Paraneoplastic Subacute Sensory Neuronopathy Research Articles

Dixièmes Journées des Maladies du Système Nerveux Périphérique: Ganglionopathies : évolution du concept et prise en charge

Sensory ganglionopathies have a frequent association with neoplastic disorders (paraneoplastic subacute sensory neuronopathy, or SSN) or dysimmune disorders, with drugs, such as cisplatin or pyridoxine, and with inherited disorders with degeneration of dorsal root ganglion cells. Unsteady gait and pseudoathetoid movements of the hand are the distinctive signs encountered in these disorders. The chronic disorders are characterized by non-length-dependent abnormalities of sensory nerve action potentials (SNAPs) and differ from other sensory neuropathies in showing a global, rather than distal, decrease in SNAP amplitudes. This review focuses on recent advances in defining the mechanisms involved in sensory ganglionopathies, and describes the differential diagnosis including the rarely encountered hereditary neuronopathies and the infectious causes.

Traitement par chimiothérapie d’un syndrome neurologique paranéoplasique anti-Hu sans cancer actif associé

Anti-Hu associated paraneoplastic neurological syndromes are rare and characterized by poor prognosis. The research and treatment of a related cancer, a small-cell lung cancer most of the time, remains the best therapeutic strategy. We describe the clinical course of a paraneoplastic subacute sensory neuronopathy associated with anti-Hu antibodies in a male smoker treated by an early chemotherapy active against a small-cell lung cancer although no tumor could be found at repeated evaluations. In spite of this treatment, the neurological state deteriorated with the appearance of a cerebellar degeneration, and limbic encephalitis which resulted in a loss of autonomy. A small-cell lung cancer was found and treated 65 months after the onset of the neurological symptoms. The treatment of the underlying malignancy, when it can be found, is still considered as the optimal treatment for paraneoplastic neurological syndromes. Although no tumor could be found, we treated our patient with an empirical chemotherapy active against the most frequent malignancy associated to anti-Hu syndrome in a smoker man, without any improvement. Active and repeated research for a cancer related to an anti-Hu neurological syndrome and its treatment are undispensable. For our patient without any identified cancer empirical chemotherapy treatment was unable to stop neurological worsening. When no tumor can be identified by conventional imaging techniques, an early FDG-PET scan should be considered and then repeated if normal.

Paraneoplastic Subacute Sensory Neuronopathy Secondary to a Malignant Mixed Müllerian Tumor

Paraneoplastic subacute sensory neuronopathy is a rapidly progressive autoimmune disorder commonly associated with small cell cancers. Relentless destruction of dorsal root ganglion cells by cytotoxic T cells leads to a poor prognosis. A 42-year-old woman developed sensory loss in both lower extremities 10 days after debulking of a uterine malignant mixed müllerian tumor. She progressed to sensory loss over the entire body, with initially preserved strength, severe dysmetria, and truncal ataxia. Her serum was positive for antineuronal nuclear antibody-1 (anti-Hu), confirming the diagnosis of paraneoplastic subacute sensory neuronopathy. Despite treatment with intravenous immunoglobulin, methylprednisolone, and plasmapheresis, she remained severely disabled. Because neuronal damage is irreversible, early recognition may be the only means to prevent severe neurologic disability.

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.

Clinical features and pathophysiological basis of sensory neuronopathies (ganglionopathies).

Sensory ganglionopathies have a frequent association with neoplastic disorders (paraneoplastic subacute sensory neuronopathy, or SSN) or dysimmune disorders (Sjögren's syndrome, SS; Miller Fisher syndrome; and Bickerstaff's brainstem encephalitis, BBE), with drugs, such as cisplatin or pyridoxine, and with inherited disorders with degeneration of dorsal root ganglion cells. Unsteady gait and pseudoathetoid movements of the hand are the distinctive signs encountered in these disorders. The chronic disorders are characterized by non-length-dependent abnormalities of sensory nerve action potentials (SNAPs) and differ from other sensory neuropathies in showing a global, rather than distal, decrease in SNAP amplitudes. This review focuses on recent advances in defining the mechanisms involved in sensory ganglionopathies. Specific topics include a summary of their clinical features, pathological findings, and immunopathology. In SSN, early diagnosis by the detection of anti-Hu antibodies and early treatment of the cancer gives the best chance of stabilizing the disorder. In SS sensory ganglionitis, response to treatment has been disappointing, but immunomodulating treatments are emerging. The immunological profile common to BBE and Fisher syndrome supports a common pathogenesis. In toxic sensory neuronopathy, no treatment is available. The differential diagnosis involves separating sensory ganglionopathies from other ataxic polyneuropathies, such as infectious neuropathies, sensory neuropathies with various autoantibodies, and the neuropathies seen in celiac disease.

Paraneoplastic subacute sensory neuronopathy associated with anti‐ri antibodies

Introduction: Subacute sensory neuronopathy (SSN) is characterized by degeneration of T cells of dorsal root ganglia. This syndrome is associated with autoimmune diseases (i.e., Sjogren's Syndrome), tumours (i.e., small‐cell lung cancer), or idiopathic. Paraneoplastic SSN is frequently associated with the presence in the serum of anti‐Hu antibodies (or ANNA 1). Conversely, anti‐Ri antibodies (or ANNA 2) have been associated with paraneoplastic neurological syndromes as opsoclonus‐myoclonus or cerebellar degeneration. Case Report: A 62‐year‐old man presented subacute back pain, gait difficulty, four limbs movement uncoordination and paresthesias/dysesthesias. Neurological examination also revealed involuntary pseudoathetoid movements at upper limbs, loss of vibration sense at lower limbs and diffuse absence of deep tendon reflexes. Nerve conduction studies revealed an axonal sensory polyneuropathy. Cerebrospinal fluid proteins were raised, with increased cell count. Chest CT disclosed a lung neoplasm. Serum anti‐Ri antibodies were detected using indirect immunofluorescence and confirmed by Western blotting, while anti‐Hu were absent. Conclusion: We report a case of paraneoplastic subacute sensory neuronopathy associated with serum anti‐Ri antibodies. To our knowledge this is the first description of such an association.

Paraneoplastic Peripheral Neuropathy Associated With Anti‐hu Antibodies. A Clinical And Electrophysiological Study Of 20 Patients

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 neuro‐ pathy, 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.

High-dose intravenous immunoglobulin therapy in dysimmune neuropathies

Immune-mediated neuropathies, including Guillain-Barre syndrome, Miller Fisher syndrome, chronic inflammatory demyelinating neuropathy, multifocal motor neuropathy, neuropathies associated with monoclonal gammopathy, and paraneoplastic subacute sensory neuronopathy (Table 1), are a group of disorders believed to be caused by an immune response directed against peripheral nerve antigens. The role of the immune system in the pathogenesis of these neuropathies has been first convincingly demonstrated by Latov et al. in 1980 [1] in a patient with neuropathy associated with IgM monoclonal gammopathy, whose IgM were found to react with the myelin-associated glycoprotein (MAG), a minor component of nerve myelin. Since then antibody reactivities against a number of peripheral nerve antigens have been reported in patients with different forms of dysimmune neuropathies, contributing not only to clarify their pathogenesis [2] but also to their identification and diagnosis. Several immune therapies including steroids, plasma exchange (PE) and a number of immunosuppressive agents, have been reported to be effective in these neuropathies. These therapies are however far from being invariably effective and may be associated with a number of side effects which limit their use, leading to the search for new immune therapies. In particular, in the last decade high-dose intravenous immunoglobulin (IVIg) therapy has been shown to be particularly effective in some of these neuropathies, broadening the spectrum of therapeutical options for these diseases (reviewed in [3, 4]). We review the rationale for using IVIg therapy and the results of its application in these neuropathies, in order to give some indications for its use in these diseases.

Paraneoplastic peripheral neuropathy associated with anti-Hu antibodies. A clinical and electrophysiological study of 20 patients.

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.

Internalization of anti-Hu IgG is not Fc gamma receptor mediated.

Patients with paraneoplastic subacute sensory neuronopathy or encephalomyelitis associated with small cell lung cancer cells (SCLC) frequently harbor anti-Hu antibodies (also called antineuronal nuclear antibodies type 1) in serum and CSF. [1] These antibodies react with a family of nuclear proteins, with apparent molecular mass ranging from 35 to 45 kD, expressed in neurons and SCLC cells. [2] Anti-Hu antibodies are one example of ANA associated with autoimmune disease. ANA occur in a variety of autoimmune disorders, most classically systemic lupus erythematosus. The ability of these antibodies to interact with nuclear antigens in living cells has been questioned and the relevance of the antibodies to disease production doubted. However, several groups have demonstrated that autoantibodies can penetrate living cells. [3] Anti-Hu IgG penetrates viable Hu-positive SCLC cells and localizes in the nucleus. [4] How this IgG internalizes into the cell and translocates to the nucleus is unknown. Immunocytochemistry, immunoprecipitation, and flow cytometry show no Hu antigen on the cell surface (Lieberman and Hormigo, unpublished data; Posner, personal communication). Alternatively, internalization may be mediated by receptors that recognize the Fc portion of immunoglobulin molecules, the Fc gamma receptors (Fc gamma Rs). Fc gamma Rs comprise a family of molecules within the immunoglobulin superfamily. There are three main classes: Fc gamma RI, Fc gamma RII, and Fc gamma RIII. [5] For example, the internalization of …

Intrathecal synthesis of the anti‐Hu antibody in patients with paraneoplastic encephalomyelitis or sensory neuronopathy

We studied the intrathecal synthesis of the anti-Hu antibody (also called type 1 antineuronal nuclear autoantibody) in 14 patients with isolated paraneoplastic subacute sensory neuronopathy (SSN) and 16 with paraneoplastic encephalomyelitis (PEM). Patients with PEM had higher anti-Hu titers in the CSF (p = 0.003) but not in the serum than those with SSN. Only one patient (7%) with SSN had a positive intrathecal anti-Hu antibody synthesis whereas this was present in 14 (88%) of the 16 patients with PEM (p < 0.0001). The correlation between the intrathecal production of anti-Hu antibodies and PEM supports the role of autoimmune mechanisms in the pathogenesis of PEM. The absent intrathecal synthesis of anti-Hu antibodies in patients with SSN suggests easier accessibility of the systemic immune reaction to the sensory neurons probably due to the partial absence of blood-nerve barrier in the dorsal root ganglia.

Sensory neuronopathy and small cell lung cancer: antineuronal antibody reacting with neuroblastoma cells.

The anti-Hu antibody is associated with a paraneoplastic subacute sensory neuronopathy (SSN) described in cases of small cell lung cancer (SCLC). The Hu antigen is a pan-neuronal nuclear antigen with a molecular weight of 35-40 kDa. In this study we demonstrated the presence of the paraneoplastic Hu antigen in different neuroblastoma cell lines. We showed that by indirect immunocytochemistry the serum of patients with SSN and SCLC reacts with the nuclei of neuroblastoma cell lines SKN-SH and LAN-1. Western blot analysis of nuclear extracts from neuroblastoma cell lines SKN-SH, IMR-32 and LAN-1 confirmed the presence of the Hu antigen in these neuroblastoma cell lines. By comparing the immunocytochemical method and the Western blot analysis we were able to determine that the Western blot analysis was a more sensitive test. Screening of the sera of a large population (a total of 122 patients with SCLC, 17 with paraneoplastic disorders as well as 121 controls with other neurological disorders) was performed and showed all 5 of the patients with SSN and SCLC to be positive for the anti-Hu antibody, whereas only 11 of the 122 SCLC patients and none of the controls were positive, thereby suggesting that this test has a very high degree of sensitivity.

Neuronal antinuclear antibodies in a patient with Lambert‐Eaton myasthenic syndrome and small‐cell lung carcinoma

A patient with small-cell lung carcinoma and the Lambert-Eaton myasthenic syndrome had circulating neuronal antinuclear antibodies. Serum stained the nuclei of all neurons in sections of human brain and identified a closely spaced group of 33-39 kDa proteins in immunoblots of human neuronal nuclei. These autoantibodies are indistinguishable from those recently identified in patients with paraneoplastic subacute sensory neuronopathy.

Physiological hyperbilirubinemia in the newborn and the reservoir function of the spleen.

Paraneoplastic syndromes arise infrequently in prostate cancer and paraneoplastic subacute sensory neuronopathy has not previously been reported in association with prostate cancer. When paraneoplastic syndromes occur, it is usually in the setting of small-cell carcinoma of the prostate or advanced, hormone-resistant disease. Here the authors report a 64- year-old man who developed a progressive, severe, sensory neuronopathy in the setting of a recently diagnosed stage T4 hormone-responsive prostate adenocarcinoma. Anti-Hu antibodies were positive and screening for a concurrent neoplasm at another site was negative. Sensory neuronopathy progressed, despite hormone responsiveness of his prostate adenocarcinoma, and resulted in a severe level of disability. His symptoms did not respond to intravenous corticosteroid therapy but there was a partial response to intravenous immunoglobulin.