Incidence and determinants of seizures in multiple sclerosis: a meta-analysis of randomised clinical trials.

BACKGROUND: Seizures are reported to be more prevalent in individuals with multiple sclerosis (MS) compared with the general population. Existing data predominantly originate from population-based studies, which introduce variability in methodologies and are vulnerable to selection and reporting biases. METHODS: This meta-analysis aims to assess the incidence of seizures in patients participating in randomised clinical trials and to identify potential contributing factors. Data were extracted from 60 articles published from 1993 to 2022. The pooled effect size, representing the incidence rate of seizure events, was estimated using a random-effect model. Metaregression was employed to explore factors influencing the pooled effect size. RESULTS: The meta-analysis included data from 53 535 patients and 120 seizure events in a median follow-up of 2 years. The pooled incidence rate of seizures was 68.0 per 100 000 patient-years, significantly higher than the general population rate of 34.6. Generalised tonic-clonic seizures were the most common type reported, although there was a high risk of misclassification for focal seizures with secondary generalisation. Disease progression, longer disease duration, higher disability levels and lower brain volume were associated with a higher incidence of seizures. Particularly, sphingosine-1-phosphate receptor (S1PR) modulators exhibited a 2.45-fold increased risk of seizures compared with placebo or comparators, with a risk difference of 20.5 events per 100 000 patient-years. CONCLUSIONS: Patients with MS face a nearly twofold higher seizure risk compared with the general population. This risk appears to be associated not only with disease burden but also with S1PR modulators. Our findings underscore epilepsy as a significant comorbidity in MS and emphasise the necessity for further research into its triggers, preventive measures and treatment strategies.

Assessing treatment response to oral drugs for multiple sclerosis in real-world setting: a MAGNIMS Study.

BACKGROUND: The assessment of treatment response is a crucial step for patients with relapsing-remitting multiple sclerosis on disease-modifying therapies (DMTs). We explored whether a scoring system developed within the MAGNIMS (MRI in Multiple Sclerosis) network to evaluate treatment response to injectable drugs can be adopted also to oral DMTs. METHODS: A multicentre dataset of 1200 patients who started three oral DMTs (fingolimod, teriflunomide and dimethyl fumarate) was collected within the MAGNIMS network. Disease activity after the first year was classified by the 'MAGNIMS' score based on the combination of relapses (0-≥2) and/or new T2 lesions (<3 or ≥3) on brain MRI. We explored the association of this score with the following 3-year outcomes: (1) confirmed disability worsening (CDW); (2) treatment failure (TFL); (3) relapse count between years 1 and 3. The additional value of contrast-enhancing lesions (CELs) and lesion location was explored. RESULTS: At 3 years, 160 patients experienced CDW: 12% of them scored '0' (reference), 18% scored '1' (HR=1.82, 95% CI 1.20 to 2.76, p=0.005) and 37% scored '2' (HR=2.74, 95% CI 1.41 to 5.36, p=0.003) at 1 year. The analysis of other outcomes provided similar findings. Considering the location of new T2 lesions (supratentorial vs infratentorial/spinal cord) and the presence of CELs improved the prediction of CDW and TFL, respectively, in patients with minimal MRI activity alone (one or two new T2 lesions). CONCLUSIONS: Early relapses and substantial MRI activity in the first year of treatment are associated with worse short-term outcomes in patients treated with some of the oral DMTs.

Disability patterns in multiple sclerosis: A meta-analysis on RAW and PIRA in the real-world context.

OBJECTIVE: To summarize the current evidence on relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) through a quantitative synthesis of real-world studies. METHODS: Scientific databases were searched to identify suitable articles. Random-effects meta-analyses, subgroup analyses and meta-regression models were ran to provide pooled estimates of RAW and PIRA events and to identify their potential moderators (PROSPERO registration: CRD42024503895). RESULTS: Eighteen articles met the eligibility criteria, with a pooled sample size of 52,667 patients (93% relapsing-remitting, 6% clinically isolated syndrome and 1% progressive) followed for 2.4 to 12.1 years, yielding to 415,825 patient-years. Pooled event rates for RAW and PIRA were 1.6 (95 confidence interval (CI) = 1.1-2.1) and 3.1 (95% CI = 2.3-3.9) per 100 patient-years, respectively. Less RAW events were found in cohorts including patients with progressive course (ß = -0.069, p = 0.006) and under high-efficacy disease-modifying treatments (DMTs) (ß = -0.031, p = 0.007), while PIRA events were directly related to older age (ß = 0.397, p = 0.027). In addition, we found significant differences in PIRA event rates according to the criteria adopted to define confirmed disability accrual (p < 0.05). DISCUSSION: PIRA accounts for most events causing disability accumulation in the real-world setting, even at the earlier disease stages, whereas RAW represents a less frequent phenomenon, likely due to effective treatments. The detection and statistical analysis of PIRA outcomes pose challenges, raising the risk of erroneous inference. When interpreting our findings, caution is needed given the wide heterogeneity of included studies.

Influence of cognition on the correlation between objective and subjective upper limb measures in people with multiple sclerosis.

BACKGROUND: A comprehensive assessment of upper limb (UL) function is mandatory in people with multiple sclerosis (PwMS), and the use of multiple objective and subjective measures is advisable. Findings on the role of cognitive impairment on the assessment of UL function are scant and inconclusive. The present study investigated the influence of cognitive function on the distribution of objective and subjective UL measures and on their association. METHODS: In the cross-sectional study, subjects with a diagnosis of MS, age ≥ 18 years, right-hand dominance, no presence of orthopedic UL impairment, or other neurological diseases were recruited. The assessment protocol included the Nine-Hole Peg Test (9-HPT), Box and Block Test (BBT), and hand grip strength (HGS), a validated PROM (MAM-36), and the Symbol Digit Modalities Test (SDMT). RESULTS: Two hundred forty-six PwMS were recruited (158 females, mean age = 51.65 ± 13.45 years; mean EDSS = 5.10 ± 1.88) Subject with mild-to-moderate cognitive impairment (SDMT ≤ - 2 SD of normative values) scored lower on the 9-HPT and higher on the BBT and MAM-36 when compared with subject with no cognitive impairment. Cognitive impairment showed a small but significant effect on the association between 9-HPT scores and the MAM-36. DISCUSSION: Findings suggest that cognitive impairment is associated with subjects' performance on 9-HPT, BBT, and MAM-36 (but not HGS), resulting in scores indicating a poorer UL function. Interestingly, cognitive impairment slightly affected the congruence between subjective and objective UL measures, although only minor differences in the correlation pattern across groups reporting different cognitive performances emerged.

Longitudinal characterisation of B and T-cell immune responses after the booster dose of COVID-19 mRNA-vaccine in people with multiple sclerosis using different disease-modifying therapies.

BACKGROUND: The decline of humoral response to COVID-19 vaccine led to authorise a booster dose. Here, we characterised the kinetics of B-cell and T-cell immune responses in patients with multiple sclerosis (PwMS) after the booster dose. METHODS: We enrolled 22 PwMS and 40 healthcare workers (HCWs) after 4-6 weeks from the booster dose (T3). Thirty HCWs and 19 PwMS were also recruited 6 months (T2) after the first dose. Antibody response was measured by anti-receptor-binding domain (RBD)-IgG detection, cell-mediated response by an interferon (IFN)-γ release assay (IGRA), Th1 cytokines and T-cell memory profile by flow cytometry. RESULTS: Booster dose increased anti-RBD-IgG titers in fingolimod-treated, cladribine-treated and IFN-ß-treated patients, but not in ocrelizumab-treated patients, although antibody titres were lower than HCWs. A higher number of fingolimod-treated patients seroconverted at T3. Differently, T-cell response evaluated by IGRA remained stable in PwMS independently of therapy. Spike-specific Th1-cytokine response was mainly CD4+ T-cell-mediated, and in PwMS was significantly reduced (p<0.0001) with impaired IL-2 production compared with HCWs at T3. In PwMS, total Th1 and IFN-γ CD4+ T-cell responders to spike protein were increased from T2 to T3.Compared with HCWs, PwMS presented a higher frequency of CD4+ and CD8+ terminally differentiated effector memory cells and of CD4+ effector memory (TEM) cells, independently of the stimulus suggesting the association of this phenotype with MS status. CD4+ and CD8+ TEM cell frequency was further increased at T3 compared with T2. CONCLUSIONS: COVID-19 vaccine booster strengthens humoral and Th1-cell responses and increases TEM cells in PwMS.

Symptomatic COVID-19 course and outcomes after three mRNA vaccine doses in multiple sclerosis patients treated with high-efficacy DMTs.

BACKGROUND: Little is known about COVID-19 course and outcomes after a third booster dose of mRNA vaccine against SARS-CoV-2 (mRNA-Vax) in patients with multiple sclerosis (pwMS) treated with ocrelizumab (OCR) and fingolimod (FNG), which showed a weakened immune response to mRNA-vax. OBJECTIVES: The aim of this study was to evaluate COVID-19 course and outcomes in pwMS on OCR and FNG after receiving the third dose of mRNA-Vax and to compare it with pwMS on natalizumab (NTZ). METHODS: Inclusion criteria: >18 years of age, being treated with OCR/FNG/NTZ since the first mRNA-Vax dose; COVID-19 after a third booster dose of mRNA-Vax; no steroids use. RESULTS: Overall, 290 pwMS (79 NTZ, 126 OCR, and 85 FNG) from 17 Italian MS centers were included. Age, Expanded Disability Status Scale (EDSS) score, MS phenotype, disease, and treatment duration were significantly different across groups. PwMS who had COVID-19 on OCR and FNG compared with those on NTZ were slightly more symptomatic with higher hospitalization rates (11.1% vs 7.1% vs 1.3%, respectively). Regression models showed that the majority of the differences observed were not related to the disease-modifying treatments (DMTs) used. No fatal cases were observed. CONCLUSION: Our results support the effectiveness of the third booster dose of mRNA-Vax against severe forms of COVID-19 in pwMS treated with OCR and FNG.

Correlation between patient-reported manual ability and three objective measures of upper limb function in people with multiple sclerosis.

BACKGROUND AND PURPOSE: Upper limb (UL) function is often affected in people with multiple sclerosis (PwMS) and is typically assessed through objective measures, including the Nine Hole Peg Test (9-HPT), Box and Block Test (BBT), and Hand Grip Strength (HGS). It is important to include the subjective perspective of PwMS in the assessment. This study aims to evaluate associations between Manual Ability Measure-36 (MAM-36) and 9-HPT, BBT, and HGS in MS. METHODS: The cross-sectional study included five Italian centers. Inclusion criteria were age ≥ 18 years, MS diagnosis, and stable disease course. Exclusion criteria were bilateral UL paralysis, and concomitant orthopedic or neurological diseases. RESULTS: A total of 199 PwMS were included: 128 female, mean age = 50.7 ± 13.0 years, 119 relapsing-remitting MS (RRMS), 31 primary and 49 secondary progressive MS, mean disease duration = 14.0 ± 10.4, years, mean Expanded Disability Status Scale (EDSS) = 4.6 ± 2.0. The MAM-36 showed small correlations with 9-HPT, BBT, and HGS. Correlations between MAM-36 and 9-HPT and BBT were highest among subjects with EDSS ≥ 6 and progressive MS. MAM-36 and HGS showed the highest correlations in subjects with EDSS ≤ 5 and RRMS. Combining 9-HPT and HGS provided the strongest predictive power over the MAM-36. CONCLUSIONS: Correlations between objective measures and MAM-36 were small to moderate, meaning that objective measures do not match subjects' perception of UL function. The combination of 9-HPT and HGS measures can help improve the assessment of UL function in activities of daily living.

Brain and cognitive reserve mitigate balance dysfunction in multiple sclerosis.

BACKGROUND: Approximately two-thirds of patients with multiple sclerosis (MS) complain different degrees of balance dysfunction, but some of them are able to withstand considerable disease burden without an overt balance impairment. Here, we tested the hypothesis that brain and cognitive reserve lessen the effect of MS-related tissue damage on balance control. METHODS: We measured the postural sway of 148 patients and 74 sex- and age-matched healthy controls by force platform under different conditions reflecting diverse neuro-pathological substrates of balance dysfunction: eyes opened (EO), eyes closed (EC), and while performing the Stroop test, i.e., dual-task (DT). Lesion volumes on T2-hyperintense and T1-hypointense sequences, and normalized brain volume provided estimations of MS-related tissue damage in patients with MS. Hierarchical linear regressions explored the protective effect against the MS-related tissue damage of intracranial volume and educational attainment (proxies for brain and cognitive reserve, respectively) on balance. RESULTS: Larger intracranial volume and high educational attainment mitigated the detrimental effect of MS-related tissue damage on postural sway under EO (adjusted-R2=0.20 and 0.27, respectively, p<0.01) and DT (adjusted-R2=0.22 and 0.30, respectively, p<0.06) conditions. Neither educational level nor brain size was associated with postural sway under EC condition. CONCLUSION: Our findings suggest a protective role of brain and cognitive reserve even on balance, an outcome that relies on both motor control and higher order processing resources. The lack of a protective effect on postural sway under EC condition confirms that this latter outcome is closer associated with spinal cord rather than brain damage.

Evaluation of mild-to-moderate COVID-19 through dual-task paradigm: a longitudinal case-controlled study.

INTRODUCTION: Coronavirus disease (COVID-19) was associated with cognitive alterations affecting everyday life activities. These need input integration of both motor and cognitive systems. The study aim is to evaluate cognitive-motor interference phenomenon in previously independent patients with mild-to-moderate COVID-19 (PwMCOVID-19) compared with healthy controls (HC), through dual-task (DT) paradigm. METHODS: PwMCOVID-19 were included if being independent at home, had no previous referred cognitive impairment, mechanical ventilation or oxygen need. They were assessed at admission and after 6 months with a motor-cognitive DT test (counting backward by twos while walking 2 min). HC were enrolled as control group. Differences between single-task (ST) and DT performance, DT effect (DTE) and task prioritization amongst groups and during time points were analyzed. RESULTS: One-hundred PwMCOVID-19 [mean age=67.32(12.08) years; 53 M/47 F] and 39 HC [mean age=63.11(9.90) years; 20 M/19 F] were recruited. Upon T0, PwMCOVID-19 showed lower cognitive and motor DT performances than ST and HC. Mutual interference pattern was predominant in PwMCOVID-19. At T1, 41 PwMCOVID-19 were examined [mean age=64.85(10.75); 22 M/19 F]. They had a worse DT performance compared to ST, although DT improved at T1. A stronger cognitive ST-DT difference was present at T0, compared to ST-DT difference at T1, while motor ST-DT difference was unchanged over time in PwCOVID-19. CONCLUSION: In PwMCOVID-19, there is an impairment of DT counting while walking at baseline and after 6 months from hospitalization, with a more pronounced DT mutual interference pattern at T0. After 6 months, the motor and cognitive ST and DT performances ameliorated, not reaching the HC level.

Dynamic Evolution of Humoral and T-Cell Specific Immune Response to COVID-19 mRNA Vaccine in Patients with Multiple Sclerosis Followed until the Booster Dose.

This study characterizes antibody and T-cell immune responses over time until the booster dose of COronaVIrus Disease 2019 (COVID-19) vaccines in patients with multiple sclerosis (PwMS) undergoing different disease-modifying treatments (DMTs). We prospectively enrolled 134 PwMS and 99 health care workers (HCWs) having completed the two-dose schedule of a COVID-19 mRNA vaccine within the last 2-4 weeks (T0) and followed them 24 weeks after the first dose (T1) and 4-6 weeks after the booster (T2). PwMS presented a significant reduction in the seroconversion rate and anti-receptor-binding domain (RBD)-Immunoglobulin (IgG) titers from T0 to T1 (p < 0.0001) and a significant increase from T1 to T2 (p < 0.0001). The booster dose in PwMS showed a good improvement in the serologic response, even greater than HCWs, as it promoted a significant five-fold increase of anti-RBD-IgG titers compared with T0 (p < 0.0001). Similarly, the T-cell response showed a significant 1.5- and 3.8-fold increase in PwMS at T2 compared with T0 (p = 0.013) and T1 (p < 0.0001), respectively, without significant modulation in the number of responders. Regardless of the time elapsed since vaccination, most ocrelizumab- (77.3%) and fingolimod-treated patients (93.3%) showed only a T-cell-specific or humoral-specific response, respectively. The booster dose reinforces humoral- and cell-mediated-specific immune responses and highlights specific DMT-induced immune frailties, suggesting the need for specifically tailored strategies for immune-compromised patients to provide primary prophylaxis, early SARS-CoV-2 detection and the timely management of COVID-19 antiviral treatments.

Shift of multiple sclerosis onset towards older age.

OBJECTIVE: To explore whether age at onset increased over time despite a shortened interval from the initial clinical demyelinating event to the diagnosis of multiple sclerosis (MS), as promoted by updated diagnostic criteria. METHODS: This was an independent, multicentre, retrospective study based on data from 4345 patients with relapsing-onset MS attending three tertiary MS Clinics in Italy. After stratifying the year of MS onset into four periods (<1991, 1991-2000, 2001-2010, 2011-2021), we analysed the temporal trends in age at onset and interval from onset to diagnosis; we then explored the female-to-male ratio and onset location across different classes of age at onset. RESULTS: We observed an increased mean age at onset, and a shortened mean interval to diagnosis over time (p<0.0001). Accordingly, there were more MS onsets at the older age classes of 40-49, 50-59 and ≥60 years (p<0.0001). In cases with age at onset ≥40 years, we also found an increased female-to-male ratio (p=0.007), more frequent spinal cord (p=0.0004) and less frequent supratentorial onset (p=0.008). CONCLUSION: Our study shows a forward shift towards an older age at onset of MS, thus suggesting considerable thought on the place-in-therapy of most currently used disease-modifying treatments, and on the standard of care to an older population.

Multidomain and long-term cognitive evaluation in malignant glioma patients.

Aim: We performed longitudinal evaluations of the neurocognitive status in glioma patients to describe possible variations over the course of illness. Materials and methods: Glioma patients underwent a complete battery of standardized neuropsychological tests pre-radiotherapy at 6, 12 and 24 months. Results: We enrolled 130 patients, 67.7% of whom had a deficit in at least one cognitive domain. The most affected domains included executive function (n = 68, 52.3%), long-term memory (n = 46, 35.3%) and short-term memory (n = 39, 30%). At follow-up, cognitive status worsened in 31.5%, remained unchanged in 38.4% and improved in 30.1% of patients. Conclusion: This is one of few studies investigating longitudinal neurocognitive status in a wide sample of patients to monitor neuropsychological changes due to tumor progression and treatment administration.

Malignant gliomas are brain tumors with dismal prognosis that can affect patients' neurocognitive status. We performed longitudinal neuropsychological assessments to describe variations due to illness progression and treatment administration. Patients underwent a battery of standardized neuropsychological tests tapping into different cognitive domains (memory, attention, abstract reasoning, executive functions, learning), pre-radiotherapy and at 6, 12 and 24 month follow-up. We enrolled 130 patients, and almost 70% of them had at least one cognitive deficit. The most affected domains were executive function and long- and short-term memory. At follow-up assessments, cognitive status worsened in one-third of patients, whereas it remained unchanged or improved in two-thirds of patients. This is one of few longitudinal studies investigating cognitive function in a large sample of patients to monitor changes along the illness course.

Recurrent glioblastoma: which treatment? A real-world study from the Neuro-oncology Unit "Regina Elena" National Cancer Institute.

BACKGROUND: The majority of patients with glioblastoma (GBM) experience disease progression. At recurrence, treatment options have limited efficacy. Many studies report a limited and short duration response rate. Although clinical trials represent the "gold standard" for providing evidence on efficacy of specific treatment strategies, real-world data can be considered more representative of the "real" GBM population. OBJECTIVE: To describe the management of GBM recurrence in a large real-world sample. METHODS: We analysed retrospectively the data stored in the database of the Neuro-oncology Unit, IRCCS "Regina Elena" National Cancer Institute, Rome, Italy. We considered only data of patients with histological diagnosis of GBM and disease recurrence during their follow-up. We excluded patients who did not receive treatment after the diagnosis. RESULTS: We analysed 422 patients (64% males, 36% females) with a mean age of 59.6 (range 16-87) years. At GBM recurrence, 135 (32.0%) patients underwent palliative care, and 287 (68.0%) underwent other treatments. Patients on palliative care were older, had a worse performance status, and a shorter time between GBM diagnosis and its recurrence. Patients who received chemotherapy in combination with other treatments (surgery and/or radiation therapy) at GBM recurrence had a longer survival than those in palliative care (p < 0.001). Surgery or radiation therapy alone did not have any effect on survival as compared with palliative care (p < 0.001). CONCLUSION: This study confirms the importance of a multidisciplinary approach even at GBM recurrence, suggesting that combination treatments play a key role in management of disease.

'Posture second' strategy predicts disability progression in multiple sclerosis.

We assessed 168 patients with multiple sclerosis (MS) by force platform to obtain the dual-task cost (DTC) of balance, that is, the change in postural sway from quiet standing to dual-task condition (Stroop test). After a median follow-up time of 3.5 years from this assessment, disability progression occurred in 45 (27%) patients. Disability progression was predicted by the adoption of a 'posture second' strategy, that is, values of DTC of balance exceeding those obtained from 62 healthy controls, even after controlling by demographic and clinical characteristics. The DTC of balance may potentially represent a novel and easy tool to predict MS progression.

Age-related adverse events of disease-modifying treatments for multiple sclerosis: A meta-regression.

OBJECTIVE: To verify the hypothesis of an age-dependent increase of infections and neoplasms in patients with multiple sclerosis (MS) under disease-modifying treatments (DMTs) with different mechanisms of action. METHODS: We extracted relevant data from 45 randomized clinical trials (RCTs) on currently licensed DMTs. We fitted inverse-variance weighted meta-regressions with random-effects models to estimate whether age and/or mechanism of action (immunomodulatory, sequestrating, and depletive) of currently licensed DMTs influenced the difference between experimental arm and control arm in the incidence of specific adverse events, namely, overall infections, opportunistic infections, and neoplasms. RESULTS: A higher incidence of overall infections was observed in RCTs with depletive DMTs (event-rate ratio = 1.25, p < 0.001). Herpetic infections were more frequently observed in RCTs with both depletive (event-rate ratio = 3.51, p < 0.001) and, to a lesser extent, sequestrating DMTs (event-rate ratio = 1.52, p = 0.078). The interaction of age with depletive DMTs was associated with higher incidence of neoplasms (p = 0.017), especially above 45 years of age. DISCUSSION: Our study supports a detrimental effect of age on the safety profile of depletive DMTs, with an increased incidence of neoplasms especially over 45 years of age. We failed to demonstrate an age-related increased incidence of infections, possibly due to latency in their occurrence.

The risk of infection in patients with multiple sclerosis treated with disease-modifying therapies: A Delphi consensus statement.

The risk of infection associated with immunomodulatory or immunosuppressive disease-modifying drugs (DMDs) in patients with multiple sclerosis (MS) has been increasingly addressed in recent scientific literature. A modified Delphi consensus process was conducted to develop clinically relevant, evidence-based recommendations to assist physicians with decision-making in relation to the risks of a wide range of infections associated with different DMDs in patients with MS. The current consensus statements, developed by a panel of experts (neurologists, infectious disease specialists, a gynaecologist and a neuroradiologist), address the risk of iatrogenic infections (opportunistic infections, including herpes and cryptococcal infections, candidiasis and listeria; progressive multifocal leukoencephalopathy; human papillomavirus and urinary tract infections; respiratory tract infections and tuberculosis; hepatitis and gastrointestinal infections) in patients with MS treated with different DMDs, as well as prevention strategies and surveillance strategies for the early identification of infections. In the discussion, more recent data emerged in the literature were taken into consideration. Recommended risk reduction and management strategies for infections include screening at diagnosis and before starting a new DMD, prophylaxis where appropriate, monitoring and early diagnosis.

Vaccinations in patients with multiple sclerosis: A Delphi consensus statement.

BACKGROUND: Patients with multiple sclerosis (MS) are at increased risk of infection. Vaccination can mitigate these risks but only if safe and effective in MS patients, including those taking disease-modifying drugs. METHODS: A modified Delphi consensus process (October 2017-June 2018) was used to develop clinically relevant recommendations for making decisions about vaccinations in patients with MS. A series of statements and recommendations regarding the efficacy, safety and timing of vaccine administration in patients with MS were generated in April 2018 by a panel of experts based on a review of the published literature performed in October 2017. RESULTS: Recommendations include the need for an 'infectious diseases card' of each patient's infectious and immunisation history at diagnosis in order to exclude and eventually treat latent infections. We suggest the implementation of the locally recommended vaccinations, if possible at MS diagnosis, otherwise with vaccination timing tailored to the planned/current MS treatment, and yearly administration of the seasonal influenza vaccine regardless of the treatment received. CONCLUSION: Patients with MS should be vaccinated with careful consideration of risks and benefits. However, there is an urgent need for more research into vaccinations in patients with MS to guide evidence-based decision making.

Ozone-induced encephalopathy: A novel iatrogenic entity.

BACKGROUND AND PURPOSE: Ozone-based treatments can be associated with central nervous system toxicity, which we have termed ozone-induced encephalopathy (OIE). A detailed description of its phenotype is lacking. METHODS: Three cases with findings suggestive of OIE are presented, and the literature is reviewed. RESULTS: Case 1 is a healthy 59-year-old man presenting with loss of consciousness, cortical blindness, restlessness, and anterograde amnesia immediately following a cervical ozone-therapy (OT) session for chronic neck pain. Brain magnetic resonance imaging (MRI) on admission was normal. A follow-up scan demonstrated a subtle increased T2 fluid-attenuated inversion recovery signal within the left cerebellum; an echocardiography showed a patent foramen ovale (PFO). Case 2 is a 56-year-old woman with history of migraine, PFO, and lumbar pain who presented with headache, bilateral visual impairment, motor dysphasia, and agitation. All her symptoms began immediately after lumbar OT. Her brain MRI was negative. Case 3 is a healthy 27-year-old man who complained of vertigo and mild blurred vision 5 min following a cervical ozone injection. His neurological examination and brain MRI were normal. All three patients had full recovery within 48 h. We found eight additional cases of OIE in the literature. CONCLUSIONS: OIE should be considered in patients presenting with neurological symptoms in close relation to OT. OIE is likely a novel iatrogenic entity with a complex pathogenesis; it is probably underreported because it mimics other neurological conditions.

Scoring the 10-year risk of ambulatory disability in multiple sclerosis: the RoAD score.

BACKGROUND AND PURPOSE: Both baseline prognostic factors and short-term predictors of treatment response can influence the long-term risk of disability accumulation in patients with relapsing-remitting multiple sclerosis (RRMS). The objective was to develop and validate a scoring system combining baseline prognostic factors and 1-year variables of treatment response into a single numeric score predicting the long-term risk of disability. METHODS: We analysed two independent datasets of patients with RRMS who started interferon beta or glatiramer acetate, had an Expanded Disability Status Scale (EDSS) score <4.0 at treatment start and were followed for at least 10 years. The first dataset ('training set') included patients attending three MS centres in Italy and served as a framework to create the so-called RoAD score (Risk of Ambulatory Disability). The second ('validation set') included a cohort of patients followed in Barcelona, Spain, to explore the performance of the RoAD score in predicting the risk of reaching an EDSS score ≥6.0. RESULTS: The RoAD score (ranging from 0 to 8) derived from the training set (n = 1225), was based on demographic (age), clinical baseline prognostic factors (disease duration, EDSS) and 1-year predictors of treatment response (number of relapses, presence of gadolinium enhancement and new T2 lesions). The best cut-off score for discriminating patients at higher risk of reaching the disability milestone was ≥4. When applied to the validation set (n = 296), patients with a RoAD score ≥4 had an approximately 4-fold increased risk for reaching the disability milestone (p < 0.001). DISCUSSION: The RoAD score is proposed as an useful tool to predict individual prognosis and optimize treatment strategy of patients with RRMS.

Defining the course of tumefactive multiple sclerosis: A large retrospective multicentre study.

BACKGROUND AND PURPOSE: Tumefactive multiple sclerosis (TuMS) (i.e., MS onset presenting with tumefactive demyelinating lesions [TDLs]) is a diagnostic and therapeutic challenge. We performed a multicentre retrospective study to describe the clinical characteristics and the prognostic factors of TuMS. METHODS: One hundred two TuMS patients were included in this retrospective study. Demographic, clinical, magnetic resonance imaging (MRI), laboratory data and treatment choices were collected. RESULTS: TuMS was found to affect women more than men (female:male: 2.4), with a young adulthood onset (median age: 29.5 years, range: 11-68 years, interquartile range [IQR]: 38 years). At onset, 52% of TuMS patients presented with the involvement of more than one functional system and 24.5% of them with multiple TDLs. TDLs most frequently presented with an infiltrative MRI pattern (38.7%). Cerebrospinal fluid immunoglobulin G oligoclonal bands were often demonstrated (76.6%). In 25.3% of the cases, more than one acute-phase treatment was administered, and almost one-half of the patients (46.6%) were treated with high-efficacy treatments. After a median follow-up of 2.3 years (range: 0.1-10.7 years, IQR: 3.4 years), the median Expanded Disability Status Scale (EDSS) score was 1.5 (range: 0-7, IQR: 2). Independent risk factors for reaching an EDSS score ≥3 were a higher age at onset (odds ratio [OR]: 1.08, 95% confidence interval [CI]: 1.03-1.14, p < 0.01), a higher number of TDLs (OR: 1.67, 95% CI: 1.02-2.74, p < 0.05) and the presence of infiltrative TDLs (OR: 3.34, 95% CI: 1.18-9.5, p < 0.001) at baseline. CONCLUSIONS: The management of TuMS might be challenging because of its peculiar characteristics. Large prospective studies could help to define the clinical characteristics and the best treatment algorithms for people with TuMS.