Publications by authors named "Anastasia Zekeridou"

47 Publications

Neurological complications of immune checkpoint inhibitor cancer immunotherapy.

J Neurol Sci 2021 Mar 27:117424. Epub 2021 Mar 27.

Departments of Neurology and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, United States of America. Electronic address:

Neurological autoimmunity is increasingly recognized as a complication of immune checkpoint inhibitor (ICI) cancer immunotherapy. ICIs act by enhancing endogenous anti-tumor immune responses and can also lead to autoimmunity affecting all organs. ICI-related neurological autoimmunity is rare, most often manifests with neuromuscular involvement and more rarely affects the central nervous system. Neurological complications often often present in the first three months of ICI treatment but can also appear after ICI discontinuation. These can occur in patients with tumors not traditionally associated with paraneoplastic neurological autoimmunity, such as melanoma and renal-cell carcinoma and should be suspected when a new neurological symptoms present while on ICI and cannot be explained by disease progression or as a consequence of metabolic dysfunction. Treatment consists of ICI discontinuation or withdrawal depending on the severity with or without immunosuppression. Generally, improvement is observed depending on the patient's baseline characteristics and neurological presentation.
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http://dx.doi.org/10.1016/j.jns.2021.117424DOI Listing
March 2021

Seizures and memory impairment induced by patient-derived anti-N-methyl-D-aspartate receptor antibodies in mice are attenuated by anakinra, an interleukin-1 receptor antagonist.

Epilepsia 2021 Mar 17;62(3):671-682. Epub 2021 Feb 17.

Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia, USA.

Objective: Neuroinflammation associated with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis may facilitate seizures. We previously showed that intraventricular administration of cerebrospinal fluid from patients with anti-NMDAR encephalitis to mice precipitates seizures, thereby confirming that antibodies are directly pathogenic. To determine whether interleukin (IL)-1-mediated inflammation exacerbates autoimmune seizures, we asked whether blocking the effects of IL-1 by anakinra, a selective IL-1 receptor antagonist, blunts antibody-induced seizures.

Methods: We infused C57BL/6 mice intraventricularly with purified serum IgG from patients with anti-NMDAR encephalitis or monoclonal anti-NMDAR IgG; subdural electroencephalogram was continuously recorded. After a 6-day interval, mice received anakinra (25 mg/kg sc, twice daily) or vehicle for 5 days. Following a 4-day washout period, we performed behavioral tests to assess motor function, anxiety, and memory, followed by hippocampus tissue analysis to assess astrocytic (glial fibrillary acidic protein [GFAP]) and microglial (ionized calcium-binding adapter molecule [Iba]-1) activation.

Results: Of 31 mice infused with purified patient NMDAR-IgG (n = 17) or monoclonal NMDAR-IgG (n = 14), 81% developed seizures. Median baseline daily seizure count during exposure to antibodies was 3.9; most seizures were electrographic. Median duration of seizures during the baseline was 82.5 s. Anakinra administration attenuated daily seizure frequency by 60% (p = .02). Anakinra reduced seizure duration; however, the effect was delayed and became apparent only after the cessation of treatment (p = .04). Anakinra improved novel object recognition in mice with antibody-induced seizures (p = .03) but did not alter other behaviors. Anakinra reduced the expression of GFAP and Iba-1 in the hippocampus of mice with seizures, indicating decreased astrocytic and microglial activation.

Significance: Our evidence supports a role for IL-1 in the pathogenesis of seizures in anti-NMDAR encephalitis. These data are consistent with therapeutic effects of anakinra in other severe autoimmune and inflammatory seizure syndromes. Targeting inflammation via blocking IL-1 receptor-mediated signaling may be promising for developing novel treatments for refractory autoimmune seizures.
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http://dx.doi.org/10.1111/epi.16838DOI Listing
March 2021

Clinical spectrum of high-titre GAD65 antibodies.

J Neurol Neurosurg Psychiatry 2021 Feb 9. Epub 2021 Feb 9.

Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA

Objective: To determine clinical manifestations, immunotherapy responsiveness and outcomes of glutamic acid decarboxylase-65 (GAD65) neurological autoimmunity.

Methods: We identified 323 Mayo Clinic patients with high-titre (>20 nmol/L in serum) GAD65 antibodies out of 380 514 submitted anti-GAD65 samples (2003-2018). Patients classified as having GAD65 neurological autoimmunity after chart review were analysed to determine disease manifestations, immunotherapy responsiveness and predictors of poor outcome (modified Rankin score >2).

Results: On review, 108 patients were classified as not having GAD65 neurological autoimmunity and 3 patients had no more likely alternative diagnoses but atypical presentations (hyperkinetic movement disorders). Of remaining 212 patients with GAD65 neurological autoimmunity, median age at symptom onset was 46 years (range: 5-83 years); 163/212 (77%) were female. Stiff-person spectrum disorders (SPSD) (N=71), cerebellar ataxia (N=55), epilepsy (N=35) and limbic encephalitis (N=7) could occur either in isolation or as part of an overlap syndrome (N=44), and were designated core manifestations. Cognitive impairment (N=38), myelopathy (N=23) and brainstem dysfunction (N=22) were only reported as co-occurring phenomena, and were designated secondary manifestations. Sustained response to immunotherapy ranged from 5/20 (25%) in epilepsy to 32/44 (73%) in SPSD (p=0.002). Complete immunotherapy response occurred in 2/142 (1%). Cerebellar ataxia and serum GAD65 antibody titre >500 nmol/L predicted poor outcome.

Interpretation: High-titre GAD65 antibodies were suggestive of, but not pathognomonic for GAD65 neurological autoimmunity, which has discrete core and secondary manifestations. SPSD was most likely to respond to immunotherapy, while epilepsy was least immunotherapy responsive. Complete immunotherapy response was rare. Serum GAD65 antibody titre >500 nmol/L and cerebellar ataxia predicted poor outcome.
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http://dx.doi.org/10.1136/jnnp-2020-325275DOI Listing
February 2021

SARS-CoV-2 encephalitis is a cytokine release syndrome: evidences from cerebrospinal fluid analyses.

Clin Infect Dis 2021 Jan 4. Epub 2021 Jan 4.

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Italy.

Background: Recent findings indicated that SARS-CoV-2 related neurological manifestations involve cytokine release syndrome along with endothelial activation, blood brain barrier dysfunction, and immune-mediated mechanisms. Very few studies have fully investigated the CSF correlates of SARS-CoV-2 encephalitis.

Methods: Patients with PCR-confirmed SARS-CoV-2 infection and encephalitis (COV-Enc), encephalitis without SARS-CoV-2 infection (ENC) and healthy controls (HC) underwent an extended panel of CSF neuronal (NfL, T-tau), glial (GFAP, TREM2, YKL-40) and inflammatory biomarkers (IL-1β, IL-6, Il-8, TNF- α, CXCL-13 and β2-microglobulin).

Results: Thirteen COV-Enc, 21 ENC and 18 HC entered the study. In COV-Enc cases, CSF was negative for SARS-CoV-2 real-time PCR but exhibited increased IL-8 levels independently from presence of pleocytosis/hyperproteinorracchia. COV-Enc patients showed increased IL-6, TNF- α, and β2-microglobulin and glial markers (GFAP, sTREM-2, YKL-40) levels similar to ENC but normal CXCL13 levels. Neuronal markers NfL and T-Tau were abnormal only in severe cases.

Conclusions: SARS-CoV-2-related encephalitis were associated with prominent glial activation and neuroinflammatory markers, whereas neuronal markers were increased in severe cases only. The pattern of CSF alterations suggested a cytokine-release syndrome as the main inflammatory mechanism of SARS-CoV-2 related encephalitis.
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http://dx.doi.org/10.1093/cid/ciaa1933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799260PMC
January 2021

Neuronal intermediate filament IgGs in CSF: Autoimmune Axonopathy Biomarkers.

Ann Clin Transl Neurol 2021 02 28;8(2):425-439. Epub 2020 Dec 28.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.

Objectives: To describe CSF-defined neuronal intermediate filament (NIF) autoimmunity.

Methods: NIF-IgG CSF-positive patients (41, 0.03% of 118599 tested, 1996-2019) were included (serum was neither sensitive nor specific). Criteria-based patient NIF-IgG staining of brain and myenteric NIFs was detected by indirect immunofluorescence assay (IFA); NIF-specificity was confirmed by cell-based assays (CBAs, alpha internexin, neurofilament light [NF-L]), heavy-[NF-H] chain).

Results: Sixty-one percent of 41 patients were men, median age, 61 years (range, 21-88). Syndromes were encephalopathy predominant (23), cerebellar ataxia predominant (11), or myeloradiculoneuropathies (7). MRI abnormalities (T2 hyperintensities of brain, spinal cord white matter tracts. and peripheral nerve axons) and neurophysiologic testing (EEG, EMG, evoked potentials) co-localized with clinical neurological phenotypes (multifocal in 29%). Thirty patients (73%) had ≥ 1 immunological perturbation: cancer (paraneoplastic), 22; systemic infection (parainfectious [including ehrlichosis, 3] or HIV), 7; checkpoint-inhibitor cancer immunotherapy, 4; other, 5. Cancers were as follows: neuroendocrine-lineage carcinomas, 12 (small cell, 6; Merkel cell, 5; pancreatic, 1 [11/12 had NF-L-IgG detected, versus 8/29 others, P = 0.0005]) and other, 11. Onset was predominantly subacute (92%) and accompanied by inflammatory CSF (75%), and immunotherapy response (77%). In contrast, CSF controls (15684 total) demonstrated NIF-IgG negativity (100% of test validation controls), and low frequencies of autoimmune diagnoses (20% of consecutively referred clinical specimens) and neuroendocrine-lineage carcinoma diagnosis (3.1% vs. 30% of NIF cases), P < 0.0001. Median NF-L protein concentration was higher in 8 NF-L-IgG-positive patients (median, 6718 ng/L) than 16 controls.

Interpretation: Neurological autoimmunity, defined by CSF-detected NIF-IgGs, represents a continuum of treatable axonopathies, sometimes paraneoplastic or parainfectious.
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http://dx.doi.org/10.1002/acn3.51284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886032PMC
February 2021

Case Report: Innate Immune System Challenge Unleashes Paraneoplastic Neurological Autoimmunity.

Front Neurol 2020 10;11:598894. Epub 2020 Dec 10.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States.

Paraneoplastic autoimmune neurological disorders reflect tumor-initiated immune responses against onconeural antigens. Symptoms and signs can affect the central and/or peripheral nervous systems, neuromuscular junction or muscle, and typically evolve subacutely before an underlying neoplasm is discovered. We describe four patients whose neurological symptoms were precipitated by potent innate immune system challenges: bladder instillation of BCG, tick bite and an "alternative cancer therapy" with bacterial extracts and TNF-α. We hypothesize that a tumor-initiated autoimmune response (evidenced by autoantibody profiles), pre-dating the immune system challenge, was unmasked or amplified in these patients by cytokines released systemically from innate immune cells activated by microbial pathogen-associated molecular patterns (PAMPs). The resultant upregulation of cognate onconeural peptides as MHC1 protein complexes on neural cell surfaces would render those cells susceptible to killing by CD8+ T cells, thus precipitating the patient's neurological symptoms.
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http://dx.doi.org/10.3389/fneur.2020.598894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759151PMC
December 2020

Immune checkpoint inhibitor-associated myopathy: a clinicoseropathologically distinct myopathy.

Brain Commun 2020 2;2(2):fcaa181. Epub 2020 Nov 2.

Department of Neurology, Mayo Clinic, Rochester, MN, USA.

Immune checkpoint inhibitors have revolutionized the landscape of cancer treatment. Alongside their many advantages, they elicit immune-related adverse events, including myopathy, which potentially result in substantial morbidity if not recognized and treated promptly. Current knowledge of immune checkpoint inhibitor-associated myopathy is limited. We conducted a 5-year retrospective study of patients with immune checkpoint inhibitor-associated myopathy. Clinical features, survival and ancillary test findings were analysed and compared with those of immune-mediated necrotizing myopathy patients without immune checkpoint inhibitor exposure seen during the same time period. We identified 24 patients with immune checkpoint inhibitor-associated myopathy (median age 69 years; range 28-86) and 38 patients with immune-mediated necrotizing myopathy. Ocular involvement occurred in 9/24 patients with immune checkpoint inhibitor exposure, without electrodiagnostic evidence of neuromuscular transmission defect, and in none of the immune-mediated necrotizing myopathy patients ( < 0.001). Myocarditis occurred in eight immune checkpoint inhibitor-associated myopathy patients and in none of the immune-mediated necrotizing myopathy patients ( < 0.001). Median creatine kinase was 686 IU/l in the immune checkpoint inhibitor cohort (seven with normal creatine kinase) compared to 6456 IU/l in immune-mediated necrotizing myopathy cohort ( < 0.001). Lymphopenia was observed in 18 and 7 patients with and without immune checkpoint inhibitor exposure, respectively ( < 0.001). Myopathological findings were similar between patients with and without immune checkpoint inhibitor exposure, consisting of necrotic fibres with no or subtle inflammation. Necrotic fibres however arranged in clusters in 10/11 immune checkpoint inhibitor-associated myopathy patients but in none of the immune checkpoint inhibitor-naïve patients ( < 0.001). Despite the lower creatine kinase levels in immune checkpoint inhibitor-exposed patients, the number of necrotic fibres was similar in both groups. Immune checkpoint inhibitor-associated myopathy patients had a higher frequency of mitochondrial abnormalities and less number of regenerating fibres than immune-mediated necrotizing myopathy patients ( < 0.001). Anti-hydroxy-3-methylglutaryl-CoA reductase or signal recognition particle antibodies were absent in patients with immune checkpoint inhibitor exposure but positive in two-thirds of immune checkpoint inhibitor-naïve patients. Most patients with immune checkpoint inhibitor-associated myopathy responded favourably to immunomodulatory treatments, but four died from myopathy-related complications and one from myocarditis. Intubated patients had significantly shorter survival compared to non-intubated patients (median survival of 22 days;  = 0.004). In summary, immune checkpoint inhibitor-associated myopathy is a distinct, treatable immune-mediated myopathy with common ocular involvement, frequent lymphopenia and necrotizing histopathology, which contrary to immune-mediated necrotizing myopathy, is featured by clusters of necrotic fibres and not accompanied by anti-hydroxy-3-methylglutaryl-CoA reductase or signal recognition particle antibodies. Normal or mildly elevated creatine kinase level does not exclude the diagnosis.
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http://dx.doi.org/10.1093/braincomms/fcaa181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713997PMC
November 2020

Neurologic Complications of Immune Checkpoint Inhibitors in Thoracic Malignancies.

J Thorac Oncol 2021 Mar 11;16(3):381-394. Epub 2020 Nov 11.

Department of Neurology, Mayo Clinic, Rochester, Minnesota; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. Electronic address:

Immune checkpoint inhibitors (ICIs) have transformed the prognosis of cancers previously considered lethal. The spectrum of therapeutic indications is rapidly expanding, including the vast majority of thoracic malignancies. By enhancing the immune responses against cancer, the ICI treatments lead to the development of immune-related adverse events (irAEs) that may affect any organ. Severity varies from mild to fatal clinical manifestations. Neurologic involvement is relatively rare and highly heterogeneous, including central and peripheral nervous system diseases associated with neural-specific autoantibodies or not, central nervous system vasculitis, and granulomatous and demyelinating disorders. Symptoms often manifest within the first four cycles of treatment and can develop regardless of the class of ICI used. An unfavorable outcome is found in up to one-third of patients and is generally associated with the patients' clinical characteristics (e.g., age, coexistence of systemic adverse events), cancer type (e.g., lung cancer versus other), and specific clinical setting (e.g., ICI treatment in patients with preexisting paraneoplastic neurologic autoimmunity, ICI rechallenge after a first neurologic irAE). Diagnosis should be suspected in patients with new-onset neurologic symptoms while on ICI treatment which are not explained by metastatic disease or other metabolic/infectious disorders. Recommended treatment is based on clinical severity and consists of ICI discontinuation with or without immunosuppressive/immunomodulatory therapy, although alternative approaches are reasonable depending on cancer status (e.g., aggressive immunosuppression without discontinuing ICI in patients with initial cancer response). Early recognition and appropriate treatment of these neurologic irAEs are crucial for improved patient outcomes and therapeutic planning.
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http://dx.doi.org/10.1016/j.jtho.2020.11.005DOI Listing
March 2021

Neuro-Ophthalmic Complications in Patients Treated With CTLA-4 and PD-1/PD-L1 Checkpoint Blockade.

J Neuroophthalmol 2020 Oct 28. Epub 2020 Oct 28.

Department of Ophthalmology (MMS, NS, LKG), Jules Stein Eye Institute, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California; Department of Ophthalmology (JJC), Mayo Clinic, Rochester, Minnesota; Department of Neurology (JJC, AZ, ES), Mayo Clinic, Rochester, Minnesota; Department of Ophthalmology & Visual Sciences (RDW), Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Ophthalmology (JDB), Park Nicollet Health Services, Minneapolis, Minnesota; Department of Ophthalmology (OS), University of Kentucky/Retina Associates of Kentucky, Lexington, Kentucky; Department of Neurology (LJM), SUNY Upstate Medical University, Syracuse, New York; Department of Ophthalmology (LJM), SUNY Upstate Medical University, Syracuse, New York; Department of Neurology (SG), University of Missouri-Kansas City, Kansas City, Missouri; Department of Ophthalmology (PMS), University of Vermont Medical Center, Burlington, Vermont; The Medical Eye Center (DAB), Manchester, New Hampshire; Department of Ophthalmology (JF), Oregon Health & Science University, Portland, Oregon; Department of Ophthalmology (CLF), University of Sydney, Sydney, Australia; Department of Neurology & Neurophysiology (CC-S), Liverpool Hospital, NSW, Australia; Department of Neurology (SRH), Virginia Commonwealth University School of Medicine, Richmond, Virginia; Department of Neurology (BH), INI Eye Center, OSF Healthcare, University of Illinois College of Medicine, Peoria, Illinois; Department of Ophthalmology (MDS), University of Utah, Salt Lake City, Utah; Department of Ophthalmology (PSS), University of Colorado, Aurora, Colorado; and Department of Ophthalmology (ZW), University of Rochester Medical Center, Rochester, New York.

Background: In recent years, CTLA-4 and PD-1/PD-L1 checkpoint inhibitors have proven to be effective and have become increasingly popular treatment options for metastatic melanoma and other cancers. These agents work by enhancing autologous antitumor immune responses. Immune-related ophthalmologic complications have been reported in association with checkpoint inhibitor use but remain incompletely characterized. This study seeks to investigate and further characterize the neuro-ophthalmic and ocular complications of immune checkpoint blockade treatment.

Methods: A survey was distributed through the secure electronic data collection tool REDCap to neuro-ophthalmology specialists in the North American Neuro-Ophthalmology Society listserv. The study received human subjects approval through the University of California at Los Angeles Institutional Review Board. The survey identified patients sent for neuro-ophthalmic consultation while receiving one or more of a PD-1 inhibitor (pembrolizumab, nivolumab, or cemiplimab); PD-L1 inhibitor (atezolizumab, avelumab, or durvalumab); or the CTLA-4 inhibitor ipilimumab. Thirty-one patients from 14 institutions were identified. Patient demographics, neuro-ophthalmic diagnosis, diagnostic testing, severity, treatment, clinical response, checkpoint inhibitor drug used, and cancer diagnosis was obtained.

Results: The checkpoint inhibitors used in these patients included pembrolizumab (12/31), nivolumab (6/31), combined ipilimumab with nivolumab (7/31, one of whom also received pembrolizumab during their course of treatment), durvalumab (3/31), ipilimumab (2/31), and cemiplimab (1/31). Malignant melanoma (16/31) or nonsmall cell lung carcinoma (6/31) were the most common malignancies. The median time between first drug administration and the time of ophthalmological symptom onset was 14.5 weeks. Eleven patients had involvement of the optic nerve, 7 patients had inflammatory orbital or extraocular muscle involvement, 6 patients had ocular involvement from neuromuscular junction dysfunction, 4 patients had cranial nerve palsy, and 4 patients had non neuro-ophthalmic complications. Use of systemic corticosteroids with or without stopping the checkpoint inhibitor resulted in improvement of most patients with optic neuropathy, and variable improvement for the other ophthalmic conditions.

Conclusion: This study describes the variable neuro-ophthalmic adverse events associated with use of immune checkpoint inhibitors and contributes a more thorough understanding of their clinical presentations and treatment outcomes. We expect this will increase awareness of these drug complications and guide specialists in the care of these patients.
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http://dx.doi.org/10.1097/WNO.0000000000001148DOI Listing
October 2020

High-resolution epitope mapping of anti-Hu and anti-Yo autoimmunity by programmable phage display.

Brain Commun 2020 3;2(2):fcaa059. Epub 2020 Aug 3.

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.

Paraneoplastic neurological disorders are immune-mediated diseases understood to manifest as part of a misdirected anti-tumor immune response. Paraneoplastic neurological disorder-associated autoantibodies can assist with diagnosis and enhance our understanding of tumor-associated immune processes. We designed a comprehensive library of 49-amino-acid overlapping peptides spanning the entire human proteome, including all splicing isoforms and computationally predicted coding regions. Using this library, we optimized a phage immunoprecipitation and sequencing protocol with multiple rounds of enrichment to create high-resolution epitope profiles in serum and cerebrospinal fluid (CSF) samples from patients suffering from two common paraneoplastic neurological disorders, the anti-Yo ( = 36 patients) and anti-Hu ( = 44 patients) syndromes. All (100%) anti-Yo patient samples yielded enrichment of peptides from the canonical anti-Yo (CDR2 and CDR2L) antigens, while 38% of anti-Hu patients enriched peptides deriving from the nELAVL (neuronal embryonic lethal abnormal vision like) family of proteins, the anti-Hu autoantigenic target. Among the anti-Hu patient samples that were positive for nELAVL, we noted a restricted region of immunoreactivity. To achieve single amino acid resolution, we designed a novel deep mutational scanning phage library encoding all possible single-point mutants targeting the reactive nELAVL region. This analysis revealed a distinct preference for the degenerate motif, RLDxLL, shared by ELAVL2, 3 and 4. Lastly, phage immunoprecipitation sequencing identified several known autoantigens in these same patient samples, including peptides deriving from the cancer-associated antigens ZIC and SOX families of transcription factors. Overall, this optimized phage immunoprecipitation sequencing library and protocol yielded the high-resolution epitope mapping of the autoantigens targeted in anti-Yo and anti-Hu encephalitis patients to date. The results presented here further demonstrate the utility and high-resolution capability of phage immunoprecipitation sequencing for both basic science and clinical applications and for better understanding the antigenic targets and triggers of paraneoplastic neurological disorders.
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http://dx.doi.org/10.1093/braincomms/fcaa059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425417PMC
August 2020

Improving accuracy of myasthenia gravis autoantibody testing by reflex algorithm.

Neurology 2020 12 16;95(22):e3002-e3011. Epub 2020 Sep 16.

From the Departments of Neurology (S.S., P.P., H.B., D.D., M.M., E.J.S., B.A.C., R.S.L., T.L., S.J.P., A.Z., A.M., M.C.H., C.J.K.), Laboratory Medicine and Pathology (D.D., S.J.P., A.Z., A.M., J.R.M., C.J.K.), and Biomedical Statistics and Bioinformatics (J.M.), Mayo Clinic Foundation, Rochester, MN.

Objective: To improve myasthenia gravis (MG) autoantibody testing.

Methods: MG serologic tests with confirmatory or refuting clinical-electrodiagnostic (EDX) testing and cancer evaluations were reviewed over 4 years (2012-2015). All patients had acetylcholine receptor-binding (AChR-Bi), modulating (AChR-Mo), and striational (STR) autoantibody testing, and negatives reflexed to muscle-specific kinase (MuSK). Thymoma and cancer occurrences were correlated with STR and reflexed glutamic acid decarboxylase 65 (GAD65), ganglionic acetylcholine receptor (α3), collapsin response mediating protein-5, and voltage-gated potassium channel complex autoantibodies.

Results: Of 433 samples tested, 133 (31%) met clinical-EDX criteria for MG. Best sensitivity (90%) occurred at AChR-Bi >0.02 nmol/L, leaving 14 negative (6 ocular MG, 7 generalized MG, 1 MuSK MG) with specificity 90% (31 false-positives). Using AChR-Mo antibodies (>20% loss), specificity was better (92%, 24 false-positives), but sensitivity dropped (85%). Specificity improved (95%) by testing AChR-Mo when AChR-Bi are positive, resulting in 45% reduction of false-positives (31-17), maintaining AChR-Bi 90% sensitivity. Cutoff values recommended by area under the curve analysis did not outperform this approach. AChR-Bi and AChR-Mo values were significantly higher in true-positives. CT evaluations in 121 MG samples revealed 16 thymomas. Historical or subsequent cancers occurred in 22. STR and reflexed autoantibodies were not more common in MG with thymoma or other cancers. Full-body CT (n = 34) was performed in those with STR and reflex autoantibody positivity, but without additional cancers found.

Conclusion: Accuracy of MG serologic testing is improved by reflexing AChR-Bi-positive cases to AChR-Mo. STR and other reflexed cancer evaluation autoantibodies did not provide value beyond standard CT chest imaging at the time of MG diagnosis. Diagnostic certainty is informed by AChR-Bi and AChR-Mo with higher values increasing specificity.
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http://dx.doi.org/10.1212/WNL.0000000000010910DOI Listing
December 2020

Neurologic autoimmunity and immune checkpoint inhibitors: Autoantibody profiles and outcomes.

Neurology 2020 10 13;95(17):e2442-e2452. Epub 2020 Aug 13.

From the Departments of Neurology (E.S., A.M., D.D., T.L., V.A.L., C.J.K., M.M., S.J.P., E.P.F., A.Z.), Oncology (S.N.M.), Laboratory Medicine and Pathology (A.M., D.D., V.A.L., S.J.P., E.P.F., A.Z.), and Immunology (V.A.L.), Mayo Clinic, Rochester, MN; and Department of Neurology (A.S.L.-C.), Mayo Clinic, Jacksonville, FL.

Objective: To describe neural autoantibody profiles and outcomes in patients with neurologic autoimmunity associated with immune checkpoint inhibitor (ICI) cancer immunotherapy.

Methods: In this retrospective descriptive study, 63 patients with ICI-related neurologic autoimmunity were included: 39 seen at the Mayo Clinic Neurology Department (clinical cohort) and 24 whose serum/CSF was referred to the Mayo Clinic Neuroimmunology Laboratory for autoantibody testing. Serum/CSF samples were tested for neural-specific autoantibodies. Predictors of unfavorable outcome (residual adverse event severity grade ≥3) were explored (logistic regression).

Results: Median age at neurologic symptom onset was 65 years (range 31-86); 40% were female. Neurologic manifestations were CNS-restricted (n = 26), neuromuscular (n = 30), combined (n = 5), or isolated retinopathy (n = 2). Neural-specific autoantibodies were common in patients with CNS involvement (7/13 [54%] in the unbiased clinical cohort) and included known or unidentified neural-restricted specificities. Only 11/31 patients with CNS manifestations had neuroendocrine malignancies typically associated with paraneoplastic autoimmunity. Small-cell lung cancer (SCLC)-predictive antibodies were seen in 3 patients with non-neuroendocrine tumors (neuronal intermediate filament immunoglobulin G [IgG] and antineuronal nuclear antibody 1 with melanoma; amphiphysin IgG with non-SCLC). A median of 10 months from onset (range, 0.5-46), 14/39 in the clinical cohort (36%) had unfavorable outcomes; their characteristics were age ≥70 years, female, CNS involvement, lung cancer, higher initial severity grade, and lack of systemic autoimmunity. By multivariate analysis, only age remained independently associated with poor outcome ( = 0.01). Four of 5 patients with preexistent neurologic autoimmunity experienced irreversible worsening after ICI.

Conclusions: Neural-specific autoantibodies are not uncommon in patients with ICI-related CNS neurologic autoimmunity. Outcomes mostly depend on the pre-ICI treatment characteristics and clinical phenotype.
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http://dx.doi.org/10.1212/WNL.0000000000010632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682911PMC
October 2020

Expanded Clinical Phenotype, Oncological Associations, and Immunopathologic Insights of Paraneoplastic Kelch-like Protein-11 Encephalitis.

JAMA Neurol 2020 Aug 3. Epub 2020 Aug 3.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Importance: Recognizing the presenting and immunopathological features of Kelch-like protein-11 immunoglobulin G seropositive (KLHL11 IgG+) patients may aid in early diagnosis and management.

Objective: To describe expanding neurologic phenotype, cancer associations, outcomes, and immunopathologic features of KLHL11 encephalitis.

Design, Setting, And Participants: This retrospective tertiary care center study, conducted from October 15, 1998, to November 1, 2019, prospectively identified 31 KLHL11 IgG+ cases in the neuroimmunology laboratory. Eight were identified by retrospective testing of patients with rhomboencephalitis (confirmed by tissue-based-immunofluorescence and transfected-cell-based assays).

Main Outcomes And Measures: Outcome variables included modified Rankin score and gait aid use.

Results: All 39 KLHL11 IgG+ patients were men (median age, 46 years; range, 28-73 years). Initial clinical presentations were ataxia (n = 32; 82%), diplopia (n = 22; 56%), vertigo (n = 21; 54%), hearing loss (n = 15; 39%), tinnitus (n = 14; 36%), dysarthria (n = 11; 28%), and seizures (n = 9; 23%). Atypical neurologic presentations included neuropsychiatric dysfunction, myeloneuropathy, and cervical amyotrophy. Hearing loss or tinnitus preceded other neurologic deficits by 1 to 8 months in 10 patients (26%). Among patients screened for malignancy (n = 36), testicular germ-cell tumors (n = 23; 64%) or testicular microlithiasis and fibrosis concerning for regressed germ cell tumor (n = 7; 19%) were found in 83% of the patients (n = 30). In 2 patients, lymph node biopsy diagnosed metastatic lung adenocarcinoma in one and chronic lymphocytic leukemia in the other. Initial brain magnetic resonance imaging revealed T2 hyperintensities in the temporal lobe (n = 12), cerebellum (n = 9), brainstem (n = 3), or diencephalon (n = 3). Among KLHL11 IgG+ patients who underwent HLA class I and class II genotyping (n = 10), most were found to have HLA-DQB1*02:01 (n = 7; 70%) and HLA-DRB1*03:01 (n = 6; 60%) associations. A biopsied gadolinium-enhancing temporal lobe lesion demonstrated T cell-predominant inflammation and nonnecrotizing granulomas. Cerebellar biopsy (patient with chronic ataxia) and 2 autopsied brains demonstrated Purkinje neuronal loss and Bergmann gliosis, supporting early active inflammation and later extensive neuronal loss. Compared with nonautoimmune control peripheral blood mononuclear cells, cluster of differentiation (CD) 8+ and CD4+ T cells were significantly activated when patient peripheral blood mononuclear cells were cultured with KLHL11 protein. Most patients (58%) benefitted from immunotherapy and/or cancer treatment (neurological disability stabilized [n = 10] or improved [n = 9]). Kaplan-Meier curve demonstrated significantly higher probability of wheelchair dependence among patients without detectable testicular cancer. Long-term outcomes in KLHL11-IgG+ patients were similar to Ma2 encephalitis.

Conclusions And Relevance: Kelch-like protein-11 IgG is a biomarker of testicular germ-cell tumor and paraneoplastic neurologic syndrome, often refractory to treatment. Described expanded neurologic phenotype and paraclinical findings may aid in its early diagnosis and treatment.
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http://dx.doi.org/10.1001/jamaneurol.2020.2231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653501PMC
August 2020

Use of diffusion-weighted imaging to distinguish seizure-related change from limbic encephalitis.

J Neurol 2020 Nov 24;267(11):3337-3342. Epub 2020 Jun 24.

Department of Neurology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.

Objective: To determine whether diffusion-weighted imaging (DWI) can help differentiate peri-ictal signal abnormality from limbic encephalitis (LE) among patients with medial temporal lobe T2-hyperintensity.

Methods: We retrospectively identified patients with peri-ictal medial temporal lobe T2-hyperintensity using a Mayo Clinic database, and reviewed their DWI to look for unique diffusion restriction patterns. We then identified patients with medial temporal lobe T2-hyperintensity and LE, and reviewed their DWI to see if these patterns were ever present. Presence of diffusion restriction patterns was confirmed by a blinded neuro-radiologist.

Results: We identified 10 patients without LE who had peri-ictal unilateral medial temporal lobe T2-hyperintensity, ipsilateral to focal seizure onset. Nine of 10 (90%) had at least one of two diffusion restriction patterns potentially unique to seizure activity; four had gyriform hippocampal diffusion restriction ("Pattern 1"), three had diffuse hippocampal diffusion restriction that spared the most medial temporal lobe structures ("Pattern 2"), and two had both diffusion restriction patterns. The median patient age was 62 years (range 2-76 years) and 3/9 (33%) were female. In comparison, among patients with medial temporal lobe T2-hyperintensity and LE, only 5/57 (9%) had one of the diffusion restriction patterns ("Pattern 2") identified (P < 0.0001); all five had seizures reported.

Conclusions: In patients with medial temporal lobe T2-hyperintensity and one of the diffusion restriction patterns described herein, the signal abnormality may be a peri-ictal phenomenon rather than indicative of LE and should prompt investigation for seizure. Even in patients with LE, these patterns should raise concern for seizure.
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http://dx.doi.org/10.1007/s00415-020-10007-1DOI Listing
November 2020

Synaptic autoimmunity: new insights into LGI1 antibody-mediated neuronal dysfunction.

Brain 2020 06;143(6):1622-1625

Department of Neurology, Mayo Clinic, Rochester, USA.

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http://dx.doi.org/10.1093/brain/awaa153DOI Listing
June 2020

Autoimmune encephalitis management: MS centers and beyond.

Mult Scler 2020 11 13;26(13):1618-1626. Epub 2020 Feb 13.

Departments of Laboratory Medicine and Pathology, and Neurology, Mayo Clinic, Rochester, MN, USA.

Traditionally, multiple sclerosis (MS) specialists have been the go-to providers for managing certain treatable non-demyelinating inflammatory or autoimmune central nervous system (CNS) disorders. The advent of increased incidence (mostly due to improved recognition) prompts the question: who should be managing autoimmune encephalitis? These patients are generally first encountered in the hospital, as well as general neurology and subspecialty clinics, such as epilepsy. Autoimmune neurology is a specialty which gives focus to evaluation and treatment of patients with autoimmune encephalitis, among other disorders, and trains neurologists accordingly. Some of those experts are dual trained in both MS and non-MS inflammatory/autoimmune CNS disorders. Many other autoimmune specialists are trained in non-MS care, such as hospital neurology, movement disorders, and epilepsy. General and other subspecialty providers increasingly find the need to be versed in management of autoimmune encephalitis.
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http://dx.doi.org/10.1177/1352458520905485DOI Listing
November 2020

Autoimmune psychosis.

Lancet Psychiatry 2020 02;7(2):122

Departments of Laboratory Medicine and Pathology, and Neurology, Mayo Clinic, Rochester, MN 55906, USA.

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http://dx.doi.org/10.1016/S2215-0366(19)30512-7DOI Listing
February 2020

CRMP5-IgG-Associated Paraneoplastic Myelopathy With PD-L1 Inhibitor Therapy.

JAMA Neurol 2020 02;77(2):255-256

Department of Neurology, Mayo Clinic, Rochester, Minnesota.

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http://dx.doi.org/10.1001/jamaneurol.2019.4379DOI Listing
February 2020

Randomized Placebo-Controlled Trial of Intravenous Immunoglobulin in Autoimmune LGI1/CASPR2 Epilepsy.

Ann Neurol 2020 02 14;87(2):313-323. Epub 2019 Dec 14.

Department of Neurology and Immunology, Mayo Clinic, Rochester, MN.

Objective: Drug-resistant seizures are common in patients with leucine-rich, glioma-inactivated 1 (LGI1)-IgG associated and contactin-associated protein-like 2 (CASPR2)-IgG associated encephalitis. We performed the first randomized double-blind placebo-controlled trial to evaluate efficacy of intravenous immunoglobulin (IVIG) in reducing seizure frequency.

Methods: Our enrollment goal was 30 LGI1/CASPR2-IgG-seropositive adult patients with ≥2 seizures per week. Patients were randomized to receive IVIG (0.5g/kg day 1, 1g/kg day 2, 0.6g/kg weeks 3 and 5) or volume-matched intravenous normal saline. Following the blinded phase, the nonresponders in the placebo group received IVIG. The primary clinical outcome was 50% reduction in seizure frequency from baseline to 5 weeks.

Results: After enrollment of 17 patients (LGI1-IgG, 14; CASPR2-IgG, 3) over 34 months, the study was terminated due to slow enrollment. Six of 8 patients in the IVIG group were responders, compared to 2 of 9 in the placebo group (p = 0.044, odds ratio = 10.5, 95% confidence interval = 1.1-98.9). For the LGI1-IgG seropositive subgroup, 6 of 8 patients in the IVIG group were responders, compared to zero of 6 in the placebo group. Two LGI1-IgG-seropositive patients receiving IVIG, but none receiving placebo, were seizure-free at the end of the blinded phase. Four of the 6 patients entering the open-label IVIG arm reported ≥50% reduction in seizure frequency. There were no correlations with LGI1/CASPR2-IgG1-4 subclasses.

Interpretation: Superiority of IVIG to placebo reached statistical significance for the primary endpoint for all patients and the subset with LGI1-IgG. These results have to be interpreted with the caveat that the study did not reach its originally selected sample size. ANN NEUROL 2020;87:313-323.
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http://dx.doi.org/10.1002/ana.25655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003900PMC
February 2020

Neurologic Autoimmunity in the Era of Checkpoint Inhibitor Cancer Immunotherapy.

Mayo Clin Proc 2019 09 26;94(9):1865-1878. Epub 2019 Jul 26.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; Department of Neurology, Mayo Clinic, Rochester, MN; Department of Immunology, Mayo Clinic, Rochester, MN.

Neurologic autoimmune disorders in the context of systemic cancer reflect antitumor immune responses against onconeural proteins that are autoantigens in the nervous system. These responses observe basic principles of cancer immunity and are highly pertinent to oncological practice since the introduction of immune checkpoint inhibitor cancer therapy. The patient's autoantibody profile is consistent with the antigenic composition of the underlying malignancy. A major determinant of the pathogenic outcome is the anatomic and subcellular location of the autoantigen. IgGs targeting plasma membrane proteins (eg, muscle acetylcholine receptor -IgG in patients with paraneoplastic myasthenia gravis) have pathogenic potential. However, IgGs specific for intracellular antigens (eg, antineuronal nuclear antibody 1 [anti-Hu] associated with sensory neuronopathy and small cell lung cancer) are surrogate markers for CD8 T lymphocytes targeting peptides derived from nuclear or cytoplasmic proteins. In an inflammatory milieu, those peptides translocate to neural plasma membranes as major histocompatibility complex class I protein complexes. Paraneoplastic neurologic autoimmunity can affect any level of the neuraxis and may be mistaken for cancer progression. Importantly, these disorders generally respond favorably to early-initiated immunotherapy and cancer treatment. Small cell lung cancer and thymoma are commonly associated with neurologic autoimmunity, but in the context of checkpoint inhibitor therapy, other malignancy associations are increasingly recognized.
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http://dx.doi.org/10.1016/j.mayocp.2019.02.003DOI Listing
September 2019

Phosphodiesterase 10A IgG: A novel biomarker of paraneoplastic neurologic autoimmunity.

Neurology 2019 08 17;93(8):e815-e822. Epub 2019 Jul 17.

From the Departments of Laboratory Medicine and Pathology (A.Z., T.K., V.L., S.P., A.M.), Neurology (A.Z., Y.G., A.H., V.L., C.F.L., S.P., A.M.), and Immunology (V.L.), Mayo Clinic, Rochester, MN.

Objective: To describe a novel antibody biomarker of neurologic paraneoplastic autoimmunity specific for phosphodiesterase 10A (PDE10A), a striatum-enriched phosphodiesterase, and to characterize the clinical phenotype of patients with PDE10A immunoglobulin G (IgG).

Methods: We describe 7 patients with autoantibodies specific for PDE10A identified in the Mayo Clinic Neuroimmunology Laboratory. Patient specimens (sera, 7; CSF, 4) produced identical basal ganglia-predominant synaptic staining of murine brain tissue by indirect immunofluorescence. The autoantigen was identified by immunoprecipitation and mass spectrometry as PDE10A, and confirmed by antigen-specific recombinant Western blot and cell-based assays, and immune absorption experiments.

Results: The median patient age was 70 years (range 66-76); 4 were men. Four patients with clinical information available had movement disorders (hyperkinetic in 3 [chorea, ballismus, dystonia] and parkinsonism in 1). All patients but one had cancer (lung [adenocarcinoma 1, squamous cell carcinoma 1, poorly differentiated mesenchymal carcinoma 1], renal adenocarcinoma 2, and pancreatic adenocarcinoma 1). Two of the 7 patients developed hyperkinetic movement disorders during treatment with immune checkpoint inhibitors (nivolumab and pembrolizumab), though none of 26 cancer control patients treated with immune checkpoint inhibitors harbored PDE10A IgG in their serum. MRIs from those 2 patients with hyperkinetic movement disorders demonstrated fluid-attenuated inversion recovery/T2 basal ganglia hyperintensities, and their CSF harbored unique oligoclonal bands. One of those 2 patients had substantial improvement after corticosteroids. One patient's renal adenocarcinoma expressed PDE10A by immunohistochemistry.

Conclusions: PDE10A IgG defines a novel rare neurologic autoimmune syndrome and expands the spectrum of diagnosable paraneoplastic CNS disorders. The intracellular location of PDE10A suggests a T-cell-mediated pathology targeting cells displaying MHC1-bound PDE10A peptides.
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http://dx.doi.org/10.1212/WNL.0000000000007971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711657PMC
August 2019

GABA receptor autoimmunity: A multicenter experience.

Neurol Neuroimmunol Neuroinflamm 2019 05 4;6(3):e552. Epub 2019 Apr 4.

Department of Laboratory Medicine and Pathology (K.O'.C., A.Z., V.L., S.J.P., A.M.), Department of Neurology (A.Z., V.L., S.J.P., A.M.), and Department of Immunology (V.L.), Mayo Clinic, Rochester, MN; Oxford Autoimmune Neurology Group (P.J.W., V.C.M.), Nuffield Department of Clinical Neurosciences, UK; Institute for Experimental Immunology (L.K., C.P., S.M., B.T.), Affiliated to Euroimmun AG, Luebeck, Germany; and the Department of Neurology (C.Y.G., J.M.G., M.D.G.), University California, San Francisco.

Objective: We sought to validate methods for detection and confirmation of GABA receptor (R)-IgG and clinically characterize seropositive cases.

Methods: Archived serum and CSF specimens (185 total) suspected to harbor GABAR-IgG were evaluated by indirect immunofluorescence assay (IFA). Twenty-six specimens from 19 patients appeared suspicious for GABAR-IgG positivity by IFA, based on prior reports and comparison with commercial GABAR antibody staining. Aliquots of those specimens were tested at the University of Oxford, United Kingdom, and Euroimmun, Lubeck, Germany, for GABAR-IgG by cell-based assays (CBAs) using HEK293-indicator cells transfected with plasmids encoding different GABAR subunits.

Results: Eight specimens (of 26 tested; 4 serums, 4 CSFs) from 5 patients were confirmed by CBA to be GABAR-IgG positive. Patient IgGs were always reactive with α1β3 GABAR subunits. One more patient was identified clinically after this validation study. Median age for the 6 patients at serologic diagnosis was 44 years (range, 1-71 years), and 4 of them were male. Among the 4 for whom clinical information was available (2 treated by the authors), all had encephalitis and antiepileptic drug refractory seizures. Three out of 4 patients treated with a combination of immunotherapies had good outcomes. The fourth, recognized to have an autoimmune cause late in the clinical course, had severe permanent neurologic sequelae and brain atrophy.

Conclusions: Though not as common as NMDA-R encephalitis, GABAR encephalitis generally has a characteristic clinical-radiologic presentation and is treatable, making accurate laboratory diagnosis critical.
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http://dx.doi.org/10.1212/NXI.0000000000000552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501640PMC
May 2019

Paraneoplastic autoimmunity and small-cell lung cancer: Neurological and serological accompaniments.

Thorac Cancer 2019 04 27;10(4):1001-1004. Epub 2019 Feb 27.

Department of Neurology, Mayo Clinic, Rochester, USA.

Paraneoplastic neurological autoimmunity is often associated with small-cell lung cancer (SCLC), a highly malignant neuroendocrine tumor. Paraneoplastic autoimmunity often correlates with longer survival. We describe the paraneoplastic neurological manifestations of patients with SCLC with and without SCLC-predictive autoantibodies and the correlation between autoimmunity and survival. We reviewed the records of 116 patients (51% male) from the Mayo Clinic with histopathologically confirmed SCLC for whom stored serum was available for neural autoantibody testing. Cancer was limited stage in 41%; the median age at diagnosis was 64 years. Paraneoplastic neurological manifestations were recorded in 61% (decreasing frequency: peripheral neuropathy, dysautonomia, cognitive decline, cerebellar ataxia, neuromuscular junction disorder, seizures, cranial neuropathy, movement disorder, brainstem disorder, or myelopathy). Neural autoantibodies, some with pathogenic potential, were detected in the sera of SCLC patients with and without neurological autoimmunity. The most frequent among patients with neurological manifestations were: anti-neuronal nuclear antibody-type 1, voltage-gated calcium channel (VGCC)-N-type, VGCC-P/Q-type, glutamic acid decarboxylase 65 (GAD65), SOX1, and muscle acetylcholine receptor (AChR); while the most common in patients without neurological manifestations were: GAD65, muscle-AChR, and VGCC-P/Q-type. Neither cancer stage at diagnosis nor survival correlated with neurological manifestations or autoantibody-positivity, except for shorter survival in patients with myelopathy. The only predictor of longer survival was limited-stage disease at diagnosis.
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http://dx.doi.org/10.1111/1759-7714.13009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449272PMC
April 2019

Autoimmune Encephalitis Secondary to Melanoma.

Ann Intern Med 2019 06 12;170(12):905-906. Epub 2019 Feb 12.

Mayo Clinic, Rochester, Minnesota (A.D., G.G., S.M., A.Z., E.F.W., S.E.H.).

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http://dx.doi.org/10.7326/L18-0593DOI Listing
June 2019

A mouse model of seizures in anti-N-methyl-d-aspartate receptor encephalitis.

Epilepsia 2019 03 11;60(3):452-463. Epub 2019 Feb 11.

Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia.

Objective: Seizures develop in 80% of patients with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, and these represent a major cause of morbidity and mortality. Anti-NMDAR antibodies have been linked to memory loss in encephalitis; however, their role in seizures has not been established. We determined whether anti-NMDAR antibodies from autoimmune encephalitis patients are pathogenic for seizures.

Methods: We performed continuous intracerebroventricular infusion of cerebrospinal fluid (CSF) or purified immunoglobulin (IgG) from the CSF of patients with anti-NMDAR encephalitis or polyclonal rabbit anti-NMDAR IgG, in male C57BL/6 mice. Seizure status during a 2-week treatment was assessed with video-electroencephalography. We assessed memory, anxiety-related behavior, and motor function at the end of treatment and assessed the extent of neuronal damage and gliosis in the CA1 region of hippocampus. We also performed whole-cell patch recordings from the CA1 pyramidal neurons in hippocampal slices of mice with seizures.

Results: Prolonged exposure to rabbit anti-NMDAR IgG, patient CSF, or human IgG purified from the CSF of patients with encephalitis induced seizures in 33 of 36 mice. The median number of seizures recorded in 2 weeks was 13, 39, and 35 per mouse in these groups, respectively. We observed only 18 brief nonconvulsive seizures in 11 of 29 control mice (median seizure count of 0) infused with vehicle (n = 4), normal CSF obtained from patients with noninflammatory central nervous system (CNS) conditions (n = 12), polyclonal rabbit IgG (n = 7), albumin (n = 3), and normal human IgG (n = 3). We did not observe memory deficits, anxiety-related behavior, or motor impairment measured at 2 weeks in animals treated with CSF from affected patients or rabbit IgG. Furthermore, there was no evidence of hippocampal cell loss or astrocyte proliferation in the same mice.

Significance: Our findings indicate that autoantibodies can induce seizures in anti-NMDAR encephalitis and offer a model for testing novel therapies for refractory autoimmune seizures.
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http://dx.doi.org/10.1111/epi.14662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684284PMC
March 2019

Autoimmune glial fibrillary acidic protein astrocytopathy.

Curr Opin Neurol 2019 06;32(3):452-458

Department of Neurology.

Purpose Of Review: To describe a recently characterized autoimmune, inflammatory central nervous system (CNS) disorder known as autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy.

Recent Findings: Affected patients present with symptoms of one or more of meningitis (headache and neck ache), encephalitis (delirium, tremor, seizures, or psychiatric symptoms), and myelitis (sensory symptoms and weakness). Optic disc papillitis (blurred vision) is common. CNS inflammation is evident in characteristic T1 postgadolinium enhancement of GFAP-enriched CNS regions, and lymphocytic cerebrospinal fluid (CSF) white cell count elevation. CSF is more reliable than serum for GFAP-immunoglobulin G (IgG) testing. Ovarian teratoma commonly coexists, particularly among patients with accompanying N-methyl-D-aspartate receptor or aquaporin-4 autoimmunity. Parainfectious autoimmunity is suspected in some other patients, though the culprit organism is rarely verified. Pathophysiologic relevance of T cells is underscored by neuropathology and cases of dysregulated T-cell function (HIV or checkpoint inhibitor cancer therapy). Corticosteroid-responsiveness is a hallmark of the disease. Relapses occur in approximately 20% of patients, necessitating transition to a steroid-sparing drug. Reported outcomes vary, though in the authors' experience, early and sustained intervention usually portends recovery.

Summary: Autoimmune GFAP astrocytopathy is a treatable autoimmune CNS disease diagnosable by GFAP-IgG testing in CSF. This disease presents opportunities to explore novel mechanisms of CNS autoimmunity and inflammation.
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http://dx.doi.org/10.1097/WCO.0000000000000676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522205PMC
June 2019

Posttransplant autoimmune encephalitis.

Neurol Neuroimmunol Neuroinflamm 2018 Nov 20;5(6):e497. Epub 2018 Aug 20.

Department of Neurology (D.A.C., A.S.L-C., S.J.P., A.G., A.Z., E.P.F.), Department of Laboratory Medicine and Pathology (S.J.P., E.P.F.), Department of Medicine, Divisions of Cardiology (B.A.B.), Department of Hematology (W.J.H., Y.L.), Department of Gastroenterology (J.J.P.), and Mayo Medical School (K.M.W.), Mayo Clinic, Rochester, MN.

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http://dx.doi.org/10.1212/NXI.0000000000000497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117190PMC
November 2018