Paraneoplastic neuropathies and peripheral nerve hyperexcitability disorders.

Peripheral neuropathy is a common referral for patients to the neurologic clinics. Paraneoplastic neuropathies account for a small but high morbidity and mortality subgroup. Symptoms include weakness, sensory loss, sweating irregularity, blood pressure instability, severe constipation, and neuropathic pain. Neuropathy is the first presenting symptom of malignancy among many patients. The molecular and cellular oncogenic immune targets reside within cell bodies, axons, cytoplasms, or surface membranes of neural tissues. A more favorable immune treatment outcome occurs in those where the targets reside on the cell surface. Patients with antibodies binding cell surface antigens commonly have neural hyperexcitability with pain, cramps, fasciculations, and hyperhidrotic attacks (CASPR2, LGI1, and others). The antigenic targets are also commonly expressed in the central nervous system, with presenting symptoms being myelopathy, encephalopathy, and seizures with neuropathy, often masked. Pain and autonomic components typically relate to small nerve fiber involvement (nociceptive, adrenergic, enteric, and sudomotor), sometimes without nerve fiber loss but rather hyperexcitability. The specific antibodies discovered help direct cancer investigations. Among the primary axonal paraneoplastic neuropathies, pathognomonic clinical features do not exist, and testing for multiple antibodies simultaneously provides the best sensitivity in testing (AGNA1-SOX1; amphiphysin; ANNA-1-HU; ANNA-3-DACH1; CASPR2; CRMP5; LGI1; PCA2-MAP1B, and others). Performing confirmatory antibody testing using adjunct methods improves specificity. Antibody-mediated demyelinating paraneoplastic neuropathies are limited to MAG-IgM (IgM-MGUS, Waldenström's, and myeloma), with the others associated with cytokine elevations (VEGF, IL6) caused by osteosclerotic myeloma, plasmacytoma (POEMS), and rarely angiofollicular lymphoma (Castleman's). Paraneoplastic disorders have clinical overlap with other idiopathic antibody disorders, including IgG4 demyelinating nodopathies (NF155 and Contactin-1). This review summarizes the paraneoplastic neuropathies, including those with peripheral nerve hyperexcitability.

Acute sensorimotor paraneoplastic neuropathy in a patient with small cell prostate cancer.

The authors describe a patient with a background of metastatic small cell prostate cancer who presented with a rapidly evolving sensorimotor neuropathy with bulbar features closely resembling Guillain-Barré syndrome, with a good initial response to intravenous immunoglobulins and platinum-based chemotherapy. This represented a likely paraneoplastic manifestation of the patient's urological malignancy.

Chronic demyelinating polyneuropathy preceding T-cell lymphoma: differentiation between primary neurolymphomatosis and paraneoplastic neuropathy.

A 49-year-old man presented with progressive asymmetric weakness and pain. Electrodiagnostic tests and nerve biopsy suggested chronic demyelinating polyneuropathy refractory to immune-modulating therapy. The patient's symptoms were aggravated, and he was finally diagnosed with T-cell lymphoma based on the findings of the second 18F-2 fluoro-2-deoxy-glucose positron emission tomography/CT performed 16 months after symptom onset. The patient received intravenous chemotherapy, but died 2 months later because of lymphoma progression. A clinical suspicion of neurolymphomatosis and early diagnosis are important for proper management.

Chronic inflammatory demyelinating polyradiculoneuropathy-Diagnostic pitfalls and treatment approach.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is characterized by progressive weakness and sensory loss, often affecting patients' ability to walk and perform activities of daily living independently. With the lack of a diagnostic biomarker, the diagnosis relies on clinical suspicion, clinical findings, and the demonstration of demyelinating changes on electrodiagnostic (EDx) testing and nerve pathology. As a result, patients can often be misdiagnosed with CIDP and unnecessarily treated with immunotherapy. Interpreting the EDx testing and cerebrospinal fluid findings in light of the clinical phenotype, recognizing atypical forms of CIDP, and screening for CIDP mimickers are the mainstays of the approach to patients suspected of having CIDP, and are detailed in this review. We also review the currently available treatment options, including intravenous immunoglobulin (IVIg), corticosteroids (CCS), and plasma exchange (PE), and discuss how to approach treatment-refractory cases. Finally, we emphasize the need to adopt objective outcome measures to monitor treatment response.

Paraneoplastic Myeloneuropathies: Clinical, Oncologic, and Serologic Accompaniments.

OBJECTIVE: To test the hypothesis that myeloneuropathy is a presenting phenotype of paraneoplastic neurologic syndromes we retrospectively reviewed clinical, radiologic, and serologic features of 32 patients with concomitant paraneoplastic spinal cord and peripheral nervous system involvement. METHODS: Observational study investigating patients with myeloneuropathy and underlying cancer or onconeural antibody seropositivity. RESULTS: Among 32 patients with paraneoplastic myeloneuropathy, 20 (63%) were women with median age 61 years (range 27-84 years). Twenty-six patients (81%) had classified onconeural antibodies (amphiphysin, n = 8; antineuronal nuclear antibody [ANNA] type 1 [anti-Hu], n = 5; collapsin response mediator protein 5 [CRMP5] [anti-CV2], n = 6; Purkinje cell cytoplasmic antibody type 1 [PCA1] [anti-Yo], n = 1; Purkinje cell cytoplasmic antibody type 2 [PCA2], n = 2; kelch-like protein 11 [KLHL11], n = 1; and combinations thereof: ANNA1/CRMP5, n = 1; ANNA1/amphiphysin, n = 1; ANNA3/CRMP5, n = 1). Cancer was confirmed in 25 cases (onconeural antibodies, n = 19; unclassified antibodies, n = 3; no antibodies, n = 3). Paraneoplastic myeloneuropathies had asymmetric paresthesias (84%), neuropathic pain (78%), subacute onset (72%), sensory ataxia (69%), bladder dysfunction (69%), and unintentional weight loss >15 pounds (63%). Neurologic examination demonstrated concomitant distal or asymmetric hyporeflexia and hyperreflexia (81%), impaired vibration and proprioception (69%), Babinski response (68%), and asymmetric weakness (66%). MRI showed longitudinally extensive (45%), tract-specific spinal cord T2 hyperintensities (39%) and lumbar nerve root enhancement (38%). Ten of 28 (36%) were unable to ambulate independently at last follow-up (median 24 months, range 5-133 months). Combined oncologic and immunologic therapy had more favorable modified Rankin Scale scores at post-treatment follow-up compared to those receiving either oncologic or immunologic therapy alone (2 [range 1-4] vs 4 [range 2-6], p < 0.001). CONCLUSIONS: Paraneoplastic etiologies should be considered in the evaluation of subacute myeloneuropathies. Recognition of key characteristics of paraneoplastic myeloneuropathy may facilitate early tumor diagnosis and initiation of immunosuppressive treatment.

Paraneoplastic Sensory Polyneuropathy Related to Anti-PD-L1-including Anticancer Treatment in a Patient with Lung Cancer.

Paraneoplastic neurological syndromes (PNS), such as sensory polyneuropathy, are rare, and serum neuronal antibodies that are used for diagnosing this syndrome are occasionally positive. Similarly, neurological immune-related adverse events due to immune checkpoint inhibitors (ICIs) are also rare. However, their etiologies and the relationship between them remain unclear. We herein report a patient with suspected small cell lung cancer who showed sensory polyneuropathy after treatment with atezolizumab in combination with cytotoxic agents (carboplatin and etoposide) and was doubly positive for serum anti-Hu and anti-SOX-1 antibodies. Treatment with ICI and cytotoxic agents may sometimes lead to the development of PNS.

Paraneoplastic subacute sensory neuropathy with triple positive antineuronal antibodies associated with small-cell lung cancer.

A 67-year-old woman with a history of smoking and cardiovascular risk factors was admitted to the emergency room for uncontrolled diabetes, loss of appetite, nausea, significant weight loss and asthenia. The initial investigation, including cerebral and gastrointestinal explorations, were normal. One month later, she started presenting severe asymmetric proprioceptive ataxia of the lower extremities. She also reported paresthesia and neuropathic pain in both feet and ankles. A positron emission tomography (PET)-scanner showed a hypermetabolic nodule in the right lung. The neurological symptoms were attributed to paraneoplastic sensory and dysautonomic neuropathy, even though the bronchoscopic biopsies came back negative at first. Anti-Hu, anti-CV2/CRMP5 and anti-SOX1 antibodies were documented. Due to the severity and rapid progression of symptoms (from the lower to the upper limbs), corticosteroids, intravenous immunoglobulins and immunosuppressants were introduced prior to biopsies revealing a small-cell lung cancer. Despite these treatments and antineoplastic chemotherapy, her status deteriorated rapidly.

[A case of paraneoplastic sensory neuronopathy with anti-Hu antibody associated with large cell neuroendocrine carcinoma of the endometrium].

An 81-year-old woman was admitted to our hospital due to paresthesia of the extremities and difficulty in walking for three months. She underwent a total hysterectomy and bilateral salpingo-oophorectomy for large cell neuroendocrine carcinoma (LCNEC) of the endometrium seven months before the admission. The serum levels of neuron specific enolase (NSE) reduced after the surgery. She showed numbness of her limbs, disturbance of vibration, areflexia and autonomic dysfunction. Nerve conduction studies showed sensory dominant sensory neuronopathy. CT scan of her abdomen and pelvis revealed the recurrence of LCNEC of the endometrium. The serum levels of NSE was elevated and anti-Hu antibody was also positive. Other laboratory test, including autoantibodies were unremarkable. We diagnosed her as paraneoplastic sensory neuronopathy associated with postoperative recurrence of LCNEC of the endometrium. Here we show a clinical picture of anti-Hu positive paraneoplastic neurological syndrome with LCNEC of the endometrium.

A Case Report of Pediatric Paraneoplastic Dysautonomia.

We present the case of a 16-year-old girl who presented with severe refractory orthostatic hypotension secondary to pandysautonomia. Initially, she was treated for Guillain-Barré syndrome given clinical symptoms and increased protein on cerebrospinal fluid, but the severity of symptoms and lack of response to intravenous immunoglobulin prompted further evaluation for an autoimmune etiology. She was ultimately diagnosed with paraneoplastic neuropathy secondary to Hodgkin lymphoma. Paraneoplastic neurologic phenomena are rare, occurring in just 0.01% of cancers, and prompt recognition is crucial for initiating appropriate therapy. Rapid progression of severe disabling symptoms should raise suspicion for an underlying malignancy. The patient had limited response to splanchnic vasoconstrictors in addition to α-agonists, anticholinergics, and mineralocorticoids until initiation of modified Hodgkin lymphoma directed chemotherapy plus rituximab.

Ganglionopatías o neuronopatías sensoriales paraneoplásicas y disinmunes. Importancia de una detección temprana / Paraneoplastic and disimmune sensory neuronopathies or ganglionopathies. Importance of an early detection

Introducción: Las ganglionopatías o neuronopatías sensoriales son enfermedades subagudas adquiridas del ganglio raquídeo dorsal, frecuentemente asociadas con trastornos disinmunes y paraneoplásicos, y agentes tóxicos. Los pacientes presentan alteración sensorial de distribución asimétrica y ataxia temprana. La identificación temprana es esencial, ya que pueden anunciar una neoplasia subyacente o una enfermedad autoinmune. Objetivo. Estudiar las asimetrías del potencial de acción nervioso sensitivo (SNAP) de pares de nervios y la relación de amplitud del potencial de acción sensitivomotor del nervio cubital (USMAR) con estudios electroneurofisiológicos seriados para el diagnóstico precoz de las ganglionopatías sensoriales. Pacientes y métodos: Se estudió retrospectivamente a siete pacientes con ganglionopatías sensoriales con estudios electroneurofisiológicos: cuatro casos paraneoplásicos con positividad para anticuerpos onconeuronales, uno asociado al síndrome de Sjögren y dos idiopáticos. Resultados: Los estudios electroneurofisiológicos mostraron afectación sensorial axonal en todos los casos, con asimetría mayor del 50% en la amplitud de SNAP en dos pares de nervios en cuatro casos y motor normal con USMAR < 0,71 en cinco casos. Los estudios electroneurofisiológicos seriados fueron esenciales en el diagnóstico de dos casos en el inicio de la enfermedad con síntomas sensoriales leves. Conclusiones: Este trabajo evidencia la importancia del estudio de asimetrías en la amplitud del SNAP de pares de nervios, la USMAR y los estudios electroneurofisiológicos seriados en el diagnóstico temprano de ganglionopatías sensoriales, para la consiguiente identificación de los anticuerpos disinmunes y onconeuronales con afectación del sistema nervioso periférico y la búsqueda de neoplasia oculta

Introduction: Sensory ganglionopathies or sensory neuronopathies are subacute acquired diseases of the dorsal root ganglion, frequently associated with disinmune, paraneoplastic and toxic agents. Patients present sensory alteration of asymmetric distribution and early ataxia. Early identification is essential, as they may announce an underlying neoplasia or autoimmune disease. Aim: To study asymmetries of the sensory nervous action potential (SNAP) of nerve pairs and the relationship amplitude of ulnar sensory/ulnar motor potential (USMAR) with serial electroneurophysiological studies for the early diagnosis of sensory ganglionopathies. Patients and methods: Six patients with sensory ganglionopathies were retrospectively studied with electroneurophysiological studies: four paraneoplastic cases with positivity for onconeuronal antibodies, one associated with Sjögren’s syndrome and two idiopathic. Results: Electroneurophysiological studies showed axonal sensory involvement in all cases, with asymmetry > 50% in SNAP amplitude in two pairs of nerves in four cases and normal motor with USMAR < 0.71 in five cases. Serial electroneurophysiological studies were essential in the diagnosis of two cases in the beginning of the disease with mild sensory symptoms. Conclusions: This work evidences the importance of the study of asymmetries in the amplitude of the SNAP of nerve pairs, the USMAR and the serial electroneurophysiological studies in the early diagnosis of sensory ganglionopathies, to further identification of the disinmune and onconeuronal associated antibodies with the nervous system affection to search for hidden neoplasia

[Paraneoplastic and disimmune sensory neuronopathies or ganglionopathies. Importance of an early detection]. / Ganglionopatías o neuronopatías sensoriales paraneoplásicas y disinmunes. Importancia de una detección temprana.

INTRODUCTION: Sensory ganglionopathies or sensory neuronopathies are subacute acquired diseases of the dorsal root ganglion, frequently associated with disinmune, paraneoplastic and toxic agents. Patients present sensory alteration of asymmetric distribution and early ataxia. Early identification is essential, as they may announce an underlying neoplasia or autoimmune disease. AIM: To study asymmetries of the sensory nervous action potential (SNAP) of nerve pairs and the relationship amplitude of ulnar sensory/ulnar motor potential (USMAR) with serial electroneurophysiological studies for the early diagnosis of sensory ganglionopathies. PATIENTS AND METHODS: Six patients with sensory ganglionopathies were retrospectively studied with electroneurophysiological studies: four paraneoplastic cases with positivity for onconeuronal antibodies, one associated with Sjogren's syndrome and two idiopathic. RESULTS: Electroneurophysiological studies showed axonal sensory involvement in all cases, with asymmetry > 50% in SNAP amplitude in two pairs of nerves in four cases and normal motor with USMAR < 0.71 in five cases. Serial electroneurophysiological studies were essential in the diagnosis of two cases in the beginning of the disease with mild sensory symptoms. CONCLUSIONS: This work evidences the importance of the study of asymmetries in the amplitude of the SNAP of nerve pairs, the USMAR and the serial electroneurophysiological studies in the early diagnosis of sensory ganglionopathies, to further identification of the disinmune and onconeuronal associated antibodies with the nervous system affection to search for hidden neoplasia.

TITLE: Ganglionopatías o neuronopatías sensoriales paraneoplásicas y disinmunes. Importancia de una detección temprana.Introducción. Las ganglionopatías o neuronopatías sensoriales son enfermedades subagudas adquiridas del ganglio raquídeo dorsal, frecuentemente asociadas con trastornos disinmunes y paraneoplásicos, y agentes tóxicos. Los pacientes presentan alteración sensorial de distribución asimétrica y ataxia temprana. La identificación temprana es esencial, ya que pueden anunciar una neoplasia subyacente o una enfermedad autoinmune. Objetivo. Estudiar las asimetrías del potencial de acción nervioso sensitivo (SNAP) de pares de nervios y la relación de amplitud del potencial de acción sensitivomotor del nervio cubital (USMAR) con estudios electroneurofisiológicos seriados para el diagnóstico precoz de las ganglionopatías sensoriales. Pacientes y métodos. Se estudió retrospectivamente a siete pacientes con ganglionopatías sensoriales con estudios electroneurofisiológicos: cuatro casos paraneoplásicos con positividad para anticuerpos onconeuronales, uno asociado al síndrome de Sjögren y dos idiopáticos. Resultados. Los estudios electroneurofisiológicos mostraron afectación sensorial axonal en todos los casos, con asimetría mayor del 50% en la amplitud de SNAP en dos pares de nervios en cuatro casos y motor normal con USMAR menos de 0,71 en cinco casos. Los estudios electroneurofisiológicos seriados fueron esenciales en el diagnóstico de dos casos en el inicio de la enfermedad con síntomas sensoriales leves. Conclusiones. Este trabajo evidencia la importancia del estudio de asimetrías en la amplitud del SNAP de pares de nervios, la USMAR y los estudios electroneurofisiológicos seriados en el diagnóstico temprano de ganglionopatías sensoriales, para la consiguiente identificación de los anticuerpos disinmunes y onconeuronales con afectación del sistema nervioso periférico y la búsqueda de neoplasia oculta.

Breast Cancer with Paraneoplastic Syndrome in a 72 Year Old Male Patient.

Breast cancer in male is rare which accounts about 1% of all malignant breast neoplasm cases. Since paraneoplastic syndrome is unusual with male breast cancer, very few reported cases are found. A72- year-old gentleman presented with proximal myopathy in all four limbs was referred to Dr. Sirajul Islam Medical College and Hospital in April 2017. He had generalized wasting with reduced tone and reflexes. Planter responses were normal with intact sensory. There were typical Heliotrope rash bilaterally. In background, he had history of radical mastectomy due to stage IIA ductal carcinoma of left breast 7 years back. Three years later, he was found to have multiple metastases in lung and liver, however, deliberately discontinued chemotherapy after first dose. Currently he is on Tamoxifen. Two months back, he was diagnosed to have brain metastasis. Also his serum sodium level was low with low urine osmolality. Considering his background, we diagnosed him dermatomyositis with peripheal neuropathy & SIADH as paraneoplastic presentation of breast malignancy. Despite of normal CPK and NCV, we treated him with steroid as dermatomyositis can present with normal CPK. His myopathy improved after 2 weeks of steroid treatment. Fluid restriction increased his serum sodium level. The aim of reporting this case is to aware physicians about the aggressive nature of male breast cancer, its orthodox paraneoplastic presentation and to differentiate neuropathy from myopathy so that early treatment can improve the outcome.

Paraneoplastic neuropsychiatric syndrome presenting as delirium.

Delirium in patients with cancer is associated with poor outcomes, but reversible causes need to be ruled out. We report the case of a 59-year-old woman who was presented with behavioural and cognitive changes over 2 weeks. She was non-verbal and combative, requiring involuntary admission and declaration of incompetence to make healthcare treatment decisions. Infectious and metabolic investigations and initial brain imaging were unremarkable. She was diagnosed with limited-stage small cell lung cancer and a paraneoplastic neuropsychiatric syndrome. Owing to the patient's delirium, chemotherapy delivery required pharmacological and physical restraints. After 2 cycles of chemotherapy, she could participate in the decision process and was discharged home. She completed radical chemo-radiotherapy and has remained free of disease progression for 18 months. Paraneoplastic neuropsychiatric syndromes, although rare, are potentially treatable and need to be excluded as a cause of delirium.

Screening for anti-titin antibodies in patients with various paraneoplastic neurological syndromes.

Anti-titin antibodies indicate a paraneoplastic etiology pointing towards a thymoma in myasthenia gravis (MG), but their seroprevalence and potential diagnostic value in patients with other paraneoplastic neurological syndromes (PNS) is unknown. Therefore, we screened the sera of 44 PNS patients with well-characterized onconeural antibodies (anti-Hu, Yo, Ri, CV2/CRMP5, Ma1, Ma2/Ta, or amphiphysin) for anti-titin reactivity. Two patients (4.5%) were positive for anti-titin antibodies: both patients differed regarding the PNS (sensorimotor neuropathy and subacute cerebellar degeneration vs. chorea), well-characterized onconeural antibodies (CV2/CRMP5 vs. Ri), and malignoma (small cell lung cancer vs. breast cancer). However, retrospectively, the patients neither showed any symptoms of MG nor a thymoma on a computed tomographic (CT) scan. The results of this study indicate that anti-titin antibodies without a predictive relevance for MG or thymoma may be present in a small proportion of patients with PNS.