Neurology April 2009 Volume 72 Issue 17

Background: Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection that develops in immunosuppressed patients with HIV infection. Paradoxically, some of these patients may develop PML during combined antiretroviral therapy in the setting of immune reconstitution. We describe the types of PML in relation to immune reconstitution inflammatory syndrome (IRIS) and the effects of steroid use in these patients.Methods: We performed a retrospective review of the literature (1998 to 2007) and of all HIV-infected patients diagnosed with PML-IRIS at Johns Hopkins Hospital (2004 to 2007). We recorded information on clinical features, microbiologic and virological analysis, neuroimaging, pathology, treatment, and outcome.Results: Of 54 patients with PML-IRIS, 36 developed PML and IRIS simultaneously (PML-s-IRIS) and 18 had worsening of preexisting PML (PML-d-IRIS) after the initiation of combined antiretroviral therapy. PML-IRIS developed between 1 week and 26 months after initiation of antiretroviral therapy. PML-d-IRIS patients developed IRIS earlier, had higher lesion loads on MRI of the brain, had shorter durations of survival, and had higher mortality rate compared to PML-s-IRIS patients. Twelve patients received treatment with steroids, of which five died and seven showed good neurologic recovery. Patients who survived had received steroids early after IRIS diagnosis for longer durations and had contrast enhancement on IRIS neuroimaging.Conclusions: Immune reconstitution following initiation of combined antiretroviral therapy may lead to activation of an inflammatory response to detectable or latent JC virus infection. Early and prolonged treatment with steroids may be useful in these patients but requires further investigation.(C)2009AAN Enterprises, Inc.

Background: Diabetic neuropathy is a common complication in diabetes, with patients typically experiencing diverse sensory symptoms including dysesthesias in the feet and usually accompanied by sleep disturbance. There is still no comprehensive understanding of the underlying biologic processes responsible for diabetic neuropathic pain. Thus, the current symptomatic therapy remains unsatisfactory. Recent experimental evidence suggests that botulinum toxin type A (BoNT/A) may not only inhibit the release of acetylcholine at the neuromuscular junctions, but also modulate afferent sensory fiber firing, thereby relieving neuropathic pain.Methods: A double-blind crossover trial of intradermal BoNT/A for diabetic neuropathic pain in 18 patients was conducted to evaluate the effectiveness.Results: We find significant reduction in visual analog scale (VAS) of pain by 0.83 +/- 1.11 at 1 week, 2.22 +/- 2.24 at 4 weeks, 2.33 +/- 2.56 at 8 weeks, and 2.53 +/- 2.48 at 12 weeks after injection in the BoNT/A group, as compared to the respective findings for a placebo group of 0.39 +/- 1.18, -0.11 +/- 2.04, 0.42 +/- 1.62, and 0.53 +/- 1.57 at the same timepoints (p < 0.05). Within the BoNT/A group, 44.4% of the participants experienced a reduction of VAS >=3 within 3 months after injection, whereas there was no similar response in the placebo group. At the 4-week postinjection stage, improvement in sleep quality was measured using the Chinese version of the Pittsburgh Sleep Quality Index.Conclusions: This pilot study found that botulinum toxin type A significantly reduced diabetic neuropathic pain and transiently improved sleep quality. Further large-scaled study is warranted.(C)2009AAN Enterprises, Inc.

Objective: To examine the influence of the APOE genotype on levels of [beta]-amyloid (A[beta]) plaque load and atrophy in patients with Alzheimer disease (AD) in vivo.Methods: Thirty-two patients with moderate AD were divided into carriers and noncarriers of the [varepsilon]4 allele. These groups were matched for age, disease duration, education, and cognitive impairment. In all subjects, [11C]PIB-PET was performed for measurement of cerebral A[beta] plaque deposition and cranial MRI for the assessment of gray matter volume by voxel-based morphometry (VBM) and for correction of partial volume effects (PVE) in the PET data. Voxel-based comparisons (SPM5) were performed between patient groups and healthy control populations and completed with multiple regression analyses between imaging data and [varepsilon]4 allele frequency.Results: Compared to controls, AD-typical patterns of [11C]PIB retention and atrophy were detected in both [varepsilon]4-positive and [varepsilon]4-negative patient groups. In direct comparison, significantly stronger and more extended [11C]PIB uptake was found in [varepsilon]4-positive patients in bilateral temporoparietal and frontal cortex, surviving PVE correction. VBM analysis demonstrated comparable levels of atrophy in both patient groups. Regression analyses revealed a linear association between higher [varepsilon]4 allele frequency and stronger temporoparietal A[beta] plaque deposition, independently of other confounds. No major correlation between [varepsilon]4 allele frequency and gray matter decrease was observed.Conclusion: These results indicate that the [varepsilon]4-positive APOE genotype not only represents a risk factor for Alzheimer disease (AD), but also results in higher levels of A[beta] plaque deposition in [varepsilon]4-positive patients with AD compared to age-matched [varepsilon]4-negative patients with similar levels of cognitive impairment and brain atrophy. The potential role of A[beta] plaque imaging for patient inclusion and follow-up in anti-amyloid therapy trials is strengthened by these findings.(C)2009AAN Enterprises, Inc.

Objective: To study the relationship between gray matter atrophy and amyloid deposition in Alzheimer disease (AD).Methods: Volumetric magnetic resonance (MR) and [11C]-PIB PET were acquired from 23 patients with AD and 17 healthy older persons. Standardized [11C]-PIB uptake values were coregistered to MR scans in a standard space. Decreased density of and increased [11C]-PIB uptake in the gray matter of patients with AD vs controls were assessed with both voxel-based (p < 0.05 corrected) and region-of-interest (ROI) analyses. The relationship between decreased density of and increased [11C]-PIB uptake in the gray matter was investigated with voxel-based Pearson r maps (thresholded at p < 0.05) and ROI linear regression plots.Results: Atrophy mapped to the hippocampus and increased [11C]-PIB uptake to large frontal, parietal, and posterior cingulate cortical areas. ROI analysis showed the largest effect size for atrophy in the hippocampus (2.01) and amygdala (1.27) and the highest effect size for [11C]-PIB uptake in frontal (2.66), posterior cingulate/retrosplenial (2.43), insular (2.41), and temporal (2.23) regions. In the hippocampus, [11C]-PIB uptake was significantly increased, but effect size was milder (1.72). Significant correlations between atrophy and increased [11C]-PIB uptake were found in the hippocampal (r = -0.54) and amygdalar ROIs (r = -0.40) but not in the frontal, temporal, posterior cingulate/retrosplenial, insular, and caudate ROIs (r between 0.04 and 0.25).Conclusion: The medial temporal lobe might be highly susceptible to amyloid toxicity, whereas neocortical areas might be more resilient.(C)2009AAN Enterprises, Inc.

Objective: To investigate the combined ability of hippocampal volumes, 1H magnetic resonance spectroscopy (MRS) metabolites, and cerebrovascular disease to predict the risk of progression to dementia in mild cognitive impairment (MCI).Methods: We identified 151 consecutively recruited subjects with MCI from the Mayo Clinic Alzheimer's Disease Research Center and Patient Registry who underwent MRI and 1H MRS studies at baseline and were followed up with approximately annual clinical examinations. A multivariable proportional hazards model that considered all imaging predictors simultaneously was used to determine whether hippocampal volumes, posterior cingulate gyrus 1H MRS metabolites, white matter hyperintensity load, and presence of cortical and subcortical infarctions are complementary in predicting the risk of progression from MCI to dementia.Results: Seventy-five subjects with MCI progressed to dementia by last follow-up. The model that best predicted progression to dementia included age, sex, hippocampal volumes, N-acetylaspartate (NAA)/creatine (Cr) on 1H MRS, and cortical infarctions. Based on age- and sex-adjusted Kaplan-Meier plots, we estimated that by 3 years, 26% of the MCI patients with normal hippocampal volumes, NAA/Cr ratios >1 SD, and no cortical infarctions will progress to dementia, compared with 78% of the MCI patients with hippocampal atrophy, low NAA/Cr (<=1 SD), and cortical infarction.Conclusions: Multiple magnetic resonance (MR) markers of underlying dementia pathologies improve the ability to identify patients with prodromal dementia over a single MR marker, supporting the concept that individuals with multiple brain pathologies have increased odds of dementia compared with individuals with a single pathology.(C)2009AAN Enterprises, Inc.