The radiologically isolated syndrome: revised diagnostic criteria.

The radiologically isolated syndrome (RIS) was defined in 2009 as the presence of asymptomatic, incidentally identified demyelinating-appearing white matter lesions in the CNS within individuals lacking symptoms typical of multiple sclerosis (MS). The RIS criteria have been validated and predict the transition to symptomatic MS reliably. The performance of RIS criteria that require fewer MRI lesions is unknown. 2009-RIS subjects, by definition, fulfil three to four of four criteria for 2005 dissemination in space (DIS) and subjects fulfilling only one or two lesions in at least one 2017 DIS location were identified within 37 prospective databases. Univariate and multivariate Cox regression models were used to identify predictors of a first clinical event. Performances of different groups were calculated. Seven hundred and forty-seven subjects (72.2% female, mean age 37.7 ± 12.3 years at the index MRI) were included. The mean clinical follow-up time was 46.8 ± 45.4 months. All subjects had focal T2 hyperintensities suggestive of inflammatory demyelination on MRI; 251 (33.6%) fulfilled one or two 2017 DIS criteria (designated as Groups 1 and 2, respectively), and 496 (66.4%) fulfilled three or four 2005 DIS criteria representing 2009-RIS subjects. Group 1 and 2 subjects were younger than the 2009-RIS group and were more likely to develop new T2 lesions over time (P < 0.001). Groups 1 and 2 were similar regarding survival distribution and risk factors for transition to MS. At 5 years, the cumulative probability for a clinical event was 29.0% for Groups 1 and 2 compared to 38.7% for 2009-RIS (P = 0.0241). The presence of spinal cord lesions on the index scan and CSF-restricted oligoclonal bands in Groups 1-2 increased the risk of symptomatic MS evolution at 5 years to 38%, comparable to the risk of development in the 2009-RIS group. The presence of new T2 or gadolinium-enhancing lesions on follow-up scans independently increased the risk of presenting with a clinical event (P < 0.001). The 2009-RIS subjects or Groups 1 and 2 with at least two of the risk factors for a clinical event demonstrated better sensitivity (86.0%), negative predictive value (73.1%), accuracy (59.8%) and area under the curve (60.7%) compared to other criteria studied. This large prospective cohort brings Class I evidence that subjects with fewer lesions than required in the 2009 RIS criteria evolve directly to a first clinical event at a similar rate when additional risk factors are present. Our results provide a rationale for revisions to existing RIS diagnostic criteria.

Coexistence of multiple sclerosis and spinocerebellar ataxia type-8.

Cerebellar dysfunction is likely to cause severe and treatment-resistant disability in multiple sclerosis (MS). Certain spinocerebellar ataxia (SCA)-related alleles can increase MS susceptibility, and channel polymorphisms can impact disability measures. Following an index patient with the coexistence of MS and SCA Type-8 (SCA8) in the MS clinic, an institutional engine search for MS and hereditary ataxia coexistence was conducted but did not reveal any other cases. This extremely rare coexistence of MS and SCA8 in our index patient may be incidental; however, a yet-to-be-identified contribution of coexistent hereditary ataxia(s) to the susceptibility of a prominent progressive ataxia MS phenotype cannot be ruled out.

Selective vulnerability of brainstem and cervical spinal cord regions in people with non-progressive multiple sclerosis of Black or African American and European ancestry.

BACKGROUND: We evaluated imaging features suggestive of neurodegeneration within the brainstem and upper cervical spinal cord (UCSC) in non-progressive multiple sclerosis (MS). METHODS: Standardized 3-Tesla three-dimensional brain magnetic resonance imaging (MRI) studies were prospectively acquired. Rates of change in volume, surface texture, curvature were quantified at the pons and medulla-UCSC. Whole and regional brain volumes and T2-weighted lesion volumes were also quantified. Independent regression models were constructed to evaluate differences between those of Black or African ancestry (B/AA) and European ancestry (EA) with non-progressive MS. RESULTS: 209 people with MS (pwMS) having at least two MRI studies, 29% possessing 3-6 timepoints, resulted in 487 scans for analysis. Median follow-up time between MRI timepoints was 1.33 (25th-75th percentile: 0.51-1.98) years. Of 183 non-progressive pwMS, 88 and 95 self-reported being B/AA and EA, respectively. Non-progressive pwMS demonstrated greater rates of decline in pontine volume (p < 0.0001) in B/AA and in medulla-UCSC volume (p < 0.0001) for EA pwMS. Longitudinal surface texture and curvature changes suggesting reduced tissue integrity were observed at the ventral medulla-UCSC (p < 0.001), dorsal pons (p < 0.0001) and dorsal medulla (p < 0.0001) but not the ventral pons (p = 0.92) between groups. CONCLUSIONS: Selectively vulnerable regions within the brainstem-UCSC may allow for more personalized approaches to disease surveillance and management.

Smoking, early menopause and multiple sclerosis disease course.

Smoking is associated with an increased risk of multiple sclerosis (MS), and smoking and early menopause are related to poor outcomes in MS. Smoking is also associated with early menopause. To explore this intricate relationship between smoking status, age at menopause and disease course in MS, 137 women with MS and 396 age-matched controls were included in this case-control study. Age at menopause (median 49.0 vs. 50.0 years; p = 0.79) and smoking status (40.3% vs. 47.6%; p = 0.15) were similar among MS and control women. Relapsing MS onset was earlier in ever-smoker women with early menopause compared to the rest of the women (median 30.4 vs. 37.0 years; p = 0.02) and also compared to ever-smoker women with normal age at menopause (median 30.4 vs. 41.0 years; p = 0.008) and never-smoker women with early menopause (median 30.4 vs. 41.5 years; p = 0.004). Progressive MS onset was also earlier in ever-smoker women with early menopause compared to ever-smoker women with normal age at menopause (median 41.1 vs. 49.4 years; p = 0.05) and never-smoker women with early menopause (median 41.1 vs. 50.1 years; p = 0.12). Our results suggest that smoking and menopause associate with MS disease course, including the onset of relapsing and progressive MS in women.

Imaging Biomarkers of Alzheimer Disease in Multiple Sclerosis.

OBJECTIVE: To investigate ß-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 ε4 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 ß-amyloid and tau are biomarkers of cognitive aging and AD, cortical ß-amyloid deposition was lower in MS than age-matched controls, suggesting that some aspect of MS pathobiology retards the accumulation of ß-amyloid but not the accumulation of tau. ANN NEUROL 2020;87:556-567.

Impact of Age on Multiple Sclerosis Disease Activity and Progression.

PURPOSE OF REVIEW: The purpose of this review is to discuss the interaction between aging, progressive disease course, disability worsening, and treatment strategies in multiple sclerosis (MS). RECENT FINDINGS: 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.

Behçet's disease as a causative factor of cerebral venous sinus thrombosis: subgroup analysis of data from the VENOST study.

OBJECTIVE: This study was performed to determine the rate of cerebral venous sinus thrombosis (CVST) among cases of Behçet's disease (BD) included in a multicentre study of cerebral venous sinus thrombosis (VENOST). METHODS: VENOST was a retrospective and prospective national multicentre observational study that included 1144 patients with CVST. The patients were classified according to aetiologic factors, time of CVST symptom onset, sinus involvement, treatment approach and prognosis. RESULTS: BD was shown to be a causative factor of CVST in 108 (9.4%) of 1144 patients. The mean age of patients in the BD group was 35.27 years and 68.5% were men, whereas in the non-BD CVST group, the mean age was 40.57 years and 28.3% were men (P < 0.001). Among the aetiologic factors for patients aged 18-36 years, BD was predominant for men, and puerperium was predominant for women. The onset of symptoms in the BD group was consistent with the subacute form. The transverse sinuses were the most common sites of thrombosis, followed by the superior sagittal sinuses. The most common symptom was headache (96.2%), followed by visual field defects (38%). CONCLUSIONS: BD was found in 9.4% of patients in our VENOST series. Patients with BD were younger and showed a male predominance. The functional outcome of CVST in patients with BD was good; only 12% of patients presenting with cranial nerve involvement and altered consciousness at the beginning had a poor outcome (modified Rankin Score ⩾2).

Age is a critical determinant in recovery from multiple sclerosis relapses.

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 < 0.001), and the FSS-based relapse-impact model (p < 0.001). A multivariate analysis of ΔFSS outcome linked poor recovery to older age (p = 0.015), relapse location (transverse myelitis or brainstem/cerebellar syndrome; p < 0.001), and relapse fulminance (p = 0.004). CONCLUSION: Multiple sclerosis-relapse recovery declines in a linear fashion with increased age, which should be considered when making treatment decisions.

Myelopathy in Behçet's disease: The Bagel Sign.

OBJECTIVE: To describe the clinical and distinctive imaging features of myelopathy associated with Behçet's disease (BD). METHODS: We evaluated the records of patients meeting the following criteria: (1) fulfillment of the International Study Group criteria for BD; (2) clinically suggestive of myelopathy; (3) simultaneous spinal cord and brain magnetic resonance images (MRIs) within 1 month of acute worsening of myelopathy; and (4) 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 nine follow-up MRIs. Two distinct MRI patterns of spinal cord involvement were described according to T2-weighted (T2W) axial images: (1) "Bagel Sign" pattern: a central lesion with hypointense core and hyperintense rim with or without contrast enhancement; and (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. Ann Neurol 2017;82:288-298.

Pittsburgh compound-B PET white matter imaging and cognitive function in late multiple sclerosis.

BACKGROUND: There is growing interest in white matter (WM) imaging with positron emission tomography (PET). OBJECTIVES: We studied the association of cognitive function in late multiple sclerosis (MS) with cortical and WM Pittsburgh compound-B PET (PiB-PET) binding. METHODS: In the population-based Mayo Clinic Study of Aging, 24 of 4869 participants had MS (12 underwent PiB-PET). Controls were age and sex matched (5:1). We used automated or semi-automated processing for quantitative image analyses and conditional logistic regression for group differences. RESULTS: MS patients had lower memory ( p = 0.03) and language ( p = 0.02) performance; smaller thalamic volumes ( p = 0.003); and thinner temporal ( p = 0.001) and frontal ( p = 0.045) cortices on magnetic resonance imaging (MRI) than controls. There was no difference in global cortical PiB standardized uptake value ratios between MS and controls ( p = 0.35). PiB uptake was lower in areas of WM hyperintensities compared to normal-appearing white matter (NAWM) in MS ( p = 0.0002). Reduced PiB uptake in both the areas of WM hyperintensities ( r = 0.65; p = 0.02) and NAWM ( r = 0.69; p = 0.01) was associated with decreased visuospatial performance in MS. CONCLUSION: PiB uptake in the cortex in late MS is not different from normal age-matched controls. PiB uptake in the WM in late MS may be a marker of the large network structures' integrity such as those involved in visuospatial performance.

Electrophysiological Investigations in Orthostatic Myoclonus: Preliminary Findings.

We report the clinical and electrophysiological findings in seven patients with orthostatic myoclonus (OM) associated with gait initiation failure and falls. OM is one of the causes of unsteadiness of stance and gait, and it may develop as a symptom of neurodegenerative disorders. Both positive myoclonic bursts and negative myoclonus may be seen in electrophysiological recordings, and electrophysiological analysis suggests a subcortical origin for OM.

Visually evoked startle response in a patient with epilepsy: a case report and review of the literature.

Both symptomatic and genetic, cases with hyperekplexia or startle seizures induced by acoustic stimuli, are previously reported. By contrast, startle response induced by visual stimuli is rare. While visual stimuli are more commonly associated with startle seizures, here we present an 11-year-old girl with epilepsy, motor-mental retardation, and spastic tetraparesis, who had repetitive startle responses by photic stimulation during the electroencephalogram recording, without any spike-and-wave discharges associated with the startles. We report this unique case with startle responses induced both by acoustic and photic stimuli and review the literature related to this exceptionally rare combination of symptoms.

Timing of Future Remyelination Therapies and Their Potential to Stop Multiple Sclerosis Progression.

Prior to the onset of demyelination in multiple sclerosis (MS), early oligodendrocyte injury, axonal degeneration and astroglial scarring occur. The irreversible progressive phase of MS begins when the axonal loss threshold is reached. Progressive disease onset has the highest impact on a poor prognosis in MS. Conversion to progressive disease is essentially an age-dependent process independent of disease duration and initial disease course. Although prevention of relapses has been the primary approach in the disease management, incomplete recovery from even the first relapse correlates with the long-term neurodegenerative phenotype of progressive MS onset. Therefore, the provider should review each patient's potential for relapse-related disability and start DMDs with the goal of preventing relapses. Existing immunomodulatory medications used to prevent MS relapses do not prevent long-term disability, which requires agents focused on remyelination and axonal repair. If applied immediately after a relapse rather than during the progressive phase of MS, remyelination-stimulating strategies may result in full recovery and prevention of long-term neurodegeneration and progressive disease course.

Arterial and venous thrombosis of the cerebral vasculature in GAPO syndrome.

A 37-year-old male, previously diagnosed with GAPO syndrome, was admitted to our hospital complaining of recurrent episodes of transient weakness and numbness in his left arm for 3 months, and severe headache with progressive dysphagia for 15 days. His cranial magnetic resonance (MR) images showed multiple ischemic foci in the bilateral periventricular and supraventricular white matter. Cerebral MR-angiography showed total occlusion of the right internal carotid artery and moderate stenosis in the left internal carotid. We also detected chronic thrombotic changes in the distal left sigmoid sinus, proximal right sigmoid sinus, and bilateral jugular veins on cerebral MR-venography. He was diagnosed with dilated cardiomyopathy at age 31 years, which was reported as a novel association; and later he had a myocardial infarction at age 34 years. To the best of our knowledge, this is the first patient with GAPO syndrome and arterial atherosclerosis in cerebral-as well as coronary-arteries and intracranial venous thrombosis. We report the evolution of the disease in this patient, who died at age 38 years due to respiratory failure secondary to lower respiratory tract infection.

Do magnetic resonance imaging features differ between persons with multiple sclerosis of various races and ethnicities?

Those of African American or Latin American descent have been demonstrated to have more severe clinical presentations of multiple sclerosis (MS) than non-Latin American White people with MS. Concurrently, radiological burden of disease on magnetic resonance imaging (MRI) in African Americans with MS has also been described as being more aggressive. Here, we review MRI studies in diverse racial and ethnic groups (adult and pediatric) investigating lesion burden, inflammation, neurodegeneration, and imaging response to disease modifying therapy. We also discuss why such disparities may exist beyond biology, and how future studies may provide greater insights into underlying differences.

Longitudinal cognitive function and brain metabolites in women receiving chemotherapy for stage 1 to 3 breast cancer: Observational study.

Few proton magnetic resonance spectroscopy studies have explored chemotherapy-related biochemical changes in brain regions. This observational study aimed to longitudinally assess short-term cognitive changes and brain metabolite concentrations in women undergoing chemotherapy for breast cancer. We analyzed 11 women with newly diagnosed stage 1 to 3 breast cancer. Patients were evaluated via objective cognitive testing, and patient self-report tests. Patients were examined using single voxel proton magnetic resonance spectroscopy in the medial frontal cortex, posterior cingulate gyrus, and left thalamus at baseline and after the completion of chemotherapy on a 1.5 Tesla scanner. At the posttreatment evaluation as compared to baseline, 7 of the 10 (70%) patients reported worsening memory on the MD Anderson symptom inventory (annualized change = 1.82 ± 2.88, P = .08), while the delayed recall raw score of the Rey Osterrieth complex figure test did not change from pre- to post-chemotherapy (mean annualized change = 5.00 ± 14.38, P = .30). The annualized change in the creatine concentration in the posterior cingulate gyrus was statistically significant. The annualized change in the MD Anderson symptom inventory was negatively correlated with the annualized change in the medial frontal N-acetylaspartate (Spearman correlation coefficient [rho] = -0.78, P = .01) and positively correlated with the annualized change in the posterior cingulate gyrus creatine (rho = 0.66, P = .04). Annualized changes in the Rey Osterrieth complex figure test were positively correlated with annualized changes in choline (rho = 0.83, P = .01) in the medial frontal cortex, choline (rho = 0.76, P = .04) in the left thalamus, and creatine (rho = 0.73, P = .02) in the medial frontal cortex. Our data suggest that chemotherapy may lead to the worsening of self-reported memory function, which is associated with alterations in brain metabolites.