Paraneoplastic Neurological Syndromes Research Articles

Anti-Ma2-Associated Encephalitis Presenting as Hypersomnia

Anti-Ma2-associated encephalitis is one of the paraneoplastic neurological syndromes. It has been shown to be associated with various neoplasms, mainly testicular, lung, and breast cancers. Most patients with anti-Ma2-associated encephalitis present limbic-diencephalic-brainstem dysfunctions such as seizure, mood disorder, excessive daytime sleepiness, and ophthalmoparesis. Some patients develop symptoms indicating the multifocal involvement of the limbic system, diencephalon, or brainstem. However, there are few case studies of anti-Ma2-associated encephalitis presenting as isolated hypersomnia. We report a case of anti-Ma2-associated encephalitis presenting as hypersomnia. Key Words: Hypersomnia, Anti-Ma2 antibodies, Paraneoplastic syndrome

Síndromes neurológicos paraneoplásicos asociados a anticuerpos anti-Ma y anti-Ma2

ObjectiveAnalyse the clinical profile, associated tumour types, and response to treatment of paraneoplastic neurological syndromes associated with antibodies against Ma proteins. MethodsA retrospective study of patients with antibodies against Ma proteins identified in a neuroimmunology laboratory of reference. ResultsOf the 32 patients identified, 20 showed reactivity against Ma2 only (anti-Ma2 antibodies), 11 against Ma1 and Ma2 (anti-Ma antibodies), and 1 with reactivity against Ma1 only (anti-Ma1 antibodies). The most common clinical presentations were limbic encephalopathy, diencephalic dysfunction, or brainstem encephalopathy, frequently appearing as a combination of these features. Three patients had isolated cerebellar dysfunction with anti-Ma antibodies, and 2 exhibited peripheral nervous system syndrome with anti-Ma2 antibodies. Testicular tumours were the most common neoplasms (40%) in the anti-Ma2 cases. In the group associated with anti-Ma1 antibodies, the most common were lung tumours (36%), followed by testicular tumours. All idiopathic cases were reactive to Ma2. The clinical outcome was significantly better in the anti-Ma2 group. The patient with anti-Ma1 presented with limbic encephalitis and brainstem dysfunction associated with lymphoepithelioma of the bladder. ConclusionsSpecifically determining the different reactivities of anti-Ma protein antibodies in order to differentiate between Ma1 and Ma2 antibodies is important because anti-Ma2-associated paraneoplastic syndromes have a better outcome. Lastly, this study is the first to confirm that there may be cases that react exclusively to antibodies against Ma1.

Paraneoplastic autoantibody panels: sensitivity and specificity, a retrospective cohort

Background: Experts in the autoimmune paraneoplastic field recommend autoantibody testing as “panels” to improve the poor sensitivity of individual autoantibodies in detecting paraneoplastic neurological syndromes (PNS). The sensitivity of those panels was not reported to date in a fashion devoid of incorporation bias. We aimed to assess the collective sensitivity and specificity of one of the commonly used panels in detecting PNS. Methods: A single-centered retrospective cohort of all patients tested for paraneoplastic evaluation panel (PAVAL; test ID: 83380) over one year for the suspicion of PNS. Case adjudication was based on newly proposed diagnostic criteria in line with previously published literature, but modified to exclude serological status to avoid incorporation bias. Measures of diagnostic accuracy were subsequently calculated. Cases that failed to show association with malignancy within the follow-up time studied, reflecting a possibly pure autoimmune process was considered paraneoplastic-like syndromes. Results: Out of 321 patients tested, 51 patients tested positive. Thirty-two patients met diagnostic criteria for paraneoplastic/paraneoplastic-like syndromes. The calculated collective sensitivity was 34% (95% CI: 17–53), specificity was 86% (95% CI: 81–90), Youden's index 0.2 and a positive clinical utility index 0.07 suggesting poor utility for case-detection. Conclusion: This is the first reported diagnostic accuracy measures of paraneoplastic panels without incorporation bias. Despite recommended panel testing to improve detection of PNS, sensitivity remains low with poor utility for case-detection. The high-calculated specificity suggests a possible role in confirming the condition in difficult cases suspicious for PNS, when enough supportive evidence is lacking on ancillary testing.

Aquaporin-4 IgG autoimmune syndrome and immunoreactivity associated with thyroid cancer.

Tumor cells can express so-called onconeural antigens, which are normally restricted to mature neurons and glial cells in the CNS.1 The detection of neural-reactive immunoglobulin G (IgG) aids the diagnosis of paraneoplastic neurologic syndromes (PNS)1; however, the diagnostic utility and potential pathogenicity of autoantibodies vary between neurologic diseases. By contrast, anti-aquaporin-4 (AQP4) IgG from patients with neuromyelitis optica spectrum disorder (NMOSD) is a specific biomarker for NMOSD.2 AQP4 is the most abundant water channel in the CNS, particularly abundant on astrocytes, forming the glia limitans of the blood–brain barrier.3 There is compelling evidence that AQP4-IgG reactivity and pathogenicity is restricted to the CNS, probably through an impaired blood–brain barrier.2,3 The clinical features of NMOSD include inflammation of the optic nerve, spinal cord, and specific brain areas coinciding with sites of high AQP4 expression.2,3 Some cases of NMOSD thus far reported may reflect a paraneoplastic immune response.4 Acknowledgment: The authors thank The Lundbeck Foundation, The Region of Southern Denmark, and The University of Southern Denmark for support; and the Owens group for discussion. F.P. is supported by Bundesministerium fur Bildung und Forschung (Competence Network Multiple Sclerosis).

Lambert‐Eaton Myasthenic Syndrome: A Review

Lambert‐Eaton myasthenic syndrome (LEMS) is an auto‐immune disorder caused by neuromuscular transmission failure, and is a representative pre‐neuromuscular junctional disorder. The auto‐immune antibody is anti‐P/Q‐type voltage‐gated calcium channel (P/Q‐type VGCC) antibody detected in approximately 80 to 90% of LEMS patients. Approximately 60% of LEMS patients have small cell lung cancer (SCLC), approximately 10% of patients have other malignant tumors, and the remaining 30% have no malignancy. Thus, the therapeutic strategy for LEMS depends on the presence of a malignant tumor. LEMS with a malignant tumor is also considered to be a representative paraneoplastic neurological syndrome. Recently, new chemotherapeutic drugs for malignant tumors including SCLC have been developed. In cases with no malignancy, several new immune‐mediated therapies have become available. Therefore, we can expect improved therapeutic responses for this disorder.

Utility of 18F-FDG-PET/CT in patients suspected of paraneoplastic neurological syndrome: importance of risk classification.

To assess the diagnostic impact of 18F-FDG-PET/CT in patients suspected of paraneoplastic neurological syndrome (PNS) based on our own pre-test risk classification (PRC). A multicenter retrospective longitudinal study was conducted from 2006 to 2014. We designed a seven-point scoring system using the clinical syndrome characteristics [classical (CS) and non-classical syndromes (NCS)] and its location (central, peripheral, in the neuromuscular junction or combined), onconeural antibodies and tumor markers. Patients were classified as low (score 0-2), intermediate (3-4) and high (5-7) pre-test risk of PNS. FDG-PET/CT was classified as negative or positive. Final diagnosis according Graus' criteria (definite, possible or no PNS) was established. Relations between clinical and metabolic variables with the final diagnosis were studied. 73 patients were included, with a follow-up time of 33months. Eleven (15%) patients were finally diagnosed with neoplasm (8 invasive cancers). Ultimately, 13 (18%) and 24 (33%) subjects were diagnosed as definite or possible PNS. All the patients with final diagnosis of neoplasm had a CS (p=0.005). PET/CT was helpful to diagnose 6/8 (75%) invasive cancers. PET/CT findings were associated with the final diagnosis of neoplasm (p=0.003) and the diagnosis of PNS attending to Graus' criteria (p=0.019). PRC showed significant association with the final diagnosis of neoplasm and PET/CT results. A majority of patients (10/11) diagnosed of neoplasm had intermediate/high-risk. Our PRC seems to be a valid tool to select candidates for PET/CT imaging in this setting. PET/CT detected malignancy in a significant proportion of patients with invasive cancer.

Is peripheral paraneoplastic neurological syndrome possible in primary brain tumors?

IntroductionSystemic malignant diseases cause the induction of autoimmunity, for example, paraneoplastic syndromes. There are no proofs of paraneoplastic syndromes in primary brain tumors. The aim of the study was to evaluate the involvement of the peripheral nervous system, together with an assessment of onconeuronal and antineural antibodies as indicators of humoral immune response against nervous system in patients with primary brain tumors.Materials and MethodsClinical examinations, electrophysiological studies of peripheral nerves (motor and sensory conduction velocity studies, conduction velocity distribution tests, thermal and vibratory quantitative sensory tests, and sympathetic skin response tests) and muscles, blood sampling collection (assessment of onconeuronal, and antineural antibodies) were performed on 33 patients with newly recognized primary brain tumors within 2–4 days after their admission to our department.ResultsWe revealed statistically significant changes of peripheral nerves, more pronounced in the peroneal nerve in standard and conduction velocity distribution tests, as well as in sympathetic skin responses. We revealed significantly higher vibratory thresholds, and pain thresholds for cold and warm in the upper and lower limbs in the study group than in the controls. In five patients, we have identified anti‐neuroendothelium, anti‐GFAP, anti‐MAG, anti‐PCNA, and anti‐Ro52 antibodies.ConclusionsIn patients with primary brain tumors, electrophysiological changes in peripheral nerves, together with the presence of the antineural antibodies suggest an autoimmune humoral response, and make the diagnosis of paraneoplastic neurological syndrome possible.

Short hystory of the study of paraneopastic neurological syndrome

Paraneoplastic neurological syndromes (PNS) can be defined as remote effects of cancer that are neither caused by the tumor and its metastases, nor by infection, ischemia or metabolic disturbances. The authors presented the lecture highlighting the actuality of the problem and definition of PNS, main part of the article is devoted to the history of the study of PNS in the our country and abroad.

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.

Paraneoplastic Neurological Syndrome with Dementia

Paraneoplastic neurological syndrome with limbic encephalopathy tends to progress rapidly, presenting with physical symptoms such as ataxia or sensory disturbance. However, some affected patients demonstrate amnesia, inactivity, or abnormal behavior, which lead to the diagnosis of dementia. It is important to perform an extensive differential diagnosis with autoantibody-examination and tumor survey, so as not to overlook potentially treatable dementia.

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.

Motor cortex and hippocampus are the two main cortical targets in LGI1-antibody encephalitis.

Encephalitis associated with antibodies against leucine-rich glioma-inactivated 1 (LGI1) protein is increasingly recognized as an auto-immune disorder associated with characteristic tonic-dystonic seizures. The cortical or subcortical origin of these motor events is not clear. Some patients also present with different epileptic seizures and with cognitive impairment. The frequency of these features and their timing during the natural history of this encephalitis have not been fully described. We therefore reviewed data from 34 patients harbouring antibodies against LGI1 protein (21-81 years, median age 64) referred to the French Reference Centre for Neurological Paraneoplastic Syndrome. Three types of evidence suggested tonic-dystonic seizures were of cortical origin: (i) a slow, unilateral, frontal electroencephalographic wave, of duration ∼580 ms and amplitude ∼71 µV, preceded the contralateral tonic-dystonic seizures in simultaneous electroencephalographic and myographic records from seven of seven patients tested; (ii) 18-Fluorodeoxyglucose imaging revealed a strong hypermetabolism in primary motor cortex, controlateral to the affected limb, during encephalitis for five patients tested, as compared with data from the same patients after remission or from 16 control subjects; and (iii) features of polymyographic records of tonic-dystonic seizure events pointed to a cortical origin. Myoclonic patterns with brief, rhythmic bursts were present in three of five patients tested and a premyoclonic potential was identified in the cortex of one patient. Initially during encephalitis, 11 of 34 patients exhibited tonic-dystonic seizures (32%). Distinct epileptic syndromes were evident in 13 patients (38%). They were typically simple, focal seizures from the temporal lobe, consisting of vegetative symptoms or fear. At later stages, 22 of 32 patients displayed tonic-dystonic seizures (68%) and 29 patients presented frequent seizures (91%) including status epilepticus. Cognitive impairment, either anterograde amnesia or confusion was evident in 30 of 34 patients (88%). Brain imaging was normal in patients with isolated tonic-dystonic seizures; in patients with limbic symptoms it revealed initially a hippocampal hyperintensity in 8 of 19 patients (42%) and 17 of 24 patients (70%) at later stages. Our data suggest that the major signs of LGI1-antibody encephalitis can be linked to involvement of motor cortex and hippocampus. They occur in parallel with striatum involvement. One of these cortical targets is involved, often unilaterally at disease onset. As the encephalitis progresses, in the absence of immunomodulatory treatment, the second cortical target is affected and effects become bilateral. Progression to the second cortical target occurs with a variable delay of days to several months.

A case study of paraneoplastic cauda equina syndrome caused by a gastric adenocarcinoma

Introduction: cauda equina syndrome results from dysfunction of multiple sacral and lumbar nerve roots in the lumbar vertebral canal, leading to impairment of bladder, bowel, or sexual function, and perianal or “saddle” numbness. the most common cause of cauda equina syndrome is disc herniation resulting in compression at L4/5 and L5/s1. However, we will discuss the case of cauda equine syndrome with a paraneoplastic cause. there are only a handful of cases in literature of paraneoplastic cauda equine syndrome, and none specifically as a result of gastric adenocarcinoma. Paraneoplastic neurological syndromes (of which paraneoplastic cauda equine syndrome is one) are described as remote effects of cancer on the neurological system. they are rare, affecting less than 1/10,000 patients with cancer. In this case, the cauda equina was the target for an autoimmune response directed against antigens common to both the cancer and the nervous system. case report: A 71-year-old female was admitted with a two-month history of lumbar back pain, radiating down her thigh, progressive weakness of both legs, numbness of the sacral area, urinary incontinence and 6.4 kilogram unintentional weight loss within 2 months. Abdominal radiograph, breast examination, lumbar puncture, and autoantibodies screens

抗NMDA受容体脳炎における高次脳機能障害と回復過程の検討

We report five cases of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Five women (27-38 years), Who-presented with psychiatric symptoms, neurological complications, and decreased consciousness, were diagnosed with anti-NMDAR encephalitis after testing positive for serum anti-NMDAR antibodies. The mean（±SD）for hospitalization duration was 272.4（±144.8)days. All patients presented with respiratory failure due to central hypoventilation and required mechanical ventilation for 50.2（±13.1）days on average. Four patients showed no abnormal findings upon brain MRI, one showed high intensity lesions in the right temporal cortex and bilaterally in the hippocampus on T2 weighted images. Higher brain function assessment revealed an overall decrease in intelligence, attention, memory, and executive function in all patients. Temporal assessments revealed progressive improvement in these dysfunctions over several years. Four patients presented with deep venous thrombosis, articular contracture, ectopic ossification, and compression paralysis during the first immobility episode. Two had severely impaired communication and ability to perform activities of daily living when admitted for rehabilitation. However, eventually all the patients attained a premorbid state. Anti-NMDAR encephalitis possibly results from reversible synaptic dysfunction；therefore, it has a better functional prognosis compared with classical limbic encephalitis and other paraneoplastic neurologic syndromes. Previous studies found abnormalities in the limbic area on MRI in about 25％ of patients, although other findings were non-specific. Prevention of disuse syndrome due to prolonged immobility is important in acute phase rehabilitation. Our study shows that long-term temporal assessments of higher brain function are necessary and useful in the chronic stage.

Composed Paraneoplastic Neurological Syndrome, Disseminated in Time and Space, in the Course of Non-Small Cell Neuro-Endocrine Lung Cancer

Introduction: Paraneoplastic neurological syndrome is a rare complication of different types of cancer. Non-small cell neuro-endocrine lung cancer is very rare and there are few descriptions of paraneoplastic syndrome in patients with such types of cancer. Paraneoplastic movement disorders, among them chorea, have an exceptionally rare occurrence. Clinical presentation: A 64-year-old woman presented paraneoplastic chorea with non-typical coincidence of anti-Hu and anti-GD1b antibodies. Chorea was the last sign of the disease and was comorbid with encephalitis, chronic polyradiculoneuropathy and autonomic dysfunction; the clinical symptoms were disseminated in time. A very rare type of lung cancer i.e., poorly differentiated non-small cell neuroendocrine cancer was found. Conclusions: The diversity of the clinical picture in this patient with non-small cell neuro-endocrine lung cancer can be explained by the complexity of the neurological pathomechanisms of paraneoplastic syndromes.

傍腫瘍性神経症候群患者に対するリハビリテーション

〔目的〕傍腫瘍性神経症候群（PNS）患者の運動機能・日常生活活動（ADL）経過の分析から，リハビリテーション（リハ）の効果を検討すること．〔対象〕リハ処方されたPNS患者8例とした．〔方法〕人口統計学的および医学的データ，運動機能・ADLのデータを診療録より後方視的に情報収集した．〔結果〕5例で評価項目値が改善し，そのうち4例は発症後3ヵ月以内に抗腫瘍療法が開始され，1例は発症後4ヵ月で免疫療法が施された．また，評価項目値が改善した5例では，治療開始時から退院時までのBI得点変化量が大きい症例でリハ実施期間が長かった．〔結語〕早期治療と十分なリハ実施期間の確保が，PNS患者の運動機能・ADL改善に重要である．

多彩な神経症状を呈した小細胞肺癌に伴う傍腫瘍性神経症候群の1例

多彩な神経症状を呈した小細胞肺癌に伴う傍腫瘍性神経症候群の1例

Accuracy of FDG-PET/CT and paraneoplastic antibodies in diagnosing cancer in paraneoplastic neurological syndromes

ObjectiveThere is still no consensus about whether to perform PET/CT to detect carcinoma in paraneoplastic neurological syndromes (PNS) in patients with or without antibodies. The aim of this study is to determine the diagnostic accuracy of PET/CT and antibodies in patients with PNS. Material and MethodsA retrospective study was conducted on patients with clinically suspected PNS between 2008 and 2013. The association between histopathological findings, paraneoplastic antibodies, and PET/CT findings were evaluated. Sensitivity and specificity for the detection of underlying malignancy were calculated for PET/CT and paraneoplastic antibodies. ResultsA total of 42 patients were analyzed. Of these 42 patients, 32 (75%) had a classical PNS, 6 (14%) had positive PET/CT findings, and 34 were tested for the presence of antibodies (anti-Hu Ab, anti-Yo Ab, and anti-Ri Ab). Twenty one of 34 patients had positive antibodies. Of the 6 patients with positive PET/CT findings, 6 had positive histopathological results. Among 21 patients with positive biomarkers, carcinoma was confirmed only in 5 patients. One patient with negative antibodies, but positive PET/CT findings, was diagnosed with a tumor. Gastric carcinoma was detected in 1 patient with negative PET/CT findings and antibodies during follow-up. Based on the results, PET/CT was found to have 85.71% sensitivity, 100% specificity, 100% positive and 97.22% negative predictive values in the detection of tumors. ConclusionPET/CT has a certain diagnostic accuracy for detecting underlying malignancy in patients with PNS, regardless of the presence of paraneoplastic antibodies.

Clinical significance of paraneoplastic neurological antibodies detection

Paraneoplastic neurological syndromes (PNS) were defined as neurological syndromes associated with cancer. In many cases, autoantibodies against neural antigens expressed by the tumor (paraneoplastic neurological antibody or onconeural antibodies) were detected. The neuronal antibodies, which were associated with syndromes resulting from central nervous system neuronal dysfunction, were classified into two groups according to the location of the antigen: inside the neuron or in the cell membrane. Group Ⅰ antibodies targeted on intracellular antigens and were predominantly dependent on T-cell-mediated responses. Group Ⅱ antibodies recognized neuronal surface antigens and were predominantly dependent on B-cell-mediated responses. Onconeural antibodies were useful diagnostic markers of the brain disease, and in some cases, they might reveal an underlying malignancy. Moreover, the presence of antibodies against surface(group Ⅱ) antigens might predict a more favorable response to immunotherapy than that against intracellular (group Ⅰ) antigens.(Chin J Lab Med, 2015, 38: 801-804) Key words: Paraneoplastic syndromes, nervous system; Antibodies, neoplasm; Tumor markers, biological

Pitfalls in the detection of CV2 (CRMP5) antibodies

CV2 antibodies (CV2-ab) associate with paraneoplastic neurological syndromes (PNS) and small-cell lung cancer. This study was designed to assess the sensitivity of two widely used anti-CV2 commercial kits. Fifty three sera with CV2-ab identified by immunohistochemistry on paraformaldehyde-perfused rat brain were tested with two commercial immunoblot kits (Euroimmun AG, and Ravo Diagnostika) and 4 (7.5%) of them were negative with the commercial kits. The 4 samples were positive by immunofluorescence on HEK293 cells transfected with CRMP5 and immunoblot of these cells lysate. A few CV2-ab-positive sera may be missed by commercial immunoblots. Negative samples from patients with high suspicion for PNS should be tested by alternative methods.