Paraneoplastic Sensory Neuronopathy Research Articles

Anti-CV2-mediated sensory neuronopathy with lesions of posterior columns in spinal MRI

•CV2-antibodies cause radiculitis and secondary damage to the posterior fasciculi. •Paraneoplastic sensory neuronopathy should be considered in differential diagnosis of dorsal column lesions. •Paraneoplastic sensory neuronopathy causes delayed spinal cord lesions, initial MRI can show no imaging correlate.

Anti-Hu (ANNA-1) Associated Paraneoplastic Sensory Neuronopathy in a Large Cell Neuroendocrine Carcinoma of the Lung.

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Clinical features and treatment of paraneoplastic neurological syndrome associated with small cell lung cancer

The aim of this study is to explore the clinical characteristics, treatment and prognosis of pareneoplastic neurological syndrome (PNS) associated with small cell lung cancer (SCLC) in a single-center cohort. We retrospectively and consecutively reviewed 34 patients (22 male and 12 female, mean age 55.4 years old) diagnosed as PNS associated with SCLC in our hospital from 2001 to 2014 and investigated the clinical features, related antibodies, treatment and prognosis in this cohort. In a total of 34 patients, 31 (91.4%) presented with neurological symptoms prior to the diagnosis of cancer. Lambert-Eaton syndrome (13/34, 38.2%) was the most common subtype, followed by paraneoplastic sensory neuronopathy (10/34, 29.4%), paraneoplastic cerebellar degeneration (7/34, 20.6%), limbic encephalitis (6/34, 17.6%) and brainstem encephalitis (1/34, 3%). Anti-neuronal antibodies were positive in 9 out of a total of 24 patients (37.5%) who performed the tests. There were 28 (82.4%) patients who received the treatment for the primary tumor. Of them, operation of removing the tumor was performed in 4 patients. 5 patients received treatment of suppression of the immune response to PNS. Significant neurological improvement was found in a patient who received operation combined with immunotherapy after a 3-year follow-up. The majority of patients with PNS are unknown to have cancer at the time of diagnosis. Early recognition of PNS is helpful to the treatment of the tumor. PNS has diverse presentations, affecting both the central and peripheral nervous system, which makes the diagnosis hard. Operation of removing the tumor and immune suppression may slow the immune response, creating the greatest chance for neurologic improvement or symptom stabilization.

Francesc Graus: solving paraneoplastic puzzles

Francesc Graus: solving paraneoplastic puzzles

POC19 Anti-Hu paraneoplastic sensory neuronopathy with underlying squamous cell carcinoma of the lung

Type 1 anti-neuronal nuclear antibody (ANNA-1), also known as anti-Hu, recognises a family of RNA binding proteins, expressed in neuronal nuclei throughout the human neuraxis. Its presence usually reflects immunity...

Slowly progressive sensory hemisyndrome: unusual presentation of paraneoplastic sensory neuronopathy

Slowly progressive sensory hemisyndrome: unusual presentation of paraneoplastic sensory neuronopathy

Reversible Extralimbic Paraneoplastic Encephalopathies With Large Abnormalities on Magnetic Resonance Images

To describe reversible extralimbic paraneoplastic encephalopathies with large, lobar lesions on magnetic resonance imaging (MRI). Case series. Autoimmune Neurology Clinic, Mayo Clinic, Rochester, Minnesota. Three patients had large confluent areas of signal abnormality on T2-weighted MRI, including frontal in 2 and frontal and occipital in 1. Patient 1, a woman aged 63 years, experienced hemiparesis with hemianopia 3 years after a diagnosis of adenocarcinoma of the breast. Nine years later, rapidly progressive dementia developed. Patient 2, a woman aged 79 years, presented with monoparesis and epilepsia partialis continua, 1 year after a diagnosis of adenocarcinoma of the breast. Patient 3, a man aged 65 years, had paraneoplastic sensory neuronopathy, limbic encephalitis, antineuronal nuclear autoantibody type 1 (ANNA-1), and squamous cell carcinoma of the lung. He was stable for 3 years after treatment. Subacute onset of aphasia, delirium, worsening seizures, and rising ANNA-1 titers led to a diagnosis of recurrent limited carcinoma. Brain MRI abnormalities in all patients improved dramatically after immunotherapy. Two patients had sustained clinical remission. Recognition of paraneoplastic extralimbic lobar encephalopathies is important because these disorders and their underlying cancers are treatable.

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.

Spontaneous remission of small cell lung cancer: A case report and review in the literature

Spontaneous remission (SR) of cancer, especially of lung tumor, is a rare biological event. Only seven cases in which small cell lung cancer (SCLC) regressed spontaneously had been previously reported. We report here a rare case of complete SR of SCLC in an 86-year-old man. Paraneoplastic sensory neuronopathy (PSN) is a rare syndrome, which is associated with malignancy such as SCLC and starts with dysesthetic pain and numbness in the distal extremities, then spreading all four limbs and trunk causing severe sensory ataxia. In the previous reports, SR of SCLC is suggested to result from surgical trauma or PSN, which may be able to enhance anti-tumoral immunity. Our report is the case of SR of SCLC, without any therapies nor any invasive examinations. Although the reason of SR of SCLC in the present case is unknown, PSN could be one of the diagnosis by exclusion.

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.

Numb cheek syndrome as the first manifestation of anti–Hu paraneoplastic neuronopathy

Sirs: Unilateral numb cheek syndrome (NCS) has rarely been described as the first manifestation of malignancy due to neoplastic involvement of the trigeminal nerve, more specifically the maxillary branch [1, 2]. NCS as the first symptom of subacute paraneoplastic sensory neuronopathy has, to the best of our knowledge, never been reported. We present this case because its rarity led to a diagnostic delay of several months. A 47-year-old man presented with a one month history of numbness in the left cheek, both inner and outer surfaces. The area of numbness corresponded with the mandibular division of the left trigeminal nerve (V3). His medical history was unremarkable. Neurological examination was normal including the left V3 area. As the main part of the cheek is innervated by the buccal nerve we considered that our patient had a mandibular sensory neuropathy probably due to compression or infiltration of the nerve by local malignancy, as seen in other types of trigeminal mononeuropathy [3]. Ancillary investigations including contrast enhanced brain MRI, thorax CT and extensive laboratory examinations of the blood and urine were normal. Cerebrospinal fluid (CSF) examination revealed mild lymphocytic pleocytosis, slightly elevated protein of 0.69 g/l (0.2–0.5) and no malignant cells or oligoclonal bands. Although intracranial malignancy could not be ruled out an expectant policy was chosen by the patient. Two months later he complained of slightly unsteady gait. A second MRI of the brain and skull base was normal. Another 4 months later he noticed numbness of his left hand and foot. Neurological examination showed only left sided facial hypalgesia. Nerve conduction studies were consistent with a non uniformly distributed, predominantly axonal, sensorimotor neuropathy, most pronounced in the left extremities. Repeated conventional CSF examination only showed an increased protein level of 0.86 g/l. Anti-Hu antibodies in CSF were detected with indirect immunofluorescence and Western blotting techniques. A second thorax CT and whole body PET-scan eventually showed a solitary lesion in the right hilus, which proved to be a metastasis of an anaplastic small cell carcinoma on histological examination. Although the primary tumour remained unrevealed, a paraneoplastic multifocal mainly sensory neuronopathy associated with presumed primary small cell lung carcinoma was diagnosed and combined chemotherapy started. Fifteen months after the initial complaint the primary tumour remained undetected and no metastases were found. The neuropathy progressed resulting in very severe sensorimotor neuropathy with asymmetric painful paresthesias, diffuse proprioceptive loss and weakness in all extremities. In patients with paraneoplastic anti-Hu associated neuropathy (AHN) involvement of the cranial nerves may be present but is very rarely the presenting symptom. AHN most commonly presents as a subacute sensory neuropathy, less frequently as a sensorimotor neuropathy [5, 6]. These neurological symptoms typically antedate the diagnosis of cancer and most commonly involve the extremities [4–7]. In 306 patients with malignancy and associated anti-Hu antibodies, 50 % of the patients had a sensory neuropathy [4–6]. Three of them had trigeminal nerve involvement, but in no one was cheek numbness described as the only presenting symptom. As initially no primary tumour was found, we did not consider AHN as a potential cause of the unilateral cheek numbness in our patient. The final diagnosis was reached because of the extension of the sensory symptoms and eventually the evidence of an asymmetric sensorimotor neuropathy. The diagnostic delay between the NCS and final diagnosis was 6 months, which lies within the range of reported diagnostic delays in AHN patients [4–7]. As early treatment of the underlying malignancy is the mainstay of treatment, we report this patient in order to add NCS to the list of presenting symptoms of AHN.

Adie's pupils in paraneoplastic ganglionopathy with ANNA-1

Autonomic disturbances are common in patients with paraneoplastic syndromes associated with type-1 antineuronal nuclear autoantibodies (ANNA-1), although pupillary disturbances are infrequent. The authors describe a patient with ANNA-1 associated paraneoplastic sensory neuronopathy and bilateral Adie's pupils.

A follow up study of patients with paraneoplastic neurological disease in the United Kingdom

Objectives: To examine the range of clinical phenotypes, tumour associations, relevant investigations, response to therapy and outcome in a large series of non-selected patients with paraneoplastic neurological disease (PND) affecting...

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 Sensory Neuronopathy and Spontaneous Regression of Small Cell Lung Cancer

Spontaneous tumour regression in small cell lung cancer has previously been suggested in patients with paraneoplastic neurologic syndromes. Rare documentation of this event has occurred in the literature. The authors report a patient with anti-Hu associated paraneoplastic sensory neuronopathy who had a spontaneous regression of her small cell lung cancer. This case supports the hypothesis that anti-Hu neurologic syndromes are the consequence of a misdirected immune response to small cell tumours.

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.