Paraneoplastic Neurological Symptoms Research Articles

Update on Paraneoplastic Cerebellar Degeneration.

Purpose of review: To provide an update on paraneoplastic cerebellar degeneration (PCD), the involved antibodies and tumors, as well as management strategies. Recent findings: PCD represents the second most common presentation of the recently established class of immune mediated cerebellar ataxias (IMCAs). Although rare in general, PCD is one of the most frequent paraneoplastic presentations and characterized clinically by a rapidly progressive cerebellar syndrome. In recent years, several antibodies have been described in association with the clinical syndrome related to PCD; their clinical significance, however, has yet to be determined. The 2021 updated diagnostic criteria for paraneoplastic neurologic symptoms help to establish the diagnosis of PCD, direct cancer screening, and to evaluate the presence of these newly identified antibodies. Recognition of the clinical syndrome and prompt identification of a specific antibody are essential for early detection of an underlying malignancy and initiation of an appropriate treatment, which represents the best opportunity to modulate the course of the disease. As clinical symptoms can precede tumor diagnosis by years, co-occurrence of specific symptoms and antibodies should prompt continuous surveillance of the patient. Summary: We provide an in-depth overview on PCD, summarize recent findings related to PCD, and highlight the transformed diagnostic approach.

Paraneoplastic Neurologic Symptoms in a Pediatric Patient with Hodgkin Lymphoma

Neurological paraneoplastic syndromes are exceedingly rare, and often difficult to recognize clinically. Paraneoplastic achalasia is a condition characterized by new-onset dysphagia that is unrelated to tumor burden, most often due to the development of auto-immune antibodies targeting esophageal tissue. Due to the rarity of this condition, diagnosis is often delayed, leading to increased time to treatment. Here we report a case of a rare paraneoplastic achalasia in a female child with EBV + Hodgkin lymphoma (HL), review literature describing paraneoplastic achalasia, and discuss treatment strategies for improving clinical outcome in these patients.

Abstract 2220: Autoantibody detection of high-grade serous ovarian cancer with paraneoplastic antigens

Abstract Improved early detection methods for ovarian cancer are necessary as the majority of cases present at late stage metastatic disease with a poor prognosis. Early stages of tumor development initiate an immune response, eliciting antibodies that target tumor associated antigens. Paraneoplastic neurological syndromes are rare autoimmune disorders that develop when the unregulated immune response against a tumor also targets healthy cells, due to shared tumor antigen expression with nervous system and muscle tissue. As these syndromes generally precede detection of a tumor, paraneoplastic antibodies are previously unexplored candidate biomarkers for early diagnosis of ovarian cancer. We have detected paraneoplastic antibodies in serum samples from patients with high-grade serous ovarian cancer (HGSOC) that did not present with paraneoplastic neurological syndrome symptoms using paraneoplastic diagnostic line blots. Ovarian cancer specific epitopes discovered previously in our laboratory by phage-display biopanning were evaluated for both homology to paraneoplastic antigens and for reactivity with paraneoplastic neurological syndrome patient sera. Western blot screening revealed a panel of paraneoplastic antigens that distinguished HGSOC patient sera autoantibody reactivity from healthy and benign sera. An indirect ELISA for measuring patient serum autoantibody reactivity was developed and correlated with western blot results. A panel consisting of 8 antigens: 5 paraneoplastic antigens, 2 well-characterized tumor associated antigens, and a non-reactive control was selected for screening on ELISA against patient serum samples representing each group of HGSOC early stage, HGSOC late stage, healthy, and benign. Biomarkers identified can contribute to an autoantibody diagnostic panel for early clinical diagnosis of ovarian cancer, which would allow for timely therapeutic intervention with potential to improve patient outcome. Citation Format: Laura C. Hurley, Nancy K. Levin, Madhumita Chatterjee, Michael A. Tainsky. Autoantibody detection of high-grade serous ovarian cancer with paraneoplastic antigens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2220.

Neuronal antibodies and paraneoplastic sensory neuropathy in thymoma

Thymoma, a common anterior mediastinal tumour, may present with paraneoplastic neurological symptoms. The presence of neuronal anti-Hu paraneoplastic antibodies in thymoma patients is very rare. Here, we describe a patient who presented with symptoms of a sensory peripheral neuropathy in the presence of onconeural antibodies cross-reactive with Hu antigen, in whom an underlying thymoma was diagnosed. Subsequent minimally invasive thymomectomy improved her neurological symptoms significantly.

Paraneoplastic Opsoclonus-Myoclonus Syndrome as a New and Single Manifestation of Relapsing Disease in a Patient with Small Cell Lung Cancer

A 55-year-old woman smoker with a history of cough, weight loss, and chest pain, without neurologic complaints, presented with a mass in the right lung. A bronchoscopy revealed a tumor in the right intermediate bronchus. The biopsy of the lesion showed small cell carcinoma. A FDGpositron emission tomography (PET)-computed tomography (CT) scan was performed and is displayed in Figure 1A. A brain CT was normal. After the diagnosis of limited-stage small cell lung cancer, the patient was treated with four cycles of cisplatin and etoposide combined with normofractionated thoracic radiotherapy (55 Gy) concurrent with the last two cycles. A radiological complete response was assessed, and treatment was completed with prophylactic cranial irradiation. Seven months after complete response, the patient experienced rapidly progressive dizziness and gait instability, followed by gaze disturbances and involuntary, continuous, conjugate, and chaotic saccadic eye movements. The gait disorder worsened, leaving the patient absolutely bedridden. On examination, intermittent myoclonic movements were apparent in the limbs and trunk (see video, part 1, Supplemental Digital Content 1, http://links.lww.com/JTO/A73, which shows these findings). She had neither cognitive impairment nor motor/sensory losses. Brain magnetic resonance imaging and cerebrospinal fluid examination were without noteworthy alterations. Serum antineuronal antibodies (antiHu, anti-Ri, anti-CV2, and antiamphiphysin) were negative. She was diagnosed with opsoclonus-myoclonus syndrome (OMS), and intravenous corticoids were administered for 5 days without improvement. There was no evidence of relapse on the chest CT, and the patient refused a bronchoscopy. A positron emission tomography-CT examination was strictly normal (Figure 1B). Although there was no visible tumor, we considered OMS as its herald, and second-line chemotherapy was started with carboplatin and etoposide in an attempt to reverse her devastating neurologic condition. After just the first cycle, opsoclonus and gait instability improved and the myoclonus resolved completely (see video, part 2, Supplemental Digital Content 1, http://links.lww.com/JTO/A73, which demonstrates her clinical improvement). The patient has completed three cycles of chemotherapy and continued free of recurrence for a total of 31 months, when a right supraclavicular relapse was detected and pathologically confirmed. Nevertheless, paraneoplastic neurologic symptoms did not recur, and third-line chemotherapy with oral topotecan was started.

Cerebellar ataxia associated with neuroendocrine thymic carcinoma and GAD antibodies

Cerebellar ataxia may arise as a consequence of autoimmune damage of the cerebellum. Adult patients with autoimmunity against the cerebellum often have an underlying neoplasm (paraneoplastic cerebellar degeneration). These patients...

Small-Cell Carcinoma of the Esophagus Associated with a Paraneoplastic Neurological Syndrome: A Case Report Documenting a Complete Response

We describe a case of small-cell carcinoma of the esophagus associated with a paraneoplastic neurological syndrome. Sensorimotor neuropathy had developed 3 years earlier, and neurological symptoms had slowly worsened. Small-cell carcinoma of the esophagus was incidentally diagnosed while investigating the cause of the neurological symptoms. A paraneoplastic neurological syndrome was diagnosed on the basis of cancer and exclusion of other known causes of neurological symptoms. The patient was given combination chemoradiotherapy. There was a complete response to three courses of chemoradiotherapy, with no evidence of disease recurrence 6 years after the diagnosis. There was no progression of paraneoplastic neurological symptoms after the complete response.

Anti–Ri antibodies and limbic encephalitis in a patient with carcinoid tumour of the lung

Sirs: The anti-Ri syndrome is defined as the coexistence of typical paraneoplastic neurological symptoms and anti-Ri antibodies. These antibodies typically occur in patients with a subacute neurological disorder usually in association with carcinoma of breast or lung [3–5]. The associated tumours seem to express ectopic neuro-onconal proteins, initiating an immune response cross reacting with neuronal nuclear tissue [6]. The clinical value of anti-Ri antibodies is their indicator function for a so far undetected tumour [7]. A 68-year-old man presented in August 2002, with slowly progressive personality changes and neuropsychological disorders. In February 1992 an endobronchial carcinoid tumour (pT2pN0) of the left upper lobe of the lung was resected in toto without evidence of metastasis on follow-up. Onset of neuropsychological symptoms was approximately July 2000. In August 2002 the patient scored 20 of 30 points in Folstein’s mini-mentalstate test. Detailed neuropsychological testing showed distinct apraxia, impaired short-term memory and deficits in complex actions and spatial-constructive exercises. Physical examination was otherwise unremarkable. Cranial magnetic resonance imaging (MRI) revealed modest fronto-temporal brain atrophy. Electroencephalogram (EEG) demonstrated slight general slowing and a focal slowing with continuous deltawaves fronto-temporal on the left and intermittent delta-waves temporal on the right side. Cerebrospinal fluid (CSF) showed a normal cell count, a slightly disturbed blood brain barrier (total protein of 48 mg/dL (< 45 mg/dL)), and negative oligoclonal bands. Examination excluded neurotropic viruses, bacteria or fungi in serum or CSF. Vasculitis screening and thyroid function were unobtrusive. Liver enzymes (GOT, GPT) were slightly increased while routine haematology and biochemistry were otherwise normal. Immunofluorescence analysis (IFA) with neuronal tissue revealed a high concentration of a serum antibody reactive with a nuclear antigen on cerebral and cerebellar sections, showing a typical pattern for anti-Ri antibody by Western blot (in house immunoblot with cerebellum extract and recombinant Ri-antigen). Serial dilutions revealed a specific antibody titre of 1:25600. In addition, the antibodies were identified as anti-Ri antibodies by a commercial immunofluorescence test, following the recommendations of the manufacturers (Euroimmun, Germany) and by a dot blot assay (onconeuronal antigens, Milenia Biotec, Germany). The serum was not reactive with tissue of peripheral nerve in IFA. Screening by CT and MRI revealed an asymptomatic metastatic invasion of multiple segments of the patient’s liver, lingula of the lung, and osteoplastic metastasis of several thoracal and lumbal vertebral bodies and of the sacrum. Bone scintigram was normal. Hydroxyindoleacetic acid was tenfold elevated in a 24 hour urine sample and neuron-specific enolase was elevated to levels of 17.7 μg/L (< 12.5 μg/L). Due to a negative somatostatin-receptor scintigram, treatment by somatostatin was not given. Biphosphonates were given intravenously every four weeks to prevent pathological bone fractures. 12 months after discharge the patient reported (by telephone) a good physical condition, neuropsychological impairment had not remarkably progressed. The clinical findings, and the detection of anti-Ri antibodies in serum together with the exclusion of other differential diagnosis findings are very consistent with paraneoplastic limbic encephalitis (PLE) [2]. The association of anti-Ri antibodies and carcinoid tumour is new, though not surprising, as bronchial carcinoids belong to the same histological family as small cell lung cancers (SCLC), detected in 5/28 patients with anti-Ri syndrome [5] and in 20/50 patients with PLE [2]. However, anti-Ri antibodies were not found in the latter series and have been described in only one patient with PLE before [5]. The fact that the neurological symptoms arose after an eight year latency to the diagnosis of the primary tumour may be surprising. Unfortunately we do not have a serum sample from the time before the neurological disease developed. Therefore, we cannot estimate the beginning of the anti-Ri immune response. However, as tumour recurrence was found around the time of the beginning of neurological symptoms it may be speculated, that coexpression of other factors (e. g. MHC molecules) in addition to the Ri-antigen by metastases may generate the antineuronal immune response. Such a mechanism is suggested for the anti-Hu syndrome [1]. In conclusion, this is the first reLETTER TO THE EDITORS

Recent advance in immunological tests in paraneoplastic neurological syndrome.

Paraneoplastic neurological syndromes are uncommon, however; their diagnosis is of major practical importance. Any portion of the nervous system may be involved in paraneoplastic syndromes. There is increasing evidence that the pathogenesis of many paraneoplastic neurological syndromes appears to be an immune reaction against antigen shared by the cancer and the nervous system. The identification of antibodies in the serum or cerebrospinal fluid in the central nervous system of paraneoplastic syndrome patient confirms the clinical diagnosis of paraneoplastic syndrome, and allows early identification of an underlying tumor at a stage when it is localized and more amenable to treatment. Cancer therapy (surgery, radiotherapy, chemotherapy) seems to be the most efficient treatment for the paraneoplastic neurological symptoms. Immunomodulatory therapy (intravenous immunoglobulin, plasmapheresis, immunosuppression) can halt or even reverse the neurological syndrome. The recent advances in understanding of the autoimmune pathology of these disorders should lead to more effective treatment options.

Quantification of circulating anti-Hu antibody in serial samples from patients with paraneoplastic neurological syndromes: Possible correlation of antibody concentration and course of neurological symptoms

Serial samples, spanning an observation period of 4 to 10 years, from five patients with anti-Hu associated paraneoplastic neurological syndromes (PNS) were investigated with an enzyme linked immunosorbent assay (ELISA) employing recombinant HuD protein as antigen. In one patient the anti-Hu antibody concentration converted from negative to highly positive levels after the onset of neurological symptoms. These findings argue in favour of the idea that an autoimmune process, which is generated at the beginning of the neurological disease, causes the anti-Hu associated PNS. Serum samples obtained shortly after the beginning of the PNS were available from two other patients. The anti-Hu antibody levels in these latter patients increased from modest to highly positive anti-Hu antibody in follow up samples. In two patients a clear decrease of the anti-HuD antibody concentration together with an improvement of paraneoplastic neurological symptoms after successful tumour treatment were seen. Overall these data suggest that there might be a correlation between the anti-HuD antibody level and the clinical course of paraneoplastic neurological symptoms which supports further the hypothesis that an autoimmune process is responsible for the anti-Hu associated paraneoplastic neurological symptoms.

Ma1, a novel neuron- and testis-specific protein, is recognized by the serum of patients with paraneoplastic neurological disorders.

The identification of antineuronal antibodies has facilitated the diagnosis of paraneoplastic neurological disorders and the early detection of the associated tumours. It has also led to the cloning of possibly important neuron-specific proteins. In this study we wanted to identify novel antineuronal antibodies in the sera of patients with paraneoplastic neurological disorders and to clone the corresponding antigens. Serological studies of 1705 sera from patients with suspected paraneoplastic neurological disorders resulted in the identification of four patients with antibodies that reacted with 37 and 40 kDa neuronal proteins (anti-Ma antibodies). Three patients had brainstem and cerebellar dysfunction, and one had dysphagia and motor weakness. Autopsy of two patients showed loss of Purkinje cells, Bergmann gliosis and deep cerebellar white matter inflammatory infiltrates. Extensive neuronal degeneration, gliosis and infiltrates mainly composed of CD8+ T cells were also found in the brainstem of one patient. In normal human and rat tissues, the anti-Ma antibodies reacted exclusively with neurons and with testicular germ cells; the reaction was mainly with subnuclear elements (including the nucleoli) and to a lesser degree the cytoplasm. Anti-Ma antibodies also reacted with the cancers (breast, colon and parotid) available from three anti-Ma patients, but not with 66 other tumours of varying histological types. Preincubation of tissues with any of the anti-Ma sera abrogated the reactivity of the other anti-Ma immunoglobulins. Probing of a human complementary DNA library with anti-Ma serum resulted in the cloning of a gene that encodes a novel 37 kDa protein (Mal). Recombinant Mal was specifically recognized by the four anti-Ma sera but not by 337 control sera, including those from 52 normal individuals, 179 cancer patients without paraneoplastic neurological symptoms, 96 patients with paraneoplastic syndromes and 10 patients with non-cancer-related neurological disorders. The expression of Mal mRNA is highly restricted to the brain and testis. Subsequent analysis suggested that Mal is likely to be a phosphoprotein. Our study demonstrates that some patients with paraneoplastic neurological disorders develop antibodies against Mal, a new member of an expanding family of 'brain/testis' proteins.