerebellar signs (67%), and neuropsychiatric symptoms (67%). Immunopathologic and clinical findings did not differ between autoantibody-negative patients and patients with antineuronal antibodies.Conclusions:It is important to consider immune-mediated disorders in the differential diagnosis of rapidly progressive neurologic deficits.

“Non-classical” paraneoplastic neurological syndromes associated with well-characterized antineuronal antibodies as compared to “classical” syndromes — More frequent than expected

ObjectivesParaneoplastic neurological syndromes (PNSs) are rare disorders in association with cancer and sub-divided into “classical” and “non-classical” syndromes according to a 2004 consensus paper proposed by a panel of PNS experts. “Classical” PNSs are regarded to account for the vast majority of cases. However, systematic reports on clinical PNS manifestations are rare. Therefore, we analyzed the spectrum of PNS in our clinic. MethodsWe retrospectively investigated medical records from consecutive patients diagnosed with definite PNS and serological evidence of well-characterized onconeural antibodies (anti-Hu, Yo, Ri, CV2/CRMP5, Ma1, Ma2, and amphiphysin) analyzed between 1991 and 2014 in our clinic. ResultsOf the 50 patients identified with onconeural antibody-positive PNS, 28 patients (56.0%) had “classical” PNS, and 22 (44.0%) “non-classical” PNS. Subacute cerebellar degeneration was the most frequent “classical” syndrome, brainstem encephalitis and subacute sensorimotor neuronopathy the most frequent “non-classical” syndromes. Anti-Hu antibodies were most frequent in both groups. 86.1% of patients developed neurological symptoms before the cancer was known. No differences between “classical” and “non-classical” syndromes were detected with respect to age, tumor entities and median time to diagnosis. However, whereas most patients with “classical” syndromes were females, there was no gender predominance in patients with “non-classical” PNS and the latter had significantly more frequent peripheral neurological syndromes. ConclusionsThe so-called “non-classical” PNSs in association with well-characterized onconeural antibodies were more common in our patient population than expected. Therefore, in neurological disorders of unclear etiology with a subacute onset and atypical presentation further diagnostic work-up including investigation of onconeural antibodies is necessary.

Antibodies and neuronal autoimmune disorders of the CNS

We review the neuronal antibodies described in CNS disorders in order to clarify their diagnostic value, emphasize potentials pitfalls and limitations in the diagnosis of paraneoplastic neurological syndromes (PNS), and examine the current evidence for a possible pathogenic role. We propose to classify the neuronal antibodies associated with syndromes resulting from CNS neuronal dysfunction into two groups according to the location of the antigen: inside the neuron or in the cell membrane. Group I includes antibodies which target intracellular antigens and probably are not pathogenic. They are further subdivided into three groups. Group Ia comprises well-characterized onconeural antibodies (Hu (ANNA1), Yo (PCA1), Ri (ANNA2), CV2 (CRMP5), amphiphysin, Ma2) that are useful for the diagnosis of PNS. Group Ib antibodies (SOX and ZIC) are cancer-specific but there is no evidence that the immune response is in any way pathogenically related to the PNS. Antibodies in group Ic (glutamic acid decarboxylase (GAD), adenylate kinase 5 and Homer 3) identify non-PNS: stiff-person syndrome (SPS), cerebellar ataxia, and limbic encephalitis (LE). Group II antibodies recognize neuronal surface antigens. Antibodies in group IIa associate with characteristic CNS syndromes but their detection does not indicate that the disorder is paraneoplastic. Antibodies to potassium channels, AMPA and GABA(B) receptors are associated with LE, NMDA receptor antibodies identify a well-defined encephalitis, and antibodies against glycine receptors associate with SPS with encephalitis. A pathogenic role of the antibodies is suggested by the response of symptoms to immunotherapy and the correlation between antibody titers and neurological outcome. Lastly, Group IIb includes antibodies that are found in patients with paraneoplastic cerebellar ataxia associated with lung cancer (P/Q type calcium channels antibodies) or Hodgkin disease (metabotropic glutamate receptor type 1 antibodies).

Onconeural antibodies are essential to diagnose paraneoplastic neurological syndromes

Paraneoplastic neurological syndromes (PNS) can be defined as remote effects of cancer that are not caused by the tumor and its metastasis or by infection, ischemia or metabolic disruptions. In most patients, the neurological disorder develops before the cancer becomes clinically overt and the patient is referred to the neurologist who has the charge of identifying a neurological disorder as paraneoplastic. They are usually severely disabling. PNS are rare and are seen in less than 1% of patients with cancer. PNS depend on an autoimmune process triggered by cancer and directed to antigens common to both the cancer and the nervous system designated as onconeural antigens. Because of their high specificity (>90%), the best way to diagnose neurological disorders as paraneoplastic is to identify one of the well-characterized onconeural antibodies in the patient's serum. In addition, as these antibodies are associated with a restricted range of cancer, they permit orientating the search of the underlying tumor at a stage where it is frequently not clinically overt. This is a critical point, as today the best way to stabilize PNS is probably to treat the cancer as soon as possible. Unfortunately, about one-third of the patients do not have detectable antibodies and 5-10% have an atypical antibody that is not well characterized.