Classical Paraneoplastic Neurological Syndromes Research Articles

Breast cancer-associated opsoclonus-myoclonus syndrome: a case report

BackgroundParaneoplastic neurological syndromes constitute rare neurological complications of malignant disease, manifesting in <1% of patients with cancer. Opsoclonus-myoclonus syndrome (OMS) presents with chaotic ocular saccades (opsoclonus), spontaneous muscular jerking (myoclonus) that may be accompanied by ataxia, strabismus, aphasia, or mutism. Its paraneoplastic variant in the adult is most commonly associated with small-cell lung cancer, followed by breast cancer. Importantly, neurological symptoms usually precede the diagnosis of breast cancer and tend to recure after its treatment.Case presentationA 43-year-old premenopausal Caucasian woman with a medical history of hypertension was admitted following an episode of focal seizure. This progressed to generalised tonic-clonic seizures and she was subsequently loaded with phenytoin, valproate, and levetiracetam. Initial workup included whole body CT scan, viral and autoimmune serology. The CT scan revealed an enhancing right axillary lymph node, which in combination with Anti-Ri antibody positivity raised the spectre of paraneoplastic OMS. MRI of the head revealed subtle nonspecific white matter signal change within the centrum semiovale without any mass lesions, while MRI of the spine was unremarkable. An uncomplicated right mastectomy and axillary lymph node clearance was performed: histopathology revealed a 9-mm, grade 2, oestrogen receptor-positive, progesterone receptor-negative (ER8, PR0), Her2-negative invasive ductal carcinoma, and 4/6 positive lymph nodes (T1b N2 M0). Two months later, she was readmitted with vertigo, diplopia, facial weakness, and ataxia, setting the diagnosis anti-Ri syndrome recurrence. MDT recommended mammogram and ultrasound of the left breast, which were normal. Subsequently, four months after initial discharge, she suffered another neurological recurrence; due to concomitant abdominal pain, PET-CT was performed demonstrating a hypermetabolic right ovarian focus. Bilateral salpingo-oophorectomy was performed as per gynaecology MDT and final histology showed normal tubes and ovaries. She has remained on remission since then, with a negative annual mammogram follow-up.ConclusionsIn conclusion, we report a case of OMS associated with breast cancer anti-Ri onconeural antibody. Its manifestations preceded the diagnosis of malignancy and it persisted after cancer treatment, underlining the importance for high clinical suspicion in cases of classical paraneoplastic neurological syndromes as well as the need for long-term clinical follow-up.

Clinical Spectrum, Therapeutic Outcomes and Prognostic predictors in Paraneoplastic Neurological Syndromes - Experiences from a Tertiary Care Center in India.

Background:Paraneoplastic Neurological Syndromes (PNSs) are a heterogeneous group of immune-mediated disorders that often precede tumor diagnosis. There are few systematic studies on the spectrum and follow-up of PNSs.Objective:To analyze the clinical spectrum, associated tumors, antibody profile, outcomes, and prognostic predictors in a cohort of PNSs admitted in a tertiary care center.Methods:This retrospective study included 97 patients (2008-2019). PNSs were further classified as “classical,” “nonclassical,” “definite,” and “possible.” Clinical profile, diagnostic strategies, therapeutic options, and predictors of outcomes were identified.Results:The median age was 54 years (range 17–81). Thirty-nine (40.2%) had classical PNS, and 58 (59.8%) had nonclassical PNS, 74 (76.3%) had “Definite” PNS while 23 (23.7%) had “Possible” PNS. Cerebellar degeneration, peripheral neuropathy, and encephalopathy were the three most common neurological syndromes. Tumors were diagnosed in 66 (68%) patients; Lung cancer was the most common primary tumor. Antibodies were positive in 52 (53.6%). Anti-Yo antibody and anti-Ma2 antibody were the most common antibodies. The majority (57.7%) received immunotherapy in addition to definitive treatment for the tumor. A good outcome was seen in 53 (54.6%). Factors associated with good outcome were: early diagnosis, mRS <3 at presentation, absence of metastatic disease, and adjuvant immunotherapy.Conclusion:A high index of clinical suspicion is essential for early diagnosis and prompt management of PNS, especially the nonclassical syndromes. Multimodality diagnostic imaging techniques and antibody profiling play a crucial role in the diagnosis. A favorable prognosis can be expected with the judicious use of immunotherapy and definitive treatment of malignancy.

Imaging Workup of Suspected Classical Paraneoplastic Neurological Syndromes: A Systematic Review and Retrospective Analysis of 18F-FDG-PET-CT

This study aimed to assess the clinical efficacy of positron emission tomography (PET) or combined PET-computed tomography (CT) with 18F-fluorodeoxyglucose (FDG) for whole-body cancer screening in patients with suspected paraneoplastic neurological syndromes (PNS). The following main research questions were addressed: What is the percentage of positive findings to be expected in whole-body FDG-PET-CT in adult patients with PNS? How many false positives can be expected as assessed by clinical and histopathological workup? Are there patients who present with a tumor despite initially negative findings? This is a systematic review of the literature and retrospective analysis of FDG-PET-CT and clinical follow-up data from 45 consecutive patients (age: 56.6 ± standard deviation 15.8 years, 14 female, 31 male). Suspicious lesions were identified and correlated with immediate workup and clinical follow-up. Fourteen studies were included in the review. Eleven malignancies (24.4% of patients) were identified by FDG-PET-CT in this sample. This is a higher percentage of positive findings compared to most previous reports. There was one initially negative finding. Whole-body FDG-PET-CT is suitable to identify additional malignancies in patients with suspected classical PNS referred to a tertiary medical center. The utility by means of true-positive findings is higher in classical PNS than suggested by studies in less select patient populations.

CLINICAL PROFILE AND DIFFERENTIAL DIAGNOSIS OF CLASSICAL PARANEOPLASTIC NEUROLOGIC SYNDROMES IN LYMPHOMAS

Clinical heterogeneity of lymphomas is associated with both tumor localization and its morphological and immunological variants, moreover, in some cases with paraneoplastic neurological syndromes (PNS). As the immuno-oncology advances, the antineuronal antibodies were investigated. They are revealed in case of malignant neoplasms and explain the pathological mechanisms of PNS development. The presented literature review provides data on main clinical and laboratory characteristics of classical PNS associated with lymphomas and characterizes the antineuronal antibodies determined in patients with PNS.

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.

Paraneoplastische neurologische Syndrome und Autoimmunenzephalitiden

Paraneoplastic neurological syndromes (PNS) are defined as remote effects on the central and peripheral nervous system that are not caused directly by the tumor, its metastases and treatment, or metabolic disorders. The most probable cause is a falsely initiated immune reaction. Well-defined classical PNSs are associated with distinct tumors and occur with onconeural antibodies directed against intracellular neuronal antigens. However, response to therapy is limited. Recently, new antibodies directed against neuronal surface antigens were described in encephalitic syndromes of autoimmune origin. These probably antibody-mediated disorders are more frequent than classical PNS, occur with or without tumor association and often show a good response to immunosuppressive treatment.

Onconeural antibodies in patients with neurological symptoms: detection and clinical significance

Onconeural antibodies are strongly associated with cancer and paraneoplastic neurological syndromes (PNS). Most of these antibodies are well-characterized (antibodies against Hu, Yo, Ri, CRMP5, amphiphysin, Ma2 and Tr) and are in common use for the diagnosis of definite PNS. Literature on detection and clinical significance of onconeural antibodies were identified by using relevant search terms in PubMed and reviewed. The onconeural antibodies are directed against intracellular antigens and their pathogenic role is still largely unknown. They are highly specific markers of paraneoplastic aetiology in patients with neurological symptoms. Detection of an onconeural antibody in a patient with neurological symptoms should lead to prompt investigation for cancer. However, absence of detectable onconeural antibodies does not exclude the PNS diagnosis. In particular, failure to detect antibodies in patients without classical PNS symptoms may result in less vigorous cancer screening and diagnostic delay. Neuronal antibodies that are directed to synaptic proteins or proteins of the cell membrane are also associated with neurological symptoms, and probably have pathogenic effects. The association between these antibodies and cancer is less robust, and they are usually not included among the onconeural antibodies.

Brainstem and spinal cord involvement in a paraneoplastic syndrome associated with anti-Yo antibody and breast cancer

Paraneoplastic neurological syndromes (PNS) are associated with breast cancer in\1% of cases [1]. Anti-Yo/PCA1 antibody is usually detected in female patients with breast or gynaecologic cancer and is most commonly associated with progressive cerebellar degeneration (PCD) [2–5]. Here we describe a case of a 60-year-old woman who, in May 2008, complained of progressive weakness of lower limbs followed, after 2 months, by dysesthesias in the four limbs, dysphagia, diplopia and sensory ataxia. Total body computed tomography (CT) scan, brain and spinal cord magnetic resonance imaging (MRI) were normal, electromyography (EMG) showed evidence of acute and chronic denervation in the four limb muscles, oligoclonal bands were present in the cerebrospinal fluid and serum anti-onconeural antibodies were negative. She was treated with steroids for several months with partial benefit but soon after drug discontinuation her symptoms worsened. At our first neurological examination in January 2010, the patient was unable to walk for severe sensory ataxia and showed lower limb weakness and spasticity, mild dysarthria, dysphagia, diplopia and dysesthesias in the four limbs. Sensory and motor evoked potentials were altered both at upper and lower limbs and EMG showed evidence of acute and chronic denervation in the muscles of upper and lower extremities. At that time, serum anti-Yo/PCA-1 antibody was positive. Total body CT scan and mammography showed evidence of a nodular opacity associated with two clusters of retroareolar microcalcifications in the left breast. A total body 2-deoxy-2-F-fluoro-D-glucose positron emission tomography (FDG PET)/CT imaging showed high metabolic activity in the right axillary lymph nodes but ultrasound scan (US) and MRI confirmed the left breast calcifications with no evidence of axillary lymph node pathological alterations bilaterally. The left mammary lesion was surgically removed in March 2010. Histopathological examination revealed the presence of foci of ductal carcinoma in situ of G2 grade. Radiotherapy and hormonal therapy were started in April 2010. Soon after the surgery, the neurological symptoms progressively improved. At the last neurological examination in July 2010, the ataxia was reduced and the patient was ambulatory without aid or rest for about 10 m, with only a mild proximal weakness of the legs and diplopia persisting. The EMG evaluation showed improvement mainly at the lower limbs with reduction of acute denervation signs. Despite the fact that, in our patient, the clinical picture was not evocative of a classical PNS, we suspected a paraneoplastic encephalomyelitis; we repeated tests for anti-onconeural antibodies and diagnostic investigations for cancer, and we found serum positivity for anti-Yo/ PCA-1 antibody associated with a ductal breast carcinoma in situ. Very few cases of anti-Yo/PCA-1 antibody associated PNS, different from PCD, have already been described including several cases of peripheral neuropathy [6, 7] and a case of motor neuron disease involving both the upper and the lower motor neurons [8]. All patients with PNS and anti-Yo/PCA-1 antibody associated breast cancer previously reported showed axillary lymph node metastases [9]. D. Plantone P. Caliandro R. Iorio G. Frisullo V. Nociti A. K. Patanella A. Marti P. A. Tonali A. P. Batocchi (&) Department of Neurosciences, Institute of Neurology, Catholic University, Largo Gemelli 8, 00168 Rome, Italy e-mail: annapaola.batocchi@rm.unicatt.it

Screening for tumours in paraneoplastic syndromes: report of an EFNS Task Force

paraneoplastic neurological syndromes (PNS) almost invariably predate detection of the malignancy. Screening for tumours is important in PNS as the tumour directly affects prognosis and treatment and should be performed as soon as possible. an overview of the screening of tumours related to classical PNS is given. Small cell lung cancer, thymoma, breast cancer, ovarian carcinoma and teratoma and testicular tumours are described in relation to paraneoplastic limbic encephalitis, subacute sensory neuronopathy, subacute autonomic neuropathy, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus-myoclonus, Lambert-Eaton myasthenic syndrome (LEMS), myasthenia gravis and paraneoplastic peripheral nerve hyperexcitability. many studies with class IV evidence were available; one study reached level III evidence. No evidence-based recommendations grade A-C were possible, but good practice points were agreed by consensus. the nature of antibody, and to a lesser extent the clinical syndrome, determines the risk and type of an underlying malignancy. For screening of the thoracic region, a CT-thorax is recommended, which if negative is followed by fluorodeoxyglucose-positron emission tomography (FDG-PET). Breast cancer is screened for by mammography, followed by MRI. For the pelvic region, ultrasound (US) is the investigation of first choice followed by CT. Dermatomyositis patients should have CT-thorax/abdomen, US of the pelvic region and mammography in women, US of testes in men under 50 years and colonoscopy in men and women over 50. If primary screening is negative, repeat screening after 3-6 months and screen every 6 months up till 4 years. In LEMS, screening for 2 years is sufficient. In syndromes where only a subgroup of patients have a malignancy, tumour markers have additional value to predict a probable malignancy.

PET scan in clinically suspected paraneoplastic neurological syndromes: a 6-year prospective study in a regional neuroscience unit

The role of PET in the diagnosis of paraneoplastic neurological syndromes (PNS) has previously been reported in retrospective studies, from specialized neuro-oncology units, often selecting patients with positive paraneoplastic antibodies. To prospectively assess the usefulness of PET in detecting malignancy in patients clinically suspected of having PNS. PET was performed in patients suspected of PNS within 4 weeks of the normal CT body scan. All patients were followed up. Eighty patients suspected of having PNS underwent PET. 18/80 (23%) were abnormal and suspicious of malignancy. The total number of definite and probable PNS with abnormal PET was 11/18 (61%). The total number of definite and probable PNS with a normal PET was 3/62 (5%). Only 50% of patients with biopsy-proven malignancy were positive for paraneoplastic antibodies. The prevalence of abnormal PET in patients presenting with classical PNS was 41% as opposed to 21% in patients with non-classical PNS. The sensitivity and specificity of PET in diagnosing PNS was 75% and 87% respectively. PET is a valuable tool in clinically suspected PNS. Its use should not be restricted to specialized neuro-oncology units or in patients with positive paraneoplastic antibodies. Positive yield is the highest amongst patients with classical PNS.

Detection of Autoantibodies to the BTB‐kelch Protein KLHL7 in Cancer Sera

The aim of the study was to search for novel targets of autoantibodies in patients with paraneoplastic neurological syndromes (PNS). PNS are mediated by immune reactions against autoantigen(s) shared by the cancer cells and the nervous system. By serological screening of a rat cerebellum cDNA expression library using anti-Hu-positive sera from three patients with paraneoplastic encephalomyelitis (PEM), we identified an open reading frame encoding an isoform of the BTB-kelch protein KLHL7. Immunohistochemical studies demonstrated that the KLHL7 protein is expressed in the nuclei of neurones, but not in other tissues including various cancers. However, the KLHL7 protein was detected in the nuclei of cancer cell lines. Antibodies to KLHL7 were detected by an immunoprecipitation assay in sera from 12 of 254 (4.7%) patients with various cancers and 2 of 170 blood donors (1.2%). None of 50 sera from patients with multiple sclerosis were positive for KLHL7 antibodies. Sixteen patients with classical PNS and anti-Hu or anti-Yo antibodies were also negative for KLHL7 antibodies. Seven cancer patients with KLHL7 antibodies had various signs of neurological disease that could be related to cancer, whereas the remaining five seropositive cancer patients had no clinical signs of possible PNS. The present results indicate that KLHL7 antibodies are associated with various cancers, and in some patients also with neurological disease. Whether KLHL7 antibodies can be used as paraneoplastic markers for PNS remains to be determined.

Management of paraneoplastic neurological syndromes: report of an EFNS Task Force

Paraneoplastic neurological syndromes (PNS) are remote effects of cancer on the nervous system. An overview of the management of classical PNS, i.e. paraneoplastic limbic encephalitis, subacute sensory neuronopathy, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus-myoclonus, Lambert-Eaton myasthenic syndrome and paraneoplastic peripheral nerve hyperexcitability is given. Myasthenia gravis and paraproteinemic neuropathies are not included in this report. No evidence-based recommendations were possible, but good practice points were agreed by consensus. Urgent investigation is indicated, especially in central nervous system (CNS) syndromes, to allow tumour therapy to be started early and prevent progressive neuronal death and irreversible disability. Onconeural antibodies are of great importance in the investigation of PNS and can be used to focus tumour search. PDG-PET is useful if the initial radiological tumour screen is negative. Early detection and treatment of the tumour is the approach that seems to offer the greatest chance for PNS stabilization. Immune therapy usually has no or modest effect on the CNS syndromes, whereas such therapy is beneficial for PNS affecting the neuromuscular junction. Symptomatic therapy should be offered to all patients with PNS.