Eric C. Klawiter

Radial diffusivity predicts demyelination in ex vivo multiple sclerosis spinal cords.

OBJECTIVE Correlation of diffusion tensor imaging (DTI) with histochemical staining for demyelination and axonal damage in multiple sclerosis (MS) ex vivo human cervical spinal cords. BACKGROUND In MS, demyelination, axonal degeneration, and inflammation contribute to disease pathogenesis to variable degrees. Based upon in vivo animal studies with acute injury and histopathologic correlation, we hypothesized that DTI can differentiate between axonal and myelin pathologies within humans. METHODS DTI was performed at 4.7 T on 9 MS and 5 normal control fixed cervical spinal cord blocks following autopsy. Sections were then stained for Luxol fast blue (LFB), Bielschowsky silver, and hematoxylin and eosin (H&E). Regions of interest (ROIs) were graded semi-quantitatively as normal myelination, mild (<50%) demyelination, or moderate-severe (>50%) demyelination. Corresponding axonal counts were manually determined on Bielschowsky silver. ROIs were mapped to co-registered DTI parameter slices. DTI parameters evaluated included standard quantitative assessments of apparent diffusion coefficient (ADC), relative anisotropy (RA), axial diffusivity and radial diffusivity. Statistical correlations were made between histochemical gradings and DTI parameters using linear mixed models. RESULTS Within ROIs in MS subjects, increased radial diffusivity distinguished worsening severities of demyelination. Relative anisotropy was decreased in the setting of moderate-severe demyelination compared to normal areas and areas of mild demyelination. Radial diffusivity, ADC, and RA became increasingly altered within quartiles of worsening axonal counts. Axial diffusivity did not correlate with axonal density (p=0.091). CONCLUSIONS Increased radial diffusivity can serve as a surrogate for demyelination. However, radial diffusivity was also altered with axon injury, suggesting that this measure is not pathologically specific within chronic human MS tissue. We propose that radial diffusivity can serve as a marker of overall tissue integrity within chronic MS lesions. This study provides pathologic foundation for on-going in vivo DTI studies in MS.

MRI characteristics of neuromyelitis optica spectrum disorder An international update

Since its initial reports in the 19th century, neuromyelitis optica (NMO) had been thought to involve only the optic nerves and spinal cord. However, the discovery of highly specific anti–aquaporin-4 antibody diagnostic biomarker for NMO enabled recognition of more diverse clinical spectrum of manifestations. Brain MRI abnormalities in patients seropositive for anti–aquaporin-4 antibody are common and some may be relatively unique by virtue of localization and configuration. Some seropositive patients present with brain involvement during their first attack and/or continue to relapse in the same location without optic nerve and spinal cord involvement. Thus, characteristics of brain abnormalities in such patients have become of increased interest. In this regard, MRI has an increasingly important role in the differential diagnosis of NMO and its spectrum disorder (NMOSD), particularly from multiple sclerosis. Differentiating these conditions is of prime importance because early initiation of effective immunosuppressive therapy is the key to preventing attack-related disability in NMOSD, whereas some disease-modifying drugs for multiple sclerosis may exacerbate the disease. Therefore, identifying the MRI features suggestive of NMOSD has diagnostic and prognostic implications. We herein review the brain, optic nerve, and spinal cord MRI findings of NMOSD.

Optical coherence tomography differs in neuromyelitis optica compared with multiple sclerosis

Background: Neuromyelitis optica (NMO) is associated with destructive inflammatory lesions, resulting in necrosis and axonal injury. Disability from multiple sclerosis (MS) is due to a combination of demyelination and varying axonal involvement. Optical coherence tomography (OCT), by measuring retinal nerve fiber layer (RNFL) as a surrogate of axonal injury, has potential to discriminate between these two conditions. Methods: Included were 22 subjects with NMO or NMO spectrum disorders and 47 with MS. Seventeen subjects with NMO and all with MS had a remote history of optic neuritis (ON) in at least one eye, at least 6 months before OCT. Linear mixed modeling was used to compare the two diagnoses for a given level of vision loss, while controlling for age, disease duration, and number of episodes of ON. Results: After ON, NMO was associated with a thinner mean RNFL compared to MS. This was found when controlling for visual acuity (56.7 vs 66.6 μm, p = 0.01) or for contrast sensitivity (61.2 vs 70.3 μm, p = 0.02). The superior and inferior quadrants were more severely affected in NMO than MS. Conclusions: Optic neuritis (ON) within neuromyelitis optica (NMO) is associated with a thinner overall average retinal nerve fiber layer compared to multiple sclerosis, with particular involvement of the superior and inferior quadrants. This suggests that NMO is associated with more widespread axonal injury in the affected optic nerves. Optical coherence tomography can help distinguish the etiology of these two causes of ON, and may be useful as a surrogate marker of axonal involvement in demyelinating disease.

Optical coherence tomography is less sensitive than visual evoked potentials in optic neuritis

Objectives: Determine the utility of optical coherence tomography (OCT) to detect clinical and subclinical remote optic neuritis (ON), its relationship to clinical characteristics of ON and visual function, and whether the retinal nerve fiber layer (RNFL) thickness functions as a surrogate marker of global disease severity. Methods: Cross-sectional study of 65 subjects with at least 1 clinical ON episode at least 6 months prior. Measures included clinical characteristics, visual acuity (VA), contrast sensitivity (CS), OCT, and visual evoked potentials (VEP). Results: Ninety-six clinically affected optic nerves were studied. The sensitivity of OCT RNFL after ON was 60%, decreasing further with mild onset and good recovery. VEP sensitivity was superior at 81% (p = 0.002). Subclinical ON in the unaffected eye was present in 32%. VEP identified 75% of all subclinically affected eyes, and OCT identified <20%. RNFL thickness demonstrated linear correlations with VA (r = 0.65) and CS (r = 0.72) but was unable to distinguish visual categories <20/50. RNFL was thinner with severe onset and disease recurrence but was unaffected by IV glucocorticoids. OCT measurements were not related to overall disability, ethnicity, sex, or age at onset. The greatest predictor for RNFL in the unaffected eye was the RNFL in the fellow affected eye. Conclusions: Visual evoked potentials (VEP) remains the preferred test for detecting clinical and subclinical optic neuritis. Optical coherence tomography (OCT) measures were unrelated to disability and demographic features predicting a worse prognosis in multiple sclerosis. OCT may provide complementary information to VEP in select cases, and remains a valuable research tool for studying optic nerve disease in populations.

NMO-IgG DETECTED IN CSF IN SERONEGATIVE NEUROMYELITIS OPTICA

Neuromyelitis optica (NMO) is an inflammatory and demyelinating disease characterized by recurrent attacks of optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM).1 NMO is associated with antibodies against the aquaporin-4 (AQP4) water channel.2 NMO–immunoglobulin G (IgG) predicts a relapsing course and is a supportive criterion for NMO.3–5 The high risk of relapse, sometimes with devastating effects, makes early diagnosis important. Early identification permits counseling and consideration for immunosuppressive therapy. The serum NMO-IgG assay, using indirect immunofluorescence, is 73% sensitive and 91% specific for clinically defined NMO.6 While helpful when positive, the sensitivity is insufficient to exclude the diagnosis. We describe 3 of 26 patients with NMO at our institution with NMO-IgG positivity restricted to CSF. ### Case reports. #### Case 1. A 25-year-old African American woman presented with leg numbness and mild tetraparesis that resolved over 1 month. Two months later, she developed a midthoracic sensory level, again with recovery. The next month, bilateral leg weakness impaired her ability to ambulate. MRI (figure, A–C) demonstrated T2 hyperintensities (T2H) and patchy enhancement spanning the medulla through C7 and T2–T11. Brain MRI revealed a single nonspecific T2H. Visual evoked potentials (VEPs) were normal. Serum NMO-IgG was negative but CSF NMO-IgG was positive. IgG index was elevated to 0.79, CSF leukocytes were 24/μL, but albumin index, IgG synthesis, and oligoclonal bands (OCBs) were normal. Serum antinuclear antibodies (ANA) were negative. Treatment included IV glucocorticoids and rituximab with no further exacerbations. After 8 months of disease, Expanded Disability Status Scale (EDSS) was 6.0. Figure Neuroimaging of CSF antibody-positive neuromyelitis optica Case 1: Sagittal T2-weighted STIR …

The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative

Over the past few years, MRI has become an indispensable tool for diagnosing multiple sclerosis (MS). However, the current MRI criteria for MS diagnosis have imperfect sensitivity and specificity. The central vein sign (CVS) has recently been proposed as a novel MRI biomarker to improve the accuracy and speed of MS diagnosis. Evidence indicates that the presence of the CVS in individual lesions can accurately differentiate MS from other diseases that mimic this condition. However, the predictive value of the CVS for the development of clinical MS in patients with suspected demyelinating disease is still unknown. Moreover, the lack of standardization for the definition and imaging of the CVS currently limits its clinical implementation and validation. On the basis of a thorough review of the existing literature on the CVS and the consensus opinion of the members of the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative, this article provides statements and recommendations aimed at helping radiologists and neurologists to better understand, refine, standardize and evaluate the CVS in the diagnosis of MS.

CXCL13 is a biomarker of inflammation in multiple sclerosis, neuromyelitis optica, and other neurological conditions.

CXCL13, a B-cell chemokine, has been proposed as a biomarker in a variety of conditions, some of which can mimic multiple sclerosis and can have very high levels. In this case-control study, cerebrospinal fluid (CSF) CXCL13 was elevated in multiple sclerosis, neuromyelitis optica and other inflammatory neurological controls compared with noninflammatory controls. Levels did not differentiate disease groups. For all subjects taken together, CSF CXCL13 correlated with CSF WBC, oligoclonal band numbers, CSF protein, EDSS, and neurofilament levels. In subgroup analyses, CSF CXCL13 correlated with CSF WBC in neuromyelitis optica and IgG index in multiple sclerosis. Additionally, serum CXCL13 was elevated in neuromyelitis optica.

The neuroinflammatory component of gray matter pathology in multiple sclerosis

In multiple sclerosis (MS), using simultaneous magnetic resonance–positron emission tomography (MR‐PET) imaging with 11C‐PBR28, we quantified expression of the 18kDa translocator protein (TSPO), a marker of activated microglia/macrophages, in cortex, cortical lesions, deep gray matter (GM), white matter (WM) lesions, and normal‐appearing WM (NAWM) to investigate the in vivo pathological and clinical relevance of neuroinflammation.

Improved in vivo diffusion tensor imaging of human cervical spinal cord

We describe a cardiac gated high in-plane resolution axial human cervical spinal cord diffusion tensor imaging (DTI) protocol. Multiple steps were taken to optimize both image acquisition and image processing. The former includes slice-by-slice cardiac triggering and individually tiltable slices. The latter includes (i) iterative 2D retrospective motion correction, (ii) image intensity outlier detection to minimize the influence of physiological noise, (iii) a non-linear DTI estimation procedure incorporating non-negative eigenvalue priors, and (iv) tract-specific region-of-interest (ROI) identification based on an objective geometry reference. Using these strategies in combination, radial diffusivity (λ(⊥)) was reproducibly measured in white matter (WM) tracts (adjusted mean [95% confidence interval]=0.25 [0.22, 0.29] μm(2)/ms), lower than previously reported λ(⊥) values in the in vivo human spinal cord DTI literature. Radial diffusivity and fractional anisotropy (FA) measured in WM varied from rostral to caudal as did mean translational motion, likely reflecting respiratory motion effect. Given the considerable sensitivity of DTI measurements to motion artifact, we believe outlier detection is indispensable in spinal cord diffusion imaging. We also recommend using a mixed-effects model to account for systematic measurement bias depending on cord segment.

Spinal cord tract diffusion tensor imaging reveals disability substrate in demyelinating disease

Objective: This study assessed the tissue integrity of major cervical cord tracts by using diffusion tensor imaging (DTI) to determine the relationship with specific clinical functions carried by those tracts. Methods: This was a cross-sectional study of 37 patients with multiple sclerosis or neuromyelitis optica with remote cervical cord disease. Finger vibratory thresholds, 25-foot timed walk (25FTW), 9-hole peg test (9HPT), and Expanded Disability Status Scale were determined. DTI covered cervical regions C1 through C6 with 17 5-mm slices (0.9 × 0.9 mm in-plane resolution). Regions of interest included posterior columns (PCs) and lateral corticospinal tracts (CSTs). Hierarchical linear mixed-effect modeling included covariates of disease subtype (multiple sclerosis vs neuromyelitis optica), disease duration, and sex. Results: Vibration thresholds were associated with radial diffusivity (RD) and fractional anisotropy (FA) in the PCs (both p < 0.01), but not CSTs (RD, p = 0.29; FA, p = 0.14). RD and FA in PCs, and RD in CSTs were related to 9HPT (each p < 0.0001). 25FTW was associated with RD and FA in PCs (p < 0.0001) and RD in CSTs (p = 0.008). Expanded Disability Status Scale was related to RD and FA in PCs and CSTs (p < 0.0001). Moderate/severe impairments in 9HPT (p = 0.006) and 25FTW (p = 0.017) were more likely to show combined moderate/severe tissue injury within both PCs and CSTs by DTI. Conclusions: DTI can serve as an imaging biomarker of spinal cord tissue injury at the tract level. RD and FA demonstrate strong and consistent relationships with clinical outcomes, specific to the clinical modality.