Aj Thompson

Diffusion tensor imaging of lesions and normal-appearing white matter in multiple sclerosis

Objective: To determine whether diffusion tensor imaging (DTI) can detect structural changes in normal-appearing white matter, and to distinguish between plaques of different pathologic severity, in patients with MS. Background: Conventional MRI detects lesions sensitively in MS but has limited pathologic specificity. The diffusion of water molecules in brain tissue, most fully expressed mathematically by a tensor quantity, reflects its intrinsic microstructure. It is now possible to estimate the diffusion tensor noninvasively in the human brain using MR DTI. This method is unique in providing precise and rotationally invariant measurements of the amount and directional bias (anisotropy) of diffusion in white matter tracts relating to tissue integrity and orientation. Methods: DTI was performed in six patients with MS and in six age-matched control subjects. Diffusion was characterized in normal-appearing white matter in both groups, and in lesions of different pathologic subtypes (inflammatory, noninflammatory, T1 hypointense, and T1 isointense). Results: DTI identified significantly altered water diffusion properties in the normal-appearing white matter of patients compared with control subjects (p < 0.001), and distinguished between lesion types. The highest diffusion was seen in destructive (T1 hypointense) lesions, whereas the greatest change in anisotropy was found in inflammatory (gadolinium-enhancing) lesions. Conclusions: DTI detects diffuse abnormalities in the normal-appearing white matter of MS patients, and the findings in lesions appear to relate to pathologic severity. Its use in serial studies and in larger clinical cohorts may increase our understanding of pathogenetic mechanisms of reversible and persistent disability.

Measuring the impact of MS on walking ability The 12-Item MS Walking Scale (MSWS-12)

Objective: To develop a patient-based measure of walking ability in MS. Methods: Twelve items describing the impact of MS on walking (12-Item MS Walking Scale [MSWS-12]) were generated from 30 patient interviews, expert opinion, and literature review. Preliminary psychometric evaluation (data quality, scaling assumptions, acceptability, reliability, validity) was undertaken in the data generated by 602 people from the MS Society membership database. Further psychometric evaluation (including comprehensive validity assessment, responsiveness, and relative efficiency) was conducted in two hospital-based samples: people with primary progressive MS (PPMS; n = 78) and people with relapses admitted for IV steroid treatment (n = 54). Results: In all samples, missing data were low (≤3.8%), item test–retest reproducibility was high (≥0.78), scaling assumptions were satisfied, and reliability was high (≥0.94). Correlations between the MSWS-12 and other scales were consistent with a priori hypotheses. The MSWS-12 (relative efficiency = 1.0) was more responsive than the Functional Assessment of Multiple Sclerosis mobility scale (0.72), the 36-Item Short Form Health Survey physical functioning scale (0.33), the Expanded Disability Status Scale (0.03), the 25-ft Timed Walk Test (0.44), and Guy’s Neurologic Disability Scale lower limb disability item (0.10). Conclusions: The MSWS-12 satisfies standard criteria as a reliable and valid patient-based measure of the impact of MS on walking. In these samples, the MSWS-12 was more responsive than other walking-based scales.

Diagnostic criteria for primary progressive multiple sclerosis: a position paper.

The unique clinical characteristics of primary progressive multiple sclerosis (PPMS) pose particular diagnostic difficulties, both in excluding other causes of progressive syndromes and in confirming the diagnosis of MS, which is not adequately addressed by current diagnostic criteria. This article presents new diagnostic criteria developed by a group of investigators on the basis of a review of their considerable experience with PPMS. (We conclude that at least 1 year of clinical progression must be documented before a diagnosis of PPMS is made.) Three levels of diagnostic certainty have been defined—definite, probable, and possible—based on clinical findings, abnormal cerebrospinal fluid, abnormalities on magnetic resonance imaging (MRI) of the brain and spinal cord, and evoked potentials. In definite PPMS, evidence of intrathecal synthesis of immunoglobulin G together with one of the following three MRI criteria is required: (1) nine brain lesions, (2) two spinal cord lesions, or (3) four to eight brain lesions and one spinal cord lesion. Preliminary testing of these criteria was carried out on a cohort of 156 patients participating in a European natural history study of PPMS: 64% fulfilled the criteria for definite PPMS, 35% for probable PPMS, and only 1% for possible PPMS. These criteria now require prospective validation in a cohort of newly diagnosed patients and by postmortem examination. Ann Neurol 2000;47:831–835

Clinical, CSF, and MRI findings in Devic's neuromyelitis optica.

OBJECTIVES: Since Devics original description of neuromyelitis optica in 1894 there has been much debate regarding its aetiology. A specific cause has been identified in a minority of cases but in most the question has arisen whether or not Devics neuromyelitis optica is a variant of multiple sclerosis. This study was undertaken to help clarify this issue. METHODS: Neuromyelitis optica was defined as (1) a severe transverse myelitis; (2) an acute unilateral or bilateral optic neuropathy; (3) no clinical involvement beyond the spinal cord or optic nerves, and (4) a monophasic or multiphasic illness. The clinical and autoantibody status was documented. Patients underwent CSF examination and MRI of brain and spinal cord. RESULTS: Twelve patients, with a mean age of presentation of 35.1 years, were seen. Eleven were women; vision was reduced to counting fingers or worse in 10 patients and seven became confined to a wheelchair. Examination of CSF showed local synthesis of oligoclonal bands in only two patients and a neutrophil pleocytosis in two. A possible aetiology was identified in five: a specific connective tissue disorder (two), pulmonary tuberculosis (one), and possible acute disseminated encephalomyelitis (two). Six had non-specific increases in various autoantibodies. Eleven patients underwent MRI of the brain and spinal cord. In 10 there were diffuse abnormalities involving cervical and thoracic cords with extensive swelling in the acute phase. Brain MRI was normal in five; in five there were multiple deep white matter lesions, and one patient had minor age related changes. CONCLUSION: It is proposed that Devics neuromyelitis optica is a distinctive disorder with some clinical, CSF, and MRI features different from those found in classic multiple sclerosis. In most cases a specific aetiology is not identified, but an immunological mechanism of tissue damage seems likely.

Magnetic resonance imaging in monitoring the treatment of multiple sclerosis: concerted action guidelines.

Serial gadolinium enhanced MRI of the brain detects much clinically silent disease activity in early relapsing-remitting and secondary progressive multiple sclerosis (MS), and thus has an important role in monitoring the effects of therapy. Based on the proceedings of a recent Commission of the European Communities (CEC) workshop and a review of the literature, guidelines are presented for using MRI to monitor treatment trials in MS. The guidelines consider: A) MRI system and techniques; B) patient selection; C) trial design; D) analysis of results. Priorities for future research are also indicated.

Spinal cord MRI using multi-array coils and fast spin echo. II: Findings in multiple sclerosis

We performed MRI of brain and spinal cord on 80 patients with multiple sclerosis (MS). Using multi-array coils and fast spin echo, 139 intrinsic lesions were identified in 59 patients (74%). Lesions were more common in the cervical than in the thoracic cord. Cross-sectional areas of the cord, measured from axial images at four levels, showed atrophy in 40%. Clinical disability correlated with cord atrophy but not with cord lesion load. These results show that the use of multi-array coils and fast spin echo allows rapid and sensitive detection of spinal cord lesions in MS and that the cord is involved in the majority of patients. A lack of association between cord lesions and disability may relate to limitations in MR resolution but also suggests that the mechanisms of disability in MS are complex and multifactorial.

Investigation of MS normal-appearing brain using diffusion tensor MRI with clinical correlations

Objective: To quantitatively investigate water diffusion changes in normal-appearing white matter (NAWM) and gray matter in patients with MS, and to evaluate whether these changes are correlated with clinical disability and disease duration. Background: Diffusion tensor imaging provides quantitative information about the magnitude and directionality (anisotropy) of water diffusion in vivo and detects pathologic changes in MS brain tissue. Methods: Diffusion tensor imaging was performed in 39 patients with MS and in 21 age-matched control subjects. Quantitative indices, including fractional anisotropy, volume ratio, and mean diffusivity, were obtained in 30 regions of interest located in normal-appearing basal ganglia, cerebellar gray matter, and supratentorial and infratentorial NAWM. Results: Patients with MS showed significantly reduced anisotropy and a trend toward increased diffusivity in the infratentorial and supratentorial NAWM, and significantly increased anisotropy in the basal ganglia. In all patients with MS, both fractional anisotropy and mean diffusivity in the cerebral peduncles were inversely correlated with the Expanded Disability Status Scale and pyramidal functional scores. In patients with relapsing-remitting MS, there was a strong correlation between Expanded Disability Status Scale score and fractional anisotropy in both supratentorial and infratentorial NAWM. In primary and secondary progressive MS, disease duration correlated strongly with mean diffusivity in infratentorial NAWM and fractional anisotropy in the cerebral peduncles, respectively. Conclusion: The most striking finding of decreased fractional anisotropy in supratentorial and infratentorial NAWM and increased fractional anisotropy in basal ganglia may result from axonal degeneration due to fiber transection in remote focal lesions. Diffusion tensor imaging indices, in particular fractional anisotropy, appear sensitive to structural damage in NAWM that is associated with disability and progression in MS.

Correlations between changes in disability and T2‐weighted brain MRI activity in multiple sclerosis A follow‐up study

Article abstract—We obtained two conventional unenhanced T2-weighted brain MRI scans, separated by an interval of 24 to 36 months, in 281 patients with multiple sclerosis (MS). At the time of each scan, clinical disability was rated using the Kurtzke Expanded Disability Status Scale (EDSS). Changes in disability between the two examinations correlated weakly but significantly with the number of new (Spearmans rank correlation coefficient = 0.13; p = 0.02) and enlarging (Spearmans rank correlation coefficient = 0.18; p = 0.002) MRI lesions. This result suggests that brain T2--weighted MRI is a useful supplementary marker of disease activity in definitive (phase 111) clinical treatment trials in MS.

Measuring change in disability after inpatient rehabilitation: comparison of the responsiveness of the Barthel Index and the Functional Independence Measure

BACKGROUND The importance of evaluating disability outcome measures is well recognised. The Functional Independence Measure (FIM) was developed to be a more comprehensive and “sensitive” measure of disability than the Barthel Index (BI). Although the FIM is widely used and has been shown to be reliable and valid, there is limited information about its responsiveness, particularly in comparison with the BI. This study compares the appropriateness and responsiveness of these two disability measures in patients with multiple sclerosis and stroke. METHODS Patients with multiple sclerosis (n=201) and poststroke (n=82) patients undergoing inpatient neurorehabilitation were studied. Admission and discharge scores were generated for the BI and the three scales of the FIM (total, motor, and cognitive). Appropriateness of the measures to the study samples was determined by examining score distributions, floor and ceiling effects. Responsiveness was determined using an effect size calculation. RESULTS The BI, FIM total, and FIM motor scales show good variability and have small floor and ceiling effects in the study samples. The FIM cognitive scale showed a notable ceiling effect in patients with multiple sclerosis. Comparable effect sizes were found for the BI, and two FIM scales (total and motor) in both patients with multiple sclerosis and stroke patients. CONCLUSION All measures were appropriate to the study sample. The FIM cognitive scale, however, has limited usefulness as an outcome measure in progressive multiple sclerosis. The BI, FIM total, and FIM motor scales show similar responsiveness, suggesting that both the FIM total and FIM motor scales have no advantage over the BI in evaluating change.

1H magnetic resonance spectroscopy of chronic cerebral white matter lesions and normal appearing white matter in multiple sclerosis

OBJECTIVES To test the hypothesis that irrecoverable neurological deficit in multiple sclerosis is associated with axonal loss. METHODS 1H magnetic resonance spectroscopy (MRS) was carried out in a group of patients with clinically definite multiple sclerosis (n=31). Using this technique, the apparent concentration of NA ([NA] the sum of N-acetyl aspartate (NAA), a neuronal marker, and N-acetylaspartylglutamate has been compared in four groups of patients with multiple sclerosis classified as relapsing-remitting, secondary progressive, primary progressive, benign, and a control group. RESULTS In the patients with relapsing-remitting disease (n=9) there was a highly significant reduction of apparent NA (median 8.73 mM, range 6.86 mM-10.74 mM, P=0.0008) from an area of high signal compared with the control group (median 11.97 mM, range 10.55 mM-14.5 mM). In the patients with secondary progressive disease (n=10), there was again a highly significant reduction of apparent NA (median 7.82 mM, range 3.5 mM-10.3 mM, P=0.0003) from an area of high signal compared with the control group. In the patients with primary progressive disease (n=6) there was once again a highly significant reduction of apparent NA (median 8.83 mM, range 6.95 mM-9.89 mM, P<0.002) from an area of high signal compared with the control group. In the patients with benign disease, however, there was no significant difference in the apparent NA (median 10.5 mM, range 8.53 mM-12.8 mM, P>0.05) from an area of high signal compared with the control group. In the patients with benign disease (n=5) there was also no significant difference in the apparent NA (median 10.74 mM, range 8.58 mM-13.4 mM, P>0.3) from an area of normal appearing white matter compared with the control group. In the patients with primary progressive disease, however, there was a significant reduction of apparent NA from an area of normal appearing white matter (median 8.78 mM, range 8.7 mM-12.38 mM, P< 0.025) compared with the control group.  There was a significant inverse correlation between [NA] from lesions in the patients with multiple sclerosis and disability as measured on the Kurtzke expanded disability scale score (r= -0.364, 0.05>P> 0.02). CONCLUSION These findings support the hypothesis that axonal loss is important in the development of disability in multiple sclerosis. They also provide evidence for axonal loss in normal appearing white matter in patients with primary progressive disease.