Faculty Bibliography

Background. Brain lesions are common in neuromyelitis optica spectrum disorder (NMOsd) and may resemble lesions of multiple sclerosis (MS). Objectives. To describe the imaging characteristics of supratentorial lesions in NMOsd on ultrahigh-field (7 T) MRI with special attention to vessel-lesion relationship. Methods. Ten NMOsd patients, all women and all seropositive for NMO IgG, with mean age of 51.3 +/- 15.4 years and disease duration of 9.2 +/- 6.4 years, were scanned at a 7 T whole-body human MR system with high-resolution 2D gradient echo sequence optimized to best visualize lesions and venous structures, T2- and T1-weighted imaging. Results. In 10 patients with NMOsd, a total of 92 lesions were observed (mean: 9.2 +/- 8.8; range: 2-30), but only 8 lesions (9%) were traversed by a central venule. All lesions were <5 mm in diameter, and 83% were located in subcortical white matter. There were no lesions in the cortex or basal ganglia. Two patients exhibited diffuse periependymal abnormalities on FLAIR. Conclusions. Small, subcortical lesions without a central venule are the most consistent finding of NMOsd on 7 T MRI of the brain. Ultrahigh-field imaging may be useful for differentiating between NMOsd and MS.

The North American Research Committee on Multiple Sclerosis (NARCOMS) Registry is a database that contains information from over 35,000 patient volunteers on symptom severity in 11 domains commonly affected in multiple sclerosis (MS): mobility, hand function, vision, fatigue, cognition, bowel/bladder function, sensory, spasticity, pain, depression, and tremor/coordination. The Registry affords a unique opportunity to study the frequency and severity of domain-specific impairment in a contemporary, mostly treated MS cohort over the course of the disease. The objective of this work was to calculate symptom prevalence in each of the 11 domains for years 0 to 30 from symptom onset. The resulting "symptom prevalence tables" demonstrate that a majority of participants perceive at least some degree of impairment in most domains as early as the first year of disease. The severity of impairment increases with disease duration across all domains, but the patterns of disability accumulation differ. The symptom prevalence tables illustrate the magnitude of perceived impact of the disease and highlight the extent of unmet need in symptomatic management. The tables are easy to use and allow MS patients and their clinicians to compare an individual's own impairment in any of the 11 domains to that of NARCOMS participants with the same disease duration.

Background: Multiple Sclerosis Severity Score (MSSS; Roxburgh et al, Neurology; 64:1144) is a mean rank of Expanded Disability Status Scale (EDSS) among patients with same disease duration. MSSS has been used to compare disease severity in different patient populations and for monitoring treatment response in groups of patients. Clinical utility of MSSS is limited by the requirement for objective assessment of EDSS score by a trained MS specialist. Patient-Determined Disability Steps (PDDS).is a validated, nine-point disability scale that does not require clinician input. A ranking scale of PDDS, an analogue of MSSS, may be a practical and cost-effective tool for monitoring long-term outcomes in groups of patients. Objective: To develop a ranking scale of Patient-Determined Disability Steps (PDDS) using the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry as the reference population. Design/Methods: All NARCOMS registrants with known PDDS and disease duration of 1-45 years at PDDS were included in the study. Frequency-ranking methodology (Roxburgh, et al. Neurology; 64:1144) was applied to the NARCOMS dataset to derive disease duration-adjusted mean ranks of PDDS scores. We termed the new measure, 'Patient-derived MS Severity Score' (P-MSSS). We also calculated disease duration-adjusted maximum rank (or prevalence) of each PDDS. The data for mean rank (P-MSSS) and maximum rank (prevalence) of all PDDS scores for the first 45 years of disease was graphically represented in the form of P-MSSS Reference Table. Results: The cohort was comprised of 27,918 NARCOMS enrollees, of whom 72.7% were female and 90.1% were White. Mean age of symptom onset was 30.1 (+10.1) years, and age at enrollment was 47.1 (+11.0) years. P-MSSS Reference Table represents frequency-rank of disability for each of the first 45 years since symptom onset. About half of the enrollees described their disability as "limiting daily activities" or worse just one year after disease, and two-thirds - after 5!

Objectives: To compare supratentorial lesions in patients with neuromyelitis optica spectrum disorders (NMOsd) and multiple sclerosis (MS) on ultra-high-field (7-Tesla) MRI. 508Background: Brain lesions are common in NMOsd. The distinction between NMOsd and MS is not always possible with conventional brain MRI. The aim of this study is to compare supratentorial lesions in NMOsd and MS on ultra-high-field (7-Tesla) MRI, and to attempt to develop criteria for differentiating the two conditions on neuro-radiologic basis. Design/methods: NMOsd and MS patients matched by age and disease duration were recruited from the NYU-MS Center. Imaging data were acquired on a 7T whole-body human MR system (MAGNETOM, Siemens). NMO and MS patients were scanned using identical imaging protocol that included a high-resolution 2D gradient echo sequence optimized to best visualize venous structures (TR/TE/flip angle = 500ms/25ms/35degree, voxel size = 0.23x0.23x2 mm³). This sequence is highly sensitive to venous vasculature and is used to visually examine for presence of central venule in supratentorial brain lesions. Results: 10 patients with NMOsd and 5 patients with MS underwent 7T brain MRI. NMOsd patients were all women, all NMO IgG-seropositive, with average age of 47.8+9.0 years and disease duration of 11.4+6.5 years. MS patients were 80% women, with mean age of 43.6+10.0 years, and disease duration of 15.5+10.1 years. NMOsd patients had a total of 74 supratentorial lesions (7.4 per patient), versus 152 in MS patients (30.4 per patient). There were striking differences in lesion distribution: in NMOsd, 93% of lesions were subcortical versus 30% in MS group; by contrast, only 1% of NMOsd lesions were periventricular v. 53% for MS. MS patients also exhibited more lesions in juxtocortical white matter (9% v. 3 % in NMOsd) and in corpus callosum (11% v. 3% in NMOsd). Importantly, we did not detect any cortical lesions in NMOsd, while 3 out of 5 MS patients had detectable cortical lesions. Central venul!

Background: Sound lateralization is dependent upon precise timing of neuronal discharges in the auditory brainstem. Slowed processing speed in auditory brainstem pathways interferes with MS patients' ability to lateralize sound. A test of sound lateralization may be useful for detecting subtle brainstem deficits even among minimally impaired MS subjects. Objective: To determine whether a test of sound lateralization may be more sensitive to differences between controls and minimally impaired MS subjects than standard cognitive tasks. Design/Methods: 16 healthy controls and 45 MS subjects were recruited. Patients were divided into three disability strata: No Disability (Expanded Disability Status Scale (EDSS) =0; N=15), Mild Disability (EDSS=1 to 3.5; N=17), and Moderate Disability (EDSS=4 to 6.5; N=13). Using an interleaved staircase method, the interaural time difference (ITD) to a dichotically presented 910 Hz tone burst was varied to determine ITD thresholds for the tone localized just to the right or just to the left of center. Two standard tests used to assess processing speed, the Paced Auditory Serial Addition Test (PASAT3 and PASAT2) and the Symbol Digit Modalities Test (SDMT), were also administered. Results: Right and left threshold ITDs were averaged to provide a deviation score for each subject. The mean threshold ITD score was lowest for controls (M=196.9 mus, SD=76.4), increased for the No and Mild Disability groups (M=280.7 mus, SD=77.5 and M=268.8 mus, SD=105.3, respectively), and was greatest for the Moderate Disability group ( M=342.3 mus, SD=62.2). A MANOVA showed highly significant effects for IDT (p<.001, eta2=.28) and for the three other dependent variables (PASAT3, p<0.02; eta2=.23; PASAT2, p<.01, eta2=.18; SDMT, p<.001, eta2=.30). However, post hoc analysis showed that only the IDT test was sensitive to differences between controls and each MS group including, most importantly, the No Disability group(p<0.02). Conclusions: In our study, sound localization was the only te!

Objective: To test the utility of a backward masking task for assessing speed of processing in Multiple Sclerosis (MS) on a millisecond scale. Background: Slowed speed of processing is a central component of cognitive impairment in patients with MS. Standard methods of assessing speed of processing, such as the Processing Speed Index, Symbol Digit Modalities Test, or the Paced Auditory Serial Addition Test provide a global measure of processing speed, but do not capture more subtle changes that might occur in the millisecond range. In the present study, we used a backward masking paradigm, in which the stimulus to be reported is followed by a masking pattern. A longer interstimulus interval (ISI) needed to correctly identify the primary stimulus is indicative of slower processing speed and the ISIs producing backward masking would be expected to occur in the range of less than 100 milliseconds. Method/Design: 11 healthy controls and 42 MS patients with scores on the Expanded Disability Status Scale (EDSS) ranging from 0 to 6.5 were recruited for the study. Stimuli consisted of 4 to 6 lower-case- letter words presented on a computer screen. The stimulus word was followed by a mask of upper-case letters forming a nonsense word. The letters of the mask overlay the stimulus word. The ISI between the stimulus word and mask was increased in increments of 5 milliseconds (msec) until the subject was unable to report the word correctly. At that point, 5 iterations of the staircase method were presented to zero in on the threshold ISI. Results: A regression analysis with EDSS as the independent variable and Backward Masking ISI threshold as the dependent measure showed that EDSS was a significant predictor of ISI threshold (unstandardized coefficient B=7.51, t(51)=4.58, p<.001). EDSS also accounted for a significant amount of the variance in ISI scores (R2=.28, F(1,51)=20.96, p<.001). ISI thresholds ranged from an average of 45 msec for controls to an average of 115 msec for EDSS of 6.5. The slope (B) in!

Purpose: Normal neuronal activity is tightly linked to and depends on the increase of blood flow for instantaneous supply of oxygen and glucose. This study is to evaluate whether there are cerebral blood flow (CBF) regulation abnormalities in MS with measurement of cerebrovascular reactivity (CVR) using hypercapnia perfusion MRI. Materials and Methods: Sixteen patients with MS (14 relapsing remitting and 2 secondary progressive) (mean age: 45.1+14.2 years, mean EDSS: 2.9+1.6) and age-matched 13 healthy controls (mean age: 44.5+12.2 years) were recruited for this study. CO2 is a potent vasodilator, and an increase of CO2 tension in blood (referred to as hypercapnia) is known to cause CBF increase. Such CBF changes were measured with a standard pseudo-continuous arterial spin labeling (pCASL) MRI at 3T, with quantitative CBF (ml/min/100g) maps generated during both room air and hypercapnia (mixed 5%CO2, 21%O2, and 74%N2) exposure. The imaging parameters of pCASL include TR/TE=3950/17ms, 52 repetitions, FOV=22cm, in-plane matrix=64x64, slice thickness=5mm, labeling duration=1500ms, postlabeling delay=1230ms, and label location = 84mm below AC-PC line. End-tidal CO2 (EtCO2) was recorded continuously during the scan with a capnograph device and was used as an input function in the analysis. The CVR was calculated as (% change in CBF comparing CO2 inhalation to room-air breathing) divided by (EtCO2 during CO2 inhalation - EtCO2 during room-air breathing). Segmented whole brain grey matter (GM), white matter (WM), and brain parenchymal CVR were calculated for the group analysis. Results: The averaged CVR (%CBF/mmHg EtCO2) showed significant difference for whole brain parenchymal (P=0.009), GM (P=0.008), and WM (P=0.03) between patients (4.74+0.88%, 4.89+1.08%, and 4.73+1.02%) and healthy controls (3.46+1.51%, 3.51+1.47%, and 3.53+1.83%, respectively). There was a significant correlation between brain parenchymal CVR and EDSS (r=-0.69, P=0.007). Whole brain CVR changes correlate with fractional brain p!

OBJECTIVE: To analyze time-trends in age at disability milestones among MS patients who were enrolled into the MSBase International Registry during 1996-2010 period. METHODS: We used linear regression to describe the relationship between mean age at major EDSS benchmarks and calendar time. We then assessed time-trend in age at initial EDSS rating with a three level linear growth model specifying that patients were nested within each of 20 participating countries. The model estimated the average of time-trends in mean age at initial clinical assessment within each country while controlling for patients' EDSS and sex in each country. Analyses were repeated in subsamples of patients diagnosed according to Poser or McDonald criteria. RESULTS: The MSBase Registry contained data on 11,108 MS patients enrolled between 1996 and 2010 who fulfilled our inclusion criteria. During the 1996-2010 period, enrollment age for patients with EDSS 4/4.5 increased by 7.9years, from 43 to 51years (p<0.001), and for EDSS 6/6.5 - by 4.9years, from 48 to 53year (p<0.001). These trends were consistent across 20 investigator countries and were observed in Poser-diagnosed as well as McDonald-diagnosed patient subsets. CONCLUSIONS: The more recent MSBase enrollees in each of the mild-to-moderate disability strata were significantly older than earlier enrollees. Possible explanations for this phenomenon are discussed.