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Paraneoplastic neurological syndromes (PNS) are rare autoimmune disorders triggered by the presence of a cancer. The autoimmunity is herein directed against proteins expressed both in the tumor and in the nervous system, namely the onconeural antigens, against which are directed specific autoantibodies, each of them characterizing a neurological syndrome. The mechanisms of the immune tolerance breakdown in PNS leading to the production of specific autoantibodies directed against the nervous system and leading to the immune attack begins to be explained. Each syndrome is associated with a specific histo-molecular subtype of tumor suggesting a link between the PNS genesis and oncogenesis. The expression of the onconeural antigen by these tumors is insufficient to explain the immune tolerance breakdown. In some PNS tumors, alterations of the antigen have been identified: mutations, gene copy number variation and overexpression of transcript and protein. But in others PNS, no such molecular alterations of the onconeural antigens have been demonstrated. In these cases, other mechanisms of neoantigen generation that may be involved remain to be deciphered. Cancer outcomes of PNS tumors are also characterized by the high frequency of lymph node metastasis at diagnosis. At the primary tumor site, the antitumor immune reaction seems to be particularly intense and characterized by a prominence of B-cell and Ig-secreting plasma cells that may generate the autoantibody secretion. The immune control mechanisms leading to such organization of the immune attack are not known to date. Renewed research efforts are thus needed to better understand the mechanism of immune tolerance breakdown in each PNS and determine potential targets to meet the therapeutic challenges posed by these rare disorders.
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Anti-Hu is the most commonly associated antibody in paraneoplastic syndromes (PNS) - mainly secondary to small cell lung cancer (SCLC), breast cancer, thymoma, and lymphoma. This case is about a 65-year-old female patient presenting with slurred speech, headache, and loss of balance for one day. On examination, she was found to have downbeat and bilateral gaze-evoked nystagmus, dysarthria, and bilateral intention tremors. The rest of the neurological examination was unremarkable. Upon investigation, a CT scan showed a pre-sacral mass and a PET scan showed a lobulated soft tissue mesenteric mass at L5/S1, thought to possibly be a gastrointestinal stromal tumour, and mediastinal lymph nodes including right lower pre-tracheal, subcarinal and right hilar lymph nodes. Additionally, paraneoplastic antibody testing was positive for anti-Hu antibodies. She was given a five-day course of intravenous immunoglobulin without significant clinical improvement. The patient was discharged on a fast-track pathway and did not undergo chemotherapy, radiotherapy or surgical resection as the primary tumour could not be diagnosed. Paraneoplastic antibodies are a family of autoantibodies occurring as a result of malignancy that act to recognize antigens in the brain, resulting in a variety of neurological manifestations. Despite well-known literature on this entity, PNS is notoriously difficult to diagnose and manage. The first step in the management of PNS is to treat the underlying malignancy. Beyond this, the other key component of PNS treatment is immune modulation which may involve immunosuppression with high-dose corticosteroids, IV immunoglobulins, plasma exchange or plasmapheresis. It is therefore important for PNS to be diagnosed early and to adopt a comprehensive multidisciplinary approach to improve the outcomes of those presenting with PNS.
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Introduction: The last few decades have increased our understanding of autoimmune encephalitis (AE). In both the pediatric and adult populations, it proves to be a disease of dramatic acute onset of heterogeneous clinical manifestations, notably encephalopathy with neuropsychiatric symptoms, seizures, and extrapyramidal symptoms. More often, it is triggered by a viral infection in the pediatric age groups, as suggested by the preceding febrile symptoms in over half of cases, and more ostensibly, NMDAR encephalitis post herpes encephalitis. An underlying neoplasm may be present in certain types (i.e., NMDAR encephalitis). The rising rate of antibody detection and subsequent confirmation has been boosted by improved live cellular assay detection methods. The corresponding clinical phenotypes, common underlying malignancies, and histopathological findings have helped improve our management regarding intervention and choice of immunotherapy. New assessment tools such as the Clinical Assessment Scale in Autoimmune Encephalitis (CASE score) have helped improve the objective assessment of impact on cognitive functions (1). Early intervention with immunotherapy (and tumor removal in proven underlying neoplasms) has improved overall outcomes in most presenting patients. But nearly 40% of cases fail to respond to the first tier of treatment (2). The complex interplay between pathogenic autoantibodies, T-cells, B-cells, and cytokines has led to the emergence of additional immunotherapy agents (i.e., tocilizumab and bortezomib). Methods: In this retrospective observational study of pediatric AE conducted at two tertiary care centers, we observed the clinical characteristics, autoantibody yield, treatment modalities used, and disability scores during presentation and follow-up. Our secondary aim was to delineate prognostic factors for poor outcomes. Results: Neuropsychiatric symptoms, encephalopathy, and seizures were the predominant manifestations in most of our patients. Younger age groups, refractory seizures, profound encephalopathy, and refractory disease harbored higher disability scores. The group that received combined immunotherapy has shown mitigation of disability score from severe to mild during long-term follow-up, signifying the role of multifaceted immunotherapy in pediatric refractory AE. Conclusion: Early implementation of combined immunotherapy in refractory cases significantly improved longterm disability scores, in spite of lingering residual effects on neurologic functions, notably cognition, behavior, and speech.
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Dermoid cysts, or mature cystic teratomas, are germ cell neoplasms that can arise on the ovaries. Being of germ cell origin, such cysts can have extensive variance in presentation, including a rare paraneoplastic effect where they produce N-methyl-D-aspartate receptor (NMDAR) antibodies, resulting in anti-NMDAR encephalitis. This can cause various neuropsychiatric symptoms, including confusion, hallucinations, psychosis, disorientation, and a change in cognition. This case study presents the unusual occurrence of a 39-year-old female patient who presented to the emergency department with encephalitis, headaches, and auditory hallucinations after recent glucocorticoid use. Through an extensive workup, imaging, and various physician consults, the patient was diagnosed with anti-NMDAR encephalitis secondary to a paraneoplastic effect originating from an ovarian dermoid cyst.
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Dermatomyositis (DM) is an autoimmune inflammatory disease, characterized by symmetrical proximal myopathy and cutaneous manifestations. DM is associated with upto a 6-fold increased risk of cancer. Complications secondary to underlying cancer are a leading cause of mortality in DM. Here, we discuss the two year clinical course of an elderly male with recalcitrant DM. This case was complicated by tubercular lymphadenitis followed by gumma. Subsequently, he was diagnosed with lymphoma and succumbed to death. This case emphasizes the need to do extensive malignancy screening at regular intervals in DM.
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Hidradenitis suppurativa patients have an increased risk of developing cancer. This includes not only hematologic malignancies and solid tumors, but also cutaneous squamous cell carcinoma originating within the hidradenitis suppurativa lesions. The development of squamous cell carcinoma is most commonly associated with Caucasian men who smoke and have severe gluteal or perianal lesions of more than 25 years duration. Other factors that have occasionally been associated with hidradenitis suppurativa-related squamous cell carcinoma include treatment with a tumor necrosis factor-alpha inhibitor (such as infliximab and adalimumab), genodermatoses (such as keratitis-ichthyosis-deafness syndrome and Dowling-Degos disease), and paraneoplastic syndromes (such as hypercalcemia, hypercalcemia-leukocytosis, and paraneoplastic neuropathy). The tumor may demonstrate the presence of human papillomavirus; even after treatment, patients have a poor prognosis since cancer metastasis, or recurrence, or both commonly occurs. The potential role of human papillomavirus vaccination for cancer prevention and early treatment of squamous cell carcinoma with targeted therapy (with an epidermal growth factor inhibitor such as cetuximab) and/or checkpoint inhibitor immunotherapy (such as cemiplimab and pembrolizumab) remains to be determined. Rarely, hidradenitis suppurativa lesions have mimicked cutaneous metastases in patients with visceral malignancy by demonstrating an increased uptake of fluorine-18 fluorodeoxyglucose on positron emission tomography and/or computerized tomography scans. Also, both primary cancers (such as cutaneous squamous cell carcinoma and mucinous adenocarcinoma) and breast cancer skin metastases can masquerade as hidradenitis suppurativa lesions. Therefore, when a lesion is located at a current or prior site of hidradenitis suppurativa that is new or rapidly growing and/or does not respond to hidradenitis suppurativa-directed therapy, prompt evaluation to establish or exclude the diagnosis of cancer should be considered.
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Acquired pure red cell aplasia (PRCA), caused by thymic hyperplasia, is extremely rare. We herein report a previously healthy 41-year-old man who presented with severe anemia, lymphadenopathy, an upper mediastinal mass, and hypogammaglobulinemia. The patient was eventually diagnosed with PRCA and adult T-cell leukemia/lymphoma (ATLL). The mediastinal mass was pathologically diagnosed as thymic hyperplasia without clear ATLL invasion. Although his anemia improved rapidly after thymectomy, PRCA recurred approximately 500 days later and was accompanied by ATLL exacerbation. The findings in this patient suggest that the Good's syndrome-like symptoms (thymic hyperplasia and hypogammaglobulinemia) in this patient and PRCA may have been paraneoplastic syndromes caused by ATLL.
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INTRODUCTION: The prevalence of preoperative paraneoplastic syndromes (PNS) in renal cell carcinoma (RCC) is poorly understood. Many laboratory abnormalities representative of PNS have demonstrated prognostic value when incorporated into predictive survival models in RCC. We sought to characterize the relationship between baseline prevalence of PNS with overall survival (OS) and cancer-specific survival (CSS) in RCC patients following nephrectomy. METHODS: Our prospectively maintained nephrectomy database was retrospectively reviewed for any stage, major histology RCC patients that underwent surgery from 2000 to 2022. Baseline laboratory values within 90 days (closest used) were required. Presence of PNS was defined according to established laboratory cutoffs. Kaplan-Meier curves estimated survival rates, and multivariable Cox proportional hazards models examined the association between PNS with OS and CSS following nephrectomy. RESULTS: 2599 patients were included with listed staging: 1494 Stage I; 180 Stage II; 616 Stage III; 306 Stage IV. Proportion of patients presenting with >1 PNS significantly increased from stage I (31.3%) to stage IV (74.2%) RCC (P < .001). Elevated C-reactive protein was the most prevalent PNS (45.4%). On multivariable analysis, the presence of >1 PNS was associated with higher risk of all-cause (HR 2.09; P < .001) and cancer-specific mortality (HR 2.55; P < .001). The 10-year OS estimates as reported: 65.2% (no PNS), 52.3% (1 PNS), 36.6% (>1 PNS); and 10-year CSS estimates: 88.3% (no PNS), 79.3% (1 PNS), 61.6% (>1 PNS). DISCUSSION: Increased prevalence of PNS in major histology RCC was associated with a significant increase in the risk of all-cause and cancer-specific mortality even when accounting for patient and disease characteristics.
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Introduction: Paraneoplastic syndromes are frequent in patients with renal cell carcinoma. Dermatomyositis is an idiopathic inflammatory myopathy that may be associated with neoplasms. This case aims to describe the rare association of dermatomyositis with renal cell carcinoma and to increase clinical suspicion of this neoplasm when systemic rheumatologic symptoms are present. Case presentation: A 35-year-old female developed severe rheumatologic symptoms (progressive muscle weakness, heliotrope rash, and Gottron's papules). Clinical and laboratory findings indicated dermatomyositis. During the investigation, computed tomography revealed a left kidney solid mass. She underwent a left radical nephrectomy, and histology confirmed renal cell carcinoma. After 3 months, dermatomyositis manifestations disappeared and the patient withdrawn steroid therapy. Conclusion: Most paraneoplastic syndromes associated with renal cell carcinoma are only cured with nephrectomy. We highlight the potential role of surgery in dermatomyositis caused by renal cell carcinoma. The recurrence of symptoms related to the syndrome should alert for disease progression.
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Focal Opercular Myoclonic - Anarthric Status Epilepticus (OMASE) is a rare form of focal motor status epilepticus caused by several etiologies. It is characterized by fluctuating dysarthria and epileptic myoclonus involving the bilateral glossopharyngeal musculature. We present the case of a 52-year-old woman who experienced gradual and progressive paralysis and myoclonus of facial and bulbar muscles; additional tests revealed the presence of right breast ductal adenocarcinoma and positive serum anti-Hu and anti-GAD65 antibodies. High doses of steroid pulses, anti-seizure therapy, and rituximab partially controlled myoclonus; the tumor resection improved dysphagia and dysarthria.
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Paraneoplastic neurologic syndromes (PNS) are a group of disorders that affect the central and the peripheral nervous system and frequently occur in patients with cancer which usually still is undiagnosed by the time the patient presents the first neurological manifestations. The discovery in the serum and cerebrospinal fluid of PNS patients of antibodies that target tumor antigens that also are normally expressed in the nervous system had a significant impact. First, the research on neuronal antibodies confirmed that most PNS are autoimmune disorders triggered by the underlying cancer supporting the use of immunotherapy to treat them; second, although the first antibodies described recognized intracellular neuronal antigens and therefore they were not pathogenic, these antibodies became robust biomarkers for the strict diagnosis of PNS; and third, the methodological approach used to characterize the first neuronal antibodies paved the way to the identification of antibodies against neuronal surface antigens that are pathogenic and responsible for some PNS and non-paraneoplastic encephalitis. Future studies should address several issues: (1) to improve the efficiency of commercial kits; (2) to provide strict criteria to select which neural antibodies should be used for the diagnosis of PNS; and (3) define in more detail the autoimmune mechanisms responsible for the brain injury in the PNS.
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Ovarian cancer, although not among the most commonly diagnosed cancers, remains a significant cause of cancer-related mortality in females. Several paraneoplastic syndromes have been associated, and this case study represents a rare manifestation of ovarian cancer, presenting as non-islet cell tumor hypoglycemia (NICTH), characterized by the excessive production of insulin-like growth factor-II (IGF-II) by tumor cells. We report a 55-year-old woman who presented to our hospital with abdominal distension and severe refractory hypoglycemia. The laboratory data revealed the suppression of serum insulin and C-peptide levels. The insulin-like growth factor II (IGF-II)/insulin-like growth factor 1 (IGF1) ratio was >32. The hypoglycemia was hence attributed to the non-islet cell tumor type, and it is likely driven by tumoral secretion of incompletely processed IGF-II. The lab findings suggested the existence of NICTH. Abdominal computed tomography demonstrated the presence of a left ovarian mass and peritoneal carcinomatosis. CT-guided biopsy of the peritoneal lesions showed poorly differentiated malignancy consistent with ovarian carcinosarcoma (OCS). The patient was treated with a continuous infusion of glucose. She even received oral prednisone and glucagon infusion. Chemotherapy with carboplatin and paclitaxel was initiated, but unfortunately, she died from complications of multiorgan failure. To our knowledge, this is the first novel case of an initial presentation of metastatic OCS with NICTH, underscoring the complexity of ovarian cancer presentations and the necessity of a comprehensive approach in managing rare paraneoplastic syndromes, such as NICTH.
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OBJECTIVES: Selection of autoimmune/paraneoplastic antibody panels remains challenging because health-care professionals often lack familiarity with panel contents, recommended specimen types, and antibody combinations for a given patient. Inappropriate use adds cost, prompts unnecessary additional workup, and delays the identification of the true cause of patient symptoms. In this study, we assessed whether order-entry clinical decision support can improve autoimmune/paraneoplastic antibody panel utilization. METHODS: An order-entry clinical decision support tool was embedded in the electronic health record system. Using a nested panel structure, the decision support tool prompted clinicians to identify their patient's clinical presentation and guided selection of the appropriate tests. In addition, the tool featured a duplicate checking function to alert clinicians when placing multiple orders with substantially similar antibody content within a 3-month period. Panel ordering practices were assessed during the 12 months before implementation and compared with the 6 months immediately following implementation. RESULTS: Clinical decision support significantly reduced the monthly test volume of all orderables from 75.8 per month before implementation to 54.5 per month after implementation (incident rate ratio [IRR], 0.72; 95% CI, 0.63-0.81; P < .001). Placement of multiple orders for panels with substantially overlapping antibody content also decreased significantly, from 7.0 per month to 1.2 per month (IRR, 0.17; 95% CI, 0.07-0.33; P < .001). The number of neural-specific antibodies detected remained unchanged, but the reduction in total test volume increased the neural-specific antibody positivity rate from 4.2% to 6.8% (IRR, 1.61; 95% CI, 0.94-2.70; P = .075). CONCLUSIONS: Order-entry clinical decision support offers an efficient and effective approach to improve the utilization of autoimmune/paraneoplastic antibody panels.
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Paraneoplastic encephalomyelitis (PEM) is a rare complication associated with malignancies, often presenting before the cancer diagnosis. A 42-year-old male with a history of chronic smoking presented with acute urinary retention and neurological deficits, all evolving in a febrile context with general deterioration. Laboratory tests were conducted, followed by a cerebral MRI which revealed multiple T2 and FLAIR hyperintense lesions in the periventricular and periaqueductal regions, medial temporal lobes, and bilateral postero-medial thalamus. Enhanced CT scans of the chest and abdomen identified multiple cervical, axillary, and inguinal lymphadenopathies. Subsequently, an ultrasound-guided biopsy of a cervical node was performed. His condition deteriorated rapidly, requiring intubation and sedation. A subsequent MRI revealed worsening cerebral and spinal cord lesions with new contrast enhancement in the brainstem. The differential diagnosis included toxic/metabolic and paraneoplastic causes. Biopsy results confirmed Hodgkin's lymphoma, leading to a diagnosis of progressive paraneoplastic encephalomyelitis (PEM). Despite adequate treatment, the patient's condition worsened, leading to death from pneumonitis and metabolic complications. This case underscores the importance of considering PEM in patients with neurological deficits and malignancy, with MRI playing a crucial role in diagnosis. Early detection and treatment are essential to improving outcomes.
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Paraneoplastic leukocytosis (PNL) in genitourinary cancer, though rare, can indicate aggressive behavior and poor outcomes. It has been potentially linked to cancer expressing G-CSF and GM-CSF, along with their respective receptors, exerting an autocrine/paracrine effect. In our study, we successfully established four patient-derived xenograft (PDX) lines and related cell lines from urothelial cancer (UC), conducting next-generation sequencing (NGS) for genetic studies. UC-PDX-LN1, originating from bladder cancer, exhibited two druggable targets - HRAS and ERCC2 - responding well to chemotherapy and targeted therapy, though not to tipifarnib, an HRAS inhibitor. Transcriptome analysis post-treatment illuminated potential mechanisms, with index protein analysis confirming their anticancer pathways. Mice implanted with UC-PDX-LN1 mirrored PNL observed in the patient's original tumor. Cytokine array and RT-PCR analyses revealed high levels of G-CSF and GM-CSF in our PDX and cell lines, along with their presence in culture media and tumor cysts.Leukocytosis within small vessels in and around the tumor, associated with NETosis and thrombus formation, suggested a mechanism wherein secreted growth factors were retained, further fueling tumor growth via autocrine/paracrine signaling. Disrupting this cancer cell-NETosis-thrombosis cycle, we demonstrated that anti-neutrophil or anticoagulant interventions enhanced chemotherapy's antitumor effects or prolonged survival in mice, even though these drugs lacked direct antitumor efficacy when used independently. Clinical observations in bladder cancer patients revealed PNL in 1.61% of cases (35/2162) with associated poor prognosis. These findings propose a novel approach, advocating for the combination of anticancer/NETosis/thrombosis strategies for managing UC patients presenting with PNL in clinical settings.
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Paraneoplastic hypoglycemia, also known as non-islet cell tumor hypoglycemia (NICTH), is a rare but critical condition occurring in patients with different types of malignancy. This condition is commonly linked to tumors producing insulin-like growth (IGF) factors, particularly IGF-2 and its precursors, which disrupt glucose homeostasis and lead to excessive glucose consumption. The diagnosis typically involves documenting symptomatic hypoglycemia and ruling out other potential causes. Essential diagnostic tools include imaging studies and laboratory tests, specifically measuring IGF-2 levels and the IGF-2:IGF-1 ratio. Treatment strategies for NICTH are multifaceted and may include surgical resection of the tumor if feasible, pharmacological interventions such as corticosteroids to suppress IGF-2 production, or supportive measures to manage acute hypoglycemic episodes. Novel therapeutic approaches targeting IGF-2, such as monoclonal antibodies or siRNA, are also being explored and hold promise for future treatment options. This review aims to enhance understanding of paraneoplastic hypoglycemia, focusing on its pathogenesis and diagnosis, to guide optimal medical treatment.
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Stiff-person syndrome (SPS) is a rare neurological disorder characterized by chronic and progressive axial muscle rigidity and paroxysmal painful muscle spasms. The present case study described an SPS patient (increased anti-GAD65 antibody in serum and cerebrospinal fluid) with co-occurring Hashimoto's thyroiditis and decreased C3 complement levels. The clinical presentation, diagnostic approach, and treatment employed for this unique case were comprehensively described in detail. In this case, we comprehensively presented a case of SPS with co-occurring Hashimoto's thyroiditis and an associated decrease in serum C3 complement, as well as a discussion on the current data on this topic.
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Purpose: To present the longitudinal, multimodal imaging of Bilateral Diffuse Uveal Melanocytic Proliferation secondary to gallbladder carcinoma over a 17 month period, demonstrating the natural history, the evolution with treatment and salient features to support timely diagnosis of this condition with life-threatening associations. Observations: A systemically well 73 year old woman presented with a 2 month history of progressive visual loss in the right eye. We report the initial findings on clinical examination and with retinal imaging including fluorescein and indocyanine angiography, optical coherence tomography and autoflourescence. An initial diagnosis of atypical central serous chorioretinopathy with secondary choroidal neovascularisation led to treatment with intravitreal aflibercept before the correct diagnosis of BDUMP was made 2 months later, aided by evolution of signs on imaging and examination. Subsequent investigation led to detection of gallbladder adenocarcinoma. The patient underwent systemic chemotherapy and eventual phacoemulsification and insertion of intraocular lens to both eyes. The patient died 21 months after presentation of visual symptoms, with latest imaging at 17 months. Conclusion: We report the evolution of BDUMP utilising multi-modal imaging pre-treatment and during treatment with chemotherapy, and highlight peripheral progression of disease despite consolidation at the macula.
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Autoimmune encephalitis (AE) is a rare immune-mediated disorder comprised of non-infectious neuroinflammatory disease processes. Clinical presentation overlaps with a broad range of neurodegenerative disorders and infectious encephalitis; therefore, AE remains a diagnosis of exclusion. Patients may present with nonspecific symptoms such as psychiatric disturbances, cognitive deficits, seizures, movement disorders, and confusion. Prompt diagnosis and management are necessary for patients with AE to decrease mortality and improve quality of life. First-line therapy includes immunosuppression with corticosteroids, intravenous immunoglobulin, and plasmapheresis. We report the case of an 86-year-old female with a medical history of Parkinson's disease who presented with nonspecific seizure-like activity and was diagnosed with AE.