Paradigm shifts in multiple sclerosis management: Implications for daily clinical practice.

Multiple sclerosis (MS) is the most common chronic inflammatory neurological disease. The emergence of disease-modifying therapies (DMTs) has greatly improved disease activity control and progression of disability in MS patients. DMTs differ in their mode of action, route of administration, efficacy, and safety profiles, offering multiple options for clinicians. Personalized medicine aims at tailoring the therapeutic strategy to patients' characteristics and disease activity but also patients' needs and preferences. New therapeutic options have already changed treatment paradigms for patients with active relapsing MS (RMS). The traditional approach consists in initiating treatment with moderate-efficacy DMTs and subsequently, escalating to higher-efficacy DMTs when there is evidence of clinical and/or radiological breakthrough activity. Recent real-world studies suggest that initiation of high-efficacy DMTs from disease onset can improve long-term outcomes for RMS patients. In this article, we review different treatment strategies and discuss challenges associated with personalized therapy.

Different clinical outcomes between cerebral amyloid angiopathy-related inflammation and non-inflammatory form.

OBJECTIVE: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare manifestation related to CAA, thought to be more severe. We aimed to compare the clinical and radiological outcomes of CAA-ri and non-inflammatory CAA. MATERIALS AND METHODS: We retrospectively included all patients with CAA-ri from 13 French centers. We constituted a sex- and age-matched control cohort with non-inflammatory CAA and similar disease duration. Survival, autonomy and cognitive evolution were compared after logistic regression. Cerebral microbleeds (CMB), intracerebral hemorrhage, cortical superficial siderosis and hippocampal atrophy were analyzed as well as CSF biomarker profile and APOE genotype when available. Outcomes were compared using Kaplan-Meier curves and log-rank tests. RESULTS: Data from 48 CAA-ri patients including 28 already reported and 20 new patients were analyzed. Over a mean of 3.1 years, 11 patients died (22.9%) and 18 (37.5%) relapsed. CAA-ri patients were more frequently institutionalized than non-inflammatory CAA patients (30% vs 8.3%, p < 0.001); mortality rates remained similar. MMSE and modified Rankin scale scores showed greater severity in CAA-ri at last follow-up. MRI showed a higher number of CMB at baseline and last follow-up in CAA-ri (p < 0.001 and p = 0.004, respectively). CSF showed lower baseline levels of Aß42 in CAA-ri than non-inflammatory CAA (373.3 pg/ml vs 490.8 pg/ml, p = 0.05). CAA-ri patients more likely carried at least one APOE ε4 allele (76% vs 37.5%, adjusted p = 0.05) particularly as homozygous status (56% vs 6.2%, p < 0.001). INTERPRETATION: CAA-ri appears to be more severe than non-inflammatory CAA with a significant loss of autonomy and global higher amyloid burden, shown by more CMB and a distinct CSF profile. This burden may be partially promoted by ε4 allele.

A regional strategy to decrease the time to thrombectomy in patients with low probability of treatment by thrombolysis.

BACKGROUND AND PURPOSE: The best transportation strategy for patients with suspected large vessel occlusion (LVO) is unknown. Here, we evaluated a new regional strategy of direct transportation to a Comprehensive Stroke Center (CSC) for patients with suspected LVO and low probability of receiving intravenous thrombolysis (IVT) at the nearest Primary Stroke Center (PSC). METHODS: Patients could be directly transported to the CSC (bypass group) if they met our pre-hospital bypass criteria: high LVO probability (i.e., severe hemiplegia) with low IVT probability (contraindications) and/or travel time difference between CSC and PSC<15 minutes. The other patients were transported to the PSC according to a "drip-and-ship" strategy. Treatment time metrics were compared in patients with pre-hospital bypass criteria and confirmed LVO in the bypass and drip-and-ship groups. RESULTS: In the bypass group (n=79), 54/79 (68.3%) patients met the bypass criteria and 29 (36.7%) had confirmed LVO. The positive predictive value of the hemiplegia criterion for LVO detection was 0.49. In the drip-and-ship group (n=457), 92/457 (20.1%) patients with confirmed LVO met our bypass criteria. Among the 121 patients with bypass criteria and confirmed LVO, direct routing decreased the time between symptom discovery and groin puncture by 55 minutes compared with the drip-and-ship strategy (325 vs. 229 minutes, P<0.001), without significantly increasing the time to IVT (P=0.19). CONCLUSIONS: Our regional strategy led to the correct identification of LVO and a significant decrease of the time to mechanical thrombectomy, without increasing the time to IVT, and could be easily implemented in other territories.

Atypical myelitis in patients with multiple sclerosis: Characterization and comparison with typical multiple sclerosis and neuromyelitis optica spectrum disorders.

BACKGROUND: Atypical myelitis in multiple sclerosis (MS) is characterized by extensive myelitis in the longitudinal (longitudinally extensive transverse myelitis) or axial plane (transverse myelitis). OBJECTIVE: To characterize a cohort of MS patients with atypical myelitis. METHODS: Atypical myelitis was extracted from the French and Luxembourg MS databases and compared to two cohorts of MS patients with typical myelitis and neuromyelitis optica spectrum disorders (NMOSDs) patients with myelitis. RESULTS: We enrolled 28 MS patients with atypical myelitis, 68 MS patients with typical myelitis and 119 NMOSD patients with a first episode of myelitis. MS patients with atypical myelitis were characterized by a mean age of 34.0 (±10.7) years and 64.3% were women. In 82.1% of the patients, atypical myelitis was the first episode of MS. Mean Expanded Disability Status Scale (EDSS) scores at nadir and 3-6 months after onset were 4.1 ± 2.1 and 3.3 ± 2, respectively. Differences between groups revealed a predominance of cervicothoracic myelitis and a higher level of disability in NMOSD patients. Disability in MS patients with atypical myelitis was more severe than in the MS patients with typical myelitis; 28% had already converted to progressive MS within our mean follow-up of 39.6 (±30.4) months. CONCLUSION: Atypical myelitis may be the first presentation of MS and is associated with poorer prognosis.

MRI characteristics of MOG-Ab associated disease in adults: An update.

Our knowledge of the radiological spectrum of myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD) is growing rapidly. An update on the radiological features of the disease, and its evolution is thus necessary. Magnetic resonance imaging (MRI) has an increasingly important role in the differential diagnosis of MOGAD particularly from aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), and multiple sclerosis (MS). Differentiating these conditions is of prime importance because the management is different between the three inflammatory diseases, and thus could prevent further attack-related disability. Therefore, identifying the MRI features suggestive of MOGAD has diagnostic and prognostic implications. We herein review optic nerve, spinal cord and the brain MRI findings from MOGAD adult patients, and compare them to AQP4-NMOSD and MS.

Acute retinal arterial ischaemia: silent brain infarcts prevalence and short-term recurrence.

BACKGROUND AND PURPOSE: The purpose was to evaluate, in a consecutive series of patients with isolated acute retinal ischaemia, the proportion of patients with acute silent brain infarcts (SBIs) on diffusion-weighted imaging (DWI) and to assess risk of recurrence within 3 months. METHODS: In all, 103 consecutive patients with isolated acute retinal ischaemia (central retinal artery occlusion, branch retinal artery occlusion or transient monocular vision loss) were included between January 2015 and December 2016. They all had cerebral magnetic resonance imaging including DWI as well as a standardized aetiological workup and 3 months of follow-up. The presence of DWI-positive cerebral lesions was recorded. Main clinical and radiological characteristics between DWI-positive and DWI-negative patients were compared. RESULTS: Of the 103 patients (including 42 transient monocular vision loss), 20 (19.5%) had SBIs on DWI, which were ipsilateral to the acute retinal ischaemia in 30% and involved different and/or multiple vascular territories in 70% of cases. Ipsilateral carotid stenosis and occlusion were respectively identified in 17 and eight patients whereas cardioaortic embolism was found in 19 patients. Overall, patients with and without acute SBIs were comparable. The topography of SBIs was related to the aetiology of the acute retinal ischaemia. At 3 months of follow-up, one patient suffered from ischaemic stroke and five had recurrent retinal ischaemia. CONCLUSIONS: Irrespective of the baseline characteristics of the patients, SBIs are present in about 20% of patients with isolated acute retinal ischaemia and may be of interest in the aetiological workup. Overall risk of recurrence is low, favoured by rapid aetiological workup and appropriate treatment.

Microangiopathie cérébrale: du diagnostic à la prise en charge small vessel disease of the brain: Diagnosis and management.

Small vessel disease of the brain is commonly identified among ageing people. It causes almost 25% of strokes and is associated with cognitive impairment and dementia as well as gait difficulties. Its diagnosis is usually made on MRI in the presence of deep white matter and basal ganglia hyperintensities as well as deep lacunar infarcts (lacunes), microbleeds and enlarged perivascular spaces. MRI is also of importance to identify the main differential diagnoses including inflammatory disorders, cerebral amyloid angiopathy and other genetic causes of microangiopathy. Small vessel disease is associated with the main vascular risk factors including notably age and hypertension but whether controlling these vascular risk factors is beneficial is still not clear. Here, we provide a comprehensive review underlining the main diagnostic features of cerebral microangiopathy and summarise the main therapeutic approaches (notably blood pressure normalisation and physical activity) used to control its development and prevent strokes as well as the development of cognitive involvement and gait impairment.

Diagnostic and therapeutic issues of inflammatory diseases of the elderly.

Inflammatory diseases of the central nervous system (CNS) mainly occur during early adulthood and multiple sclerosis (MS) represents the overwhelming majority of these disorders. Nevertheless, MS only rarely begins after 50 years and a diagnosis of late-onset MS should only be done when clinical as well as radiological and biological findings are typical of MS since the probability of misdiagnosis is higher in elderly patients. Indeed, in patients aged over 50 years, along with a relative decrease of MS incidence, other inflammatory diseases of the CNS but also differential diagnoses including neoplastic as well as infectious disorders should be thoroughly searched to avoid diagnostic mistakes and the prescription of inadequate and potentially harmful immunomodulatory/immunosuppressive therapies. Moreover, aging is associated with diverse immune changes also known as immunosenescence resulting in, notably, higher risk of comorbidities (including vascular diseases) and infections which need to be considered when planning medical treatments of elderly patients with inflammatory diseases of the CNS. Herein, therapeutic and diagnostic challenges faced by neurologists are reviewed to ease patient management.

Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia: An MRI Study of 16 French Cases.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia is an autosomal dominant leukoencephalopathy related to CSF1R gene mutations. A growing number of clinicoradiologic phenotypes have been described. In this study, we analyzed brain imaging findings in 16 patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia to refine radiologic diagnostic clues. T2/FLAIR white matter hyperintensities were present in all patients with frontal or frontoparietal predilection, with asymmetric distribution in more than one-third. Brain atrophy and callosal involvement were almost constant, and corticospinal tract involvement was frequent. Moreover, deep white matter hyperintense dots on DWI and deep punctate calcifications on CT were often found. Conversely, deep gray matter nuclei, external capsules, and brain stem were rarely involved. Our series emphasized the great variability of MR imaging findings seen in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. A complete imaging screening including DWI, T2*, and CT is mandatory to accurately assess patients with suspected inherited adult-onset leukoencephalopathy.

Atypical inflammatory demyelinating lesions and atypical multiple sclerosis.

Atypical idiopathic inflammatory demyelinating disorders (IIDDs) of the brain have long been known to be disorders closely related to multiple sclerosis (MS), despite having distinctive clinical and radiological characteristics. Originally, they mostly corresponded to acute-onset variants of MS that classically had poor prognoses, such as Baló's concentric sclerosis, Marburg variant of MS and Schilder's disease, and their relationship with MS was based on their shared pathological findings and the co-occurrence of these variants in patients with typical MS. More recently, other atypical disorders, such as solitary sclerosis, have also been described as belonging to the MS spectrum, raising the question of their links with MS. Meanwhile, multiple MS mimics have been described and need to be considered in the differential diagnosis of MS. In addition, thorough characterization of these atypical entities, including advanced MRI and biological studies, is now warranted to further improve their management.

Cognitive Impairment and Basal Ganglia Functional Connectivity in Vascular Parkinsonism.

BACKGROUND AND PURPOSE: Patients with vascular parkinsonism have higher cognitive decline and more basal ganglia lesions. We aimed to evaluate the relationship of cognitive impairment with functional connectivity between the basal ganglia and cingulate cortex in vascular parkinsonism. MATERIALS AND METHODS: Thirty patients (8 with vascular parkinsonism and 22 with Parkinson disease) and 23 controls were enrolled. The Mattis Dementia Rating Scale and the Stroop Task were used to assess cognitive decline. MR imaging examinations included T1-MPRAGE, FLAIR, and resting-state fMRI sequences. MPRAGE was segmented to obtain basal ganglia and cingulate cortex volumes. FLAIR was segmented to obtain white matter hyperintensity lesion volume. Resting-state fMRI sequences were used to compare basal ganglia functional connectivity with the cingulate cortex between patients and controls. RESULTS: Patients with vascular parkinsonism exhibited impaired attention, resistance to interference, and inhibitory control and an increased number of errors on the Stroop Task. They also had higher caudate nucleus and white matter hyperintensity lesion volumes, which were positively correlated (ρ = 0.75, P < .0001). Caudate nucleus functional connectivity with the perigenual anterior cingulate cortex was increased in patients with vascular parkinsonism compared with controls and patients with Parkinson disease, and it was positively correlated with the caudate nucleus volume (ρ = 0.44, P = .016). Caudate nucleus functional connectivity with the posterior cingulate cortex was decreased in patients with vascular parkinsonism compared with controls and negatively correlated with the number of errors on the Stroop test (ρ = -0.51, P = .0003). CONCLUSIONS: In patients with vascular parkinsonism, cognitive decline could be related to changes of caudate nucleus functional connectivity with the cingulate cortex at resting-state, which may be induced by ischemia-related remodelling.

Two cases of relapses in primary progressive multiple sclerosis after fingolimod withdrawal.

We report two cases of primary progressive multiple sclerosis (PPMS) included in the INFORMS cohort, experiencing a relapse related to a single MRI gadolinium-enhancing lesion 3 months after fingolimod withdrawal. These two patients share similarities with relapsing-remitting multiple sclerosis cases described in the same situation, suggesting that the initiating process of the active demyelinating plaques is also present in PPMS, even without relapses, but may be triggered as fingolimod is withdrawn. Although the results of the INFORMS study suggest that fingolimod may not slow down the progression, some PPMS patients might still benefit from a disease-modifying treatment.

Endovascular Management of Tandem Occlusion Stroke Related to Internal Carotid Artery Dissection Using a Distal to Proximal Approach: Insight from the RECOST Study.

BACKGROUND AND PURPOSE: Internal carotid artery dissection is a common cause of stroke in young adults. It may be responsible for tandem occlusion defined by a cervical steno-occlusive carotid wall hematoma associated with an intracranial large-vessel stroke. Intravenous thrombolysis is associated with a poor clinical outcome in these cases, and endovascular treatment has not been specifically evaluated to date. Our aim was to evaluate endovascular treatment technical and clinical efficiency in this specific occlusion topography, in comparison with treatment of isolated anterior circulation stroke. MATERIALS AND METHODS: As part of our ongoing prospective stroke data base started in August 2009 (Prognostic Factors Related to Clinical Outcome Following Thrombectomy in Ischemic Stroke [RECOST] Study), we analyzed all carotid artery dissection tandem occlusion strokes and isolated anterior circulation occlusions. All patients were selected for endovascular treatment according to clinical-radiologic mismatch, NIHSS ≥ 7 and DWI-ASPECTS ≥5, within 6 hours after onset. For carotid artery dissection, the revascularization procedure consisted first of distal recanalization by a stent retriever in the intracranial vessel. Following assessment of the circle of Willis, internal carotid artery stent placement was only performed in case of insufficiency. Carotid artery dissection treatment efficacy, safety, and clinical outcome were compared with the results of the isolated anterior circulation occlusion cohort. RESULTS: Two hundred fifty-eight patients with an anterior circulation stroke were analyzed, including 57 with tandem occlusions (22%); among them, 20 were carotid artery dissection-related occlusions (7.6%). The median age of patients with tandem occlusions with internal carotid dissection was 52.45 versus 66.85 years for isolated anterior circulation occlusion (P < .05); the mean initial NIHSS score was 17.53 ± 4.11 versus 17.55 ± 4.8 (P = .983). The median DWI-ASPECTS was 6.05 versus 6.64 (P = .098), and the average time from onset to puncture was 4.38 for tandem occlusions versus 4.53 hours in isolated anterior circulation occlusion (P = .704). Complication rates and symptomatic intracranial hemorrhage were comparable in both groups (5% versus 3%, P = .49). The duration of the procedure was significantly prolonged in case of tandem occlusion (80.69 versus 65.45 minutes, P = .030). Fourteen patients with carotid artery dissection (70%) had a 3-month mRS of ≤ 2, without a significant difference from patients with an isolated anterior circulation occlusion (44%, P = .2). Only 5 carotid artery dissections (25%) necessitated cervical stent placement. No early ipsilateral stroke recurrence was recorded, despite the absence of stent placement in 15 patients (75%) with carotid artery dissection. CONCLUSIONS: Mechanical endovascular treatment of carotid artery dissection tandem occlusions is safe and effective compared with isolated anterior circulation occlusion stroke therapy. Hence, a more conservative approach with stent placement only in cases of circle of Willis insufficiency may be a reliable and safe strategy.

Brain magnetic resonance imaging helps to differentiate atypical multiple sclerosis with cavitary lesions and vanishing white matter disease.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) patients can present with atypical cavitary lesions mimicking vanishing white matter disease (VWMD). Our objective was to identify brain magnetic resonance imaging (MRI) findings that differentiate these two disorders. METHODS: A cross-sectional study was performed including 14 patients with MS with cavitary lesions and 14 patients with VWMD. Two neuroradiologists retrospectively reviewed the MRI including at least T1-, T2- and fluid-attenuated inversion recovery weighted images. RESULTS: The main differences included ovoid lesions perpendicular to the lateral ventricle, punctate isolated juxtacortical lesions (both 100% in MS versus 0% in VWMD) and symmetrical infratentorial hyperintensities (0% in MS versus 50% in VWMD). Other statistically significant differences included midbrain (79% in MS versus 29% in VWMD) and thalamus lesions (71% vs. 7%) as well as extensive external capsule involvement (29% vs. 86%) and extensive corpus callosum lesions (64% vs. 100%). Cavitary lesions usually had periventricular predominance in MS (36% vs. 0%) whereas they were more frequently anterior in VWMD (0% in MS versus 57% in VWMD). CONCLUSION: Despite many similar MRI findings, our results suggest that a careful analysis of the morphology and the location of the lesions is helpful to differentiate these distinct disorders.

Favorable Bridging Therapy Based on DWI-FLAIR Mismatch in Patients with Unclear-Onset Stroke.

BACKGROUND AND PURPOSE: Standard selection criteria for revascularization therapy usually exclude patients with unclear-onset stroke. Our aim was to evaluate the efficacy and safety of revascularization therapy in patients with unclear-onset stroke in the anterior circulation and to identify the predictive factors for favorable clinical outcome. MATERIALS AND METHODS: We retrospectively analyzed 41 consecutive patients presenting with acute stroke with unknown time of onset treated by intravenous thrombolysis and/or mechanical thrombectomy. Only patients without well-developed fluid-attenuated inversion recovery changes of acute diffusion lesions on MR imaging were enrolled. Twenty-one patients were treated by intravenous thrombolysis; 19 received, simultaneously, intravenous thrombolysis and mechanical thrombectomy (as a bridging therapy); and 1 patient, endovascular therapy alone. Clinical outcome was evaluated at 90 days by using the mRS. Mortality and symptomatic intracranial hemorrhage were also reported. RESULTS: Median patient age was 72 years (range, 17-89 years). Mean initial NIHSS score was 14.5 ± 5.7. Successful recanalization (TICI 2b-3) was assessed in 61% of patients presenting with an arterial occlusion, symptomatic intracranial hemorrhage occurred in 2 patients (4.9%), and 3 (7.3%) patients died. After 90 days, favorable outcome (mRS 0-2) was observed in 25 (61%) patients. Following multivariate analysis, initial NIHSS score (OR, 1.43; 95% CI, 1.13-1.82; P = .003) and bridging therapy (OR, 37.92; 95% CI, 2.43-591.35; P = .009) were independently associated with a favorable outcome at 3 months. CONCLUSIONS: The study demonstrates the safety and good clinical outcome of acute recanalization therapy in patients with acute stroke in the anterior circulation and an unknown time of onset and a DWI/FLAIR mismatch on imaging. Moreover, bridging therapy versus intravenous thrombolysis alone was independently associated with favorable outcome at 3 months.

Use of quantitative susceptibility mapping (QSM) in progressive multifocal leukoencephalopathy.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is an opportunistic demyelinating encephalopathy related to JC virus. Its characteristics on conventional brain MRI are well known and are important for the diagnosis. OBJECTIVE: To analyze SWI hypointensities recently described in U-fibers and cortex adjacent to the white matter lesions of PML. METHODS: Prospective study including four patients with an history of definite diagnosis of PML. Clinical data were collected retrospectively. Brain MRI exams were done on a 3T magnet, including FLAIR, T2 GRE sequences and SWI. RESULTS: Four males were included (mean age: 47 years, mean PML duration: 24.2 months). Immunosuppression was related to AIDS (n=2), natalizumab for multiple sclerosis (n=1), B-cell lymphoma treated by chemotherapeutic agents and rituximab (n=1). All patients had SWI hypointensities in cortex and/or U-fibers adjacent to the white matter lesions. QSM always suggested a paramagnetic effect. CONCLUSION: SWI and T2 GRE hypointensities in cortex and U-fibers adjacent to the white matter lesions seem highly prevalent in PML, irrespective of the delay between PML onset and the MRI. QSM data suggest a paramagnetic effect.