Valerie Stevenson

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

Primary and transitional progressive MS A clinical and MRI cross-sectional study

Background: Ten percent of patients with MS have a progressive course from onset with no history of relapses or remissions. A smaller subgroup follow a similar progressive course but have a single relapse at some point (transitional progressive [TP] MS). To date these patients have been excluded from receiving licensed treatments for MS and from most therapeutic trials. Objective: To document the clinical and MRI characteristics of a large cohort of progressive patients, including 158 with primary progressive (PP) MS and 33 with TPMS. Data from a small reference group of 20 patients with secondary progressive (SP) MS are also presented for reference. Methods: Patients were recruited from six European centers. All underwent a clinical assessment including scoring on the Expanded Disability Status Scale (EDSS) and MRI of the brain and spinal cord. Results: The men-to-women ratio was 81:77 (51% men) in the PP group, 14:19 (42% men) in the TP group, and 5:15 (25% men) in the SP group. The mean age at disease onset was significantly higher in the PP group than it was in the other two groups (PP 40.2 years, TP 34.9 years, SP 28.7 years). On MRI the PP group had lower mean brain T2 and T1 hypointensity lesion loads than the SP group (T2 12.02 versus 27.74 cm3, p = 0.001; T1 4.34 versus 7.04 cm3, p = 0.015). The SP and TP cohorts had significantly more T2-weighted lesions in the spinal cord than the PP patients, and the SP cohort had the greatest degree of atrophy. There was a correlation in the PP and TP patients between EDSS score and brain and spinal cord atrophy (r = 0.3, 0.2, p ≤ 0.006) but not with brain lesion load. The PP and TP patients who presented with spinal cord pathology had significantly lower brain T2 and T1 lesion loads than those with non-spinal cord presentations (p = 0.002). Conclusions: The monitoring of disease progression in PPMS is difficult, although measures of atrophy correlate with the EDSS and appear most promising. This study increases our understanding of this unique patient group, which will be further expanded with the acquisition of serial data.

1H magnetic resonance spectroscopy of normal appearing white matter in primary progressive multiple sclerosis

Abstract Recent magnetic resonance imaging (MRI) and pathological studies have indicated that axonal loss is a major contributor to disease progression in multiple sclerosis. 1H magnetic resonance spectroscopy (MRS), through measurement of N-acetyl aspartate (NAA), a neuronal marker, provides a unique tool to investigate this. Patients with primary progressive multiple sclerosis have few lesions on conventional MRI, suggesting that changes in normal appearing white matter (NAWM), such as axonal loss, may be particularly relevant to disease progression in this group. To test this hypothesis NAWM was studied with MRS, measuring the concentration of N-acetyl derived groups (NA, the sum of NAA and N-acetyl aspartyl glutamate). Single-voxel MRS using a water-suppressed PRESS sequence was carried out in 24 patients with primary progressive multiple sclerosis and in 16 age-matched controls. Ratios of metabolite to creatine concentration (Cr) were calculated in all subjects, and absolute concentrations were measured in 18 patients and all controls. NA/Cr (median 1.40, range 0.86–1.91) was significantly lower in NAWM in patients than in controls (median 1.70, range 1.27–2.14; P = 0.006), as was the absolute concentration of NA (patients, median 6.90 mM, range 4.62–10.38 mM; controls, median 7.77 mM, range 6.60–9.71 mM; P = 0.032). There was no significant difference in the absolute concentration of creatine between the groups. This study supports the hypothesis that axonal loss occurs in NAWM in primary progressive multiple sclerosis and may well be a mechanism for disease progression in this group.

Imaging of the spinal cord and brain in multiple sclerosis : a comparative study between fast flair and fast spin echo

Abstract Recent reports have suggested that fluid attenuated inversion recovery (FLAIR) is a technique superior to conventional (CSE) or fast spin echo (FSE) T2-weighted sequences in detecting intrinsic lesions both in the brain and spinal cord. We report our experience of an inversion recovery prepared FSE, which we refer to as fast FLAIR, in a comparative study of ten patients with clinically definite multiple sclerosis (MS) who underwent cervical cord and brain imaging with both FSE and fast FLAIR. The results showed that in the cerebral hemispheres fast FLAIR detected more lesions than FSE (P < 0.001). However, FSE detected more lesions than fast FLAIR in the posterior fossa (P = 0.02) and in the cord fast FLAIR was much inferior detecting only 2 of 33 lesions seen on FSE. Estimating the T2 relaxation times of lesions in each of three areas (periventricular, posterior fossa, cervical cord) showed that the T2 value of posterior fossa and cervical cord lesions was significantly lower than that of periventricular lesions, suggesting that the lesion composition is different and consequently their imaging appearances are different. In conclusion, although fast FLAIR improves the detection of MS lesions in the cerebral hemispheres, its substantially lower sensitivity in the posterior fossa and spinal cord is a potentially important limitation to its use as a tool for the diagnosis of MS and for monitoring therapies. Further studies are needed to elucidate the mechanisms underlying the loss of sensitivity.

Long-term clinical outcome of primary progressive MS: Predictive value of clinical and MRI data

The authors sought to identify clinical and MRI predictors of outcome in primary progressive multiple sclerosis (PPMS). Clinical and MRI assessments were performed at baseline and 2 and 5 years (clinical only). At baseline, disease duration, expanded disability status scale (EDSS) and brain volume predicted outcome. Adding short-term change variables, baseline EDSS, changes in T2* lesion load and cord area, and number of new lesions were predictive. Clinical and MRI variables predict long-term outcome in PPMS.

Acanthocytosis and neurological disorders

Abstract Acanthocytosis occurs because of ultrastructural abnormalities of the erythrocyte membranous skeleton resulting in reduced membrane fluidity. At least three hereditary neurological conditions are associated with it, although as yet the pathogenesis of the neurological features is unknown. In abetalipoproteinaemia, an autosomal recessive condition, vitamin E deficiency results in a progressive spinocerebellar syndrome associated with peripheral neuropathy and retinitis pigmentosa. Neuroacanthocytosis is also probably an autosomal recessive condition and is characterised by chorea, orofaciolingual dyskinesia, dysarthria, areflexia, seizures and dementia. McLeod syndrome is an X-linked recessive disorder usually presneting in males as a benign myopathy within areflexia, in association with a particular abnormality of expression of Kell blood group antigens. However, occasionally the neurological features are more severe and indistinguishable from those of neuroacanthocytosis. Recent advances in molecular genetics may assist better understanding of the disease mechanisms and the search for more effective treatment.

Magnetisation transfer of normal appearing white matter in primary progressive multiple sclerosis

Patients with primary progressive multiple sclerosis may develop severe disability despite a paucity of lesions on conventional magnetic resonance imaging, raising the possibility that intrinsic changes in normal appearing white matter (NAWM) contribute to disability. This study has measured magnetisation transfer ratio (MTR), an index of tissue damage, of NAWM in 52 patients with primary progressive multiple sclerosis and 26 healthy controls. Absolute values of MTR were obtained from the genu of the corpus callosum and pons, and mean values were calculated from bilateral regions in the centrum semiovale, frontal white matter, parieto-occipital white matter and posterior limb of the internal capsule. The median MTR was lower in all regions in patients compared to controls. Median values (per cent units) were significantly lower in corpus callosum (39.73 vs 40.63; P=0.01), frontal white matter (39.11 vs 39.59; P=0.01) and centrum semiovale (37.21 vs 37.82; P50.05). This study has demonstrated small but widespread decreases in MTR in NAWM in primary progressive multiple sclerosis supporting the hypothesis that there are intrinsic changes in NAWM which may contribute to disability in this patient group.

Two-year follow-up study of primary and transitional progressive multiple sclerosis

This study documents changes in clinical and magnetic resonance imaging (MRI) characteristics in a large cohort of patients with primary and transitional progressive multiple sclerosis (PP and TPMS) over 2 years. Patients with PPMS and TPMS were recruited from six European centres and underwent clinical and MRI examination at three time points: baseline, year one and year two. Of the 190 patients recruited clinical data were available on 125 patients (66%, five centres) and MRI data were available on 113 patients (59%, four centres) at 2 years. Significant increases were seen in T2 load and T1 hypointensity, while brain and cord volume decreased. In PPMS significantly higher lesion loads were found in those who presented with non-cord syndromes when compared to cord presentation and there was a trend to greater brain atrophy in those who deteriorated clinically over the course of the study compared to those who remained stable. Significant cord atrophy was only seen in those with a cord presentation. Measurable changes in MRI parameters can be detected in PPMS patients over a relatively short period of time. MRI quantification is likely to be useful in elucidating disease mechanisms in PPMS and in the execution of clinical trials.

Monitoring disease activity and progression in primary progressive multiple sclerosis using MRI: sub-voxel registration to identify lesion changes and to detect cerebral atrophy.

Objective To explore the potential usefulness of two new magnetic resonance imaging (MRI) analysis techniques for assessment of progressive cerebral atrophy and T2 lesion activity in primary progressive multiple sclerosis (PPMS), and thereby assess the relationship between MRI activity and atrophy in this patient group. Background Measurements of cerebral atrophy and net change in T2 lesion volumes are currently used as surrogate markers of disease progression in multiple sclerosis (MS). However, manual implementation of these techniques is time-consuming and the pathological specificity of T2 lesion change is low. Advances in serial scan registration have facilitated the development of a new, fully-automated technique to measure cerebral volume (SIENA; Structural Image Evaluation, using Normalisation, of Atrophy), and a technique to measure the total new T2 lesion volume selectively (MRI difference imaging). Method SIENA measures changes in cerebral size based on sub-voxel detection of shifts in edge contours. The lesion difference imaging method measures differences in lesion volumes over time as defined by a semi-automated outlining technique. The two new methods were validated against the T2 lesion volume contour technique and a previously described measure of partial brain volume (which uses six slices centred on the presumed area of greatest change around the lateral ventricles). All were applied to serially acquired MR images from a cohort of 39 patients with PPMS, who also underwent scoring on the expanded disability status scale (EDSS) twice, two years apart. Results The two measures reflecting cerebral atrophy correlated strongly (r = 0.58, p < 0.001). T2 lesion load measurements using the two techniques correlated very highly (r = 0.999, p < 0.001). 91 % of the total new T2 lesion volume was from enlargement of pre-existent lesions and only 9 % from new, discrete, lesions. No relationship was seen between the traditional measure of net gain in T2 lesion load and either measure of atrophy. However, the fully-automated measure of total new T2 load correlated with both measures of atrophy (SIENA technique, r= −0.37, p= 0.02; six slice measure, r = −0.41, p = 0.01). There was no relationship between the MRI measures and changes in the EDSS. Conclusion Both of the new image analysis techniques appear to be promising as sensitive markers for disease progression in PPMS. The correlation of total new T2 lesion volume with the progression of cerebral atrophy (which is known to be a consequence of axonal loss in progressive disease), compared with a lack of correlation with the traditional net gain in T2 lesion load is interesting and suggests that the total new T2 lesion volume may ultimately be the most useful measure.

Intrathecal baclofen in multiple sclerosis: Too little, too late?

The majority of patients with multiple sclerosis (MS) have symptoms of spasticity that increasingly impair function as the disease progresses. With appropriate treatment, however, quality of life can be improved. Oral antispasticity medications are useful in managing mild spasticity but are frequently ineffective in controlling moderate to severe spasticity, because patients often cannot tolerate the adverse effects of increasing doses. Intrathecal baclofen (ITB) therapy can be an effective alternative to oral medications in patients who have a suboptimal response to oral medications or who cannot tolerate dose escalation or multidrug oral regimens. ITB therapy may be underutilized in the MS population because clinicians (a) are more focused on disease-modifying therapies rather than symptom control, (b) underestimate the impact of spasticity on quality of life, and (c) have concerns about the cost and safety of ITB therapy. Delivery of ITB therapy requires expertly trained staff and proper facilities for pump management. This article summarizes the findings and recommendations of an expert panel on the use of ITB therapy in the MS population and the role of the physician and comprehensive care team in patient selection, screening, and management.