Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease.

DExD/H-box RNA helicases (DDX/DHX) are encoded by a large paralogous gene family; in a subset of these human helicase genes, pathogenic variation causes neurodevelopmental disorder (NDD) traits and cancer. DHX9 encodes a BRCA1-interacting nuclear helicase regulating transcription, R-loops, and homologous recombination and exhibits the highest mutational constraint of all DDX/DHX paralogs but remains unassociated with disease traits in OMIM. Using exome sequencing and family-based rare-variant analyses, we identified 20 individuals with de novo, ultra-rare, heterozygous missense or loss-of-function (LoF) DHX9 variant alleles. Phenotypes ranged from NDDs to the distal symmetric polyneuropathy axonal Charcot-Marie-Tooth disease (CMT2). Quantitative Human Phenotype Ontology (HPO) analysis demonstrated genotype-phenotype correlations with LoF variants causing mild NDD phenotypes and nuclear localization signal (NLS) missense variants causing severe NDD. We investigated DHX9 variant-associated cellular phenotypes in human cell lines. Whereas wild-type DHX9 was restricted to the nucleus, NLS missense variants abnormally accumulated in the cytoplasm. Fibroblasts from an individual with an NLS variant also showed abnormal cytoplasmic DHX9 accumulation. CMT2-associated missense variants caused aberrant nucleolar DHX9 accumulation, a phenomenon previously associated with cellular stress. Two NDD-associated variants, p.Gly411Glu and p.Arg761Gln, altered DHX9 ATPase activity. The severe NDD-associated variant p.Arg141Gln did not affect DHX9 localization but instead increased R-loop levels and double-stranded DNA breaks. Dhx9-/- mice exhibited hypoactivity in novel environments, tremor, and sensorineural hearing loss. All together, these results establish DHX9 as a critical regulator of mammalian neurodevelopment and neuronal homeostasis.

Heat shock protein is a key therapeutic target for nerve repair in autoimmune peripheral neuropathy and severe peripheral nerve injury.

Guillain-Barré syndrome (GBS) is an autoimmune peripheral neuropathy and a common cause of neuromuscular paralysis. Preceding infection induces the production of anti-ganglioside (GD) antibodies attacking its own peripheral nerves. In severe proximal peripheral nerve injuries that require long-distance axon regeneration, motor functional recovery is virtually nonexistent. Damaged axons fail to regrow and reinnervate target muscles. In mice, regenerating axons must reach the target muscle within 35 days (critical period) to reform functional neuromuscular junctions and regain motor function. Successful functional recovery depends on the rate of axon regeneration and debris removal (Wallerian degeneration) after nerve injury. The innate-immune response of the peripheral nervous system to nerve injury such as timing and magnitude of cytokine production is crucial for Wallerian degeneration. In the current study, forced expression of human heat shock protein (hHsp) 27 completely reversed anti-GD-induced inhibitory effects on nerve repair assessed by animal behavioral assays, electrophysiology and histology studies, and the beneficial effect was validated in a second mouse line of hHsp27. The protective effect of hHsp27 on prolonged muscle denervation was examined by performing repeated sciatic nerve crushes to delay regenerating axons from reaching distal muscle from 37 days up to 55 days. Strikingly, hHsp27 was able to extend the critical period of motor functional recovery for up to 55 days and preserve the integrity of axons and mitochondria in distal nerves. Cytokine array analysis demonstrated that a number of key cytokines which are heavily involved in the early phase of innate-immune response of Wallerian degeneration, were found to be upregulated in the sciatic nerve lysates of hHsp27 Tg mice at 1 day postinjury. However, persistent hyperinflammatory mediator changes were found after chronic denervation in sciatic nerves of littermate mice, but remained unchanged in hHsp27 Tg mice. Taken together, the current study provides insight into the development of therapeutic strategies to enhance muscle receptiveness (reinnervation) by accelerating axon regeneration and Wallerian degeneration.

Subcutaneous immunoglobulin treatment for chronic inflammatory demyelinating polyneuropathy.

Immunoglobulin G (IgG) therapy is an established long-term treatment in chronic inflammatory demyelinating polyneuropathy (CIDP) that is commonly administered intravenously (IVIg). The subcutaneous immunoglobulin (SCIg) administration route is a safe and effective alternative option, approved by the United States Food and Drug Administration (FDA) in 2018, for maintenance treatment of adults with CIDP. Physicians and patients alike need to be aware of all their treatment options in order to make informed decisions and plan long-term treatment strategies. In this review, we collate the evidence for SCIg in CIDP from all published studies and discuss their implications and translation to clinical practice. We also provide guidance on the practicalities of how and when to transition patients from IVIg to SCIg and ongoing patient support. Evidence suggests that IVIg and SCIg have comparable long-term efficacy in CIDP. However, SCIg can provide additional benefits for some patients, including no requirement for venous access or premedication, and reduced frequency of systemic adverse events. Local-site reactions are more common with SCIg than IVIg, but these are mostly well-tolerated and abate with subsequent infusions. Data suggest that many patients prefer SCIg following transition from IVIg. SCIg preference may be a result of the independence and flexibility associated with self-infusion, whereas IVIg preference may be a result of familiarity and reliance on a healthcare professional for infusions. In practice, individualizing maintenance dosing based on disease behavior and determining the minimally effective IgG dose for individuals are key considerations irrespective of the administration route chosen.

Long-term neuromuscular outcomes of west nile virus infection: A clinical and electromyographic evaluation of patients with a history of infection.

INTRODUCTION: Neuromuscular clinical manifestations during acute West Nile virus (WNV) infection are well documented; however, long-term neurologic outcomes still require investigation. METHODS: We conducted a long-term follow-up study in patients with history of WNV infection. Of the 117 patients who participated in neurologic and neurocognitive evaluations, 30 were referred for neuromuscular and electrodiagnostic evaluation based on abnormal findings. RESULTS: We found that 33% of these patients (10 of 30) showed abnormalities on nerve conduction and/or needle electromyography due to primary or secondary outcomes of WNV infection. Most common electrodiagnostic findings and causes of long-term disability were related to anterior horn cell poliomyelitis (WNV poliomyelitis). Electrical data on these patient populations were similar to those observed in chronic poliomyelitis. DISCUSSION: With more than 16,000 cases of WNV neuroinvasive disease reported across the USA since 1999, understanding clinical outcomes from infection will provide a resource for physicians managing long-term care of these patients. Muscle Nerve 57: 77-82, 2018.

Anti-Ganglioside Antibodies Induce Nodal and Axonal Injury via Fcγ Receptor-Mediated Inflammation.

Guillain-Barré syndrome (GBS) is a postinfectious autoimmune neuropathy and anti-ganglioside antibodies (Abs) are strongly associated with this disorder. Several studies have implied that specific anti-ganglioside Abs induce neuropathy in patients with axonal forms of GBS. To study the mechanisms of anti-ganglioside Abs-induced neuropathy, we established a new passive transfer mouse model by L5 spinal nerve transection (L5SNT; modified Chung's model) and systemic administration of anti-ganglioside Abs. L5SNT causes degeneration of a small proportion of fibers that constitute sciatic nerve and its branches, but importantly breaks the blood-nerve barrier, which allows access to circulating Abs and inflammatory cells. Our studies indicate that, in this mouse model, anti-ganglioside Abs induce sequential nodal and axonal injury of intact myelinated nerve fibers, recapitulating pathologic features of human disease. Notably, our results showed that immune complex formation and the activating Fc gamma receptors (FcγRs) were involved in the anti-ganglioside Abs-mediated nodal and axonal injury in this model. These studies provide new evidence that the activating FcγRs-mediated inflammation plays a critical role in anti-ganglioside Abs-induced neuropathy (injury to intact nerve fibers) in GBS.

Cost analysis of tonsillectomy in children using medicaid data.

OBJECTIVE: To evaluate the cost-effectiveness of adenotonsillectomy (T&A) for adenotonsillar hypertrophy and recurrent tonsillitis through the use of Missouri Medicaid data. STUDY DESIGN: Children ages 2-16 years who had a diagnosis of adenotonsillar hypertrophy (based on medical claim codes) in 2006 (n = 4276) were included in this population-based study. The main outcome was direct total costs paid by Medicaid. Costs 2 years before and after T&A were compared in children who underwent surgical intervention with those who did not as well as costs comparison pre- and post-T&A. Wilcoxon rank-sum or Wilcoxon Signed-rank test was used for costs comparisons. RESULTS: Children with adenotonsillar hypertrophy who underwent T&A were significantly less likely to be African American. They had more adenotonsillar infections before undergoing T&A and greater total costs (median costs $2313 vs. $1945; P = .009). The median costs were $1228 pre-T&A, compared with $823 post-T&A (P < .0001). This reduction in costs of $405 (33%) compares with a median cost of the procedure of $1088. The reduction in costs was mostly because of less antibiotic use and outpatient visits. CONCLUSIONS: African American children have fewer T&A procedures for adenotonsillar hypertrophy than white children, which represents an unexplained racial disparity. Children with adenotonsillar hypertrophy who underwent T&A compared with those who did not had more adenotonsillar infections and greater health care costs. T&A leads to a reduction in costs that, after 2 years, is 37% of the costs of the procedure. Future studies should examine the effects of demographics, obesity, and disease severity on health care costs in children with adenotonsillar hypertrophy.

High resolution diffusion tensor imaging of human nerves in forearm.

PURPOSE: To implement high resolution diffusion tensor imaging (DTI) for visualization and quantification of peripheral nerves in human forearm. MATERIALS AND METHODS: This HIPAA-compliant study was approved by our Institutional Review Board and written informed consent was obtained from all the study participants. Images were acquired with T1 -and T2 -weighted turbo spin echo with/without fat saturation, short tau inversion recovery (STIR). In addition, high spatial resolution (1.0 × 1.0 × 3.0 mm(3) ) DTI sequence was optimized for clearly visualizing ulnar, superficial radial and median nerves in the forearm. Maps of the DTI derived indices, fractional anisotropy (FA), mean diffusivity (MD), longitudinal diffusivity (λ// ) and radial diffusivity (λ⊥ ) were generated. RESULTS: For the first time, the three peripheral nerves, ulnar, superficial radial, and median, were visualized unequivocally on high resolution DTI-derived maps. DTI delineated the forearm nerves more clearly than other sequences. Significant differences in the DTI-derived measures, FA, MD, λ// and λ⊥ , were observed among the three nerves. A strong correlation between the nerve size derived from FA map and T2 -weighted images was observed. CONCLUSION: High spatial resolution DTI is superior in identifying and quantifying the median, ulnar, and superficial radial nerves in human forearm. Consistent visualization of small nerves and nerve branches is possible with high spatial resolution DTI. These normative data could potentially help in identifying pathology in diseased nerves. J. Magn. Reson. Imaging 2014;39:1374-1383. © 2013 Wiley Periodicals, Inc.

Sural sparing pattern discriminates Guillain-Barré syndrome from its mimics.

INTRODUCTION: Electrodiagnostic features of demyelination are essential for establishing the diagnosis in demyelinating subtypes of Guillain-Barré syndrome (GBS), but they may also occur in disorders that mimic GBS clinically. Information about their frequency in GBS mimics is sparse. METHODS: Evaluation of electrodiagnostic features from 38 patients with suspected GBS in whom the diagnosis was later refuted (GBS mimics). Their diagnostic accuracy was analyzed by comparison with nerve conduction studies (NCS) from 73 confirmed GBS patients. RESULTS: Disorders that mimicked GBS clinically at the time of hospital admission included other inflammatory, metabolic, toxic, or infectious neuropathies and spinal cord disorders. The sural sparing pattern was the most specific electrodiagnostic feature for demyelinating GBS. CONCLUSIONS: Common electrodiagnostic abnormalities in early demyelinating GBS do not usually exclude other rare differential diagnoses. An exception to this is the sural sparing pattern described here, which strongly supports the diagnosis of demyelinating GBS.

Blockade of Rho-associated kinase prevents inhibition of axon regeneration of peripheral nerves induced by anti-ganglioside antibodies.

Anti-ganglioside antibodies are associated with delayed/poor clinical recovery in Guillain-Barrè syndrome, mostly related to halted axon regeneration. Cross-linking of cell surface gangliosides by anti-ganglioside antibodies triggers inhibition of nerve repair in in vitro and in vivo paradigms of axon regeneration. These effects involve the activation of the small GTPase RhoA/ROCK signaling pathways, which negatively modulate growth cone cytoskeleton, similarly to well stablished inhibitors of axon regeneration described so far. The aim of this work was to perform a proof of concept study to demonstrate the effectiveness of Y-27632, a selective pharmacological inhibitor of ROCK, in a mouse model of axon regeneration of peripheral nerves, where the passive immunization with a monoclonal antibody targeting gangliosides GD1a and GT1b was previously reported to exert a potent inhibitory effect on regeneration of both myelinated and unmyelinated fibers. Our results demonstrate a differential sensitivity of myelinated and unmyelinated axons to the pro-regenerative effect of Y-27632. Treatment with a total dosage of 9 mg/kg of Y-27632 resulted in a complete prevention of anti-GD1a/GT1b monoclonal antibody-mediated inhibition of axon regeneration of unmyelinated fibers to skin and the functional recovery of mechanical cutaneous sensitivity. In contrast, the same dose showed toxic effects on the regeneration of myelinated fibers. Interestingly, scale down of the dosage of Y-27632 to 5 mg/kg resulted in a significant although not complete recovery of regenerated myelinated axons exposed to anti-GD1a/GT1b monoclonal antibody in the absence of toxicity in animals exposed to only Y-27632. Overall, these findings confirm the in vivo participation of RhoA/ROCK signaling pathways in the molecular mechanisms associated with the inhibition of axon regeneration induced by anti-GD1a/GT1b monoclonal antibody. Our findings open the possibility of therapeutic pharmacological intervention targeting RhoA/Rock pathway in immune neuropathies associated with the presence of anti-ganglioside antibodies and delayed or incomplete clinical recovery after injury in the peripheral nervous system.

A National Cross-Sectional Survey of EMG Physician Volume.

Background and Objectives: This study presents results from a survey of physicians performing electrodiagnostic studies to assess average volume. We also assessed how different factors (trainees, technologists, age of the physician, and case complexity) affected volume. Productivity is an important factor for physicians across practice settings. However, unlike evaluation and management services for neurologists, there are no published data for benchmarks of average volume of electrodiagnostic studies. Methods: A 34-question survey was designed collecting information on demographics, electrodiagnostic study volume, technologists, trainees, referrals, and case complexity. The anonymous survey was disseminated through a QR code or hyperlink to multiple online neurology, physical medicine and rehabilitation, electromyography, and neuromuscular forums. The primary outcome was EMG volume including number of EMGs per half-day and EMG volume per year. We conducted bivariate association analysis between primary outcomes and respondent characteristics using the Pearson χ2 test. Multivariable regression models determined factors associated with each of our outcome variables. Results: A total of 201 respondents initiated the survey. 71% were certified in adult neurology, 19.6% in physical medicine and rehabilitation, and 2.7% in pediatric neurology. 37.5% practiced in academic medicine. The remaining respondents were from private practice, group, solo, hospital employed, or other. 83% of respondents allotted a dedicated half-day to performing EMGs. The median number of EMGs scheduled during a half-day was within 3-4 (45%). 30% and 7% scheduled 5-6 or more than 7 patients per half-day, respectively. The median number of EMGs performed per year was within 251-500 (37%). Discussion: This national, cross-sectional survey evaluates average metrics of EMG volume. Our survey showed that the median number of EMGs annually lies between 251 and 500 studies (37%). In addition, for those respondents who allotted a dedicated half-day to performing EMGs, the median number of EMG studies scheduled per half-day lies between 3 and 4 studies (45%). In multivariate analysis, respondent characteristics of age of the physician (older than 45), working with nerve conduction technologists, and holding the position of EMG director were associated with increased EMG volume.

Rejuvenating fecal microbiota transplant enhances peripheral nerve repair in aged mice by modulating endoneurial inflammation.

Peripheral nerve injury (PNI) resulting from trauma or neuropathies can cause significant disability, and its prognosis deteriorates with age. Emerging evidence suggests that gut dysbiosis and reduced fecal short-chain fatty acids (SCFAs) contribute to an age-related systemic hyperinflammation (inflammaging), which hinders nerve recovery after injury. This study thus aimed to evaluate the pro-regenerative effects of a rejuvenating fecal microbiota transplant (FMT) in a preclinical PNI model using aged mice. Aged C57BL/6 mice underwent bilateral crush injuries to their sciatic nerves. Subsequently, they either received FMT from young donors at three and four days after the injury or retained their aged gut microbiota. We analyzed gut microbiome composition and SCFA concentrations in fecal samples. The integrity of the ileac mucosal barrier was assessed by immunofluorescence staining of Claudin-1. Flow cytometry was utilized to examine immune cells and cytokine production in the ileum, spleen, and sciatic nerve. Various assessments, including behavioural tests, electrophysiological studies, and morphometrical analyses, were conducted to evaluate peripheral nerve function and repair following injury. Rejuvenating FMT reversed age-related gut dysbiosis by increasing Actinobacteria, especially Bifidobacteriales genera. This intervention also led to an elevation of gut SCFA levels and mitigated age-related ileac mucosal leakiness in aged recipients. Additionally, it augmented the number of T-helper 2 (Th2) and regulatory T (Treg) cells in the ileum and spleen, with the majority being positive for anti-inflammatory interleukin-10 (IL-10). In sciatic nerves, rejuvenating FMT resulted in increased M2 macrophage counts and a higher IL-10 production by IL-10+TNF-α- M2 macrophage subsets. Ultimately, restoring a youthful gut microbiome in aged mice led to improved nerve repair and enhanced functional recovery after PNI. Considering that FMT is already a clinically available technique, exploring novel translational strategies targeting the gut microbiome to enhance nerve repair in the elderly seems promising and warrants further evaluation.

Tumor necrosis factor α receptor 1A transduces the inhibitory effect on axon regeneration triggered by IgG anti-ganglioside GD1a antibodies.

Anti-ganglioside antibodies (anti-Gg Abs) have been linked to delayed/poor clinical recovery in both axonal and demyelinating forms of Guillain-Barrè Syndrome (GBS). In many instances, the incomplete recovery is attributed to the peripheral nervous system's failure to regenerate. The cross-linking of cell surface gangliosides by anti-Gg Abs triggers inhibition of nerve repair in both in vitro and in vivo axon regeneration paradigms. This mechanism involves the activation of the small GTPase RhoA, which negatively modulates the growth cone cytoskeleton. At present, the identity/es of the receptor/s responsible for transducing the signal that ultimately leads to RhoA activation remains poorly understood. The aim of this work was to identify the transducer molecule responsible for the inhibitory effect of anti-Gg Abs on nerve repair. Putative candidate molecules were identified through proteomic mass spectrometry of ganglioside affinity-captured proteins from rat cerebellar granule neurons (Prendergast et al., 2014). These candidates were evaluated using an in vitro model of neurite outgrowth with primary cultured dorsal root ganglion neurons (DRGn) and an in vivo model of axon regeneration. Using an shRNA-strategy to silence putative candidates on DRGn, we identified tumor necrosis factor receptor 1A protein (TNFR1A) as a transducer molecule for the inhibitory effect on neurite outgrowth from rat/mouse DRGn cultures of a well characterized mAb targeting the related gangliosides GD1a and GT1b. Interestingly, lack of TNFr1A expression on DRGn abolished the inhibitory effect on neurite outgrowth caused by anti-GD1a but not anti-GT1b specific mAbs, suggesting specificity of GD1a/transducer signaling. Similar results were obtained using primary DRGn cultures from TNFR1a-null mice, which did not activate RhoA after exposure to anti-GD1a mAbs. Generation of single point mutants at the stalk region of TNFR1A identified a critical amino acid for transducing GD1a signaling, suggesting a direct interaction. Finally, passive immunization with an anti-GD1a/GT1b mAb in an in vivo model of axon regeneration exhibited reduced inhibitory activity in TNFR1a-null mice compared to wild type mice. In conclusion, these findings identify TNFR1A as a novel transducer receptor for the inhibitory effect exerted by anti-GD1a Abs on nerve repair, representing a significant step forward toward understanding the factors contributing to poor clinical recovery in GBS associated with anti-Gg Abs.

Peripheral neuropathy: assessment of proximal nerve integrity by diffusion tensor imaging.

INTRODUCTION: We investigated the utility of diffusion tensor imaging (DTI) for detecting neuropathic changes in proximal nerve segments in patients with peripheral neuropathy. METHODS: Twenty-one individuals with (n = 11) and without (n = 10) peripheral neuropathy underwent DTI of a defined sciatic nerve segment. Patients and controls were evaluated by clinical examination and nerve conduction studies at baseline and 6 months after the initial DTI scan. RESULTS: The mean fractional anisotropy (FA) value was significantly lower in sciatic nerves from patients with peripheral neuropathy as compared with controls. Sciatic nerve FA values correlated with clinical disability scores and electrophysiological parameters of axonal damage at baseline and 6 months after MRI scan. CONCLUSIONS: DTI-derived FA values are a sensitive measure to discriminate healthy from functionally impaired human sciatic nerve segments. DTI of proximal nerve segments may be useful for estimating the proximal axonal degeneration burden in patients with peripheral neuropathies.

Anti-ganglioside antibody-mediated activation of RhoA induces inhibition of neurite outgrowth.

Anti-ganglioside antibodies (Abs) are strongly associated with axonal forms of Guillain Barré syndrome (GBS). Some studies indicate that these Abs, including those with GD1a reactivity, are associated with poor prognosis and/or incomplete recovery. We recently demonstrated that a disease-relevant anti-ganglioside Ab with GD1a reactivity inhibits axon regeneration after PNS injury in an animal model (Lehmann et al., 2007). An implication of these findings is that anti-GD1a Abs can mediate inhibition of axon regeneration and limit recovery in some patients with GBS. The downstream inhibitory intracellular signaling that mediates anti-ganglioside Ab-induced axon inhibition remains unclear. In the current study, we show that disease-relevant and GBS patient's anti-ganglioside Abs can inhibit neurite outgrowth in dissociated primary neuronal cultures. Activation of small GTPase RhoA and its key downstream effector Rho kinase (ROCK) are critical mediators of growth cone and neurite outgrowth inhibition. Therefore, we examined the role of these intracellular signaling molecules in our primary neuronal cultures by molecular and pharmacologic approaches. Our results show that the Ab-mediated inhibition of neurite outgrowth involves the activation of RhoA and ROCK pathway and this activation is through the engagement of specific cell-surface gangliosides by Abs. In summary, these studies directly link patient autoantibodies to an intracellular inhibitory signaling pathway involved in anti-ganglioside Ab-mediated inhibition of neurite outgrowth.

Diffusion tensor imaging of forearm nerves in humans.

PURPOSE: To implement a diffusion tensor imaging (DTI) protocol for visualization of peripheral nerves in human forearm. MATERIALS AND METHODS: This Health Insurance Portability and Accountability Act (HIPAA)-compliant study was approved by our Institutional Review Board and written informed consent was obtained from 10 healthy participants. T(1) - and T(2) -weighted turbo spin echo with fat saturation, short tau inversion recovery (STIR), and DTI sequences with 21 diffusion-encoding directions were implemented to acquire images of the forearm nerves with an 8 channel knee coil on a 3T MRI scanner. Identification of the nerves was based on T(1) -weighted, T(2) -weighted, STIR, and DTI-derived fractional anisotropy (FA) images. Maps of the DTI-derived indices, FA, mean diffusivity (MD), longitudinal diffusivity (λ(//) ), and radial diffusivity (λ(⟂) ) along the length of the nerves were generated. RESULTS: DTI-derived maps delineated the forearm nerves more clearly than images acquired with other sequences. Only ulnar and median nerves were clearly visualized on the DTI-derived FA maps. No significant differences were observed between the left and right forearms in any of the DTI-derived measures. Significant variation in the DTI measures was observed along the length of the nerve. Significant differences in the DTI measures were also observed between the median and ulnar nerves. CONCLUSION: DTI is superior in visualizing the median and ulnar nerves in the human forearm. The normative data could potentially help distinguish normal from diseased nerves.

Behavioral, electrophysiological, and histopathological characterization of a severe murine chronic demyelinating polyneuritis model.

The objective of this study was to define the behavioral, electrophysiological, and morphological characteristics of spontaneous autoimmune peripheral polyneuropathy (SAPP) in female B7-2 deficient non-obese diabetic (NOD) mice. A cohort of 77 female B7-2 deficient and 31 wild-type control NOD mice were studied from 18 to 40 weeks of age. At pre-defined time points, the dorsal caudal tail and sciatic motor nerve conduction studies (MNCS) were performed. Sciatic nerves were harvested for morphological evaluation. SAPP mice showed slowly progressive severe weakness in hind and forelimbs without significant recovery after 30 weeks of age. MNCS showed progressive reduction in mean compound motor action potential amplitudes and conduction velocities, and increase in mean total waveform duration from 24 to 27 weeks of age, peaking between 32 and 35 weeks of age. Toluidine blue-stained, semi-thin plastic-embedded sections demonstrated focal demyelination associated with mononuclear cell infiltration early in the disease course, with progressively diffuse demyelination and axonal loss associated with more intense mononuclear infiltration at peak severity. Immunohistochemistry confirmed macrophage-predominant inflammation. This study verifies SAPP as a progressive, unremitting chronic inflammatory demyelinating polyneuropathy with axonal loss.

COVID-19 Outcomes in Myasthenia Gravis Patients: Analysis From Electronic Health Records in the United States.

Background: Myasthenia gravis (MG) is an autoimmune, neuromuscular condition and patients with MG are vulnerable due to immunosuppressant use and disease manifestations of dyspnea and dysphagia during the coronavirus disease 2019 (COVID-19) pandemic. Methods: We conducted a retrospective cohort study using the Optum® de-identified COVID-19 Electronic Health Record (EHR) dataset. Primary outcomes, such as hospitalization, ventilator use, intensive care unit (ICU) admission, and death in COVID-19 patients with MG, were compared with those of COVID-19 patients without MG: the subgroups of non-MG included those with rheumatoid arthritis (RA), systemic lupus (SLE), and multiple sclerosis (MS). We further analyzed factors affecting mortality, such as age, race/ethnicity, comorbidities, and MG treatments. Results: Among 421,086 individuals with COVID-19, there were 377 patients with MG, 7,362 patients with RA, 1,323 patients with SLE, 1,518 patients with MS, and 410,506 patients without MG. Patients with MG were older and had more comorbidities compared with non-MG patients and had the highest rates of hospitalization (38.5%), ICU admission (12.7%), ventilator use (3.7%), and mortality (10.6%) compared with all other groups. After adjusting for risk factors, patients with MG had increased risks for hospitalization and ICU compared with patients with non-MG and with RA but had risks similar to patients with SLE and with MS. The adjusted risk for ventilator use was similar across all groups, but the risk for mortality in patients with MG was lower compared with the SLE and MS groups. Among patients with MG, age over 75 years and dysphagia were predictors for increased COVID-19 mortality, but the recent MG treatment was not associated with COVID-19 mortality. Conclusions: COVID-19 patients with MG are more likely to be admitted to the hospital and require ICU care. Older age and patients with dysphagia had an increased risk of mortality.

Passive transfer of IgG anti-GM1 antibodies impairs peripheral nerve repair.

Anti-GM1 antibodies are present in some patients with autoimmune neurological disorders. These antibodies are most frequently associated with acute immune neuropathy called Guillain-Barré syndrome (GBS). Some clinical studies associate the presence of these antibodies with poor recovery in GBS. The patients with incomplete recovery have failure of nerve repair, particularly axon regeneration. Our previous work indicates that monoclonal antibodies can inhibit axon regeneration by engaging cell surface gangliosides (Lehmann et al., 2007). We asked whether passive transfer of human anti-GM1 antibodies from patients with GBS modulate axon regeneration in an animal model. Human anti-GM1 antibodies were compared with other GM1 ligands, cholera toxin B subunit and a monoclonal anti-GM1 antibody. Our results show that patient derived anti-GM1 antibodies and cholera toxin beta subunit impair axon regeneration/repair after PNS injury in mice. Comparative studies indicated that the antibody/ligand-mediated inhibition of axon regeneration is dependent on antibody/ligand characteristics such as affinity-avidity and fine specificity. These data indicate that circulating immune effectors such as human autoantibodies, which are exogenous to the nervous system, can modulate axon regeneration/nerve repair in autoimmune neurological disorders such as GBS.

Precision Intravenous Immunoglobulin Dosing and Clinical Outcomes: A Retrospective Chart Review.

OBJECTIVES: Intravenous immunoglobulin (IVIg) is used for treatment of acute neurologic conditions such as Guillain-Barre syndrome, chronic inflammatory demyelinating polyradiculoneuropathy relapse, and myasthenia gravis exacerbation. Precision dosing (adjusted or ideal body weight) is proposed to conserve IVIg. There have been no published studies comparing clinical outcomes in traditional dosing (actual body weight) with precision dosing. In 2014, our institution began dosing patients with precision dosing. This decision was largely performed by administration rather than physicians' preference. We sought to analyze our retrospective data to understand the change in dosing methods with neurologic outcomes. METHODS: We performed a retrospective review of all patients hospitalized at a single center who received IVIg for myasthenia gravis, Guillain-Barre syndrome, and chronic inflammatory demyelinating polyradiculoneuropathy from January 2010 to October 2017. We collected baseline information and clinical outcomes including mortality, readmission, need for second rescue treatment, length of stay, discharge disposition, treatment-related adverse events, and modified research council posttreatment sum score. RESULTS: Length of stay was significantly shorter with precision dosing. There was no statistically significant difference in discharge disposition, readmission, rescue treatment, or modified research council posttreatment sum score with precision dosing. CONCLUSION: Precision dosing did not adversely affect short-term neurologic outcomes.