Christina Azevedo

Early CNS neurodegeneration in radiologically isolated syndrome

Objective: Increasing evidence indicates that the thalamus may be a location of early neurodegeneration in multiple sclerosis (MS). Our objective was to identify the presence of gray matter volume loss and thinning in patients with radiologically isolated syndrome (RIS). Methods: Sixty-three participants were included in this case-control study. Twenty-one patients with RIS were age- and sex-matched to 42 healthy controls in a 1:2 ratio. All participants underwent brain MRIs on a single 3T scanner. After lesion segmentation and inpainting, 1 mm3-isometric T1-weighted images were submitted to FreeSurfer (v5.2). Normalized cortical and deep gray matter volumes were compared between patients with RIS and controls using t tests, and thalamic volumes were correlated with white matter lesion volumes using Pearson correlation. Exploratory cortical thickness maps were created. Results: Although traditional normalized total gray and white matter volumes were not statistically different between patients with RIS and controls, normalized left (0.0046 ± 0.0005 vs 0.0049 ± 0.0004, p = 0.006), right (0.0045 ± 0.0005 vs 0.0048 ± 0.0004, p = 0.008), and mean (0.0045 ± 0.0005 vs 0.0049 ± 0.0004, p = 0.004) thalamic volumes were significantly lower in patients with RIS (n = 21, mean age 41.9 ± 12.7 years) than in controls (n = 42, mean age 41.4 ± 11.2 years). Thalamic volumes correlated modestly with white matter lesion volumes (range: r = −0.35 to −0.47). Conclusion: Our data provide novel evidence of thalamic atrophy in RIS and are consistent with previous reports in early MS stages. Thalamic volume loss is present early in CNS demyelinating disease and should be further investigated as a metric associated with neurodegeneration.

Primary Progressive Multiple Sclerosis Evolving from Radiologically Isolated Syndrome

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).

Primary Progressive MS evolving from Radiologically Isolated Syndrome

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).

The Vitamin D to Ameliorate Multiple Sclerosis (VIDAMS) trial: Study design for a multicenter, randomized, double-blind controlled trial of vitamin D in multiple sclerosis

BACKGROUND Lower levels of vitamin D are associated with increased MS risk and with greater clinical and brain MRI activity in established relapsing MS. OBJECTIVE The VIDAMS trial (NCT01490502) is evaluating whether high-dose vitamin D supplementation reduces the risk of MS activity. DESIGN/METHODS Eligibility criteria include diagnosis of RRMS, age 18 to 50 years, and Expanded Disability Status Scale ≤4.0. Disease duration and activity requirements depend on whether 2005 or 2010 criteria are used for diagnosis. Enrollment is restricted based on prior MS therapy exposure and recent vitamin D use. After completing a one-month run-in of glatiramer acetate, 172 patients will be randomized 1:1 to oral vitamin D(3) 5000 IU versus 600 IU daily. Clinical visits occur every 12 weeks for 96 weeks. RESULTS Sixteen sites throughout the United States are participating in the trial. Complete enrollment is expected by late 2014, with follow-up through 2016. No interim analyses are planned. The primary outcome for the trial is the proportion of patients experiencing a relapse in each group. Other clinical, patient-reported, and MRI outcomes will be evaluated. CONCLUSIONS The VIDAMS trial will provide critical information about the safety and efficacy of vitamin D therapy in RRMS, with implications for MS patients worldwide.

In vivo evidence of glutamate toxicity in multiple sclerosis

There is increasing evidence that altered glutamate (Glu) homeostasis is involved in the pathophysiology of multiple sclerosis (MS). The aim of this study was to evaluate the in vivo effects of excess brain Glu on neuroaxonal integrity measured by N‐acetylaspartate (NAA), brain volume, and clinical outcomes in a large, prospectively followed cohort of MS subjects.

Whole-brain atrophy: ready for implementation into clinical decision-making in multiple sclerosis?

PURPOSE OF REVIEW The article provides an overview of the importance of whole-brain atrophy in multiple sclerosis (MS) and proposes steps that would be necessary prior to incorporating whole-brain volume measurements into routine clinical practice. RECENT FINDINGS Whole-brain atrophy is clinically relevant, present early in the disease, and measureable in a reproducible manner using MRI. Several of the currently available approved disease-modifying therapies can slow the rate of whole-brain atrophy at the group level. As such, clinicians may want to use whole-brain volume measurements for clinical decision-making. SUMMARY Despite its relevance and face validity, several steps must be taken before whole-brain volume measurements are ready to be incorporated into clinical practice, including the adoption of a standardized MRI protocol for MS, the establishment of a gold-standard image postprocessing software to measure whole-brain volume, and the development of specific statistical methods to translate whole-brain volume measurements into clinically relevant metrics at the individual level. As neurodegeneration becomes the focus of MS research worldwide and the likely target of the next generation of disease-modifying therapies, MRI metrics associated with neurodegeneration will be critically important to monitor disease progression and treatment response at the group and individual levels.

Longitudinal associations between brain structural changes and fatigue in early MS

BACKGROUND Fatigue is a common and disabling symptom of multiple sclerosis (MS) patients. Structural changes in several brain areas have been reported to correlate with fatigue in MS patients but none consistently. OBJECTIVE To study the association between global and regional measures of brain atrophy and fatigue in patients with early relapsing MS. METHODS Clinically isolated syndrome and relapsing MS patients within 12 months of clinical onset were enrolled in a neuroprotection trial of riluzole versus placebo with up to 36 months of follow-up. MRI metrics included brain volumes measured by SIENAX normalized measurements [normalized brain parenchymal volume (nBPV), normalized normal-appearing white and gray matter volume (nNAWMV and nGMV)] and T2 lesion volume (T2LV). Cortical thickness, thalamic volume and cerebellar cortical volume were measured using Freesurfers longitudinal pipeline (v5.3) and a lesion inpainting approach. Fatigue was evaluated using the Modified Fatigue Impact Scale (MFIS). Mixed model regression measured time trends and associations between imaging and fatigue severity, adjusting for age and sex. RESULTS Forty-three patients (mean age 36 years; 31 females) were enrolled within 7.5 ± 4.9 months of symptom onset. Baseline and change over baseline in lesion volumes, grey matter, white matter, basal ganglia and total parenchymal volumes were not associated with change in MFIS score over time. Lower thalamic volume at baseline predicted increasing physical subscale of MFIS score during the study (p=0.017). There was a trend toward baseline thalamic volume and cerebellar cortical volume predicting subsequent change in total MFIS score (p=0.055 and 0.082 respectively). On-study change in thalamic or cerebellar cortical volume was not associated with on-study change in MFIS score. CONCLUSION Global measures of tissue loss are not strongly associated with fatigue in patients with early MS. However, thalamic and cerebellar cortical atrophy may be predictive of subsequent changes in fatigue in these patients.

A comparison of continuous video-EEG monitoring and 30-minute EEG in an ICU

AIM To determine whether there is added benefit in detecting electrographic abnormalities from 16-24 hours of continuous video-EEG in adult medical/surgical ICU patients, compared to a 30-minute EEG. METHODS This was a prospectively enroled non-randomized study of 130 consecutive ICU patients for whom EEG was requested. For 117 patients, a 30-minute EEG was requested for altered mental state and/or suspected seizures; 83 patients continued with continuous video-EEG for 16-24 hours and 34 patients had only the 30-minute EEG. For 13 patients with prior seizures, continuous video-EEG was requested and was carried out for 16-24 hours. We gathered EEG data prospectively, and reviewed the medical records retrospectively to assess the impact of continuous video-EEG. RESULTS A total of 83 continuous video-EEG recordings were performed for 16-24 hours beyond 30 minutes of routine EEG. All were slow, and 34% showed epileptiform findings in the first 30 minutes, including 2% with seizures. Over 16-24 hours, 14% developed new or additional epileptiform abnormalities, including 6% with seizures. In 8%, treatment was changed based on continuous video-EEG. Among the 34 EEGs limited to 30 minutes, almost all were slow and 18% showed epileptiform activity, including 3% with seizures. Among the 13 patients with known seizures, continuous video-EEG was slow in all and 69% had epileptiform abnormalities in the first 30 minutes, including 31% with seizures. An additional 8% developed epileptiform abnormalities over 16-24 hours. In 46%, treatment was changed based on continuous video-EEG. CONCLUSION This study indicates that if continuous video-EEG is not available, a 30-minute EEG in the ICU has a substantial diagnostic yield and will lead to the detection of the majority of epileptiform abnormalities. In a small percentage of patients, continuous video-EEG will lead to the detection of additional epileptiform abnormalities. In a sub-population, with a history of seizures prior to the initiation of EEG recording, the benefits of continuous video-EEG in monitoring seizure activity and influencing treatment may be greater.

Clinical applications of imaging disease burden in multiple sclerosis: MRI and advanced imaging techniques

This review will address the critical role of radiographic techniques in monitoring multiple sclerosis disease course and response to therapeutic interventions using conventional imaging. We propose an algorithm of obtaining a contrast-enhanced brain MRI 6 months after starting a disease-modifying therapy, and considering a gadolinium-enhancing lesion on that scan to indicate suboptimal response to therapy. New or enlarging T2 lesions should be followed on scans at 6-month intervals to assess for change, and the presence of one or more enhancing lesions on a 6- or 12-month scan, or two or more new or enlarging T2 lesions on a 12-month scan should prompt consideration of therapy change. New techniques such as PET imaging, magnetic resonance spectroscopy, magnetic resonance relaxometry, iron-sensitive imaging and perfusion MRI will also be overviewed, with their potential roles in monitoring disease course and activity.

Thalamic atrophy in multiple sclerosis: A magnetic resonance imaging marker of neurodegeneration throughout disease

Thalamic volume is a candidate magnetic resonance imaging (MRI)‐based marker associated with neurodegeneration to hasten development of neuroprotective treatments. Our objective is to describe the longitudinal evolution of thalamic atrophy in MS and normal aging, and to estimate sample sizes for study design.