Cerebrospinal fluid/serum gradient of IgG is associated with disability at acute attacks of neuromyelitis optica

Kim, Sung Min; Waters, Patrick; Vincent, Angela; Go, Min Jin; Park, Kyung Seok; Sung, Jung‐Joon; Lee, Kwang Woo

doi:10.1007/s00415-011-6086-x

Cited by 24 publications

(23 citation statements)

References 15 publications

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“…NMO IgG is detected in CSF and levels are predicted by recent relapse and high serum NMO IgG titer [26, 43]. Increased total CSF protein and elevated CSF lactate and albumin levels also correlate with NMO disease severity and acute relapse, suggesting a relationship between dysfunction at the blood–CSF barrier and disability [26, 31, 82]. Conversely, in a study of ten NMO patients with CSF NMO IgG measured at relapse, follow-up measurements after treatment revealed that a reduction in NMO IgG in CSF correlated with clinical improvement, though serum levels were not correlated with remission [11].…”

Section: Discussionmentioning

confidence: 99%

Pathogenic implications of cerebrospinal fluid barrier pathology in neuromyelitis optica

et al. 2017

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Pathogenic autoantibodies associated with neuromyelitis optica (NMO) induce disease by targeting aquaporin-4 (AQP4) water channels enriched on astrocytic endfeet at blood–brain interfaces. AQP4 is also expressed at cerebrospinal fluid (CSF)–brain interfaces, such as the pial glia limitans and the ependyma and at the choroid plexus blood–CSF barrier. However, little is known regarding pathology at these sites in NMO. Therefore, we evaluated AQP4 expression, microglial reactivity, and complement deposition at pial and ependymal surfaces and in the fourth ventricle choroid plexus in 23 autopsy cases with clinically and/or pathologically confirmed NMO or NMO spectrum disorder. These findings were compared to five cases with multiple sclerosis, five cases of choroid plexus papilloma, and five control cases without central nervous system disease. In the NMO cases, AQP4 immunoreactivity was reduced relative to control levels in the pia (91%; 21/23), ependyma (56%; 9/16), and choroid plexus epithelium (100%; 12/12). AQP4 immunoreactivity was normal in MS cases in these regions. Compared to MS, NMO cases also showed a focal pattern of pial and ependymal complement deposition and more pronounced microglial reactivity. In addition, AQP4 loss, microglial reactivity, and complement deposition colocalized along the pia and ependyma only in NMO cases. Within the choroid plexus, AQP4 loss was coincident with C9neo immunoreactivity on epithelial cell membranes only in NMO cases. These observations demonstrate that NMO immunopathology extends beyond perivascular astrocytic foot processes to include the pia, ependyma, and choroid plexus, suggesting that NMO IgG-induced pathological alterations at CSF–brain and blood–CSF interfaces may contribute to the occurrence of ventriculitis, leptomeningitis, and hydrocephalus observed among NMO patients. Moreover, disruption of the blood–CSF barrier induced by binding of NMO IgG to AQP4 on the basolateral surface of choroid plexus epithelial cells may provide a unique portal for entry of the pathogenic antibody into the central nervous system.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1682-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Pathogenic implications of cerebrospinal fluid barrier pathology in neuromyelitis optica

et al. 2017

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“…NMO is distinguished from MS by the presence in the serum of a pathogenic autoantibody to aquaporin-4 (AQP4-Ab) [7], by severe optic and spinal attacks [8], and by the presence of a severely disrupted blood–brain barrier [9]. The relative frequency of NMO to that of MS (NMO/MS ratio) was previously reported to be high in Thailand (1.4) [10] and Japan (0.29–0.59) [11,12], compared to that in Europe (0.024) [13] and Latin America (0.073–0.26) [14].…”

Section: Introductionmentioning

confidence: 99%

Characterization of the spectrum of Korean inflammatory demyelinating diseases according to the diagnostic criteria and AQP4-Ab status

et al. 2014

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BackgroundThe relative frequencies of demyelinating diseases among Korean patients with idiopathic inflammatory demyelinating disease of the central nervous system (IIDD) have not been sufficiently studied. We therefore describe a cohort of 203 patients with IIDD from three centers in Korea whose syndromes were identified precisely according to international clinical criteria and autoantibody to aquaporin 4 (AQP4-Ab) status.MethodsIn total, 260 consecutive patients were screened and 203 were included from three hospitals in Korea. All were tested for AQP4-Ab by using a cell-based assay. Patients who met the criteria for definite neuromyelitis optica (NMO) or had a positive AQP4-Ab test result were defined as the NMO group. Among the others, patients were assessed if they had acute disseminated encephalomyelitis, multiple sclerosis (MS), acute transverse myelitis, optic neuritis, or other demyelinating disease as a clinically isolated syndrome of the brain.ResultsEighteen percent of patients were classified as the NMO group, 2% as acute disseminated encephalomyelitis, 18% as MS, 41% as acute transverse myelitis, 11% as optic neuritis, and 8% as other clinically isolated syndrome of the brain. AQP4-Ab was positive in 18% of patients and the relative frequency of NMO to MS (NMO/MS ratio) was 1.06. The mean duration of follow up in our patients was 64 months.ConclusionsAmong Korean patients with idiopathic inflammatory demyelinating diseases, the incidence of NMO may be similar to that of MS, and the overall positivity of AQP4-Ab could be lower than previously reported. In addition, acute transverse myelitis that is not associated with MS or NMO can be relatively common in these patients. Further population-based studies with AQP4-Ab are needed to determine the exact incidence of NMO and other idiopathic inflammatory demyelinating diseases in Korea.

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“…Serum from NMO patients was tested for the presence of AQP4-Ab at the Weatherall Institute of Molecular Medicine (John Radcliffe Hospital, Oxford, UK) using a cell-based assay as described previously [33]. Serum and CSF samples were obtained from NMO patients during the acute stage and before the initiation of steroid pulse treatment [34]. The number of white blood cells (WBC) and levels of protein, glucose, albumin, and IgG were also assessed in the CSF of patients.…”

Section: Methodsmentioning

confidence: 99%

“…Patients who have severe attacks of NMO can experience disruption of the blood brain barrier (BBB) [34]. Considering that some OHCs, such as 27-OHC, can enter into the CNS from the circulation, the disruption of the BBB in severe NMO patients may affect the CSF OHC concentration.…”

Section: Methodsmentioning

confidence: 99%

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Hydroxycholesterol Levels in the Serum and Cerebrospinal Fluid of Patients with Neuromyelitis Optica Revealed by LC-Ag+CIS/MS/MS and LC-ESI/MS/MS with Picolinic Derivatization: Increased Levels and Association with Disability during Acute Attack

et al. 2016

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Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system (CNS). Hydroxycholesterols (OHCs), metabolites of CNS cholesterol, are involved in diverse cellular responses to inflammation and demyelination, and may also be involved in the pathogenesis of NMO. We aimed to develop a sensitive and reliable method for the quantitative analysis of three major OHCs (24S-, 25-, and 27-OHCs), and to evaluate their concentration in the cerebrospinal fluid (CSF) and serum of patients with NMO. The levels of the three OHCs in the serum and CSF were measured using liquid chromatography-silver ion coordination ionspray tandem mass spectrometry and liquid chromatography-electrospray ionization tandem mass spectrometry with picolinyl ester derivatization, respectively. The linear range was 5–250 ng/mL for 24S- and 27-OHC, and 0.5–25 ng/mL for 25-OHC in serum, and was 0.1–5 ng/mL for 24S- and 27-OHC, and 0.03–1 ng/mL for 25-OHC in CSF. Precision and accuracy were 0.5%–14.7% and 92.5%–109.7%, respectively, in serum, and were 0.8%–7.7% and 94.5%–119.2%, respectively, in CSF. Extraction recovery was 82.7%–90.7% in serum and 68.4%–105.0% in CSF. When analyzed in 26 NMO patients and 23 control patients, the 25-OHC (0.54 ± 0.96 ng/mL vs. 0.09 ± 0.04 ng/mL, p = 0.032) and 27-OHC (2.68 ± 3.18 ng/mL vs. 0.68 ± 0.25 ng/mL, p = 0.005) were increased in the CSF from NMO patients. When we measured the OHCCSF index that controls the effects of blood–brain barrier disruption on the level of OHC in the CSF, the 27-OHCCSF index was associated with disability (0.723; 95% confidence interval (CI)– 0.181, 0.620; p = 0.002), while the 24-OHCCSF index (0.518; 95% CI– 1.070, 38.121; p = 0.040) and 25-OHCCSF index (0.677; 95% CI– 4.313, 18.532; p = 0.004) were associated with the number of white blood cells in the CSF of NMO patients. Our results imply that OHCs in the CNS could play a role in the pathogenesis of NMO.

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Cerebrospinal fluid/serum gradient of IgG is associated with disability at acute attacks of neuromyelitis optica

Cited by 24 publications

References 15 publications

Pathogenic implications of cerebrospinal fluid barrier pathology in neuromyelitis optica

Pathogenic implications of cerebrospinal fluid barrier pathology in neuromyelitis optica

Characterization of the spectrum of Korean inflammatory demyelinating diseases according to the diagnostic criteria and AQP4-Ab status

Hydroxycholesterol Levels in the Serum and Cerebrospinal Fluid of Patients with Neuromyelitis Optica Revealed by LC-Ag+CIS/MS/MS and LC-ESI/MS/MS with Picolinic Derivatization: Increased Levels and Association with Disability during Acute Attack

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