Disclosing the Novel Protective Mechanisms of Ocrelizumab in Multiple Sclerosis: The Role of PKC Beta and Its Down-Stream Targets.

Ocrelizumab (OCR) is a humanized anti-CD20 monoclonal antibody approved for both Relapsing and Primary Progressive forms of Multiple Sclerosis (MS) treatment. OCR is postulated to act via rapid B cell depletion; however, by analogy with other anti-CD20 agents, additional effects can be envisaged, such as on Protein Kinase C (PKC). Hence, this work aims to explore novel potential mechanisms of action of OCR in peripheral blood mononuclear cells from MS patients before and after 12 months of OCR treatment. We first assessed, up-stream, PKCßII and subsequently explored two down-stream pathways: hypoxia-inducible factor 1 alpha (HIF-1α)/vascular endothelial growth factor (VEGF), and human antigen R (HuR)/manganese-dependent superoxide dismutase (MnSOD) and heat shock proteins 70 (HSP70). At baseline, higher levels of PKCßII, HIF-1α, and VEGF were found in MS patients compared to healthy controls (HC); interestingly, the overexpression of this inflammatory cascade was counteracted by OCR treatment. Conversely, at baseline, the content of HuR, MnSOD, and HSP70 was significantly lower in MS patients compared to HC, while OCR administration induced the up-regulation of these neuroprotective pathways. These results enable us to disclose the dual positive action of OCR: anti-inflammatory and neuroprotective. Therefore, in addition to B cell depletion, the effect of OCR on these molecular cascades can contribute to counteracting disease progression.

Beyond Myelin Oligodendrocyte Glycoprotein and Aquaporin-4 Antibodies: Alternative Causes of Optic Neuritis.

Optic neuritis (ON) is the most common cause of vision loss in young adults. It manifests as acute or subacute vision loss, often accompanied by retrobulbar discomfort or pain during eye movements. Typical ON is associated with Multiple Sclerosis (MS) and is generally mild and steroid-responsive. Atypical forms are characterized by unusual features, such as prominent optic disc edema, poor treatment response, and bilateral involvement, and they are often associated with autoantibodies against aquaporin-4 (AQP4) or Myelin Oligodendrocyte Glycoprotein (MOG). However, in some cases, AQP4 and MOG antibodies will return as negative, plunging the clinician into a diagnostic conundrum. AQP4- and MOG-seronegative ON warrants a broad differential diagnosis, including autoantibody-associated, granulomatous, and systemic disorders. These rare forms need to be identified promptly, as their management and prognosis are greatly different. The aim of this review is to describe the possible rarer etiologies of non-MS-related and AQP4- and MOG-IgG-seronegative inflammatory ON and discuss their diagnoses and treatments.

A score that predicts aquaporin-4 IgG positivity in patients with longitudinally extensive transverse myelitis.

BACKGROUND AND PURPOSE: Longitudinally extensive transverse myelitis (LETM) associated with aquaporin-4 autoantibodies (AQP4-IgG) can cause severe disability. Early diagnosis and prompt treatment are critical to prevent relapses. A novel score is described based on clinical and neuroimaging characteristics that predicts AQP4-IgG positivity in patients with LETM. METHODS: Patients were enrolled both retrospectively and prospectively from multiple Italian centers. Clinical and neuroimaging characteristics of AQP4-IgG positive and negative patients were compared through univariate and multivariate analysis. RESULTS: Sixty-six patients were included. Twenty-seven (41%) were AQP4-IgG positive and median age at onset was 45.5 years (range 19-81, interquartile range 24). Female sex (odds ratio [OR] 17.9, 95% confidence interval [CI] 2.6-381.9; p = 0.014), tonic spasms (OR 45.6, 95% CI 3.1-2197; p = 0.017) and lesion hypointensity on T1-weighted images (OR 52.9, 95% CI 6.8-1375; p = 0.002) were independently associated with AQP4-IgG positivity. The AQP4-IgG positivity in myelitis (AIM) score predicted AQP4-IgG positivity with 85% sensitivity and 95% specificity. Positive and negative likelihood ratios were 16.6 and 0.2 respectively. The inter-rater and intra-rater agreement in the score application were both excellent. CONCLUSIONS: The AIM score predicts AQP4-IgG positivity with good sensitivity and specificity in patients with a first episode of LETM. The score may assist clinicians in early diagnosis and treatment of AQP4-IgG positive LETM.

Gender Differences in the Clinical Presentation of Cluster Headache: A Role for Sexual Hormones?

Introduction: Cluster Headache (CH) is a well-characterized primary headache that mostly affects men, although a progressive decrease in the male-to-female ratio has occurred over time. Available, but partly discordant, data on gender-related differences in CH suggest a more marked overlapping with migraine features in female subjects. The aim of this study is to carefully evaluate the female/male distribution of the typical migraine-associated symptoms and of other features of the disease in a large and well-characterized clinical population of CH subjects. Materials and Methods: We enrolled consecutive CH patients regularly followed at the tertiary Headache Science Center of the IRCCS Mondino Foundation of Pavia (Italy) who attended the Center for a CH bout between September 2016 and October 2018. The subjects were requested to fill in a semi-structured questionnaire focused on the presence of migraine-associated symptoms, familiarity for migraine and, for women, the relationship of CH onset with the reproductive events of their life. These data were compared and integrated with those recorded over time in our clinical database, including demographics and clinical characteristics. The primary outcome was the gender distribution of subjects who satisfied ICHD-III criterion D for migraine-associated symptoms. The secondary outcomes were represented by the gender distribution of individual migraine-associated symptoms and of other disease features included in the questionnaire and/or in the clinical database. Results: Data from 163 males (mean age 41.46 ± 10.37) and 87 females suffering of CH (mean age 42.24 ± 11.95) were analyzed. We did not find a different distribution between sexes as regards the primary outcome measure (F 73.6%, M 65.6%, p = 0.200). However, when we analyzed the occurrence of individual symptoms, nausea and osmophobia were reported more frequently by women (p = 0.048, p = 0.037, respectively). Ptosis and nasal congestion were predominant in females (p = 0.017 and p = 0.01, respectively), while enlarged temporal artery was more frequently reported by men (p = 0.001). Distribution of pain across the head tended to be larger in women, extending more frequently to the zygomatic (p = 0.050), parietal (p = 0.049), and frontal (p = 0.037) regions. Women had a longer mean attack duration (p = 0.004) than men. In CH women the onset of disease often corresponded with moments of important changes in the levels of sexual hormones (menarche, post-partum, menopause). Concomitant thyroid diseases and psychiatric disorders were observed more frequently in women than in men, while snoring and smoking habit was reported by a higher percentage of men than women. Conclusion: We confirmed the presence of distinct gender-related differences in CH and added some novel information that lends credibility to the hypothesis of a closer phenotypical similarity between CH and migraine in the female sex. These observations are relevant for advancing our knowledge on CH pathophysiology, as well as for a more refined diagnostic framing and improved management of the disease.