Charlie Davie

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.

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.

Lesion heterogeneity in multiple sclerosis: a study of the relations between appearances on T1 weighted images, T1 relaxation times, and metabolite concentrations

OBJECTIVES Multiple sclerosis lesions appear as areas of high signal on T2 weighted MRI. A proportion of these lesions, when viewed on T1 weighted MRI, appear hypointense compared with surrounding white matter. These hypointense T1 lesions are thought to represent areas of greater tissue damage compared with the more non-specific, total T2 lesion load. This study aimed to better characterise the properties of high signal T2 lesions with differing appearances on T1 weighted MRI using quantitative MR techniques. METHODS Eleven patients with secondary progressive multiple sclerosis were studied. Two high signal T2 lesions were selected from each patient—one of which appeared hypointense and one isointense on a T1 weighted image. A voxel was positioned around each lesion and for this volume of brain the metabolite concentrations were estimated using proton MR spectroscopy (1H-MRS) and the T1 relaxation time within each voxel calculated from a T1 map generated using a multislice technique. RESULTS Compared with isointense T1 lesions, hypointense T1 lesions exhibited a significantly lower absolute concentration of N-acetyl derived metabolites (tNAA) and a significantly higher absolute concentration of myo-inositol (Ins). T1 relaxation time correlated significantly with both tNAA (r=−0.8, p < 0.001) and Ins (r=0.5, p=0.012). There was no correlation between T1 relaxation times and creatine/phosphocreatine or choline containing compounds. CONCLUSIONS Prolonged T1 relaxation times seem to reflect the severity of axonal damage or dysfunction (inferred by a low tNAA) and possibly also gliosis (inferred by a high Ins) in chronic multiple sclerosis lesions.

Stroke and pregnancy

Pregnancy-related stroke is, fortunately, a rare event. However, when it occurs, there may be implications for management of the patient and delivery of the child. This article reviews the mechanisms and risk factors for stroke related to pregnancy, the presenting features, diagnosis and management of the different stroke types, and the implications for pregnancy and delivery.

Does the extent of axonal loss and demyelination from chronic lesions in multiple sclerosis correlate with the clinical subgroup

OBJECTIVE To determine non-invasively the relation between the degree of axonal loss and the extent of demyelination in chronic lesions visible on MRI in patients with different subgroups of clinically definite multiple sclerosis using 1H magnetic resonance spectroscopy (1H MRS) and magnetisation transfer imaging (MT). Conventional MRI is unable to differentiate between the various pathological processes occurring in the multiple sclerosis lesion. There are, however, newer MR techniques which show promise in this respect. METHODS 1H MRS and MT were performed in 18 patients with clinically definite multiple sclerosis who had a wide range of disability and disease duration. RESULTS A significant correlation was found between a reduction in the concentration of N-acetyl aspartate (NAA; an in vivo marker of axonal loss or dysfunction) and a reduction in MT ratio (a probable marker of demyelination) in patients who had entered the secondary progressive stage of the disease. Patients with minimal disability after a disease duration of greater than 10 years—so called benign multiple sclerosis—showed a relative preservation of NAA and MT. CONCLUSIONS Because a reduction in MT seems to be a relative marker for demyelination and a reduction of NAA from chronic lesions is indicative of axonal loss, this study supports the hypothesis that demyelination and axonal loss occur in the same chronic multiple sclerosis lesions. In addition, the degree of axonal loss and demyelination correlates with clinical heterogeneity.

Serial magnetisation transfer ratios in gadolinium-enhancing lesions in multiple sclerosis.

Abstract The magnetisation transfer (MT) ratio of eight multiple sclerosis lesions has been studied serially. Initially, when the lesions showed gadolinium enhancement, there was a marked reduction in their MT ratio compared with normal white matter. Follow-up a mean of 11 months later (range 3–23 months), when the lesions no longer enhanced, revealed a consistent and usually marked recovery of the MT ratios towards normal. The MT ratio is thought to reflect the structural integrity of tissues with an important contribution from myelin and axons. MT imaging is a promising tool for elucidating pathophysiology and monitoring treatment in multiple sclerosis.

Impact on Clinical and Cost Outcomes of a Centralized Approach to Acute Stroke Care in London: A Comparative Effectiveness Before and After Model

Background In July 2010 a new multiple hub-and-spoke model for acute stroke care was implemented across the whole of London, UK, with continuous specialist care during the first 72 hours provided at 8 hyper-acute stroke units (HASUs) compared to the previous model of 30 local hospitals receiving acute stroke patients. We investigated differences in clinical outcomes and costs between the new and old models. Methods We compared outcomes and costs ‘before’ (July 2007–July 2008) vs. ‘after’ (July 2010–June 2011) the introduction of the new model, adjusted for patient characteristics and national time trends in mortality and length of stay. We constructed 90-day and 10-year decision analytic models using data from population based stroke registers, audits and published sources. Mortality and length of stay were modelled using survival analysis. Findings In a pooled sample of 307 patients ‘before’ and 3156 patients ‘after’, survival improved in the ‘after’ period (age adjusted hazard ratio 0.54; 95% CI 0.41–0.72). The predicted survival rates at 90 days in the deterministic model adjusted for national trends were 87.2% ‘before’ % (95% CI 86.7%–87.7%) and 88.7% ‘after’ (95% CI 88.6%–88.8%); a relative reduction in deaths of 12% (95% CI 8%–16%). Based on a cohort of 6,438 stroke patients, the model produces a total cost saving of £5.2 million per year at 90 days (95% CI £4.9-£5.5 million; £811 per patient). Conclusion A centralized model for acute stroke care across an entire metropolitan city appears to have reduced mortality for a reduced cost per patient, predominately as a result of reduced hospital length of stay.

Magnetic resonance spectroscopic study of parkinsonism related to boxing.

Proton magnetic resonance spectroscopy, localised to the lentiform nucleus, was carried out in three ex-professional boxers who developed a parkinsonian syndrome, six patients with idiopathic Parkinsons disease, and six age matched controls. The three ex-boxers all showed a pronounced reduction in the absolute concentration of N-acetylaspartate compared with the patients with idiopathic Parkinsons disease and the control group. This reduction is likely to reflect neuronal loss occurring in the putamen and globus pallidus and supports the hypothesis that the extrapyramidal syndrome that may occur in ex-boxers is a distinct entity from idiopathic Parkinsons disease.

Toward an Outcomes-Based Health Care System: A View From the United Kingdom

THE CORE PURPOSE OF A HEALTH SYSTEM SHOULD BE to maximize the health of the population. When the main challenge is managing long-term conditions, maintaining health rather than delivering health care per se should be the goal. In a comprehensive, publicly funded system like the United Kingdom’s National Health Service (NHS) there is an overriding imperative to deliver maximum health benefit per pound spent. Quality, effectiveness, and efficiency are the goals. Traditionally, physicians and other health care professionals have regarded financial efficiency as outside the scope of their professionalism (indeed, often at odds with it). The concept of value—useful health outputs divided by the resources needed to achieve them—as advocated by Porter and Teisberg and others is relatively new and unfamiliar to many clinicians. However, the need to achieve more with less puts the need to strive for value into sharp focus. Following a decade of above-inflation increases in NHS funding, the urgent need to reduce the United Kingdom’s national debt means the NHS is entering a sustained period of flat or declining funding, while demand for services continues to increase (from technological progress, an aging population, increasing expectations, and population growth). Striving for value therefore becomes an ethical imperative. However, to make progress on value requires being clear about what the numerator of the value equation should describe. This must be quality of care as expressed by useful health outcomes, relevant to patients. Although the principle of measuring and reporting quality is now widely accepted, what should be measured to drive maximum improvement in quality is far from clear. The new coalition government has a system reform agenda for the NHS in England that is focused on outcomes. These reforms must correct some serious shortcomings in the NHS’s current approach to measuring quality, in particular: 1. A focus on process and proxies, not on outcomes that matter to patients. To date, the dominant focus of quality measurement and reporting has been on processes and inputs to care, not on patient-relevant outcomes. Process measures can have advantages. For example, they are often easier to measure than outcomes, they require less risk adjustment, and there are many examples in which a favorable patient outcome has resulted despite a defective process (or in which an unfavorable outcome has followed a faultless process). However, undue focus on process and proxy measures can have serious and often surprising consequences. Patients may have worse outcomes as a result. For example, higher mortality in high-risk patients with type 2 diabetes was associated with aggressive intervention to achieve normal glycated hemoglobin levels. 2. Only viewing the tip of the quality iceberg. An English hospital’s quality rating today depends largely on its standardized mortality rate and rates of hospitalacquired infection. While these measures are important, they are only part of what high-quality hospital care includes. Indeed, mortality and infection rates are irrelevant to many specialties. Furthermore, standardized mortality rates do not control adequately for severity of case mix. By overemphasizing outcomes that are at best marginal to the activities of many specialties, there is a risk of conveying a message that measuring quality is relevant for some, but not for the majority of health care professionals. The potential for public reporting of outcome measures to drive improvement across all care is restricted. Finding and using those quality measures that matter most to patients, comparing performance to relevant peers, and continually striving to improve results over time should be core to what clinicians do. However, the NHS focus on eliminating errors and on complying with minimum standards has not encouraged clinicians to view quality measurement and improvement as central to their professionalism. 3. Focus on snapshots, not on the whole pathway. A less well-recognized flaw in the current approach to measuring outcomes is the episodic or “snapshot” nature of current quality measures that are designed for isolated activities within a fragmented health care system. But health, not health care, is the aim. This requires taking a longitudinal, whole-system approach to measuring and managing quality.

Anticoagulation in cerebral venous sinus thrombosis.

Cerebral venous sinus thrombosis (CVST) is a relatively rare condition that may present variably with headache, seizures, focal neurology and impaired conscious level. Prognosis is equally variable. Despite few randomized studies, treatment has moved resolutely in the last two decades towards anticoagulation even in patients with significant cerebral haemorrhage being supported by consensus guidelines from several national and international sources [1,2]. A recent Cochrane review [3] has also looked again at the evidence. There are only two small randomized controlled trials (RCT) of anticoagulation use in CSVT that meet the Cochrane inclusion criteria: a trial by Einhäupl et al. [4] in 20 patients (using unfractionated heparin compared to placebo and stopped at an interim analysis having planned to recruit 60 patients) and another by de Bruijn and colleagues in 59 patients [using low-molecular weight heparin (LMWH) compared to placebo] [5]. Both studies showed poorer outcomes including death and dependency in the untreated patients with no increase in intracerebral haemorrhage (ICH) in the heparinized patients. In terms of primary outcome measures, meta-analysis showed a non-significant relative risk of 0.46 (95% CI 0.16–1.31) in death or dependency associated with anticoagulant therapy. The absolute reduction in the risk of death or dependency at follow-up in the treated patients was )13% (95% CI )30% to 3%). In both trials, no new symptomatic ICHs were diagnosed after initiation of anticoagulant therapy, despite the fact that many patients who received heparin had some degree of ICH on their pretreatment CT scans. Haemorrhage present on imaging prior to anticoagulation was associated with significantly worse outcomes. It is probably fair to say that the term meta-analysis should be used cautiously in this context given that there are only two small eligible studies using different types of anticoagulation. Other small studies have been performed but have been published only in abstract form or had insufficient imaging to be certain of diagnosis. In the international Study on Cerebral Vein and dural sinus Thrombosis (ISCVT) [6] of 624 patients, the largest prospective cohort study to date, 64% treated with intravenous heparin and 35% with therapeutic dosages of LMWH, the mortality rate was 6.8% at 6 months (with no comparison analysis of the two treatments) and few patients remaining dependent at the end of follow-up, therefore a better long-term outcome than in arterial stroke. In terms of prognosis, the ISCVT study showed better outcomes in patients presenting with isolated intracranial hypertension and substantially worse outcomes in patients with underlying malignancy or infection, a Glasgow Coma Score (GCS) < 9, or the presence of deep venous system thrombosis. On this background of minimal evidence, Misra and colleagues have published a randomized controlled trial of LMWH versus unfractionated heparin (UFH) in CVST [7]. Patients were diagnosed by MR venography and randomized to LMWH (34 patients) versus UFH (32 patients) for 14 days followed by oral anticoagulation. Six patients died all in the unfractionated group. There were few significant side effects reported: extracranial haemorrhage in three patients and one case of heparininduced thrombosis all in the UFH group. Improved outcomes were reported in the LMWH group at 3 months with 30 patients recovering completely compared to 20 in the UFH group. While these results appear clear cut, a number of issues should be considered. The number of deaths in the UFH group seems surprisingly high at over 18%. The mortality rate in the previous published study using UFH [4] was nil at 3 months though of course the number of patients treated was very small. There were a higher number of patients in the UFH group with deep drainage CSVT and lower GCS scores both of which, as previously mentioned, are associated with poorer prognosis. It is, therefore, quite feasible that the treatment effect of LMWH in the current study is overestimated. The authors did not carry out follow-up scans to determine whether adverse outcome in the UFH group related to the original haemorrhagic infarction, further propagation of thrombus or development of new ICH on treatment. Anticoagulation was sub-optimal for a significant period in the UFH group which is likely to have adversely influenced outcome. Despite these criticisms, the paper by Misra adds to the few RCTs of anticoagulation use in CVST and shows some partial evidence to support the preferential use of LMWH in the acute phase of the disease. The patient numbers are, low and a larger comparative trial as suggested by the authors appears warranted. There remain a number of unresolved issues in the management of CVST. A significant minority of patients will