Dorsal cauda equina nerve root enhancement on magnetic resonance imaging due to ANNA-1-associated paraneoplastic polyneuropathy.

A 69-year-old female presented with subacute onset ascending weakness and paraesthesias. She was initially diagnosed with Guillain-Barré syndrome (GBS) based on her clinical presentation and cerebrospinal fluid (CSF) analysis showing albuminocytological dissociation. However, she was later found to have anti-neuronal nuclear antibody 1 (ANNA-1/anti-Hu)-positive CSF and was subsequently diagnosed with small-cell lung cancer. Her neurological symptoms were ultimately attributed to ANNA-1/anti-Hu-associated paraneoplastic polyneuropathy. During the course of her evaluation, she had magnetic resonance imaging findings of dorsal predominant cauda equina nerve root enhancement, which has not been previously described. The only previously reported case of cauda equina enhancement due to ANNA-1-associated polyneuropathy described ventral predominant findings. The distinction between ventral and dorsal enhancement is important, since it suggests that different patterns of nerve root involvement may be associated with this paraneoplastic syndrome. Therefore, ANNA-1-associated paraneoplastic inflammatory polyneuropathy can be considered in the differential diagnosis of cauda equina nerve root enhancement with ventral and/or dorsal predominance. This can potentially be helpful in differentiating ANNA-1 polyneuropathy from GBS, which classically has ventral predominant enhancement.

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.

Small Cell Lung Cancer Accompanied by Tonsillar Metastasis and Anti-Hu Antibody-Associated Paraneoplastic Neuropathy: A Rare Case Report With Long-Term Survival.

Tonsillar metastatic small cell lung cancer (SCLC) is rare, while anti-Hu antibodies are frequently found in SCLC. A 66-year-old man was admitted to our hospital with painful dysesthesia and muscle weakness in the distal extremities for over 1 year, progressive dysphagia for over 1 month, and severe cough and dyspnea for over 1 week. He was diagnosed with SCLC accompanied by tonsillar metastasis and anti-Hu antibody-associated paraneoplastic sensory neuropathy (PSN). The patient tolerated 6 cycles of sequential chemoradiotherapy and gradually recovered. The patient's disease remained in remission 2 years after the diagnosis with a remarkable reduction of tumor burden and a persisting high titer of anti-Hu antibodies. To our knowledge, this is the first case of tonsillar metastatic SCLC accompanied by anti-Hu antibody-associated PSN, whereby the anticancer immune response was presumed to play a vital role in disease control. Unilateral tonsillar metastasis of SCLC accompanied by anti-Hu antibody-associated PSN can occur and in certain circumstances, may have a favorable prognosis.

Anti-SOX1 antibodies in patients with paraneoplastic and non-paraneoplastic neuropathy.

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.

Small cell lung carcinoma presenting as collapsin response-mediating protein (CRMP) -5 paraneoplastic optic neuropathy.

A 77-year-old woman presenting with progressive visual loss in both eyes was found to have small cell lung cancer. Assay for collapsin response-mediating protein (CRMP) -5 was positive suggesting a paraneoplastic optic neuropathy (PON). During treatment of the small cell lung cancer, the patient died of pneumonia and autopsy disclosed neuropathologic abnormalities consistent with PON. This is only the second case of CRMP-5-confirmed PON to report neuropathologic findings.

Antibodies associated with paraneoplastic neurological disorders.

Certain cancers, particularly small cell lung cancer, gynaecological or breast and also testicular, prostate, bowel and other cancers, can be associated with diverse and often heterogeneous neurological syndromes. In those cases with neurological syndromes, a proportion of patients will have a serum antibody to a defined antigen that is expressed both by the tumour and by the nervous system. The presence of the neurological syndrome often precedes the recognition of the tumour, and thus the detection of one of the specific antibodies leads to a search for the relevant tumour. In general, the antibodies are detected by immunohistochemistry or immunofluorescence on brain tissue. Their specificity can then be confirmed either by western blotting of neuronal or brain extracts, or by western blotting of the specific recombinant protein. There are also some ELISA assays available for detection of antibodies to specific antigens.

Anti-Hu antibody neuropathy: a clinical, electrophysiological, and pathological study.

OBJECTIVE: The objective is to report the clinical, electrophysiological, and histopathological features of 16 patients with anti-Hu antibody neuropathy. METHODS: Clinical and electrophysiological data in 16 patients (11 females and 5 males) with positive anti-Hu antibody and nerve biopsy data in 9 cases were analyzed. RESULTS: Cancer was detected in 11 patients, including 9 with small-cell lung cancer. Classical paraneoplastic subacute sensory neuronopathy (SSN) and/or encephalomyelitis (EM) was observed in 7 patients (44%), including 5 with SSN. The most common clinical feature was sensory-motor neuropathy (SMN), accounting for 50% of cases. Though sensory nerve conduction abnormality was the prominent feature in 14 (88%) cases, sensory and motor nerve conduction was abnormal in all cases. Motor nerve conduction findings were typical of axonal degeneration. The most common nerve conduction pattern was that of SMN, with a sensory neuronopathy pattern being observed in only 3 cases. Sural nerve biopsy in 9 patients showed axonal degeneration in all cases and inflammatory cells in 4 cases. CONCLUSIONS: Classical sensory neuronopathy is rarer than expected, both clinically and electrophysiologically. Motor involvement is not uncommon and motor nerve conduction abnormality is frequently seen. A diverse clinical and electrophysiological, and histopathological spectrum was observed in this neuropathy. SIGNIFICANCE: New guidelines for the selection of patients for anti-Hu antibody test are recommended.

Gangliosides act as onconeural antigens in paraneoplastic neuropathies.

We describe two patients with progressive neuropathy and lung cancer in whom gangliosides (GS) may represent the oncoantigens. Patient 1 had motor neuropathy, high titers of IgG1 and IgG3 to GD1a and GM1, and expansion of circulating gamma-delta T lymphocytes, a T-cell subset responding to glycolipids. Patient 2 presented with Miller-Fisher-like syndrome and IgG3 activity to disialo-GS. In both cases, decreased autoimmune responses and stabilization of neuropathy were accomplished by tumor treatment. By immunohistochemistry, patient 1's IgG bound to his own tumor and to structures of normal nervous system expressing GD1a or GM1. Infiltration of IgG in the same neural structures was found at his autopsy. Regarding cellular immunity, the proportion of gamma-delta T lymphocytes infiltrating carcinoma from patient 1 was significantly higher than in neoplastic controls. These results indicate that GS may represent onconeural antigens in paraneoplastic neuropathy (PNN); their expression on neoplastic tissue may elicit autoimmune responses, which also target neural structures.

Anti-Hu associated paraneoplastic sensory neuronopathy with upper motor neurone involvement.

Paraneoplastic neurological syndrome is characterised by neuronal degeneration with lymphocytic infiltration in various regions of the central and peripheral nervous systems. Motor neurone symptoms may occur as a remote effect of malignancy, and have been considered because of the involvement of lower motor neurones. A case is reported of an 80 year old woman suffering from paraneoplastic sensory neuronopathy with anti-Hu antibody. Postmortem examination showed adenocarcinoma of the gall bladder and small cell carcinoma of the duodenum. Neuronal loss with lymphocytic infiltration was found in the dorsal root ganglia, brain stem, and cerebellum. Despite the absence of upper motor neurone signs, there was severe loss of Betz cells and degeneration of the bilateral pyramidal tracts. To our knowledge, this is the first demonstration of upper motor neurone involvement in anti-Hu associated paraneoplatic syndrome.

Antibodies to Zic4 in paraneoplastic neurologic disorders and small-cell lung cancer.

OBJECTIVE: To determine whether serum Zic4 antibodies associate with paraneoplastic neurologic disorders (PND) and small-cell lung cancer (SCLC), and the association of these antibodies with other onconeuronal immunities associated with SCLC. DESIGN/METHODS: The authors studied 498 patients (215 with PND and 283 without PND or without cancer). The presence of antibodies was tested with immunoblots of Zic4, HuD, and CRMP5 proteins. The tumor expression of these proteins was determined by immunohistochemistry. RESULTS: Zic4 antibodies were identified in 61 patients. Ninety-two percent of patients with Zic4 antibodies had SCLC; detection of these antibodies segregated with the presence of PND (p = 0.031). Intrathecal synthesis of Zic4 antibodies was demonstrated in 5/7 patients with PND. None of 175 control patients without PND or cancer had Zic4 antibodies. Because of the robust association between Zic autoimmunity and SCLC, all patients were tested for other SCLC-related antibodies; concurrent Zic4, Hu, or CRMP5 antibodies occurred in the serum or CSF of 27% of SCLC patients with PND. Patients with isolated Zic4 antibodies were more likely to develop predominant cerebellar dysfunction than patients with several immunities (p < 0.001). Tumors of patients with and without onconeuronal antibodies coexpressed Zic, Hu, and CRMP5 proteins, indicating that the tumor expression of these antigens is necessary, but not sufficient, for immunologic activation. CONCLUSIONS: In patients with neurologic symptoms of unknown cause detection of Zic4 antibodies predicts a neoplasm, usually a SCLC, and suggests that the neurologic disorder is paraneoplastic. Detection of Zic4 antibodies often associates with anti-Hu or CRMP5 antibodies. Patients with isolated Zic4 antibodies are more likely to develop cerebellar dysfunction than those with concurrent immunities.