Clinical and serological insights into paraneoplastic brachial amyotrophic diplegia.

BACKGROUND: Brachial amyotrophic diplegia (BAD) is typically linked to a neurodegenerative etiology such as amyotrophic lateral sclerosis (ALS). Clinical and serological characterizations of paraneoplastic neurologic syndromes resembling BAD are limited. METHODS: A retrospective chart review of patients with BAD-like presentations was conducted. Clinical/paraclinical features of paraneoplastic BAD and neurodegenerative BAD cases were compared. RESULTS: Between 2017 and 2023, 13 cases of BAD were identified, of these 10 were neurodegenerative BAD (ALS variant), and 3 cases associated with paraneoplastic autoimmunity. An additional paraneoplastic BAD case diagnosed in 2005 was included. LUZP4-IgG was detected in all four paraneoplastic cases, with coexisting KLHL11-IgG in three cases and ANNA1 (anti-Hu)-IgG in one case. Out of the four paraneoplastic cases, two patients had seminoma, while the remaining two had limited cancer investigation. Three patients exhibited bi-brachial weakness as the initial symptom before the onset of brainstem symptoms or seizures. Compared to BAD patients with a neurodegenerative etiology, a higher proportion of paraneoplastic cases had ataxia (75% vs 0%, p = 0.011). Other clinical features only detected in the paraneoplastic BAD group were vertigo (n = 2), hearing loss (n = 2) and ophthalmoplegia (n = 2). Electrodiagnostic studies in these patients revealed cervical myotome involvement, supportive of motor neuronopathy. All paraneoplastic cases but none of the neurodegenerative BAD cases exhibited inflammatory cerebrospinal fluid (CSF) findings (lymphocytic pleocytosis and/or supernumerary oligoclonal bands; p = 0.067). Despite the administration of immunotherapy and/or cancer treatment, none of the paraneoplastic patients reported clinical improvement. DISCUSSION: BAD or bi-brachial neurogenic weakness is a rare phenotypic presentation associated with paraneoplastic autoimmunity. Co-existing features of brainstem dysfunction or cerebellar ataxia should prompt further paraneoplastic evaluation. Common serological and cancer associations among these cases include LUZP4-IgG and KLHL11-IgG, along with testicular germ cell tumors, respectively.

Diagnostic Utility of MOG Antibody Testing in Cerebrospinal Fluid.

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.

Paraneoplastic Calmodulin Kinase-Like Vesicle-Associated Protein (CAMKV) Autoimmune Encephalitis.

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.

Magnetic Resonance Imaging Characteristics of LGI1-Antibody and CASPR2-Antibody Encephalitis.

Importance: Rapid and accurate diagnosis of autoimmune encephalitis encourages prompt initiation of immunotherapy toward improved patient outcomes. However, clinical features alone may not sufficiently narrow the differential diagnosis, and awaiting autoantibody results can delay immunotherapy. Objective: To identify simple magnetic resonance imaging (MRI) characteristics that accurately distinguish 2 common forms of autoimmune encephalitis, LGI1- and CASPR2-antibody encephalitis (LGI1/CASPR2-Ab-E), from 2 major differential diagnoses, viral encephalitis (VE) and Creutzfeldt-Jakob disease (CJD). Design, Setting, and Participants: This cross-sectional study involved a retrospective, blinded analysis of the first available brain MRIs (taken 2000-2022) from 192 patients at Oxford University Hospitals in the UK and Mayo Clinic in the US. These patients had LGI1/CASPR2-Ab-E, VE, or CJD as evaluated by 2 neuroradiologists (discovery cohort; n = 87); findings were validated in an independent cohort by 3 neurologists (n = 105). Groups were statistically compared with contingency tables. Data were analyzed in 2023. Main Outcomes and Measures: MRI findings including T2 or fluid-attenuated inversion recovery (FLAIR) hyperintensities, swelling or volume loss, presence of gadolinium contrast enhancement, and diffusion-weighted imaging changes. Correlations with clinical features. Results: Among 192 participants with MRIs reviewed, 71 were female (37%) and 121 were male (63%); the median age was 66 years (range, 19-92 years). By comparison with VE and CJD, in LGI1/CASPR2-Ab-E, T2 and/or FLAIR hyperintensities were less likely to extend outside the temporal lobe (3/42 patients [7%] vs 17/18 patients [94%] with VE; P < .001, and 3/4 patients [75%] with CJD; P = .005), less frequently exhibited swelling (12/55 [22%] with LGI1/CASPR2-Ab-E vs 13/22 [59%] with VE; P = .003), and showed no diffusion restriction (0 patients vs 16/22 [73%] with VE and 8/10 [80%] with CJD; both P < .001) and rare contrast enhancement (1/20 [5%] vs 7/17 [41%] with VE; P = .01). These findings were validated in an independent cohort and generated an area under the curve of 0.97, sensitivity of 90%, and specificity of 95% among cases with T2/FLAIR hyperintensity in the hippocampus and/or amygdala. Conclusions and Relevance: In this study, T2 and/or FLAIR hyperintensities confined to the temporal lobes, without diffusion restriction or contrast enhancement, robustly distinguished LGI1/CASPR2-Ab-E from key differential diagnoses. These observations should assist clinical decision-making toward expediting immunotherapy. Their generalizability to other forms of autoimmune encephalitis and VE should be examined in future studies.

Immune Checkpoint Inhibitor-Associated Kelch-Like Protein-11 IgG Brainstem Encephalitis.

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.

Neurological autoimmunity in patients with non-pulmonary neuroendocrine neoplasms: clinical manifestations and neural autoantibody profiles.

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.

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.

Paraneoplastic neurologic syndrome and autoantibody accompaniments of germ cell tumors.

Paraneoplastic neurologic syndromes (PNSs) are a group of diseases affecting the central and/or peripheral nervous system caused by immune-mediated processes directed toward antigens with shared expression in tumor and neural tissue. Germ cell tumors (GCTs) are associated with PNSs with varied clinical phenotypes. Early diagnosis of PNS is vital to potentially uncover and treat underlying tumors, improving the chances of recovery, and preventing permanent neurologic complications. In this chapter, we outline the pathophysiology and epidemiology of PNS. We briefly provide a summary of GCTs in males and females. We review the neural-specific autoantibodies and PNSs associated with GCTs and their clinical and radiologic accompaniments. We also provide an overview of the treatment and prognosis of these disorders.

Pearls & Oy-sters: KLHL11 IgG Paraneoplastic-Associated Hearing Loss and Rhombencephalitis in a Woman With Metastatic Müllerian Tumor.

Kelch-like protein-11 (KLHL11) immunoglobulin G (IgG) is a recently reported paraneoplastic autoantibody associated with rhombencephalitis, which commonly presents with ataxia, diplopia, vertigo, hearing loss, tinnitus, and gaze palsies. The association of this high-risk paraneoplastic autoantibody with testicular germ cell tumors is widely accepted, but it has not been associated with Müllerian tumors. In this study, we report a woman without a known germ cell tumor presenting with signs and symptoms suggesting autoimmune encephalitis. She was found to have metastatic ovarian serous carcinoma with KLHL11 immunoreactivity on histopathology. This case demonstrates a rare cancer association of KLHL11 IgG-seropositive rhombencephalitis with Müllerian tumor and highlights that this autoantibody can also be detected in female patients. Thus, this case expands on the current knowledge of KLHL11-related autoimmune encephalitis including the paraneoplastic presentation, associated tumor types, and management of this syndrome in women.

Peripheral nervous system manifestations of MOG antibody associated disease.

Recent studies have reported the involvement of peripheral nervous system (PNS) in association with MOG-IgG, including isolated neuropathies. In this retrospective study we characterized the PNS involvement in MOG antibody associated disease (MOGAD). Six out of 215 MOGAD patients had PNS involvement (all polyradiculopathy) that occurred concurrently with a CNS demyelinating episode. We also demonstrated MOG expression in healthy human controls' proximal nerve root. Nine patients with true-positive MOG-IgG1 had PNS involvement temporally unrelated to a CNS demyelinating event. All these patients had an alternate etiology of PNS involvement. Isolated peripheral neuropathy is not a feature of MOGAD, but inflammatory nerve root involvement can occur concurrently with CNS demyelinating events.

Clinicopathologic Findings in Patients With Paraneoplastic Neuropathies and Antibodies Strongly Associated With Cancer.

BACKGROUND AND OBJECTIVES: Pathologic descriptions of peripheral nerve involvement in paraneoplastic neuropathies are sparse, mostly from autopsies focusing on CNS and dorsal root ganglia tissues. Here, we describe the clinicopathologic features of peripheral nerve biopsies in patients with paraneoplastic neurologic syndromes to expand the currently limited knowledge. METHODS: Retrospective review of the Mayo Clinic electronic medical record from 1995 to 2022 for patients identified to have subacute onset neuropathy with paraneoplastic antibodies identified in our neuroimmunology laboratory having available nerve biopsies performed at the time of diagnosis. Patients with another cause of neuropathy not linked to their subacute onset were excluded. RESULTS: Nineteen patients met inclusion criteria: 4 with amphiphysin antibodies, 6 with antineuronal nuclear antibody (ANNA)-1 only, 3 with both ANNA-1 and collapsin response-mediator protein 5 (CRMP-5), 2 with ANNA-2, and 4 with CRMP-5 antibodies only. Fifteen biopsies had reduced the density of myelinated nerve fibers-4 with multifocality. Subperineurial edema was present in 17 biopsies. Prominent epineurial perivascular inflammation was present in 3 biopsies, all belonging to patients with a lumbosacral radiculoplexus neuropathy (LRPN) phenotype. DISCUSSION: Axonal loss, subperineurial edema, and an absence of prominent inflammation are the most common findings in nerve biopsies of patients with paraneoplastic antibodies strongly associated with cancer. The LRPN phenotype was the only subset with inflammatory collections. Paraneoplastic autoantibody testing should be considered in patients with subacute onset neuropathies, with or without interstitial inflammatory findings.

Cerebellar leptomeningeal enhancement: An imaging finding of rapidly progressive Purkinje cell cytoplasmic autoantibody type 1 paraneoplastic cerebellar syndrome.

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.

Nerve transcriptomes in autoimmune and genetic demyelinating neuropathies: Pathogenic pathway assessment of nerve demyelination.

The pathogenesis of autoimmune demyelinating neuropathies is poorly understood compared to inherited demyelinating forms. We performed whole transcriptome (RNA-Seq) using nerve biopsy tissues of patients with different autoimmune and inherited demyelinating neuropathies (CIDP n = 10, POEMS n = 18, DADS n = 3, CMT1 n = 3) versus healthy controls (n = 6). A limited number of differentially expressed genes compared to healthy controls were identified (POEMS = 125, DADS = 15, CMT = 14, CIDP = 5). Divergent pathogenic pathways including inflammatory, demyelinating and neurite regeneration such as with the triggering receptor expressed on myeloid cells (TREM1) part of the immunoglobulin superfamily and RhoGD1 are found. Shared and discordant pathogenic injury are discovered between autoimmune and inherited forms.

CDR2 and CDR2L line blot performance in PCA-1/anti-Yo paraneoplastic autoimmunity.

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.

Identification of SKOR2 IgG as a novel biomarker of paraneoplastic neurologic syndrome.

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.

Utility of Protein Microarrays for Detection of Classified and Novel Antibodies in Autoimmune Neurologic Disease.

BACKGROUND AND OBJECTIVES: Neural antibodies are detected by tissue-based indirect immunofluorescence assay (IFA) in Mayo Clinic's Neuroimmunology Laboratory practice, but the process of characterizing and validating novel antibodies is lengthy. We report our assessment of human protein arrays. METHODS: Assessment of arrays (81% human proteome coverage) was undertaken using diverse known positive samples (17 serum and 14 CSF). Samples from patients with novel neural antibodies were reflexed from IFA to arrays. Confirmatory assays were cell-based (CBA) or line blot. Epitope mapping was undertaken using phage display immunoprecipitation sequencing (PhiPSeq). RESULTS: Control positive samples known to be reactive with linear epitopes of intracellular antigens (e.g., ANNA-1 [anti-Hu]) were readily identified by arrays in 20 of 21 samples. By contrast, 10 positive controls known to be enriched with antibodies against cell surface protein conformational epitopes (e.g., GluN1 subunit of NMDA-R) were indistinguishable from background signal. Three antibodies, previously characterized by other investigators (but unclassified in our laboratory), were unmasked in 4 patients using arrays (July-December 2022): Neurexin-3α, 1 patient; regulator of gene protein signaling (RGS)8, 1 patient; and seizure-related homolog like 2 (SEZ6L2), 2 patients. All were accompanied by previously reported phenotypes (encephalitis, 1; cerebellar ataxia, 3). Patient 1 had subacute onset of seizures and encephalopathy. Neurexin-3α ranked high in CSF (second ranked neural protein) but low in serum (660th overall). Neurexin-3α CBA was positive in both samples. Patient 2 presented with rapidly progressive cerebellar ataxia. RGS8 ranked the highest neural protein in available CSF sample by array (third overall). RGS8-specific line blot was positive. Patients 3 and 4 had rapidly progressive cerebellar ataxia. SEZ6L2 was the highest ranked neural antigen by arrays in all samples (CSF, 1, serum, 2; Patient 3, ranked 9th overall in CSF, 11th in serum; Patient 4, 6th overall in serum]). By PhIPSeq, diverse neurexin-3α epitopes (including cell surface) were detected in CSF from patient 1, but no SEZ6L2 peptides were detected for serum or CSF samples from Patient 3. DISCUSSION: Individualized autoimmune neurologic diagnoses may be accelerated using protein arrays. They are optimal for detection of intracellular antigen-reactive antibodies, though certain cell surface-directed antibodies (neurexin-3α and SEZ6L2) may also be detected.

Clinical, Neurophysiologic, and Pathologic Features in Patients With Early-Onset Postradiation Neuropathy.

OBJECTIVES: The objective of this study was to study early-onset radiation-induced neuropathy reviewing neurologic course, steroid response, and available nerve biopsies. METHODS: Patients coded with radiation-induced neuropathy within 6 months of radiation were reviewed from January 1,1999, to August 31, 2022. Patients had to have electrodiagnostically confirmed neuropathy localized within or distal to radiation fields. Neurologic course and nerve biopsies were reviewed. RESULTS: Twenty-eight patients (16 male and 12 female patients, mean age 63.8 years) were identified. The average radiation dose was 4,659 cGy (range 1,000-7,208). Tumor infiltration was not observed on MRI and PET. Postradiation onsets averaged 2 months (range 0-5). Localizations included brachial (n = 4) plexopathies, lumbosacral (n = 12) plexopathies, radiculopathies (n = 10), and mononeuropathies (n = 2). Neuropathic pain (n = 25) and weakness (n = 25) were typical. The clinical courses were subacute monophasic (n = 14), chronic progressive (n = 8), or static (n = 1), and 5 were without follow-up. Nerve biopsies (n = 8) showed an inflammatory ischemic process with perivascular inflammatory infiltrates (n = 7) or microvasculitis (n = 2). Nine patients, 7 with monophasic courses, received steroid burst therapy with symptom improvement in 8. No patients recovered entirely back to baseline. DISCUSSION: In contrast to chronic radiation-induced neuropathy, early-onset patients most commonly have painful monophasic courses with residual deficits, possibly steroid responsive. An ischemic inflammatory pathogenesis is suggested.