Neuromyelitis optica (NMO, Devic's syndrome), long considered a clinical variant of multiple sclerosis, is now regarded as a distinct disease entity Major progress has been made in the diagnosis and treatment of NMO since aquaporin-4 antibodies (AQP4-Ab; also termed NMO-IgG) were first described in 2004 In this review, the Neuromyelitis Optica Study Group (NEMOS) summarizes recently obtained knowledge on NMO and highlights new developments in its diagnosis and treatment, based on current guidelines, the published literature and expert discussion at regular NEMOS meetings Testing of AQP4-Ab is essential and is the most important test in the diagnostic work-up of suspected NMO, and helps to distinguish NMO from other autoimmune diseases Furthermore, AQP4-Ab testing has expanded our knowledge of the clinical presentation of NMO spectrum disorders (NMOSD) In addition, imaging techniques, particularly magnetic resonance imaging of the brain and spinal cord, are obligatory in the diagnostic workup It is important to note that brain lesions in NMO and NMOSD are not uncommon, do not rule out the diagnosis, and show characteristic patterns Other imaging modalities such as optical coherence tomography are proposed as useful tools in the assessment of retinal damage Therapy of NMO should be initiated early Azathioprine and rituximab are suggested as first-line treatments, the latter being increasingly regarded as an established therapy with long-term efficacy and an acceptable safety profile in NMO patients Other immunosuppressive drugs, such as methotrexate, mycophenolate mofetil and mitoxantrone, are recommended as second-line treatments Promising new therapies are emerging in the form of anti-IL6 receptor, anti-complement or anti-AQP4-Ab biologicals

https://link.springer.com/content/pdf/10.1007%2Fs00415-013-7169-7.pdf

Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS)

Transient ischemic attack

Leuko-araiosis と血管性痴呆

The term 'neuromyelitis optica' ('Devic's syndrome', NMO) refers to a syndrome characterized by optic neuritis and myelitis. In recent years, the condition has raised enormous interest among scientists and clinical neurologists, fuelled by the detection of a specific serum immunoglobulin (Ig)G reactivity (NMO-IgG) in up to 80% of patients with NMO. These autoantibodies were later shown to target aquaporin-4 (AQP4), the most abundant water channel in the central nervous system (CNS). Here we give an up-to-date overview of the clinical and paraclinical features, immunopathogenesis and treatment of NMO. We discuss the widening clinical spectrum of AQP4-related autoimmunity, the role of magnetic resonance imaging (MRI) and new diagnostic means such as optical coherence tomography in the diagnosis of NMO, the role of NMO-IgG, T cells and granulocytes in the pathophysiology of NMO, and outline prospects for new and emerging therapies for this rare, but often devastating condition.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cei.12271

Neuromyelitis optica: clinical features, immunopathogenesis and treatment

Objective: To investigate distinct white matter and cortical gray matter pathology in neuromyelitis optica spectrum disorders (NMOSDs) and multiple sclerosis (MS) at 7-T MRI in a cross-sectional study. Methods: We included 10 patients with NMOSDs and 18 patients with MS in our 7-T MRI study. The imaging protocol comprised T2*-weighted fast low angle shot and turbo inversion recovery magnitude sequences. White matter and cortical gray matter lesions were assessed with special regard to their (perivascular) localization as well as the expression of a hypointense rim. Results: In total, we detected 140 white matter lesions in 7 of 10 patients with NMOSDs. In contrast to MS plaques, which were nearly exclusively centered by a small vein (92%) and showed a characteristic hypointense rim (23%), white matter changes in patients with NMOSDs were nonspecific in appearance and were only infrequently neighbored by a blood vessel (49 lesions [35%], p = 0.003). Hypointense rims were very rarely detectable (3 lesions [2%], p Conclusion: The MRI features of white matter and the absence of cortical gray matter findings substantially differentiate NMOSDs from MS and can be used as a potential marker to distinguish these 2 entities. The fact that cortical pathology is common in MS but is not present in patients with NMOSDs may reflect the difference in the underlying pathogenesis.

Distinct lesion morphology at 7-T MRI differentiates neuromyelitis optica from multiple sclerosis

Preserving the integrity of the blood-brain barrier (BBB) is beneficial to avoid further brain damage after acute ischemic stroke (AIS). Astrocytes, an important component of the BBB, promote BBB breakdown in subjects with AIS by secreting inflammatory factors. The glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) protects the BBB and reduces brain inflammation from cerebral ischemia, and GLP-1R is expressed on astrocytes. However, the effect of Ex-4 on astrocytes in subjects with AIS remains unclear. In the present study, we investigated the effect of Ex-4 on astrocytes cultured under oxygen-glucose deprivation (OGD) plus reoxygenation conditions and determined whether the effect influences bEnd.3 cells. We used various methods, including permeability assays, western blotting, immunofluorescence staining, and gelatin zymography, in vitro and in vivo. Ex-4 reduced OGD-induced astrocyte-derived vascular endothelial growth factor (VEGF-A), matrix metalloproteinase-9 (MMP-9), chemokine monocyte chemoattractant protein-1 (MCP-1), and chemokine C-X-C motif ligand 1 (CXCL-1). The reduction in astrocyte-derived VEGF-A and MMP-9 was related to the increased expression of tight junction proteins (TJPs) in bEnd.3 cells. Ex-4 improved neurologic deficit scores, reduced the infarct area, and ameliorated BBB breakdown as well as decreased astrocyte-derived VEGF-A, MMP-9, CXCL-1, and MCP-1 levels in ischemic brain tissues from rats subjected to middle cerebral artery occlusion. Ex-4 reduced the activation of the JAK2/STAT3 signaling pathway in astrocytes following OGD. Based on these findings, ischemia-induced inflammation and BBB breakdown can be improved by Ex-4 through an astrocyte-dependent manner.

/pdf/the-glucagon-like-peptide-1-receptor-agonist-reduces-34z4nel1a1.pdf

The glucagon-like peptide-1 receptor agonist reduces inflammation and blood-brain barrier breakdown in an astrocyte-dependent manner in experimental stroke

Cerebral small vessel disease (CSVD) is a broad category of cerebrovascular diseases which primarily affect the perforating arterioles, capillaries and venules with multiple distinct etiologies. In spite of distinctive pathogenesis, CSVD shares similar neuroimaging markers, including recent small subcortical infarct, lacune of presumed vascular origin, white matter hyperintensity of presumed vascular origin, perivascular space and cerebral microbleeds. The radiological features of neuroimaging markers are indicative for etiological analysis. Furthermore, in sporadic arteriosclerotic pathogenesis associated CSVD, the total CSVD burden is a significant predictor for stroke events, global cognitive impairment, psychiatric disorders and later life quality. This review aims to summarize the radiological characteristics as well as the clinical implication of CSVD markers and neuroimaging interpretation for CSVD symptomatology.

Cerebral small vessel disease: neuroimaging markers and clinical implication

Background 
Brain stem lesions are common in patients with acute disseminated encephalomyelitis (ADEM), neuromyelitis optica (NMO), and multiple sclerosis (MS).


Objectives 
To investigate comparative brain stem lesions on magnetic resonance imaging (MRI) among adult patients with ADEM, NMO, and MS.


Methods 
Sixty-five adult patients with ADEM (n = 17), NMO (n = 23), and MS (n = 25) who had brain stem lesions on MRI were enrolled. Morphological features of brain stem lesions among these diseases were assessed.


Results 
Patients with ADEM had a higher frequency of midbrain lesions than did patients with NMO (94.1% vs. 17.4%, P<0.001) and MS (94.1% vs. 40.0%, P<0.001); patients with NMO had a lower frequency of pons lesions than did patients with MS (34.8% vs. 84.0%, P<0.001) and ADEM (34.8% vs. 70.6%, P = 0.025); and patients with NMO had a higher frequency of medulla oblongata lesions than did patients with ADEM (91.3% vs. 35.3%, P<0.001) and MS (91.3% vs. 36.0%, P<0.001). On the axial section of the brain stem, the majority (82.4%) of patients with ADEM showed lesions on the ventral part; the brain stem lesions in patients with NMO were typically located in the dorsal part (91.3%); and lesions in patients with MS were found in both the ventral (44.0%) and dorsal (56.0%) parts. The lesions in patients with ADEM (100%) and NMO (91.3%) had poorly defined margins, while lesions of patients with MS (76.0%) had well defined margins. Brain stem lesions in patients with ADEM were usually bilateral and symmetrical (82.4%), while lesions in patients with NMO (87.0%) and MS (92.0%) were asymmetrical or unilateral.


Conclusions 
Brain stem lesions showed various morphological features among adult patients with ADEM, NMO, and MS. The different lesion locations may be helpful in distinguishing these diseases.

/pdf/comparative-brain-stem-lesions-on-mri-of-acute-disseminated-zork1uymkd.pdf

Comparative Brain Stem Lesions on MRI of Acute Disseminated Encephalomyelitis, Neuromyelitis Optica, and Multiple Sclerosis

BACKGROUND A recent study demonstrated that the inflammatory response accompanying necrotic brain injury played an important role in stroke. Thus, inhibition of this response may help to stop the expansion of infarcts. It has been also shown that the spleen, a major peripheral immune organ, plays a role in stroke-induced immune responses. This study aimed to establish rat models of middle cerebral artery occlusion (MCAO) and to investigate the effect of splenectomy and possible mechanisms in that rat models. METHODS Infarct size in a stroke model was measured with the Nissl body staining method, numbers of inflammatory cells in ischemic regions were detected by immunofluorescence staining, and inflammatory factors were assayed by enzyme-linked immunosorbent assay and real-time polymerase chain reaction (PCR) in brain homogenates and sera. The significance of differences was determined by one-way analysis of variance (ANOVA) followed by the least significant difference post hoc test. RESULTS Infarct size in the brain of rats that underwent splenectomies 2 weeks before permanent MCAO ((34.93 ± 3.23)%) was over 50% smaller than that of rats subjected to the stroke surgery alone ((74.33 ± 2.36)%, P < 0.001; (77.30 ± 2.62)%, P < 0.001). Lower numbers of T cells, neutrophils, and macrophages in brain tissue and lower levels of pro-inflammatory cytokines, such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α, were observed in rats that underwent splenectomies, compared with the two other groups, but splenectomized rats showed higher levels of the anti-inflammatory factor IL-10 in the brain. CONCLUSION The mechanism(s) by which splenectomy protects brain from damage induced by stroke may correlate with the decreased numbers of inflammatory cells and changes in inflammatory cytokines.

Splenectomy protects experimental rats from cerebral damage after stroke due to anti-inflammatory effects.

Neuromyelitis optica spectrum disorder (NMOSD) can coexist with non-organ-specific or organ-specific autoimmune diseases. The aim of this study was to investigate and compare the features between NMOSD without and with autoimmune diseases, and NMOSD with non-organ-specific and organ-specific autoimmune diseases. One hundred and fifty five NMOSD patients without autoimmune diseases (n = 115) and with autoimmune diseases (n = 40) were enrolled. NMOSD with autoimmune diseases were divided by organ-specific autoimmune diseases. The clinical, laboratory and magnetic resonance imaging features between two groups were assessed. Motor deficit was less frequent in NMOSD patients with non-organ-specific autoimmune diseases (p = 0.024). Cerebrospinal fluid white blood cell and protein, serum C-reactive protein and immunoglobulin G were lower in NMOSD patients without autoimmune diseases, while several autoantibodies seropositivity and thyroid indexes were significantly higher in NMOSD patients with autoimmune diseases (p   0.05). NMOSD patients with autoimmune diseases had higher brain abnormalities than NMOSD without autoimmune diseases (p < 0.001). The characteristics between NMOSD without and with autoimmune diseases were similar. NMOSD with autoimmune diseases have high frequency of brain abnormalities.

/pdf/neuromyelitis-optica-spectrum-disorders-without-and-with-2e7rgzgsd8.pdf

Bingjun Zhang

Papers

The glucagon-like peptide-1 receptor agonist reduces inflammation and blood-brain barrier breakdown in an astrocyte-dependent manner in experimental stroke

Cerebral small vessel disease: neuroimaging markers and clinical implication

Comparative Brain Stem Lesions on MRI of Acute Disseminated Encephalomyelitis, Neuromyelitis Optica, and Multiple Sclerosis

Splenectomy protects experimental rats from cerebral damage after stroke due to anti-inflammatory effects.

Neuromyelitis optica spectrum disorders without and with autoimmune diseases