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OBJECTIVE: This article reviews the clinical presentations, neural antibody associations, and oncologic accompaniments of paraneoplastic neurologic syndromes and neurologic autoimmunity in the context of immune checkpoint inhibitor (ICI) cancer immunotherapy. LATEST DEVELOPMENTS: Neural antibody discovery has improved the diagnosis of paraneoplastic neurologic syndromes. Neural antibodies also delineate the underlying disease pathophysiology and thus inform outcomes and treatments. Neural antibodies specific for extracellular proteins have pathogenic potential, whereas antibodies specific for intracellular targets are biomarkers of a cytotoxic T-cell immune response. A recent update in paraneoplastic neurologic syndrome criteria suggests high- and intermediate-risk phenotypes as well as neural antibodies to improve diagnostic accuracy in patients with paraneoplastic neurologic syndromes; a score was created based on this categorization. The introduction of ICI cancer immunotherapy has led to an increase in cancer-related neurologic autoimmunity with distinct clinical phenotypes. ESSENTIAL POINTS: Paraneoplastic neurologic syndromes reflect an ongoing immunologic response to cancer mediated by effector T cells or antibodies. Paraneoplastic neurologic syndromes can present with manifestations at any level of the neuraxis, and neural antibodies aid diagnosis, focus cancer screening, and inform prognosis and therapy. In patients with high clinical suspicion of a paraneoplastic neurologic syndrome, cancer screening and treatment should be undertaken, regardless of the presence of a neural antibody. ICI therapy has led to immune-mediated neurologic complications. Recognition and treatment lead to improved outcomes.
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Síndromes Paraneoplásicos del Sistema Nervioso , Humanos , Síndromes Paraneoplásicos del Sistema Nervioso/diagnóstico , Síndromes Paraneoplásicos del Sistema Nervioso/terapia , Síndromes Paraneoplásicos del Sistema Nervioso/inmunología , Síndromes Paraneoplásicos del Sistema Nervioso/fisiopatología , Inmunoterapia/métodos , Inhibidores de Puntos de Control Inmunológico , Masculino , Femenino , Neoplasias/complicaciones , Neoplasias/inmunología , Autoanticuerpos/inmunologíaRESUMEN
With the lack of distinctive features or diagnostic biomarkers, peripheral neuropathy in patients with excessive alcohol consumption is often misdiagnosed as alcohol-related neuropathy, influenced by underlying implicit and explicit bias against patients with an alcohol use disorder (AUD). Alcohol-related nerve toxicity has been attributed to various underlying mechanisms including altered trophic factor signaling, disrupted protein synthesis, free radical injury from oxidative stress, and nutritional deficiencies. Alcohol-related neuropathy has been most described as mild but painful, predominantly affecting small sensory fibers, without major functional limitations. This phenotype may be indistinguishable from a chronic idiopathic axonal neuropathy; hence, a causal relationship with AUD cannot be established with certainty. Searching for alternative causes is warranted, especially in patients with a more severe or rapidly progressive peripheral neuropathy. At the same time, there is underlying implicit and explicit bias in the medical field against patients with AUDs. Patients often experience devaluation and stigma, which can affect their adherence to medical advice and may lead to social reclusion. Addressing biases in health care workers is crucial to ensure that individuals receive proper care and are not subjected to stigmatization. In this article, we present a comprehensive narrative review of the literature on the clinical presentation and underlying pathomechanisms of alcohol-related peripheral neuropathy, raising awareness of the bias in the medical field against patients with AUD.
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Background and objectives: Up to 46% of patients with presumed autoimmune limbic encephalitis are seronegative for all currently known central nervous system (CNS) antigens. We developed a cell-based assay (CBA) to screen for novel neural antibodies in serum and cerebrospinal fluid (CSF) using neurons and astrocytes derived from human-induced pluripotent stem cells (hiPSCs). Methods: Human iPSC-derived astrocytes or neurons were incubated with serum/CSF from 99 patients [42 with inflammatory neurological diseases (IND) and 57 with non-IND (NIND)]. The IND group included 11 patients with previously established neural antibodies, six with seronegative neuromyelitis optica spectrum disorder (NMOSD), 12 with suspected autoimmune encephalitis/paraneoplastic syndrome (AIE/PNS), and 13 with other IND (OIND). IgG binding to fixed CNS cells was detected using fluorescently-labeled antibodies and analyzed through automated fluorescence measures. IgG neuronal/astrocyte reactivity was further analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMCs) were used as CNS-irrelevant control target cells. Reactivity profile was defined as positive using a Robust regression and Outlier removal test with a false discovery rate at 10% following each individual readout. Results: Using our CBA, we detected antibodies recognizing hiPSC-derived neural cells in 19/99 subjects. Antibodies bound specifically to astrocytes in nine cases, to neurons in eight cases, and to both cell types in two cases, as confirmed by microscopy single-cell analyses. Highlighting the significance of our comprehensive 96-well CBA assay, neural-specific antibody binding was more frequent in IND (15 of 42) than in NIND patients (4 of 57) (Fisher's exact test, p = 0.0005). Two of four AQP4+ NMO and four of seven definite AIE/PNS with intracellular-reactive antibodies [1 GFAP astrocytopathy, 2 Hu+, 1 Ri+ AIE/PNS)], as identified in diagnostic laboratories, were also positive with our CBA. Most interestingly, we showed antibody-reactivity in two of six seronegative NMOSD, six of 12 probable AIE/PNS, and one of 13 OIND. Flow cytometry using hiPSC-derived CNS cells or PBMC-detected antibody binding in 13 versus zero patients, respectively, establishing the specificity of the detected antibodies for neural tissue. Conclusion: Our unique hiPSC-based CBA allows for the testing of novel neuron-/astrocyte-reactive antibodies in patients with suspected immune-mediated neurological syndromes, and negative testing in established routine laboratories, opening new perspectives in establishing a diagnosis of such complex diseases.
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Astrocitos , Autoanticuerpos , Inmunoglobulina G , Células Madre Pluripotentes Inducidas , Neuronas , Humanos , Astrocitos/inmunología , Astrocitos/metabolismo , Inmunoglobulina G/inmunología , Inmunoglobulina G/sangre , Neuronas/inmunología , Neuronas/metabolismo , Células Madre Pluripotentes Inducidas/inmunología , Masculino , Femenino , Persona de Mediana Edad , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Adulto , Anciano , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico , Adulto Joven , Enfermedades del Sistema Nervioso/inmunología , Enfermedades del Sistema Nervioso/diagnósticoRESUMEN
OBJECTIVE: To evaluate the cerebrospinal fluid (CSF) cytokine/chemokine profile of central nervous system (CNS) neurosarcoidosis (NS), and its utility in differential diagnosis, treatment, and prognostication. METHODS: In this case-control study, we validated 17 cytokines/chemokines (interleukin [IL]-1-beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, IL-17A, BAFF, IL-8/CXCL8, CXCL9, CXCL10, CXCL13, GM-CSF, interferon-gamma, and tumor necrosis factor [TNF]-alpha) in a multiplexed automated immunoassay system (ELLA; Bio-Techne, Minneapolis, MN, USA), and assessed them in CSF and serum of symptomatic patients with probable or definite CNS NS (01/2011-02/2023) with gadolinium enhancement and/or CSF pleocytosis. Patients with multiple sclerosis, primary CNS lymphoma, aquaporin-4 immunoglobulin G positivity, non-inflammatory disorders, and healthy individuals were used as controls. RESULTS: A total of 32 NS patients (59% women; median age, 59 years [19-81]) were included; concurrent sera were available in 12. CSF controls consisted of 26 multiple sclerosis, 8 primary CNS lymphoma, 84 aquaporin-4 immunoglobulin G positive, and 34 patients with non-inflammatory disorders. Gadolinium enhancement was present in 31 of 32 NS patients, and CSF pleocytosis in 27 of 32 (84%). CSF IL-2, IL-6, IL-10, IL-13, BAFF, IL-8/CXCL8, CXCL9, CXCL10, CXCL13, GM-CSF, interferon-gamma, and TNF-alpha levels were significantly higher in NS patients compared with non-inflammatory controls (p ≤ 0.02); elevations were more common in CSF than serum. Concurrent elevation of IL-6, CXCL9, CXCL10, GM-CSF, interferon-gamma, and TNF-alpha was present in 18 of 32 NS patients, but only in 1 control. Elevated IL-6, IL-10, IL-13, CXCL9, CXL10, GM-CSF, and TNF-alpha associated with measures of disease activity. INTERPRETATION: NS CSF cytokine/chemokine profiles suggest T cell (mainly T helper cell type 1), macrophage, and B-cell involvement. These signatures aid in NS diagnosis, indicate disease activity, and suggest therapeutic avenues. ANN NEUROL 2024.
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Objectives: To study the frequency, causes, and consequences of seizure-related falls and near falls in LGI1-IgG autoimmune encephalitis. Methods: We retrospectively reviewed 136 patients seen at Mayo Clinic with (1) LGI1-IgG seropositivity, (2) clinical phenotypes compatible with LGI1-IgG autoimmune encephalitis, and (3) falls or near falls related to seizures. The clinical documentation, MRI, and EEG data were collected and reviewed. Results: In this cohort of 136 patients, 27% (n = 36) had falls or near falls related to seizures. The median age was 67 years (range 49-86 years) and 23/36 (64%) were male. Facio-brachio-crural dystonic seizures (21/36, 58%) and drop attacks (9/36, 25%) were the most common causes. Seizure-related falls resulted in injuries in 18/30 (60%), ranging from skin lacerations, joint dislocations, bone fractures to life-threatening intracranial hemorrhage. The injuries occurred most with drop attacks 8/9 (89%). Seizure-related falls or near falls resolved with immunotherapy in 24/32 (75%) whereas the responsiveness to anti-seizure medication alone was poor (4/32, 13%). Discussion: Our study demonstrates that seizure-related falls and near falls are common in LGI1-IgG autoimmune encephalitis. Early diagnosis, prompt immunotherapy initiation, and proper counseling are key to improving functional outcomes and preventing secondary injuries.
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OBJECTIVES: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an autoimmune demyelinating disease rarely associated with malignancy. We report the clinical, MRI, immunopathology, and treatment response in a person with MOGAD and melanoma. METHODS: This is a case report of a person with a multidisciplinary evaluation at a tertiary referral center. RESULTS: A 52-year-old man presented with progressive encephalomyelitis that led to identification of metastatic melanoma. Investigations revealed positive MOG-IgG at high titers in serum (1:1,000; normal, <1:20) and CSF (1:4,096; normal, <1:2). MRI demonstrated multifocal T2 lesions with enhancement in the brain and spine. Brain biopsy showed demyelination and inflammation. MOG immunostaining was not present in the tumor tissue. He initially improved with methylprednisolone, plasmapheresis, prolonged oral steroid taper, and cancer-directed treatment with BRAF and MEK 1/2 inhibitors, but then developed bilateral optic neuritis. IV immunoglobulin (IVIG) was initiated. Five months later, he developed metastases and immune checkpoint inhibitor (ICI) treatment was started, which precipitated optic neuritis and myelitis despite IVIG and prednisone. Tocilizumab, an interleukin-6 receptor blocker, was started with excellent and sustained clinical and radiologic response. DISCUSSION: This case revealed a presentation of MOGAD concurrent with melanoma without tumor MOG immunostaining. We highlight tocilizumab as a dual-purpose treatment of MOGAD and the neurologic immune-related adverse effect of ICI.
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Inhibidores de Puntos de Control Inmunológico , Melanoma , Glicoproteína Mielina-Oligodendrócito , Humanos , Masculino , Melanoma/tratamiento farmacológico , Persona de Mediana Edad , Glicoproteína Mielina-Oligodendrócito/inmunología , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Autoanticuerpos/sangre , Autoanticuerpos/líquido cefalorraquídeo , Enfermedades Autoinmunes Desmielinizantes SNC/inmunología , Enfermedades Autoinmunes Desmielinizantes SNC/tratamiento farmacológico , Enfermedades Autoinmunes Desmielinizantes SNC/inducido químicamenteRESUMEN
OBJECTIVE: The aim of this study was to assess the diagnostic utility of cerebrospinal fluid (CSF) myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) testing. METHODS: We retrospectively identified patients for CSF MOG-IgG testing from January 1, 1996, to May 1, 2023, at Mayo Clinic and other medical centers that sent CSF MOG-IgG for testing including: controls, 282; serum MOG-IgG positive MOG antibody-associated disease (MOGAD), 74; serum MOG-IgG negative high-risk phenotypes, 73; serum false positive MOG-IgG with alternative diagnoses, 18. A live cell-based assay assessed CSF MOG-IgG positivity (IgG-binding-index [IBI], ≥2.5) using multiple anti-human secondary antibodies and end-titers were calculated if sufficient sample volume. Correlation of CSF MOG-IgG IBI and titer was assessed. RESULTS: The pan-IgG Fc-specific secondary was optimal, yielding CSF MOG-IgG sensitivity of 90% and specificity of 98% (Youden's index 0.88). CSF MOG-IgG was positive in: 4/282 (1.4%) controls; 66/74 (89%) serum MOG-IgG positive MOGAD patients; and 9/73 (12%) serum MOG-IgG negative patients with high-risk phenotypes. Serum negative but CSF positive MOG-IgG accounted for 9/83 (11%) MOGAD patients, and all fulfilled 2023 MOGAD diagnostic criteria. Subgroup analysis of serum MOG-IgG low-positives revealed CSF MOG-IgG positivity more in MOGAD (13/16[81%]) than other diseases with false positive serum MOG-IgG (3/15[20%]) (p = 0.01). CSF MOG-IgG IBI and CSF MOG-IgG titer (both available in 29 samples) were correlated (Spearman's r = 0.64, p < 0.001). INTERPRETATION: CSF MOG-IgG testing has diagnostic utility in patients with a suspicious phenotype but negative serum MOG-IgG, and those with low positive serum MOG-IgG results and diagnostic uncertainty. These findings support a role for CSF MOG-IgG testing in the appropriate clinical setting. ANN NEUROL 2024;96:34-45.
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Autoanticuerpos , Inmunoglobulina G , Glicoproteína Mielina-Oligodendrócito , Humanos , Glicoproteína Mielina-Oligodendrócito/inmunología , Estudios Retrospectivos , Femenino , Masculino , Autoanticuerpos/líquido cefalorraquídeo , Autoanticuerpos/sangre , Adulto , Persona de Mediana Edad , Inmunoglobulina G/líquido cefalorraquídeo , Inmunoglobulina G/sangre , Sensibilidad y Especificidad , Anciano , Adolescente , Adulto Joven , NiñoRESUMEN
OBJECTIVES: To report an autoimmune paraneoplastic encephalitis characterized by immunoglobulin G (IgG) antibody targeting synaptic protein calmodulin kinase-like vesicle-associated (CAMKV). METHODS: Serum and cerebrospinal fluid (CSF) samples harboring unclassified antibodies on murine brain-based indirect immunofluorescence assay (IFA) were screened by human protein microarray. In 5 patients with identical cerebral IFA staining, CAMKV was identified as top-ranking candidate antigen. Western blots, confocal microscopy, immune-absorption, and mass spectrometry were performed to substantiate CAMKV specificity. Recombinant CAMKV-specific assays (cell-based [fixed and live] and Western blot) provided additional confirmation. RESULTS: Of 5 CAMKV-IgG positive patients, 3 were women (median symptom-onset age was 59 years; range, 53-74). Encephalitis-onset was subacute (4) or acute (1) and manifested with: altered mental status (all), seizures (4), hyperkinetic movements (4), psychiatric features (3), memory loss (2), and insomnia (2). Paraclinical testing revealed CSF lymphocytic pleocytosis (all 4 tested), electrographic seizures (3 of 4 tested), and striking MRI abnormalities in all (mesial temporal lobe T2 hyperintensities [all patients], caudate head T2 hyperintensities [3], and cortical diffusion weighted hyperintensities [2]). None had post-gadolinium enhancement. Cancers were uterine adenocarcinoma (3 patients: poorly differentiated or neuroendocrine-differentiated in 2, both demonstrated CAMKV immunoreactivity), bladder urothelial carcinoma (1), and non-Hodgkin lymphoma (1). Two patients developed encephalitis following immune checkpoint inhibitor cancer therapy (atezolizumab [1], pembrolizumab [1]). All treated patients (4) demonstrated an initial response to immunotherapy (corticosteroids [4], IVIG [2]), though 3 died from cancer. INTERPRETATION: CAMKV-IgG is a biomarker of immunotherapy-responsive paraneoplastic encephalitis with temporal and extratemporal features and uterine cancer as a prominent oncologic association. ANN NEUROL 2024;96:21-33.
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Autoanticuerpos , Encefalitis , Humanos , Femenino , Persona de Mediana Edad , Anciano , Encefalitis/líquido cefalorraquídeo , Autoanticuerpos/líquido cefalorraquídeo , Autoanticuerpos/sangre , Masculino , Enfermedad de Hashimoto/líquido cefalorraquídeo , Inmunoglobulina G/líquido cefalorraquídeo , Inmunoglobulina G/sangre , Síndromes Paraneoplásicos del Sistema Nervioso/líquido cefalorraquídeo , Síndromes Paraneoplásicos del Sistema Nervioso/inmunología , RatonesRESUMEN
BACKGROUND AND PURPOSE: Paraneoplastic neurological autoimmunity is well described with small-cell lung cancer, but information is limited for other neuroendocrine neoplasms (NENs). METHODS: Adult patients with histopathologically confirmed non-pulmonary NENs, neurological autoimmunity within 5 years of NEN diagnosis, and neural antibody testing performed at the Mayo Clinic Neuroimmunology Laboratory (January 2008 to March 2023) were retrospectively identified. Control sera were available from patients with NENs without neurological autoimmunity (116). RESULTS: Thirty-four patients were identified (median age 68 years, range 31-87). The most common primary tumor sites were pancreas (nine), skin (Merkel cell, eight), small bowel/duodenum (seven), and unknown (seven). Five patients received immune checkpoint inhibitor (ICI) therapy before symptom onset; symptoms preceded cancer diagnosis in 62.1% of non-ICI-treated patients. The most frequent neurological phenotypes (non-ICI-treated) were movement disorders (12; cerebellar ataxia in 10), dysautonomia (six), peripheral neuropathy (eight), encephalitis (four), and neuromuscular junction disorders (four). Neural antibodies were detected in 55.9% of patients studied (most common specificities: P/Q-type voltage-gated calcium channel [seven], muscle-type acetylcholine receptor [three], anti-neuronal nuclear antibody type 1 [three], and neuronal intermediate filaments [two]), but in only 6.9% of controls. Amongst patients receiving cancer or immunosuppressive therapy, 51.6% had partial or complete recovery. Outcomes were unfavorable in 48.3% (non-ICI-treated) and neural autoantibody positivity was associated with poor neurological outcome. DISCUSSION: Neurological autoimmunity associated with non-pulmonary NENs is often multifocal and can be treatment responsive, underscoring the importance of rapid recognition and early treatment.
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Autoanticuerpos , Tumores Neuroendocrinos , Humanos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Tumores Neuroendocrinos/inmunología , Tumores Neuroendocrinos/complicaciones , Adulto , Anciano de 80 o más Años , Estudios Retrospectivos , Autoinmunidad/inmunología , Síndromes Paraneoplásicos del Sistema Nervioso/inmunología , Síndromes Paraneoplásicos del Sistema Nervioso/sangre , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/sangreRESUMEN
PURPOSE OF REVIEW: The increasing recognition and diagnosis of autoimmune encephalitis (AE) and paraneoplastic neurological syndromes (PNS) is partly due to neural autoantibody testing and discovery. The past two decades witnessed an exponential growth in the number of identified neural antibodies. This review aims to summarize recent rare antibody discoveries in the context of central nervous system (CNS) autoimmunity and evaluate the ongoing debate about their utility. RECENT FINDINGS: In the last 5âyears alone 15 novel neural autoantibody specificities were identified. These include rare neural antibody biomarkers of autoimmune encephalitis, cerebellar ataxia or other movement disorders, including multifocal presentations. SUMMARY: Although the clinical applications of these rare antibody discoveries may be limited by the low number of positive cases, they still provide important diagnostic, prognostic, and therapeutic insights.
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Autoanticuerpos , Encefalitis , Enfermedad de Hashimoto , Síndromes Paraneoplásicos del Sistema Nervioso , Humanos , Autoanticuerpos/inmunología , Encefalitis/inmunología , Encefalitis/diagnóstico , Síndromes Paraneoplásicos del Sistema Nervioso/inmunología , Síndromes Paraneoplásicos del Sistema Nervioso/diagnóstico , Enfermedad de Hashimoto/inmunología , Enfermedad de Hashimoto/diagnóstico , Biomarcadores/sangreRESUMEN
OBJECTIVES: Kelch-like protein-11 (KLHL11)-IgG is associated with rhombencephalitis and seminoma. It has not previously been described as a neurologic immune checkpoint inhibitor (ICI)-related adverse event (nirAE) or in association with esophageal adenocarcinoma. METHODS: We describe a 61-year-old man with metastatic esophageal adenocarcinoma treated with folinic acid, fluorouracil, oxaliplatin (FOLFOX), and nivolumab, who subsequently developed diplopia, vertigo, and progressive gait ataxia after 8 weeks of treatment. RESULTS: Owing to a concern for ICI-associated myasthenia gravis, nivolumab was held and he was treated with prednisone and pyridostigmine. EMG showed no neuromuscular junction dysfunction, and acetylcholine-receptor antibodies were negative. Brain MRI was unrevealing. Murine brain tissue immunofluorescence assay revealed KLHL11-IgG in both serum and CSF, confirmed by cell-based assay. Tumor histopathology demonstrated poorly differentiated, highly proliferative adenocarcinoma with increased mitotic figures and cytoplasmic KLHL11 immunoreactivity. He was initiated on 6 months of cyclophosphamide in addition to FOLFOX for post-ICI-associated KLHL11-IgG rhombencephalitis. DISCUSSION: We report KLHL11-IgG rhombencephalitis associated with poorly differentiated esophageal cancer as a novel nirAE. Tumor staining revealed KLHL11 immunoreactivity, supporting a cancer-antigen-driven ICI-associated paraneoplastic syndrome. Recognition of novel nirAEs can expedite treatment and potentially prevent progressive neurologic disability.
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Adenocarcinoma , Encefalitis , Neoplasias Esofágicas , Neoplasias Testiculares , Masculino , Humanos , Animales , Ratones , Persona de Mediana Edad , Nivolumab/efectos adversos , Inhibidores de Puntos de Control Inmunológico , Encefalitis/inducido químicamente , Adenocarcinoma/inducido químicamente , Neoplasias Testiculares/inducido químicamente , Tronco Encefálico , Inmunoglobulina GRESUMEN
Immune checkpoint inhibitors (ICIs) are cancer immunotherapies that enhance the body's own immune system to treat cancer. ICI treatment, however, can cause immune-related adverse events (irAEs) that can affect any organ, resulting in significant morbidity and mortality. Neurologic irAEs (nirAEs) are rare and can affect the peripheral nervous system more commonly than the central nervous system. Treatment is dependent on the severity of the neurologic manifestations and often includs discontinuation of the ICI and initiation of steroid therapy as the first line; other treatments have also been used. NirAEs and cardiac irAEs have higher fatality rates underlying the importance of early recognition and appropriate management. This chapter reviews the clinical manifestations of neurologic immune-related adverse events associated with ICI treatment as well as diagnostic and therapeutic modalities.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Autoinmunidad , Neoplasias/tratamiento farmacológico , Inmunoterapia/efectos adversos , Inmunoterapia/métodosRESUMEN
Anti-glial fibrillary acidic protein (GFAP) meningoencephalomyelitis (autoimmune GFAP astrocytopathy) is a new autoimmune central nervous system (CNS) disease diagnosable by the presence of anti-GFAP autoantibodies in the cerebrospinal fluid and presents as meningoencephalomyelitis in the majority of patients. Only few neuropathological reports are available and little is known about the pathogenic mechanisms. We performed a histopathological study of two autopsies and nine CNS biopsies of patients with anti-GFAP autoantibodies and found predominantly a lymphocytic and in one autopsy case a granulomatous inflammatory phenotype. Inflammatory infiltrates were composed of B and T cells, including tissue-resident memory T cells. Although obvious astrocytic damage was absent in the GFAP-staining, we found cytotoxic T cell-mediated reactions reflected by the presence of CD8+/perforin+/granzyme A/B+ cells, polarized towards astrocytes. MHC-class-I was upregulated in reactive astrocytes of all biopsies and two autopsies but not in healthy controls. Importantly, we observed a prominent immunoreactivity of astrocytes with the complement factor C4d. Finally, we provided insight into an early phase of GFAP autoimmunity in an autopsy of a pug dog encephalitis that was characterized by marked meningoencephalitis with selective astrocytic damage with loss of GFAP and AQP4 in the lesions.Our histopathological findings indicate that a cytotoxic T cell-mediated immune reaction is present in GFAP autoimmunity. Complement C4d deposition on astrocytes could either represent the cause or consequence of astrocytic reactivity. Selective astrocytic damage is prominent in the early phase of GFAP autoimmunity in a canine autopsy case, but mild or absent in subacute and chronic stages in human disease, probably due to the high regeneration potential of astrocytes. The lymphocytic and granulomatous phenotypes might reflect different stages of lesion development or patient-specific modifications of the immune response. Future studies will be necessary to investigate possible implications of pathological subtypes for clinical disease course and therapeutic strategies.
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Enfermedades Autoinmunes del Sistema Nervioso , Encefalomielitis , Meningoencefalitis , Humanos , Animales , Perros , Proteína Ácida Fibrilar de la Glía/metabolismo , Encefalomielitis/patología , Astrocitos/patología , Enfermedades Autoinmunes del Sistema Nervioso/líquido cefalorraquídeo , Enfermedades Autoinmunes del Sistema Nervioso/terapia , Meningoencefalitis/líquido cefalorraquídeo , Meningoencefalitis/patología , AutoanticuerposRESUMEN
OBJECTIVES: To describe papillitis as a clinical phenotype of IgLON5 autoimmunity. METHODS: We retrospectively reviewed patients with IgLON5 autoimmunity who had optic neuropathy, optic neuritis, or optic disc edema. Sera from patients with recurrent papillitis were tested for IgLON5 antibodies. RESULTS: We found two elderly males presenting with papillitis in the presence of IgLON5 antibodies. CSF pleocytosis was present and partial vision improvement occurred in one patient despite immunotherapy. Sera from 18 patients with recurrent papillitis were negative for IgLON5 antibodies. CONCLUSION: Papillitis could be a manifestation of IgLON5 disease, with or without accompanying cognitive, sleep, and movement disorders.
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Neuritis Óptica , Papiledema , Masculino , Humanos , Anciano , Autoinmunidad , Estudios Retrospectivos , Neuritis Óptica/complicaciones , Nervio Óptico , Moléculas de Adhesión Celular Neuronal/uso terapéuticoRESUMEN
Purkinje cell cytoplasmic autoantibody type 1 (PCA1), also known as anti-Yo, is a 'high-risk' paraneoplastic antibody, associated with rapidly progressive cerebellar syndrome. In patients with this syndrome, various MRI abnormalities have been documented, including atrophy in the cerebellum and brainstem, T2 hyperintensity in the brainstem and spinal cord, and cranial nerve enhancement. This report introduces an imaging finding, cerebellar leptomeningeal enhancement, which was observed in all three cases at early stages. Despite neurological deterioration, all patients underwent immunotherapy, and subsequent follow-up MRI revealed resolution of the leptomeningeal enhancement, suggesting that this feature is distinct from meningeal carcinomatosis.
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Enfermedades Cerebelosas , Degeneración Cerebelosa Paraneoplásica , Síndromes Paraneoplásicos , Humanos , Degeneración Cerebelosa Paraneoplásica/diagnóstico por imagen , Degeneración Cerebelosa Paraneoplásica/metabolismo , Células de Purkinje/metabolismo , Autoanticuerpos , Proteínas del Tejido Nervioso , Cerebelo/metabolismo , Enfermedades Cerebelosas/diagnóstico por imagen , Enfermedades Cerebelosas/metabolismoRESUMEN
Immune checkpoint inhibitors, a class of oncological treatments that enhance antitumour immunity, can trigger neurological adverse events closely resembling paraneoplastic neurological syndromes. Unlike other neurological adverse events caused by these drugs, post-immune checkpoint inhibitor paraneoplastic neurological syndromes predominantly affect the CNS and are associated with neural antibodies and cancer types commonly found also in spontaneous paraneoplastic neurological syndromes. Furthermore, post-immune checkpoint inhibitor paraneoplastic neurological syndromes have poorer neurological outcomes than other neurological adverse events of immune checkpoint inhibitors. Early diagnosis and initiation of immunosuppressive therapy are likely to be crucial in preventing the accumulation of neurological disability. Importantly, the neural antibodies found in patients with post-immune checkpoint inhibitor paraneoplastic neurological syndromes are sometimes detected before treatment, indicating that these antibodies might help to predict the development of neurological adverse events. Experimental and clinical evidence suggests that post-immune checkpoint inhibitor paraneoplastic neurological syndromes probably share immunological features with spontaneous paraneoplastic syndromes. Hence, the study of post-immune checkpoint inhibitor paraneoplastic neurological syndromes can help in deciphering the immunopathogenesis of paraneoplastic neurological syndromes and in identifying novel therapeutic targets.
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Neoplasias , Síndromes Paraneoplásicos del Sistema Nervioso , Síndromes Paraneoplásicos , Humanos , Inhibidores de Puntos de Control Inmunológico , Síndromes Paraneoplásicos del Sistema Nervioso/terapia , AutoanticuerposRESUMEN
Introduction: The development of new autoantigen discovery techniques, like programmable phage immunoprecipitation sequencing (PhIP-Seq), has accelerated the discovery of neural-specific autoantibodies. Herein, we report the identification of a novel biomarker for paraneoplastic neurologic syndrome (PNS), Sloan-Kettering-Virus-Family-Transcriptional-Corepressor-2 (SKOR2)-IgG, utilizing PhIP-Seq. We have also performed a thorough clinical validation using normal, healthy, and disease/cancer control samples. Methods: Stored samples with unclassified staining at the junction of the Purkinje cell and the granule cell layers were analyzed by PhIP-Seq for putative autoantigen identification. The autoantigen was confirmed by recombinant antigen-expressing cell-based assay (CBA), Western blotting, and tissue immunofluorescence assay colocalization. Results: PhIP-Seq data revealed SKOR2 as the candidate autoantigen. The target antigen was confirmed by a recombinant SKOR-2-expressing, and cell lysate Western blot. Furthermore, IgG from both patient samples colocalized with a commercial SKOR2-specific IgG on cryosections of the mouse brain. Both SKOR2 IgG-positive patients had central nervous system involvement, one presenting with encephalitis and seizures (Patient 1) and the other with cognitive dysfunction, spastic ataxia, dysarthria, dysphagia, and pseudobulbar affect (Patient 2). They had a refractory progressive course and were diagnosed with adenocarcinoma (Patient 1: lung, Patient 2: gallbladder). Sera from adenocarcinoma patients without PNS (n=30) tested for SKOR2-IgG were negative. Discussion: SKOR2 IgG represents a novel biomarker for PNS associated with adenocarcinoma. Identification of additional SKOR2 IgG-positive cases will help categorize the associated neurological phenotype and the risk of underlying malignancy.
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Adenocarcinoma , Síndromes Paraneoplásicos del Sistema Nervioso , Ratones , Animales , Humanos , Biomarcadores , Autoantígenos , Inmunoglobulina GRESUMEN
Background: Purkinje cytoplasmic autoantibody type 1 (PCA-1)/anti-Yo autoimmunity is a common high-risk paraneoplastic neurological disorder, traditionally attributed antigenically to cerebellar degeneration-related protein 2 (CDR2), predominantly affecting women with gynecologic or breast adenocarcinoma. Single-modality CDR2 testing may produce false-positive results. We assessed the performance characteristics of the more recently purported major PCA-1/Yo antigen, CDR2-like (CDR2L), side by side with CDR2, in a line blot format. Methods: CDR2 and CDR2L were tested in six specimen groups (serum and cerebrospinal fluid (CSF)). Group 1, PCA-1/Yo mouse brain indirect immunofluorescence assay (IFA) positives; Group 2, PCA-1/Yo IFA mimics; Group 3, suspected CDR2 line blot false positives; Group 4, consecutive patient samples tested for neural antibodies over 1 year; Group 5, healthy subject serums; and Group 6, polyclonal (non-specific) immunoglobulin G (IgG)-positive serums. Results: Group 1: Of 64 samples tested, all but two were CDR2 positive (both CSF samples) and all were CDR2L positive. In individual patients, CDR2L values were always higher than CDR2. The two "CDR2L-only" positives were CSF samples with low titer PCA-1/Yo by IFA with serum negativity but with typical clinical phenotype. Group 2: All 51 PCA-1/Yo mimics were CDR2/CDR2L negative. Group 3: Nine samples [six of 1289 (0.47%) serums and three of 700 CSF samples (0.43%) were PCA-1/Yo IFA negative/CDR2 positive; two of the six available (serums from the same patient) were also CDR2L positive; the other four CDR2L negative had low CDR2 values (17-22). Group 4: Twenty-two patients had unexpected CDR2 or CDR2L positivity; none had tissue IFA positivity. Eleven of the 2,132 serum (0.5%) and three of the 677 CSF (0.4%) samples were CDR2 positive; median value was 19 (range, 11-48). Seven of the 2,132 serum (0.3%) and three of the 677 CSF (0.4%) samples were CDR2L positive; median value was 18 (range, 11-96). Group 5: All 151 healthy serum samples were negative. Group 6: One of the 46 polyclonal serum samples was CDR2L positive. Optimum overall performance was accomplished by requiring both CDR2 and CDR2L positivity in serum (sensitivity, 100%; and specificity, 99.9%) and positivity for CDR2L in CSF (sensitivity, 100%; and specificity, 99.6%). Conclusion: CDR2L provides additional PCA-1/anti-Yo sensitivity in CSF, and dual positivity with CDR2 provides additional specificity assurance in serum. Combining antigen-specific and tissue-based assays optimizes PCA-1/anti-Yo testing.
Asunto(s)
Enfermedades Neurodegenerativas , Degeneración Cerebelosa Paraneoplásica , Animales , Ratones , Humanos , Femenino , Autoanticuerpos , Autoinmunidad , Proteínas del Tejido Nervioso/metabolismo , Citoplasma/metabolismoRESUMEN
OBJECTIVE: Co-occurring anti-tripartite motif-containing protein 9 and 67 autoantibodies (TRIM9/67-IgG) have been reported in only a very few cases of paraneoplastic cerebellar syndrome. The value of these biomarkers and the most sensitive methods of TRIM9/67-IgG detection are not known. METHODS: We performed a retrospective, multicenter study to evaluate the cerebrospinal fluid and serum of candidate TRIM9/67-IgG cases by tissue-based immunofluorescence, peptide phage display immunoprecipitation sequencing, overexpression cell-based assay (CBA), and immunoblot. Cases in which TRIM9/67-IgG was detected by at least 2 assays were considered TRIM9/67-IgG positive. RESULTS: Among these cases (n = 13), CBA was the most sensitive (100%) and revealed that all cases had TRIM9 and TRIM67 autoantibodies. Of TRIM9/67-IgG cases with available clinical history, a subacute cerebellar syndrome was the most common presentation (n = 7/10), followed by encephalitis (n = 3/10). Of these 10 patients, 70% had comorbid cancer (7/10), 85% of whom (n = 6/7) had confirmed metastatic disease. All evaluable cancer biopsies expressed TRIM9 protein (n = 5/5), whose expression was elevated in the cancerous regions of the tissue in 4 of 5 cases. INTERPRETATION: TRIM9/67-IgG is a rare but likely high-risk paraneoplastic biomarker for which CBA appears to be the most sensitive diagnostic assay. ANN NEUROL 2023;94:1086-1101.