Acute and non-resolving inflammation associate with oxidative injury after human spinal cord injury.

Traumatic spinal cord injury is a devastating insult followed by progressive cord atrophy and neurodegeneration. Dysregulated or non-resolving inflammatory processes can disturb neuronal homeostasis and drive neurodegeneration. Here, we provide an in-depth characterization of innate and adaptive inflammatory responses as well as oxidative tissue injury in human traumatic spinal cord injury lesions compared to non-traumatic control cords. In the lesion core, microglia were rapidly lost while intermediate (co-expressing pro- as well as anti-inflammatory molecules) blood-borne macrophages dominated. In contrast, in the surrounding rim, TMEM119+ microglia numbers were maintained through local proliferation and demonstrated a predominantly pro-inflammatory phenotype. Lymphocyte numbers were low and mainly consisted of CD8+ T cells. Only in a subpopulation of patients, CD138+/IgG+ plasma cells were detected, which could serve as candidate cellular sources for a developing humoral immunity. Oxidative neuronal cell body and axonal injury was visualized by intracellular accumulation of amyloid precursor protein (APP) and oxidized phospholipids (e06) and occurred early within the lesion core and declined over time. In contrast, within the surrounding rim, pronounced APP+/e06+ axon-dendritic injury of neurons was detected, which remained significantly elevated up to months/years, thus providing mechanistic evidence for ongoing neuronal damage long after initial trauma. Dynamic and sustained neurotoxicity after human spinal cord injury might be a substantial contributor to (i) an impaired response to rehabilitation; (ii) overall failure of recovery; or (iii) late loss of recovered function (neuro-worsening/degeneration).

Neuregulin-1 beta 1 is implicated in pathogenesis of multiple sclerosis.

Multiple sclerosis is characterized by immune mediated neurodegeneration that results in progressive, life-long neurological and cognitive impairments. Yet, the endogenous mechanisms underlying multiple sclerosis pathophysiology are not fully understood. Here, we provide compelling evidence that associates dysregulation of neuregulin-1 beta 1 (Nrg-1ß1) with multiple sclerosis pathogenesis and progression. In the experimental autoimmune encephalomyelitis model of multiple sclerosis, we demonstrate that Nrg-1ß1 levels are abated within spinal cord lesions and peripherally in the plasma and spleen during presymptomatic, onset and progressive course of the disease. We demonstrate that plasma levels of Nrg-1ß1 are also significantly reduced in individuals with early multiple sclerosis and is positively associated with progression to relapsing-remitting multiple sclerosis. The functional impact of Nrg-1ß1 downregulation preceded disease onset and progression, and its systemic restoration was sufficient to delay experimental autoimmune encephalomyelitis symptoms and alleviate disease burden. Intriguingly, Nrg-1ß1 therapy exhibited a desirable and extended therapeutic time window of efficacy when administered prophylactically, symptomatically, acutely or chronically. Using in vivo and in vitro assessments, we identified that Nrg-1ß1 treatment mediates its beneficial effects in EAE by providing a more balanced immune response. Mechanistically, Nrg-1ß1 moderated monocyte infiltration at the blood-CNS interface by attenuating chondroitin sulphate proteoglycans and MMP9. Moreover, Nrg-1ß1 fostered a regulatory and reparative phenotype in macrophages, T helper type 1 (Th1) cells and microglia in the spinal cord lesions of EAE mice. Taken together, our new findings in multiple sclerosis and experimental autoimmune encephalomyelitis have uncovered a novel regulatory role for Nrg-1ß1 early in the disease course and suggest its potential as a specific therapeutic target to ameliorate disease progression and severity.

Acute flaccid paralysis due to Echovirus 30 in an immunosuppressed transplant recipient.

An Italian 13-year-old boy immunosuppressed due to kidney transplant presented in November 2018 with acute flaccid paralysis with anterior horn cell involvement resembling the clinical, radiological, and laboratory features of poliomyelitis. Enterovirus was molecularly identified in cerebral spinal fluid and stool samples and the sequence analysis of the VP1 gene of enterovirus genome revealed the presence of Echovirus 30 both in CSF and in stool samples. Echovirus 30 is an emerging neurotropic virus able to cause outbreaks of aseptic meningitis and meningoencephalitis all over the world, but acute flaccid paralysis is not a classical manifestation. A 6-month follow-up revealed a poor outcome with severe motor deficits and only slight improvement in disability. Clinicians must be aware of the possible role of Echovirus 30 in acute flaccid paralysis and active surveillance should consider the possible influence of immunosuppression on the symptoms caused by the widening spectrum of enterovirus infections.

Clinical spectrum and prognosis of neurological complications of reactivated varicella-zoster infection: the role of immunosuppression.

Immunosuppressed patients are at higher risk for developing herpes zoster (HZ), and neurological complications are frequent in them. However, the influence of immunosuppression (IS) on the severity and prognosis of neurological complications of varicella-zoster virus (VZV) reactivation is unknown. We studied retrospectively patients with neurological complications due to VZV reactivation who attended our hospital between 2004 and 2019. We aimed to assess the clinical spectrum, potential prognostic factors, and the influence of the immune status on the severity of neurological symptoms. A total of 98 patients were included (40% had IS). Fifty-five patients (56%) had cranial neuropathies which included Ramsay-Hunt syndrome (36 patients) and cranial multineuritis (23 patients). Twenty-one patients developed encephalitis (21%). Other diagnosis included radiculopathies, meningitis, vasculitis, or myelitis (15, 10, 6, and 4 patients, respectively). Mortality was low (3%). At follow-up, 24% of patients had persistent symptoms although these were usually mild. IS was associated with severity (defined as a modified Rankin scale greater than 2) (odds ratio, 4.23; 95% confidence interval, 1.74-10.27), but not with prognosis. Shorter latency between HZ and neurologic symptoms was the only factor associated with an unfavorable course (death or sequelae) (odds ratio, 0.82; 95% confidence interval, 0.71-0.95). In conclusion, the clinical spectrum of neurological complications in VZV reactivation is wide. Mortality was low and sequelae were mild. The presence of IS may play a role on the severity of neurological symptoms, and a shorter time between HZ and the onset of neurological symptoms appears to be a negative prognostic factor.

MOG-related disorders: A new cause of imaging-negative myelitis?

Knowledge on the clinical and radiological phenotype of myelin oligodendrocyte glycoprotein (MOG)-related disorders has been growing. We report the case of a patient who presented with subacute onset myelitis after an upper respiratory tract infection with normal cord imaging at onset and follow-up after 4 months (absence of lesions and atrophy), high-titer positive MOG-IgG, and a broad workup excluding other etiologies. The full clinical and radiological spectrum of MOG-related disorders is yet to be completely understood. Testing for MOG-IgG using cell-based assays should be considered in imaging-negative myelitis particularly if initial testing is non-revealing.

Frequency and characteristics of short versus longitudinally extensive myelitis in adults with MOG antibodies: A retrospective multicentric study.

OBJECTIVES: We aim to (1) determine the frequency and distinctive features of short myelitis (SM) and longitudinally extensive transverse myelitis (LETM) in a cohort of adults with myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated myelitis and (2) determine baseline prognostic factors among MOG-Ab-positive patients whose disease started with myelitis. MATERIAL AND METHODS: We retrospectively analyzed clinical and paraclinical variables from a multicentric French cohort of adults with MOG-Ab-associated myelitis. At last follow-up, patients were classified into two groups according to the severity of the Expanded Disability Status Scale (EDSS) as ⩽2.5 or ⩾3.0. RESULTS: Seventy-three patients with at least one episode of myelitis over disease course were included; among them, 28 (38.4%) presented with SM at the time of the first myelitis. Motor and sphincter involvement was less frequently observed in SM (51.9% and 48.2%, respectively) than in LETM patients (83.3% and 78.6%, respectively), p = 0.007 and p = 0.017; 61% of LETM patients displayed brain lesions compared to 28.6% in the SM group, p = 0.008, and the thoracic segment was more frequently involved in the LETM (82.2%) than in the SM group (39.3%), p < 0.001. EDSS at last follow-up was higher in LETM (median 3.0 (interquartile range: 2.0-4.0)) compared to SM patients (2.0, (1.0-3.0)), p = 0.042. Finally, a higher EDSS at onset was identified as the only independent risk factor for EDSS ⩾3.0 (odds ratio, 1.40, 95% confidence interval (CI): 1.01-1.95, p = 0.046). CONCLUSION: SM in MOG-Ab-associated disease is not rare. The severity at onset was the only independent factor related to the final prognosis in MOG-Ab-associated myelitis.

Autoimmune glial fibrillary acidic protein astrocytopathy manifesting as subacute meningoencephalitis with descending myelitis: a case report.

BACKGROUND: Glial fibrillary acidic protein (GFAP) autoimmune astrocytopathy is characterized by GFAP autoantibody positive encephalitis, meningoencephalitis or meningoencephalomyelitis. The initial clinical presentation may be similar to central nervous system infections making early diagnosis challenging. CASE PRESENTATION: A Chinese female patient presented with subacute meningitis with symptoms of headache, vomiting, and fever. Cerebrospinal fluid (CSF) analysis showed monocytic pleocytosis, elevated protein level, low glucose level, and negative basic microbiological studies including Xpert MTB/RIF. Brain magnetic resonance imaging (MRI) showed bilateral cerebral cortical and white matter hyperintensities on FLAIR sequences. The patient was diagnosed with possible tuberculous meningitis and started on anti-tuberculosis therapy (ATT). Three months later, the patient developed cervical myelopathy and encephalopathy with persistent CSF pleocytosis. Five months later, tissue-based and cell-based assays demonstrated GFAP antibodies in blood and CSF. Her symptoms improved with repeated administration of intravenous immunoglobulin (IVIG) and corticosteroids. One-and-a-half -year follow-up showed neither clinical progression nor relapses. CONCLUSIONS: Anti-GFAP astrocytopathy should be included in the differential diagnosis of patients who present with subacute meningitis with negative microbiological studies and a progressive clinical course including encephalitis and/or myelitis.

Recurrent myelitis and asymptomatic hypophysitis in IgG4-related disease: case-based review.

IgG4-related disease (IgG4-RD) is a disorder with various clinical manifestations. Central nervous system (CNS) involvement is well recognized, with hypertrophic pachymeningitis and hypophysitis being the most common manifestations. Spinal cord involvement is an extremely rare manifestation. We present the first case of an IgG4-RD patient with spinal cord parenchymal disease and concurrent hypophysitis. We review also the current literature about CNS parenchymal involvement in the context of IgG4-RD. A young female presented with clinical symptoms of myelitis. Cervical spinal cord magnetic resonance imaging (MRI) displayed features of longitudinally extensive transverse myelitis (LETM). Brain MRI showed a small number of high-intensity lesions in the deep white matter and enlargement of hypophysis with homogeneous gadolinium enhancement (asymptomatic hypophysitis). Diagnostic workup revealed elevated IgG4 serum levels (146 mg/dL). Our patient fulfilled the organ-specific diagnostic criteria of IgG4-hypophysitis. Treatment with intravenous glucocorticoids led to rapid clinical response, and to the substantial resolution of imaging findings. Azathioprine was used as a maintenance treatment. One relapse occurred 2 years after the initial diagnosis and patient was re-treated with glucocorticoids. Three years after relapse, patient is in remission with azathioprine. We present the first case of myelitis with radiological features of LETM associated with increased IgG4 serum levels and the simultaneous presence of asymptomatic IgG4-related hypophysitis.

Persistent MOG-IgG positivity is a predictor of recurrence in MOG-IgG-associated optic neuritis, encephalitis and myelitis.

BACKGROUND: MOG-IgG-associated optic neuritis, encephalitis and myelitis (MONEM) is a recently recognized group of inflammatory central nervous system (CNS) disorders distinct from multiple sclerosis and neuromyelitis optica spectrum disorders. Limited data are available regarding the predictors of relapse in this condition. OBJECTIVE: We aimed to evaluate the longitudinal serostatus of patients with MOG-IgG and to correlate serostatus with long-term clinical outcomes. METHODS: Of 574 consecutive patients who presented with demyelinating inflammatory CNS disorders, we included 31 patients who were MOG-IgG-positive. Patients with MOG-IgG were followed up from 2011 to 2017 at the School of Medicine, University of São Paulo, Brazil. RESULTS: Relapsing disease occurred in 23 out of 31 patients (74%), while 8 (26%) exhibited a monophasic course. All monophasic patients, as well as the majority of relapsing patients, became seronegative during clinical remission. Patients exhibiting disease activity in the last 2 years were more likely to remain positive, with higher medium titres than those found in patients in clinical remission. CONCLUSION: MOG-IgG patients usually present with a relapsing course, and the risk of relapse was associated with longitudinally persistent MOG-IgG seropositivity. In contrast, patients who experienced a single attack became spontaneously seronegative for MOG-IgG during long-term follow-up.

Clinical Heterogeneity in Patients with Glutamate Decarboxylase Antibody.

OBJECTIVE: To explore the diversity and clinical features of anti-glutamate decarboxylase (GAD) antibody-associated neurological diseases. METHODS: Clinical data of a series of 5 patients positive for anti-GAD antibodies were retrospectively analyzed. RESULTS: All 5 patients were female, with a median age of 41.5 years (range 19-60 years). Their neurological symptoms included stiff-person syndrome (SPS), encephalitis, myelitis, cramp, visual loss, and paresthesia. Three patients (60%) were diagnosed with tumors, 2 cases of thymic tumor and 1 of breast cancer. On immunohistochemistry for tumor pathology, expression of GAD65 was found only in 1 patient. Four patients (80%) had abnormal brain MRI findings. All patients received immunotherapy and improved significantly after treatment, but 4 (80%) then experienced a relapse. CONCLUSIONS: Neurological manifestations in anti-GAD-positive patients are diverse and include SPS, encephalitis, myelitis, cramp, visual loss, and paresthesia.

Magnetic resonance imaging in enterovirus-71, myelin oligodendrocyte glycoprotein antibody, aquaporin-4 antibody, and multiple sclerosis-associated myelitis in children.

AIM: We used magnetic resonance imaging (MRI) to compare the neuroimaging of children with their first episode of clinical enterovirus 71-associated transverse myelitis (EV71-TM), myelin oligodendrocyte glycoprotein antibody positive transverse myelitis (MOG-TM), aquaporin-4 antibody positive transverse myelitis (AQP4-TM), transverse myelitis in multiple sclerosis (MS-TM), and unclassified transverse myelitis (UNC-TM). METHOD: We performed a retrospective blinded radiological assessment and compared the neuroimaging of 52 children (32 females, 20 males; mean age 9y 8mo, SD 5y 5mo, range 5mo-17y) presenting with their first episode of myelitis caused by EV71-TM (n=11), MOG-TM (n=10), AQP4-TM (n=9), MS-TM (n=13), and UNC-TM (n=9). RESULTS: In the EV71-TM group, lesions were distributed throughout the cord and enhancement of nerve roots (ventral and dorsal) was common. The MOG-TM group had lesions distributed throughout the cord and most commonly longitudinally extensive transverse myelitis and lesions involving the grey matter alone on axial scans. The AQP4-TM group had lesions distributed in the cervicothoracic spine, cavitation, and contrast enhancing lesions. All patients with AQP4-TM had an abnormal brain MRI scan. The MS-TM group characteristically had multiple short segment lesions of the cord involving the cervicothoracic spine. The UNC-TM group did not have distinctive spinal MRI findings but had a relative paucity of lesions on their brain MRI scans. INTERPRETATION: There are neuroimaging findings that are helpful in differentiating between myelitis associated with EV71, MOG, AQP4, and multiple sclerosis in children. These features may be useful early in the presentation of transverse myelitis while awaiting infectious/immunological testing, and/or further demyelinating events. WHAT THIS PAPER ADDS: Magnetic resonance imaging can help identify aetiologies for children presenting with a first episode of myelitis. Entervirus-71-associated myelitis lesions are distributed throughout the cord and enhancement of nerve roots is common. Lesions distributed throughout the cord are commonly seen in myelin oligodendrocyte-associated myelitis. Aquaporin-4-associated myelitis lesions are distributed in the cervicothoracic spine, cavitation and contrast enhancing lesions are common. Short segment lesions in the cervicothoracic spine are commonly seen in multiple sclerosis-associated myelitis.

IMÁGENES DE RESONANCIA MAGNÉTICA EN ENTEROVIRUS-71, ANTICUERPOS DE GLICOPROTEÍNA DE LA MIELINA DEL OLIGODENDROCITO, ANTICUERPOS AQUAPORIN-4, Y ESCLEROSIS MÚLTIPLE-ASOCIADA A MIELITIS EN NIÑOS: OBJETIVO: Utilizamos imágenes de resonancia magnética (IRM) para comparar la neuroimagen de los niños con su primer episodio clínico de enterovirus 71-asociado a mielitis transversa (EV71-TM), mielitis transversa con anticuerpos de glicoproteína de la mielina del oligodendrocito positivos (MOG-TM), mielitis transversa con anticuerpos aquaporin-4 positivos (AQP4-TM), mielitis transversa en esclerosis múltiple (MS-TM) y mielitis transversa no clasificada (UNC-TM). MÉTODO: Se realizó un análisis radiológico, ciego, retrospectivo y se comparó la neuroimagen de 52 niños (32 mujeres, 20 varones; con edad promedio 9 años 8 meses, La DS 5 años 5 meses, el rango de 5 meses -17 años) que presentaron su primer episodio de mielitis causada por EV71-TM (n= 11), MOG-TM (n= 10), AQP4-TM (n= 9), MS-TM (n= 13) y UNC-TM (n= 9). RESULTADOS: En el grupo de EV71-TM, fue común observar lesiones distribuidas a través de la medula con realce de las raíces de nervio (ventrales y dorsales). El grupo de MOG-TM tenía lesiones distribuidas a través de la médula, más comúnmente mielitis transversa longitudinalmente extensa y lesiones que implican solamente la sustancia gris en exploraciones axiales. El grupo AQP4-TM tenía lesiones distribuidas en la medula cervicodorsal, cavitación y lesiones con realce en el contraste. Todos Pacientes con AQP4-TM tenían una IRM cerebral anormal. El grupo de MS-TM característicamente tenía lesiones múltiples de segmentos pequeños de la medula que involucran las regiones cervical y dorsal. El grupo UNC-TM no tenía hallazgos de IRM distintivos en la medula espinal, pero tenía una relativa escasez de lesiones cerebrales IRM. INTERPRETACIÓN: Hay hallazgos de neuroimagen en niños que son útiles en diferenciar entre mielitis asociada a EV71, a MOG, a AQP4, y esclerosis múltiple. Estas características pueden ser útiles al inicio de la presentación de la mielitis transversa mientras se espera la prueba infecciosa/inmunológica y/u otros acontecimientos desmielinizantes.

IMAGEM POR RESSONÂNCIA MAGNÉTICA EM ENTEROVÍRUS-71, ANTICORPO DA GLICOPROTEÍNA DE OLIGODENDRÓCITO DA MIELINA, ANTICORPO AQUAPORINA-4, E MIELITE ASSOCIADA A ESCLEROSE MÚLTIPLA EM CRIANÇAS: OBJETIVO: Usamos imagens de ressonância funcional (IRM) para comparar as neuroimagens de crianças com o primeiro episósio de mielite transversa clínica associada a enterovírus-71 (MT-EV71), mielite transversa positiva para anticorpo da glicoproteína de oligodendrócit oda mielina (MT-GOM), mielite transversa positiva para anticorpo aquaporina-4 (MT-AQP4), mielite transversa em esclerose múltipla (MT-EM), e mielite transversa não classificada (MT-NC). MÉTODO: Realizamos uma avaliação radiológica retrospectiva cega, e comparamos a neuroimagem de 52 crianças (32 do sexo feminino, 20 do sexo masculino; média de idade 9a 8m, DP 5a 5m, variação 5m-17a) apresentando seu primeiro episódio de mielite causada por MT-EV71 (n=11), MT-GOM (n=10), MT-AQP4 (n=9), MT-EM (n=13), e MT-NC (n=9). RESULTADOS: No grupo MT-EV71, as lesões se distribuíram por toda a medula, e realces das raízes nervosas (ventrais e dorsais) eram comuns. O grupo MT-GOM teve lesões distribuídas por toda a medula, e mais comumente mielite transversa extensiva longitudinalmente e lesões envolvendo apenas a substância cinzenta nas imagens axiais. O grupo MT-AQP4 teve lesões distribuídas na coluna cérvico-torácica, cavitação, e lesões realçadas pelo contraste. Todos os pacientes com MT-AQP4 -tiveram uma IRM cerebral anormal. O grupo MT-EM caracteristicamente teve múltiplas lesões de segmentos curtos da medula envolvendo a região cérvico-torácica. O grupo MT-NC não teve achados distintivos de IRM espinhal, mas tiveram relativamente menos lesões nas imagens cerebrais. INTERPRETAÇÃO: Há achados de neuroimagem úteis para diferenciar a mielite associada com EV71, GOM, AQP4 e esclerose múltipla em crianças. Estes aspectos podem ser úteis na apresentação precoce da mielite transversa, enquanto se aguarda testes infecciosos/imunológicos, e e/ou outros eventos desmielinizantes.

MRI features of demyelinating disease associated with anti-MOG antibodies in adults.

The spectrum of Myelin Oligodendrocytes Glycoprotein (MOG) antibody disease constitutes a recently described challenging entity, referring to a relatively new spectrum of autoimmune disorders with antibodies against MOG predominantly involving the optic nerve and spinal cord. The purpose of this article is to describe MRI features of MOG-AD involvement in the optic nerves, spinal cord and the brain of adults.

Zika virus-induced acute myelitis and motor deficits in adult interferon αß/γ receptor knockout mice.

Zika virus (ZIKV) has received widespread attention because of its effect on the developing fetus. It is becoming apparent, however, that severe neurological sequelae, such as Guillian-Barrë syndrome (GBS), myelitis, encephalitis, and seizures can occur after infection of adults. This study demonstrates that a contemporary strain of ZIKV can widely infect astrocytes and neurons in the brain and spinal cord of adult, interferon α/ß receptor knockout mice (AG129 strain) and cause progressive hindlimb paralysis, as well as severe seizure-like activity during the acute phase of disease. The severity of hindlimb motor deficits correlated with increased numbers of ZIKV-infected lumbosacral spinal motor neurons and decreased numbers of spinal motor neurons. Electrophysiological compound muscle action potential (CMAP) amplitudes in response to stimulation of the lumbosacral spinal cord were reduced when obvious motor deficits were present. ZIKV immunoreactivity was high, intense, and obvious in tissue sections of the brain and spinal cord. Infection in the brain and spinal cord was also associated with astrogliosis as well as T cell and neutrophil infiltration. CMAP and histological analysis indicated that peripheral nerve and muscle functions were intact. Consequently, motor deficits in these circumstances appear to be primarily due to myelitis and possibly encephalitis as opposed to a peripheral neuropathy or a GBS-like syndrome. Thus, acute ZIKV infection of adult AG129 mice may be a useful model for ZIKV-induced myelitis, encephalitis, and seizure activity.

Clinical and immunological characteristics of the spectrum of GFAP autoimmunity: a case series of 22 patients.

OBJECTIVE: To report the clinical and immunological characteristics of 22 new patients with glial fibrillar acidic protein (GFAP) autoantibodies. METHODS: From January 2012 to March 2017, we recruited 451 patients with suspected neurological autoimmune disease at the Catholic University of Rome. Patients' serum and cerebrospinal fluid (CSF) samples were tested for neural autoantibodies by immunohistochemistry on mouse and rat brain sections, by cell-based assays (CBA) and immunoblot. GFAP autoantibodies were detected by immunohistochemistry and their specificity confirmed by CBA using cells expressing human GFAPα and GFAPδ proteins, by immunoblot and immunohistochemistry on GFAP-/- mouse brain sections. RESULTS: Serum and/or CSF IgG of 22/451 (5%) patients bound to human GFAP, of which 22/22 bound to GFAPα, 14/22 to both GFAPα and GFAPδ and none to the GFAPδ isoform only. The neurological presentation was: meningoencephalomyelitis or encephalitis in 10, movement disorder (choreoathetosis or myoclonus) in 3, anti-epileptic drugs (AED)-resistant epilepsy in 3, cerebellar ataxia in 3, myelitis in 2, optic neuritis in 1 patient. Coexisting neural autoantibodies were detected in five patients. Six patients had other autoimmune diseases. Tumours were found in 3/22 patients (breast carcinoma, 1; ovarian carcinoma, 1; thymoma, 1). Nineteen patients were treated with immunotherapy and 16 patients (84%) improved. Histopathology analysis of the leptomeningeal biopsy specimen from one patient revealed a mononuclear infiltrate with macrophages and CD8+ T cells. CONCLUSIONS: GFAP autoimmunity is not rare. The clinical spectrum encompasses meningoencephalitis, myelitis, movement disorders, epilepsy and cerebellar ataxia. Coexisting neurological and systemic autoimmunity are relatively common. Immunotherapy is beneficial in most cases.

Autoimmune and Paraneoplastic Myelopathies.

Prompt recognition of an inflammatory myelopathy is critical, as a specific diagnosis and management plan allows for optimal patient outcomes. Many treatment options are now available for autoimmune and paraneoplastic myelopathies, but specific management strategies and expected prognosis vary widely depending on the underlying etiology. An understanding of the relevant clinical details, imaging findings, and other diagnostic information that can help achieve a specific myelopathy diagnosis and treatment plan is essential for all neurologists, given the variety of contexts in which myelopathies are encountered. We provide an outline of the diagnostic evaluation and treatment of various inflammatory myelopathies seen in autoimmune and paraneoplastic diseases, including multiple sclerosis, aquaporin-4 immunoglobulin G (IgG) seropositive neuromyelitis optica spectrum disorder, sarcoidosis, myelin oligodendrocyte glycoprotein IgG associated disease, and other rare inflammatory myelopathies; we also highlight common mimickers of inflammatory myelopathies.

Glutamic Acid Decarboxylase Antibody in a Patient with Myelitis: A Retrospective Study.

OBJECTIVE: The aim of this study was to evaluate the positive rate of serum glutamic acid decarboxylase (GAD) autoantibody in patients with myelitis and to describe the clinical findings in patients with positive GAD antibody. METHODS: Serum samples were collected from 390 patients with myelitis, including 210 patients positive for aquaporin 4 (AQP4) antibody and 180 patients negative for AQP4. GAD65 antibody was measured by an indirect immunofluorescence assay. RESULTS: Only 1 serum and cerebral spinal fluid sample from 390 patients (0.26%) was positive for anti-GAD antibodies. The patient was a female with relapsing myelitis and a thymic mass. Thymic resection was undertaken, and pathological examination revealed a benign thymic cyst. Extensive infiltration of lymphocytes positive for CD3, CD4, CD8 and CD20 was found. Immunohistochemistry showed positive expression of GAD65 in the cyst. CONCLUSIONS: Although serum GAD65 antibodies were present in a patient, it is not recommended to routinely screen for GAD65 antibodies in patients with myelitis because of their rare occurrence. However, screening for GAD65 antibodies should be considered in patients who have been diagnosed with cancer or a thymic abnormality.

Interleukin-37 (IL-37) Suppresses Pertussis Toxin-Induced Inflammatory Myopathy in a Rat Model.

BACKGROUND Recent data have demonstrated the potential immunosuppressive roles of interleukin-37 (IL-37) in several diseases, but whether it is involved in the pathogenesis of inflammatory myopathy has not been elucidated. MATERIAL AND METHODS An experimental autoimmune myositis (EAM) model was built by subcutaneous injections of pertussis toxin (PTX) and purified rabbit myosin (10mg/kg) emulsified with an equal volume of conventional complete Freund's adjuvant (CFA) in a Lewis model. Autoimmune myositis Lewis model rats were divided into 3 groups: group A rats (control group) were injected with CFA in saline weekly; group B (IL-37 group) rats were injected with saline with IL-37 and CFA in saline weekly; and group C (IL-37 + SIS3 group) rats were injected with IL-37, CFA, and SIS3. ELISA was also used to assess the expressions of TNF-α, IL-6, IL-1ß, TGF-ß1, and CK. HE staining was performed to assess pathological changes in lung and muscle tissues. RESULTS The expressions of TNF-α, IL-6, IL-1ß, TGF-ß1, and CK significantly increased in autoimmune myositis Lewis model rats. After IL-37 treatment, the expression of TNF-α, IL-6, IL-1ß, TGF-ß1, and CK was significantly reduced, as were the inflammatory responses of lung and muscle. However, SIS3 reduced the effects of IL-37 on the autoimmune myositis Lewis model rats. CONCLUSIONS These findings indicate that IL-37 protects against inflammatory response via regulating Smad3 in autoimmune myositis Lewis model rats.

MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 1: Frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin.

BACKGROUND: Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have been suggested to play a role in a subset of patients with neuromyelitis optica and related disorders. OBJECTIVE: To assess (i) the frequency of MOG-IgG in a large and predominantly Caucasian cohort of patients with optic neuritis (ON) and/or myelitis; (ii) the frequency of MOG-IgG among AQP4-IgG-positive patients and vice versa; (iii) the origin and frequency of MOG-IgG in the cerebrospinal fluid (CSF); (iv) the presence of MOG-IgG at disease onset; and (v) the influence of disease activity and treatment status on MOG-IgG titers. METHODS: 614 serum samples from patients with ON and/or myelitis and from controls, including 92 follow-up samples from 55 subjects, and 18 CSF samples were tested for MOG-IgG using a live cell-based assay (CBA) employing full-length human MOG-transfected HEK293A cells. RESULTS: MOG-IgG was detected in 95 sera from 50 patients with ON and/or myelitis, including 22/54 (40.7 %) patients with a history of both ON and myelitis, 22/103 (21.4 %) with a history of ON but no myelitis and 6/45 (13.3 %) with a history of longitudinally extensive transverse myelitis but no ON, and in 1 control patient with encephalitis and a connective tissue disorder, all of whom were negative for AQP4-IgG. MOG-IgG was absent in 221 further controls, including 83 patients with AQP4-IgG-seropositive neuromyelitis optica spectrum disorders and 85 with multiple sclerosis (MS). MOG-IgG was found in 12/18 (67 %) CSF samples from MOG-IgG-seropositive patients; the MOG-IgG-specific antibody index was negative in all cases, indicating a predominantly peripheral origin of CSF MOG-IgG. Serum and CSF MOG-IgG belonged to the complement-activating IgG1 subclass. MOG-IgG was present already at disease onset. The antibodies remained detectable in 40/45 (89 %) follow-up samples obtained over a median period of 16.5 months (range 0-123). Serum titers were higher during attacks than during remission (p < 0.0001), highest during attacks of simultaneous myelitis and ON, lowest during acute isolated ON, and declined following treatment. CONCLUSIONS: To date, this is the largest cohort studied for IgG to human full-length MOG by means of an up-to-date CBA. MOG-IgG is present in a substantial subset of patients with ON and/or myelitis, but not in classical MS. Co-existence of MOG-IgG and AQP4-IgG is highly uncommon. CSF MOG-IgG is of extrathecal origin. Serum MOG-IgG is present already at disease onset and remains detectable in the long-term course. Serum titers depend on disease activity and treatment status.

MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 3: Brainstem involvement - frequency, presentation and outcome.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) are present in a subset of aquaporin-4 (AQP4)-IgG-negative patients with optic neuritis (ON) and/or myelitis. Little is known so far about brainstem involvement in MOG-IgG-positive patients. OBJECTIVE: To investigate the frequency, clinical and paraclinical features, course, outcome, and prognostic implications of brainstem involvement in MOG-IgG-positive ON and/or myelitis. METHODS: Retrospective case study. RESULTS: Among 50 patients with MOG-IgG-positive ON and/or myelitis, 15 (30 %) with a history of brainstem encephalitis were identified. All were negative for AQP4-IgG. Symptoms included respiratory insufficiency, intractable nausea and vomiting (INV), dysarthria, dysphagia, impaired cough reflex, oculomotor nerve palsy and diplopia, nystagmus, internuclear ophthalmoplegia (INO), facial nerve paresis, trigeminal hypesthesia/dysesthesia, vertigo, hearing loss, balance difficulties, and gait and limb ataxia; brainstem involvement was asymptomatic in three cases. Brainstem inflammation was already present at or very shortly after disease onset in 7/15 (47 %) patients. 16/21 (76.2 %) brainstem attacks were accompanied by acute myelitis and/or ON. Lesions were located in the pons (11/13), medulla oblongata (8/14), mesencephalon (cerebral peduncles; 2/14), and cerebellar peduncles (5/14), were adjacent to the fourth ventricle in 2/12, and periaqueductal in 1/12; some had concomitant diencephalic (2/13) or cerebellar lesions (1/14). MRI or laboratory signs of blood-brain barrier damage were present in 5/12. Cerebrospinal fluid pleocytosis was found in 11/14 cases, with neutrophils in 7/11 (3-34 % of all CSF white blood cells), and oligoclonal bands in 4/14. Attacks were preceded by acute infection or vaccination in 5/15 (33.3 %). A history of teratoma was noted in one case. The disease followed a relapsing course in 13/15 (87 %); the brainstem was involved more than once in 6. Immunosuppression was not always effective in preventing relapses. Interferon-beta was followed by new attacks in two patients. While one patient died from central hypoventilation, partial or complete recovery was achieved in the remainder following treatment with high-dose steroids and/or plasma exchange. Brainstem involvement was associated with a more aggressive general disease course (higher relapse rate, more myelitis attacks, more frequently supratentorial brain lesions, worse EDSS at last follow-up). CONCLUSIONS: Brainstem involvement is present in around one third of MOG-IgG-positive patients with ON and/or myelitis. Clinical manifestations are diverse and may include symptoms typically seen in AQP4-IgG-positive neuromyelitis optica, such as INV and respiratory insufficiency, or in multiple sclerosis, such as INO. As MOG-IgG-positive brainstem encephalitis may take a serious or even fatal course, particular attention should be paid to signs or symptoms of additional brainstem involvement in patients presenting with MOG-IgG-positive ON and/or myelitis.