Dorlan Kimbrough

Predictors of recurrence following an initial episode of transverse myelitis

Objective: This study sought to identify factors that increased the risk of recurrence after an initial transverse myelitis (TM) presentation. Methods: Retrospective cohort study of 192 patients initially presenting with TM of unknown etiology. Patients diagnosed with multiple sclerosis during the first myelitis episode were excluded. Demographic and laboratory data were analyzed for associations with recurrence. Results: One hundred ten of 192 patients (57%) eventually developed recurrent symptoms: 69 (63%) neuromyelitis optica (NMO) or NMO spectrum disorder, 34 (31%) non-NMO recurrent TM, and 7 (6%) systemic autoimmune disease. Multiple independent risk factors for recurrence were identified: African American race (risk ratio 1.60, p < 0.001, 95% confidence interval 1.26–2.03; similarly noted hereafter), female sex (1.88, p = 0.007, 1.19–2.98), longitudinally extensive myelitis at onset (1.34, p = 0.036, 1.01–1.78), Sjogren syndrome antigen A (1.89, p = 0.003, 1.44–2.48), vitamin D insufficiency (4.00, p < 0.001, 1.60–10.0), antinuclear antibody titer ≥1:160 (1.69, p = 0.006, 1.23–2.32), and the presence of inflammatory markers (e.g., immunoglobulin G index) in the CSF (2.14, p < 0.001, 1.44–3.17). Conclusions: Sex, race, and serologic biomarkers warrant consideration when assessing risk of TM recurrence. Male sex and Caucasian American race were independently associated with risk of monophasic idiopathic TM. Recurrence risk in female and African American patients appears driven by a greater likelihood of developing NMO or NMO spectrum disorder.

Retinal damage and vision loss in African American multiple sclerosis patients

To determine whether African American (AA) multiple sclerosis (MS) patients exhibit more retinal damage and visual impairment compared to Caucasian American (CA) MS patients.

Sample size requirements for one-year treatment effects using deep gray matter volume from 3T MRI in progressive forms of multiple sclerosis.

ABSTRACT Objective: The subcortical deep gray matter (DGM) develops selective, progressive, and clinically relevant atrophy in progressive forms of multiple sclerosis (PMS). This patient population is the target of active neurotherapeutic development, requiring the availability of outcome measures. We tested a fully automated MRI analysis pipeline to assess DGM atrophy in PMS. Design/Methods: Consistent 3D T1-weighted high-resolution 3T brain MRI was obtained over one year in 19 consecutive patients with PMS [15 secondary progressive, 4 primary progressive, 53% women, age (mean±SD) 50.8±8.0 years, Expanded Disability Status Scale (median, range) 5.0, 2.0–6.5)]. DGM segmentation applied the fully automated FSL-FIRST pipeline (http://fsl.fmrib.ox.ac.uk). Total DGM volume was the sum of the caudate, putamen, globus pallidus, and thalamus. On-study change was calculated using a random-effects linear regression model. Results: We detected one-year decreases in raw [mean (95% confidence interval): –0.749 ml (–1.455, –0.043), p = 0.039] and annualized [–0.754 ml/year (–1.492, –0.016), p = 0.046] total DGM volumes. A treatment trial for an intervention that would show a 50% reduction in DGM brain atrophy would require a sample size of 123 patients for a single-arm study (one-year run-in followed by one-year on-treatment). For a two-arm placebo-controlled one-year study, 242 patients would be required per arm. The use of DGM fraction required more patients. The thalamus, putamen, and globus pallidus, showed smaller effect sizes in their on-study changes than the total DGM; however, for the caudate, the effect sizes were somewhat larger. Conclusions: DGM atrophy may prove efficient as a short-term outcome for proof-of-concept neurotherapeutic trials in PMS.

Agreement analysis comparing iPad LCVA and Sloan testing in multiple sclerosis patients

Background: Visual symptoms are common in multiple sclerosis (MS). Low-contrast visual acuity (LCVA) testing using Sloan charts has demonstrated increased sensitivity for visual deficits compared to high-contrast acuity testing. Computerized testing of visual acuity may facilitate use in the clinic setting. Objectives: To evaluate the agreement between an iPad-based and Sloan testing of LCVA in a cohort of MS patients. Methods: A total of 38 patients with relapsing-remitting MS were enrolled after providing informed written consent at Partners MS Center, Brigham and Women’s hospital. Monocular LCVA was measured using retroilluminated Sloan chart and iPad-based LogMAR chart. Number of correct letters and agreement between two measurements were assessed for each eye using Bland–Altman analysis and paired t-test. Results: For both eyes, there was no significant difference in number correct between the two measurements using a paired t-test, and there was high correlation between two measurements (oculus dextrus (OD) r = 0.89, p < 0.001; oculus sinister (OS) r = 0.78, p < 0.001). The limits of agreement were −7.9 to +8.5 letters for the right eye and −10.9 to +11.2 letters for the left eye. Conclusion: An iPad-based LCVA test shows good agreement with Sloan testing in MS patients.

Visual Fixation Instability in Multiple Sclerosis Measured Using SLO-OCT

Purpose Precise measurements of visual fixation and its instability were recorded during optical coherence tomography (OCT) as a marker of neural network dysfunction in multiple sclerosis (MS), which could be used to monitor disease progression or response to treatment. Methods A total of 16 MS patients and 26 normal subjects underwent 30 seconds of scanning laser ophthalmoscope (SLO)-based eye tracking during OCT scanning of retinal layer thickness. Study groups consisted of normal eyes, MS eyes without prior optic neuritis (MS wo ON), and MS eyes with prior optic neuritis (MS + ON). Kernel density estimation quantified fixation instability from the distribution of fixation points on the retina. In MS wo ON eyes, fixation instability was compared to other measures of visual and neurologic function. Results Fixation instability was increased in MS wo ON eyes (0.062 deg2) compared to normal eyes (0.030 deg2, P = 0.015). A further increase was seen for MS + ON eyes (0.11 deg2) compared to MS wo ON (P = 0.04) and normal (P = 0.006) eyes. Fixation instability correlated weakly with ganglion cell layer (GCL) volume and showed no correlation with low-contrast letter acuity, EDSS score, or SDMT score. Conclusions Fixation instability reflects the integrity of a widespread neural network germane to visual processing and ocular motor control, and is disturbed in MS. Further study of visual fixation, including the contribution of microsaccades to fixation instability, may provide insight into the localization of fixation abnormalities in MS and introduce innovative and easily measured outcomes for monitoring progression and treatment response.

Brain and retinal atrophy in African-Americans versus Caucasian-Americans with multiple sclerosis: a longitudinal study

On average, African Americans with multiple sclerosis demonstrate higher inflammatory disease activity, faster disability accumulation, greater visual dysfunction, more pronounced brain tissue damage and higher lesion volume loads compared to Caucasian Americans with multiple sclerosis. Neurodegeneration is an important component of multiple sclerosis, which in part accounts for the clinical heterogeneity of the disease. Brain atrophy appears to be widespread, although it is becoming increasingly recognized that regional substructure atrophy may be of greater clinical relevance. Patient race (within the limitations of self-identified ancestry) is regarded as an important contributing factor. However, there is a paucity of studies examining differences in neurodegeneration and brain substructure volumes over time in African Americans relative to Caucasian American patients. Optical coherence tomography is a non-invasive and reliable tool for measuring structural retinal changes. Recent studies support its utility for tracking neurodegeneration and disease progression in vivo in multiple sclerosis. Relative to Caucasian Americans, African American patients have been found to have greater retinal structural injury in the inner retinal layers. Increased thickness of the inner nuclear layer and the presence of microcystoid macular pathology at baseline predict clinical and radiological inflammatory activity, although whether race plays a role in these changes has not been investigated. Similarly, assessment of outer retinal changes according to race in multiple sclerosis remains incompletely characterized. Twenty-two African Americans and 60 matched Caucasian Americans with multiple sclerosis were evaluated with brain MRI, and 116 African Americans and 116 matched Caucasian Americans with multiple sclerosis were monitored with optical coherence tomography over a mean duration of 4.5 years. Mixed-effects linear regression models were used in statistical analyses. Grey matter (-0.9%/year versus -0.5%: P =0.02), white matter (-0.7%/year versus -0.3%: P =0.04) and nuclear thalamic (-1.5%/year versus -0.7%/year: P =0.02) atrophy rates were approximately twice as fast in African Americans. African Americans also exhibited higher proportions of microcystoid macular pathology (12.1% versus 0.9%, P =0.001). Retinal nerve fibre layer (-1.1% versus -0.8%: P =0.02) and ganglion cell+ inner plexiform layer (-0.7%/year versus -0.4%/year: P =0.01) atrophy rates were faster in African versus Caucasian Americans. African Americans on average exhibited more rapid neurodegeneration than Caucasian Americans and had significantly faster brain and retinal tissue loss. These results corroborate the more rapid clinical progression reported to occur, in general, in African Americans with multiple sclerosis and support the need for future studies involving African Americans in order to identify individual differences in treatment responses in multiple sclerosis.

Radiation-Induced Myelitis: Initial and Follow-Up MRI and Clinical Features in Patients at a Single Tertiary Care Institution during 20 Years

SUMMARY: Myelitis is a rare complication of radiation exposure to the spinal cord and is often a diagnosis of exclusion. A retrospective review of clinical records and serial imaging was performed to identify subjects with documented myelitis and a history of prior radiation. Eleven patients fulfilled the inclusion criteria. All patients had longitudinally extensive cord involvement with homogeneous precontrast T1 hyperintense signal in the adjacent vertebrae, corresponding to the radiation field. T2 signal abnormalities involving the central two-thirds of the cord were seen in 6/11 patients (55%). The degree of cord expansion and contrast enhancement was variable but was seen in 6 (54%) and 5 (45%) patients, respectively. On follow-up, 2 patients developed cord atrophy, while complete resolution was noted in 1. Clinical improvement was noted in 5 patients, with symptom progression in 2 patients. Our results suggest that radiation myelitis is neither universally progressive nor permanent, and some radiographic and clinical improvement may occur.

Case Report: Two Cases of Nicolau Syndrome Associated with Glatiramer Acetate

We report two cases of Nicolau syndrome (embolia cutis medicamentosa), a rare complication of injectable medications, both associated with the administration of 20 mg of subcutaneous glatiramer acetate. Both patients required surgical debridement and were subsequently treated conservatively without additional complications. Patient 1 opted to discontinue disease-modifying therapy. Patient 2 continued glatiramer acetate therapy without complications by using other injection sites. These cases highlight the need for prompt investigation of new unusual skin lesions in patients receiving injectable multiple sclerosis treatments (regardless of length of treatment and previous minor cosmetic concerns) and illustrate the clinical distinction between Nicolau syndrome and drug-induced skin necrosis.