Paraneoplastic Neuropathy Research Articles

Anti-collapsin response mediator protein 5 encephalitis masquerading as a low-grade brain tumour

A 71-year-old woman presented acutely with seizures; her MRI suggested a low-grade glioma of the right temporal lobe. Over the preceding 18 months, she had developed progressive limb chorea and...

Bilateral Vocal Cord Paralysis and Cervicolumbar Radiculopathy as the Presenting Paraneoplastic Manifestations of Small Cell Lung Cancer: A Case Report and Literature Review.

Introduction. Bilateral vocal cord paralysis (BVCP) is a potential medical emergency. The Otolaryngologist plays a crucial role in the diagnosis and management of BVCP and must consider a broad differential diagnosis. We present a rare case of BVCP secondary to anti-Hu paraneoplastic syndrome. Case Presentation. A 58-year-old female presented to an Otolaryngology clinic with a history of progressive hoarseness and dysphagia. Flexible nasolaryngoscopy demonstrated BVCP. Cross-sectional imaging of the brain and vagus nerves was negative. An antiparaneoplastic antibody panel was positive for anti-Hu antibodies. This led to an endobronchial biopsy of a paratracheal lymph node, which confirmed the diagnosis of small cell lung cancer. Conclusion. Paraneoplastic neuropathy is a rare cause of BVCP and should be considered when more common pathologies are ruled out. This is the second reported case of BVCP as a presenting symptom of paraneoplastic syndrome secondary to small cell lung cancer.

Chapter 22 - Autoimmune autonomic disorders

Autoimmune autonomic disorders occur because of an immune response directed against sympathetic, parasympathetic, and enteric ganglia, autonomic nerves, or central autonomic pathways. In general, peripheral autoimmune disorders manifest with either generalized or restricted autonomic failure, whereas central autoimmune disorders manifest primarily with autonomic hyperactivity. Some autonomic disorders are generalized, and others are limited in their anatomic extent, e.g., isolated gastrointestinal dysmotility. Historically, these disorders were poorly recognized, and thought to be neurodegenerative. Over the last 20 years a number of autoantibody biomarkers have been discovered that have enabled the identification of certain patients as having an autoimmune basis for either autonomic failure or hyperactivity. Peripheral autoimmune autonomic disorders include autoimmune autonomic ganglionopathy (AAG), paraneoplastic autonomic neuropathy, and acute autonomic and sensory neuropathy. AAG manifests with acute or subacute onset of generalized or selective autonomic failure. Antibody targeting the α3 subunit of the ganglionic-type nicotinic acetylcholine receptor (α3gAChR) is detected in approximately 50% of cases of AAG. Some other disorders are characterized immunologically by paraneoplastic antibodies with a high positive predictive value for cancer, such as antineuronal nuclear antibody, type 1 (ANNA-1: anti-Hu); others still are seronegative. Recognition of an autoimmune basis for autonomic disorders is important, as their manifestations are disabling, may reflect an underlying neoplasm, and have the potential to improve with a combination of symptomatic and immune therapies.

Generalized pruritus preceding paraneoplastic neuropathy

Paraneoplastic syndromes are a group of rare disorders involving non-metastatic systemic effects accompanying malignancies, and occur remotely from the tumor itself. Chronic pruritus lasting more than 6weeks can be from paraneoplastic origin. A 65-year-old woman was admitted for generalized pruritus lasting for 1month, despite treatment with prednisolone, levocetirizine and hydroxyzine. General examination was normal. Biological data and gastroscopy were normal. One month later, the patient was readmitted for worsening of her pruritus and walking impairment, revealing a severe sensory neuropathy. Blood anti-Hu antibodies returned positive at a level of 400 (normal <100). Bronchoscopy and bronchial biopsies revealed small-cell lung carcinoma. To our knowledge, the association of generalized pruritus and paraneoplastic neuropathy has been rarely reported. Our observation raises the question of a pathophysiological continuum between pruritus and neuropathy in a paraneoplastic context.

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.

Neuropathies associated with lymphoma†

Neuropathy occurs with various manifestations as a consequence of lymphoma, and an understanding of the etiology is necessary for proper treatment. Advances in medical imaging have improved the detection of peripheral nerve involvement in lymphoma, yet tissue diagnosis is often equally important. The neoplastic involvement of the peripheral nervous system (PNS) in lymphoma can occur within the cerebrospinal fluid (CSF), inside the dura, or outside of the CSF space, affecting nerve root plexuses and peripheral nerves. The infiltration of either cranial or peripheral nerves in lymphoma is termed neurolymphomatosis (NL). These infiltrations can occur as mononeuropathy, multifocal neuropathy, symmetric neuropathies, or plexopathies. In rare cases, intravascular lymphoma (IL) can affect the PNS and an even rarer condition is the combination of NL and IL. Immune-mediated and paraneoplastic neuropathies are important considerations when treating patients with lymphoma. Demyelinating neuropathies, such as Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy, occur more frequently in non-Hodgkin's lymphoma than in Hodgkin's disease. Paraproteinemic neuropathies can be associated with lymphoma and paraneoplastic neuropathies are rare. While the treatment of lymphomas has improved, a knowledge of neurotoxic, radiotherapy, neoplastic, immune-mediated and paraneoplastic effects are important for patient care.

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)

98. Early neurophysiological modifications in subacute polyneuropathy associated with meningeal carcinomatosis in linitis plastica

A 31-year-old woman came to Emergency Room in February 2014 for acute onset of cervical pain, vomiting and diplopia. Neurological examination showed right sixth nerve palsy, absent tendon reflexes and ataxia. General examination showed axillary skin lesions. Cerebrospinal fluid analysis showed low glucose and high total cell count; brain and spinal cord gadolinium-enhanced MRI was not conclusive. Neurophysiological evaluation (electroneurography, electromyography, blink reflex), was normal. Symptoms partially spontaneously resolved and she was discharged. Two days after she was re-admitted because of worsening of pain and vomiting, cranial multineuropathy, arm paralysis, ataxia. Neurophysiological study showed slow conduction velocities, reduced CMAP and SAP amplitudes, absent F waves, abnormal blink reflex and reduced muscle recruitment. Pain and vomiting were not referable to these findings, another MRI was not conclusive. Last MRI, performed one month after symptoms onset, documented meningeal carcinomatosis. Skin lesions biopsy disclosed gastric cancer cells, subsequent gastroscopy allowed to diagnose linitis plastica; she died shortly after the diagnosis. Peripheral or central nervous system involvement in paraneoplastic syndromes is not rare, but this case is peculiar for clinical presentation and association between paraneoplastic neuropathy and a rare primitive gastric cancer. Only cerebrospinal fluid analysis and neurophysiological tests early documented the worsening of clinical conditions.

Paraneoplastic Neuropathies

This article provides an approach to the recognition and management of paraneoplastic neuropathies. Paraneoplastic neuropathies may have unique phenotypic presentations, such as sensory neuronopathy, autonomic enteric neuropathy, demyelinating neuropathy, and, rarely, motor neuropathy. Paraneoplastic sensorimotor neuropathy, on the other hand, may be indistinguishable from other common types of axonal polyneuropathy. Certain patterns of neuropathies are commonly seen with different types of cancers, but this relationship is not exclusive and not all patients whose pattern of neuropathy suggests a paraneoplastic disorder have an underlying cancer. In addition to definitive therapy for malignancy, immunomodulatory therapy, such as corticosteroids, IV immunoglobulin (IVIg), or immunosuppressants, may benefit some patients, but there are very few published treatment data for paraneoplastic neuropathies. Prompt recognition of paraneoplastic neuropathies may lead to identification and treatment of an occult cancer. Treatment can potentially arrest the progression of neuropathy.

THE WIDENING SPECTRUM OF PARANEOPLASTIC DISORDERS: TWO CASES

Paraneoplastic neurological syndromes are non-metastatic disorders triggered by an altered immune response to a neoplasm. Uncommon presentations are increasingly reported, widening the recognised spectrum of these disorders. We present two patients with atypical neurological manifestations that heralded malignancy. <b>Case 1</b> A 79 year old woman presented with progressive asymmetrical (R&gt;L) leg weakness. Examination confirmed significant paraparesis (MRC 2/5 bilaterally) with normal muscle bulk and tone, normal sensation and sphincter control, hyporeflexia and downgoing plantars. MRI of the lumbosacral spine was normal. Nerve conduction studies showed an axonal and demyelinating motor neuropathy. CSF was acellular with high protein (2.5 gr/dl) and normal glucose. Body CT revealed a large retrosternal mass consistent with thymoma. Her paraneoplastic motor neuropathy was treated with intravenous immunoglobulin, which clinically stabilised her progression, and referred for surgical removal. <b>Case 2</b> A 72 year old woman presented with painless, progressive left-sided visual loss. Fundoscopy excluded arterial occlusion or vasculitis. Investigations for autoimmune or infective causes were normal. Chest X-ray, echocardiogram, lumbar puncture and a temporal artery biopsy were diagnostically non-contributory. Body CT showed multiple lytic and sclerotic bone lesions, with abnormal lymphadenopathy in the left axilla. Fine needle aspiration of a node showed adenocarcinoma consistent with metastatic oestrogen receptor positive breast cancer. The final diagnosis was non-metastatic paraneoplastic optic neuropathy.

Peripheral neuropathies associated with antibodies directed to intracellular neural antigens

Antibodies directed to intracellular neural antigens have been mainly described in paraneoplastic peripheral neuropathies and mostly includes anti-Hu and anti-CV2/CRMP5 antibodies. These antibodies occur with different patterns of neuropathy. With anti-Hu antibody, the most frequent manifestation is sensory neuronopathy with frequent autonomic involvement. With anti-CV2/CRMP5 the neuropathy is more frequently sensory and motor with an axonal or mixed demyelinating and axonal electrophysiological pattern. The clinical pattern of these neuropathies is in keeping with the cellular distribution of HuD and CRMP5 in the peripheral nervous system. Although present in high titer, these antibodies are probably not directly responsible for the neuropathy. Pathological and experimental studies indicate that cytotoxic T-cells are probably the main effectors of the immune response. These disorders contrast with those in which antibodies recognize a cell surface antigen and are probably responsible for the disease. The neuronal cell death and axonal degeneration which result from T-cell mediated immunity explains why treating these disorders remains challenging.

Suspected Paraneoplastic Autonomic Neuropathy in a Patient with Newly Diagnosed Glioblastoma Multiforme (P3.322)

Suspected Paraneoplastic Autonomic Neuropathy in a Patient with Newly Diagnosed Glioblastoma Multiforme (P3.322)

A case of paraneoplastic optic neuropathy and outer retinitis positive for autoantibodies against collapsin response mediator protein-5, recoverin, and α-enolase

BackgroundSpecific cross-reacting autoimmunity against recoverin or collapsin response mediator protein (CRMP)-5 is known to cause cancer-associated retinopathy or paraneoplastic optic neuropathy, respectively. We report a rare case with small cell lung carcinoma developing bilateral neuroretinitis and unilateral focal outer retinitis positive for these antibodies.Case presentationA 67-year-old man developed bilateral neuroretinitis and foveal exudation in the right eye. Optical coherence tomography showed a dome-shaped hyperreflective lesion extending from inner nuclear layer to the photoreceptor layer at the fovea in the right eye. Single-flash electroretinography showed normal a-waves in both eyes and slightly reduced b-wave in the left eye. Results of serological screening tests for infection were within normal limits. The patient’s optic disc swelling and macular exudation rapidly improved after oral administration of prednisolone. Systemic screening detected lung small cell carcinoma and systemic chemotherapy was initiated. Immunoblot analyses using the patient’s serum detected autoantibodies against recoverin, CRMP-5, and α-enolase, but not carbonic anhydrase II. Neuroretinitis once resolved after almost remission of carcinoma on imaging but it recurred following the recurrence of carcinoma.ConclusionsThe development of neuroretinitis in this cancer patient with anti-retinal and anti-optic nerve antibodies depended largely on the cancer activity, suggesting the possible involvement of paraneoplastic mechanisms. Patients with paraneoplastic optic neuropathy and retinopathy are likely to develop autoimmune responses against several antigens, thus leading to various ophthalmic involvements.

A case of metastatic high grade neuroblastoma with undetected primary in adult presenting with soft tissue lumps and bilateral choroidal metastases

An adult male patient got hospitalized with fever, anorexia, weight loss, generalized weakness, and visual problem. Examination revealed solitary axillary lymphadenopathy and soft tissue swellings over scalp and left shoulder. Tests detected severe anemia and raised erythrocyte sedimentation rate (ESR), lactate dehydrogenase, and uric acid. Magnetic resonance imaging (MRI) brain showed irregular soft tissue swellings both outside and inside the skull with pressure effect on brain. Fundoscopy revealed bilateral choroidal metastatic deposits with papilledema. Histopathology findings of biopsy from scalp mass and bone marrow were consistent with metastatic high grade neuroblastoma. No primary lesion was found on computed tomography (CT) scan of thorax, abdomen, and pelvis. There was also suggestion of paraneoplastic neuropathy. The patient responded fairly to chemotherapy. Neuroblastoma is usually known to be a childhood malignancy that often presents with vague symptoms or symptoms due to tumor mass or with metastatic or paraneoplastic features. Most common metastatic sites are bone, lymph node, liver, cranium, and chest. But in this case apart from bony and dural metastases there was also choroidal metastasis which is previously not reported in adults. Likewise, non-detection of primary tumor is also uncommon.

Orthostatic hypotension secondary to CRMP-5 paraneoplastic autonomic neuropathy

The collapsin response mediator protein 5 (CRMP-5) autoantibody is one of only several paraneoplastic antibodies associated with autonomic neuropathy. Such paraneoplastic neuropathies manifest with a constellation of autonomic abnormalities. We present a unique case of orthostatic hypotension as the sole feature of a CRMP-5 paraneoplastic autonomic neuropathy in a patient with small cell lung cancer. Given the poor prognosis of paraneoplastic autonomic dysfunction, it is important to accurately diagnose the cause of orthostatic hypotension occurring on a background of malignancy.

Paraneoplastic neuropathies

This review describes relevant advances in paraneoplastic neuropathies with emphasis on particular syndromes and the impact of new therapies. Sensory neuronopathy may present with symptoms that do not raise the suspicion of a paraneoplastic origin. A recent study on sensory neuronopathies of different causes identified paraneoplastic cases in a group of older (>60 years) male patients with subacute onset early pain, and frequent involvement of the arms. Paraneoplastic sensorimotor polyneuropathies may be confused with chronic inflammatory demyelinating polyneuropathy (CIDP) and in lymphomas with direct infiltration of nerves (neurolymphomatosis). Recent neurophysiological studies indicate that the polyneuropathy of POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M component, and skin changes) can be differentiated from CIDP by the presence of diffuse demyelination and more severe axonal loss. Neuropathy in Waldenström macroglobulinemia is heterogeneous. Up to 38% have demyelinating features and the rest show axonal degeneration due to different causes (dysimmune, amyloidosis, or tumoral infiltration). Isolated case reports suggest that the combination of cyclophosphamide and rituximab may be effective in paraneoplastic neuronopathies. Lenalidomide and dexamethasone are effective to control the neuropathy of POEMS patients who are not suitable for or progress after autologous stem cell transplantation. Clinical and neurophysiological studies are helpful to correctly identify particular paraneoplastic neuropathies.

Treatment for paraneoplastic neuropathies

Paraneoplastic neuropathies are the most frequently reported paraneoplastic syndromes. They are, however, heterogeneous and require several therapeutic approaches. This review was undertaken to systematically assess any data available from randomised controlled trials (RCTs) on the treatment of paraneoplastic syndromes of the peripheral nervous system.

Peripheral paraneoplastic neuropathy, an uncommon clinical onset of sigmoid cancer

Peripheral paraneoplastic neuropathy, an uncommon clinical onset of sigmoid cancer

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

Clinicopathological features of neuropathy associated with lymphoma

Lymphoma causes various neurological manifestations that might affect any part of the nervous system and occur at any stage of the disease. The peripheral nervous system is one of the major constituents of the neurological involvement of lymphoma. In this study we characterized the clinical, electrophysiological and histopathological features of 32 patients with neuropathy associated with non-Hodgkin's lymphoma that were unrelated to complications resulting from treatment for lymphoma. Nine patients had pathologically-proven neurolymphomatosis with direct invasion of lymphoma cells into the peripheral nervous system. These patients showed lymphomatous cell invasion that was more prominent in the proximal portions of the nerve trunk and that induced demyelination without macrophage invasion and subsequent axonal degeneration in the portion distal from the demyelination site. Six other patients were also considered to have neurolymphomatosis because these patients showed positive signals along the peripheral nerve on fluorodeoxyglucose positron emission tomography imaging. Spontaneous pain can significantly disrupt daily activities, as frequently reported in patients diagnosed with neurolymphomatosis. In contrast, five patients were considered to have paraneoplastic neuropathy because primary peripheral nerve lesions were observed without the invasion of lymphomatous cells, with three patients showing features compatible with chronic inflammatory demyelinating polyneuropathy, one patient showing sensory ganglionopathy, and one patient showing vasculitic neuropathy. Of the other 12 patients, 10 presented with multiple mononeuropathies. These patients showed clinical and electrophysiological features similar to those of neurolymphomatosis rather than paraneoplastic neuropathy. Electrophysiological findings suggestive of demyelination were frequently observed, even in patients with neurolymphomatosis. Eleven of the 32 patients, including five patients with neurolymphomatosis, fulfilled the European Federation of Neurological Societies/Peripheral Nerve Society electrodiagnostic criteria of definite chronic inflammatory demyelinating polyneuropathy. Some of these patients, even those with neurolymphomatosis, responded initially to immunomodulatory treatments, including the administration of intravenous immunoglobulin and steroids. Patients with lymphoma exhibit various neuropathic patterns, but neurolymphomatosis is the major cause of neuropathy. Misdiagnoses of neurolymphomatosis as chronic inflammatory demyelinating polyneuropathy are frequent due to a presence of a demyelinating pattern and the initial response to immunomodulatory treatments. The possibility of the concomitance of lymphoma should be considered in various types of neuropathy, even if the diagnostic criteria of chronic inflammatory demyelinating polyneuropathy are met, particularly in patients complaining of pain.