Jeremy Chataway

Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives.

Progressive multiple sclerosis is characterised clinically by the gradual accrual of disability independent of relapses and can occur with disease onset (primary progressive) or can be preceded by a relapsing disease course (secondary progressive). An effective disease-modifying treatment for progressive multiple sclerosis has not yet been identified, and so far the results of clinical trials have generally been disappointing. Ongoing advances in the knowledge of pathogenesis, in the identification of novel targets for neuroprotection, and in improved outcome measures could lead to effective treatments for progressive multiple sclerosis. In this Series paper, we summarise the lessons learned from completed clinical trials and perspectives from trials in progress in progressive multiple sclerosis. We review promising clinical, imaging, and biological markers, along with novel designs, for clinical trials. The use of more refined outcomes and truly neuroprotective drugs, coupled with more efficient trial design, has the capacity to deliver a new era of therapeutic discovery in this challenging area.

A practical approach to diagnosing adult onset leukodystrophies

The term leukodystrophy refers to a group of conditions that are inherited and involve the progressive destruction or loss of previously acquired myelin.1 The most commonly reported of these disorders have a metabolic origin and are associated with abnormalities on specialist biochemical testing. Recently, a number of conditions caused by genes coding for proteins not directly involved in metabolic pathways and for which the diagnosis relies directly on gene analysis have also been described. In clinical practice, distinguishing ‘classical’ inherited leukodystrophies from other causes of white matter disease, including vascular and inflammatory disorders, may not always be straightforward.nnAlthough individually rare, with no single condition having a prevalence of >1 in 20u2005000, the reported prevalence of adult onset leukodystrophies is rising. This is likely to be related to the increased use of brain MRI and new genetic insights. Collectively their incidence may rival that of multiple sclerosis (MS).2 Nonetheless, the rarity of each condition and the wide differential means that diagnosis can be challenging and most clinicians will lack experience in the area. Currently, a significant proportion of individuals may remain without a precise diagnosis despite intensive investigations.nnMuch has been written in the paediatric literature about leukodystrophies,3 but the adult neurologist, with a new case, is often left with an extensive and detailed table of rare disorders to consider, without an obvious diagnostic pathway to follow. In addition, leukodystrophies that classically present in infancy or childhood may have a very different or attenuated clinical presentation in adulthood, making diagnostic features less familiar. In this review, taking a clinical case as a starting point, we address: nnTablexa01 summarises the most …

Testing for urinary tract colonization before high-dose corticosteroid treatment in acute multiple sclerosis relapses: prospective algorithm validation.

To evaluate a dipstick algorithm for urinary tract colonization, prior to high‐dose corticosteroid treatment in acute relapses of multiple sclerosis (MS).

Hereditary leukoencephalopathy with axonal spheroids: a spectrum of phenotypes from CNS vasculitis to parkinsonism in an adult onset leukodystrophy series

Background Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) is a hereditary, adult onset leukodystrophy which is characterised by the presence of axonal loss, axonal spheroids and variably present pigmented macrophages on pathological examination. It most frequently presents in adulthood with dementia and personality change. HDLS has recently been found to be caused by mutations in the colony stimulating factor-1 receptor (CSF1R) gene. Methods In this study, we sequenced the CSF1R gene in a cohort of 48 patients from the UK, Greece and Ireland with adult onset leukodystrophy of unknown cause. Results Five pathogenic mutations were found, including three novel mutations. The presentations ranged from suspected central nervous system (CNS) vasculitis to extrapyramidal to cognitive phenotypes. The case histories and imaging are presented here, in addition to neuropathological findings from two cases with novel mutations. Conclusion We estimate that CSF1R mutations account for 10% of idiopathic adult onset leukodystrophies and that genetic testing for CSF1R mutations is essential in adult patients presenting with undefined CNS vasculitis or a leukodystrophy with prominent neuropsychiatric signs or dementia.

The corpus callosum in the diagnosis of multiple sclerosis and other CNS demyelinating and inflammatory diseases

Lesions in the corpus callosum (CC) are important radiological clues to the diagnosis of multiple sclerosis (MS), but may also occur in other neuroinflammatory and non-neuroinflammatory conditions. In this article, we discuss the radiological features of lesions within the CC in MS and other central nervous system inflammatory and acquired demyelinating diseases. An understanding of the appearance and location of lesions in the CC is important not only for accurate diagnosis and treatment of these various conditions, but as it also provides insights into pathogenesis.

Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial

Summary Background In the 24-month MS-STAT phase 2 trial, we showed that high-dose simvastatin significantly reduced the annualised rate of whole brain atrophy in patients with secondary progressive multiple sclerosis (SPMS). We now describe the results of the MS-STAT cognitive substudy, in which we investigated the treatment effect on cognitive, neuropsychiatric, and health-related quality-of-life (HRQoL) outcome measures. Methods We did a secondary analysis of MS-STAT, a 24-month, double-blind, controlled trial of patients with SPMS done at three neuroscience centres in the UK between Jan 28, 2008, and Nov 4, 2011. Patients were randomly assigned (1:1) to either 80 mg simvastatin (n=70) or placebo (n=70). The cognitive assessments done were the National Adult Reading Test, Wechsler Abbreviated Scale of Intelligence, Graded Naming Test, Birt Memory and Information Processing Battery (BMIPB), Visual Object and Space Perception battery (cube analysis), Frontal Assessment Battery (FAB), and Paced Auditory Serial Addition Test. Neuropsychiatric status was assessed using the Hamilton Depression Rating Scale and the Neuropsychiatric Inventory Questionnaire. HRQoL was assessed using the self-reported 36-Item Short Form Survey (SF-36) version 2. Assessments were done at study entry, 12 months, and 24 months. Patients, treating physicians, and outcome assessors were masked to treatment allocation. Analyses were by intention to treat. MS-STAT is registered with ClinicalTrials.gov, number NCT00647348. Findings Baseline assessment revealed impairments in 60 (45%) of 133 patients on the test of frontal lobe function (FAB), and in between 13 (10%) and 43 (33%) of 130 patients in tests of non-verbal and verbal memory (BMIPB). Over the entire trial, we noted significant worsening on tests of verbal memory (T score decline of 5·7 points, 95% CI 3·6–7·8; p<0·0001) and non-verbal memory (decline of 6·8 points, 4·8–8·7; p<0·0001). At 24 months, the FAB score was 1·2 points higher in the simvastatin-treated group than in the placebo group (95% CI 0·2–2·3). The simvastatin group also had a 2·5 points better mean physical component score of the SF-36 (95% CI 0·3–4·8; p=0·028). A treatment effect was not noted for any other outcomes. Interpretation To our knowledge, this SPMS cohort is the largest studied to date with comprehensive longitudinal cognitive, neuropsychiatric, and HRQoL assessments. We found evidence of a positive effect of simvastatin on frontal lobe function and a physical quality-of-life measure. Although we found no effect of simvastatin on the other outcome measures, these potential effects warrant confirmation and underline the importance of fully assessing cognition and quality of life in progressive multiple sclerosis treatment trials. Funding The Moulton Foundation, the Berkeley Foundation, the Multiple Sclerosis Trials Collaboration, the Rosetrees Trust, a personal contribution from A W Pidgley CBE, and the National Institute for Health Research University College London Hospitals Biomedical Research Centre and University College London.

Clinical and genetic characterization of leukoencephalopathies in adults

Leukoencephalopathies are a diverse group of white matter disorders that can be difficult to diagnose. Using focused and whole-exome sequencing, Lynch et al. expand the known clinical and mutational spectrum of genetic leukoencephalopathy in adulthood, and describe the frequency and clinical and radiological phenotype of the most commonly mutated genes.

Urinary tract infections in multiple sclerosis

Background: Urinary tract infections (UTIs) are commonly reported by people with multiple sclerosis (PwMS) and significantly impact quality of life. Objective: To provide an overview of the problem of UTIs in PwMS and offer a practical approach for the diagnosis and management. Methods: A review of the literature through a Pubmed search up to October 2015 was performed using the following keywords: multiple sclerosis, neurogenic bladder, urinary tract infections, relapse, dipsticks, culture, recurrent and prevention. Results: Noteworthy topics include the definition of a confirmed symptomatic UTI as a positive urine culture defined by >105 colony-forming units (CFU)/mL or >104u2009CFU/mL if a urethral catheter urine sample is taken, or any count of bacteria in a suprapubic bladder puncture specimen, both in addition to symptoms including fever, pain, changes in lower urinary tract symptoms or neurological status. Urinalysis is useful to exclude a UTI; however, on its own is insufficient to confirm a UTI, for which urine culture is required. Experts advise asymptomatic UTIs should not be treated except in the context of an acute relapse. From international guidelines, there is no validated strategy to prevent recurrent UTIs in PwMS. Conclusion: This review provides an overview of the diagnosis, treatment and prevention of UTIs in the setting of multiple sclerosis (MS).

The successful long-term management of an intracranial inflammatory myofibroblastic tumor with corticosteroids.

Inflammatory myofibroblastic tumors (IMFTs) are a clinically nd histologically heterogeneous group of inflammatory lesions of nknown aetiology, which are most commonly described in the ungs, but have been described in most organs including: ovary, ancreas, liver, stomach, kidney, bladder, thyroid, orbit, breast, and entral nervous system [1–3]. Intracranially located lesions are often diagnosed at biopsy of n unspecified intracranial mass or suspected meningioma [2,4]. hey are typified by an inflammatory infiltrate with fibrous tissue nd abundant polyclonal plasma cells [1,4]. Due to the low incience of disease and difficulty with nomenclature the number of revious intracranial cases has probably been underestimated [1]. f the cases reported in the literature the most common treatent has been debulking surgery with or without radiotherapy, lthough anti-metabolites and both “bolus” and long-term steroids ave been tried with varying degrees of success [2,4,5]. However, he incidence of the disease is so low, and the pathology so varied, hat there is no bank of evidence to develop an optimum treatment trategy appropriate for the histopathological appearance of the esion. Here we describe the successful long-term treatment of an ntracranial IMFT with corticosteroids alone, and refer to the availble literature to justify this method as an alternative treatment ption in cases where surgery is high-risk or impossible.

Inadequate outcome measures are the biggest impediment to successful clinical trials in progressive MS - YES.

The closer progressive multiple sclerosis (MS) is approached, the more awkward it is to define and the more slippery it is to measure. Of course on one level it is easy – if 5 years previously a person affected by MS can walk or see or balance normally, but now they walk with a stick or have a visual acuity of 6/60 or are falling over, then it is clear (to anyone) that progression has occurred, whichever yardstick is used. No, the problem is that progression is (generally) slow, it is multi-dimensional and the time frequency of such very hard clinical end points is too low to be of value in the 2to 3-year life span of trials in progressive MS.