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    • Brain biopsy was performed from the white matter lesion arou

    2022-11-30

    Brain biopsy was performed from the white matter lesion around the posterior horn of the right lateral ventricle, and revealed inflammatory demyelination, such as myelin loss with relative preservation of axons, astrocytosis immnolabeled by NHS-SS-Biotin against glial fibrillary acidic protein, infiltration of the mononuclear cells around blood vessels, and numerous macrophages (Fig. 1C, D). CD3-positive T lymphocytes were mixed with foamy macrophages and reactive astrocytes in the brain parenchyma and perivascular spaces (Fig. 1E, F). In the biopsied tissue, some CD8-positve lymphocytes were observed; however, CD4-positive or CD20-positive lymphocytes were absent. No acid-fast bacteria were disclosed by Ziehl-Neelsen stain in the brain tissue obtained. Moreover, no malignant cells were observed. The clinicopathological diagnosis of MS was given according to the McDonald criteria (Polman et al., 2011), neuroimaging findings, and the neuropathological features. We started intravenous methylprednisolone pulse therapy followed by oral corticosteroid therapy. Both his symptoms and the abnormal findings on the brain and cervical MRI improved rapidly after beginning of the treatments. In addition, the ADA levels in the CSF also decreased (13.0IU/L). After nine months, he had a relapse with dysarthria, dysphagia, and ataxia of the right arm. Brain MRI revealed hyperintense lesions in the right midbrain and the right occipital lobe with gadolinium enhancement. ADA levels in the CSF increased to 20.6IU/L. Serum ADA was not remarkably increased (20.4IU/L; normal range, 5.0–20.0IU/L). His manifestations were ameliorated after high-dose methylprednisolone pulse therapy.
    Discussion In this patient, old age at the onset and an elevation of the CSF levels of ADA initially suggested tuberculous meningitis with tuberculoma formation, although the ring-enhanced lesion might support a clinical diagnosis of MS. The brain biopsy, negative results in laboratory tests for Mycobacterium tuberculum, and clinical course showing relapse with remission after the therapy confirmed the diagnosis of MS. Corticosteroid therapy also resulted in decrease of the CSF ADA levels. ADA is an enzyme that catalyzes the deamination of adenosine, and is related to lymphocytic proliferation and differentiation (Erel et al., 1998). Although expression of ADA is found in many tissues in humans, the number of CD4-positive T lymphocytes have been reported to be associated with ADA activity in tuberculous pleural effusions (Gaga et al., 2005). High ADA levels in tuberculosis would be related to response of a subset of activated T lymphocytes to tuberculosis antigens. Similar lymphocytic activation may underlie other disorders reported with elevation of ADA in the CSF (Pettersson et al., 1991). Elevation of serum ADA activities in patients with MS was reported (Polachini et al., 2014); however, alterations of ADA in CSF have never been observed. At the time of the relapse, we examined ADA levels in both the CSF and the serum. Elevation of ADA levels in CSF was remarkable; however, serum concentration of ADA was slightly increased. It is obvious that elevation of ADA in the CSF in our patient was unconnected with alterations of ADA in serum. Our patient indicates that MS could be one of the inflammatory CNS disorders associated with elevation of ADA levels in CSF. T lymphocytes observed in the biopsied tissue of our patient were mainly CD8-positive in contrast to the report that CD4-positive T lymphocytes may be related to ADA activity in pleural tuberculous effusion (Gaga et al., 2005). Although further investigation is essential to elucidate the mechanisms underlying elevation of ADA levels in patients with inflammatory demyelinating lesions, ADA in CSF could be an useful biomarker for diagnosis and treatment in patients with MS.
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    Declaration of conflicting interests
    Acknowledgement
    Introduction Adenosine, a homeostatic neuromodulator, is an emerging candidate neurobiological substrate with effects on multiple neurotransmitter pathways (Boison, 2008). In addition, adenosine plays an important role in early brain development and regulation of brain immune responses (Cunha and Cunha, 2001), and may contribute to the neurodevelopmental deviations implicated in schizophrenia. Serum level of adenosine deaminase (ADA), an adenosine metabolizing enzyme, has been suggested as an important peripheral biomarker of adenosine signaling in neuropsychiatric disorders (Elgün et al., 1999; Herken et al., 2007; Stubbs et al., 1982) especially in schizophrenia, given that a hypoadenosinergic state has been linked to its pathogenesis (Lara et al., 2006).