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Background: Progressive motor impairment anatomically associated with a “critical” lesion has been described in primary demyelinating disease. Most “critical” lesions occur within the spinal cord. Objective: To describe the clinical and radiological features of “critical” lesions of the cervicomedullary junction (CMJ). Methods: Observational study on people presenting with a CMJ lesion associated with primary demyelinating disease-related progressive motor impairment. Clinical data were extracted by chart review. Brain and spinal cord magnetic resonance images were reviewed to characterize the CMJ lesion and determine additional demyelination burden. Results: Forty-one people were included: 29 (71%) had progression from onset and 12 (29%) had a relapse onset (secondary progressive) course. Most had progressive hemiparesis (21 (51%)) or progressive quadriparesis (15 (37%)) with a median Expanded Disability Status Scale (EDSS) of 5.5 (2.0–8.5) at last follow-up. No “critical” CMJ lesion enhanced; most were bilateral (25 (61%)). Brain magnetic resonance images were otherwise normal in 16 (39%) or with a restricted demyelination burden in 15 (37%). Cervical and thoracic cord MRIs were without additional lesions in 25 (61%) and 22/37 (59%), respectively. Conclusion: CMJ “critical” lesions can correlate with progressive motor impairment even with few or no additional magnetic resonance imaging (MRI) lesions. Lesion location is an important determinant of progressive motor impairment in demyelinating disease.

Severity score represents disease duration–adjusted mean rank of disability in multiple sclerosis (MS) patients from the reference population. This measure allows one to compare the relative rates of disease progression among patients, patient subgroups, and across epochs, which opens up new question of what accounts for the observed differences in severity, and can be used to assess correlation between disease severity and clinical, radiologic, immunologic, genetic, and environmental variables of interest. Severity score can also prove useful for developing prognostic tools in MS. This article discusses the diverse applications of severity score concept in MS research, and (re)introduces Herbert’s proposal of severity-based MS classification in the context of variability of MS severity.

Most prevalent gastrointestinal symptoms in multiple sclerosis (MS) relate to lower bowel dysfunction, often in association with bladder manifestations.To assess clinical and objective gastrointestinal motor dysfunctions in patients with MS.This was a single-center, retrospective study of 166 patients evaluated between 1996 and 2020. We reviewed characterization of the MS, gastrointestinal and neurological symptoms, measurements of gastrointestinal and colonic transit, and anorectal manometry.At the time of the gastrointestinal evaluations of the 166 patients with MS (138 women; 83%), 111 were in the relapsing-remitting phase and 52 were in the progressive phase. In 3 patients, disease phase was not assigned due to insufficient data. Constipation was identified in 82% (136/166) of patients. Most [103/116 (88%)] patients with bladder symptoms also had constipation or fecal incontinence. Delayed gastric emptying at 4 h and colonic transit at 24 h was identified in 16% and 7% of the cohort, respectively; 22% had accelerated gastric emptying. On anorectal manometry, resting anal sphincter pressure90 mm Hg and rectoanal pressure differential below -50mm Hg suggested evacuation disorder in patients with constipation.In addition to slow colonic transit and anorectal dysfunction leading to constipation in MS, 22% of patients had accelerated gastric emptying.

A 35-year-old man sought care for a severe, acute-onset, pounding, bifrontal headache, photopsias, and nausea for 1 day. Initially, bilateral red eyes developed, and within 24 hours he had central blurred vision problems in the left eye. He reported that objects had a yellow tint with the left eye and looked “wavy” supranasally. An emergent evaluation documented bilateral red eyes, and an initial diagnosis of bilateral panuveitis was given. By 48 hours after symptom onset, he started vomiting. He also was feeling feverish and off-balance. He reported no tinnitus or hearing loss, any change in color of his eyelashes or eyebrows, alopecia, poliosis, or cognitive difficulties. An initial work-up for infectious processes was negative. Given the patient’s ethnic background, including Chinese, Japanese, and Filipino origin, and typical findings of uveomeningitis, he was diagnosed with probable Vogt-Koyanagi-Harada syndrome. There is no specific diagnostic test for this entity, and the diagnosis remains reliant on a combined interpretation of clinical and ancillary testing. The patient was kept on oral prednisone daily, and azathioprine was initiated, as well as prophylaxis against Pneumocystis carinii pneumonia and gastrointestinal tract hemorrhage. During the tapering phase of prednisone, liver function test abnormalities were found, so azathioprine was discontinued. At 1-year follow-up, he had some mild skin flaking and weight gain from the corticosteroid therapy but no other symptoms, despite having discontinued azathioprine for 3 months. He continued to taper off prednisone. He had development of bilateral hip pain; imaging showed bilateral aseptic hip necrosis. A decision was made to initiate tumor necrosis factor (TNF)-α‎ inhibitors. He lost all the weight gained and recovered from the aseptic necrosis of the hip to be able to continue running. The final diagnosis was recurrent Vogt-Koyanagi-Harada syndrome. Vogt-Koyanagi-Harada syndrome is an idiopathic inflammatory disease with panuveitis and neurologic involvement in the form of aseptic meningitis and/or hearing loss. Although the full spectrum of the disorder may involve many skin changes and additional findings, most patients have incomplete disease because they are urgently treated with corticosteroids and the disorder is steroid responsive.

A 21-year-old woman with baseline depression, 1-year history of recurrent, painful, oral and vaginal ulcers, and cellulitis had a new, severe, acute-onset, left posterior headache with left shoulder pain. On neurologic examination, she had mild right oculomotor and abducens nerve weakness and marked left upper extremity and moderate left lower extremity upper motor neuron–type paresis. Initial brain magnetic resonance imaging showed acute ischemia involving the right pons, right midbrain, right cerebral peduncle, and internal capsule, extending into the right diencephalic region. Neck computed tomography angiography identified a right vertebral artery dissection at the C3 level. Cerebrospinal fluid analysis showed a marked neutrophilic pleocytosis with a reported “high” white blood cell count. HLA-B51 testing was positive. Biopsies of her ulcers indicated nonspecific inflammation with no infectious sources. Her severe headache preceding the manipulations, along with recurrent, painful, oral and genital ulcers (recurrent aphthous stomatitis), cerebrospinal fluid pleocytosis, and brainstem involvement after a vertebral artery dissection, raised concern for Behçet syndrome and eventually neurologic involvement of Behçet syndrome. Recurrent corticosteroid-responsive oral ulcers plus recurrent genital ulcers and skin lesions (cellulitis) fulfill the criteria for Behçet syndrome, with possible neurologic involvement (neuro-Behçet syndrome). The positive HLA-B51 testing was consistent with the diagnosis of Behçet syndrome. Treatment was initiated with low-dose aspirin and intravenous methylprednisolone, after which her neurologic status started to improve. Oral prednisone and azathioprine were added for long-term treatment. At age 25 years, she discontinued azathioprine because she planned pregnancy. At age 27 years, she started having recurrence of oral and genital ulcers, along with axillary ulcerative skin lesions. New-onset diplopia and left-sided weakness also developed before corticosteroid and azathioprine could be reinitiated. Magnetic resonance imaging of the brain showed a new left pontine and cerebellar peduncle lesion with subtle contrast enhancement. Intravenous methylprednisolone was initiated, followed by reinitiation of oral prednisone and the azathioprine regimen for long-term maintenance immunotherapy. The prednisone was slowly tapered after 3 months. The final diagnosis for this patient was relapsing neuro-Behçet syndrome because she had 2 recurrent neurologic episodes associated with 1) vertebral artery dissection and 2) brainstem involvement. If she were to have further relapses, the plan was to administer a tumor necrosis factor-α‎ inhibitor. The case of this patient highlights 3 aspects of Behçet syndrome: 1) diagnosis of systemic Behçet syndrome is made on clinical grounds only, but even if the diagnostic criteria are not fulfilled, once neuro-Behçet syndrome develops, treatment should be initiated to curtail significant morbidity; 2) although rare, arterial involvement in neuro-Behçet syndrome should be recognized; and 3) there are notable sex-dependent factors in the evolution of Behçet syndrome.

A comprehensive and ideal approach to treatment of multiple sclerosis (MS) has 5 levels of intervention. They are 1) prevention of active disease (clinical or subclinical relapses) in the first place, to prevent cumulative relapse-associated disability burden; 2) shortening the duration of active inflammatory demyelination associated with relapses, to limit the extent of irreversible central nervous system injury; 3) induction of more complete recovery after a relapse, to prevent or delay an ensuing chronic progressive neurodegeneration; 4) slowing the progressive phase of MS after progression ensues; and 5) treatment of symptoms and complications. The ultimate combined goal of these intervention levels is to alter the natural history of MS and prevent progression responsible for the main quantity of disability in MS, thereby improving the quality of life for patients with MS. Currently, treating physicians can accomplish levels 1, 2, and 5. Level 3 and level 4 interventions are yet to be developed sufficiently to affect the disease course meaningfully.

PET imaging with β-amyloid ligands is emerging as a molecular imaging technique targeting white matter integrity and demyelination. β-amyloid PET ligands such as (11)C-Pittsburgh compound B ((11)C-PiB) have been considered for quantitative measurement of myelin content changes in multiple sclerosis, but (11)C-PiB is not commercially available given its short half-life. A (18)F PET ligand such as flutemetamol with a longer half-life may be an alternative, but its ability to differentiate white matter hyperintensities (WMH) from normal-appearing white matter (NAWM) and its relationship with age remains to be investigated. Methods: Cognitively unimpaired (CU) older and younger adults (n = 61) were recruited from the community responding to a study advertisement for β-amyloid PET. Participants prospectively underwent MRI, (11)C-PiB, and (18)F-flutemetamol PET scans. MRI fluid-attenuated inversion recovery images were segmented into WMH and NAWM and registered to the T1-weighted MRI. (11)C-PiB and (18)F-flutemetamol PET images were also registered to the T1-weighted MRI. (11)C-PiB and (18)F-flutemetamol SUV ratios (SUVrs) from the WMH and NAWM were calculated using cerebellar crus uptake as a reference for both (11)C-PiB and (18)F-flutemetamol. Results: The median age was 38 y (range, 30–48 y) in younger adults and 67 y (range, 61–83 y) in older adults. WMH and NAWM SUVrs were higher with (18)F-flutemetamol than with (11)C-PiB in both older (P < 0.001) and younger (P < 0.001) CU adults. (11)C-PiB and (18)F-flutemetamol SUVrs were higher in older than in younger CU adults in both WMH (P < 0.001) and NAWM (P < 0.001). (11)C-PiB and (18)F-flutemetamol SUVrs were higher in NAWM than WMH in both older (P < 0.001) and younger (P < 0.001) CU adults. There was no apparent difference between (11)C-PiB and (18)F-flutemetamol SUVrs in differentiating WMH from NAWM in older and in younger adults. Conclusion: (11)C-PiB and (18)F-flutemetamol show a similar topographic pattern of uptake in white matter with a similar association with age in WMH and NAWM. (11)C-PiB and (18)F-flutemetamol can also effectively distinguish between WMH and NAWM. However, given its longer half-life, commercial availability, and higher binding potential, (18)F-flutemetamol can be an alternative to (11)C-PiB in molecular imaging studies specifically targeting multiple sclerosis to evaluate white matter integrity.

Background and ObjectivesTo evaluate the predictive value of serum neurofilament light chain (sNfL) and CSF NfL (cNfL) in patients with radiologically isolated syndrome (RIS) for evidence of disease activity (EDA) and clinical conversion (CC).MethodssNfL and cNfL were measured at RIS diagnosis by single-molecule array (Simoa). The risk of EDA and CC according to sNfL and cNfL was evaluated using the Kaplan-Meier analysis and multivariate Cox regression models including age, spinal cord (SC) or infratentorial lesions, oligoclonal bands, CSF chitinase 3–like protein 1, and CSF white blood cells.ResultsSixty-one patients with RIS were included. At diagnosis, sNfL and cNfL were correlated (Spearman r = 0.78,p< 0.001). During follow-up, 47 patients with RIS showed EDA and 36 patients showed CC (median time 12.6 months, 1–86). When compared with low levels, medium and high cNfL (>260 pg/mL) and sNfL (>5.0 pg/mL) levels were predictive of EDA (log rank,p< 0.01 andp= 0.02, respectively). Medium-high cNfL levels were predictive of CC (log rank,p< 0.01). In Cox regression models, cNfL and sNfL were independent factors of EDA, while SC lesions, cNfL, and sNfL were independent factors of CC.DiscussioncNfL >260 pg/mL and sNfL >5.0 pg/mL at diagnosis are independent predictive factors of EDA and CC in RIS. Although cNfL predicts disease activity better, sNfL is more accessible than cNfL and can be considered when a lumbar puncture is not performed.Classification of EvidenceThis study provides Class II evidence that in people with radiologic isolated syndrome (RIS), initial serum and CSF NfL levels are associated with subsequent evidence of disease activity or clinical conversion.

Radiologically isolated syndrome (RIS), in which asymptomatic demyelinating-appearing lesions are detected incidentally on MRI, can be a pre-clinical form of multiple sclerosis (MS). In this study, we measured cerebellar volumes on 3D T1-weighted 3T MR images in 21 individuals with RIS and 38 age- and sex-matched healthy controls (HC). Normalized cerebellar white matter volume and the anterior cerebellar gray matter volume were significantly decreased in RIS compared to HC ( p = 0.003 and p = 0.005, respectively). Our findings support reports of regional brain atrophy in RIS prior to the development of a seminal attack related to inflammatory demyelination.

Objective To investigate the associations of Pittsburgh compound‐B (PiB) uptake in white matter hyperintensities (WMH) and normal appearing white matter (NAWM) with white matter (WM) integrity measured with DTI and cognitive function in cognitively unimpaired older adults. Methods Cognitively unimpaired older adults from the population‐based Mayo Clinic Study of Aging (n = 537, age 65–95) who underwent both PiB PET and DTI were included. The associations of WM PiB standard uptake value ratio (SUVr) with fractional anisotropy (FA) and mean diffusivity (MD) in the WMH and NAWM were tested after adjusting for age. The associations of PiB SUVr with cognitive function z‐scores were tested after adjusting for age and global cortical PiB SUVr. Results The WMH PiB SUVr was lower than NAWM PiB SUVr (P

This cohort study investigates risk factors associated with time to a multiple sclerosis clinical event among patients with radiologically isolated syndrome., Key Points Question Are there clinical or demographic factors associated with time to clinical symptoms of multiple sclerosis among patients with radiologically isolated syndrome? Findings In this cohort study of 372 individuals with radiologically isolated syndrome, young age, the presence of spinal cord lesions, and gadolinium-enhancing lesions on the index magnetic resonance imaging scan were associated with increased risk of onset of clinical symptoms of multiple sclerosis. Meaning These findings identify 3 risk factors associated with multiple sclerosis at the preclinical stage of central nervous system demyelinating disease defined by radiologically isolated syndrome., Importance Younger age, oligoclonal bands, and infratentorial and spinal cord lesions are factors associated with an increased 10-year risk of clinical conversion from radiologically isolated syndrome (RIS) to multiple sclerosis (MS). Whether disease-modifying therapy is beneficial for individuals with RIS is currently unknown. Objectives To evaluate the 2-year risk of a clinical event (onset of clinical symptoms of MS) prospectively, identify factors associated with developing an early clinical event, and simulate the sample size needed for a phase III clinical trial of individuals with RIS meeting 2009 RIS criteria. Design, Setting, and Participants This cohort study used data on prospectively followed-up individuals with RIS identified at 1 of 26 tertiary centers for MS care in France that collect data for the Observatoire Français de la Sclérose en Plaques database. Participants were aged 10 to 80 years with 2 or more magnetic resonance imaging (MRI) scans after study entry and an index scan after 2000. All diagnoses were validated by an expert group, whose review included a double centralized MRI reading. Data were analyzed from July 2020 to January 2021. Exposure Diagnosis of RIS. Main Outcomes and Measures Risk of clinical event and associated covariates at index scan were analyzed among all individuals with RIS. Time to the first clinical event was compared by covariates, and sample size estimates were modeled based on identified risk factors. Results Among 372 individuals with RIS (mean [SD] age at index MRI scan, 38.6 [12.1] years), 354 individuals were included in the analysis (264 [74.6%] women). A clinical event was identified among 49 patients (13.8%) within 2 years, which was associated with an estimated risk of conversion of 19.2% (95% CI, 14.1%-24.0%). In multivariate analysis, age younger than 37 years (hazard ratio [HR], 4.04 [95% CI, 2.00-8.15]; P

Background: New inflammatory activity is of unclear frequency and clinical significance in progressive multiple sclerosis (MS); it is uncertain in patient cohorts with motor progression due to critical demyelinating lesions. Objectives: The aim of this study is to determine the likelihood of central nervous system (CNS) inflammatory activity, assessed by new clinical relapses or active magnetic resonance imaging (MRI) lesions, following onset of motor progression due to critical demyelinating lesions. Methods: Patients with progressive upper motor neuron impairment for ⩾1 year attributable to critical demyelinating lesions with single CNS lesion (progressive solitary sclerosis (PSS)), 2 to 5 total CNS demyelinating lesions (progressive “pauci-sclerosis” (PPS)), or >5 CNS demyelinating lesions and progressive exclusively unilateral monoparesis or hemiparesis (PUHMS) were identified. Clinical data were reviewed for acute MS relapses, and subsequent MRI was reviewed for active T1-gadolinium-enhancing or T2-demyelinating lesions. Results: None of the 91 patients (22 PSS, 40 PPS, 29 PUHMS) identified experienced clinical relapses over a median clinical follow-up of 93 months (range: 12–518 months). Nine patients (10%) developed active lesions over median 84 months radiologic follow-up (range: 12–518 months). Active lesions occurred in 24% PUHMS, 5% PSS, and 3% PPS cohorts. Conclusion: New inflammatory activity, defined by active lesions and clinical relapses following motor progression in patients with critical demyelinating lesions, is low. Disease-modifying therapies that reduce demyelinating relapses and active MRI lesions are of uncertain benefit in these cohorts.

Objective: To compare progressive motor impairment onset attributable to a “critical” central nervous system (CNS) demyelinating lesion in patients with highly restricted versus unlimited magnetic resonance imaging (MRI) lesion burden. Methods: We identified 135 patients with progressive motor impairment for ⩾1 year attributable to a “critical” demyelinating lesion with: MRI burden of 1 lesion (“progressive solitary sclerosis”), 2–5 lesions (“progressive paucisclerosis”), or unrestricted (>5) lesions and “progressive unilateral hemiparesis.” Neuroradiology review of brain and spinal cord MRI documented unequivocally demyelinating lesions. Results: A total of 33 (24.4%) patients had progressive solitary sclerosis; 56 (41.5%) patients had progressive paucisclerosis; and 46 (34.1%) patients had progressive unilateral hemiparesis. Median age at onset of progressive motor impairment was younger in progressive solitary sclerosis (49 years; range 24–73) and progressive paucisclerosis (50 years; range 30–64) than in progressive unilateral hemiparesis (54 years; range 39–77; p = 0.02 and p = 0.003, respectively). Within progressive unilateral hemiparesis, motor-progression onset was similar between those with 4–10, 11–20, or >20 brain lesions (55, 54, 53 years of age, respectively; p = 0.44). Conclusion: Motor-progression age is similar, but paradoxically earlier, in cohorts with highly restricted CNS lesion burden than in those with unrestricted lesion burden with progressive unilateral hemiparetic MS. The “critical” demyelinating lesion rather than total brain MRI lesion burden is the major contributor to motor-progression onset in these cohorts.

Background:Progressive motor impairment anatomically attributable to prominent, focally atrophic lateral column spinal cord lesions (“critical lesions”) can be seen in multiple sclerosis (MS), for example, progressive hemiparetic MS.Objective:The aim of this study was to investigate whether similar spinal cord lesions are more frequent in long-standing MS patients with secondary progressive motor impairment (secondary progressive MS (SPMS)) versus those maintaining a relapsing-remitting course (relapsing-remitting MS (RRMS)).Methods:We retrospectively identified Olmsted County (MN, USA) residents on 31 December 2011 with (1) RRMS or SPMS for ⩾25 years, and (2) available brain and spine magnetic resonance imaging (MRI). A blinded neuroradiologist determined demyelinating lesion burden and presence of potential critical lesions (prominent focally atrophic spinal cord lateral column lesions).Results:In total, 32 patients were included: RRMS, 18; SPMS, 14. Median (range) disease duration (34 (27–53) vs. 39 (29–47) years) and relapse number (4 (1–10) vs. 3 (1–15)) were similar. In comparison to RRMS, SPMS patients more commonly showed potential critical spinal cord lesions (8/18 (44%) vs. 14/14 (100%)), higher spinal cord (median (range) 4 (1–7) vs. 7.5 (3–12)), and brain infratentorial (median (range) 1 (0–12) vs. 2.5 (1–13)) lesion number; p Conclusion:Critical spinal cord lesions may be important contributors to motor progression in MS.

The purpose of this review is to discuss the interaction between aging, progressive disease course, disability worsening, and treatment strategies in multiple sclerosis (MS). The transition from the relapsing-remitting phase to the progressive phase in MS often happens in the fifth decade. In MS, structural central nervous system reserve decreases with aging and MS-associated mechanisms. While clinical and subclinical disease activity decreases with aging, the post-relapse recovery potential decreases with aging as well. Moreover, the efficacy of disease-modifying treatments declines with older age. Aging emerges as the ultimate target for prevention of progressive disease course, which is the most important determinant of disability worsening in MS. While none of our current treatment strategies targets the association between aging and progressive disease in MS, future treatment targets will likely consider the neuron-astrocyte complex, microglia, and oligodendrocyte functions impacted by the aging process.

Being a woman is one of the strongest risk factors for multiple sclerosis. The natural reproductive period from menarche to natural menopause corresponds to the active inflammatory disease period in multiple sclerosis. The fifth decade marks both the peri-menopausal transition in the reproductive aging and a transition from the relapsing-remitting to the progressive phase in multiple sclerosis. A short reproductive period with premature/early menopause and/or low number of pregnancies may be associated with an earlier onset of the progressive multiple sclerosis phase. A cross-sectional study of survey-based reproductive history in a multiple sclerosis clinical series enriched for patients with progressive disease, and a case–control study of multiple sclerosis and age/sex matched controls from a population-based cohort were conducted. Menarche age, number of complete/incomplete pregnancies, menopause type and menopause age were compared between 137 cases and 396 control females. Onset of relapsing-remitting phase of multiple sclerosis, progressive disease onset and reaching severe disability (expanded disability status scale 6) were studied as multiple sclerosis-related outcomes (n = 233). Menarche age was similar between multiple sclerosis and control females (P = 0.306). Females with multiple sclerosis had fewer full-term pregnancies than the controls (P, Premature/early menopause or nulliparity was associated with earlier progressive multiple sclerosis onset with a ‘dose effect’ of pregnancies on delaying progressive multiple sclerosis and severe disability. Zeydan et al.’s findings suggest a beneficial impact of oestrogen in delaying progressive multiple sclerosis and may have implications for counselling women on reproductive health., Graphical Abstract

Background The association of trigeminal neuralgia with pontine lesions has been well documented in multiple sclerosis, and we tested the hypothesis that occipital neuralgia in multiple sclerosis is associated with high cervical spinal cord lesions. Methods We retrospectively reviewed the records of 29 patients diagnosed with both occipital neuralgia and demyelinating disease by a neurologist from January 2001 to December 2014. We collected data on demographics, clinical findings, presence of C2-3 demyelinating lesions, and treatment responses. Results The patients with both occipital neuralgia and multiple sclerosis were typically female (76%) and had a later onset (age > 40) of occipital neuralgia (72%). Eighteen patients (64%) had the presence of C2-3 lesions and the majority had unilateral symptoms (83%) or episodic pain (78%). All patients with documented sensory loss (3/3) had C2-3 lesions. Most patients with progressive multiple sclerosis (6/8) had C2-3 lesions. Of the eight patients with C2-3 lesions and imaging at onset of occipital neuralgia, five (62.5%) had evidence of active demyelination. None of the patients with progressive multiple sclerosis (3/3) responded to occipital nerve blocks or high dose intravenous steroids, whereas all of the other phenotypes with long term follow-up (eight patients) had good responses. Conclusions A cervical spine MRI should be considered in all patients presenting with occipital neuralgia. In patients with multiple sclerosis, clinical features in occipital neuralgia that were predictive of the presence of a C2-3 lesion were unilateral episodic symptoms, sensory loss, later onset of occipital neuralgia, and progressive multiple sclerosis phenotype. Clinical phenotype predicted response to treatment.

Radiologically isolated syndrome (RIS) was defined in 2009 for asymptomatic patients who presented incidentally identified white matter anomalies within the central nervous system suggestive of multiple sclerosis (MS). Approximately one-third of RIS subjects will have a seminal clinical demyelinating event within 5 years of the identification of their abnormal MRI. Clinical evolution mirrors relapsing remitting or progressive forms of MS. Pejorative factors for clinical conversion are male gender, age younger than 35 years, and spinal cord lesions.

In multiple sclerosis (MS), disease course is defined by a subclinical or clinical relapsing remitting phase, a progressive phase, and the overlapping phase in-between. Each phase can have intermittently active or inactive periods. Subclinical activity in radiologically isolated syndrome evolving to primary-progressive MS is mostly indistinguishable from relapsing-remitting MS evolving to secondary-progressive MS. The onset of progressive-phase MS is age-dependent but time and pre-progressive phase agnostic. Pathologic hallmarks of progressive MS onset also appear to be age-dependent but pre-progressive phase agnostic. Onset of progressive MS is characterized by a peak in smoldering plaques.

Objective: To describe the clinical and distinctive imaging features of myelopathy associated with Behcet's disease. Methods: We evaluated the records of patients meeting the following criteria: a) fulfillment of the International Study Group criteria for Behcet's disease; b) clinically suggestive of myelopathy; c) simultaneous spinal cord and brain MRIs within 1 month of acute worsening of myelopathy; d) follow-up duration ≥1 year after initial MRI evaluation. Patients not fulfilling all inclusion criteria and having MRIs with poor quality or missing sequences were excluded. Results: In 11 patients (9 men, 2 women), we studied 14 MRIs during distinct myelopathy episodes and 9 follow-up MRIs. Two distinct MRI patterns of spinal cord involvement were described according to T2W axial images: 1) “Bagel Sign” pattern: A central lesion with hypo-intense core and hyper-intense rim with or without contrast enhancement; 2) “Motor Neuron” pattern: A symmetric involvement of the anterior horn cells. “Bagel Sign” was present in 13 of 14 myelopathy episodes whereas “Motor Neuron” pattern was observed in 1 of 14 MRIs. Of the 13 MRIs with “Bagel Sign” long myelopathy (n=9), both long and short myelopathy (n=2), and short myelopathy (n=2) was observed. All patterns cleared with some residual lesions after steroid use and immunomodulation with associated clinical recovery in patients. Interpretation: The signal characteristics of the “Bagel Sign” potentially represent venous engorgement and/or acute blood products within the spinal cord. To our knowledge, “Bagel Sign” has not been observed in other forms of longitudinal myelopathy outside of BD including neuromyelitis optica. This article is protected by copyright. All rights reserved.

BACKGROUND AND PURPOSE Glutamate levels may be informative about the declining neuronal health in the central nervous system. We used an advanced proton MR spectroscopy (1H-MRS) protocol composed of semi-localization by adiabatic selective refocusing (sLASER) localization and FAST(EST)MAP shimming for detection of alterations in brain glutamate concentrations in patients with amnestic mild cognitive impairment. METHODS Participants with amnestic mild cognitive impairment (n = 14; median age = 80) and age- and sex-matched clinically normal controls (n = 32; median age = 79) from the population-based Mayo Clinic Study of Aging were recruited prospectively to the 3T single-voxel 1H-MRS study that examined metabolite changes in the posterior cingulate gyri. To be included, controls had to have low β-amyloid load on [11C] Pittsburgh Compound B (PiB)-PET (standard uptake value ratio; SUVr < 1.42) and patients with amnestic mild cognitive impairment had to have high β-amyloid load (SUVr ≥ 1.42). RESULTS Glutamate concentration and the glutamate/myo-inositol ratio were lower in patients with amnestic mild cognitive impairment than clinically normal controls (P < .05). Higher global cortical PiB-PET SUVr correlated with lower glutamate/myo-inositol (r = –.3, P = .04). CONCLUSIONS The advanced sLASER with FAST(EST)MAP shimming is a promising protocol for identifying glutamate alterations. Advanced 1H-MRS protocols may add to the understanding of early Alzheimer's disease pathophysiology through detection of glutamate concentration in posterior cingulate gyri of individuals with amnestic mild cognitive impairment.

Objective To investigate β-amyloid and tau depositions using Pittsburgh compound B (PiB) positron emission tomography (PET) and AV1451 tau PET imaging in aging multiple sclerosis (MS) patients. Methods Patients with MS (n = 16) and controls (n = 80) matched for age, sex, and APOE e4 status from the population-based Mayo Clinic Study of Aging who underwent PiB PET imaging were studied. Of these individuals, 12 patients with MS and 60 matching controls also underwent AV1451 tau PET. Cortical PiB and AV1451 standard uptake value ratios (SUVrs) from the entire cortex and previously determined Alzheimer disease (AD) signature regions in the same population were calculated for group comparisons and testing for associations with age. Results AD signature PiB SUVr (odds ratio [OR] [95% confidence interval (CI)] = 0.52 [0.27-0.98], p = 0.044), total cortical PiB SUVr (OR [95% CI] = 0.52 [0.28-0.99], p = 0.048), and the frequency of abnormal PiB SUVrs (OR [95% CI] = 0.10 [0.01-0.90], p = 0.040) were lower in MS than controls. Although AD-signature and total cortical AV1451 SUVrs were not different between the groups, the frequency of abnormal AV1451 SUVrs was higher (OR [95% CI] = 10.65 [1.10-103.35], p = 0.041) in MS than controls. The association of AD signature PiB SUVr with age was steeper in the controls compared to patients with MS (estimate [95% CI] = -0.14 [-0.023 to -0.006], p = 0.002). Similarly, the association of total cortical PiB SUVr with age was steeper in the controls compared to patients with MS (estimate [95% CI] = -0.13 [-0.021 to -0.005], p = 0.002). There was no difference in the association of AV1451 SUVr findings with age between the MS patients and controls. Interpretation Although both β-amyloid and tau are biomarkers of cognitive aging and AD, cortical β-amyloid deposition was lower in MS than age-matched controls, suggesting that some aspect of MS pathobiology retards the accumulation of β-amyloid but not the accumulation of tau. ANN NEUROL 2020;87:556-567.

Purpose of review This article describes the dynamic evolution of multiple sclerosis (MS) through its phases and the impact of this understanding on treatment decisions. Recent findings MS consists of three phases: (1) the high-risk phase, (2) the relapsing-remitting phase, and (3) the progressive phase. Increasingly, subclinical disease activity is becoming an integral part of our definition of disease course in MS. In many patients, the relapsing-remitting phase starts as subclinical activity, likely long before they present with a clinically isolated syndrome. Differentiating progressive MS subgroups is also becoming less relevant. This is illustrated by comparing progressive MS that evolves from an asymptomatic state in individuals with radiologically isolated syndrome (primary progressive MS) and symptomatic individuals with relapsing-remitting MS (secondary progressive MS). In each case, the background disease activity and pathology can be indistinguishable. These phases evolve on a continuum and largely follow the aging process with little influence by the preceding clinical activity level. Recently, it also became evident that one or a few poorly recovered relapses at the beginning of clinical manifestations of MS predict much earlier progressive MS onset. Summary These findings suggest that interventions to prevent progressive MS, when they become available for clinical practice, may need to be considered as early as when the asymptomatic radiologically isolated syndrome is detected. This early treatment approach is being evaluated with ongoing trials with available disease-modifying therapies. In contrast, continuing the use of disease-modifying therapy beyond a certain age may have little benefit. However, being in the progressive phase of MS is not, in itself, an argument against disease-modifying therapy use in active disease in younger patients.

Therapeutic monoclonal antibodies have the potential to work as biological therapeutics. OKT3, Herceptin, Keytruda and others have positively impacted healthcare. Antibodies evolved naturally to provide high specificity and high affinity once mature. These characteristics can make them useful as therapeutics. However, we may be missing characteristics that are not obvious. We present a means of measuring antibodies in an unbiased manner that may highlight therapeutic activity. We propose using a microarray of random peptides to assess antibody properties. We tested twenty-four different commercial antibodies to gain some perspective about how much information can be derived from binding antibodies to random peptide libraries. Some monoclonals preferred to bind shorter peptides, some longer, some preferred motifs closer to the C-term, some nearer the N-term. We tested some antibodies with clinical activity but whose function was blinded to us at the time. We were provided with twenty-one different monoclonal antibodies, thirteen mouse and eight human IgM. These antibodies produced a variety of binding patterns on the random peptide arrays. When unblinded, the antibodies with polyspecific binding were the ones with the greatest therapeutic activity. The protein target to these therapeutic monoclonals is still unknown but using common sequence motifs from the peptides we predicted several human and mouse proteins. The same five highest proteins appeared in both mouse and human lists.

Background: Steps towards the development of diagnostic criteria are needed for children with the radiologically isolated syndrome to identify children at risk of clinical demyelination. Objectives: To evaluate the 2005 and 2016 MAGNIMS magnetic resonance imaging criteria for dissemination in space for multiple sclerosis, both alone and with oligoclonal bands in cerebrospinal fluid added, as predictors of a first clinical event consistent with central nervous system demyelination in children with radiologically isolated syndrome. Methods: We analysed an international historical cohort of 61 children with radiologically isolated syndrome (

A 73-year-old man was admitted for evaluation of acute ischemic strokes. His medical history was notable for pulmonary sarcoidosis treated with oral prednisone 40 mg daily, type 2 diabetes mellitus, hypertension, and hyperlipidemia. Approximately 1 month prior to admission, he underwent elective right total knee arthroplasty at an outside institution and 1 week postoperatively developed acute delirium and fluctuating fevers. No infectious cause was identified. His mental status continued to decline and head MRI was obtained (figure, A), showing small acute infarcts in multiple vascular territories.

Objective: To report patients with progressive motor impairment resulting from an isolated CNS demyelinating lesion in cerebral, brainstem, or spinal cord white matter that we call progressive solitary sclerosis. Methods: Thirty patients were identified with (1) progressive motor impairment for over 1 year with a single radiologically identified CNS demyelinating lesion along corticospinal tracts, (2) absence of other demyelinating CNS lesions, and (3) no history of relapses affecting other CNS pathways. Twenty-five were followed prospectively in our multiple sclerosis (MS) clinic and 5 were identified retrospectively from our progressive MS database. Patients were excluded if an alternative etiology for progressive motor impairment was found. Multiple brain and spinal cord MRI were reviewed by a neuroradiologist blinded to the clinical details. Results: The patients9 median age was 48.5 years (range 23–71) and 15 (50%) were women. The median follow-up from symptom onset was 100 months (range 15–343 months). All had insidiously progressive upper motor neuron weakness attributable to the solitary demyelinating lesion found on MRI. Clinical presentations were hemiparesis/monoparesis (n = 24), quadriparesis (n = 5), and paraparesis (n = 1). Solitary MRI lesions involved cervical spinal cord (n = 18), cervico-medullary/brainstem region (n = 6), thoracic spinal cord (n = 4), and subcortical white matter (n = 2). CSF abnormalities consistent with MS were found in 13 of 26 (50%). Demyelinating disease was confirmed pathologically in 2 (biopsy, 1; autopsy, 1). Conclusions: Progressive solitary sclerosis results from an isolated CNS demyelinating lesion. Future revisions to MS diagnostic criteria could incorporate this presentation of demyelinating disease.

Objective The aim of this work was to evaluate the preprogressive phase in subjects with radiologically isolated syndrome (RIS) who evolve to primary progressive multiple sclerosis (PPMS). Methods A multicenter RIS cohort was previously established. Demographic, clinical, and radiological characteristics of subjects with RIS that evolved directly to PPMS were compared to those that developed a relapsing disease course from onset (clinically isolated syndrome [CIS] or relapsing-remitting MS) and were also compared to two other population- and clinic-based PPMS cohorts. Results Of the 453 subjects with RIS, 128 evolved to symptomatic MS during the follow-up (113 developed a first acute clinical event consistent with CIS/MS, 15 evolved to PPMS). PPMS prevalence (11.7%) and onset age (mean ± standard deviation; 49.1 ± 12.1) in the RIS group were comparable to other PPMS populations (p > 0.05). Median time to PPMS was 3.5 years (range, 1.6–5.4). RIS evolved to PPMS more commonly in men (p = 0.005) and at an older age (p

To compare the temporal changes in the 3-dimensional (3D) structure of the medulla-upper cervical spinal cord region in African American (AA) and white multiple sclerosis (MS) patients to identify early patterns of anatomical change prior to progressive symptom development.Standardized 3-Tesla 3D brain MRI studies were performed at two time points on AA and white MS patients along with controls. Longitudinal changes in volume, surface area, tissue compliance, and surface texture measured in total and within ventral and dorsal compartments were studied. Independent regression models were constructed to evaluate differences between groups.Thirty-five individuals were studied, 10 AA with MS (female (F): 8; median age [IQR]=33.8 years (y) [10.9], median disease duration: 11.8y [11.3]), 20 white MS patients (F: 10; 35.6y [17.4], 7.23y [8.83], and 5 controls (F: 2, 51.8y [10.2]). Expanded Disability Status Scale scores were 0.0 at baseline and at the second MRI time point. Within the medulla-upper cervical spinal cord, AA versus white MS patients exhibited greater rates of atrophy in total (p0.0001) and within the ventral (p0.0001) and dorsal (p0.0001) compartments, reduced surface area (p0.0001), and reduced tissue compliance in the ventral (p=0.002) and dorsal (p=0.0005) compartments. The rate of change at the dorsal surface, but not the ventral surface, between MRI time points was also greater in AA relative to white MS patients (p0.0001).Structural changes in distinct anatomical regions of the medulla-upper cervical spinal cord may be reflective of early and disproportionate neurodegeneration in AA MS as compared to whites.

This case-control study examines the inflammatory CNS event outcome among patients with an autoimmune disease who were treated with tumor necrosis factor inhibitors., Key Points Question Is exposure to tumor necrosis factor inhibitors associated with risk of inflammatory demyelinating and nondemyelinating central nervous system events in patients with an autoimmune disease? Findings In this case-control study of 212 patients with or without inflammatory CNS events, exposure to tumor necrosis factor inhibitors was associated with an increased risk of inflammatory central nervous system events. The association was similar for both inflammatory demyelinating and nondemyelinating central nervous system events. Meaning The association observed between exposure to tumor necrosis factor inhibitor and increased risk of inflammatory demyelinating and nondemyelinating central nervous system events warrants future research to ascertain whether the association may indicate de novo inflammation or exacerbation of already aberrant inflammatory pathways., Importance Tumor necrosis factor (TNF) inhibitors are common therapies for certain autoimmune diseases, such as rheumatoid arthritis. An association between TNF inhibitor exposure and inflammatory central nervous system (CNS) events has been postulated but is poorly understood. Objective To evaluate whether TNF inhibitor exposure is associated with inflammatory demyelinating and nondemyelinating CNS events in patients with an indication for TNF inhibitor use and to describe the spectrum of those CNS events. Design, Setting, and Participants A nested case-control study was conducted using the medical records of patients with autoimmune diseases treated at 3 Mayo Clinic locations (Rochester, Minnesota; Scottsdale, Arizona; and Jacksonville, Florida) between January 1, 2003, and February 20, 2019. Patients were included if their records reported International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, diagnostic codes for US Food and Drug Administration–approved autoimmune disease indication for TNF inhibitor use (ie, rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, Crohn disease, and ulcerative colitis) and diagnostic codes for inflammatory CNS events of interest. Patients were matched 1:1 with control participants by year of birth, type of autoimmune disease, and sex. Exposures TNF inhibitor exposure data were derived from the medical records along with type of TNF inhibitor, cumulative duration of exposure, and time of exposure. Main Outcomes and Measures The main outcome was either inflammatory demyelinating (multiple sclerosis and other diseases such as optic neuritis) or nondemyelinating (meningitis, meningoencephalitis, encephalitis, neurosarcoidosis, and CNS vasculitis) CNS event. Association with TNF inhibitor was evaluated with conditional logistic regression and adjusted for disease duration to determine the odds ratios (ORs) and 95% CIs. Secondary analyses included stratification of outcome by inflammatory demyelinating and nondemyelinating CNS events and by autoimmune disease (rheumatoid arthritis and non–rheumatoid arthritis). Results A total of 212 individuals were included: 106 patients with inflammatory CNS events and 106 control participants without such events. Of this total, 136 were female (64%); the median (interquartile range) age at disease onset for patients was 52 (43-62) years. Exposure to TNF inhibitors occurred in 64 patients (60%) and 42 control participants (40%) and was associated with an increased risk of any inflammatory CNS event (adjusted OR, 3.01; 95% CI, 1.55-5.82; P = .001). These results were similar when the outcome was stratified by demyelinating and nondemyelinating CNS events. Secondary analyses found the association was predominantly observed in patients with rheumatoid arthritis (adjusted OR, 4.82; 95% CI, 1.62-14.36; P = .005). Conclusions and Relevance This study found that exposure to TNF inhibitors in patients with autoimmune diseases appeared to be associated with increased risk for inflammatory CNS events. Whether this association represents de novo or exacerbated inflammatory pathways requires further research.

The recent expansion of the radiological criteria and the use of a highly specific biomarker, anti-aquaporin 4-IgG (AQP4 IgG), has significantly improved the ability of clinicians to provide a timely and accurate diagnosis for neuromyelitis optica spectrum disorder (NMOSD), especially when faced with an abnormal disease presentation. Here, we report on the 5-year clinical experience of a 69-year-old right-handed African American woman who initially presented following symptoms suggestive of transient global amnesia. Her clinical history was only remarkable for a single episode of visual decline with poor recovery experienced 35 years prior, with prior unrevealing serological investigations. Brain MRI features were significant for diffuse, bilateral white matter abnormalities throughout the supratentorial, deep gray matter, and infratentorial regions. Spinal cord imaging studies were within normal limits with no intramedullary high-signal abnormalities identified. Serological studies were significant for the presence of anti-aquaporin 4-IgG. The clinical features were supportive of the diagnosis of NMOSD. The data provided here highlight both the clinical and radiological heterogeneity of NMOSD.

Objective: To evaluate the impact of age on recovery from multiple sclerosis relapses. Background: Increasing disability in multiple sclerosis is a consequence of progressive disease and incomplete relapse recovery. Methods: The first and last-ever relapse data (357 relapses in 193 patients) from the Olmsted County population-based multiple sclerosis cohort were systematically reviewed for age, fulminance, location (optic nerve, brainstem/cerebellar, spinal cord), peak deficit, and maximum recovery. Three different relapse-outcome measures were studied both as paired analyses and as an overall group effect: change from peak deficit to maximum recovery in raw functional system score related to the relapse (ΔFSS), a previously published FSS-based relapse-impact model, and change from peak deficit to maximum recovery in Extended Disability Status Scale (ΔEDSS) score. Results: Older age was linearly associated with worse recovery in the ΔFSS outcome ( p = 0.002), ΔEDSS outcome ( p Conclusion: Multiple sclerosis-relapse recovery declines in a linear fashion with increased age, which should be considered when making treatment decisions.

ObjectiveTo determine whether basing the decision to initiate immediate vs delayed disease-modifying therapy (DMT) on extent of recovery after initial relapse affects long-term disability accumulation in a multiple sclerosis (MS) evidence-based setting.MethodsWe analyzed the double-blind, placebo-controlled interferon beta-1a 30 mc once a week in clinically isolated syndrome and 10-year-follow-up extension trial. Good recovery after presenting relapse was defined as (1) full early recovery within 28 days of symptom onset (Expanded Disability Status Scale [EDSS] score of 0 at enrollment maintained ≥6 months) and (2) delayed good recovery (EDSS score > 0 at enrollment and improvement from peak deficit to 6th-month or 1-year visit ≥ median). Time from recovery assignment to future disability (EDSS score ≥ 2.5 or ≥4.0) was studied on a relapse-recovery-stratified age axis and immediate vs 3-year delayed treatment initiation with Kaplan-Meier statistics and hazard ratios (HRs).ResultsOne hundred seventy-five/328 patients had good recovery (94 immediate and 81 delayed treatment); 153 did not have good recovery (77 immediate and 76 delayed treatment). HRs for EDSS score ≥2.5 outcome were: delayed treatment without good recovery as reference (HR = 1.0), delayed treatment with good recovery (HR6th-month: 0.67, p = 0.207; HR1st-year: 0.40, p = 0.027), immediate treatment without good recovery (HR6th-month: 0.56, p = 0.061; HR1st-year: 0.40, p = 0.011), and immediate treatment with good recovery (HR6th-month: 0.43, p = 0.014; HR1st-year: 0.48, p = 0.034). Placebo patients were switched to long-term treatment after 3 years, and insufficient EDSS score ≥4.0 outcome events were available to study.ConclusionsIn patients with MS presenting without good recovery after the initial relapse, immediate DMT initiation favorably influences the likelihood of more ambulatory-benign disease akin to patients with good recovery after the initial relapse.Classification of evidenceThis study provides Class III evidence that for patients with MS without good recovery after the initial relapse, immediate DMT initiation increases the likelihood of a benign disease course.

ObjectiveTo determine the persistence of no evident disease activity (NEDA) in a population-based relapsing-remitting MS (RRMS) cohort.MethodsAll incident cases of RRMS in Olmsted County between 2000 and 2011 were identified using a medical records linkage system. Persistence of NEDA after RRMS diagnosis was determined by retrospective chart review. MRI activity, relapse, or Expanded Disability Status Scale (EDSS) worsening resulted in failure of NEDA.ResultsWe identified 93 incident cases of RRMS including 82 individuals with sufficient follow-up to determine the persistence of NEDA. There were 44 individuals not on disease-modifying therapy (DMT), whereas 37 individuals were prescribed an injectable DMT and 1 received mitoxantrone during the interval over which NEDA was maintained. NEDA was maintained by 63% at 1 year, 38% at 2 years, 19% at 5 years, and 12% at 10 years according to routine care assessment. At 10 years, there was no difference in EDSS disability among patients who maintained NEDA vs those who failed NEDA at 1 year (p = 0.3).ConclusionsNEDA infrequently persists beyond 2 years in a population-based cohort of newly diagnosed patients with RRMS.

Objective: To report progressive motor impairment from a critically located central nervous system (CNS) demyelinating lesion in patients with restricted magnetic resonance imaging (MRI)-lesion burden. Methods: We identified 38 patients with progressive upper motor-neuron impairment for >1 year, 2–5 MRI CNS-demyelinating lesions, with one seemingly anatomically responsible for progressive motor impairment. Patients with any alternative etiology for progressive motor impairment were excluded. A neuroradiologist blinded to clinical evaluation reviewed multiple brain and spinal-cord MRI, selecting a candidate critically located demyelinating lesion. Lesion characteristics were determined and subsequently compared with clinical course. Results: Median onset age was 47.5 years (24–64); 23 (61%) women. Median follow-up was 94 months (18–442); median Expanded Disability Status Scale Score (EDSS) at last follow-up was 4.5 (2–10). Clinical presentations were progressive: hemiparesis/monoparesis 31; quadriparesis 5; and paraparesis 2; 27 patients had progression from onset; 11 progression post-relapse. Total MRI lesions were 2 ( n = 8), 3 ( n = 12), 4 ( n = 12), and 5 ( n = 6). Critical lesions were located on corticospinal tracts, chronically atrophic in 26/38 (68%) and involved cervical spinal cord in 27, cervicomedullary/brainstem region in 6, thoracic spinal cord in 4, and subcortical white matter in 1. Conclusion: Progressive motor impairment may ascribe to a critically located CNS-demyelinating lesion in patients with highly restricted MRI burden. Motor progression from a specific demyelinating lesion has implications for understanding multiple sclerosis (MS) progression.

BACKGROUND AND PURPOSE: The 2010 McDonald criteria are designed to sensitively detect MS; however, the low specificity of these criteria can occasionally lead to the misdiagnosis of MS. The purpose of this study was to determine whether a novel double inversion recovery MR imaging technique has the potential to increase the specificity of diagnostic criteria distinguishing MS from non-MS white matter lesions. MATERIALS AND METHODS: This was a cross-sectional observational study. MR imaging data were acquired between 2011 and 2016. A novel double inversion recovery sequence that suppresses CSF and GM signal was used (GM-double inversion recovery). We compared WM lesions in a group of patients with multiple sclerosis and in a second group of positive controls with white matter lesions who did not have a diagnosis of MS. The presence of a rim on the GM-double inversion recovery MR imaging sequence was combined with the 2001 and 2010 McDonald disseminated-in-space criteria. Multiple MR imaging markers, including lesion location, size, and the presence of a rim, were compared between groups as well as a quantitative measure of lesion T1 hypointensity. RESULTS: MR images from 107 patients with relapsing-remitting MS (median age, 32 years) and 36 positive control (median age, 39 years) subjects were analyzed. No significant differences were found in age and sex. In patients with MS, 1120/3211 lesions (35%) had a rim on GM-double inversion recovery; the positive control group had only 9/893 rim lesions (1%). Rims were associated with a decrease in the lesion T1 ratio. Using the 2010 MR imaging criteria plus the presence of rims on GM-double inversion recovery, we achieved 78% and 97% specificity in subjects with ≥1 and ≥2 rim lesions, respectively. CONCLUSIONS: The addition of a novel GM-double inversion recovery technique enhanced specificity for diagnosing MS compared with established MR imaging criteria.