Expanding our understanding of Guillain-Barré syndrome: Recent advances and clinical implications.

Guillain-Barré syndrome (GBS) is a rare yet potentially life-threatening disorder of the peripheral nervous system (PNS), characterized by substantial clinical heterogeneity. Although classified as an autoimmune disease, the immune mechanisms underpinning distinct GBS subtypes remain largely elusive. Traditionally considered primarily antibody-mediated, the pathophysiology of GBS lacks clarity, posing challenges in the development of targeted and effective treatments. Nevertheless, recent investigations have substantially expanded our understanding of the disease, revealing an involvement of autoreactive T cell immunity in a major subtype of GBS patients and opening new biomedical perspectives. This review highlights these discoveries and offers a comprehensive overview of current knowledge about GBS, including ongoing challenges in disease management.

Chronic Pain in Patients with Spinal Muscular Atrophy in Switzerland: A Query to the Spinal Muscular Atrophy Registry.

Background and Objectives: Chronic pain is a common symptom in various types of neuromuscular disorders. However, for patients with spinal muscular atrophy (SMA), the literature regarding chronic pain is scarce. Thus, this study assessed the prevalence of chronic pain in children, adolescents, and adults with SMA and investigated the influence of clinical characteristics on chronic pain. Materials and Methods: This study used data from 141 patients, which were collected by the Swiss Registry for Neuromuscular Disorders. Extracted data included information on pain (present yes/no, pain location, and pain medication) and clinical characteristics, such as SMA type, motor function, wheelchair use, scoliosis, and contractures. Results: The analyses revealed that the highest prevalence of chronic pain was observed in adolescents with 62%, followed by adults with 48%, children (6-12 years) with 39%, and children < 6 years with 10%. The legs, back, and hips were most frequently reported as pain locations. Sex (females), age (adolescents), and the presence of contractures and scoliosis (with surgery) were factors that were associated with chronic pain. Conclusions: These findings contribute to a better understanding of pain in SMA, shedding light on its prevalence and characteristics in different age groups, which underscores the importance of assessing and managing pain in patients with SMA.

Accuracy of Repetitive Ocular Vestibular-Evoked Myogenic Potentials to Diagnose Myasthenia Gravis in Patients With Ptosis or Diplopia.

BACKGROUND AND OBJECTIVES: We developed repetitive ocular vestibular-evoked myogenic potentials (roVEMP) as an electrophysiologic test that allows us to elicit the characteristic decrement of extraocular muscles in patients with ocular myasthenia gravis (OMG). Case-control studies demonstrated that roVEMP reliably differentiates patients with OMG from healthy controls. We now aimed to evaluate the diagnostic accuracy of roVEMP for OMG diagnosis in patients with ptosis and/or diplopia. METHODS: In this blinded prospective diagnostic accuracy trial, we compared roVEMP in 89 consecutive patients presenting with ptosis and/or diplopia suspicious of OMG with a multimodal diagnostic approach, including clinical examination, antibodies, edrophonium testing, repetitive nerve stimulation of accessory and facial nerves, and single-fiber EMG (SFEMG). We calculated the roVEMP decrement as the ratio between the mean of the first 2 responses compared with the mean of the sixth-ninth responses in the train and used cutoff of >9% (unilateral decrement) in a 30 Hz stimulation paradigm. RESULTS: Following a complete diagnostic work-up, 39 patients (44%) were diagnosed with ocular MG, while 50 patients (56%) had various other neuro-ophthalmologic conditions, but not MG (non-MG). roVEMP yielded 88.2% sensitivity, 30.2% specificity, 50% positive predictive value (PPV), and 76.5% negative predictive value (NPV). For comparison, SFEMG resulted in 75% sensitivity, 56% specificity, 55.1% PPV, and 75.7% NPV. All other diagnostic tests (except for the ice pack test) also yielded significantly higher positive results in patients with MG compared with non-MG. DISCUSSION: The study revealed a high sensitivity of 88.2% for roVEMP in OMG, but specificity and PPV were too low to allow for the OMG diagnosis as a single test. Thus, differentiating ocular MG from other neuro-ophthalmologic conditions remains challenging, and the highest diagnostic accuracy is still obtained by a multimodal approach. In this study, roVEMP can complement the diagnostic armamentarium for the diagnosis of MG. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with diplopia and ptosis, roVEMP alone does not accurately distinguish MG from non-MG disorders. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov: NCT03049956.

HLA-DQB1*05 subtypes and not DRB1*10:01 mediates risk in anti-IgLON5 disease.

Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement and bulbar-associated dysfunction. The presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01∼DQB1*05:01, supports an autoimmune basis. In this study, a multicentric human leukocyte antigen (HLA) study of 87 anti-IgLON5 patients revealed a stronger association with HLA-DQ than HLA-DR. Specifically, we identified a predisposing rank-wise association with HLA-DQA1*01:05∼DQB1*05:01, HLA-DQA1*01:01∼DQB1*05:01 and HLA-DQA1*01:04∼DQB1*05:03 in 85% of patients. HLA sequences and binding cores for these three DQ heterodimers were similar, unlike those of linked DRB1 alleles, supporting a causal link to HLA-DQ. This association was further reflected in an increasingly later age of onset across each genotype group, with a delay of up to 11 years, while HLA-DQ-dosage dependent effects were also suggested by reduced risk in the presence of non-predisposing DQ1 alleles. The functional relevance of the observed HLA-DQ molecules was studied with competition binding assays. These proof-of-concept experiments revealed preferential binding of IgLON5 in a post-translationally modified, but not native, state to all three risk-associated HLA-DQ receptors. Further, a deamidated peptide from the Ig2-domain of IgLON5 activated T cells in two patients, compared with one control carrying HLA-DQA1*01:05∼DQB1*05:01. Taken together, these data support a HLA-DQ-mediated T-cell response to IgLON5 as a potentially key step in the initiation of autoimmunity in this disease.

Neuropathies related to hepatitis E virus infection: A prospective, matched case-control study.

BACKGROUND: Acute hepatitis E virus (HEV) infection has recently emerged as a potential trigger for acute dysimmune neuropathies, but prospective controlled studies are lacking. AIMS: To compare the frequency of concomitant acute HEV infection in patients with neuralgic amyotrophy (NA), Guillain-Barré syndrome (GBS), and Bell's palsy with a matched control population. METHODS: Swiss multicenter, prospective, observational, matched case-control study over 3 years (September 2019-October 2022). Neurological cases with NA, GBS, or Bell's palsy were recruited within 1 month of disease onset. Healthy controls were matched for age, sex, geographical location, and timing of blood collection. Diagnostic criteria for acute hepatitis E were reactive serum anti-HEV IgM and IgG assays (ELISA test) and/or HEV RNA detection in serum by real-time polymerase chain reaction (RT-PCR). RT-PCR was performed on sera to confirm IgM positivity. RESULTS: We included 180 patients (59 GBS, 51 NA, 70 Bell's palsy cases) and corresponding matched controls (blood donors) with median age 51 years for both groups and equal gender distribution. Six IgM+ cases were detected in the NA, two in the GBS, and none in the Bell's palsy group. Two controls were anti-HEV IgM-positive. At disease onset, most cases with acute HEV infection had increased liver enzymes. A moderate association (p = 0.027, Fisher's exact test; Cramér's V = -0.25) was observed only between acute HEV infection and NA. CONCLUSION: This prospective observational study suggests an association between concomitant acute HEV infection and NA, but not with GBS or Bell's palsy.

B cell depletion attenuates CD27 signaling of T helper cells in multiple sclerosis.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system. Whereas T cells are likely the main drivers of disease development, the striking efficacy of B cell-depleting therapies (BCDTs) underscore B cells' involvement in disease progression. How B cells contribute to multiple sclerosis (MS) pathogenesis-and consequently the precise mechanism of action of BCDTs-remains elusive. Here, we analyze the impact of BCDTs on the immune landscape in patients with MS using high-dimensional single-cell immunophenotyping. Algorithm-guided analysis reveals a decrease in circulating T follicular helper-like (Tfh-like) cells alongside increases in CD27 expression in memory T helper cells and Tfh-like cells. Elevated CD27 indicates disrupted CD27/CD70 signaling, as sustained CD27 activation in T cells leads to its cleavage. Immunohistological analysis shows CD70-expressing B cells at MS lesion sites. These results suggest that the efficacy of BCDTs may partly hinge upon the disruption of Th cell and B cell interactions.

Guideline for the management of myasthenic syndromes.

Myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and congenital myasthenic syndromes (CMS) represent an etiologically heterogeneous group of (very) rare chronic diseases. MG and LEMS have an autoimmune-mediated etiology, while CMS are genetic disorders. A (strain dependent) muscle weakness due to neuromuscular transmission disorder is a common feature. Generalized MG requires increasingly differentiated therapeutic strategies that consider the enormous therapeutic developments of recent years. To include the newest therapy recommendations, a comprehensive update of the available German-language guideline 'Diagnostics and therapy of myasthenic syndromes' has been published by the German Neurological society with the aid of an interdisciplinary expert panel. This paper is an adapted translation of the updated and partly newly developed treatment guideline. It defines the rapid achievement of complete disease control in myasthenic patients as a central treatment goal. The use of standard therapies, as well as modern immunotherapeutics, is subject to a staged regimen that takes into account autoantibody status and disease activity. With the advent of modern, fast-acting immunomodulators, disease activity assessment has become pivotal and requires evaluation of the clinical course, including severity and required therapies. Applying MG-specific scores and classifications such as Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Foundation of America allows differentiation between mild/moderate and (highly) active (including refractory) disease. Therapy decisions must consider age, thymic pathology, antibody status, and disease activity. Glucocorticosteroids and the classical immunosuppressants (primarily azathioprine) are the basic immunotherapeutics to treat mild/moderate to (highly) active generalized MG/young MG and ocular MG. Thymectomy is indicated as a treatment for thymoma-associated MG and generalized MG with acetylcholine receptor antibody (AChR-Ab)-positive status. In (highly) active generalized MG, complement inhibitors (currently eculizumab and ravulizumab) or neonatal Fc receptor modulators (currently efgartigimod) are recommended for AChR-Ab-positive status and rituximab for muscle-specific receptor tyrosine kinase (MuSK)-Ab-positive status. Specific treatment for myasthenic crises requires plasmapheresis, immunoadsorption, or IVIG. Specific aspects of ocular, juvenile, and congenital myasthenia are highlighted. The guideline will be further developed based on new study results for other immunomodulators and biomarkers that aid the accurate measurement of disease activity.

IL-12 sensing in neurons induces neuroprotective CNS tissue adaptation and attenuates neuroinflammation in mice.

Interleukin-12 (IL-12) is a potent driver of type 1 immunity. Paradoxically, in autoimmune conditions, including of the CNS, IL-12 reduces inflammation. The underlying mechanism behind these opposing properties and the involved cellular players remain elusive. Here we map IL-12 receptor (IL-12R) expression to NK and T cells as well as neurons and oligodendrocytes. Conditionally ablating the IL-12R across these cell types in adult mice and assessing their susceptibility to experimental autoimmune encephalomyelitis revealed that the neuroprotective role of IL-12 is mediated by neuroectoderm-derived cells, specifically neurons, and not immune cells. In human brain tissue from donors with multiple sclerosis, we observe an IL-12R distribution comparable to mice, suggesting similar mechanisms in mice and humans. Combining flow cytometry, bulk and single-nucleus RNA sequencing, we reveal an IL-12-induced neuroprotective tissue adaption preventing early neurodegeneration and sustaining trophic factor release during neuroinflammation, thereby maintaining CNS integrity in mice.

[Neuromuscular Practical Knowledge: Focus On Muscle Weakness]. / Neuromuskuläres Praxiswissen: Fokus Muskelschwäche.

INTRODUCTION: Muscle weakness is a common symptom in the general practice. The diagnostic work-up starts with distinguishing true muscle weakness from fatigue. The localization, time course and severity of muscle weakness as well as associated symptoms, concomitant diseases, medication and family history can help classify the weakness into certain main categories. These are genetic, inflammatory, infectious, neoplastic, toxic and metabolic/endocrine causes. Further laboratory investigations, ENMG, MRI, muscle biopsy and genetic testing can help to further narrow the differential diagnosis. Due to recent advances, particularly in the field of genetics and targeted immunomodulatory therapies, a growing number of diseases which present with muscular weakness can be treated successfully.

Immune checkpoint inhibitors induced side effects of the peripheral nervous system.

PURPOSE OF REVIEW: This review highlights recent knowledge on the diagnosis and treatment of immune checkpoint inhibitor-induced neurological side effects (irNAE) focussing on the neuromuscular system. RECENT FINDINGS: irNAEs mainly resemble sporadic neuromuscular autoimmune diseases and paraneoplastic neurological syndromes. However, neurological symptoms may be unspecific (muscle weakness, fatigue) in the oncological setting and carry the risk of misdiagnosis and delayed therapeutic intervention. The role of disease-specific neuromuscular autoantibodies in the diagnosis is controversial as preexisting autoantibodies may otherwise be present before immune checkpoint inhibitor (ICI) treatment without clinical symptoms and may not develop in case of irNAE manifestation. A new necrotising form of myositis (irMyositis) has been described presenting with facial weakness and ptosis mimicking myasthenia gravis. It comes along with a high rate of severe myocarditis accounting for a triad overlap syndrome (myasthenia/myositis/myocarditis). The role of modern biologicals in the treatment of irNAEs has to be determined. SUMMARY: irNAEs are rare but carry the risk of permanent morbidity and mortality. Early suspicion and diagnosis are key to prevent neurological sequelae. Beyond interruption of ICI administration, treatment corresponds to sporadic autoimmune diseases. The myasthenia/myositis/myocarditis overlap syndrome deserves special attention as it carries the highest risk of mortality. The role of neurotoxic pretreatment regimens, preexisting subclinical neurological autoimmune diseases and the risk of ICI-re-challenge after irNAEs has to be further investigated.

Antibodies Produced by CLL Phenotype B Cells in Patients With Myasthenia Gravis Are Not Directed Against Neuromuscular Endplates.

BACKGROUND AND OBJECTIVES: Myasthenia gravis (MG) can in rare cases be an autoimmune phenomenon associated with hematologic malignancies such as chronic lymphocytic leukemia (CLL). It is unclear whether in patients with MG and CLL, the leukemic B cells are the ones directly driving the autoimmune response against neuromuscular endplates. METHODS: We identified patients with acetylcholine receptor antibody-positive (AChR+) MG and CLL or monoclonal B-cell lymphocytosis (MBL), a precursor to CLL, and described their clinical features, including treatment responses. We generated recombinant monoclonal antibodies (mAbs) corresponding to the B-cell receptors of the CLL phenotype B cells and screened them for autoantigen binding. RESULTS: A computational immune cell screen revealed a subgroup of 5/38 patients with MG and 0/21 healthy controls who displayed a CLL-like B-cell phenotype. In follow-up hematologic flow cytometry, 2 of these 5 patients were diagnosed with an MBL. An additional patient with AChR+ MG as a complication of manifest CLL presented at our neuromuscular clinic and was successfully treated with the anti-CD20 therapy obinutuzumab plus chlorambucil. We investigated the specificities of expanding CLL-like B-cell clones to assess a direct causal link between the 2 diseases. However, we observed no reactivity of the clones against the AChR, antigens at the neuromuscular junction, or other common autoantigens. DISCUSSION: Our study suggests that AChR autoantibodies are produced by nonmalignant, polyclonal B cells The new anti-CD20 treatment obinutuzumab might be considered in effectively treating AChR+ MG. CLASSIFICATION OF EVIDENCE: This is a single case study and provides Class IV evidence that obinutuzumab is safe to use in patients with MG.

Diabetes insipidus and Guillain-Barré-like syndrome following CAR-T cell therapy: a case report.

BACKGROUND: Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common adverse event of CD19-directed chimeric antigen receptor (CAR) T cell therapy. Other neurological adverse events, however, have not methodically been described and studied. Furthermore, safety data on CAR-T cell therapy in patients with central nervous system (CNS) lymphoma remain limited. MAIN BODY: We here report occurrence of a Guillain-Barré-like syndrome (GBS) and central diabetes insipidus (cDI) following tisagenlecleucel therapy for relapsed high-grade lymphoma with CNS involvement. Both complications were refractory to standard treatment of ICANS. Weakness of respiratory muscles required mechanical ventilation and tracheostomy while cDI was treated with desmopressin substitution for several weeks. Muscle-nerve biopsy and nerve conduction studies confirmed an axonal pattern of nerve damage. T cell-rich infiltrates and detection of the CAR transgene in muscle-nerve sections imply a direct or indirect role of CAR-T cell-mediated inflammation. In line with current treatment guidelines for GBS, intravenous immunoglobulin was administered and gradual but incomplete recovery was observed over the course of several months. CONCLUSIONS: This case report highlights the risk of rare but severe neurological adverse events, such as acute GBS or cDI, in patients treated with CAR-T cells. It further underlines the importance of appropriate patient surveillance and systematic reporting of rare complications to eventually improve treatment.

Azathioprine therapy induces selective NK cell depletion and IFN-γ deficiency predisposing to herpesvirus reactivation.

BACKGROUND: Azathioprine is a widely prescribed drug for patients with chronic inflammatory diseases such as myasthenia gravis or organ transplant recipients. Azathioprine exerts immunosuppressive effects by inhibiting intracellular purine synthesis and reducing the numbers of circulating B and T lymphocytes. Case reports indicate increased risk for serious infections that can occur despite regular measurements of lymphocyte counts during azathioprine therapy. OBJECTIVE: We sought to comprehensively investigate therapy-associated patient risks and the underlying immune dysfunction of azathioprine use. METHODS: Peripheral blood leukocytes were analyzed using single-cell mass and spectral flow cytometry to detect specific effects of azathioprine use on the systemic immune signature. Therapy-associated clinical features were analyzed in 2 independent cohorts of myasthenia gravis patients. RESULTS: Azathioprine therapy selectively induced pronounced CD56dimCD16+ natural killer cell depletion and concomitant IFN-γ deficiency. Cytokine profiling revealed a specific contraction of classical TH1 cells during azathioprine treatment. We further observed an increased occurrence of reactivation of endogenous latent herpesviruses in the azathioprine-treated group versus in patients with myasthenia gravis who were not receiving immunomodulatory treatment; this increased occurrence was validated in an independent cohort. CONCLUSION: Our study highlights the risk of development of adverse events during azathioprine therapy and suggests that natural killer cell monitoring could be valuable in clinical practice.

Skeletal Muscle Disorders: A Noncardiac Source of Cardiac Troponin T.

BACKGROUND: Cardiac troponin (cTn) T and cTnI are considered cardiac specific and equivalent in the diagnosis of acute myocardial infarction. Previous studies suggested rare skeletal myopathies as a noncardiac source of cTnT. We aimed to confirm the reliability/cardiac specificity of cTnT in patients with various skeletal muscle disorders (SMDs). METHODS: We prospectively enrolled patients presenting with muscular complaints (≥2 weeks) for elective evaluation in 4 hospitals in 2 countries. After a cardiac workup, patients were adjudicated into 3 predefined cardiac disease categories. Concentrations of cTnT/I and resulting cTnT/I mismatches were assessed with high-sensitivity (hs-) cTnT (hs-cTnT-Elecsys) and 3 hs-cTnI assays (hs-cTnI-Architect, hs-cTnI-Access, hs-cTnI-Vista) and compared with those of control subjects without SMD presenting with adjudicated noncardiac chest pain to the emergency department (n=3508; mean age, 55 years; 37% female). In patients with available skeletal muscle biopsies, TNNT/I1-3 mRNA differential gene expression was compared with biopsies obtained in control subjects without SMD. RESULTS: Among 211 patients (mean age, 57 years; 42% female), 108 (51%) were adjudicated to having no cardiac disease, 44 (21%) to having mild disease, and 59 (28%) to having severe cardiac disease. hs-cTnT/I concentrations significantly increased from patients with no to those with mild and severe cardiac disease for all assays (all P<0.001). hs-cTnT-Elecsys concentrations were significantly higher in patients with SMD versus control subjects (median, 16 ng/L [interquartile range (IQR), 7-32.5 ng/L] versus 5 ng/L [IQR, 3-9 ng/L]; P<0.001), whereas hs-cTnI concentrations were mostly similar (hs-cTnI-Architect, 2.5 ng/L [IQR, 1.2-6.2 ng/L] versus 2.9 ng/L [IQR, 1.8-5.0 ng/L]; hs-cTnI-Access, 3.3 ng/L [IQR, 2.4-6.1 ng/L] versus 2.7 ng/L [IQR, 1.6-5.0 ng/L]; and hs-cTnI-Vista, 7.4 ng/L [IQR, 5.2-13.4 ng/L] versus 7.5 ng/L [IQR, 6-10 ng/L]). hs-cTnT-Elecsys concentrations were above the upper limit of normal in 55% of patients with SMD versus 13% of control subjects (P<0.01). mRNA analyses in skeletal muscle biopsies (n=33), mostly (n=24) from individuals with noninflammatory myopathy and myositis, showed 8-fold upregulation of TNNT2, encoding cTnT (but none for TNNI3, encoding cTnI) versus control subjects (n=16, PWald<0.001); the expression correlated with pathological disease activity (R=0.59, Pt-statistic<0.001) and circulating hs-cTnT concentrations (R=0.26, Pt-statistic=0.031). CONCLUSIONS: In patients with active chronic SMD, elevations in cTnT concentrations are common and not attributable to cardiac disease in the majority. This was not observed for cTnI and may be explained in part by re-expression of cTnT in skeletal muscle. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03660969.

Twin study reveals non-heritable immune perturbations in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system underpinned by partially understood genetic risk factors and environmental triggers and their undefined interactions1,2. Here we investigated the peripheral immune signatures of 61 monozygotic twin pairs discordant for MS to dissect the influence of genetic predisposition and environmental factors. Using complementary multimodal high-throughput and high-dimensional single-cell technologies in conjunction with data-driven computational tools, we identified an inflammatory shift in a monocyte cluster of twins with MS, coupled with the emergence of a population of IL-2 hyper-responsive transitional naive helper T cells as MS-related immune alterations. By integrating data on the immune profiles of healthy monozygotic and dizygotic twin pairs, we estimated the variance in CD25 expression by helper T cells displaying a naive phenotype to be largely driven by genetic and shared early environmental influences. Nonetheless, the expanding helper T cells of twins with MS, which were also elevated in non-twin patients with MS, emerged independent of the individual genetic makeup. These cells expressed central nervous system-homing receptors, exhibited a dysregulated CD25-IL-2 axis, and their proliferative capacity positively correlated with MS severity. Together, our matched-pair analysis of the extended twin approach allowed us to discern genetically and environmentally determined features of an MS-associated immune signature.

Single-cell profiling of myasthenia gravis identifies a pathogenic T cell signature.

Myasthenia gravis (MG) is an autoimmune disease characterized by impaired neuromuscular signaling due to autoantibodies targeting the acetylcholine receptor. Although its auto-antigens and effector mechanisms are well defined, the cellular and molecular drivers underpinning MG remain elusive. Here, we employed high-dimensional single-cell mass and spectral cytometry of blood and thymus samples from MG patients in combination with supervised and unsupervised machine-learning tools to gain insight into the immune dysregulation underlying MG. By creating a comprehensive immune map, we identified two dysregulated subsets of inflammatory circulating memory T helper (Th) cells. These signature ThCD103 and ThGM cells populated the diseased thymus, were reduced in the blood of MG patients, and were inversely correlated with disease severity. Both signature Th subsets rebounded in the blood of MG patients after surgical thymus removal, indicative of their role as cellular markers of disease activity. Together, this in-depth analysis of the immune landscape of MG provides valuable insight into disease pathogenesis, suggests novel biomarkers and identifies new potential therapeutic targets for treatment.

Pericytes regulate vascular immune homeostasis in the CNS.

Pericytes regulate the development of organ-specific characteristics of the brain vasculature such as the blood-brain barrier (BBB) and astrocytic end-feet. Whether pericytes are involved in the control of leukocyte trafficking in the adult central nervous system (CNS), a process tightly regulated by CNS vasculature, remains elusive. Using adult pericyte-deficient mice (Pdgfbret/ret ), we show that pericytes limit leukocyte infiltration into the CNS during homeostasis and autoimmune neuroinflammation. The permissiveness of the vasculature toward leukocyte trafficking in Pdgfbret/ret mice inversely correlates with vessel pericyte coverage. Upon induction of experimental autoimmune encephalomyelitis (EAE), pericyte-deficient mice die of severe atypical EAE, which can be reversed with fingolimod, indicating that the mortality is due to the massive influx of immune cells into the brain. Additionally, administration of anti-VCAM-1 and anti-ICAM-1 antibodies reduces leukocyte infiltration and diminishes the severity of atypical EAE symptoms of Pdgfbret/ret mice, indicating that the proinflammatory endothelium due to absence of pericytes facilitates exaggerated neuroinflammation. Furthermore, we show that the presence of myelin peptide-specific peripheral T cells in Pdgfbret/ret ;2D2tg mice leads to the development of spontaneous neurological symptoms paralleled by the massive influx of leukocytes into the brain. These findings indicate that intrinsic changes within brain vasculature can promote the development of a neuroinflammatory disorder.

Anti-IgLON5 Disease: A New Bulbar-Onset Motor Neuron Mimic Syndrome.

OBJECTIVE: To expand the spectrum of anti-IgLON5 disease by adding 5 novel anti-IgLON5-seropositive cases with bulbar motor neuron disease-like phenotype. METHODS: We characterized the clinical course, brain MRI and laboratory findings, and therapy response in these 5 patients. RESULTS: Patients were severely affected by bulbar impairment and its respiratory consequences. Sleep-related breathing disorders and parasomnias were common. All patients showed clinical or electrophysiologic signs of motor neuron disease without fulfilling the diagnostic criteria for amyotrophic lateral sclerosis. One patient regained autonomy in swallowing and eating, possibly related to immunotherapy. CONCLUSION: IgLON5 disease is an important differential diagnosis to evaluate in patients with bulbar motor neuron disease-like phenotype and sleep disorders. There is need for a deeper understanding of the underlying pathobiology to determine whether IgLON5 disease is an immunotherapy-responsive condition.