Relevance of CSF, Serum and Neuroimaging Markers in CNS and PNS Manifestation in COVID-19: A Systematic Review of Case Report and Case Series

Background: The data on neurological manifestations in COVID-19 patients has been rapidly increasing throughout the pandemic. However, data on CNS and PNS inflammatory disorders in COVID-19 with respect to CSF, serum and neuroimaging markers is still lacking. Methods: We 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” and “SARS-CoV-2 and PNS Complication” looking for transverse myelitis, vasculitis, acute disseminated encephalomyelitis, acute hemorrhagic necrotizing encephalitis (AHNE), cytotoxic lesion of the corpus callosum (CLOCC) and Guillain-Barré syndrome (GBS), published between 1 December 2019 to 15 July 2021. Results: Of the included 106 CNS manifestations in our study, CNS inflammatory disorders included transverse myelitis (17, 14.7%), AHNE (12, 10.4%), ADEM (11, 9.5%), CLOCC/MERS (10, 8.6%) and vasculitis (4, 3.4%). Others were nonspecific encephalopathy, encephalitis, seizures and stroke. Most patients were >50 years old (75, 70.8%) and male (64, 65.3%). Most (59, 63.4%) were severe cases of COVID-19 and 18 (18%) patients died. Of the included 94 PNS manifestations in our study, GBS (89, 92.7%) was the most common. Most of these patients were >50 years old (73, 77.7%) and male (59, 64.1%). Most (62, 67.4%) were non-severe cases of COVID-19, and ten patients died. Conclusion: Our comprehensive review of the clinical and paraclinical findings in CNS and PNS manifestations of COVID-19 provide insights on the pathophysiology of SARS-CoV-2 and its neurotropism. The higher frequency and severity of CNS manifestations should be noted by physicians for increased vigilance in particular COVID-19 cases

Anti-CD20 monoclonal antibody therapy in postpartum women with neurological conditions.

OBJECTIVE: Postpartum, patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) have increased risk for disease activity. Anti-CD20 IgG1 monoclonal antibodies (mAb) are increasingly used as disease-modifying therapies (DMTs). Patients may wish to both breastfeed and resume DMT postpartum. This study aimed to determine the transfer of anti-CD20 IgG1 mAbs, ocrelizumab, and rituximab (OCR/RTX), into mature breastmilk and describe maternal and infant outcomes. METHODS: Fifty-seven cis-women receiving OCR/RTX after 59 pregnancies and their infants were enrolled and followed up to 12M postpartum or 90 days post-infusion. Breastmilk was collected pre-infusion and serially up to 90 days and assayed for mAb concentration. Medical records and patients questionnaire responses were obtained to assess neurologic, breastfeeding, and infant development outcomes. RESULTS: The median average concentration of mAb in breastmilk was low (OCR: 0.08 μg/mL, range 0.05-0.4; RTX: 0.03 μg/mL, range 0.005-0.3). Concentration peaked 1-7 days post-infusion in most (77%) and was nearly undetectable after 90 days. Median average relative infant dose was <1% (OCR: 0.1%, range 0.07-0.7; RTX: 0.04%, range 0.005-0.3). Forty-three participants continued to breastfeed post-infusion. At 8-12 months, the proportion of infants growth between the 3rd and 97th World Health Organization percentiles did not differ for breastfed (36/40) and non-breastfed (14/16, p > 0.05) infants; neither did the proportion with normal development (breastfed: 37/41, non-breastfed: 11/13; p > 0.05). After postpartum infusion, two mothers experienced a clinical relapse. INTERPRETATION: These confirm minimal transfer of mAb into breastmilk. Anti-CD20 mAb therapy stabilizes MS activity before conception to the postpartum period, and postpartum treatments appears to be safe and well-tolerated for both mother and infant

Anti‐CD20 monoclonal antibody therapy in postpartum women with neurological conditions

Abstract Objective Postpartum, patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) have increased risk for disease activity. Anti‐CD20 IgG1 monoclonal antibodies (mAb) are increasingly used as disease‐modifying therapies (DMTs). Patients may wish to both breastfeed and resume DMT postpartum. This study aimed to determine the transfer of anti‐CD20 IgG1 mAbs, ocrelizumab, and rituximab (OCR/RTX), into mature breastmilk and describe maternal and infant outcomes. Methods Fifty‐seven cis‐women receiving OCR/RTX after 59 pregnancies and their infants were enrolled and followed up to 12M postpartum or 90 days post‐infusion. Breastmilk was collected pre‐infusion and serially up to 90 days and assayed for mAb concentration. Medical records and patients' questionnaire responses were obtained to assess neurologic, breastfeeding, and infant development outcomes. Results The median average concentration of mAb in breastmilk was low (OCR: 0.08 μg/mL, range 0.05–0.4; RTX: 0.03 μg/mL, range 0.005–0.3). Concentration peaked 1–7 days post‐infusion in most (77%) and was nearly undetectable after 90 days. Median average relative infant dose was  0.05) infants; neither did the proportion with normal development (breastfed: 37/41, non‐breastfed: 11/13; p > 0.05). After postpartum infusion, two mothers experienced a clinical relapse. Interpretation These confirm minimal transfer of mAb into breastmilk. Anti‐CD20 mAb therapy stabilizes MS activity before conception to the postpartum period, and postpartum treatments appears to be safe and well‐tolerated for both mother and infant

Differential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity

A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20dimCD8+ T cells with a highly inflammatory and central nervous system (CNS)-homing phenotype, were significantly inversely correlated with pretreatment MRI gadolinium-lesion counts, and also predictive of early disease activity observed after anti-CD20 initiation. Direct removal of pretreatment proinflammatory CD20dimCD8+ T cells had a greater contribution to treatment-associated changes in the CD8+ T cell pool than was the case for CD4+ T cells. Early disease activity following anti-CD20 initiation was not associated with reconstituting CD20dimCD8+ T cells, which were less proinflammatory compared with pretreatment. Similarly, this disease activity did not correlate with early reconstituting B cells, which were predominantly transitional CD19+CD24highCD38high with a more anti-inflammatory profile. We provide insights into the mode-of-action of anti-CD20 and highlight a potential role for CD20dimCD8+ T cells in MS relapse biology; their strong inverse correlation with both pretreatment and early posttreatment disease activity suggests that CD20-expressing CD8+ T cells leaving the circulation (possibly to the CNS) play a particularly early role in the immune cascades involved in relapse development