Fredric K. Cantor

Evidence-based guideline update: Plasmapheresis in neurologic disorders Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology

Objective: To reassess the role of plasmapheresis in the treatment of neurologic disorders. Methods: We evaluated the available evidence based on a structured literature review for relevant articles from 1995 through September 2009. In addition, due to revision of the definitions of classification of evidence since the publication of the previous American Academy of Neurology assessment in 1996, the evidence cited in that manuscript was reviewed and reclassified. Results and Recommendations: Plasmapheresis is established as effective and should be offered in severe acute inflammatory demyelinating polyneuropathy (AIDP)/Guillain-Barré syndrome (GBS) and in the short-term management of chronic inflammatory demyelinating polyneuropathy (Class I studies, Level A). Plasmapheresis is established as ineffective and should not be offered for chronic or secondary progressive multiple sclerosis (MS) (Class I studies, Level A). Plasmapheresis is probably effective and should be considered for mild AIDP/GBS, as second-line treatment of steroid-resistant exacerbations in relapsing forms of MS, and for neuropathy associated with immunoglobulin A or immunoglobulin G gammopathy, based on at least one Class I or 2 Class II studies (Level B). Plasmapheresis is probably not effective and should not be considered for neuropathy associated with immunoglobulin M gammopathy, based on one Class I study (Level B). Plasmapheresis is possibly effective and may be considered for acute fulminant demyelinating CNS disease (Level C). There is insufficient evidence to support or refute the use of plasmapheresis for myasthenia gravis, pediatric autoimmune neuropsychiatric disorders associated with streptococcus infection, and Sydenham chorea (Class III evidence, Level U).

Relationship of Cortical Atrophy to Fatigue in Patients With Multiple Sclerosis

BACKGROUND Fatigue is a common and disabling symptom of multiple sclerosis (MS). Previous studies reported that damage of the corticostriatothalamocortical circuit is critical in its occurrence. OBJECTIVE To investigate the relationship between fatigue in MS and regional cortical and subcortical gray matter atrophy. DESIGN Case-control study. SETTING National Institutes of Health. PARTICIPANTS Twenty-four patients with MS and 24 matched healthy volunteers who underwent 3.0-T magnetic resonance imaging and evaluations of fatigue (Modified Fatigue Impact Scale) and depression (Center for Epidemiologic Studies Depression Scale). MAIN OUTCOME MEASURES Relationship between thalamic and basal ganglia volume, cortical thickness of frontal and parietal lobes, and, in patients, T2 lesion volume and normal-appearing white matter volume and the extent of fatigue. RESULTS Patients were more fatigued than healthy volunteers (P = .04), while controlling for the effect of depression. Modified Fatigue Impact Scale score correlated with cortical thickness of the parietal lobe (r = -0.50, P = .01), explaining 25% of its variance. The posterior parietal cortex was the only parietal area significantly associated with the Modified Fatigue Impact Scale scores. CONCLUSIONS Cortical atrophy of the parietal lobe had the strongest relationship with fatigue. Given the implications of the posterior parietal cortex in motor planning and integration of information from different sources, our preliminary results suggest that dysfunctions in higher-order aspects of motor control may have a role in determining fatigue in MS.

Chronic Multiple Sclerosis Lesions: Characterization with High-Field-Strength MR Imaging

PURPOSE To elucidate the mechanism of magnetic resonance (MR) imaging contrast in multiple sclerosis (MS) lesion appearance by using susceptibility-weighted imaging and to assess with histologic correlation the role of iron and myelin in generating this MR imaging contrast. MATERIALS AND METHODS Each patient provided written consent to a human subject protocol approved by an institutional review board. High-spatial-resolution susceptibility-weighted 7.0-T MR images were obtained in 21 patients with MS. Contrast patterns in quantitative phase and R2* images, derived from 7.0-T data, were investigated in 220 areas defined as chronic MS lesions on conventional T2-weighted fluid-attenuated inversion recovery, T2-weighted, and T1-weighted spin-echo images. The presence of positive or negative phase shifts (ie, decreased or increased MR frequency, respectively) was assessed in each lesion. In addition, postmortem MR imaging was performed at 7.0 T and 11.7 T, and its results were correlated with those of immunohistochemical staining specific for myelin, iron, and ferritin. RESULTS The majority (133 [60.5%] of 220) of the identified lesions had a normal phase and reduced R2*. A substantial fraction of the lesions (84 [38.2%] of 220) had negative phase shift, either uniformly or at their rim, and a variety of appearances on R2* maps. These two lesion contrast patterns were reproduced in the postmortem MR imaging study. Comparison with histologic findings showed that, while R2* reduction corresponded to severe loss of both iron and myelin, negative phase shift corresponded to focal iron deposits with myelin loss. CONCLUSION Combined analysis of 7.0-T R2* and phase data may help in characterizing the pathologic features of MS lesions. The observed R2* decreases suggest profound myelin loss, whereas negative phase shifts suggest a focal iron accumulation.

MULTISEQUENCE-IMAGING PROTOCOLS TO DETECT CORTICAL LESIONS OF PATIENTS WITH MULTIPLE SCLEROSIS: OBSERVATIONS FROM A POST-MORTEM 3 TESLA IMAGING STUDY

Neocortical lesions (NLs) are an important component of multiple sclerosis (MS) pathology and may account for part of the physical and cognitive disability. Visualizing NLs of patients with MS using magnetic resonance imaging (MRI) poses several significant challenges. We optimized the inversion time (TI) of T(1)-based magnetization-prepared rapid acquisition gradient-echo (MPRAGE) images by suppressing the signal of the lesions and enhancing their appearance as hypointensities, on the basis of the derived quantitative T(1) measurements. The latter were achieved by the means of 2D inversion recovery fast spin echo (IR-FSE), repeated using different inversion times (TI). Comparisons of detection of NLs by MPRAGE and dual echo T(2) weighted (T(2)W) and proton density (PD) W. Four coronal brain slices from a deceased MS patient and two coronal brain slices from two formerly healthy donors were imaged using a 3 Tesla magnet (3 T) equipped with a multi-channel coil. Based upon the averaged T1 values computed from the MS specimen as well as visual inspection, an optimal TI of 380 ms was selected for the MPRAGE image. No NLs were seen in the specimens of the two healthy donors. Of the 40 total NLs observed, 8 (20%) were visible in all three sequences employed. Three (7.5%) NLs were visible only in the PDW image and 5 (12.5%) were seen only in the T(2)W image. Four NLs (10%) had clearly unique conspicuity in the MPRAGE image. Of those, 3 were retrospectively scored in the PDW image (1 NL) or in the T2W image (2 NLs). We conclude that for the detection of MS-related NLs, high-resolution T(1)-based MPRAGE and T(2)-W images offer complementary information and the combination of the two image sequences is crucial for increasing the sensitivity of detecting MS-induced NLs.

T1 cortical hypointensities and their association with cognitive disability in multiple sclerosis

Background: Neocortical lesions (NLs) largely contribute to the pathology of multiple sclerosis (MS), although their relevance in patients’ disability remains unknown. Objective: To assess the incidence of T1 hypointense NLs by 3.0-Tesla magnetic resonance imaging (MRI) in patients with MS and examine neocortical lesion association with cognitive impairment. Methods: In this case-control study, 21 MS patients and 21 age-, sex- and years of education-matched healthy volunteers underwent: (i) a neuropsychological examination rating cognitive impairment (Minimal Assessment of Cognitive Function in MS); (ii) a 3.0-Tesla MRI inclusive of an isotropic 1.0 mm3 three-dimensional inversion prepared spoiled gradient-recalled-echo (3D-IRSPGR) image and T1- and T2-weighted images. Hypointensities on 3D-IRSPGR lying in the cortex, either entirely or partially were counted and association between NLs and cognitive impairment investigated. Results: A total of 95 NLs were observed in 14 (66.7%) patients. NL+ patients performed poorer (p = 0.020) than NLpatients only on the delayed recall component of the California Verbal Learning Test. This difference lost statistical significance when a correction for white matter lesion volume was employed. Conclusions: Although T 1 hypointense NLs may be present in a relatively high proportion of multiple sclerosis patients, the impact that they have in cognitive impairment is not independent from white matter disease.

Heterogeneity in Response to Interferon Beta in Patients With Multiple Sclerosis: A 3-Year Monthly Imaging Study

OBJECTIVES To investigate the heterogeneity in magnetic resonance image (MRI) patterns of response to interferon beta across patients with multiple sclerosis or within an individual patient over time. DESIGN, SETTING, AND PATIENTS Fifteen patients with relapsing-remitting multiple sclerosis underwent monthly MRIs and clinical examinations (6-month pretherapy phase and 36-month therapy phase) and bimonthly neutralizing antibody tests. On each MRI, the total number of contrast-enhancing lesions was noted. Therapy MRI responders were defined as those with a reduction of 60% or more in the total number of contrast-enhancing lesions during each semester of therapy. INTERVENTION Subcutaneous administration of interferon beta-1b, 250 microg, every other day for 3 years. MAIN OUTCOME MEASURE Reduction in the number of contrast-enhancing lesions. RESULTS Eight patients (53.3%) were MRI responders and 7 (46.7%) were nonresponders. Of those 7, 3 (20.0%) had only an initial optimal reduction of the total number of contrast-enhancing lesions, 2 (13.3%) never reached an optimal response, and 2 (13.3%) had a delayed optimal response. No clear association between neutralizing antibody profile and MRI response was evident. CONCLUSIONS Multiple MRI evaluations disclose that approximately only half of the patients treated with interferon beta achieve and maintain a full response to the drug over time, although an additional small number of individuals may still restore an optimal response to the drug after an initial failure.

Quality and Quantity of Diffuse and Focal White Matter Disease and Cognitive Disability of Patients with Multiple Sclerosis

Using high‐field magnetic resonance imaging (MRI), we investigated the relationships between white matter (WM) lesion volume (LV), normal‐appearing WM (NAWM) normalized volume, WM‐lesion and NAWM magnetization transfer ratios (MTRs), brain parenchyma fraction (BPF), and cognitive impairment (CI) in multiple sclerosis (MS).

Cognitive Impairment and Its Relation to Imaging Measures in Multiple Sclerosis: A Study Using a Computerized Battery

Cognitive impairment (CI) is an important component of multiple sclerosis (MS) disability. A complex biological interplay between white matter (WM) and gray matter (GM) disease likely sustains CI. This study aims to address this issue by exploring the association between the extent of normal WM and GM disease and CI.

Lesions by tissue specific imaging characterize multiple sclerosis patients with more advanced disease.

Background: Cerebrospinal fluid tissue specific imaging (CSF-TSI), a newly implemented magnetic resonance imaging (MRI) technique, allows visualization of a subset of chronic black holes (cBHs) with MRI characteristics suggestive of the presence of CSF-like fluid, and representing lesions with extensive tissue destruction. Objective: To investigate the relationship between lesions in CSF-TSI and disease measures in patients with multiple sclerosis (MS). Methods: Twenty-six patients with MS were imaged at 3.0 T, obtaining T1-weighted (T1-w) and T2-w spin echo (SE), T1 volumetric images and CSF-TSI images. We measured: (i) lesion volume (LV) in T1-w (cBH-LV) and T2-w SE images, and in CSF-TSI; (ii) brain parenchyma fraction (BPF). Differences between patients with and without CSF-TSI lesions were analyzed and association between clinical and MRI metrics were investigated. Results: cBHs were seen in 92% of the patients while lesions in CSF-TSI were seen in 40%. Patients with CSF-TSI lesions were older, with longer disease duration, higher disability scores, larger cBH-LV and T2-LV, and lower BPF than patients without CSF-TSI lesions (≤0.047). Partial correlation analysis correcting for T2-LV, cBH-LV and BPF showed an association (p < 0.0001, r = 0.753) between CSF-TSI LV and disability score. Conclusions: CSF-TSI lesions characterize patients with more advanced disease and probably contribute to the progress of disability.

Heterogeneity of Multiple Sclerosis White Matter Lesions Detected With T2*-Weighted Imaging at 7.0 Tesla

Postmortem studies in multiple sclerosis (MS) indicate that in some white matter lesions (WM‐Ls), iron is detectable with T2*‐weighted (T2*‐w), and its reciprocal R2* relaxation rate, magnetic resonance imaging (MRI) at 7.0 Tesla (7T). This iron appears as a hyperintense rim in R2* images surrounding a hypointense core. We describe how this observation relates to clinical/radiological characteristics of patients, in vivo.