Paraneoplastic Sensory Neuropathy Research Articles

KNOCK KNOCK, HU'S THERE? POSITIVE ANTI-HU ANTIBODY IN EXTRAPULMONARY SMALL CELL CARCINOMA OF LYMPH NODE

SESSION TITLE: Tuesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: To date, small cell carcinoma (SCC) has been primarily recognized as a pulmonary malignancy and research has been skewed towards this area. Extrapulmonary SCC is rare, accounting for 2.5% of SCC, out of which lymph node SCC are far and few between. CASE PRESENTATION: A 59-year-old gentleman was initially admitted to neurology for sensory neuropathy and weight loss. He was referred to the respiratory medicine team after imaging revealed subcarinal and left hilar lymphadenopathy. He is a chronic smoker and there was a concern for malignancy. Initial endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) using 22 gauge needle showed lymphoid yield. Serum paraneoplastic panel (Hu, Yo, Ri, CV2, Amphiphysin, PNMA2/Ta, recoverin, SOX1, titin, zic4, GAD65, Tr(DNER)) was performed as part of the diagnostic work up. Anti-Hu antibody was 1:101 (strongly positive); reference titer 1:<10. Fluorodeoxyglucose-positron emission tomography-computed tomography (FDG-PET-CT) scan revealed FDG avid subcarinal (SUVmax:11.1) and left hilar (SUVmax:13.2) nodes. In view of the anti-Hu antibody results and FDG-PET-CT findings, a repeat EBUS-TBNA using 19 gauge needle was performed and histology confirmed SCC. DISCUSSION: Paraneoplastic syndrome was first described by M. Auché in 1890 and is known to affect up to 8% of patients with cancer; most notably small cell lung cancer. Anti-Hu is an onconeural antibody first discovered by F. Grouse in 1985. Its moniker is type I anti-neuronal nuclear antibody (ANNA-1) and has been a signpost for paraneoplastic sensory neuropathy or encephalomyelitis. (Positive anti-Hu antibody titers have a reported specificity of 99% and sensitivity of 82%). It is recognized as a distinct clinical disease, “anti-Hu syndrome”, with characteristic clinical picture and imaging findings. A Dutch study in 2002 found that 85% of patients with positive anti-Hu antibody also have a tumor. Of note, anti-Hu antibodies can also be positive in antecedent inflammatory diseases like systemic lupus erythematosus or Sjogren’s syndrome which can confound the diagnosis. Thus, positive anti-Hu antibody levels should prompt further evaluation and follow up even in absence of concurrent malignancy. Early diagnosis of lymph node SCC has prognostic implications when compared to pulmonary and extrapulmonary SCC, thus making the distinction necessary. CONCLUSIONS: This study highlights the diagnostic implications of an abnormal paraneoplastic panel, emphasizing the role of anti-Hu antibody in its specificity for SCC. The presence of FDG avid thoracic lymph nodes with elevated anti-Hu antibody titers warrants a repeat biopsy. It is imperative for clinicians to identify occult neoplasms in the setting of paraneoplastic syndromes. Reference #1: Koike H, Sobue G. Paraneoplastic neuropathy. Handb Clin Neurol. 2013;115:713-26. Reference #2: Graus F, Cordon-Cardo C, Posner JB. Neuronal antinuclear antibody in sensory neuronopathy from lung cancer. Neurology. 1985 Apr;35(4):538–43. Sehgal IS, Kaur H, Dhooria S, et al. Extrapulmonary small cell carcinoma of lymph node: Pooled analysis of all reported cases. World J Clin Oncol. 2016;7(3):308-20. Graus F, Keime-Guibert F, Reñe R, Benyahia B, Ribalta T, Ascaso C, Escaramis G, Delattre JY. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain. 2001;124(6):1138-1148. Senties-Madrid H, Vega-Boada F. Paraneoplastic syndromes associated with anti-Hu antibodies. Isr Med Assoc J. 2001 Feb;3(2):94-103. Reference #3: Benyahia B, Amoura Z, Rousseau A, Le Clanche C, Carpentier A, Piette JC, Delattre JY. Paraneoplastic antineuronal antibodies in patients with systemic autoimmune diseases. J Neurooncol. 2003 May;62(3):349-51. Sillevis Smitt P, Grefkens J, de Leeuw B, van den Bent M, van Putten W, Hooijkaas H, Vecht C. Survival and outcome in 73 anti-Hu positive patients with paraneoplastic encephalomyelitis/sensory neuronopathy. J Neurol. 2002 Jun;249(6):745-53. Kim KO, Lee HY, Chun SH, et al. Clinical overview of extrapulmonary small cell carcinoma. J Korean Med Sci. 2006;21(5):833-7. Kannoth S. Paraneoplastic neurologic syndrome: A practical approach. Ann Indian Acad Neurol. 2012;15(1):6-12. DISCLOSURES: No relevant relationships by John Abisheganaden, source=Web Response No relevant relationships by Caroline Choong, source=Web Response No relevant relationships by Sharlene Ho, source=Web Response No relevant relationships by Chuen Peng Lee, source=Web Response No relevant relationships by Ziqin Ng, source=Web Response No relevant relationships by Ser Hon Puah, source=Web Response No relevant relationships by HUIJIA WANG, source=Web Response No relevant relationships by Kim Hoong Yap, source=Web Response

Dorsal root enhancement in paraneoplastic sensory ataxic neuropathy with anti‐Hu antibody

AbstractMagnetic resonance imaging findings of paraneoplastic sensory ataxic neuropathy have previously shown that spinal cord lesions are located in the dorsal column. We report a 65‐year‐old man with paraneoplastic sensory ataxic neuropathy of subacute onset presenting dorsal root enhancement on magnetic resonance imaging. Pathological studies found that, in patients with sensory ataxic neuropathy associated with lung cancer, the dorsal roots and ganglia were severely degenerated with inflammatory cell infiltration, whereas the dorsal columns of the spinal cord were simply degenerated without inflammatory reaction, indicating centripetal Wallerian degeneration. There have been no radiological reports describing the preceding steps of Wallerian degeneration in the dorsal column, indicating the disruption of dorsal root ganglia. In the present case, we showed direct evidence of root inflammation detected as dorsal root enhancement in a patient with paraneoplastic sensory ataxic neuropathy of subacute onset.

CRMP-5 Antibody in Paraneoplastic Optic Neuritis and Sensory Motor Neuropathy Associated with Small Cell Lung Cancer (P4.236)

CRMP-5 Antibody in Paraneoplastic Optic Neuritis and Sensory Motor Neuropathy Associated with Small Cell Lung Cancer (P4.236)

Follicular Lymphoma Patient Relapsing with Paraneoplastic Sensory Neuronopathy (Ganglioneuropathy)

Neurological symptoms can be seen in 5%-8% of lymphoma patients. The most frequent causes of neurological symptoms are herpes virus infection, neurotoxicity due to vincristine, Guillain–Barre syndrome, and the nerve involvement of the tumor [1]. Paraneoplastic polyneuropathy is a rare neurological complication of lymphoma [2]. Here we report a case of relapsed follicular lymphoma presenting with paraneoplastic sensory neuropathy (ganglioneuropathy). A 45-year-old woman was admitted to the hospital 2 years ago with the complaints of numbness in the hands and feet, unsteadiness, weight loss, fever, and swellings in the neck, axilla, and inguinal region. She was diagnosed with follicular lymphoma through the excisional biopsy of the cervical lymph node. She was diagnosed with stage 3B disease based on the presence of lymphadenopathies in the paratracheal, precarinal, axillary, and inguinal regions and no infiltration by bone marrow examination. The treatment started with rituximab (500 mg/day), cyclophosphamide (1125 mg/day), adriablastine (80 mg/day), vincristine (2 mg/day), and prednisolone (80 mg/day). Therapy was completed in 8 courses with 21-day intervals. After the therapy, all of the symptoms had regressed and the case was evaluated as in remission with a follow-up PET scan (Figure 1). Gradually increasing unsteadiness, numbness, and pain and burning sensation in the hands and feet developed 1 month following that PET study. She applied to the neurology service and it was found that she had normal muscle strength but mild ataxia, positive Romberg test, and prominent hypoesthesia in the distal regions of the extremities and bilateral impairment of the deep tendon reflexes and indifferent plantar responses. Informed consent was obtained. An electromyography revealed sensorial gangliopathy. On physical examination the positioning and the vibration sensations of the patient were found to be diminished. Intravenous pulse steroid therapy (1000 mg/day) was administered for 5 days. Two days after this therapy, a severe and generalized pain developed in all of the extremities and joints. In neurological examination, distinct quadriparesis, ataxia, dysmetria, dysdiadochokinesia, hypoesthesia of the 4 extremities, and bilateral abolished deep tendon reflex with indifferent plantar responses were determined. There was Letter to the Editor DOI: 10.4274/TJH-2013.0125

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 sensory neuropathy and ganglionic acetylcholine receptor antibody

Paraneoplastic sensory neuropathy and ganglionic acetylcholine receptor antibody

肺扁平上皮癌に対する治療により改善をみた亜急性感覚性ニューロノパチーの１例

We report a 59-year-old man who developed dysesthesia in all extremities with severe loss of deep sensation over three months. A radiating radicular pain was also noted in the extremities. The nerve conduction study barely elicited sensory nerve action potentials both in the median and in the sural nerve. An extensive search for anti-neuronal antibodies including anti-Hu and anti-CV2 antibody was negetive. The biopsy specimen of an enlarged tracheobronchial lymph node revealed squamous cell carcinoma. The subsequent chemotherapy and radiation therapy for the neoplasm improved the radicular pain and the deep sensation to a moderate extent, leading to the diagnosis of paraneoplastic subacute sensory neuropathy (SSN). In general, cases with paraneoplastic SSN are associated mostly with small cell lung cancer, and quite rarely with squamous cell lung cancer. The early detection and the treatment of the primary tumor are crucial in a patient with subacute progression of sensory-dominant neuropathy.

Paraneoplastic sensory neuropathy associated with small cell carcinoma of the gallbladder

A small number of patients with carcinoma of the gallbladder can present with a variety of paraneoplastic syndromes, including the Cushing syndrome, hypercalcemia, acanthosis nigricans, bullous pemphigoid, dermatomyositis, and the Leser-Trélat sign. We report on what appears to be the first case of a patient, a 48-year-old woman, with anti-Hu paraneoplastic sensory neuropathy and small cell carcinoma of the gallbladder. The patient's neurologic symptoms preceded the diagnosis of small cell carcinoma by 11 months. These symptoms improved after surgical removal of the tumor and chemotherapy. The small cell carcinoma was relatively small and was not associated with gallstones. In spite of the small size of the tumor, it metastasized to a celiac lymph node and probably to the liver. Anti-Hu paraneoplastic sensory neuropathy should be added to the list of paraneoplastic syndromes associated with small cell carcinoma of the gallbladder.

A case of spontaneous regression of small cell lung cancer with progression of paraneoplastic sensory neuropathy

We report here a rare case of small cell lung cancer (SCLC) accompanied by a partial spontaneous regression with a progression of paraneoplastic sensory neuropathy (PSN). A 55-year-old woman was admitted to our hospital with dry cough and progressive numbness in the distal extremities over 1 month. She was diagnosed as small cell lung cancer associated with paraneoplastic sensory neuropathy. About 1 month later, partial spontaneous regression of tumor with a progression of paraneoplastic sensory neuropathy was observed. A complete response was achieved through chemotherapy and concurrent radiotherapy. As the tumor size decreased, her neurological symptoms improved. A short interval between onset of PSN and the start of therapy may be essential for successful treatment for not only SCLC but also PSN.

A case report of paraneoplastic neurological syndrome associated with occuft breast cancer

Paraneoplastic syndromes are the rarest neurological complications in patients with breast cancer. Here, we present a case of occult breast cancer presenting as paraneoplastic sensory neuropathy. A 47-year-old woman developed progressive upper and lower extremity weaknesses with paresthesia and gait ataxia. Multiple cerebrospinal fluid (CSF) analyses and magnetic resonance image (MRI) scans of her brain and spine offered no diagnosis. Although no paraneoplastic antibodies were found, paraneoplastic neurological syndrome was suspected after examination by the neurologist eliminated other possibilities. Her mammogram demonstrated pleomorphic calcifications. Although local and systemic therapies were given, no significant improvement in the neurologic condition was found.

Complicated paraneoplastic neurological syndromes: a report of two patients with small cell or non-small cell lung cancer

Paraneoplastic neurological syndromes are frequently associated in patients with small cell lung cancer (SCLC) and antineuronal antibodies are involved in the autoimmune mechanism. Multiple syndromes are sometimes complicated in a single patient with SCLC. However, little is known about non-SCLC-associated neurological manifestations. We report two patients with complicated paraneoplastic neurological syndromes. Patient 1 showed paraneoplastic limbic encephalitis (PLE), paraneoplastic sensory neuropathy (PSN) and Lambert–Eaton myasthenic syndrome (LEMS) associated with SCLC. Patient 2 developed opsoclonus-ataxia and probable PLE associated with non-SCLC. Analysis of various antineuronal antibodies revealed that anti-Hu and P/Q-type voltage-gated calcium channel (VGCC) antibodies were positive in Patient 1 but any antibodies were not in Patient 2. Brain MRI demonstrated high intensity signals in temporal lobes particularly on fluid-attenuated inversion recovery (FLAIR) or diffusion-weighted images. These findings suggest that complicated paraneoplastic neurological syndromes occur in non-SCLC as well as SCLC and that unidentified antineuronal autoantibodies may underlie the pathophysiology.

Paraneoplastic sensory neuropathy and Purkinje cell antibodies

Paraneoplastic sensory neuropathy and Purkinje cell antibodies

Utility of anti-Hu antibodies in the diagnosis of paraneoplastic sensory neuropathy.

Anti-Hu antibodies (Hu-Abs) were positive in 40 patients with paraneoplastic sensory neuropathy (PSN) and in 1 patient with idiopathic sensory neuropathy in a series of 126 patients who presented with clinical features suggestive of PSN. The specificity of Hu-Abs was 99% and the sensitivity was 82%. Nine (18%) PSN patients were Hu-Ab-negative, and their sera did not harbor other specific anti-neuronal or anti-ganglioside antibodies. Small cell lung carcinoma (SCLC) was the leading neoplasm in the Hu-Ab-positive (79%) and Hu-Ab-negative (44%) groups. This study confirms the value of Hu-Abs for the diagnosis of PSN and SCLC and also emphasizes that in patients with possible PSN, the absence of Hu-Abs does not exclude cancer, particularly in those patients with risk factors for SCLC.

Anti-Hu-associated paraneoplastic sensory neuropathy with peripheral nerve demyelination and microvasculitis

A patient had a paraneoplastic autonomic, then sensory, then sensory-motor neuropathy with small cell lung carcinoma and a high titer Anti-Hu antibody to nuclei of neuronal cells. As an unusual finding there was electrophysiological and pathological evidence of demyelination and a peripheral nerve microvasculitis. The relationship of microvasculitis and peripheral nerve demyelination is discussed and their occurrence with paraneoplastic anti-Hu-associated sensory neuropathy is suggested not to be by chance.

Selection of recombinant anti-HuD Fab fragments from a phage display antibody library of a lung cancer patient with paraneoplastic encephalomyelitis

Antibodies against the HuD antigen expressed in small-cell lung cancer (SCLC) cross-react with proteins expressed in neurons of the central and peripheral nervous system and are associated with paraneoplastic encephalomyelitis and sensory neuropathy (PEM/SN). We isolated anti-HuD Fab fragments from an antibody phage display library that was constructed from mRNA of a metastatic lymph node from a patient with SCLC and PEM/SN. Fab GLN495 recognized HuD and other related proteins (HuC and Hel-N1, or Hu antigens) in immunoblots of these recombinant proteins and in immunohistochemical and Western blot analysis of SCLC and neurons. Fab GLN495 inhibited up to 75% of the anti-Hu antibodies of the patient from which it was derived, suggesting that it recognizes a dominant epitope in the polyclonal anti-Hu antibody response. Fab GLN495 also competed with anti-Hu sera from most but not all patients with PEM/SN, indicating that the same epitope is recognized by a large subgroup of patients. Human monoclonal anti-HuD antibodies may be useful in diagnosis of HuD expressing tumors and in clarifying the autoimmune etiology of PEM/SN. This study, the first to demonstrate that tumor specific recombinant antibodies can be isolated from metastatic lymph node tissue, shows that this approach may be generally applicable to isolate human antibodies against tumor specific antigens.

Anti-Hu-associated paraneoplastic sensory neuronopathy responding to early aggressive immunotherapy: Report of two cases and review of literature

Anti-Hu-associated paraneoplastic sensory neuropathy (PSN) has been reported to be nonresponsive to immunotherapy or cancer therapy. We report 2 patients with anti-Hu-associated PSN who achieved sustained clinical improvement with early and aggressive immunotherapy 10-15 months before the diagnosis of small-cell lung carcinoma. Both had chronic "sensory neuronopathy plus"; in addition to sensory neuronopathy, case 1 had a motor-autonomic dysfunction with encephalopathy, and case 2 had a motor-autonomic dysfunction with swallowing difficulty. These two cases were unusual in that sustained clinical improvement was achieved with early aggressive immunotherapy before the detection of cancer and without any concomitant anticancer therapy or lowering of anti-Hu antibody titer. We believe that early and aggressive immunotherapy should be tried in any patient with anti-Hu-associated PSN, as it may induce sustained clinical improvement.

Acquired intestinal aganglionosis and circulating autoantibodies without neoplasia or other neural involvement

The clinical course, diagnosis, and treatment of 2 patients with acquired intestinal aganglionosis without other neurological involvement or neoplasia are described. They initially presented with constipation and abdominal pain in late childhood. They were found to have enteric ganglionitis with a loss of neurons together with vacuolated nerve cells surrounded by CD3- and CD4-positive T lymphocytes. This process initially affected only the colon but later the entire gastrointestinal tract was involved in 1 patient. Associated with this process there were circulating immunoglobulin G class enteric neuronal antibodies in high titer (1:5000-8000). The staining of central nervous system neuronal nuclei and Western blotting indicated the presence of antineuronal nuclear protein antibodies of the ANNA-1 (anti-Hu) type usually associated with paraneoplastic sensory neuropathy. However, the reaction pattern in enteric neurons was quite different with strong reaction to perikarya and only weak staining of nuclear antigens. (Gastroenterology 1997 Apr;112(4):1366-71)

Spontaneous neurological improvement in anti-Hu associated encephalomyelitis.

Symptoms of anti-Hu associated paraneoplastic encephalomyelitis (PEM) and sensory neuropathy (PSN) are usually severe and irreversible. Two patients are reported whose symptoms improved spontaneously, and in one of them they...

Molecular analysis of the HuD gene encoding a paraneoplastic encephalomyelitis antigen in human lung cancer cell lines: Sekido Y, Bader SA, Carbone DP, Johnson BE, Minna JD. Simmons Cancer Center, Texas University SW Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-8590. Cancer Res 1994;54:4988–4992

Small cell lung cancer (SCLC) is known to express the HuD protein, the neuronal antigen homologous to Drosophila Elav and Sxl genes involved in neuronal and sex development. HuD is the target of an immune response including high titered antibodies causing paraneoplastic encephalomyelitis and sensory neuropathy. Because the p53 recessive oncogene is mutated and anti-p53 antibodies frequently occur in cancer patients, we wondered if the development of anti-HuD antibodies signaled the presence of HuD mutations in lung cancer. The HuD gene was mapped to chromosome region 1p using a human-mouse hybrid cell panel. We confirmed that 26 of 46 cancer (43 lung cancer and 3 mesothelioma) cell lines expressed HuD mRNA and that this expression, as well as protein expression by Western blot, correlated strongly with the SCLC neuroendocrine phenotype. Southern blot and single-strand conformation polymorphism analyses showed that HuD was not mutated in 78 lung cancers, including patients with the severe paraneoplastic syndrome. Northern blot analysis showed that lung cancer cell lines expressed two major mRNAs (4.3 and 4.0 kilobases) of HuD. We found the three previously described alternative spliced mRNA forms (HuDpro, HuD, and HuDmex). In addition, we also found HuD mRNA had an alternative splicing form in its 5'-coding region. This alternative splice introduced 87 base pairs of sequence and a termination codon resulting in a predicted small, truncated protein (11 amino acids) reminiscent of the male-specific truncated protein in the Sex-lethal (Sxl) gene of Drosophila. However, mRNAs encoding both full-length and truncated proteins were expressed in all SCLCs. These results show that the HuD gene is not mutated in lung cancer, including tumors from patients producing anti-HuD antibodies, but HuD expression is an independent marker or determinant of the neuroendocrine differentiation seen in SCLC.

Immune responses in the peripheral nervous system

A specialised endoneurial endothelium and perineurial barrier confer a relative immunological privilege on the peripheral nervous system that is overcome in disease. Non-specific inflammatory, vasculitic or granulomatous disorders damage the blood-nerve barrier, and are associated with ischaemia, release of inflammatory mediators and axonal degeneration of motor and sensory nerve fibres. In paraneoplastic sensory neuropathy, damage to dorsal root ganglion neurons is mediated by anti-neuronal antibodies. In immunoglobulin M paraproteinaemic neuropathy, demyelination is caused by the antibody property of the paraprotein, which is directed against epitopes shared by myelin-associated glycoprotein, and glycolipids which are confined to peripheral nerve myelin. In acute and chronic acquired demyelinating neuropathy, demyelination is probably produced by T cells and antibody directed against several different autoantigens.