Autonomic nervous system involvement in autoimmune encephalitis and paraneoplastic neurological syndromes.

In autoimmune neurological diseases, the autonomic nervous system can be the primary target of autoimmunity (e.g. autoimmune autonomic ganglionopathy), or, more frequently, be damaged together with other areas of the nervous system (e.g. Guillain-Barré syndrome). Patients with autoimmune encephalitis and paraneoplastic neurological syndromes (PNS) often develop dysautonomia; however, the frequency and spectrum of autonomic signs and symptoms remain ill defined except for those scenarios in which dysautonomia is a core feature of the disease. Such is the case of Lambert-Eaton myasthenic syndrome, Morvan syndrome or anti-NMDAR encephalitis; in the latter, patients with dysautonomia have been reported to carry a more severe disease and to retain higher disability than those without autonomic dysfunction. Likewise, the presence of autonomic involvement indicates a higher risk of death due to neurological cause in patients with anti-Hu PNS. However, in anti-Hu and other PNS, as well as in the context of immune checkpoint inhibitors' toxicities, the characterization of autonomic involvement is frequently overshadowed by the severity of other neurological symptoms and signs. When evaluated with tests specific for autonomic function, patients with autoimmune encephalitis or PNS usually show a more widespread autonomic involvement than clinically suggested, which may reflect a potential gap of care when it comes to diagnosing dysautonomia. This review aims to revise the autonomic involvement in patients with autoimmune encephalitis and PNS, using for that purpose an antibody-based approach. We also discuss and provide general recommendations for the evaluation and management of dysautonomia in these patients.

Autoimmune and paraneoplastic neurological disorders: A review of relevant neuroimaging findings.

INTRODUCTION: Paraneoplastic neurologic syndromes (PNS) and autoimmune encephalitis (AIE) are immune-mediated disorders. PNS is linked to cancer, while AIE may not Their clinical manifestations and imaging patterns need further elucidation. OBJECTIVE/AIMS: To investigate the clinical profiles, antibody associations, neuroimaging patterns, treatments, and outcomes of PNS and AIE. METHODS: A systematic review of 379 articles published between 2014 and 2023 was conducted. Of the 55 studies screened, 333 patients were diagnosed with either PNS or AIE and tested positive for novel antibodies. Data on demographics, symptoms, imaging, antibodies, cancer associations, treatment, and outcomes were extracted. RESULTS: The study included 333 patients (mean age 54 years, 67% males) with PNS and AIE positive for various novel antibodies. 84% had central nervous system issues like cognitive impairment (53%), rhombencephalitis (17%), and cerebellar disorders (24%). Neuroimaging revealed distinct patterns with high-risk antibodies associated with brainstem lesions in 98%, cerebellar in 91%, hippocampal in 98%, basal ganglia in 75%, and spinal cord in 91%, while low/intermediate-risk antibodies were associated with medial temporal lobe lesions in 71% and other cortical/subcortical lesions in 55%. High-risk antibodies were associated with younger males, deep brain lesions, and increased mortality of 61%, while low/intermediate-risk antibodies were associated with females, cortical/subcortical lesions, and better outcomes with 39% mortality. Associated cancers included seminomas (23%), lung (19%), ovarian (2%), and breast (2%). Treatments included IVIG, chemotherapy, and plasmapheresis. Overall mortality was 25% in this cohort. CONCLUSION: PNS and AIE have distinct clinical and radiological patterns based on antibody profiles. High-risk antibodies are associated with increased mortality while low/intermediate-risk antibodies are associated with improved outcomes. Appropriate imaging and antibody testing are critical for accurate diagnosis.

[Clinical analysis of 11 cases of lymphoma complicated with paraneoplastic neurological syndrome].

Objective: To evaluate the clinical characteristics, treatment, and prognosis of patients with paraneoplastic neurological syndrome (PNS) associated with lymphoma. Methods: Between January 2012 and May 2021, the clinical data of 11 patients with lymphoma complicated with PNS treated at Peking Union Medical College Hospital were retrospectively reviewed. Results: Among the 11 patients (8 male and 3 female) , the median onset age was 61 (range, 33-78) years. The symptoms of PNS preceded lymphoma in 10 patients. The median time from the onset of PNS to the diagnosis of lymphoma was 4 months. Of the 11 patients, one had Hodgkin's lymphoma, 8 had B-cell non-Hodgkin's lymphoma, and 2 had peripheral T-cell lymphoma. Seven patients were evaluated for onconeural antibody, of whom 2 were positive (1 for anti-Ma2 antibody and 1 for anti-Yo antibody) . Of the 11 patients, the PNS symptoms of 3 patients were located in the central nervous system, 4 were located in the peripheral nervous system, and 3 were located in the muscle. Eight of the 11 patients were treated with glucocorticoid-based immunosuppressive therapy before the diagnosis of lymphoma. Patients with central nervous system involvement and dermatomyositis responded well to glucocorticoid, whereas patients with peripheral neuropathy did not significantly benefit. All 11 patients were treated with chemotherapy after the diagnosis of lymphoma. The efficacy of chemotherapy was assessed in 9 patients, 7 cases achieved complete remission, 1 case was evaluated as stable disease, and 1 case was evaluated as disease progression. The PNS symptoms of the patients who achieved complete response were almost completely recovered. The median follow-up time was 42 (range, 4-95) months. At the end of the follow-up period, 6 of the 11 patients survived, 3 were lost to follow-up, and 2 died. The median overall survival of the whole group was not reached. Conclusions: PNS can involve various parts of the nervous system and can be associated with different types of lymphoma. Through early diagnosis and treatment, the PNS symptoms could improve in most patients who achieve complete remission of lymphoma.

Paraneoplastic neurological syndromes in patients affected by SCLC: a case series.

Paraneoplastic syndromes occur in about 0.1% of patients affected by neoplastic diseases. In some types of tumors, such as Small Cell Lung Cancer (SCLC), Thymoma, and particular forms of Plasmacytoma, the association with Paraneoplastic Neurological Syndromes (PNS) is much more frequent. It seems that these syndromes are triggered by tumor production of factors normally expressed only by the individual's nervous system. The immune system stimulates an autoimmune response against these factors that induce neurological symptoms. Also, in light of the latest updates on the relationship between immunotherapy and PNS as well as of the introduction of first-line immunotherapy in SCLC, it seems that the use of immunotherapy in SCLC is associated with concomitant increase in autoimmune neurological syndromes.In this article, we report our experience at Istituto Nazionale Tumori of Milan with three patients affected by SCLC and PNS. Our experience seems to confirm that the oncological treatment scarcely impacts the paraneoplastic neurological deficits. Further research is needed to improve the treatment and recovery of patients affected by PNS.

CV2/CRMP5-antibody-related Paraneoplastic Neurologic Syndrome Associated with Gastrointestinal Stromal Tumor.

Paraneoplastic neurological syndrome (PNS) is a heterogeneous group of neurological disorders caused by immune-mediated inflammatory mechanisms. We herein report a 77-year-old man with CV2/CRMP5-antibody-related PNS associated with a gastrointestinal stromal tumor (GIST). He was admitted for forgetfulness and delusional behavior. His neurological symptoms were subacute, and a whole-body examination revealed a gastric GIST. Serology showed CV2/collapsin response mediator protein (CRMP)-5 antibodies. Partial gastrectomy was performed for the GIST, and the neurological symptoms and serum CV2/CRMP5 antibodies disappeared. No relapse has occurred since the surgery. PNS should be considered in patients with subacute neurological disorders.

Clinical analysis of 11 cases of lymphoma complicated with paraneoplastic neurological syndrome / 中华血液学杂志

Objective: To evaluate the clinical characteristics, treatment, and prognosis of patients with paraneoplastic neurological syndrome (PNS) associated with lymphoma. Methods: Between January 2012 and May 2021, the clinical data of 11 patients with lymphoma complicated with PNS treated at Peking Union Medical College Hospital were retrospectively reviewed. Results: Among the 11 patients (8 male and 3 female) , the median onset age was 61 (range, 33-78) years. The symptoms of PNS preceded lymphoma in 10 patients. The median time from the onset of PNS to the diagnosis of lymphoma was 4 months. Of the 11 patients, one had Hodgkin's lymphoma, 8 had B-cell non-Hodgkin's lymphoma, and 2 had peripheral T-cell lymphoma. Seven patients were evaluated for onconeural antibody, of whom 2 were positive (1 for anti-Ma2 antibody and 1 for anti-Yo antibody) . Of the 11 patients, the PNS symptoms of 3 patients were located in the central nervous system, 4 were located in the peripheral nervous system, and 3 were located in the muscle. Eight of the 11 patients were treated with glucocorticoid-based immunosuppressive therapy before the diagnosis of lymphoma. Patients with central nervous system involvement and dermatomyositis responded well to glucocorticoid, whereas patients with peripheral neuropathy did not significantly benefit. All 11 patients were treated with chemotherapy after the diagnosis of lymphoma. The efficacy of chemotherapy was assessed in 9 patients, 7 cases achieved complete remission, 1 case was evaluated as stable disease, and 1 case was evaluated as disease progression. The PNS symptoms of the patients who achieved complete response were almost completely recovered. The median follow-up time was 42 (range, 4-95) months. At the end of the follow-up period, 6 of the 11 patients survived, 3 were lost to follow-up, and 2 died. The median overall survival of the whole group was not reached. Conclusions: PNS can involve various parts of the nervous system and can be associated with different types of lymphoma. Through early diagnosis and treatment, the PNS symptoms could improve in most patients who achieve complete remission of lymphoma.

Paraneoplastic sensorimotor neuropathy and ventral cauda equina nerve root enhancement as initial presentation of small cell lung carcinoma: a case study.

BACKGROUND: Paraneoplastic neurologic syndromes (PNS) are rare, however, are important to recognize as oftentimes they precede the detection of an occult malignancy. Our case highlights a rare circumstance of paraneoplastic radiculoneuropathy and the importance of recognizing PNS in antibody negative disease, as is the case in up to 16% of sensory neuronopathies, and the process of excluding other etiologies. CASE PRESENTATION: We discuss a 51-year-old man who presented with asymmetric subacute sensorimotor deficits in the lower limbs. Initial clinical examination showed weakness throughout the right lower limb and normal strength on the left with objective numbness in a mixed dermatomal and stocking-glove distribution. Electrophysiology was consistent with axonal sensorimotor neuropathy. Cerebrospinal fluid showed pleocytosis and elevated protein. Intravenous immunoglobulin treatment was given with some improvement in pain symptoms but no measurable motor improvement. Following clinical and electrophysiologic deterioration the patient was transferred to a tertiary centre. Magnetic resonance imaging of the spine showed smooth enhancement of the ventral caudal nerve roots. Chest computed tomography revealed left lower vascular scarring. Further positron emission tomography scan imaging identified fluorodeoxyglucose avid right lung lymphadenopathy. Bronchoscopy-guided biopsy revealed small cell lung carcinoma. Onconeural and antiganglioside antibodies were negative. The patient was then transferred to a medical oncology ward where he underwent chemoradiotherapy and subsequently experienced improvement in his motor function, supporting that his neurological condition was indeed secondary to a paraneoplastic process. CONCLUSIONS: Onconeural negative paraneoplastic radiculoneuropathy can precede diagnosis of small cell lung carcinoma. If considered early and adequately investigated, it can allow earlier diagnosis and treatment of underlying malignancy, improving overall and neurological prognosis.

A 58-Year-Old Man With Episodic Hypercapnic Respiratory Failure.

CASE PRESENTATION: A 58-year-old man presented to the ED with a 1-week history of progressive weight loss, generalized weakness, unsteadiness, and dizziness. In hospital, he experienced a witnessed episode of loss of consciousness with no observable respirations that lasted for 15 minutes. His arterial blood gas demonstrated hypercapnic respiratory failure, and he required mask ventilation and vasoactive medications. Similar episodes occurred several more times over the course of the night that required the patient to be intubated. The paroxysmal episodes persisted necessitating continued invasive ventilatory support and admission to the ICU. The episodes occurred in both awake and asleep states and required the ventilator settings to dictate a minimum rate, but minimal ventilatory support otherwise. Further history revealed other symptomatic complaints of vertigo, dysphagia, and hypophonia that had progressed over a 2-month period. The patient's medical history was pertinent for a diagnosis of prostatic carcinoma 3 years previously that was found to be castrate resistant. He had metastases to his hip, ribs, and thoracic spine. Previous treatments had included bicalutamide, docetaxel, and abiraterone; he was receiving leuprolide therapy on presentation.

Immunophenotypical characterization of paraneoplastic neurological syndrome patients: a multicentric study.

Paraneoplastic neurological syndromes (PNS) are a group of rare and severe immune-mediated disorders that affect the nervous system in patients with cancer. The best way to diagnose a paraneoplastic neurological disorder is to identify anti-onconeural protein antibodies that are specifically associated with various cancers. The aim of this multicentric study was to clinically and immunologically characterize patients with PNS and study their association with cancer. Patients suspected to have PNS were enrolled from various clinical centres and were characterized immunologically. This study population consisted of 112 patients. Onset of PNS was mainly subacute (76 %). PNS patients had various neurological disorders and symptoms. PNS developed before the diagnosis of cancer in 28 definite PNS patients and in six suspected PNS patients. The most frequent autoantibodies detected in PNS patients were anti-Hu and anti-Yo. One definite PNS patient with cerebellar syndrome had anti-Tr antibody and seven patients had atypical antibodies. The literature associates these antibodies with various neurological disorders and cancers. Our observations confirm the important role of autoantibodies in PNS and their importance for the early diagnosis of cancer in PNS patients.

Simultaneous bilateral optic neuropathy and myelitis revealing paraneoplastic neurological syndrome associated with multiple onconeuronal antibodies.

Paraneoplastic neurological syndromes (PNS) are immune-mediated complications of cancer associated with a broad spectrum of clinical manifestations. Optic neuropathy (ON) and myelitis are frequent manifestations of multiple sclerosis and neuromyelitis optic spectrum disorders but are considered as non-classical in PNS. Here, we report a case of PNS revealed by simultaneous bilateral ON and myelitis related to a cluster of three neural autoantibodies, in the setting of small cell lung cancer.

Clinical spectrum and diagnostic pitfalls of neurologic syndromes with Ri antibodies.

OBJECTIVE: To describe the main syndrome and clinical course in a large cohort of patients with anti-Ri-associated paraneoplastic neurologic syndrome (Ri-PNS). METHODS: Twenty-year retrospective nationwide study and systematic review of the literature. RESULTS: Thirty-six patients with complete clinical information were identified (median age 66 years, range: 47-87 years). In this French cohort, the majority were women (78%). At onset, 4 main patterns were observed: cerebellar syndrome (39%), isolated tremor (24%), oculomotor disturbances (17%), and other symptoms (19%). Course was multistep for 78% of cases. At the time the disease reached the plateau phase (median 12 weeks, range: 1-64 weeks; 28% >3 months), 24 (67%) showed an overt cerebellar syndrome, which was isolated in 3 patients, and was most frequently (21/24 cases) part of a multisystem neurologic disease. Patients manifested a variety of movement disorders, including myoclonus (33%), dystonia (17%), either cervical or oromandibular, and parkinsonism (17%). Most patients had cancer (92%), mainly breast cancer (n = 22). Misdiagnoses concerned 22% of patients (n = 8) and included atypical parkinsonism (n = 2), MS (n = 2), Bickerstaff encephalitis (n = 1), hyperekplexia (n = 1), vestibular neuritis (n = 1), and functional neurologic disorder (n = 1). Survival at 12 months was 73% (95% CI [0.54-0.85]), at 24 months 62% (95% CI [0.41-0.78]), and at 36 months 47% (95% CI [0.25-0.65]). There was no major clinical difference between cases retrieved from the systematic review of the literature (n = 55) and the French cohort. CONCLUSIONS: Ri-PNS is a multisystem neurologic syndrome with prominent cerebellum/brainstem involvement. Opsoclonus-myoclonus is less common than expected, and the disorder can mimic neurodegenerative diseases.

Treatment of Movement Disorder Emergencies in Autoimmune Encephalitis in the Neurosciences ICU.

Immune response against neuronal and glial cell surface and cytosolic antigens is an important cause of encephalitis. It may be triggered by activation of the immune system in response to an infection (para-infectious), cancer (paraneoplastic), or due to a patient's tendency toward autoimmunity. Antibodies directed toward neuronal cell surface antigens are directly pathogenic, whereas antibodies with intracellular targets may become pathogenic if the antigen is transiently exposed to the cell surface or via activation of cytotoxic T cells. Immune-mediated encephalitis is well recognized and may require intensive care due to status epilepticus, need for invasive ventilation, or dysautonomia. Patients with immune-mediated encephalitis may become critically ill and display clinically complex and challenging to treat movement disorders in over 80% of the cases (Zhang et al. in Neurocrit Care 29(2):264-272, 2018). Treatment options include immunotherapy and symptomatic agents affecting dopamine or acetylcholine neurotransmission. There has been no prior published guidance for management of these movement disorders for the intensivist. Herein, we discuss the immune-mediated encephalitis most likely to cause critical illness, clinical features and mechanisms of movement disorders and propose a management algorithm.

Parkinsonism in autoimmune diseases.

Parkinsonism can be manifested and complicate either systemic or organ-specific autoimmune diseases. Even though it is a rare co-morbidity, it merits attention from clinicians as it affects the quality of life of patients. In systemic autoimmune diseases such as systemic lupus erythematosus, antiphospholipid syndrome and Sjogren's syndrome reported cases of parkinsonism are attributed to the underlying disease and its mechanisms, whether this is brain vasculitis or immune complexes. Regarding antibody-mediated autoimmune neurological disorders, parkinsonism is, in most cases, a manifestation within the spectrum of each disorder and is attributed to the action of humoral and cellular immunity in brain regions such as the basal ganglia. Depending on the pathophysiology, immunotherapy can be effective, while Parkinson's specific therapies are usually less effective.

Paraneoplastic Syndromes in Neuro-ophthalmology.

PURPOSE OF REVIEW: This article discusses the varied types of paraneoplastic syndromes that commonly have neuro-ophthalmologic manifestations. Diagnostic considerations and therapeutic options for individual diseases are also discussed. RECENT FINDINGS: Paraneoplastic syndromes can affect the afferent and efferent visual systems. Paraneoplastic syndromes may result in reduced visual acuity from retinal degeneration, alterations in melanocyte proliferation and uveal thickening, or acquired nystagmus. Ocular motor abnormalities related to paraneoplastic syndromes may present with symptoms from opsoclonus or from neuromuscular junction disease. Diagnosis remains challenging, but serologic identification of some specific antibodies may be helpful or confirmatory. Treatment, in addition to directed therapies against the underlying cancer, often requires systemic corticosteroids, plasma exchange, or immunosuppression, but some specific syndromes improve with use of targeted pharmacologic therapy. SUMMARY: Diagnosis and therapy of paraneoplastic syndromes presenting with neuro-ophthalmic symptoms remain a challenge, but strategies are evolving and new approaches are on the horizon.

Paraneoplastic movement disorders: phenomenology, diagnosis, and treatment.

Paraneoplastic syndromes include, by definition, any symptomatic and non-metastatic condition associated with a neoplasm. Paraneoplastic movement disorders are a heterogeneous group of syndromes encompassing both hyperkinetic and hypokinetic conditions, characterized by acute/sub-acute onset, rapidly progressive evolution, and multifocal localizations with several overlapping features. These movement disorders are immune-mediated, as shown by the rapid onset and by the presence of antineuronal antibodies in biological samples of patients, fundamental for the diagnosis. Antineuronal antibodies could be targeted against intracellular or neuronal surface antigens. Paraneoplastic movement disorders associated with anti-neuronal surface antigens antibodies respond more frequently to immunotherapy. The underlying tumors may be different, according to the clinical presentation, age, and gender of patients. Our search considered articles involving human subjects indexed in PubMed. Abstracts were independently reviewed for eligibility criteria by one author and validated by at least one additional author. In this review, we sought to critically reappraise the clinical features and the pathophysiological mechanisms of paraneoplastic movement disorders, focusing on diagnostic and therapeutic strategies. Our main aim is to make clinicians aware of paraneoplastic movement disorders, and to provide assistance in the early diagnosis and management of these rare but life-threatening conditions.

Neurological autoimmune disorders with prominent gastrointestinal manifestations: A review of presentation, evaluation, and treatment.

BACKGROUND: The identification of autoantibodies directed against neuronal antigens has led to the recognition of a wide spectrum of neurological autoimmune disorders (NAD). With timely recognition and treatment, many patients with NAD see rapid improvement. Symptoms associated with NAD can be diverse and are determined by the regions of the nervous system affected. In addition to neurological symptoms, a number of these disorders present with prominent gastrointestinal (GI) manifestations such as nausea, diarrhea, weight loss, and gastroparesis prompting an initial evaluation by gastroenterologists. PURPOSE: This review provides a general overview of autoantibodies within the nervous system, focusing on three scenarios in which nervous system autoimmunity may initially present with gut symptoms. A general approach to evaluation and treatment, including antibody testing, will be reviewed.

Clinical characteristics of patients with paraneoplastic myelopathy.

Paraneoplastic myelopathy is rare paraneoplastic neurological syndromes. We reviewed patients through medical records system and screened patients who presented with myelopathy, and/or coexisting cancer, and/or onconeural antibodies. Nine patients were identified as paraneoplastic myelopathy presenting with progressive subacute (2/9) or insidious (7/9) myelopathy. CSF abnormalities included elevated protein, 5; pleocytosis, 4; excess oligoclonal bands, 6. Seven patients had onconeural antibody. Cancer was confirmed histopathologically in 6 and diagnosed by PET-CT in 1. Four patients had symmetric, longitudinally extensive grey matter or tract-specific changes on spinal cord MRI. It was associated with significant morbidity and had poor response to treatment.