Inflammatory Disorder Of Central Nervous System Research Articles

COVID-19 and neuroinflammation: a literature review of relevant neuroimaging and CSF markers in central nervous system inflammatory disorders from SARS-COV2.

BackgroundThe literature on neurological manifestations in COVID-19 patients has been rapidly increasing with the pandemic. However, data on CNS inflammatory disorders in COVID-19 are still evolving. We performed a literature review of CNS inflammatory disorders associated with coronavirus disease-2019 (COVID-19).MethodsWe screened all articles resulting from a search of PubMed, Google Scholar and Scopus, using the keywords; “SARS-CoV-2 and neurological complication”, “SARS-CoV-2 and CNS Complication” looking for reports of transverse myelitis, longitudinally extensive transverse myelitis, neuromyelitis optica, myelitis, Myelin Oligodendrocyte Glycoprotein Antibody Disorder (MOGAD), Acute Disseminated Encephalomyelitis (ADEM), Acute Hemorrhagic Necrotizing Encephalitis/Acute Hemorrhagic Leukoencephalitis (AHNE/AHLE), Cytotoxic lesion of the Corpus Callosum/Mild Encephalopathy Reversible Splenium Lesion(CLOCC/MERS) and Optic neuritis published between December 01, 2019 and March 15, 2021.ResultsOur literature search revealed 43 patients meeting the diagnosis of myelitis, including Transverse Myelitis, ADEM, AHNE/AHLE or CLOCC/MERS and Optic neuritis. Acute myelitis was most commonly associated with non-severe COVID-19 and all reported cases of AHNE/AHLE had severe COVID-19 infection. Based on IDSA/ATS criteria of either requiring vasopressor for septic shock or mechanical ventilation, 49% (n = 18) patients were considered to have a severe COVID infection. There were 7 (n = 19%) fatalities.ConclusionTo our knowledge, this is among the first reviews that includes the clinical features, neuroimaging, CSF findings and outcomes in COVID-19-associated CNS inflammatory disorders. Our observational review study reveals that although rare, myelitis, ADEM, AHNE and CLOCC can be associated with COVID-19 infection. Further studies using MRI imaging and CSF analysis in early diagnosis and intervention of these disorders are warranted.

Microglial Activation Is Associated With Vasoprotection in a Rat Model of Inflammatory Retinal Vasoregression

Vascular dysfunction and vasoregression are hallmarks of a variety of inflammatory central nervous system disorders and inflammation-related retinal diseases like diabetic retinopathy. Activation of microglia and the humoral innate immune system are contributing factors. Anti-inflammatory approaches have been proposed as therapies for neurovascular diseases, which include the modulation of microglial activation. The present study aimed at investigating the effects of microglial activation by clodronate-coated liposomes on vasoregression in a model of retinal degeneration. Clodronate treatment over 5 weeks led to an increase in activated CD74+ microglia and completely prevented acellular capillaries and pericyte loss. Gene expression analyses indicated that vasoprotection was due to the induction of vasoprotective factors such as Egr1, Stat3, and Ahr while expression of pro-inflammatory genes remained unchanged. We concluded that activated microglia led to a shift toward induction of pleiotropic protective pathways supporting vasoprotection in neurovascular retinal diseases.

Neural stem cells traffic functional mitochondria via extracellular vesicles.

Neural stem cell (NSC) transplantation induces recovery in animal models of central nervous system (CNS) diseases. Although the replacement of lost endogenous cells was originally proposed as the primary healing mechanism of NSC grafts, it is now clear that transplanted NSCs operate via multiple mechanisms, including the horizontal exchange of therapeutic cargoes to host cells via extracellular vesicles (EVs). EVs are membrane particles trafficking nucleic acids, proteins, metabolites and metabolic enzymes, lipids, and entire organelles. However, the function and the contribution of these cargoes to the broad therapeutic effects of NSCs are yet to be fully understood. Mitochondrial dysfunction is an established feature of several inflammatory and degenerative CNS disorders, most of which are potentially treatable with exogenous stem cell therapeutics. Herein, we investigated the hypothesis that NSCs release and traffic functional mitochondria via EVs to restore mitochondrial function in target cells. Untargeted proteomics revealed a significant enrichment of mitochondrial proteins spontaneously released by NSCs in EVs. Morphological and functional analyses confirmed the presence of ultrastructurally intact mitochondria within EVs with conserved membrane potential and respiration. We found that the transfer of these mitochondria from EVs to mtDNA-deficient L929 Rho0 cells rescued mitochondrial function and increased Rho0 cell survival. Furthermore, the incorporation of mitochondria from EVs into inflammatory mononuclear phagocytes restored normal mitochondrial dynamics and cellular metabolism and reduced the expression of pro-inflammatory markers in target cells. When transplanted in an animal model of multiple sclerosis, exogenous NSCs actively transferred mitochondria to mononuclear phagocytes and induced a significant amelioration of clinical deficits. Our data provide the first evidence that NSCs deliver functional mitochondria to target cells via EVs, paving the way for the development of novel (a)cellular approaches aimed at restoring mitochondrial dysfunction not only in multiple sclerosis, but also in degenerative neurological diseases.

The influence of smoking on the pattern of disability and relapse risk in AQP4-positive Neuromyelitis Optica Spectrum Disorder, MOG-Ab Disease and Multiple Sclerosis

Background: the role of smoking on clinical outcomes of central nervous system (CNS) inflammatory disorders is unclear. To assess the effect of smoking on relapses and disability in neuromyelitis optica with aquaporin-4-antibodies (NMOSD-AQP4-Ab), Myelin Oligodendrocyte Glycoprotein-antibodies associated disease (MOGAD) and relapsing remitting Multiple Sclerosis (MS) patients.Methods: in a UK cohort of 101 NMOSD-AQP4-Ab, 70 MOGAD and 159 MS, and a Korean cohort of 97 NMOSD-AQ4-Ab, time to first relapse, annualised relapse rate, onset relapse severity and recovery, time to Expanded Disability Status Score(EDSS)/secondary progressive MS (SPMS) were compared between never-smokers and ever-smokers. All clinical data were collected under the local ethics between January 2017 and January 2019.Results: Smoking did not affect the risk of relapse in any of the diseases. The risk of reaching EDSS 6.0 in the UK NMOSD-AQP4-Ab cohort was higher in ever smokers but this did not achieve significance (HR 2.12, p=0.068). When combining the UK and Korea NMOSD-AQP4-Ab cohorts, poorer recovery from the onset attack was significantly more frequent in the ever-smokers versus the never smokers (55% vs 38%, p=0.04). In the MS cohort the risk of reaching EDSS 6 and SPMS was significantly higher in the ever-smokers (HR=2.67, p=0.01 and HR=3.18, p=0.001). In MOGAD similar patterns were seen without reaching significance.Conclusions: In NMOSD-AQP4-Ab smoking associates with worse disability not through an increased risk of relapses but through poor relapse recovery. As in MS, smoking cessation should be encouraged in NMOSD-AQP4-Ab.

Pituitary adenylate cyclase-activating polypeptide/vasoactive intestinal peptide [Part 1]: biology, pharmacology, and new insights into their cellular basis of action/signaling which are providing new therapeutic targets.

To discuss recent advances of vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating polypeptide (PACAP) receptors in pharmacology, cell biology, and intracellular signaling in cancer. Recent studies provide new insights into the pharmacology, cell biology of the VIP/PACAP system and show they play important roles in a number of human cancers, as well as in tumor growth/differentiation and are providing an increased understanding of their signaling cascade that is suggesting new treatment targets/approaches. Recent insights from studies of VIP/PACAP and their receptors in both central nervous system disorders and inflammatory disorders suggest possible new treatment approaches. Elucidation of the exact roles of VIP/PACAP in these disorders and development of new therapeutic approaches involving these peptides have been limited by lack of specific pharmacological tools, and exact signaling mechanisms involved, mediating their effects. Reviewed here are recent insights from the elucidation of structural basis for VIP/PACAP receptor activation as well as the signaling cascades mediating their cellular effects (using results primarily from the study of their effects in cancer) that will likely lead to novel targets and treatment approaches in these diseases.

Pituitary adenylate cyclase-activating polypeptide/vasoactive intestinal peptide (Part 2): biology and clinical importance in central nervous system and inflammatory disorders.

To discuss recent advances of vasoactive intestinal peptide/pituitary adenylate cyclase-activating polypeptide (VIP/PACAP) receptors in the selected central nervous system (CNS) and inflammatory disorders. Recent studies provide evidence that PACAP plays an important role in a number of CNS disorders, particularly the pathogenesis of headaches (migraine, etc.) as well as posttraumatic stress disorder and drug/alcohol/smoking addiction. VIP has important therapeutic effects in a number of autoimmune/inflammatory disorder such as rheumatoid arthritis. In some cases, these insights have advanced to therapeutic trials. Recent insights from studies of VIP/PACAP and their receptors in both CNS disorders (migraine, posttraumatic stress disorder, addiction [drugs, alcohol, smoking]) and inflammatory disorders [such as rheumatoid arthritis] are suggesting new treatment approaches. The elucidation of the importance of VIP/PACAP system in these disorders combined recent development of specific drugs acting on this system (i.e., monoclonal VIP/PACAP antibodies) will likely lead to importance novel treatment approaches in these diseases.

Myelin Oligodendrocyte Glycoprotein (MOG) Antibody Positive Patients in a Multi-Ethnic Canadian Cohort.

Introduction: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease is a recently described central nervous system (CNS) inflammatory disorder with phenotypic overlap with Neuromyelitis Optica Spectrum Disorder (NMOSD). NMOSD seronegative patients, and those with limited forms of the disorder, become suspects for MOG antibody-associated disease. We describe a multi-ethnic population with MOG antibody seropositivity from the University of British Columbia MS/NMO clinic.Methods: AQP4-antibody seronegative patients presenting 2005–2016 with CNS inflammatory disease suspicious for NMOSD, as well as 20 MS controls, were retrospectively tested for MOG-IgG1 antibodies by live cell-based assay at Oxford Autoimmune Neurology Diagnostic Laboratory (UK) and by a commercial fixed cell-based assay at MitogenDx (Calgary, Canada). Additional MOG seropositive cases were identified through routine clinical interaction (2016–2018) using one of these laboratories. Clinical data was reviewed retrospectively.Results: Retrospective testing identified 21 MOG seropositives (14 by live assay only, 3 by fixed assay only and 4 by both) representing 14% of the “NMOSD suspects” cohort. One multiple sclerosis (MS) control serum was MOG seropositive. Twenty additional MOG positive cases were identified prospectively. Of 42 patients (27 female), median disease onset age was 29 years (range 3–62; 9 pediatric cases), 20 (47%) were non-Caucasian, and 3 (7%) had comorbid autoimmune disease. Most common onset phenotypes were optic neuritis (23, 55%; 8 bilateral) and myelitis (9, 21%; 6 longitudinally extensive) Three of the patients in our cohort experienced cortical encephalitis; two presented with seizures. Onset was moderate-severe in 64%, but 74% had good response to initial steroid therapy. Cumulative relapse probability for the MOG positive group at 1 year was 0.428 and at 4 years was 0.628. Most had abnormal brain imaging, including cortical encephalitis and poorly demarcated subcortical and infratentorial lesions. Few “classic MS” lesions were seen. Optic nerve lesions (frequently bilateral) were long and predominantly anterior, but 5 extended to the chiasm. Spinal cord lesions were long and short, with involvement of multiple spinal regions simultaneously, including the conus medullaris.Conclusions: Our MOG seropositive patients display phenotypes similar to previous descriptions, including cortical lesions with seizures and conus medullaris involvement. Many patients relapsed, predominantly in a different CNS location from onset. Serologic data from two different cell-based antibody assays highlight the discrepancies between live and fixed testing for MOG antibodies.

The changing landscape of optic neuritis: a narrative review.

Optic neuritis (ON) is an inflammatory optic neuropathy that is often a harbinger of central nervous system (CNS) demyelinating disorders. ON is frequently misdiagnosed in the clinical arena, leading to either inappropriate management or diagnostic delays. As a result, patients may fail to achieve optimal recovery. The treatment response to corticosteroids and long term risk of multiple sclerosis was established in the first clinical trials conducted roughly 30years ago. Spontaneous resolution was observed in the vast majority of patients and intravenous high-dose corticosteroids hastened recovery; half of the patients eventually developed multiple sclerosis. Over the ensuing decades, the number of inflammatory conditions associated with ON has significantly expanded exposing substantial variability in the prognosis, treatment, and management of ON patients. ON subtypes can frequently be distinguished by distinct clinical, serological, and radiological profiles allowing expedited and specialized treatment. Guided by an increased understanding of the immunopathology underlying optic nerve and associated CNS injuries, novel disease management strategies are emerging to minimize vision loss, improve long-term surveillance strategies, and minimize CNS injury and disability. Knowledge regarding the clinical signs and symptoms of different ON subtypes is essential to guide acute therapy, prognosticate recovery, accurately identify underlying CNS inflammatory disorders, and facilitate study design for the next generation of clinical and translational trials.

Atypical optic neuritis: An overview.

Optic neuritis (ON) refers to conditions that involve inflammation of the optic nerve. Various autoantibodies have been found, which are associated with central nervous system inflammatory disorders and have provided much information about the immune targets and mechanisms that impact the prognosis, treatment, and recurrence of atypical ON. Therefore, neurologists and ophthalmologists together should work to find out clinical, laboratory, and imaging findings that may provide important clues to the etiology of atypical ON and its management. Various biomarkers have been identified to confirm and distinguish atypical optic neuritis from others. The purpose of this review is to present the current scenario of atypical ON and its clinical management.

The Role of Smoking on Patient with Multiple Sclerosis, Three Cases from Vlora City

Multiple Sclerosis (MS) is a chronic, inflammatory disorder of the central nervous system (CNS) with presumed autoimmune etiology. Lifestyle changes such as quitting smoking or reducing smoking doses, alcoholabstinence and maintaininghealthy weight are important for treatment success. Smoking has negative effect on MS patients, by worsening symptoms, creating more relapses and making it harder to treat the disease. Smoking MS patients that quit, may improve their condition. Method and materials: this study is performed in the hospital of Vlore during 2019 and we interviewed three MS hospitalized patients. We used 15 questions interview to get the patients opinion and information. They voluntarily participated in this study. Results: We interviewed three patients, from whom two smoked and one never did. The condition of the patients who smoked clearly became worse from the smoking, while the patient who did not smoke had a better prognosis by keeping the condition stable. One of the patients who smoked had quit two years ago. The three patients were aware of the negative effects that smoking had on their condition. Conclusions: Life quality of two of our patients changed when one of them started smoking and when one quit, the third keeps on deteriorating. In Albania there is an undisputable need to conduct such studies in order to follow up patients with MS, their smoking and the effect that it has on the progress of the disease.

Functional consequences of a close encounter between microglia and brain-infiltrating monocytes during CNS pathology and repair.

Neuroinflammation is recognized as an important factor contributing to the development and progression of several central nervous system (CNS) disorders. Upon CNS trauma or disease, parenchymal microglia highly proliferate and accumulate in and around the lesion site. In addition, blood-derived monocytes can infiltrate the inflamed CNS in response to cellular damage and/or a compromised blood-brain barrier. Both microglia and infiltrating monocytes are characterized by multiple functional states and can either display highly proinflammatory properties or promote resolution of inflammation and tissue regeneration. Despite sharing some basic immunologic functions, microglia and monocytes display many distinctive features, which ultimately define their contribution to neuropathology. Understanding how the innate immune system participates to brain disease is imperative to identify novel treatment options for CNS inflammatory disorders. In this context, existing and newly developed in vitro platforms for disease modeling are fundamental tools to investigate and modulate microglia and monocyte immune functions within a specific neuropathologic context. In this review, we first briefly summarize the current knowledge on microglia and monocyte ontogenesis, as well as their complex and interconnected contributions to the development of various CNS pathologies. Following the well-recognized concept that both microglia and monocytes can either exert neuroprotective functions or exacerbate tissue damage, we provide a comprehensive overview of cellular models currently available for in vitro study of neuroinflammatory responses. In this context, we highlight how simplified single-cell models may not always correctly recapitulate in vivo biology, hence future research should move toward novel models with higher and multicellular complexity.

Management of Idiopathic CNS inflammatory diseases during the COVID-19 pandemic: Perspectives and strategies for continuity of care from a South East Asian Center with limited resources.

The Covid-19 pandemic poses a grave health management challenge globally of unprecedented nature. Management of idiopathic Central Nervous system inflammatory disorders (iCNSID) such as Multiple sclerosis, Neuromyelitis optica and its spectrum disorders and related conditions during this pandemic needs to be addressed with affirmative and sustainable strategies in order to prevent disease related risks, medication related complications and possible COVID-19 disease associated effects.Global international iCNSIDs agencies and recent publications are attempting to address this but such guidance is not available in South East Asia. Here we outline prospectively qualitatively and quantitatively novel strategies at a tertiary center in Malaysia catering for neuroimmunological disorders despite modest resources during this pandemic.In this retrospective study with longitudinal follow-up, we describe stratification of patients for face to face versus virtual visits in the absence of formal teleneurology, stratification of patients for treatment according to disease activity, rescheduling, deferring initiation or extending treatment intervals of certain disease modifying therapies(DMT's) or immunosuppressants(IS), especially those producing lymphocyte depletion in MS and the continuation of IS in patients with NMO/NMOSD.Furthermore, we highlight the use off-label treatments such as Intravenous immunoglobulins/rituximab,bridging interferons/Teriflunomide temporarily replacing more potent DMT choices,supply challenges of IS/DMT's and tailoring blood watches and neuroimaging surveillance based on the current health needs to stave off the pandemic and prevent at risk patients with iCNSID/health care workers from possibly being exposed to the COVID-19.

NEUROPSYCHOLOGICAL CHARACTERISTIC OF COGNITIVE DISORDERS IN PATIENT WITH CLIPPERS SYNDROME

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a novel inflammatory central nervous system disorder. The diagnosis is made on the basis of the radiological, neurological, neuropathological data and responsiveness to steroids treatment. The aim of this paper is to present a neuropsychological characteristic of cognitive, executive and linguistic symptoms characteristic for patient with CLIPPERS disease. In this paper we present the case of a 42-year-old woman with hyperintense punctate foci in the pons, cerebellum, midbrain, thalamus, white matter of occipital lobes, with a short-term verbal memory deficits, mild deficiency in verbal and procedural learning, executive dysfunctions, hand-eye coordination impairment, psychomotor speed disabilities and dysarthria, associated with a chronic lymphocytic inflammation. In this challenging diagnosis of CLIPPERS, neuropsychological analysis of cognitive functions can be important to optimize the diagnosis and treatment.

Sarm1 knockout protects against early but not late axonal degeneration in experimental allergic encephalomyelitis.

Programmed axonal degeneration, also known as Wallerian degeneration, occurs in immune-mediated central nervous system (CNS) inflammatory disorders such as multiple sclerosis and the animal model experimental allergic encephalomyelitis (EAE). Sterile alpha and TIR domain containing protein 1 (SARM1) functions to promote programmed axonal degeneration. To test the hypothesis that loss of SARM1 will reduce axonal degeneration in immune-mediated CNS inflammatory disorders, the course and pathology of EAE was compared in Sarm1 knockout mice and wild type littermates. The clinical course of EAE was similar in Sarm1 knockout and wild type. Analysis of EAE in mice expressing neuronal yellow fluorescent protein (YFP) showed significantly less axonal degeneration in Sarm1 knockout mice compared to wild type littermates at 14 days post-induction of EAE. At 21 days post-induction, however, difference in axonal degeneration was not significant. At 42 days post-induction, Sarm1 knockout mice were indistinguishable from wild type with respect to markers of axonal injury, and were similar with respect to axonal density in the lumbar cords. There was no significant change in peripheral immune activation or CNS inflammatory cell infiltration associated with EAE in Sarm1 knockout mice. In conclusion, Sarm1 deletion delayed axonal degeneration early in the course of CNS inflammation, but did not confer long-term protection from axonal degeneration in an animal model of immune-mediated CNS inflammation.

Reactive Astrocytes Display Pro-inflammatory Adaptability with Modulation of Notch-PI3K-AKT Signaling Pathway Under Inflammatory Stimulation

Astrocytes are major glial cells critical in assisting the function of the central nervous system (CNS), but the functional changes and regulation mechanism of reactive astrocytes are still poorly understood in CNS diseases. In this study, mouse primary astrocytes were cultured, and inflammatory insult was performed to observe functional changes in astrocytes and the involvement of Notch-PI3K-AKT signaling activation through immunofluorescence, PCR, Western blot, CCK-8, and inhibition experiments. Notch downstream signal Hes-1 was clearly observed in the astrocytes, and Notch signal inhibitor GSI dose-dependently decreased the cleaved Notch-l level without an influence on cell viability. Inflammatory insult of lipopolysaccharide plus interferon-γ (LPS+IFNγ) induced an increase in pro-inflammatory cytokines, that is, iNOS, IL-1β, IL-6, and TNF, at the protein and mRNA levels in activated astrocytes, which was reduced or blocked by GSI treatment. The cell viability of the astrocytes did not show significant differences among different groups. While an increase in MyD88, NF-кB, and phosphor-NF-кB was confirmed, upregulation of PI3K, AKT, and phosphor-AKT was observed in the activated astrocytes with LPS+IFNγ insult and was reduced by GSI treatment. Inhibitor experiments showed that inhibition of Notch-PI3K-AKT signaling activation reduced the pro-inflammatory cytokine production triggered by LPS+IFNγ inflammatory insult. This study showed that the reactive astrocytes displayed pro-inflammatory adaptability through Notch-PI3K-AKT signaling activation in response to inflammatory stimulation, suggesting that the Notch-PI3K-AKT pathway in reactive astrocytes may serve as a promising target against CNS inflammatory disorders.

Neurological Spectrum Disorders Associated with Anti–MOG Antibody

Optic neuritis (ON) is an inflammatory disease of the optic nerve characterized by pain and visual lossand often associated with multiple sclerosis (MS) or neuromyelitis optica spectrum disorders (NMOSD).Autoantibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) have been reported in patientswith inflammatory central nervous system disorders including isolated optic neuritis (ON).Objective: To investigate the differences of clinical features, cerebrospinal fluid (CSF), MRI findings andresponse to steroid therapies between patients with optic neuritis (ON) who have myelin oligodendrocyteglycoprotein (MOG) antibodies and seronegative group. This study was done in a period between June2015 and July 2018, 65 patients were included in this study with ON who ophthalmologists had diagnosedas having or suspected to have ON with acute visual impairment and declined critical flicker frequency,abnormal findings of brain MRI, optical coherence tomography and fluorescein fundus angiography at theironset or recurrence. After exclusion of all patients who fulfilled the diagnostic criteria of neuromyelitisoptica (NMO)/NMO spectrum disorders (NMOSD), MS McDonald’s criteria, we defined 40 patients withidiopathic ON (12 males, 28 females, age range 15-60 years). Sera from patients were tested for antibodiesto MOG and aquaporin-4 (AQP4) with a cell-based assay.Results: 37.5% (15/40) were positive for MOG antibodies, 2.5% (1/40) were positive for AQP4 and 25(62.5%) were seronegative. Among the 15 patients with MOG antibodies, four had optic pain (p=0.007) andfive had prodromal infection (p=0.05). Two of the 15 MOG-positive patients showed significantly high CSFlevels of myelin basic protein (p=0.05) and none were positive for oligoclonal band in CSF. On MRIs, fiveMOG-positive patients showed high signal intensity on optic nerve, four had a cerebral lesion and two had aspinal cord lesion. Six of the eight MOG-positive patients had a good response to steroid therapy.Conclusions: The present results indicate that Patients with NMOSD and MOG positive antibodies havedistinct clinical features, fewer attacks and better recovery than seronegative patients.

Clippers the Brain Biter: An Adolescent’s Experience

Introduction: Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids is a rare inflammatory Central Nervous System disorder prominently affecting the brainstem. We present an adolescent’s reflection on this condition complicated with Epstein-Barr virus induced CNS Lymphoma. Case report: A 16-year-old boy presented about 5 years ago with a balance problem. He was diagnosed by MRI after ongoing debate whether this is juvenile multiple sclerosis. He initially responded to methylprednisolone but developed acute deterioration requiring 8 cycles of Infliximab and Methylprednisolone. He then confirmed cerebellar lymphoma 2 years later hence commenced on chemotherapy and radiotherapy after posterior fossa decompression. He gradually losses his motor skills, left hemiparesis and spasticity. He needs tracheostomy and gastrostomy due to poor bulbar function. Now, he is fully dependent and requires chest physiotherapy and suctioning and cystostomy for urinary incontinence. He has multiple PICU admissions due to recurrent aspiration, acute cerebellar oedema and post posterior fossa decompression. He worries about family breakdown as mum is his sole carer and having regular nightmare. He changed school to meet his care demands and unsure how to adapt to new environment. Social experience makes him anxious due to lack of understanding about his condition. He is evidently having low self-esteem and confidence. Discussion: Children palliative care team has been involved since diagnosis to support him and family. He is understandably depressed and clinical psychologist input bear minimal impact. He is fully aware of the current situation and his wish to rap Eminem’s songs like he used to do it before. Conclusion: Early aggressive treatment in CLIPPERS aim to prevent neuroaxonal loss. However, due to bellicose nature of the condition, the prognosis is relatively poor. Managing adolescent expectation after gradual deterioration is challenging especially, he is aware that achieving ‘normality’ is impossible as the treatment advancement still in limbo.

Tacrolimus is effective for neuromyelitis optica spectrum disorders with or without anti-AQP4 antibody

BackgroundNeuromyelitis optica spectrum disorders (NMOSD) are a group of inflammatory central nervous system disorders characterized by optic neuritis, transverse myelitis, and anti-aquaporin 4 (AQP4) antibody production. However, it has recently been shown that some cases of typical NMOSD can be anti-AQP4 antibody-negative as well. In this study, we retrospectively investigated the disorder relapse-suppressing effect of tacrolimus (TAC) when combined with prednisolone (PSL) in anti-AQP4 antibody-positive and -negative NMOSD cases. MethodsSubjects were NMOSD outpatients treated at our hospital in August 2016 who fulfilled the 2015 International Panel for NMO Diagnosis criteria and whose medical history before visiting our department was known; anti-myelin oligodendrocyte glycoprotein antibody-positive cases were excluded. We retrospectively investigated the annualized relapse rate (ARR) before and after combined TAC and PSL treatment in 50 NMOSD cases who had been using TAC with PSL for at least 1 year and whom we were also able to observe. ResultsThere were 42 anti-AQP4 antibody-positive cases and 8 negative cases. Observation periods of the anti-AQP4 antibody-positive cases were 1.1 years before TAC and 5.1 years after TAC. ARR before TAC was 1.0 and 0.08 after TAC, indicating a relapse-suppression rate of 92% (p < 0.001) and clear improvement. In the anti-AQP4 antibody-negative group, the observation period was 5.6 years before and 4.1 years after TAC. ARR before TAC was 0.5 and 0.07 after TAC. The relapse-suppression rate was 86% (p < 0.05), which was obviously as effective as in the anti-AQP4 antibody-positive group. PSL dose in the anti-AQP4 antibody-positive group was 15.0 mg/day at the start of TAC and was reduced to 6.3 mg/day after 2 years (p < 0.001). The Expanded Disability Status Scale (EDSS) score decreased from 4.5 at the start of TAC to 2.0 after 2 years in the anti-AQP4 antibody-positive group (p < 0.05), which was a clear improvement. ConclusionCombined use of TAC with PSL clearly suppressed relapse of both anti-AQP4 antibody-positive and -negative NMOSD. In the anti-AQP4 antibody-positive group, both PSL dose and EDSS score decreased compared with the dose at the start of the study.

Neuromyelitis optica spectrum disorders in South of Tunisia: A rare entity with low seroprevalence of anti-aquaporin 4 autoantibodies

IntroductionScreening for anti-aquaporin 4 (anti-AQP4) antibodies, a specific marker of neuromyelitis optica spectrum disorders (NMOSD), is part of the immunological investigation performed in a context of central nervous system (CNS) inflammation with optic neuritis and/or myelitis. The aim of our study was to evaluate the prevalence and the diagnostic value of anti-AQP4 antibodies in Tunisian patients with such inflammatory neurological conditions. MethodsDuring 3years, 170 consecutive serum samples of Tunisian patients with CNS inflammatory disorders and optico-spinal involvement were tested in our laboratory for anti-AQP4 antibodies using indirect immunofluorescence on transfected cells. ResultsThe global seroprevalence of anti-AQP4 in our study was 4.1% (7 cases/170). The diagnosis of NMOSD was made for the 7 seropositive patients and for 2 seronegative patients, which leads to a seroprevalence of 77.7% in our NMOSD subgroup. The detection of anti-AQP4 allowed the diagnosis of NMOSD in 4 patients with incomplete clinical presentation and 5 patients with positive antinuclear antibodies. In one case, seropositivity was detected in a second sample, one year after an initial seronegativity. ConclusionNMOSD seem to represent a rare etiology of optic neuritis and/or myelitis in Tunisian patients. Despite its low global seroprevalence in our study population, anti-AQP4 appears to be a very clinically relevant marker for NMOSD diagnosis. Repeating the screening in case of initial negativity could be interesting in clinical practice.

Cerebrospinal fluid lactate in dogs with inflammatory central nervous system disorders.

BackgroundCerebrospinal fluid (CSF) lactate is frequently used as a biomarker in humans with inflammatory central nervous system (CNS) disorders including bacterial meningitis and autoimmune disorders such as multiple sclerosis.HypothesisCerebrospinal fluid lactate concentrations are increased in a subset of dogs with inflammatory CNS disorders.AnimalsOne hundred two client‐owned dogs diagnosed with inflammatory CNS disease.MethodsCase series. Cases were identified both prospectively at the time of diagnosis and retrospectively by review of a CSF biorepository. Cerebrospinal fluid lactate was analyzed with a commercially available, handheld lactate monitor. Subcategories of inflammatory disease were created for comparison (eg, steroid‐responsive meningitis arteritis, meningoencephalitis of unknown etiology).ResultsCerebrospinal fluid lactate concentrations were above reference range in 47% of dogs (median, 2.5 mmol/L; range, 1.0‐11.7 mmol/L). There was no significant difference in lactate concentrations between disease subcategories (P = .48). Significant but weak correlations were noted between CSF lactate concentration and nucleated cell count (r = .33, P < .001), absolute large mononuclear cell count (r = .44, P < .001), absolute small mononuclear cell count (r = .39, P < .001), absolute neutrophil cell count (r = .24, P = .01), and protein (r = .44, P < .001). No correlation was found between CSF lactate concentration and CSF red blood cell count (P = .58). There was no significant association of CSF lactate concentration with survival (P = .27).Conclusions and Clinical ImportanceCerebrospinal fluid lactate concentrations could serve as a rapid biomarker of inflammatory CNS disease in dogs.