BACKGROUND:Serum neurofilament light chain (sNfL) has become an increasingly established biomarker for monitoring in multiple sclerosis (MS). Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a demyelinating disorder distinct from MS in terms of pathophysiology and treatment options, also presenting with demyelinating attacks that can result in permanent disability. Given its unpredictable disease course, the need for biomarkers reflective of the risk for poor clinical recovery or relapsing course is pressing. The purpose of this review is to summarize the current knowledge on sNfL levels in people with MOGAD, assess their utility for clinical practice and gain insights for future research. METHODS:Embase, MEDLINE, Scopus, and CINAHL databases were searched following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. Keywords used in the search included: (myelin oligodendrocyte glycoprotein OR MOG OR MOGAD) AND (neurofilament* OR neuro filament* OR NfL OR sNfL). This initial search generated 195 reports, 23 of which were original research articles investigating NfL levels in MOGAD patients, therefore meeting our inclusion criteria. RESULTS:422 MOGAD patients were involved across all studies. Most studies revealed higher sNfL in MOGAD patients (n = 292) than in healthy controls (n = 3,172) with one study finding higher sNfL in MOGAD only during relapse. sNfL levels during attacks were similar when comparing MOGAD (n = 94) to MS (n = 256) and MOGAD (n = 149) to APQ4+ neuromyelitis optica spectrum disorder (APQ4+ NMOSD) (n = 214). MOGAD patients with brain lesions on magnetic resonance imaging (MRI) during a recent attack (n = 69 samples) had higher sNfL levels than patients without brain lesions (n = 78 samples). Median sNfL concentration was higher following clinical attacks (n = 69 samples) than in remission (n = 83 samples) in 3/5 studies. sNfL were higher at disease onset than subsequent attacks in 2 studies (n = 133 samples). Onset sNfL levels were not predictive of the likelihood of future relapse (relapsing: n = 15, monophasic: n = 18). A positive correlation was found between sNfL levels and attack severity assessed through various disability scales (n = 202), but not with the severity of acute or residual visual acuity (n = 45 eyes), or with residual retinal thickness among subjects with the optic neuritis (ON) phenotype (n = 11 eyes). The sGFAP/sNfL ratio showed utility in discriminating MOGAD from other autoimmune demyelinating diseases in two studies (MOGAD: n = 56, APQ4+ NMOSD: n = 66, MS: n = 31). DISCUSSION:sNfL levels at presentation have limited utility in distinguishing MOGAD from other demyelinating disorders, but their combination with other biomarkers might improve their diagnostic utility. sNfL levels are higher in brain/spinal cord presentations than optic neuritis, correlating with clinical severity of these phenotypes but less so with the severity of visual outcome. Further studies should clarify the utility of sNfL as a biomarker for MOGAD, particularly in relation to long-term outcomes and imaging markers of central nervous system damage. Standardized sNfL testing parameters will improve study comparability and clinical application.

Objective: To look for the incidence and clinical characteristics of patients receiving ocrelizumab who fail to lower their CD19 cell counts. Background: Ocrelizumab is a humanized anti-CD20 monoclonal antibody used in the treatment of multiple sclerosis (MS). Due to its mostly human origin, ocrelizumab is expected to induce few neutralizing antibodies (NAbs), but there is a small risk of this happening. Ocrelizumab administration leads to a rapid and complete depletion of CD19 peripheral cells by 2 weeks and begins recovering after six months. Normal CD19 values despite infusions can indirectly correlate with the development of NAbs. High titers of NAbs can hinder the efficacy of MS treatments. Design/Methods: We conducted a retrospective study in which we searched our MS clinic database for all our patients who received at least one dose of ocrelizumab and had their CD19 population analyzed. Patients who were missing laboratory data or were receiving ocrelizumab infusions outside our clinic were excluded from the study. After selecting the patients with normal CD19 counts, we obtained their demographic, clinical, laboratory and radiological data. Results: We found 305 patients who at one point received ocrelizumab in our database. After eliminating those who did not meet the inclusion criteria, 224 patients were left. Of those 224 patients only 4 patients had consistently normal values of CD19, representing 1.7% of the ocrelizumab group. All patients had relapsing-remitting MS and 75% were male. None experienced clinical relapse or clinical progression, with MRI and serum neurofilament data to be presented. Conclusions: Even though rare, a small percentage of MS patients can fail to lower their CD19 values after starting ocrelizumab. If clinical or radiological activity of MS is seen, switching to a non-B-cell depleting therapy and requesting testing for human anti-chimeric antibodies could be a wise option. Disclosure: Dr. Saldivar has nothing to disclose. Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Actelion(Janssen/J&J). Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alexion. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BiogenIdec. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS/Celgene. Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for EMD Inc. Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi-Genzyme. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Freedman has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Actelion (Janssen/J&J). Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Atara Biotherapeutics. Dr. Freedman has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Bayer Healthcare. Dr. Freedman has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for BiogenIdec. Dr. Freedman has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Clene Nanomedicine. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for GRI Bio. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Magenta Therapeutics. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck Serono. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi Genzyme. Dr. Freedman has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Sanofi Genzyme. Dr. Freedman has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for EMD Serono. The institution of Dr. Freedman has received research support from Sanofi Genzyme. Dr. Rush has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche . Dr. Rush has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen . Dr. Rush has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen . Dr. Rush has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi . Dr. Rush has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi . Dr. Rush has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pendopharm . Dr. Rush has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi . John A. Brooks, MD has nothing to disclose.

BACKGROUND:A distal-predominant demyelinating symmetric pattern is most frequent in patients with neuropathy associated with anti-myelin-associated glycoprotein (MAG) antibodies. The literature however lacks longitudinal data to describe whether this is consistent over time.METHODS:From the Ottawa Neuromuscular Center database, we identified 23 patients with both immunoglobulin M gammopathy and anti-MAG antibodies. For median, ulnar and fibular motor conduction studies, we analyzed distal latency and amplitude, negative peak duration, terminal latency index (TLI), and conduction velocity. For median, ulnar, sural, and superficial fibular sensory conduction studies, we analyzed distal latency and amplitude. Results were compared for the earliest and the latest data sets.RESULTS:The mean time interval between the two assessment points was 6.5 years. Median and ulnar motor nerve conduction studies did not show a significant change for any of the parameters tested. There was disproportionate prolongation of median distal motor latency and reduction in TLI, compared to the ulnar nerve. Deep fibular motor conduction studies showed a marked reduction in amplitudes over time. Sensory potentials were recordable in the upper limb in less than 50% at the first study and less than 25% on the most recent study. There was an even larger attrition of recordable sural and superficial fibular sensory potentials.CONCLUSIONS:Our results highlight the stability of median and ulnar motor conduction study results over a mean observation period of 6.5 years. In contrast, lower limb motor and all sensory potentials show a marked trend toward becoming unrecordable.

Anti-GFAP astocytopathy is a rare and relatively new disease. Neuropathology has been hitherto only described in 4 cases. We report one other case, and discuss the uniqueness of the neuropathology in these cases based on a potential second case.

Background and Purpose: Elevation of total protein level in cerebrospinal fluid (CSF-TP) in diabetic patients is often disregarded by clinicians. However, existing studies on the topic have significant limitations, and therefore we aimed to explore the relationship between diabetes and CSF-TP in a large database of CSF samples. Methods: Retrospective review of all diagnostic lumbar punctures at the Ottawa Hospital between 1996-2016. Patients were excluded if they had elevated CSF cell counts, or a condition known to elevate CSF-TP. Multivariate linear regression modeling considered the effects of age, sex, and diabetes. Results: Among 6124 patients (746 with diabetes, 5378 without), mean CSF-TP did not differ significantly between groups (0.39 and 0.35 mmol/L, p = 0.2). When controlled for age and sex, there was no significant effect of diabetes on CSF-TP and no significant correlation between mean serum glucose and CSF-TP (R2 = 0.12). Conclusions: CSF-TP did not differ significantly between diabetic and non-diabetic groups, once the influence of age and sex was controlled. Elevated CSF-TP should be regarded as pathologic, even in the setting of diabetes.

[This corrects the article DOI: 10.1371/journal.pone.0231502.].

Wednesday, April 29April 14, 2020Free AccessCase Report of Autologous Hematopoietic Stem Cell Transplant in a Patient with Anti-IgLON5 Associated Encephalitis (2726)John Brooks, Pierre Bourque, Harold Atkins, Gregory Day, and Carolina RushAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.2726 Letters to the Editor

BACKGROUND:The diagnosis of anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis relies on the detection of NMDAR IgG autoantibodies in the serum or cerebrospinal fluid (CSF) of symptomatic patients. Commercial kits are available that allow NMDAR IgG autoantibodies to be measured in local laboratories. However, the performance of these tests outside of reference laboratories is unknown.OBJECTIVES:To report an unexpectedly low rate of NMDAR autoantibody detection in serum from patients with anti-NMDAR encephalitis tested using a commercially available diagnostic kit in an exemplar clinical laboratory.METHODS:Paired CSF and serum samples from seven patients with definite anti-NMDAR encephalitis were tested for NMDAR IgG autoantibodies using commercially available cell-based assays run according to manufacturer's recommendations. Rates of autoantibody detection in serum tested at our center were compared with those derived from systematic review and meta-analyses incorporating studies published during or before March 2019.RESULTS:NMDAR IgG autoantibodies were detected in the CSF of all patients tested at our clinical laboratory but not in paired serum samples. Rates of the detection were lower than those previously reported. A similar association was recognized through meta-analyses, with lower odds of NMDAR IgG autoantibody detection associated with serum testing performed in nonreference laboratories.CONCLUSIONS:Commercial kits may yield lower-than-expected rates of NMDAR IgG autoantibody detection in serum when run in exemplar clinical (nonreference) laboratories. Additional studies are needed to decipher the factors that contribute to lower-than-expected rates of serum positivity. CSF testing is recommended in patients with suspected anti-NMDAR encephalitis.

This article reports data pertaining to a worldwide web-based survey referenced in the publication “Adult CSF Total Protein: Higher upper reference limits should be considered worldwide ” (P.R. Bourque, et al., 2019). This survey was distributed to corresponding authors of the journal Neurology and the Journal of neurological sciences for the period of Jan–Dec 2017. The response rate was 36.9%. Additional results were collated through networking and national associations. There were 473 unique responses from clinical hospital laboratories in 69 countries: North America 178, South America 26, Europe 139, Africa 20, Asia 102 and Oceania 8. The upper reference limit for cerebrospinal fluid total protein ranged from 0.2 g/L to 0.8 g/L. 86.8% of the survey responses were 0.45 g/L or less. Data is presented separately for tertiary/academic and non-university/community centers.

ABSTRACT:Background:The antiquated standard reference range of 0.15–0.45 g/L for cerebrospinal fluid total protein (CSF-TP) is well entrenched in medical literature and laboratory operating procedures across the world.Methods:We conducted a web-based survey with a response rate of 34.9% through the listserv of the Canadian Neurological Sciences Federation. Additional laboratory reference data were collated by telephone interview of hospital laboratory technologists across Canada.Results:A total of 142 site responses were obtained: 64.1% from academic/tertiary hospitals and 35.9% from community hospitals. A strong majority (80.4%) of both types of institutions reported using a CSF-TP upper reference limit of 0.45 g/L or less. As a rule, no age adjustments were implemented in CSF-TP-level interpretation.Conclusions:Recent well-powered laboratory reference studies have documented CSF-TP upper reference limits that are above 0.6 g/L starting at age 50, with incremental limits partitioned by subsequent decades of age. The conventional 0.45 g/L limit could lead to false positive results. Our survey suggests there is a need to consider a wide adoption of data-driven, rather than historical, reference values.

Objective We conducted a retrospective review of patients with a diagnosis of Guillain-Barre syndrome (GBS) to assess the diagnostic impact of applying age-adjusted upper limits for CSF total protein (CSF-TP) supported by a systematic literature review. Methods Cases coded as GBS or inflammatory neuropathy for the period 2001-2016 at The Ottawa Hospital were reviewed. Cases were included if they met the Brighton criteria for GBS with a diagnostic certainty level 1 or 2 and had contemporaneous CSF-TP data. We excluded cases with CSF pleocytosis >50 and cases with Miller-Fisher syndrome. Age-adjusted reference limits were compared with conventional 0.45 and 0.6 g/L upper limits. Results One hundred thirty-eight cases met the study criteria, with a mean age of 47 years. The mean interval from symptom onset to lumbar puncture was 7.9 days, and mean CSF-TP was 1.23 g/L. There was a strong correlation between rising CSF-TP and time to lumbar puncture. Age-adjusted CSF-TP had a significantly lower sensitivity of only 45% in the first week (32% in the first 3 days) compared with 70% in the first week for the 0.45 g/L limit. All upper limits gained high sensitivity after the first week. Conclusions The low sensitivity of CSF-TP for the diagnosis of GBS is exacerbated by age-adjusted upper limits. The main role of lumbar puncture in GBS in the first week may be to help exclude other inflammatory or neoplastic etiologies of acute neuropathy. After the first week, the magnitude of the CSF-TP rise reduces the effect of different upper reference limits.

Cerebrospinal fluid total protein (CSF-TP) is measured in the diagnosis of a range of immune or infectious disorders of the nervous system. Most laboratories and the medical literature use an antiquated, age-independent upper limit of 0.45 g/L. Therefore, we performed a systematic review of reference studies in the medical literature, with the primary objective of determining the CSF total protein upper reference limit (URL). Secondary objectives were to assess the effects of age, gender, laboratory methods, and methodological quality.

Background: Disuse atrophy from immobilization is the result of decreased neural activity and muscle unloading. Methods: We studied the impact of disuse on hand intrinsic compound muscle action potentials (CMAPs) in a cohort of 39 patients with unilateral 6-week immobilization of the hand in a cast, after distal radius fracture. We excluded patients with nerve injury. We compared side-to-side CMAP characteristics at the time of cast removal and at a subsequent follow-up visit, after a mean interval of 7.8 weeks. Results: Statistically significant reductions in CMAP amplitude were noted for the abductor pollicis brevis (29.2%), abductor digiti minimi (19.0%), and first dorsal interosseus (24.9%). There was partial repair of the relative CMAP reduction at the follow-up visit (20.1%, 10.7%, and 8.7%, respectively). There was no significant change in CMAP duration. Conclusions: These results provide a framework for quantifying the degree of hand intrinsic CMAP amplitude reduction attributed to disuse.

A 43-year-old man described adolescence-onset abnormal muscle contractions. On examination, there was hypertrophy (figure) with normal power of thigh muscles but mild weakness of distal leg muscles (Medical Research Council grade 4+/5). Muscle percussion and stretching induced electrically silent slow rolling muscle contractions (video 1). He had mildly elevated creatine kinase (600 U/L). Family history was consistent with autosomal dominant rippling muscle disease.1 A heterozygous variant was documented in coding exons of the caveolin 3 gene (CAV c. 83A>T;p.Asp28Val).

Background: The cerebrospinal fluid total protein level (CSF-TP) is commonly used as a potential marker of infectious or immune disease of the CNS and PNS. Recent laboratory reference studies indicate that the antiquated single upper reference limit of 0.45 g/L commonly used by hospital laboratories and widely quoted in medical literature is a significant underestimation. Methods: We distributed worldwide a web-based survey comprised of three questions: 1. What is the CSF-TP upper limit used at your institution? 2. What is the source of this upper limit? 3. Do you adjust your upper limit according to age? Results: A total of 473 unique responses were obtained from North America (37.5%), South America (5.5%), Europe (29.4%), Africa (4%), Asia (21.6%) and Oceania (1/%). A strong preponderance (86.8%) of institutions reported an upper limit of 0.45 g/L or less. Only 4% reported making age-partitioned adjustments. Conclusions: Worldwide, a strong majority of hospital laboratories presently use an underestimation of CSF-TP upper reference value, particularly for older adults. Recent well powered laboratory reference studies support higher values with age adjustment.

BACKGROUND:Reference intervals are vital for interpretation of laboratory results. Many existing reference intervals for cerebrospinal fluid total protein (CSF-TP) are derived from old literature because of the invasive nature of sampling. The objective of this study was to determine reference intervals for CSF-TP using available patient data.METHODS:Twenty years of hospital database information was mined for previously reported CSF-TP results. Associated demographic, laboratory, and clinical diagnosis (International Classification of Diseases 9/10 codes) details were extracted. CSF-TP results included 3 different analytical platforms: the Siemens Vista 1500, Beckman Lx20, and Roche Hitachi 917. From an initial data set of 19591 samples, the following exclusion criteria were applied: incomplete data, white blood cells (WBCs) >5 × 106/L, red blood cells (RBCs) >50 × 106/L, and glucose <2.5 mmol/L. Patient charts were reviewed in detail to exclude 60 different conditions for which increases in CSF-TP would be expected. A total of 6068 samples were included; 63% of the samples were from females. Continuous reference intervals were determined using quantile regression. Age- and sex-partitioned intervals were established using the quantile regression equation and splitting age-groups into 5-year bins.RESULTS:CSF-TP showed a marked age dependence, and males had significantly higher CSF-TP than females across all ages. CSF-TP results from the 3 different instruments and manufacturers showed small (approximately 0.04 g/L), but statistically significant, differences. CSF-TP showed weak, but again statistically significant, correlation with WBC and RBC but was independent of serum total protein and creatinine.CONCLUSIONS:The age dependence of CSF-TP supports that age-partitioned reference intervals will be more accurate than a single cutoff, particularly in patients with advancing age.