ObjectiveTo evaluate plasma neurofilament light (NfL) levels in autoimmune neurologic disorders (AINDs) and autoimmune encephalitis (AE).BackgroundEach particular neural autoantibody syndrome has a different clinical phenotype, making one unifying clinical outcome measure difficult to assess. While this is a heterogeneous group of disorders, the final common pathway is likely CNS damage and inflammation. Defining a biomarker of CNS injury that is easily obtainable through a blood sample and reflects a positive treatment response would be highly advantageous in future therapeutic trials. Measurement of blood concentration of neurofilament light (NfL) chain, however, may provide a biomarker of central nervous system (CNS) injury in AE and other AINDs. Here we provide an initial evaluation of plasma NfL levels in AE as well as other AINDs during active and chronic phases of disease and demonstrate its potential utility as a minimally-invasive biomarker for AE and AINDs.Design/MethodsPatients were retrospectively identified who were enrolled in the biorepository at the Rocky Mountain MS Center at the University of Colorado, or were prospectively enrolled after initial presentation. Patients had a well-defined AIND and were followed between 2014 and 2021. NfL was tested using the Single Molecule Array (SIMOA) technology. Patients with headaches but without other significant neurologic disease were included as controls.ResultsTwenty-six plasma and 14 CSF samples of patients with AINDs, and 20 plasma control samples stored in the biorepository were evaluated. A positive correlation was found between plasma and CSF NfL levels for patients with an AIND (R2 = 0.83, p < 0.001). Elevated plasma levels of NfL were seen in patients with active AE compared to controls [geometric mean (GM) 51.4 vs. 6.4 pg/ml, p = 0.002]. Patients with chronic symptoms (>6 months since new or worsening symptoms) of AE or cerebellar ataxia (CA) showed a trend toward lower plasma NfL levels (GM 15.1 pg/ml) compared to active AE or CA. Six patients with longitudinal, prospective sampling available demonstrated a trend in decreased plasma NfL levels over time.ConclusionsOur findings support the use of plasma NfL as a potential minimally-invasive biomarker of CNS injury.

Biomarkers are needed to guide therapeutic decision making in autoimmune and paraneoplastic neurologic disorders. Here, we describe a case of paraneoplastic collapsing response-mediator protein-5 (CRMP5)-associated transverse myelitis (TM) where plasma neurofilament light (NfL) chain and glial fibrillary protein (GFAP) levels were observed over a 14-month clinical course, correlating with radiographical and clinical outcome measures in response to treatment. Blood and CSF samples obtained at diagnosis as well as 7 and 14 months into treatment. At the time of initial diagnosis, both plasma NfL (782.62 pg/ml) and GFAP (283.26 pg/ml) were significantly elevated. Initial treatment was with IV steroids and plasma exchange (PLEX) followed by neuroendocrine tumor removal, chemotherapy, and radiation. After initial improvement with chemotherapy, the patient experienced clinical worsening and transient elevation of plasma NfL (103.27 pg/ml and GFAP (211.58 pg/ml) levels. Whole body positron emission tomography PET scan did not demonstrate recurrence of malignancy. Repeat PLEX and rituximab induction resulted in improvements in patient function, neurologic exam, and plasma biomarker levels. To our knowledge, this is the first described longitudinal, prospective analysis of neuronal injury biomarkers and association of clinical treatment outcomes in CRMP5 myelitis. Our findings suggest that clinical improvement correlates with NfL and GFAP concentrations.

Background: Repository corticotrophin injection (RCI, Acthar Gel) and intravenous methylprednisolone (IVMP) improve the rate but not the extent of visual recovery following acute optic neuritis. RCI has adrenal-stimulating and melanocortin receptor-stimulating properties that may endow it with unique anti-inflammatory properties relative to IVMP. Methods: Individuals with acute optic neuritis of less than 2 weeks duration were prospectively enrolled and randomized 1:1 to receive either RCI or IVMP. Peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell plus inner plexiform layer thickness (GC + IPL) were serially evaluated by OCT. In addition, patient-reported outcomes (PROs) for changes in fatigue, mood, visual function, depression, and quality of life (QOL) were measured, and high and low contrast visual acuity were recorded. Results: Thirty-seven subjects were enrolled (19 RCI; 18 IVMP); the average time from symptom to treatment was 8.8 days. At 6 months, there was no difference in the primary outcome: loss of average pRNFL thickness in the affected eye (RCI vs IVMP: 213.1 vs 211.7 mm, P = 0.88) 6 months after randomization. Additional outcomes also showed no difference between treatment groups: 6-month attenuation of GC + IPL thickness (RCI vs IVMP: 213.8 vs 212.0 mm, P = 0.58) and frequency of pRNFL swelling at 1 month (RCI vs IVMP: 63% vs 72%, P = 0.73) and 3 months (RCI vs IVMP: 26% vs 31%, P = 0.99). Both treatments resulted in improvement in visual function and PROs. Conclusions: Treatment of acute optic neuritis with RCI or IVMP produced no clinically meaningful differences in optic nerve structure or visual function.

ObjectiveTo report a case of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor encephalitis (AMPARE) as a potential immune-mediated complication of palbociclib (a cyclin-dependent kinase 4/6 inhibitor).BackgroundMedication-induced autoimmune encephalitis is an increasingly recognized entity. To date, cases have been reported with immune checkpoint inhibitors (ICIs), typically within 3 months and while cancer is responding to immunotherapy.ResultsA 55-year-old woman with metastatic breast cancer presented with new-onset neurologic symptoms. After diagnosis and treatment in 2008, she was in remission from 2010 to 2021. In April 2021, she developed metastatic recurrence. She started palbociclib in June 2021. PET scan in August 2021 showed improved metastases without new lesions. In September 2021, she developed encephalopathy, vertical nystagmus, and ataxia. Workup revealed AMPA-R antibodies. Palbociclib was stopped, and she received steroids, IVIg, and rituximab with marked improvement in her neurologic symptoms.DiscussionAMPARE is a well-described paraneoplastic syndrome. However, it is now understood that paraneoplastic syndromes can be driven by immunomodulatory medications, namely ICIs. Although palbociclib primarily prevents tumor proliferation, emerging data suggest that it may also be immunomodulatory. Given that our patient's AMPARE developed shortly after initiation of palbociclib while her cancer was responding to therapy, we postulate that it may have been unmasked by palbociclib, similarly to what has been reported with ICIs.

No abstract

ObjectiveTo evaluate differences in concentrations of serum-based biomarkers obtained from a screened healthy control (HC) population compared to age and sex matched autoimmune and inflammatory neurologic disease (AIND) patients.BackgroundProtein markers of neuronal and glial injury have become important, minimally invasive biomarkers for understanding the impact of disease in various neurological disorders, including ongoing research into AINDs. Levels of these proteins in healthy individuals remain unclear.Design/MethodsNeurofilament light (NfL), glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), and total tau (Tau) levels in AIND and HC participants will be compared. Multiple Sclerosis (MS) patients, as inflammatory controls, will be analyzed as well. AIND and HC participant serum samples have been collected to obtain NfL, GFAP, UCH-L1, and Tau protein levels using Quanterix SR-XTM SIMOA. We plan to analyze and compare age and sex matched HC samples to AIND patients for each biomarker, ages ranging from 20-80 years old. Concentrations will be log transformed and analyzed with mixed model regression.ResultsHealthy Controls (130), AIND (255), and newly diagnosed/treatment naïve MS samples (681) have already been collected. Nineteen HC and AIND (includes NMDA, LGI1, TRIM46, CRMP5, MOG, DPPX, GABA-A, GAD-65) participants were analyzed. Preliminary results for HC show mean Nfl (10.3 pg/mL), GFAP (78.9 pg/mL), UCH-L1 (5.65 pg/mL), and Tau (0.53 pg/mL) levels, and for AIND patients mean Nfl (186.48 pg/mL), GFAP (434.92 pg/mL), UCH-L1 (71.38 pg/mL), and Tau (51.85 pg/mL) levels. While ongoing biomarker analysis will be completed with HC that are age and sex matched, the significantly higher levels in AIND patients highlights the importance of creating baseline values in HC to understand these same biomarkers in AIND patients.ConclusionsPreliminary results show NfL and GFAP levels are significantly higher in AIND patients versus HC. Baseline biomarker values are essential for understanding further research in biomarkers related to AIND.

ObjectiveTo describe the characteristics and outcomes in adult and pediatric patients diagnosed with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) at the two major referral centers in the Mountain West of the United States, a geographic area encompassing roughly 15% of the land mass of the continental US.BackgroundSince the development of commercial assays, MOGAD has become increasingly recognized as an etiologic diagnosis for several CNS demyelinating phenotypes, yet the epidemiological characteristics, relapse rates and outcomes of large populations are not well-describedDesign/MethodsA retrospective chart review for patients within the health systems at the University of Utah and the University of Colorado, and affiliated children's hospitals, was conducted. To identify MOGAD patients, we queried the ICD10 codes corresponding to demyelinating disease of CNS, neuromyelitis optic spectrum disease, optic neuritis, transverse myelitis, and acute disseminated encephalomyelitis. These patients were then cross matched against antibody testing results and existing research databases at each institution. Search dates included 1/1/2016-12/1/2021 to encompass the period of commercially available MOG IgG testing. Patients were cross referenced with a list of positive MOG IgG assays at each institution.ResultsWe describe the characteristics of over 50 patients (adults and children) with MOGAD, including age of onset, gender, symptoms at onset, associated autoimmunity, antibody titers, response to therapies and relapse rates.ConclusionsThis is a comprehensive characterization of a diverse population of pediatric and adult MOGAD patients seen at the two major referral hospitals in the Mountain West. The treatment regimens and outcomes in this population may inform approaches to current management and future clinical trials.