Evaluation of the cognitive benefits of intrathecal baclofen pump implantation in people with intractable multiple sclerosis related spasticity.

BACKGROUND: Spasticity is a common problematic symptom in Multiple Sclerosis with over one third of patients failing first line therapies. Intrathecal baclofen is a safe and efficacious option for treatment resistant spasticity. Anecdotally patients report improved concentration/cognitive performance when switching to intrathecal baclofen (ITB) from systemic medications. AIM: To explore whether subjects who proceed with ITB pump implantation for spasticity management and reduce oral anti-spasticity agents will have improved cognitive function. METHODS: Subjects were admitted for trial of ITB via lumbar puncture and subsequent pump implantation. Spasticity and cognitive measures before ITB trial and 3 months post implant were recorded. Paired t-test or Wilcoxon Signed Ranks test was used for within subject change and effect sizes (Cohen's dz) were calculated. Subgroup analysis of those on ≥2, or ≤ 1 spasticity medications at baseline was performed. RESULTS: 27 subjects with MS completed per protocol. Mean age 46 years [26 - 56], disease duration 15 years [6 - 26], RRMS = 3, SPMS = 17 and PPMS=7. The majority were on multiple spasticity medications. Spasticity scores significantly improved post pump implant. Mean ITB dose at 3 months was 143 mcg / day and 19 discontinued all other treatments for spasticity. There was no deterioration on any cognitive or mood measure. An improvement of moderate effect size was found in Backwards Digit Span (d=0.41, p=0.059) and HADS - anxiety (d=0.37, p=0.097). Fatigue Severity Scale score decreased substantially (d=0.81, p=0.005). Small improvements in Symbol Digit Modalities Test score (d=0.24) and Sustained Attention to Response Task response time (d=0.23) were non-significant. Performance on other measures did not change. Effect sizes were larger in subgroup on ≥2 oral spasticity medications at baseline, compared to the group on ≤1 medication (SDMT, d=0.42 vs d=0.07; Backwards digit span 0.45 vs 0.28; HADS-anxiety 0.39 vs 0.32; HADS-depression d=0.32 vs 0.05 and FSS, d= 1.14 vs 0.42). CONCLUSIONS: In a pilot study exploring the impact of ITB on cognition, spasticity scores improved universally and beneficial effects on some measures of fatigue, anxiety, auditory attention and verbal working memory were found. Improvement of speed of processing in those withdrawing higher doses of oral medication was also demonstrated suggesting that switching to ITB has added cognitive and psychological benefits for people with MS.

Evaluation of the impact of intrathecal baclofen on the walking ability of people with Multiple Sclerosis related spasticity.

BACKGROUND: Spasticity is a frequent and disabling symptom in people with Multiple Sclerosis (MS). Intrathecal baclofen (ITB) is an effective but infrequently used treatment in ambulant people. OBJECTIVE: To evaluate the impact of ITB on ambulation in people with moderate to severe MS related spasticity. METHODS: Data was collected prospectively regarding spasticity and ambulation at baseline, after ITB trial via lumbar puncture, 3 months and annually thereafter. RESULTS: 30 subjects; Mean age 47.9 (26-64), 67% female, mean EDSS 6.5 [6.5-7.5]. Reduction in mean Ashworth score (pre 1.44: post 0.98, p<0.001) and Penn spasm score (pre 3: post 1; p<0.001) was shown. 20 people (67%) proceeded with implantation; lower limb MRC power was predictive of proceeding to pump (OR 2.98; 95% CI 1.01 - 8.7; p <0.05). In those proceeding to implantation there was no difference in 10mTW at 1 year (ANOVA (F(3,24) = 2.6, p=0.13). Currently, 15 (75%) remain ambulatory (mean 3.75 years, range 1-9). After implant, 17 (85%) discontinued all oral anti-spasticity treatments conferring other benefits. CONCLUSION: Ambulation in people with MS can be preserved for several years whilst effectively treating spasticity with ITB with careful patient selection; ITB should not be considered a last resort.

A cohort study of functional electrical stimulation in people with multiple sclerosis demonstrating improvements in quality of life and cost-effectiveness.

OBJECTIVE: The objective of this study was to determine the impact on health-related quality of life of functional electrical stimulation used to improve walking in people with multiple sclerosis and to explore cost-effectiveness. DESIGN: A retrospective analysis of patient records was conducted. SETTING: This study used outpatient therapy service as the study setting. SUBJECTS: Data from 82 consecutive patients with multiple sclerosis attending for set up with functional electrical stimulation were analysed. INTERVENTIONS: Patients were seen at baseline, three and six months for support in use of functional electrical stimulation, and data were collected at baseline and six months. MAIN MEASURES: The EQ-5D-5L and walking speed were collected at baseline and six months after using functional electrical stimulation. The Psychosocial Impact of Assistive Device Scale was collected at six months. EQ-5D-3L utilities were derived and cost-effectiveness analysis was completed utilizing a five-year time horizon and methodology published by National Institute for Health and Care Excellence. RESULTS: Significant differences (P < 0.001) were seen in walking speed (baseline 0.670 m/s; with stimulation 0.768 m/s) and maintained over six months (0.772 m/s with stimulation). EQ-5D data significantly improved over six months (baseline 0.486, six months 0.596, P < 0.001) and meaningful mean scores were seen in all aspects of the Psychosocial Impact of Assistive Device Scale. However, there were no correlations between measures. In the cost utility analysis, compared to standard care, functional electrical stimulation was more expensive and more effective with an incremental cost-effectiveness ratio of £6137. CONCLUSION: Functional electrical stimulation is a cost-effective treatment to improve walking speed and health-related quality of life in people with multiple sclerosis.

The high cost of spasticity in multiple sclerosis to individuals and society.

BACKGROUND: Spasticity is an extremely common, distressing and disabling symptom of multiple sclerosis. Limited data suggest the associated health care costs correlate with increasing severity and place a high economic burden on individuals, health care systems and society. OBJECTIVE: The aim of this study was to quantify the impact of multiple sclerosis spasticity on health care resources and the associated costs at different levels of severity in people with multiple sclerosis in the United Kingdom. METHODS: An online survey was carried out to understand the resources used in the management of spasticity in multiple sclerosis. The questionnaire asked health care specialists to estimate their involvement and the resource use associated with different levels of spasticity, and the survey outputs were used to derive the resource costs. RESULTS: The level and cost of care substantially increased with the degree of spasticity. Key factors contributing to high annual costs per patient were home care, hospital admissions and high-cost items, such as hospital beds. CONCLUSIONS: Based on the survey results, it can be assumed that managing spasticity early and effectively could result in substantial cost savings, in addition to the improvements in health-related quality of life.

Rehabilitation in practice: Spasticity management.

This series of articles for rehabilitation in practice aims to cover a knowledge element of the rehabilitation medicine curriculum. Nevertheless they are intended to be of interest to a multidisciplinary audience. The competency addressed in this article is 'The trainee consistently demonstrates a knowledge of the pathophysiology of various specific impairments including spasticity'. Spasticity is an extremely common feature of chronic neurological conditions and, if badly managed, it can result in pain, contractures and pressure sores, all of which can impact on function. It is therefore essential that a multidisciplinary management strategy is in place to help the individual manage their particular situation through education with timely access to interventions including instigation of a physical management programme and medication such as baclofen, tizanidine, dantrolene, benzodiazepines and gabapentin. Further treatment options for focal spasticity are botulinum toxin and phenol nerve blocks or intrathecal baclofen or phenol for predominant lower limb spasticity. Ongoing assessment with the use of appropriate outcome measures can both guide choice of treatment and monitor efficacy.

Rehabilitation and MS.

Unfortunately, most people with MS will develop disability, which may or may not be permanent, at some point in their lives. Effective management of this is dependent on co-ordinated services that can be accessed by the person with MS in a timely and effective fashion. Neurological rehabilitation is a process of active change by which the person with MS acquires the knowledge and skills necessary for optimum physical, psychological and social function. It requires a dedicated multidisciplinary team with a clear understanding of the MS disease process, the mechanisms of disablement, and the skills to educate and treat people with disability so that they may participate fully in their chosen roles. This review considers the necessary components to the rehabilitation process and when such input may be most appropriate.

Intrathecal baclofen therapy improves functional intelligibility of speech in cerebral palsy.

OBJECTIVE: To assess the effect of intrathecal baclofen on spastic dysarthia in cerebral palsy. DESIGN: Single case study. METHODS: Functional outcome measures, including the Assessment of Intelligibility of Dysarthric Speech, were performed before and after a trial of intrathecal baclofen in an adult patient with spastic dysarthria due to cerebral palsy. The patient proceeded to intrathecal baclofen pump implantation and was reassessed after six months of continuous intrathecal baclofen therapy. RESULTS: Improvement in function including speech intelligibility was seen following the intrathecal baclofen trial. The improvement was sustained at six months post pump implantation. CONCLUSIONS: Intrathecal baclofen improved functional intelligibility of speech in a carefully selected subject. The Assessment of Intelligibility of Dysarthric Speech was found to be a useful quantitative tool to assess the effect of intrathecal baclofen on spastic dysarthria.

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.

A longitudinal study of cognition in primary progressive multiple sclerosis.

There are few longitudinal studies of cognition in patients with multiple sclerosis, and the results of these studies remain inconclusive. No serial neuropsychological data of an exclusively primary progressive series are available. Cross-sectional analyses have revealed significant correlations between cognition and magnetic resonance imaging (MRI) parameters in primary progressive multiple sclerosis (PPMS). This study investigated cognitive and MRI change in 99 PPMS patients from five European centres for 2 years. They were assessed at 12 month intervals using the Brief Repeatable Battery, a reasoning test, and a measure of depression. The MRI parameters of T1 hypointensity load, T2 lesion load, and partial brain volume were also calculated at each time point. There were no significant differences between the mean cognitive scores of the patients at year 0 and year 2. However, one-third of the patients demonstrated absolute cognitive decline on individual test scores. Results indicated that initial cognitive status on entry into the study was a good predictor of cognitive ability at 2 years. There was only a small number of significant correlations between changes in cognition and changes on MRI, notably T1 hypointensity load with the two attentional tasks (r = -0.266, P = 0.017; r = -0.303, P = 0.012). It is probable that multiple factors underlie this weak relation between the cognitive and MRI measures.

Magnetic resonance imaging predictors of disability in primary progressive multiple sclerosis: a 5-year study.

Magnetic resonance imaging (MRI) has become an accepted tool for monitoring therapeutic trials in relapsing-remitting and secondary progressive multiple sclerosis (MS); it is however unclear whether such MRI markers are equally applicable to primary progressive MS (PPMS). Forty-two patients with PPMS were reviewed five years after commencing a two-year MRI and clinical study. Clinical measures recorded at baseline and five years included both the Expanded Disability Status Scale and the MS functional composite. MRI data collected at baseline and two years included T1 and T2 lesion loads, the number of new brain and cord lesions, and measures of both brain and cord atrophy. The study demonstrated that both the number of new T2 lesions and rate of increase in ventricular volume over two years were modestly predictive of subsequent disease progression and therefore may be useful tools in the testing of new therapeutic agents in PPMS.

Primary progressive multiple sclerosis: a 5-year clinical and MR study.

Longitudinal imaging studies of primary progressive multiple sclerosis (PPMS) have shown significant changes in MR measures over 1 to 2 years. Correlation with clinical change over the same period has not been evident; we investigated the possibility that this is because the period of observation was insufficient for these associations to become apparent. Forty-one patients with PPMS were followed prospectively for 5 years. Patients had clinical [Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite Measure (MSFC)] and MRI assessment (brain and spinal cord) at baseline, 1, 2 and 5 years. At 5 years, significant deterioration was seen in all clinical and MRI measures (P<0.01, P<0.001 respectively). Associations were seen between increase in EDSS score and decrease in cord area (r=0.31, P<0.05) and between increase in MSFC and both rate of ventricular enlargement (r=0.31, P<0.05) and increase in T2 load (r=0.31, P<0.05). The rates of change of MR measures were not associated with age or disease duration and were more consistent within than between patients. Longer duration of follow-up demonstrates modest associations between change in clinical and MR measures and provides new insights into the pattern of change within and between individuals with PPMS.

Interferon beta-1a in primary progressive MS: an exploratory, randomized, controlled trial.

BACKGROUND: Patients with primary progressive MS have atypical clinical and MRI characteristics and have been excluded from most therapeutic trials. The authors report a randomized, controlled trial restricted to primary progressive MS. METHODS: Fifty subjects were randomized to weekly IM interferon beta-1a 30 microg, 60 microg, or placebo for 2 years. The primary endpoint was time to sustained progression in disability. Secondary outcomes included the timed 10-meter walk, nine-hole peg test, and on MRI, T2 and T1 brain lesion loads and brain and spinal cord atrophy. RESULTS: The 30- microg dose of interferon beta-1a was well tolerated, but the 60- microg dose caused severe flulike reactions and raised liver enzymes. No treatment effect was seen on the primary endpoint. Subjects on interferon beta-1a 30 microg had a lower rate of accumulation of T2 lesion load than controls (p = 0.025); subjects on 60 microg had a greater rate of ventricular enlargement than controls (p = 0.025). CONCLUSIONS: This study has demonstrated that interferon beta-1a 30 microg was well tolerated, identified useful outcome measures, but showed no efficacy on the primary outcome measure or on most of the secondary outcome measures.

Interleukin 1 genotypes in multiple sclerosis and relationship to disease severity.

We studied the association between clinical outcome in MS and allelic variants single nucleotide polymorphisms (SNPs) of interleukin-1alpha (IL-1alpha), IL-1beta and a variable number tandem repeat (VNTR) in IL-1 receptor antagonist (IL-1RN). A total of 377 patients with MS were studied. Significant associations between IL-1 genotypes and clinical outcome were found using logistic regression after correction for gender, onset age and disease duration. The same trends were subsequently demonstrated in a second independent group of 67 primary progressive patients. Our results suggest that genetically determined immunomodulation mediated by IL-1 influences long-term prognosis in multiple sclerosis (MS).

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.

Acanthocytosis and neurological disorders.

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 presenting in males as a benign myopathy with 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 treatments.

Factors affecting functional outcome in patients with nontraumatic spinal cord lesions after inpatient rehabilitation.

OBJECTIVE: Patients with nontraumatic spinal cord lesions account for between one fourth and one half of all spinal cord injuries. In the management of this group of patients, an understanding of factors influencing functional improvement is essential to help define the most appropriate rehabilitation programme. Although it is possible to predict accurately the functional outcome for an individual patient with a complete traumatic spinal cord injury, few studies have looked at prognostic factors in patients with nontraumatic spinal cord disease. The aim of this study was to determine which, and how well, factors assessed on admission to a rehabilitation unit relate to functional improvement in this group. METHODS: The study sample consists of 100 patients with an incomplete nontraumatic spinal cord lesion who underwent inpatient neurorehabilitation. Possible prognostic factors were sought by identifying those variables with a significant difference in the Functional Independence Measure (FIM) motor change score above and below the median. A step-wise multiple regression analysis was then performed to determine which variables influenced functional outcome. RESULTS: Patients with larger functional gains had significantly lower disability scores on admission, a shorter time between symptom onset and rehabilitation, and a longer length of stay. They were more likely to have a cervical lesion and evidence of neurologic recovery. Multiple regression analysis demonstrated that the FIM motor score on admission and the time between symptom onset and rehabilitation predicted 54% of the variance of the FIM motor score gain. CONCLUSIONS: This finding suggests that early rehabilitation is an important factor in securing a good outcome.

Variations in T1 and T2 relaxation times of normal appearing white matter and lesions in multiple sclerosis.

OBJECTIVE: To investigate the variation in T1 and T2 relaxation times of normal appearing white matter (NAWM) and lesions in multiple sclerosis (MS) throughout the brain. BACKGROUND: The magnetic resonance imaging (MRI) sequence fast FLAIR (fluid attenuated inversion recovery) has demonstrated overall increased lesion detection when compared to conventional or fast spin echo (FSE) but fewer lesions in the posterior fossa and spinal cord. The reasons for this are unknown, but may be due to variations in the T1 and T2 relaxation times within NAWM and MS lesions. METHOD: Ten patients and 10 controls underwent MRI of the brain which involved FSE, fast FLAIR and the measurement of T1 and T2 relaxation times. RESULTS: Of 151 lesions analysed (22 infra-tentorial, 129 supra-tentorial), eight were missed by the fast FLAIR sequence. T1 and T2 relaxation times in normal controls were longer in the infra-tentorial, than supra-tentorial, region. Patient NAWM relaxation times were prolonged compared with control values in both regions. Lesions demonstrated longer relaxation times than either control white matter or patient NAWM in both regions, however this difference was less marked infra-tentorially. The eight posterior fossa lesions not visible on the fast FLAIR sequence were characterised by short T1 and T2 relaxation times which overlapped with the patient NAWM for both T1 and T2 and with control values for T2 relaxation times. CONCLUSION: Both lesion and NAWM relaxation time characteristics vary throughout the brain. The T1 and T2 relaxation times of infra-tentorial lesions are closer to the relaxation times of local NAWM than supra-tentorial lesions, resulting in reduced contrast between posterior fossa lesions and the background NAWM. Consequently the characteristics of some lesions overlap with those of NAWM resulting in reduced conspicuity. By utilising this information, it may be possible to optimise fast FLAIR sequences to improve infra-tentorial lesion detection.

Neuropsychological impairment in multiple sclerosis patients: the role of (juxta)cortical lesion on FLAIR.

In this study we evaluated the correlation between neuropsychological impairment (measured with the Brief Repeatable Battery Neuropsychological Tests) and (juxta)cortical lesions detected with FLAIR and the relative sensitivity of the FLAIR sequence compared to spin-echo MRI sequences in detecting (juxta)cortical MS lesions. A total of 39 patients with definite MS were evaluated by MRI with a conventional and fast spin echo sequence and fast FLAIR sequence, and neuropsychological tests of the Brief Repeatable Battery Neuropsychological tests were performed. The Z-score of all subtests were used to calculate a Cognitive Impairment Index. The results show that a high number of (juxta)cortical lesions is detected with thin slice FLAIR (30% of all lesions seen). This percentage was not superior to spin-echo, reflecting the thin slice thickness (3 mm) we used. The lesions detected with FLAIR were to a certain degree different ones than the lesions detected with the other techniques. While the number of non-cortical lesions correlated with the expanded disability status scale (r=0.32, P=0.045), the number of (juxta)cortical lesions detected with the FLAIR showed a correlation (r=0.34, P=0.035) with the Cognitive Impairment Index. Our study underlines the high number of (juxta)cortical lesions in MS and the value of thin slice FLAIR sequence to detect such lesions with MRI. It also stresses the importance of (juxta)cortical lesions on determining neuropsychological impairment. Multiple Sclerosis (2000) 6 280 - 285