Faculty Bibliography

OBJECTIVE: To report the relationship between disease activity and health-related quality of life (HRQoL) in relapsing multiple sclerosis, and the impact of natalizumab. METHODS: HRQoL data were available from 2,113 multiple sclerosis patients in natalizumab clinical studies. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) study, patients received natalizumab 300 mg (n = 627) or placebo (n = 315); in the Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) study, patients received interferon beta-1a (IFN-beta-1a) plus natalizumab 300 mg (n = 589), or IFN-beta-1a plus placebo (n = 582). The Short Form-36 (SF-36) and a subject global assessment visual analog scale were administered at baseline and weeks 24, 52, and 104. Prespecified analyses included changes from baseline to week 104 in SF-36 and visual analog scale scores. Odds ratios for clinically meaningful improvement or worsening on the SF-36 Physical Component Summary (PCS) and Mental Component Summary were calculated. RESULTS: Mean baseline SF-36 scores were significantly less than the general US population and correlated with Expanded Disability Status Scale scores, sustained disability progression, relapse number, and increased volume of brain magnetic resonance imaging lesions. Natalizumab significantly improved SF-36 PCS and Mental Component Summary scores at week 104 in AFFIRM. PCS changes were significantly improved by week 24 and at all subsequent time points. Natalizumab-treated patients in both studies were more likely to experience clinically important improvement and less likely to experience clinically important deterioration on the SF-36 PCS. The visual analog scale also showed significantly improved HRQoL with natalizumab. INTERPRETATION: HRQoL was impaired in relapsing multiple sclerosis patients, correlated with severity of disease as measured by neurological ratings or magnetic resonance imaging, and improved significantly with natalizumab.

Type II errors may be having a significant impact on drug discovery. This is of particular importance in the clinical neurosciences, where endpoints are often subjective scores of disability rather than unequivocal events such as survival. Here we examine a recently published study [Lang AE, Gill S, Patel NK, et al. Randomized controlled study of intraputamenal glial cell-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol 2006;59:459-66] in an area of immense importance to neuroscience. This small study found no detectable clinical benefit from infused intraputamenal GDNF as a treatment for Parkinson disease. However the standard deviation of the accrued data turned out to be considerably higher than had been anticipated in the power analysis performed prior to the study. In order to determine what impact, if any, this had on the conclusions that could be drawn, the actual data were analyzed by means of both the t-test and the rank-based Somers'D. The study was found to be underpowered and thus incapable of ruling out a large effect of GDNF on Parkinson disease. It therefore does not contradict the large effects seen in previous open-label studies

OBJECTIVE: To examine the effects of natalizumab on low-contrast letter acuity as a prespecified tertiary endpoint in two randomized clinical trials and to evaluate the usefulness of low-contrast letter acuity testing as a candidate test of visual function in multiple sclerosis (MS). METHODS: AFFIRM and SENTINEL were randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trials of natalizumab in relapsing MS. Natalizumab was evaluated as monotherapy in AFFIRM and as add-on to interferon beta-1a in SENTINEL. Vision testing was performed at 100% contrast (visual acuity) and low-contrast (2.5% and 1.25%). RESULTS: The risk of clinically significant visual loss (predefined as a two-line worsening of acuity sustained over 12 weeks) at the lowest contrast level (1.25%) was reduced in the natalizumab treatment arms by 35% in AFFIRM (hazard ratio = 0.65; 95% CI: 0.47 to 0.90; p = 0.008) and by 28% in SENTINEL (hazard ratio = 0.72; 95% CI: 0.54 to 0.98; p = 0.038, Cox proportional hazards models). Mean changes in vision scores from baseline were also significantly different, reflecting worsening in non-natalizumab groups. CONCLUSIONS: Natalizumab reduces visual loss in patients with relapsing multiple sclerosis. Low-contrast acuity testing has the capacity to demonstrate treatment effects and is a strong candidate for assessment of visual outcomes in future multiple sclerosis trials.

Image data fusion has been developed over the last decade as an important additional visual diagnostic tool to integrate the growing amount of imaging data obtained from different medical imaging modalities. The overwhelming amount of digital information calls for data consolidation to improve clinical treatment strategies based upon anatomical and physiological imaging. Three different low level image data fusion techniques are described and their characteristics are illustrated with some rare yet key examples. We used MR images to show neurodegeneration in the cerebral peduncle of the midbrain and found that image data fusion using colors can be a valuable tool to visually assess and quantify the loss of neural cells in the Substantia Nigra pars compacta in Parkinson's disease

Refractory status epilepticus (SE) is a condition of continuous seizure activity in which there is a regular, rapid, succession of spike discharges in the brain. It is incompatible with normal consciousness and is associated with an extremely high morbidity and mortality. Prior to 1990, prevailing opinion held that a brief period of anesthesia (up to two weeks) was to be recommended, but that if SE persisted this was a sign of irreversible brain damage. Therefore support of the patient in SE was not recommended beyond two weeks. On the basis of the theoretical constructs of chaos theory we hypothesized that, for selected cases, anesthesia should be continued indefinitely until the SE resolved. This became the standard of care at the University of Washington and at other institutions. After several years, the accumulating evidence lends support for this hypothesis and we are now able to propose which patients will benefit from such therapy. It is hypothesized that only those patients for whom there is no underlying brain disease, beyond epilepsy, are likely to benefit. Secondly, chaos theory suggests that a strong perturbation will cause a rapid transition from the stable attractor of SE to the stable attractor representing normal consciousness. In certain ways, SE is analogous to ventricular tachycardia, where the cardiac muscle has an abnormally fast rhythm incompatible with proper cardiac function. Therefore the second hypothesis is that a brain perturbation, analogous to defibrillation, may be even more useful than anesthesia in refractory SE

RATIONALE AND OBJECTIVES: Segmented inversion recovery (IR) ratio imaging (SIRRIM) has been established as a sensitive tool to assess neurodegeneration of the substantia nigra pars compacta (SN(C)) in patients with idiopathic Parkinson disease (IPD). The obtained results suggest the possibility of magnetic resonance imaging (MRI) as a biological marker for IPD. The strength and a parsimonious analysis of the technique are discussed to assess the potential of using MRI as a biological marker for IPD and improve the differential diagnosis of sporadic Parkinson disease. Our hypothesis states that the magnetic resonance SIRRIM technique allows direct visualization and quantitation of neural cell loss in the SN(C) and therefore could become a reliable biological marker for Parkinson disease. To achieve this goal, some key aspects of data acquisition and data analysis need to be addressed. The clinical impact of the SIRRIM technique could be considerable, considering that it might become a viable surrogate to other techniques. PATIENTS AND METHODS: Twelve patients with IPD and 12 age-matched control subjects were imaged by using the SIRRIM technique based on two IR imaging sequences that were designed to suppress white and gray matter to assess loss of neural cells in situ by means of a ratio image (white matter suppressed image to gray matter suppressed image). The radiological index was correlated with the Unified Parkinson Disease Rating Scale (UPDRS) for patients with IPD. RESULTS: All patients with IPD were identified correctly, and full dichotomization between healthy volunteers and patients was obtained with our database. Our SIRRIM technique shows that it can be used to rule out Parkinson disease from essential tremor and other forms of Parkinsonism, such as progressive supranuclear palsy and multisystem atrophy. In addition, it is sensitive enough to identify patients with early-stage IPD. CONCLUSION: The hypothesis of using SIRRIM as a biological marker to assess IPD is supported by excellent correlation with clinical UPDRS scoring and has proved useful for the evaluation and quantitation of neurodegeneration with our SIRRIM technique, showing, in addition, that the differential diagnosis of IPD can be improved. Technical aspects of acquisition and data processing that need to be addressed can be overcome. It ultimately confirms that our objectives can be achieved and allows us to expect assessment of the progressive development of neurodegeneration in longitudinal studies and the putative neuroprotective approaches taken during the evolution of the disease

Common diseases tend to appear sporadically, i.e., they appear in an individual who has no first or second degree relatives with the disease. Yet diseases are often associated with a slight but definite increase in risk to the children of an affected individual. This weak pattern of inheritability cannot be explained by conventional interpretations of Mendelian genetics, and it is therefore commonly held that there is 'incomplete penetrance' of a gene, or that there are polygenic, or multifactorial modes of inheritance. However, such arguments are heuristic and lack predictive power. Here, we explore the possibility that 'incomplete penetrance' means the existence of a second, disease-related, gene. By examining in detail a specific common condition, Parkinson's disease (PD), we show that the sporadic form of the disease can be fully explained by a compact fully penetrant genotype involving an interaction between two, and only two, genes. In this model, therefore PD is fundamentally genetic. Our digenic model is complementary to Mendelian recessive genetics, but taken together with the latter forms a complete description for recessive genetics on one chromosome. It explains the slight increase in risk to the children if one parent has sporadic PD, and makes strict predictions where both parents coincidentally have sporadic PD. These predictions were verified in two large and carefully selected kindred, where the data also argue against other genetic models, including oligogenic and polygenic schemes. Since the inheritance patterns of sporadic PD are reminiscent of what is seen in many common diseases, it is plausible that similar genetic forms could apply to other diseases. Seen in this light, diseases wash in and out of every family, so that in a sense, over time every human family is equally at risk for most diseases

The two commonest, clinically well-defined, forms of parkinsonism are idiopathic Parkinson's disease (PD) and progressive supranuclear palsy (PSP). Both involve, inter alia, pathological changes in the substantia nigra pars compacta (SN(C)). In PD there is neuronal loss with associated Lewy body pathology and microglial activation. Three morphological features have been identified [Brain 114 (1991), 2283; Greenfield's Neuropathology 2 (1997), 289]. First, there is a gradient of pathological change such that the lateral segments are more affected than the medial. Second, there is thinning of the pigmented tissue, and third, there is a broadening of the overall structure in a dorsal-ventral direction, possibly caused by the migration of melanin-laden macrophages [Greenfield's Neuropathology 2 (1997), 289]. In contrast, PSP is characterized pathologically by intraneuronal neurofibrillary tangles. There are two morphological features in the SN(C) [Brain 114 (1991), 2283]. First, the gradient of pathological change is in the opposite direction to that of PD (i.e., the medial segments are more affected than the lateral). Second, there is atrophy. Any technique sensitive to neuropathology should be capable of detecting these features. We have previously reported on a new approach to detecting signal change in the substantia nigra in PD. This makes use of a ratio of images acquired by two distinct inversion recovery sequences [J. Neurol, Neurosurg. Psychiatry 67 (1999), 815; Am. J. Neuroradiol. 21 (2000) 697]. The prior work suggests that the technique is sensitive to, but not necessarily specific for, PD. We present here a preliminary report on an extension of the work. This is a semiautomated segmentation analysis that enables the substantia nigra to be displayed as an isolated structure. The technique is now given the acronym SIRRIM (segmented inversion recovery ratio imaging). In contrast to our earlier work, it allows for a more accurate assessment of the gross abnormalities. We report typical SIRRIM images of the SN(C). Images are shown for three subjects: a normal control, a patient with PD, and a 'disease control' (a patient with PSP). In these examples all three morphological features of PD, as well as both morphological features of PSP, have radiological correlates. These preliminary findings suggest that SIRRIM may be specific for both diseases