Faculty Bibliography

The AFFIRM and SENTINEL studies showed that natalizumab was effective both as monotherapy and in combination with interferon beta (IFNbeta)-1a in patients with relapsing multiple sclerosis (MS). Further analyses of AFFIRM and SENTINEL data were conducted to determine the efficacy of natalizumab in prespecified patient subgroups according to baseline characteristics: relapse history 1 year before randomization (1, 2, > or = 3), Expanded Disability Status Scale score (< or = 3.5, > 3.5), number of T2 lesions (< 9, > or = 9), presence of gadolinium-enhancing (Gd+) lesions (0, > or = 1), age (< 40, > or = 40) and gender (male, female). A post hoc analysis was conducted to determine the efficacy of natalizumab in patients with highly active disease (i. e., > or = 2 relapses in the year before study entry and > or = 1 Gd+ lesion at study entry). In both AFFIRM and SENTINEL studies natalizumab reduced the annualized relapse rates across all subgroups (except the small subgroups with < 9 baseline T2 lesions) over 2 years. In AFFIRM, natalizumab significantly reduced the risk of sustained disability progression in most subgroups. In SENTINEL, natalizumab significantly reduced the risk of sustained disability progression in the following subgroups: > or = 9 T2 lesions at baseline, > or = 1 Gd+ lesions at baseline, female patients and patients < 40 years of age. Natalizumab reduced the risk of disability progression by 64 % and relapse rate by 81 % in treatment- naive patients with highly active disease and by 58 % and 76 %, respectively, in patients with highly active disease despite IFNbeta-1a treatment. These results indicate that natalizumab is effective in reducing disability progression and relapses in patients with relapsing MS, particularly in patients with highly active disease.

BACKGROUND: The efficacy of natalizumab on clinical and radiological measures in the phase III Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study has prompted the investigation of whether natalizumab can increase the proportion of patients with relapsing-remitting multiple sclerosis who do not have disease activity. METHODS: Post-hoc analyses of data from the AFFIRM study were done to determine the effects of natalizumab compared with placebo on the proportion of patients who were free of disease activity over 2 years. Absence of disease activity was defined as no activity on clinical measures (no relapses and no sustained disability progression), radiological measures (no gadolinium-enhancing lesions and no new or enlarging T2-hyperintense lesions on cranial MRI), or a composite of the two. FINDINGS: 383 (64%) of 596 patients taking natalizumab and 117 (39%) of 301 taking placebo were free of clinical disease activity (absolute difference 25.4%, 95% CI 18.7-32.1%, p<0.0001); 342 (58%) of 593 and 42 (14%) of 296 were free of radiological disease activity (43.5%, 37.9-49.1%, p<0.0001); and 220 (37%) of 600 and 22 (7%) of 304 were free of combined activity (29.5%, 24.7-34.3%, p<0.0001) over 2 years. The effect of natalizumab versus placebo was consistent across subgroups of patients with highly active or non-highly active disease at baseline. INTERPRETATION: Disease remission might become an increasingly attainable goal in multiple sclerosis treatment with the use of newer, more effective therapies.

For several years, some sectors of the specialty of Radiology have complained about the practice of self-referral, where a nonradiologist physician provides and interprets an imaging procedure. It is argued that such practice leads to increased costs since a physician will overutilize technology because of financial incentives. Here we review the literature. The most extensive analysis to date is at odds with the conclusions drawn in the older literature in that it provides little, if any, evidence for overutilization. We performed our own investigation using a poll study and found no suggestion of overutilization in 33 self-referring neurologists when compared with 900 neurologists who referred imaging to radiologists. The main period of growth in demand for imaging was between 1999 and 2002. Since 2002 there has been a steep decline in the rate of growth, so that it is possible to predict roughly zero growth in MRI utilization by 2009 without any intervention. It is shown why the rise in demand for imaging studies cannot be explained by self-referral, and it is argued that the sudden expansion of demand 8 years ago was caused by simultaneous technological improvements in the 3 major imaging modalities. Finally, it is shown how self-referral may actually reduce costs by facilitating the transfer of care from the hospital and ER to the office

This chapter is a review of neuroimaging techniques for detecting and analyzing movement disorders. It is not intended to be an exhaustive review. The intent is rather to emphasize not merely how imaging plays a role in diagnosis, but how it has changed the way we look at movement disorders, with emphasis on its ability to illuminate the causes, from networks to genetics. Recent developments in PET, MRI, and ultrasound are described as they are applied to Parkinson disease, progressive supranuclear palsy, Huntington disease, essential blepharospasm, and torsion dystonia. This chapter will show how imaging has confirmed an old conjecture as to the etiology of dystonia. Finally, this chapter will discuss how MRI can replace brain biopsy and spinal fluid assays as a way of diagnosing Creutzfeldt-Jakob disease.

BACKGROUND AND OBJECTIVES: Diagnosis of multiple sclerosis (MS) requires exclusion of diseases that could better explain the clinical and paraclinical findings. A systematic process for exclusion of alternative diagnoses has not been defined. An International Panel of MS experts developed consensus perspectives on MS differential diagnosis. METHODS: Using available literature and consensus, we developed guidelines for MS differential diagnosis, focusing on exclusion of potential MS mimics, diagnosis of common initial isolated clinical syndromes, and differentiating between MS and non-MS idiopathic inflammatory demyelinating diseases. RESULTS: We present recommendations for 1) clinical and paraclinical red flags suggesting alternative diagnoses to MS; 2) more precise definition of "clinically isolated syndromes" (CIS), often the first presentations of MS or its alternatives; 3) algorithms for diagnosis of three common CISs related to MS in the optic nerves, brainstem, and spinal cord; and 4) a classification scheme and diagnosis criteria for idiopathic inflammatory demyelinating disorders of the central nervous system. CONCLUSIONS: Differential diagnosis leading to MS or alternatives is complex and a strong evidence base is lacking. Consensus-determined guidelines provide a practical path for diagnosis and will be useful for the non-MS specialist neurologist. Recommendations are made for future research to validate and support these guidelines. Guidance on the differential diagnosis process when MS is under consideration will enhance diagnostic accuracy and precision.

We have developed an advanced MRI technique for detecting Parkinson's Disease (PD) which depends on an image constructed as a ratio of images from two inversion recovery sequences (one generating a white matter suppressed image, the other a gray matter suppressed image). This technique was designed to be exceptionally sensitive to the spin-lattice relaxation time T(1). It was refined with the introduction of segmentation analysis and given the acronym SIRRIM (Segmented Inversion Recovery Ratio Imaging). Our objectives are, first, to reinvestigate the sensitivity of MRI with new subjects and second, to investigate whether a new form of analysis, using the gray level distribution of signal in the image, may prove more sensitive than SIRRIM. For each subject, a ratio image was constructed (WMS/GMS) and the substantia nigra segmented out to be displayed as an isolated structure. From the segmented image a measure of disease severity, the Radiological Index (RI), was calculated for each subject. Since the pixel value in the ratio image is a strong function of the local T(1) relaxation time, the distribution of pixel values gives the distribution of spin-lattice relaxation times. A refinement in the analysis is introduced, the Spin-Lattice Distribution Index (SI), which is an automated measure of MRI signal in the Substantia Nigra pars compacta (SN(C)). Both RI and SI were calculated for each of 24 subjects, 12 patients and 12 controls. The SI may further improve the separation of patient and control groups, and may therefore be more sensitive than the RI. Unlike the RI it is completely automatic and circumvents two of the limitations of the RI. The work is consistent with the proposition that MRI, when properly configured, is a highly sensitive marker for PD

OBJECTIVE: To determine the incidence and clinical effects of antibodies that develop during treatment with natalizumab. METHODS: In two randomized, double-blind, placebo-controlled studies (natalizumab safety and efficacy in relapsing remitting multiple sclerosis [MS, AFFIRM] and safety and efficacy of natalizumab in combination with interferon beta-1a [INF beta]1a] in patients with relapsing remitting MS [SENTINEL]) of patients with relapsing multiple sclerosis, blood samples were obtained at baseline and every 12 weeks to determine the presence of antibodies against natalizumab. Antibodies to natalizumab were measured using an ELISA. Patients were categorized as "transiently positive" if they had detectable antibodies (>or=0.5 microg/mL) at a single time point or "persistently positive" if they had antibodies at two or more time points >or=6 weeks apart. RESULTS: In the AFFIRM study, antibodies were detected in 57 of 625 (9%) of natalizumab-treated patients: Twenty (3%) were transiently positive and 37 (6%) were persistently positive. Persistently positive patients showed a loss of clinical efficacy as measured by disability progression (p

PMID: 17761550

ISSN: 0028-3878

CID: 174777