Search

Antibodies to the ganglioside GD1b have been reported in various forms of immune-mediated neuropathy, but their clinical relevance for diagnosis and prognosis is unknown. We investigated the prevalence of anti-GD1b antibodies in acute and chronic immune-mediated neuropathies, and the clinical presentation and outcome in Guillain-Barré syndrome (GBS) and Miller Fisher-GBS overlap syndrome (MF-GBS). Anti-GD1b, anti-GM1 and anti-GQ1b antibodies were tested in serum of patients with GBS (N = 165), Miller Fisher syndrome (N = 10), MF-GBS (N = 28), monoclonal gammopathy of unknown significance neuropathy (MGUS; N = 101), chronic inflammatory demyelinating polyneuropathy (N = 29), paraneoplastic syndrome with anti-Hu-associated neuropathy (PNS; N = 11), other auto-immune diseases (AID; N = 60), and healthy controls (HC; N = 60). All samples were tested by enzyme-linked immunosorbent assay according to the Inflammatory Neuropathy Cause and Treatment protocol. IgM anti-GD1b antibodies were found in GBS (N = 4; 2.4%), MGUS (N = 3; 3.0%), and PNS patients (N = 1; 9.1%). IgG anti-GD1b antibodies were found in GBS (N = 20; 12.1%) and MF-GBS (N = 4; 14.3%) patients, but not in the AID and HC group. In the combined group of MF-GBS and GBS patients ((MF-)GBS), 14/36 (38.9%) patients with IgG anti-GD1b antibodies also had IgG anti-GM1 antibodies, and IgG anti-GD1b and IgG anti-GQ1b antibodies were found in 3/29 (10.3%) patients. Patients with (MF-)GBS and anti-GD1b without anti-GM1 antibodies did not differ regarding sensory disturbances or disease severity but recovered faster regarding the ability to walk independently compared with patients without anti-GD1b antibodies (P = 0.031) and with patients with both anti-GD1b and anti-GM1 antibodies (P = 0.034). In conclusion, testing for anti-GD1b antibodies may identify a specific group of immune-mediated neuropathies and (MF-)GBS patients with only anti-GD1b antibodies tend to recover faster., (© 2018 Peripheral Nerve Society.)

Introduction: Voltage-gated calcium-channel autoimmunity (VGCC-P/Q and VGCC-N types) occurs beyond Lambert-Eaton syndrome and lung cancer., Methods: We reviewed records for 236 Mayo Clinic patients with VGCC antibodies found in evaluation for paraneoplastic neurological autoimmunity (generally without myasthenic syndromes)., Results: VGCC autoantibodies were detected in 3.4% of neurological patients, 1.7% of healthy controls, and 4% of neurologically asymptomatic lung cancer controls. Fifty neurological patients (21%) had ≥ 1 neoplasm, historically (46) or detected prospectively [small-cell lung carcinoma (2), breast adenocarcinoma (2), lymphoma (1), and suspected tonsillar carcinoma (1)]. Autoimmune neurological diagnosis frequencies (encephalopathy, ataxia, myelopathy, neuropathy, neuromuscular junction disorder, and myopathy) among patients with medium values (24%; 0.10-0.99 nmol/L) or low values (19%; 0.03-0.10 nmol/L) were fewer than among patients with antibody values exceeding 1.00 nmol/L (71%; P = 0.02 and 0.004, respectively)., Conclusions: Among neuronal VGCC-autoantibody-seropositive patients, autoimmune neurological phenotypes and cancer types are diverse. Cautious interpretation of results (particularly medium and low values) is advised. Muscle Nerve, 2016 Muscle Nerve 54: 220-227, 2016., (© 2016 Wiley Periodicals, Inc.)

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., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objectives: To study possibilities of immunological and electrophysiological methods for the diagnosis of paraneoplastic polyneuropathy in cancer., Methods: We studied 88 cancer patients using electromyography and immunological assay (serum neuronal antibodies)., Results: A symmetrical, distal, sensory-motor, axonal-demyelinating form of polyneuropathy can develop in breast cancer and small cell lung cancer. Onconeural antibodies were detected in the serum of more than half of study participants as well as in some healthy donors. Symptoms of polyneuropathy appeared earlier than the diagnosed tumor., Conclusion: The diagnostic value of the methods used for the early diagnosis of breast cancer and small cell lung cancer is emphasized.

The article provides an overview on the diagnosis and pathogenesis of paraneoplastic neurological disorders (PNDs), and subsequently the current therapeutic strategies in these patients. PNDs are nervous system dysfunctions in cancer patients, which are not due to a local effect of the tumor or its metastases. Most of these clinically defined syndromes in adults are associated with lung cancer, especially small-cell lung cancer, lymphoma and gynecological tumors. In a part of the PND, an overlapping of different clinical syndromes can be observed. Highly specific autoantibodies directed against onconeuronal antigens led to the current hypothesis of an autoimmune pathophysiology. Whereas the most central nervous PNDs are more T-cell-mediated, limbic encephalitis can be caused by pathogenic receptor autoantibodies. The PND of the neuromuscular junction and paraneoplastic autonomic neuropathy are mainly associated with receptor or ion channel autoantibodies. The childhood opsoclonus-myoclonus syndrome and the PNDs associated with receptor/ion channel autoantibodies often respond to immunosuppressive therapies, plasmapheresis and intravenous immunoglobulins. By contrast, most CNS PNDs associated with defined antineuronal antibodies directed against intracellular antigens only stabilize after tumor treatment.

Anti-SOX1 antibodies have been described to be positive in patients with paraneoplastic Lambert-Eaton myasthenic syndrome and, in a lower amount, in patients with anti-Hu positive paraneoplastic neurological syndromes, and with SCLC alone, respectively. We found 5/32 patients with paraneoplastic neuropathy and, surprisingly, 4/22 patients with neuropathy of unknown origin positive for anti-SOX1 antibodies, whereas no patient with inflammatory neuropathy and no healthy controls showed any reactivity (p=0.007). All patients with neuropathy of unknown origin where followed up for four years without diagnosis of a tumour so far. Anti-SOX1 antibodies are associated with paraneoplastic neuropathies and may define another group of non-paraneoplastic, immune-mediated neuropathies., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Extraskeletal myxoid chondrosarcomas usually arise deep in the proximal extremities and limb girdles. Patients with this type of sarcoma have high rates of local recurrence and metastases, but do not typically have paraneoplastic syndromes. We report an unusual case of a 49-year-old man with anti-Hu syndrome in the setting of an extraskeletal myxoid chondrosarcoma. This case shows the importance of searching for antineural antibodies in oncologic patients with new neurologic deficits, and of having a judicious workup for occult malignancies in patients with known antineural antibodies.

The association of high levels of autoantibodies to glutamic acid decarboxylase (GAD-ab) and stiff-person syndrome (SPS) is well known. However, the full spectrum of neurological syndromes associated with GAD-ab is not well established. In addition, these patients usually present type 1 diabetes mellitus (DM1) that could justify the presence of high GAD-ab levels. To clarify these issues, we reviewed the clinical and immunological features of patients in whom high GAD-ab levels were detected in a reference centre for DM1 and for the detection of antineuronal antibodies in suspected paraneoplastic neurological syndromes (PNS). High GAD-ab levels were defined as values > or =2000 U/ml by radioimmunoassay. Intrathecal synthesis (IS) of GAD-ab was calculated in paired serum/CSF samples. Values higher than the IgG index were considered indicators for positive GAD-ab-specific IS. High GAD-ab levels were identified in 61 patients, 22 (36%) had SPS, 17 (28%) cerebellar ataxia, 11 (18%) other neurological disorders (epilepsy -- four, PNS -- four; idiopathic limbic encephalitis -- two; myasthenia gravis -- one), and 11 (18%) isolated DM1. Patients with SPS and cerebellar ataxia had the same frequency of female gender (86% vs 94%), DM1 (59% vs 53%), CSF oligoclonal bands (35% vs 69%). Three of the four PNS patients, with paraneoplastic encephalomyelitis, a predominant gait cerebellar ataxia, and limbic encephalitis, had neuroendocrine carcinomas. GAD expression was confirmed in the two tumours in which the study was done. The fourth patient presented with paraneoplastic cerebellar degeneration antedating a lung adenocarcinoma. The frequency of increased IS of GAD-ab was 85% in SPS, 100% in cerebellar ataxia, and 86% in other neurological disorders. In conclusion, our study emphasizes that high GAD-ab levels associate with other neurological disorders besides SPS. Cerebellar ataxia, the second most common syndrome associated with high GAD-ab levels, shares with SPS the same demographic, clinical and immunological features. The demonstration of an increased IS of GAD-ab is important to confirm that the GAD autoimmunity is related to the neurological syndrome particularly when there is a concomitant DM1 that could justify the presence of high GAD-ab levels. Lastly, in patients who develop neurological syndromes that suggest a PNS, the finding of GAD-ab does not rule out this possibility and appropriate studies should be done to confirm an underlying cancer.

Neurological paraneoplastic syndromes (NPS) are rare disorders in association with malignancy and the presence of various antineuronal antibodies. The persistence of antineuronal antibodies for years after the eradication of the tumor without clinical manifestations of a NPS has not been reported. In a 64-year-old woman with a history of gynecologic malignancy, treated by surgery and chemotherapy with docetaxel and carboplatin, ptosis, hypertelorism, dysarthria, short stature, upper and lower limb weakness, exaggerated tendon reflexes and recurrent creatine-kinase elevation were found. Nerve conduction studies disclosed polyneuropathy and muscle biopsy nonspecific myopathic features. Though anti-Yo antibodies were repeatedly positive, the clinical findings and polyneuropathy were rather attributed to a suspected metabolic myopathy or chemotherapy than a NPS. Anti-Yo antibodies remained positive at 5 further determinations. During the 5 years of follow up there was improvement of polyneuropathy and no relapse of the malignancy, as assessed clinically, by tumor markers, computed tomography scans and 18-fluorodeoxyglucose positron emission tomography. Anti-Yo antibodies may occur without the typical clinical manifestations of a NPS and may persist for years without the development of a NPS or relapse of the tumor.

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.

Background: Paraneoplastic peripheral neuropathy is sometimes associated with unidentified neuronal autoantibodies., Objective: To examine the effects of serum from a patient with subacute sensory axonopathy on the function of the Trk high-affinity nerve growth factor receptor., Patient: An 86-year-old man with sensory neuropathy exhibiting an autoantibody to Trk., Methods: Immunoblot analyses of the brain homogenates and immunoprecipitation were performed with human sera. We further examined the effect of sera on nerve growth factor-induced neurite outgrowth and Trk autophosphorylation., Results: The patient showed sensory nerve axonopathy without well-known paraneoplastic autoantibodies. His serum inhibited nerve growth factor-induced neurite outgrowth and Trk autophosphorylation in PCtrk cells. Moreover, the patient's serum, but not control serum, immunoprecipitated Trk and recognized Trk in brain homogenates as well as in Trk immunoprecipitates., Conclusion: These data strongly suggest that an anti-Trk autoantibody might cause subacute sensory neuropathy.

We report a paraneoplastic neuropathy with severe motor involvement following sensory-ataxic disturbance. Anti-disialosyl immunoglobulin M (IgM) antibody was detected in the course of malignant lymphoma of diffuse large B-cell type, which usually spares the motor system. Onset was subacute, with relapsing and remitting sensory ataxia, muscle weakness, bulbar palsy, respiratory paralysis, and ophthalmoplegia; only neck rotation was retained in the terminal stage. Autopsy showed no lymphoma cells infiltrating the nervous system. Motor neurons survived in the spinal cord, but mean diameter of the ventral spinal nerve roots was reduced considerably. The gracile fasciculus and the sural nerve were more markedly degenerated than proximal portions. Morphometric study showed that most of the proximal motor and sensory axons did not extend distally. This autopsy report provides further definition of a neuropathy associated with malignant lymphoma and IgM antibodies against disialosyl residues.

A 62-year-old woman presented with diplopia caused by bilateral sixth cranial nerve palsies. Two weeks later, she had bulbar weakness and ataxia. Brain magnetic resonance imaging showed non-specific abnormalities and spinal fluid was acellular but contained an elevated protein and oligoclonal bands. A paraneoplastic screen showed anti-Hu antibodies. Her clinical condition improved with immunoglobulin and systemic corticosteroid treatment. Breast cancer was diagnosed 21 months later by mammography but there were no metastases detected. Four and half years after the onset of her diplopia, she died of diffuse metastatic breast cancer. This is the first reported case of anti-Hu paraneoplastic brain stem encephalitis presenting with sixth cranial nerve palsies.

Objective: To assess use of whole-body 18F fluoro-2-deoxy-glucose (FDG)-PET and CT for diagnosing tumor in patients with antibody-positive paraneoplastic neurologic syndromes (PNS)., Methods: In order to directly compare CT and FDG-PET imaging in patients with various antineuronal antibodies, the authors performed in parallel CT scanning and FDG-PET in a series of 13 consecutive patients (9 women, 4 men, aged 59 +/- 14 years) with positive antineuronal antibodies (anti-Hu: 8, anti-Yo: 4, anti-Tr: 1) in whom the authors were searching for a tumor or tumor recurrence., Results: A new tumor or tumor recurrence was found in 10/13 patients (5 small cell lung cancer, 2 ovarian cancer, and 1 each neuroblastoma, Hodgkin's lymphoma, and lymph node metastasis of adenocarcinoma). All tumors except one with good clinical evidence for small cell lung cancer were confirmed histologically. For detection of tumor or tumor recurrence, CT was positive in 3/10 patients (sensitivity of 30%), and FDG-PET in 9/10 (sensitivity of 90%, difference between methods p < 0.01), but the combination of both methods showed a sensitivity of 100%., Conclusions: FDG-PET imaging is useful in tumor screening of patients with antineuronal antibodies, but should be complemented by CT scanning to increase sensitivity and accuracy of tumor diagnosis.

We identified the IgG autoantibody ANNA-2 ("anti-Ri") in 34 patients in a 12-year period by immunofluorescence screening of sera from approximately 75000 patients with subacute neurological disorders that were suspected to be paraneoplastic. Detailed clinical information was available for 28 patients (10 men, 18 women). Cancer was diagnosed in 24 patients (86%); 21 had histologically proven carcinoma (10 lung, 9 breast, 1 cervical, 1 bladder), and 3 had an intrathoracic imaging abnormality. Cancer anteceded neurological symptoms in 4 of 28 patients. Cancer detection frequency increased with continued surveillance. Neurological disorders, in decreasing frequency, were brainstem syndrome (including opsoclonus, myoclonus, or both), cerebellar syndrome, myelopathy, peripheral neuropathy, cranial neuropathy, movement disorder, encephalopathy, Lambert-Eaton syndrome, and seizures. Four patients had laryngospasm and four had jaw opening dystonia (two with neck dystonia). Nine (32%) were wheelchair-bound 1 month after neurological symptom onset. Most improved neurologically after immunomodulatory or tumor-directed therapy. Accompanying autoantibodies, found in 73% of sera, included ANNA-1, ANNA-3, CRMP-5-IgG, P/Q-type and N-type Ca(2+) channel antibodies, and muscle-type acetylcholine receptor antibody. Some neurological accompaniments of ANNA-2 may reflect potentially pathogenic humoral or cell-mediated responses to coimmunogenic tumor antigens, for example, Lambert-Eaton syndrome (P/Q-type Ca(2+) channel antibody) and peripheral neuropathy (ANNA-1 effector T cells).

Antidisialosyl antibodies were found in two out of 13 patients with chronic idiopathic ataxic neuropathy (CIAN) and not in 32 patients with different sensory neuropathies of known cause. This finding confirms the association of antidisialosyl antibodies and CIAN regardless of the absence of the M band. These antibodies may have pathogenic relevance; however, larger series are needed to establish their clinical significance.

We reported a 62-year-old woman had sensorimotor neuropathy with small cell lung carcinoma (SCLC) and anti-GM1 antibody. She was admitted with several months history of progressive numbness, walking disturbance and anorexia. Neurologic examination revealed severe numbness and deep sensory disturbance of extremities and body, and mild weakness of distal extremities. Deep tendon reflexes were absent. Her limbs were ataxic. Nerve conduction studies showed no sensory evoked responses. CSF protein was elevated. Sural nerve biopsy revealed severe loss of myelinated fibers and perivascular mononuclear cells surrounding the perineurial vessel. Vasculitic neuropathy was diagnosed, and prednisolone was started, with no benefit. In the clinical course, she developed cough attacks and was found the lymphnode swelling in the mediastinum and supraclavicular fossa, which was diagnosed SCLC. Although anti-Hu antibody were not detected, anti-GM1 antibody was positive. She was treated with intravenous immunoglobulin, with transient improvement. The rare case of the paraneoplastic peripheral neuropathy with SCLC and anti-GM1 antibody was reported.

Although paraneoplastic subacute sensory neuronopathy is the most frequent presentation of peripheral neuropathy in patients with anti-Hu antibodies, other neuropathies have been reported. In order to investigate the clinical and electrophysiological manifestations of neuropathies associated with anti-Hu antibodies, we conducted a retrospective study of 20 patients. For the electrophysiological study, each nerve was classified as normal, demyelinating, axonal/neuronal or axonal/demyelinating. Peripheral neuropathy was the presenting symptom in 95% of patients. CNS and autonomic neuropathy were present in 40% and 30% of patients, respectively. The course of the neuropathy was acute, mimicking Guillain-Barré syndrome in one patient (5%), and subacute (55%) or progressive (40%) in the others. Clinically, the neuropathy was sensory (70%), sensorimotor (25%) or motor (5%). At onset, symptoms were symmetrical (65%), asymmetrical (25%) or multifocal (10%). Pain was a predominant manifestation (80%). Amyotrophia and fasciculations were rare. The median Rankin's score was 2, three patients having an indolent form. Electrophysiology showed the axonal/neuronal pattern to be the most frequent (46.9% of studied nerves); an axonal/demyelinating or demyelinating pattern being seen in 18.3% and 4.9% of nerves, respectively. The axonal/neuronal pattern was more frequent in sensory nerves and the mixed axonal/demyelinating pattern more frequent in motor nerves (P < 0.01). A higher proportion of abnormal nerves correlated with a progressive course (P < 0.05) or a Rankin's score between 3 and 5 (P < 0.01). In patients with sensory neuropathy, 88.5% of sensory nerves were abnormal, mostly with an axonal/neuronal pattern. In addition, 47% of motor nerves were abnormal so that only four out of 14 patients with a clinically pure sensory neuropathy (28.6%) had an electrophysiological pattern typical of sensory neuronopathy. In patients with a sensorimotor neuropathy, 96.6% of sensory and 71% of motor nerves were abnormal. The only statistical difference between sensory and sensorimotor neuropathies was that patients with sensorimotor neuropathy had more frequent motor nerve involvement (P < 0.05) without differences concerning the distribution of the abnormal patterns. Needle neuromyography showed only limited evidence of motor neurone degeneration in both sensory and sensorimotor neuropathy. The present work shows that the typical clinical and electrophysiological pattern of subacute sensory neuronopathy is rarely encountered in patients with anti-Hu antibody and that motor nerve involvement is frequently seen, even in the absence of a motor deficit. In addition to their potential pathophysiological involvement in the mechanism of the paraneoplastic neuropathy, these findings have practical consequences for the diagnosis of the disorder.

Paraneoplastic neurological syndrome is thought to be caused by an autoimmune mechanism triggered by tumor antigens which attack the neurons presenting the common antigens. We tried to prove the antibody-mediated neuronal loss by passive transfer with IgG containing Yo antibody or Hu antibody and active immunization with recombinant Yo protein or Hu protein. But in fact the antibody per se did not cause neuronal loss. On the other hand, the patients with paraneoplastic neurological syndrome show pleocytosis in the cerebrospinal fluid and massive lymphorrhage, predominant CD8+ T cells, are seen in the tumor and in the lesions in the central nervous system. Another observation that each of the patients' group with anti-Yo antibody positive paraneoplastic cerebellar degeneration or anti-Hu positive sensory neuronopathy have the common HLA class I supertype, suggested the neuronal loss might be caused by class I restricted CD8-positive cytotoxic T lymphocytes (CTL). We synthesized the peptides from Yo or Hu protein with binding capacity to each of the class I molecules. We found the CTL activities in the peripheral CD8+ T cells against the matched peptide-presenting autologous fibroblasts. We need to prove the CTL attacks neurons directly.

A 66-year-old man developed progressive painful dysesthesia in his hands and feet over 3 months. His vibration sense was impaired and sensory nerve action potentials of the limbs were not evoked. Biopsy of the peroneal nerve revealed sensory neuropathy. Positive anti-Hu antibody facilitated delineation of a right hilar mass and a metastatic lymph node in thoracic CT scan. He was diagnosed as small cell lung cancer associated with paraneoplastic sensory neuropathy. A complete response was achieved through chemotherapy (carboplatin and etoposide) and subsequent radiation therapy. Notably, his neurological conditions, although not changed during the hospitalization, gradually improved afterwards.