Is It Time for Ocrelizumab Extended Interval Dosing in Relapsing Remitting MS? Evidence from An Italian Multicenter Experience During the COVID-19 Pandemic.

In the COVID-19 pandemic era, safety concerns have been raised regarding the risk of severe infection following administration of ocrelizumab (OCR), a B-cell-depleting therapy. We enrolled all relapsing remitting multiple sclerosis (RRMS) patients who received maintenance doses of OCR from January 2020 to June 2021. Data were extracted in December 2021. Standard interval dosing (SID) was defined as a regular maintenance interval of OCR infusion every 6 months, whereas extended interval dosing (EID) was defined as an OCR infusion delay of at least 4 weeks. Three infusions were considered in defining SID vs. EID (infusions A, B, and C). Infusion A was the last infusion before January 2020. The primary study outcome was a comparison of disease activity during the A-C interval, which was defined as either clinical (new relapses) or radiological (new lesions on T1-gadolinium or T2-weighted magnetic resonance imaging (MRI) sequences). Second, we aimed to assess confirmed disability progression (CDP). A total cohort of 278 patients (174 on SID and 104 on EID) was enrolled. Patients who received OCR on EID had a longer disease duration and a higher rate of vaccination against severe acute respiratory syndrome-coronavirus 2 (p < 0.05). EID was associated with an increased risk of MRI activity during the A-C interval (OR 5.373, 95% CI 1.203-24.001, p = 0.028). Being on SID or EID did not influence CDP (V-Cramer 0.47, p = 0.342). EID seemed to be associated with a higher risk of MRI activity in our cohort. EID needs to be carefully considered for OCR-treated patients.

Secondary cluster headache due to a contralateral demyelinating periaqueductal gray matter lesion.

OBJECTIVES/BACKGROUND: Tension-type headache and migraine without aura are the most common primary headaches occurring in people with demyelinating diseases, whereas cluster headache (CH) can be considered exceptional. The location of demyelinating lesions could be strategic in these cases, involving areas interacting with the trigeminovascular system. METHODS AND RESULTS: We report a case of a 54-year-old woman with right-sided CH as the initial manifestation of multiple sclerosis and showing a left dorsal brainstem lesion on magnetic resonance imaging, in the region of the dorsal longitudinal fasciculus (DLF). CONCLUSION: Our case seems to suggest a possible role of the DLF in the process that leads to CH attacks. Because neuroimaging clearly showed a lesion contralateral to CH pain, we hypothesize that some fibers from periaqueductal gray matter project to the contralateral side, besides the known ipsilateral connections.

Antibiotic Use and Risk of Multiple Sclerosis: A Nested Case-Control Study in Emilia-Romagna Region, Italy.

INTRODUCTION: Known risk factors for multiple sclerosis (MS) include smoking, a low vitamin D status, obesity, and EBV, while the inflammatory feature of the disease strongly suggests the presence of additional infectious agents. The association between use of antibiotics and MS risk that could shed light on these factors is still undetermined. We aimed to evaluate the association between antibiotics and MS risk, in the Emilia-Romagna region (RER), Italy. METHODS: All adult patients with MS seen at any RER MS center (2015-2017) were eligible. For each of the 877 patients included, clinical information was collected and matched to 5 controls (RER residents) (n = 4,205) based on age, sex, place of residence, and index year. Information on antibiotic prescription was obtained through the linkage with the RER drug prescription database. RESULTS: Exposure to any antibiotic 3 years prior to the index year was associated with an increased MS risk (OR = 1.52; 95% CI = 1.29-1.79). Similar results were found for different classes. No dose-response effect was found. DISCUSSION/CONCLUSIONS: Our results suggest an association between the use of antibiotics and MS risk in RER population. However, further epidemiological studies should be done with information on early life and lifestyle factors.

Copper deficiency-associated myelopathy in cryptogenic hyperzincemia: a case report.

Copper deficiency syndrome is an underestimated cause of posterior myelitis. We describe the case of a 41-year-old woman, who developed a subacute ataxic paraparesis associated with low back pain. Her 3T spine MRI showed a thin hyperintense FS-Echo T2 longitudinally extensive lesion involving the posterior columns of the cervical cord (from C2 to C6). An extensive diagnostic work-up excluded other causes of myelopathy and blood tests pointed out hypocupremia and mild hyperzincemia. Patients affected by this rare form of oligoelement deficiency typically develop progressive posterior column dysfunction with sensory ataxia and spasticity, sometimes associated with sensori-motor polyneuropathy. Clinical and radiological characteristics of posterior myelopathy due to copper deficiency are briefly reviewed. Physicians should be aware of this condition since a prompt introduction of copper supplementation can avoid progression of the neurological damage.

The contribution of enhancing lesions in monitoring multiple sclerosis treatment: is gadolinium always necessary?

BACKGROUND: MRI is highly sensitive for monitoring of disease activity and treatment efficacy in MS. Patients treated with disease modifying therapy (DMT), who experience MRI activity, including contrast-enhancing lesions (CEL) or new/enlarged T2 lesions, should be evaluated for a switch to more effective treatment. Due to recent evidence of gadolinium (Gd) accumulation in the brain after repeated administration of Gd-based contrast agents, FDA recommended to limit its use. AIM: To investigate the proportion of cases in which MRI activity would be detectable only using contrast-enhanced T1-weighted sequences.Secondary aims were to assess the presence of clinical or demographic variables associated with reactivation of pre-existing lesions and to analyse therapeutic consequences of different types of MRI lesions. METHODS: We retrospectively evaluated brain MRI scans, performed between 2014 and 2018, in patients treated with DMT for at least 6 months. RESULTS: We analysed 906 scans in 255 patients. New/enlarged T2 lesions were detected in 13.7% of cases, CEL in 3.5%, CEL without new T2 lesions (old lesions reactivated) in 1.1%. No variables were associated with old lesions reactivated. CEL with T2 equivalent were at higher risk of DMT switch, compared with new/enlarged T2 lesions without corresponding CEL (OR 4.0, 95% CI 1.5-10.4, p  = 0.005). CONCLUSIONS: Reactivation of pre-existing lesions is limited to a tiny fraction of MRI studies. Gd + T1-weighted images could be omitted, in patients treated with DMT for at least 6 months, without relevant loss of information.

Five- and seven-year prognostic value of new effectiveness measures (NEDA, MEDA and six-month delayed NEDA) in relapsing-remitting multiple sclerosis.

The concept of 'no evidence of disease activity' (NEDA) has been proposed as a surrogate marker for treatment response in relapsing-remittent multiple sclerosis (MS). However, there is no agreement regarding its prognostic value, nor about the starting time for evaluation of drug effectiveness. Aim of this study was to investigate if the status preservation of two-year NEDA, 'minimal evidence of disease activity' (MEDA) and six-month delayed NEDA (6md-NEDA, with a "rebaseline" six months after the treatment start) predicts the achievement of long-term disability outcomes (EDSS score ≥ 4.0 or 6.0, 3-month confirmed disability progression (CDP) or conversion to secondary progressive MS) after five and seven years of disease. A total of 271 treatment courses (TCs) were analyzed in this retrospective study, involving all TCs started with any disease-modifying treatments (DMT). Overall, 72 (27%), 77 (28%) and 92 (34%) TCs maintained NEDA, MEDA and 6md-NEDA status after a two-year treatment. NEDA, MEDA and 6md-NEDA TCs had a lower risk of attaining all disability outcomes, compared to 'evidence of disease activity' (EDA) TCs. NEDA status determined a lower risk of CDP after five (OR 0.18, 95% CI 0.07-0.45, p < .0001) and seven years of disease (OR 0.15, 95% CI 0.05-0.44, p < .0001), with high positive (90%) and low negative (42%) predictive value, good specificity and low sensitivity. NEDA TCs had a lower risk of CDP compared to MEDA TCs after seven years (OR 0.30, 95% CI 0.10-0.91, p = .04). 6md-NEDA had a small impact on the improvement of NEDA prognostic value.

Location of first attack predicts the site of subsequent relapses in multiple sclerosis.

Predictors of attack location in relapsing-remitting multiple sclerosis (RRMS) are poorly known. It has been suggested that the site of the first relapse may influence the location of the subsequents. We aimed to ascertain this hypothesis in a sample of patients consecutively recruited in two Italian MS Centres, with at least two MS attacks. The following data were collected from medical records: demographic data, locations involved in the first two (or three) MS attacks (optic nerve, spinal cord, brain stem/cerebellum, cerebral hemispheres, according to symptoms presented), time elapsed between relapses and onset of disease-modifying treatment (DMT). We enrolled 199 patients (67% females; MS onset age 30.0 ± 8.69 years), in 148 of whom we could define the precise attack location. In 70/148 patients (47%) the second attack involved exactly the same location as the first. There was an increased risk of relapsing in the same location of the first attack when this involved the optic nerve (OR 4.5, 95% CI 2.2-9.2, p < 0.0001), the brainstem/cerebellum (OR 3.5, 95% CI 1.7-6.9, p < 0.0001), or the spinal cord (OR 3.0, 95% CI 1.5-5.9, p = 0.001). The location of third relapse (N = 90) was equally influenced by the site of first attack. In 24 patients with optic neuritis in both the two first attacks, the side coincided in 50% of cases. The location of first attack has a major role in influencing the site of subsequent ones in RRMS.

Conversion to Secondary Progressive Multiple Sclerosis: Patient Awareness and Needs. Results From an Online Survey in Italy and Germany.

Background: Few studies have investigated the experiences of patients around the conversion to secondary progressive multiple sclerosis (SPMS). ManTra is a mixed-method, co-production research project conducted in Italy and Germany to develop an intervention for newly-diagnosed SPMS patients. In previous project actions, we identified the needs and experiences of patients converting to SPMS via literature review and qualitative research which involved key stakeholders. Aims: The online patient survey aimed to assess, on a larger and independent sample of recently-diagnosed SPMS patients: (a) the characteristics associated to patient awareness of SPMS conversion; (b) the experience of conversion; (c) importance and prioritization of the needs previously identified. Methods: Participants were consenting adults with SPMS since ≤5 years. The survey consisted of three sections: on general and clinical characteristics; on experience of SPMS diagnosis disclosure (aware participants only); and on importance and prioritization of 33 pre-specified needs. Results: Of 215 participants, those aware of their SPMS diagnosis were 57% in Italy vs. 77% in Germany (p = 0.004). In both countries, over 80% of aware participants received a SPMS diagnosis from the neurologist; satisfaction with SPMS disclosure was moderate to high. Nevertheless, 28-35% obtained second opinions, and 48-56% reported they did not receive any information on SPMS. Participants actively seeking further information were 63% in Germany vs. 31% in Italy (p < 0.001). Variables independently associated to patient awareness were geographic area (odds ratio, OR 0.32, 95% CI 0.13-0.78 for Central Italy; OR 0.21, 95% CI 0.08-0.58 for Southern Italy [vs. Germany]) and activity limitations (OR 7.80, 95% CI 1.47-41.37 for dependent vs. autonomous patients). All pre-specified needs were scored a lot or extremely important, and two prioritized needs were shared by Italian and German patients: "physiotherapy" and "active patient care involvement." The other two differed across countries: "an individualized health care plan" and "information on social rights and policies" in Italy, and "psychological support" and "cognitive rehabilitation" in Germany. Conclusions: Around 40% of SPMS patients were not aware of their disease form indicating a need to improve patient-physician communication. Physiotherapy and active patient care involvement were prioritized in both countries.

Spinal cord lesions are frequently asymptomatic in relapsing-remitting multiple sclerosis: a retrospective MRI survey.

BACKGROUND: Spinal cord (SC) involvement correlates with poor prognosis in patients with multiple sclerosis (MS). Nevertheless, there is no consensus on the use of SC-MRI at follow-up, mainly because of the belief that SC lesions are nearly always symptomatic. OBJECTIVES: The aim of the present study was to investigate the frequency of asymptomatic SC combined unique activity (CUA, new/enlarging T2 or gadolinium-positive [Gd+] lesions) on MRI in a cohort of patients diagnosed with clinically isolated syndrome (CIS) or relapsing-remitting MS (RRMS). METHODS: We retrospectively investigated all scans showing SC-CUA in patients with CIS or RRMS referred to a single Italian MS centre. We determined whether they were symptomatic and whether they had associated brain radiological activity. RESULTS: In 340 SC-MRI scans with SC-CUA (230 patients), SC-CUA was asymptomatic in 31.2%; 12.1% of SC-CUA had neither clinical activity nor brain radiological activity (44.5% and 25.4%, respectively, considering only follow-up SC-CUA). At multivariate analysis asymptomatic SC-CUAs were associated with older age at onset (34.0 ± 10.37 vs 31.0 ± 9.99 years, p = 0.006), non-spinal onset (76.4 vs 47.4%, p < 0.001), lower EDSS score at MRI (1.8 ± 0.93 vs 2.4 ± 1.28, p = 0.001) and lower number of Gd+ SC lesions (0.1 ± 0.33 vs 0.3 ± 0.54, p = 0.04), compared to symptomatic SC-CUAs. CONCLUSIONS: A substantial proportion of our patients had SC-CUA without clinical symptoms and/or without concomitant brain MRI activity. In these patients, SC-CUA was the only sign of disease activity, suggesting that regular SC-MRI follow-up is required for reliable assessment of radiological activity and may improve the management of patients with MS.

The real-world effectiveness of natalizumab and fingolimod in relapsing-remitting multiple sclerosis. An Italian multicentre study.

BACKGROUND: Both natalizumab and fingolimod are highly effective in the treatment of relapsing-remitting MS (RRMS). In the absence of head-to-head trials, some observational studies have compared their efficacy with conflicting results. OBJECTIVES: To investigate the efficacy of natalizumab and fingolimod in a cohort of RRMS patients in an observational, retrospective study. METHODS: We included all consecutive RRMS patients who started natalizumab or fingolimod in three MS centres with a follow-up to 24 months and analysed clinical and brain MRI data after propensity score (PS) matching. RESULTS: After 1:1 PS-matching, we retained 102 patients in both groups, with similar baseline features. After 24 months, although both drugs resulted highly effective, patients treated with natalizumab had a lower relapse risk (HR 0.59 CI 95% 0.35-1.00, p = 0.048) and higher time to first relapse. MRI-combined-unique-activity was found in 31.8% of natalizumab vs 43.2% of fingolimod treated patients (p = 0.28). We found a higher proportion of patients with confirmed regression of disability (19.2 vs 6.7%, p = 0.03) and 2-year no evidence of disease activity (NEDA-3, 39.0% vs 22.0%, p = 0.04) in the natalizumab group. CONCLUSIONS: Both drugs were highly effective in our cohort. Natalizumab proved superior in inducing regression of disability and 2-year-NEDA-3.

Successful intravenous immunoglobulin treatment in relapsing MOG-antibody-associated disease.

Treatment of MOG Ab-associated disease is poorly standardized: several drugs have been employed, with variable results. A 50-year-old Caucasian male was admitted to hospital in 2009, with severe acute transverse myelitis. A brain and spinal cord MRI showed multiple demyelinating lesions and cerebrospinal fluid analysis revealed no oligoclonal bands (OCBs). A diagnosis of multiple sclerosis (MS) was made. He was treated with interferon-beta 1a, then with fingolimod, and finally with rituximab. All these treatments were ineffective: he experienced several spinal and brainstem relapses, with residual disability. Finally, an empirical therapy with IVIg was started. Calling into question the diagnosis of MS, we performed anti-MOG test (positive). IVIg therapy was continued and the patient experienced only one mild relapse during a 24-month follow-up. Our patient, with an aggressive and atypical MOG Ab-associated disease, showed a very good response to longterm IVIg treatment.

Correlation between cortical lesions and cognitive impairment in multiple sclerosis.

OBJECTIVES: Gray matter (GM) damage is well known as a fundamental aspect of multiple sclerosis (MS). Above all, cortical lesions (CLs) burden, detectable at MRI with double inversion recovery (DIR) sequences, has been demonstrated to correlate with cognitive impairment (CI). The aim of this study was to investigate the role of CLs number in predicting CI in a cohort of patients with MS in a clinical practice setting. MATERIALS AND METHODS: Thirty consecutive patients with MS presenting CLs (CL+) at high-field (3.0 T) MRI 3D-DIR sequences and an even group of MS patients without CLs (CL-) as a control, were investigated with the Rao Brief Repeatable Battery of Neuropsychological Tests (BRB), Version A. Total and lobar CLs number were computed in CL+ patients. RESULTS: Among the sixty patients with MS enrolled, forty-seven (78.3%) had a relapsing-remitting course, while thirteen (21.7%) a progressive one, eleven secondary progressive, and two primary progressive. Compared to CL-, CL+ patients had a greater proportion of progressive forms (p = .03). The most affected region was the frontal lobe (73.3% of patients), followed by temporal and parietal ones (both 60.0%). Multivariate (logistic regression) analysis revealed a significant correlation between total CLs number and the presence of mild cognitive impairment defined as pathologic score in at least one BRB test (p = .04); it was also correlated with deficit at PASAT 3 (p = .05) and Stroop Test (p = .02). CONCLUSIONS: We confirmed CLs number, evaluated with a technique quite commonly available in clinical practice, as a predictive factor of CI in patients with MS, in order to improve the diagnosis and management of CI and monitor potential neuroprotective effects of therapies.