Machine learning-driven diagnosis of multiple sclerosis from whole blood transcriptomics.

Multiple sclerosis (MS) is a neurological disorder characterized by immune dysregulation. It begins with a first clinical manifestation, a clinically isolated syndrome (CIS), which evolves to definite MS in case of further clinical and/or neuroradiological episodes. Here we evaluated the diagnostic value of transcriptional alterations in MS and CIS blood by machine learning (ML). Deep sequencing of more than 200 blood RNA samples comprising CIS, MS and healthy subjects, generated transcriptomes that were analyzed by the binary classification workflow to distinguish MS from healthy subjects and the Time-To-Event pipeline to predict CIS conversion to MS along time. To identify optimal classifiers, we performed algorithm benchmarking by nested cross-validation with the train set in both pipelines and then tested models generated with the train set on an independent dataset for final validation. The binary classification model identified a blood transcriptional signature classifying definite MS from healthy subjects with 97% accuracy, indicating that MS is associated with a clear predictive transcriptional signature in blood cells. When analyzing CIS data with ML survival models, prediction power of CIS conversion to MS was about 72% when using paraclinical data and 74.3% when using blood transcriptomes, indicating that blood-based classifiers obtained at the first clinical event can efficiently predict risk of developing MS. Coupling blood transcriptomics with ML approaches enables retrieval of predictive signatures of CIS conversion and MS state, thus introducing early non-invasive approaches to MS diagnosis.

Neuroaxonal damage in natalizumab-treated MS patients: The role of JCV antibody titres.

BACKGROUND: While John Cunningham virus (JCV) is known to cause neuronal damage in progressive multifocal leukoencephalopathy (PML) among natalizumab-treated MS patients, its association with axonal loss in non-PML conditions remains unclear. METHODS: In a cohort of 128 natalizumab-treated MS patients, serum neurofilament (sNfL) levels and JCV antibody titres were measured. RESULTS: Among 128 patients (mean age = 38.4 years, 71.9% female), 51 (40%) were JCV positive. NfL levels increased by 15.3% for JCV index <0.7 (95% confidence interval [CI] = 0.963-1.381), by 18.6% for index 0.7-1.5 (95% CI = 1.009-1.394) and by 21.1% for index >1.5 (95% CI = 1.040-1.409) compared to JCV negative patients. CONCLUSION: These findings indicate a potential link between JCV burden and neuroaxonal degeneration in natalizumab-treated MS patients.

Phenotypes and clinical subgroups in vestibular migraine: a cross-sectional study with cluster analysis.

OBJECTIVE: The aim of this multicentric cross-sectional study was to collect phenotypes and clinical variability on a large sample of 244 patients enrolled in different university centers in Italy, trying to differentiate subtypes of VM. BACKGROUND: VM is one of the most frequent episodic vertigo characterized by a great clinical variability for duration of attacks and accompanying symptoms. Diagnosis is based only on clinical history of episodic vertigo in 50% of cases associated with migrainous headache or photo/phonophobia. METHODS: We enrolled in different university centers 244 patients affected by definite VM according to the criteria of the Barany Society between January 2022 and December 2022. An audiometric examination and a CNS MRI were performed before inclusion. Patients with low-frequency sensorineural hearing loss were not included, as well as patients with an MRI positive otherwise that for microischemic lesions. Patients were asked to characterize vestibular symptoms choosing among (multiple answers were allowed): internal vertigo, dizziness, visuo-vestibular symptoms/external vertigo; onset of vertigo and duration, neurovegetative, and cochlear accompanying symptoms (hearing loss, tinnitus, and fullness during attacks) were collected as well as migrainous headache and/or photo/phonophobia during vertigo; autoimmune disorders were also analyzed. A bedside examination was performed including study of spontaneous-positional nystagmus with infrared video goggles, post head shaking ny, skull vibration test, and video head impulse test. RESULTS: We included 244 subjects, 181 were females (74.2%). The age of onset of the first vertigo was 36.6 ± 14.5 while of the first headache was 23.2 ± 10.1. A positive correlation has been found between the first headache and the first vertigo. The mean duration of vertigo attacks was 11 ± 16 h. We carried on a cluster analysis to identify subgroups of patients with common clinical features. Four variables allowed to aggregate clusters: age of onset of vertigo, duration of vertigo attacks, presence of migrainous headache during vertigo, and presence of cochlear symptoms during vertigo. We identified 5 clusters: cluster 1/group 1 (23 subjects, 9.4%) characterized by longer duration of vertigo attacks; cluster 2/group 2 (52 subjects, 21.3%) characterized by absence of migrainous headache and cochlear symptoms during vertigo; cluster 3/group 3 (44 subjects, 18%) characterized by presence of cochlear symptoms during vertigo but not headache; cluster 4/group 4 (57 subjects, 23.4%) by the presence of both cochlear symptoms and migrainous headache during vertigo; cluster 5/group 5 (68 subjects, 27.9%) characterized by migrainous headache but no cochlear symptoms during vertigo. CONCLUSION: VM is with any evidence a heterogeneous disorder and clinical presentations exhibit a great variability. In VM, both symptoms orienting toward a peripheral mechanism (cochlear symptoms) and central ones (long lasting positional non-paroxysmal vertigo) may coexist. Our study is the first published trying to characterize subgroups of VM subjects, thus orienting toward different pathophysiological mechanisms.

Early and sustained efficacy of fremanezumab over 24-weeks in migraine patients with multiple preventive treatment failures: the multicenter, prospective, real-life FRIEND2 study.

BACKGROUND: To verify the long-term (24-week) efficacy, safety, and tolerability of fremanezumab in real-life patients with high-frequency episodic migraine (HFEM: ≥ 8 days/month) or chronic migraine (CM: ≥ 15 days/month), and multiple preventive treatment failures. METHODS: This is a prospective, cohort, real-life study at 28 headache centers on consecutive patients affected by HFEM or CM with multiple preventive treatment failures who were prescribed subcutaneous fremanezumab (225 mg monthly/675 mg quarterly) for ≥ 24 weeks. Primary endpoint was the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM at weeks 21-24 compared to baseline. Secondary endpoints encompassed changes in monthly analgesic medications, ≥ 50%, ≥ 75%, and 100% responder rates, and variation in NRS, HIT-6 and MIDAS scores at the same time interval. Changes in MMDs/MHDs, monthly analgesic medications, ≥ 50%, ≥ 75%, and 100% responder rates, and variation in NRS and HIT-6 scores at week 4 were also monitored. RESULTS: Four hundred ten patients who had received ≥ 1 dose of fremanezumab were considered for safety analysis while 148 patients treated for ≥ 24 weeks were included in the efficacy analysis. At weeks 21-24, fremanezumab significantly (p < 0.001) reduced MMDs, MHDs, monthly analgesic medications and NRS, HIT-6, and MIDAS scores in both HFEM and CM compared to baseline. The proportions of ≥ 50%, ≥ 75% and 100% responders at weeks 21-24were 75.0%, 30.8%, 9.6% (HFEM), and 72.9, 44.8 and 1% (CM). A significant (p < 0.001) decrease in MMDs, MHDs, monthly analgesic medications and NRS, HIT-6, and MIDAS scores in both HFEM and CM was already present at week 4. The proportions of ≥ 50%, ≥ 75%, and 100% responders at week 4 were 67.6%, 32.4%, 11.8% (HFEM) and 67.3%, 40%, 1.8% (CM). CM remitted to episodic migraine and medication overuse to no-medication overuse in 83.3 and 75% of patients at week 24, and in 80 and 72.4% at week 4. Adverse events were rare (2.4%), mild and transient. No patient discontinued treatment for any reason. CONCLUSIONS: Fremanezumab is characterized by an early and sustained efficacy in HFEM and CM patients with multiple preventive treatment failures in real-life, revealing an optimal safety and tolerability profile.

Spinal Fluid Myeloid Microvesicles Predict Disease Course in Multiple Sclerosis.

OBJECTIVE: In vivo measures of myeloid activity are promising biomarkers in multiple sclerosis. We previously demonstrated that cerebrospinal fluid (CSF) myeloid microvesicles are markers of microglial/macrophage activity and neuroinflammation in multiple sclerosis. Here, we aimed at investigating the diagnostic and prognostic value of myeloid microvesicles in a clinical setting. METHODS: Six hundred one patients discharged with a diagnosis of neuroinflammatory, neurodegenerative, or no neurological disease were enrolled. Myeloid microvesicles were measured with flow cytometry as isolectin B4-positive events in fresh CSF. Clinical, demographical, and magnetic resonance imaging (MRI) data were collected at diagnosis (all patients) and during follow-up (n = 176). RESULTS: CSF myeloid microvesicles were elevated in neuroinflammatory patients compared to the neurodegenerative and control groups. In multiple sclerosis, microvesicles were higher in patients with MRI disease activity and their concentration increased along with the number of enhancing lesions (p < 0.0001, Jonckheere-Terpstra test). CSF myeloid microvesicles were also higher in patients with higher disease activity in the month and year preceding diagnosis. Microvesicles excellently discriminated between the relapsing-remitting and control groups (receiver operator characteristic curve, area under the curve = 0.939, p < 0.0001) and between radiologically isolated syndrome and unspecific brain lesions (0.942, p < 0.0001). Furthermore, microvesicles were independent predictors of prognosis for both the relapsing-remitting and progressive groups. Microvesicles independently predicted future disease activity in relapsing-remitting patients (hazard ratio [HR] = 1.967, 95% confidence interval [CI] = 1.147-3.372), correcting for prognostic factors of standard clinical use. In the progressive group, microvesicles were independent predictors of disability accrual (HR = 10.767, 95% CI = 1.335-86.812). INTERPRETATION: Our results confirm that CSF myeloid microvesicles are a clinically meaningful biomarker of neuroinflammation and microglial/macrophage activity in vivo. These findings may support a possible use in clinical practice during diagnostic workup and prognostic assessment. ANN NEUROL 2021;90:253-265.

Early Predictors of 9-Year Disability in Pediatric Multiple Sclerosis.

OBJECTIVE: The purpose of this study was to assess early predictors of 9-year disability in pediatric patients with multiple sclerosis. METHODS: Clinical and magnetic resonance imaging (MRI) assessments of 123 pediatric patients with multiple sclerosis were obtained at disease onset and after 1 and 2 years. A 9-year clinical follow-up was also performed. Cox proportional hazard and multivariable regression models were used to assess independent predictors of time to first relapse and 9-year outcomes. RESULTS: Time to first relapse was predicted by optic nerve lesions (hazard ratio [HR] = 2.10, p = 0.02) and high-efficacy treatment exposure (HR = 0.31, p = 0.005). Predictors of annualized relapse rate were: at baseline, presence of cerebellar (ß = -0.15, p < 0.001), cervical cord lesions (ß = 0.16, p = 0.003), and high-efficacy treatment exposure (ß = -0.14, p = 0.01); considering also 1-year variables, number of relapses (ß = 0.14, p = 0.002), and the previous baseline predictors; considering 2-year variables, time to first relapse (2-year: ß = -0.12, p = 0.01) entered, whereas high-efficacy treatment exposure exited the model. Predictors of 9-year disability worsening were: at baseline, presence of optic nerve lesions (odds ratio [OR] = 6.45, p = 0.01); considering 1-year and 2-year variables, Expanded Disability Status Scale (EDSS) changes (1-year: OR = 26.05, p < 0.001; 2-year: OR = 16.38, p = 0.02), and ≥ 2 new T2-lesions in 2 years (2-year: OR = 4.91, p = 0.02). Predictors of higher 9-year EDSS score were: at baseline, EDSS score (ß = 0.58, p < 0.001), presence of brainstem lesions (ß = 0.31, p = 0.04), and number of cervical cord lesions (ß = 0.22, p = 0.05); considering 1-year and 2-year variables, EDSS changes (1-year: ß = 0.79, p < 0.001; 2-year: ß = 0.55, p < 0.001), and ≥ 2 new T2-lesions (1-year: ß = 0.28, p = 0.03; 2-year: ß = 0.35, p = 0.01). INTERPRETATION: A complete baseline MRI assessment and an accurate clinical and MRI monitoring during the first 2 years of disease contribute to predict 9-year prognosis in pediatric patients with multiple sclerosis. ANN NEUROL 2021;89:1011-1022.

Neural correlates of visuospatial processing in migraine: does the pain network help?

Migraine patients frequently report cognitive symptoms during the different phases of migraine. The most affected cognitive domains are visuospatial abilities, processing speed, attention and executive functions. We explored migraine patients' performance during a visuospatial task and investigated the activity of brain areas involved in visuospatial processing. A functional magnetic resonance imaging (MRI) visuospatial task, including an angle and a colour discrimination paradigm, was administrated to 17 headache-free migraine patients and 16 controls. Correlations between functional MRI abnormalities and subjects' performance, clinical and neuropsychological variables were also investigated. Deficits at visuospatial cognitive tests were present in around 20% of patients. Migraine patients maintained a preserved behavioural performance (reaction time and number of correct responses) during the angle discrimination task, while they performed less correctly in the colour task compared to controls (p = 0.05).The comparison of angle vs. colour task revealed an increased activity of the right insula, bilateral orbitofrontal cortex and medial frontal gyrus, and decreased activity of the bilateral posterior cingulate cortex in migraine patients compared to controls. In migraine patients, a better performance in the angle task was associated with higher activation of the right insula and orbitofrontal cortex, as well as with decreased activation of the right posterior cingulate cortex. Our results suggest an adaptive functional plasticity that might help migraine patients to overcome impaired visuospatial skills and preserve an adequate performance during a visuospatial task. These compensatory mechanisms seem to take advantage of recruiting brain areas that are commonly involved also in nociception.

Rapid response to galcanezumab and predictive factors in chronic migraine patients: A 3-month observational, longitudinal, cohort, multicenter, Italian real-life study.

BACKGROUND AND PURPOSE: A rapid response to preventive therapy is of pivotal importance in severely disabled patients with chronic migraine (CM) and diverse preventive treatment failures. This prospective, observational, multicenter real-life study aimed at investigating the effectiveness of galcanezumab in the first 3 months of treatment of CM patients at 14 Italian headache centers. METHODS: All consecutive adult patients with CM diagnosis with the clinical indication for galcanezumab were considered. We collected patients' baseline characteristics, monthly headache days, monthly painkiller intake, migraine clinical characteristics, and disability scale scores during a 1-month run-in period (baseline) and the first 3 months of therapy. Possible predictive factors of treatment were considered. RESULTS: A total of 156 patients (82.4% female, aged 47.3 ± 12.3 years) were enrolled. The 65 (41.7%) patients with a consecutive ≥50% response rate (RR) in the 3 months of therapy presented a lower body mass index (p = 0.004) and more frequently presented unilateral migraine pain (p = 0.002) and good response to triptans (p = 0.003). Persistent conversion from CM to episodic migraine was observed in 55.8% (87/156) of patients. They more frequently presented a good response to triptans (p = 0.003) and unilateral pain (p = 0.046). At baseline, 131 of 156 (83.9%) patients presented medication overuse (MO). Of these, 61.8% (81/131) no longer displayed MO consistently during the 3 months. These patients were more frequently responders to triptans (p = 0.002) and less frequently suffered from gastrointestinal comorbidity (p = 0.007). CONCLUSIONS: Unilateral pain, good response to triptans, and normal weight may be associated with a persistent positive response in the first 3 months of therapy with galcanezumab in CM patients.

Subclinical anterior optic pathway involvement in early multiple sclerosis and clinically isolated syndromes.

Optical coherence tomography (OCT) is gaining increasing relevance in the assessment of patients with multiple sclerosis. Converging evidence point to the view that neuro-retinal changes, in eyes without acute optic neuritis, reflect inflammatory and neurodegenerative processes taking place throughout the CNS. The present study aims at exploring the usefulness of OCT as a marker of inflammation and disease burden in the earliest phases of the disease. Thus, a cohort of 150 consecutive patients underwent clinical, neurophysiological and brain MRI assessment as well as lumbar puncture as part of their diagnostic workup for a neurological episode suggestive of inflammatory CNS disorder; among those 32 patients had another previous misdiagnosed episode. For the present study, patients also received a visual pathway assessment (OCT, visual evoked potentials, visual acuity), measurement of CSF inflammatory markers (17 cytokines-chemokines, extracellular vesicles of myeloid origin), and dosage of plasma neurofilaments. Subclinical optic nerve involvement is frequently found in clinically isolated syndromes by visual evoked potentials (19.2%). OCT reveals ganglion cell layer asymmetries in 6.8% of patients; retinal fibre layer asymmetries, despite being more frequent (17.8%), display poor specificity. The presence of subclinical involvement is associated with a greater disease burden. Second, ganglion cell layer thinning reflects the severity of disease involvement even beyond the anterior optic pathway. In fact, the ganglion cell layer in eyes without evidence of subclinical optic involvement is correlated with Expanded Disability Status Scale, low contrast visual acuity, disease duration, brain lesion load, presence of gadolinium enhancing lesions, abnormalities along motor and somatosensory evoked potentials, and frequency of CSF-specific oligoclonal bands. Third, the inner nuclear layer thickens in a post-acute (1.1-3.7 months) phase after a relapse, and this phenomenon is counteracted by steroid treatment. Likewise, a longitudinal analysis on 65 patients shows that this swelling is transient and returns to normal values after 1 year follow-up. Notwithstanding, the clinical, MRI, serological and CSF markers of disease activity considered in the study are strictly associated with one another, but none of them are associated with the inner nuclear layer. Our findings challenge the current hypothesis that the inner nuclear layer is an acute phase marker of inflammatory activity. The present study suggests that instrumental evidence of subclinical optic nerve involvement is associated with a greater disease burden in clinically isolated syndrome. Neuro-retinal changes are present since the earliest phases of the disease and yield important information regarding the neurodegenerative and inflammatory processes occurring in the CNS.

Comparison of efficacy and safety of erenumab between over and under 65-year-old refractory migraine patients: a pivotal study.

Previous studies reported a positive effect of anti-CGRP monoclonal antibodies (mAbs) in migraine prevention, either in over (O65) and under (U65) 65-year-aged patients. The aim of our study was to evaluate and compare real-life efficacy and safety of mAbs between young and elder migraine patients. Fifteen O65 and fifteen U65 patients, treated with monthly mAbs for 6 months, were enrolled and matched for sex, monthly headache days (MHD), and monthly migraine days (MMD) at baseline. Between-group differences in MHD and MMD, number of pills and days of acute medication intake, HIT-6, MIDAS, Numeric Rating Scale (NRS), and Allodynia Symptom Checklist (ASC-12) were assessed after 3 (M3) and 6 (M6) months of treatment. Adverse events (AEs) were also investigated. In each group, thirteen patients (87%) were women and nine (60%) had chronic migraine. Baseline mean MHD and MMD of both groups were 20 (SD 9.6). Mean age was 70 (65-76) and 45 (19-55) in the O65 and U65 group, respectively. Before starting mAbs, patients have tried an average of 4 preventives in both groups. After 3 and 6 months of treatment, both groups had a reduction of all clinical features under examination, without statistically significant differences between groups. A similar proportion of patients in each group complained of AEs (M3 and M6, p = 1.0). Our real-life data showed that treatment with mAbs is as effective and safe in O65 as U65 migraine patients. Further studies are needed to confirm these findings.

Tracking the evolution of non-headache symptoms through the migraine attack.

BACKGROUND: The migraine attack is classically divided into the prodromal, aura, headache and postdromal phase. Previous studies have highlighted non-headache symptoms associated with migraine occurring during the prodromal or postdromal phase. This study aimed to track the evolution of non-headache symptoms throughout all phases of the migraine attack. We also wished to delineate the phenotype of patients with more symptomatic migraine episodes and explore the association between non-painful symptoms and migraine disease activity and patients' disability. METHODS: Two-hundred and twenty-five migraine patients were enrolled and were asked to recall retrospectively whether non-headache symptoms occurred during the prodromal, headache and postdromal phase of their attacks. The occurrence of symptoms during the different migraine phases was tested using the Cochran's Q tests, Cohen's and Fleiss' kappa. Differences between groups according to the presence of non-headache symptoms through the entire migraine attack and correlations between the frequency of non-headache symptoms experienced during all phases and patients' disease activity and disability were also assessed. RESULTS: Ninety-nine percent of patients reported having at least one non-headache symptom in one phase of the migraine attack and 54% of patients had at least one non-headache symptom occurring during all phases of migraine. The occurrence of non-headache symptoms was different throughout the three phases of migraine, being higher during the headache phase than during the prodromal and postdromal phases. Symptoms with the highest co-occurrence throughout all migraine phases were neck stiffness, thirst and abdominal pain. Patients who experienced non-headache symptoms during all three phases of migraine were more frequently females, had a higher disability, were suffering from chronic migraine and had more frequently medication overuse headache. CONCLUSION: Migraine is a complex neurological disorder with a wide constellation of non-headache symptoms that can affect the burden of the disease. A better characterization of the evolution of non-headache symptoms through the different phases of migraine can enrich our knowledge on migraine pathophysiology and improve the management of the disease.

Early evidence of disease activity during fingolimod predicts medium-term inefficacy in relapsing-remitting multiple sclerosis.

BACKGROUND: Fingolimod (FTY) is an effective second-line drug for relapsing-remitting multiple sclerosis, with ~50% patients showing no evidence of disease activity (NEDA) after 2 years. Nonetheless, the early identification of non-responders is extremely important, to promptly address them to more aggressive drugs. OBJECTIVES: This cohort study evaluates FTY medium-term effectiveness, searching for early markers of treatment failure. PATIENTS AND METHODS: Three hundred eighty patients starting FTY were enrolled and classified according to NEDA and time to first relapse criteria at 4-year follow-up. Logistic and Cox regression analyses were applied to identify early predictors of non-response. RESULTS: At 4 years, 65.6% of patients were free from relapses and 35.4% had NEDA. Female gender was associated with a higher risk of non-response. Moreover, evidence of clinical and/or magnetic resonance imaging (MRI) activity during the first year of treatment was highly predictive of disease activity in the follow-up: the positive predictive value for non-response was 0.74 for the presence of ⩾1 relapse, 0.73 for the presence of ⩾1 active MRI lesion, and 0.83 for the presence of both clinical and MRI activity. CONCLUSIONS: FTY effectiveness persists at medium-term follow-up; a close monitoring during the first year of treatment is warranted to early identify non-responders requiring treatment optimization.

Cortico-subcortical functional connectivity modifications in fatigued multiple sclerosis patients treated with fampridine and amantadine.

BACKGROUND AND PURPOSE: Fatigue in multiple sclerosis (MS) is common and disabling; medication efficacy is still not fully proven. The aim of this study was to investigate 4-week modifications of fatigue severity in 45 relapsing-remitting MS patients after different symptomatic treatments, and changes in concomitant resting state (RS) functional connectivity (FC). METHODS: Patients were randomly, blindly assigned to treatment with fampridine (n = 15), amantadine (n = 15) or placebo (n = 15), and underwent clinical assessment and 3-Tesla RS functional magnetic resonance imaging at baseline (t0) and after 4 weeks (w4) of treatment. Fifteen healthy controls (HCs) were also studied. Changes in modified fatigue impact scale (MFIS) score and network RS FC were assessed. RESULTS: In MS, abnormalities of network RS FC at t0 did not differ between treatment groups and correlated with fatigue severity. At w4, global scores and subscores on the MFIS decreased in all groups, with no time-by-treatment interaction. At w4, all patient groups had changes in RS FC in several networks, with significant time-by-treatment interactions in basal ganglia, sensorimotor and default-mode networks in fampridine-treated patients versus the other groups, and in frontoparietal network in amantadine-treated patients. In the fampridine group, RS FC changes correlated with concurrently decreased MFIS score (r range = -0.75 to 0.74, p range = 0.003-0.05). CONCLUSIONS: Fatigue improved in all MS groups, independently of treatment. Concomitant RS FC modifications were located in sensorimotor, inferior frontal and subcortical regions for fampridine- and amantadine-treated patients, and in associative sensory cortices for placebo-treated patients.

Erenumab in the prevention of high-frequency episodic and chronic migraine: Erenumab in Real Life in Italy (EARLY), the first Italian multicenter, prospective real-life study.

OBJECTIVE: To assess the effectiveness, safety, and tolerability of erenumab in a real-life migraine population, while trying to identify responsiveness predictors. BACKGROUND: Erenumab is a fully human Ig-2 monoclonal antibody blocking the calcitonin gene-related peptide receptor, indicated for migraine prophylaxis. Phase II and III trials demonstrated that erenumab is effective, safe, and well tolerated in the prevention of episodic and chronic migraine (CM), showing an early onset of action. METHODS: This is a multicenter, prospective, cohort, and real-life study. We considered for enrolment all consecutive patients aged 18-65 affected by high-frequency episodic migraine (HFEM) or CM, with or without medication overuse, visited at nine Italian Headache Centers from December 20, 2018 to September 30, 2019. Each patient was treated with erenumab 70 mg, administered subcutaneously every 4 weeks. Treatment duration was planned to last from 6 to 12 months, depending on the patient's response. The primary endpoint was the change in monthly migraine days (MMDs) at weeks 9-12 compared to baseline. Secondary endpoints included changes in monthly analgesics intake, ≥50%, ≥75%, and 100% responder rates and any variation in the Visual Analog Scale (VAS) and Headache Impact Test scores (HIT). RESULTS: In total, 372 migraine patients were treated with at least one dose of erenumab 70 mg. At weeks 9-12, erenumab decreased MMDs by 4.5 ± 4.1 days (mean ± SD) in patients with HFEM and by 9.3 ± 9.1 (mean ± SD) days in those with CM compared to baseline. At weeks 9-12 VAS score was reduced by 1.9 ± 1.9 (mean ± SD), HIT score by 10.7 ± 8.8 (mean ± SD), and median monthly analgesics intake passed from 12.0 (interquartile range [IQR] 10.0-14.0) to 5.0 (IQR 3.0-7.0) in HFEM. In CM patients, VAS was reduced by 1.7 ± 2.0 (mean ± SD), HIT by 9.7 ± 10.4 (mean ± SD), and median monthly analgesics intake passed from 20.0 (IQR 15.0-30.0) to 8.0 (IQR 5.0-15.0). At week 12, ≥50% responders were 60/101 (59.4%) for HFEM and 146/263 (55.5%) for CM, ≥75% responders were 17/101 (16.8%) and 59/263 (22.4%) and 100% responders 1/101 (1.0%) and 3/263 (1.1%), respectively. Erenumab responsiveness in HFEM was positively associated with unilateral pain localization (OR: 3.03, 95% CI: 1.24-7.40; p = 0.015), whereas in CM responsiveness was positively associated with and baseline migraine frequency (OR: 1.06, 95% CI:1.02-1.11; p = 0.031), dopaminergic symptoms (OR: 2.01, 95% CI: 1.14-3.52; p = 0.015), and negatively associated with psychiatric comorbidities (OR: 0.43, 95% CI: 0.20-0.93; p = 0.003). CONCLUSIONS: Erenumab 70 mg is effective, safe, and well tolerated in real life. Easily obtainable clinical features might be of help in predicting patient's responsiveness.

Migraine and literature: a narrative historical review.

Description of migraine pain is sometimes difficult for a patient. The simple words reported in the Classification of International Headache Society are not sufficient to explain both the patient's sense of discomfort and the emotional point of view. We analyzed works by international writers and novelists in the last centuries to explore the connotation of migraine in literature. We evaluated the literary insight of migraine, the description of migraine experience and the therapies proposed in novels, essays and short stories. In literature, migraine has still the negative connotation of an untreatable disease. It is described as a barrier for social, familial, and work activities. In more recent works, new therapies are not mentioned, confirming that scientific improvements both in acute phase and in prophylaxis are not part of the literary cultural mainstream.

Discontinuing monoclonal antibodies targeting CGRP pathway after one-year treatment: an observational longitudinal cohort study.

BACKGROUND: Monoclonal antibodies anti-calcitonin gene-related peptide (mAbs anti-CGRP) pathway are effective and safe on migraine prevention. However, some drug agencies limited these treatments to one year due to their high costs. This study aimed at evaluating the effect of discontinuing mAbs anti-CGRP on monthly migraine days (MMDs) and disability in high-frequency episodic (HFEM) and chronic migraine (CM) patients. METHODS: This observational longitudinal cohort study was conducted at 10 Italian headache centres. Consecutive adult patients were followed-up for three months (F-UP1-3) after discontinuation of a one-year erenumab/galcanezumab treatment. The primary endpoint was the change in F-UP MMDs. Secondary endpoints included variation in pain intensity (Numerical Rating Scale, NRS), monthly acute medication intake (MAMI), and HIT-6 scores. We also assessed from F-UP1 to 3 the ≥50% response rate, relapse rate to CM, and recurrence of Medication Overuse (MO). RESULTS: We enrolled 154 patients (72.1% female, 48.2 ± 11.1 years, 107 CM, 47 HFEM); 91 were treated with erenumab, 63 with galcanezumab. From F-UP1 to F-UP3, MMDs, MAMI, NRS, and HIT-6 progressively increased but were still lower at F-UP3 than baseline (Friedman's analysis of rank, p < .001). In the F-UP1-3 visits, ≥50% response rate frequency did not differ significantly between CM and HFEM patients. However, the median reduction in response rate at F-UP3 was higher in HFEM (- 47.7% [25th, - 79.5; 75th,-17.0]) than in CM patients (- 25.5% [25th, - 47.1; 75th, - 3.3]; Mann-Whitney U test; p = .032). Of the 84 baseline CM patients who had reverted to episodic migraine, 28 (33.3%) relapsed to CM at F-UP1, 35 (41.7%) at F-UP2, 39 (46.4%) at F-UP3. Of the 64 baseline patients suffering of medication overuse headache ceasing MO, 15 (18.3%) relapsed to MO at F-UP1, 26 (31.6%) at F-UP2, and 30 (42.3%, 11 missing data) at F-UP3. Lower MMDs, MAMI, NRS, and HIT-6 and higher response rate in the last month of therapy characterized patients with ≥50% response rate at F-UP1 and F-UP3 (Mann-Whitney U test; consistently p < .01). CONCLUSION: Migraine frequency and disability gradually increased after mAbs anti-CGRP interruption. Most patients did not relapse to MO or CM despite the increase in MMDs. Our data suggest to reconsider mAbs anti-CGRP discontinuation.

Serum neurofilaments increase at progressive multifocal leukoencephalopathy onset in natalizumab-treated multiple sclerosis patients.

This study analyzed serum neurofilament light chains (NfL) in 2 European cohorts of 312 multiple sclerosis (MS) patients to investigate whether NfL are biomarkers of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment. The cohort comprised 25 PML, 136 natalizumab-treated, and 151 untreated MS patients. Patients subsequently developing PML had similar NfL to other natalizumab-treated MS patients. At PML onset, NfL were 10-fold higher than in the pre-PML condition and in natalizumab-treated or untreated MS patients, and NfL continued to increase until onset of immune reconstitution inflammatory syndrome. The results suggest that in natalizumab-treated patients, NfL may represent an early and accessible marker of PML. Ann Neurol 2019;85:606-610.

Imaging correlates of hand motor performance in multiple sclerosis: A multiparametric structural and functional MRI study.

BACKGROUND: Hand motor impairment has considerable effects on daily-life activities of patients with multiple sclerosis (pwMS). Understanding its anatomo-functional substrates is relevant to provide more specific therapeutic interventions. OBJECTIVES: To investigate the association between hand motor performance and anatomo-functional magnetic resonance imaging (MRI) abnormalities in pwMS. METHODS: A total of 134 healthy controls (HC) and 366 pwMS underwent the Nine-Hole-Peg-Test (9HPT), structural and resting state (RS) functional MRI. Multivariate analyses identified the independent predictors of hand motor performance. RESULTS: PwMS versus HC showed widespread gray matter atrophy, microstructural white matter abnormalities, and decreased RS functional connectivity in motor and cognitive networks. Predictors of worse right-9HPT (R2 = 0.52) were decreased right superior cerebellar peduncle and right lemniscus fractional anisotropy (FA) (p ⩽ 0.02), left angular gyrus atrophy (p < 0.003), decreased RS connectivity in left superior frontal gyrus, and left posterior cerebellum (p < 0.001). Worse left 9HPT (R2 = 0.56) was predicted by decreased right corticospinal FA (p = 0.003), atrophy of left anterior cingulum and left cerebellum (p ⩽ 0.02), decreased RS connectivity of left lingual gyrus and right posterior cerebellum in cerebellar and executive networks (p ⩽ 0.02). CONCLUSION: Structural and functional abnormalities of regions involved in motor functions contribute to explain motor disability in pwMS. The integration of clinical and advanced MRI measures contributes to improve our understanding of multiple sclerosis clinical manifestations.

Structural connectivity in multiple sclerosis and modeling of disconnection.

BACKGROUND: Multiple sclerosis (MS) is characterized by focal white matter damage, and when the brain is modeled as a network, lesions can be treated as disconnection events. OBJECTIVE: To evaluate whether modeling disconnection caused by lesions helps explain motor and cognitive impairment in MS. METHODS: Pathways connecting 116 cortical regions were reconstructed with magnetic resonance imaging (MRI) tractography from diffusion tensors averaged across healthy controls (HCs); maps of pathways were applied to 227 relapse-onset MS patients and 50 HCs to derive structural connectivity. Then, the likelihood of individual connections passing through lesions was used to model disconnection. Patients were grouped according to clinical phenotype (113 relapsing-remitting multiple sclerosis (RRMS), 69 secondary progressive multiple sclerosis (SPMS), 45 benign MS), and then network metrics were compared between groups (analysis of variance (ANOVA)) and correlated with motor and cognitive scores (linear regression). RESULTS: Global metrics differentiated RRMS from SPMS and benign MS patients, but not benign from SPMS patients. Nodal connectivity strength replicated global results. After disconnection, few nodes were significantly different between benign MS and RRMS patients. Correlations revealed nodes pertinent to motor and cognitive dysfunctions; these became slightly stronger after disconnection. CONCLUSION: Connectivity did not change greatly after modeled disconnection, suggesting that the brain network is robust against damage caused by MS lesions.

Imaging patterns of gray and white matter abnormalities associated with PASAT and SDMT performance in relapsing-remitting multiple sclerosis.

OBJECTIVES: To map the regional patterns of white matter (WM) microstructural abnormalities and gray matter (GM) atrophy exclusively associated with reduced performance in the Symbol Digit Modalities Test (SDMT) and Paced Auditory Serial Addition Test (PASAT) in relapsing-remitting (RR) multiple sclerosis (MS) patients. METHODS: In all, 177 RRMS patients and 80 healthy controls (HC) were studied. WM microstructural abnormalities were investigated on diffusion tensor images using tract-based spatial statistics analysis, and regional GM atrophy was estimated on three-dimensional (3D) T1-weighted images using voxel-based morphometry. RESULTS: Compared to HC, RRMS patients showed the expected pattern of cortical-subcortical GM atrophy and WM microstructural abnormalities. In patients, diffusivity abnormalities of supratentorial WM tracts correlated with both SDMT and PASAT scores. Lower SDMT performance was also associated with WM damage in several infratentorial WM tracts. Lower SDMT scores correlated with atrophy of the right anterior cingulate cortex, left postcentral gyrus, and right middle temporal gyrus, whereas lower PASAT scores correlated with atrophy of the deep GM nuclei, bilaterally, and several fronto-temporo-occipital regions. CONCLUSION: In RRMS patients, regional damage of different neural systems helps explaining reduced performance in SDMT and PASAT. WM microstructural damage typified reduced SDMT performance, whereas atrophy of several GM regions distinguished reduced PASAT performance.