Showing papers in "Neurology in 2011"

Classification of primary progressive aphasia and its variants

Abstract: This article provides a classification of primary progressive aphasia (PPA) and its 3 main variants to improve the uniformity of case reporting and the reliability of research results. Criteria for the 3 variants of PPA—nonfluent/agrammatic, semantic, and logopenic—were developed by an international group of PPA investigators who convened on 3 occasions to operationalize earlier published clinical descriptions for PPA subtypes. Patients are first diagnosed with PPA and are then divided into clinical variants based on specific speech and language features characteristic of each subtype. Classification can then be further specified as “imaging-supported” if the expected pattern of atrophy is found and “with definite pathology” if pathologic or genetic data are available. The working recommendations are presented in lists of features, and suggested assessment tasks are also provided. These recommendations have been widely agreed upon by a large group of experts and should be used to ensure consistency of PPA classification in future studies. Future collaborations will collect prospective data to identify relationships between each of these syndromes and specific biomarkers for a more detailed understanding of clinicopathologic correlations.

Responsive cortical stimulation for the treatment of medically intractable partial epilepsy

Abstract: Objectives This multicenter, double-blind, randomized controlled trial assessed the safety and effectiveness of responsive cortical stimulation as an adjunctive therapy for partial onset seizures in adults with medically refractory epilepsy. Methods A total of 191 adults with medically intractable partial epilepsy were implanted with a responsive neurostimulator connected to depth or subdural leads placed at 1 or 2 predetermined seizure foci. The neurostimulator was programmed to detect abnormal electrocorticographic activity. One month after implantation, subjects were randomized 1:1 to receive stimulation in response to detections (treatment) or to receive no stimulation (sham). Efficacy and safety were assessed over a 12-week blinded period and a subsequent 84-week open-label period during which all subjects received responsive stimulation. Results Seizures were significantly reduced in the treatment (-37.9%, n = 97) compared to the sham group (-17.3%, n = 94; p = 0.012) during the blinded period and there was no difference between the treatment and sham groups in adverse events. During the open-label period, the seizure reduction was sustained in the treatment group and seizures were significantly reduced in the sham group when stimulation began. There were significant improvements in overall quality of life (p Conclusions Responsive cortical stimulation reduces the frequency of disabling partial seizures, is associated with improvements in quality of life, and is well-tolerated with no mood or cognitive effects. Responsive stimulation may provide another adjunctive treatment option for adults with medically intractable partial seizures. Classification of evidence This study provides Class I evidence that responsive cortical stimulation is effective in significantly reducing seizure frequency for 12 weeks in adults who have failed 2 or more antiepileptic medication trials, 3 or more seizures per month, and 1 or 2 seizure foci.

Heat shock proteins Multiple neuroprotective functions and implications for neurologic disease

Abstract: Heat shock proteins (Hsps) comprise a heterogeneous group of highly conserved molecules that are a critical component of proteostasis. Some Hsps are constitutively expressed in cells to promote proper folding and assembly of polypeptides. However, most Hsps are also rapidly induced in response to cellular stress, including oxidative stress and ischemic injury that results in the accumulation of denatured proteins (figure 1). Hsps provide a first line of defense against accumulation of misfolded, aggregation-prone proteins; their neuroprotective effects also include inhibition of apoptosis, cytoskeletal protection, and immune modulation. Hsps are present in the inclusions that characterize several neurodegenerative disorders, such as Alzheimer disease (AD), Parkinson disease (PD), and Huntington disease. Mutations of Hsps have been linked to some forms of distal hereditary motor neuronopathy, axonal Charcot-Marie-Tooth type 2 (CMT2) disease, myofibrillary myopathy, and progressive spastic paraparesis. Hsps are among the most potent suppressors of neurodegeneration in animal models. Thus, Hsps provide a potential target for protective pharmacotherapy in many neurologic disorders. The multiple functions and dynamics of Hsps and their involvement in neurologic diseases have been extensively reviewed.1,–,15 Figure 1 Heat shock response and chaperone functions of heat shock proteins (Hsps) Accumulation of misfolded proteins during cellular stress is the basic trigger for expression of Hsps, via a feedback loop involving heat shock factor (HSF)-1. HSF-1 is kept in an inactive, monomeric state in the cytoplasm by association with Hsp90. In response to accumulation of misfolded proteins, HSF-1 dissociates from Hsps 90, undergoes trimerization and translocation to the nucleus, and binds to heat shock elements (HSE) in Hsp genes, activating the production of Hsp70, Hsp40, and small Hsps such as Hsp27. The chaperone activity of Hsp90 and Hsp70 requires dynamic conformational changes and adenosine triphosphate (ATP) hydrolysis. Hsp40 interacts with Hsp70, coupling substrate binding with ATP hydrolysis. Once transcribed, small Hsps such as Hsp27 form large oligomeric structures; …

Parkinson disease The enteric nervous system spills its guts

Abstract: Lewy pathology in Parkinson disease (PD) extends well beyond the CNS, also affecting peripheral autonomic neuronal circuits, especially the enteric nervous system (ENS). The ENS is an integrative neuronal network also referred to as “the brain in the gut” because of its similarities to the CNS. We have recently shown that the ENS can be readily analyzed using routine colonic biopsies. This led us to propose that the ENS could represent a unique window to assess the neuropathology in living patients with PD. In this perspective, we discuss current evidence which indicates that the presence of ENS pathology may by exploited to improve our understanding and management of PD and likely other neurodegenerative disorders.

Midlife vascular risk factor exposure accelerates structural brain aging and cognitive decline.

Abstract: Objective: Our aim was to test the association of vascular risk factor exposure in midlife with progression of MRI markers of brain aging and measures of cognitive decline. Methods: A total of 1,352 participants without dementia from the prospective Framingham Offspring Cohort Study were examined. Multivariable linear and logistic regressions were implemented to study the association of midlife vascular risk factor exposure with longitudinal change in white matter hyperintensity volume (WMHV), total brain volume (TBV), temporal horn volume, logical memory delayed recall, visual reproductions delayed-recall (VR-d), and Trail-Making Test B-A (TrB-A) performance a decade later. Results: Hypertension in midlife was associated with accelerated WMHV progression ( p p = 0.012). Midlife diabetes and smoking were associated with a more rapid increase in temporal horn volume, a surrogate marker of accelerated hippocampal atrophy ( p = 0.017 and p = 0.008, respectively). Midlife smoking also predicted a more marked decrease in total brain volume ( p = 0.025) and increased risk of extensive change in WMHV (odds ratio = 1.58 [95%confidence interval 1.07–2.33], p = 0.021). Obesity in midlife was associated with an increased risk of being in the top quartile of change in executive function (1.39 [1.02–1.88], p = 0.035) and increasing waist-to-hip ratio was associated with marked decline in TBV (10.81 [1.44–81.01], p = 0.021). Longitudinal changes in brain structure were significantly correlated with decline in memory and executive function. Conclusions: Midlife hypertension, diabetes, smoking, and obesity were associated with an increased rate of progression of vascular brain injury, global and hippocampal atrophy, and decline in executive function a decade later.

Normative data for the Montreal Cognitive Assessment (MoCA) in a population-based sample

Abstract: Objective: To provide normative and descriptive data for the Montreal Cognitive Assessment (MoCA) in a large, ethnically diverse sample. Methods: The MoCA was administered to 2,653 ethnically diverse subjects as part of a population-based study of cardiovascular disease (mean age 50.30 years, range 18–85; Caucasian 34%, African American 52%, Hispanic 11%, other 2%). Normative data were generated by age and education. Pearson correlations and analysis of variance were used to examine relationship to demographic variables. Frequency of missed items was also reviewed. Results: Total scores were lower than previously published normative data (mean 23.4, SD 4.0), with 66% falling below the suggested cutoff ( Conclusion: These findings highlight the need for population-based norms for the MoCA and use of caution when applying established cut scores, particularly given the high failure rate on certain items. Demographic factors must be considered when interpreting this measure.

Evidence-based guideline: Treatment of painful diabetic neuropathy Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation

Abstract: Objective: To develop a scientifically sound and clinically relevant evidence-based guideline for the treatment of painful diabetic neuropathy (PDN). Methods: We performed a systematic review of the literature from 1960 to August 2008 and classified the studies according to the American Academy of Neurology classification of evidence scheme for a therapeutic article, and recommendations were linked to the strength of the evidence. The basic question asked was: “What is the efficacy of a given treatment (pharmacologic: anticonvulsants, antidepressants, opioids, others; and nonpharmacologic: electrical stimulation, magnetic field treatment, low-intensity laser treatment, Reiki massage, others) to reduce pain and improve physical function and quality of life (QOL) in patients with PDN?” Results and Recommendations: Pregabalin is established as effective and should be offered for relief of PDN (Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B). Other treatments have less robust evidence or the evidence is negative. Effective treatments for PDN are available, but many have side effects that limit their usefulness, and few studies have sufficient information on treatment effects on function and QOL. Neurology ® 2011;76:1–1

Defining hematoma expansion in intracerebral hemorrhage: Relationship with patient outcomes

Abstract: Background: Hematoma expansion (HE) is a surrogate marker in intracerebral hemorrhage (ICH) trials. However, the amount of HE necessary to produce poor outcomes in an individual is unclear; there is no agreement on a clinically meaningful definition of HE. We compared commonly used definitions of HE in their ability to predict poor outcome as defined by various cutpoints on the modified Rankin Scale (mRS). Methods: In this cohort study, we analyzed 531 patients with ICH from the Virtual International Stroke Trials Archive. Primary outcome was mRS at 90 days, dichotomized into 0–3 vs 4–6. Secondary outcomes included other mRS cutpoints and mRS “shift analysis.” Sensitivity, specificity, and predictive values for commonly used HE definitions were calculated. Results: Between 13% and 32% of patients met the commonly used HE definitions. All definitions independently predicted poor outcome; positive predictive values increased with higher growth cutoffs but at the expense of lower sensitivities. All HE definitions showed higher specificity than sensitivity. Absolute growth cutoffs were more predictive than relative cutoffs when mRS 5–6 or 6 was defined as “poor outcome.” Conclusion: HE robustly predicts poor outcome regardless of the growth definition or the outcome definition. The highest positive predictive values are obtained when using an absolute growth definition to predict more severe outcomes. Given that only a minority of patients may have clinically relevant HE, hemostatic ICH trials may need to enroll a large number of patients, or select for a population that is more likely to have HE.

Midlife overweight and obesity increase late-life dementia risk A population-based twin study

Abstract: Objective: The relation of overweight to dementia is controversial. We aimed to examine the association of midlife overweight and obesity with dementia, Alzheimer disease (AD), and vascular dementia (VaD) in late life, and to verify the hypothesis that genetic and early-life environmental factors contribute to the observed association. Methods: From the Swedish Twin Registry, 8,534 twin individuals aged ≥65 (mean age 74.4) were assessed to detect dementia cases ( DSM-IV criteria). Height and weight at midlife (mean age 43.4) were available in the Registry. Data were analyzed as follows: 1) unmatched case-control analysis for all twins using generalized estimating equation (GEE) models and 2) cotwin matched case-control approach for dementia-discordant twin pairs by conditional logistic regression taking into account lifespan vascular disorders and diabetes. Results: Among all participants, dementia was diagnosed in 350 subjects, and 114 persons had questionable dementia. Overweight (body mass index [BMI] >25–30) and obesity (BMI >30) at midlife were present in 2,541 (29.8%) individuals. In fully adjusted GEE models, compared with normal BMI (20–25), overweight and obesity at midlife were related to dementia with odds ratios (ORs) (95% CIs) of 1.71 (1.30–2.25) and 3.88 (2.12–7.11), respectively. Conditional logistic regression analysis in 137 dementia-discordant twin pairs led to an attenuated midlife BMI-dementia association. The difference in ORs from the GEE and the matched case-control analysis was statistically significant ( p = 0.019). Conclusions: Both overweight and obesity at midlife independently increase the risk of dementia, AD, and VaD. Genetic and early-life environmental factors may contribute to the midlife high adiposity–dementia association.

Does vigorous exercise have a neuroprotective effect in Parkinson disease

Abstract: Parkinson disease (PD) is progressive, with dementia and medication-refractory motor problems common reasons for late-stage nursing-home placement. Increasing evidence suggests that ongoing vigorous exercise/physical fitness may favorably influence this progression. Parkinsonian animal models reveal exercise-related protection from dopaminergic neurotoxins, apparently mediated by brain neurotrophic factors and neuroplasticity (predicted from in vitro studies). Similarly, exercise consistently improves cognition in animals, also linked to enhanced neuroplasticity and increased neurotrophic factor expression. In these animal models, immobilization has the opposite effect. Brain-derived neurotrophic factor (BDNF) may mediate at least some of this exercise benefit. In humans, exercise increases serum BDNF, and this is known to cross the blood–brain barrier. PD risk in humans is significantly reduced by midlife exercise, documented in large prospective studies. No studies have addressed whether exercise influences dementia risk in PD, but exercised patients with PD improve cognitive scores. Among seniors in general, exercise or physical fitness has not only been associated with better cognitive scores, but midlife exercise significantly reduces the later risk of both dementia and mild cognitive impairment. Finally, numerous studies in seniors with and without dementia have reported increased cerebral gray matter volumes associated with physical fitness or exercise. These findings have several implications for PD clinicians. 1) Ongoing vigorous exercise and physical fitness should be highly encouraged. 2) PD physical therapy programs should include structured, graduated fitness instruction and guidance for deconditioned patients with PD. 3) Levodopa and other forms of dopamine replenishment therapy should be utilized to achieve the maximum capability and motivation for patients to maintain fitness.

Encephalitis and antibodies to synaptic and neuronal cell surface proteins

Abstract: The identification of encephalitis associated with antibodies against cell surface and synaptic proteins, although recent, has already had a substantial impact in clinical neurology and neuroscience. The target antigens are receptors and proteins that have critical roles in synaptic transmission and plasticity, including the NMDA receptor, the AMPA receptor, the GABAB receptor, and the glycine receptor. Other autoantigens, such as leucine-rich glioma-inactivated 1 and contactin-associated protein-like 2, form part of trans-synaptic complexes and neuronal cell adhesion molecules involved in fine-tuning synaptic transmission and nerve excitability. Syndromes resulting from these immune responses resemble those of pharmacologic or genetic models in which the antigens are disrupted. For some immune responses, there is evidence that the antibodies alter the structure and function of the antigen, suggesting a direct pathogenic effect. These disorders are important because they can affect children and young adults, are severe and protracted, occur with or without tumor association, and respond to treatment but may relapse. This review provides an update on these syndromes and autoantigens with special emphasis on clinical diagnosis and treatment.

Incidence of epilepsy A systematic review and meta-analysis

Abstract: Objective: To estimate the pooled incidence of epilepsy from published studies and investigate sources of heterogeneity in the estimates. Methods: We searched online databases for incidence studies and used meta-analytic methods to analyze the data. Results: Thirty-three articles met the entry criteria. The median incidence of epilepsy was 50.4/100,000/year (interquartile range [IQR] 33.6–75.6), while it was 45.0 (IQR 30.3–66.7) for high-income countries and 81.7 (IQR 28.0–239.5) for low- and middle-income countries. Population-based studies had higher incidence estimates than hospital-based studies ( p = 0.02) while retrospective study design was associated with lower estimates than prospective studies ( p = 0.04). Conclusion: We provide data that could potentially be used to assess the burden and analyze the trends in incidence of epilepsy. Our results support the need for large population-based incidence studies of epilepsy.

Sun exposure and vitamin D are independent risk factors for CNS demyelination

Abstract: Objectives: To examine whether past and recent sun exposure and vitamin D status (serum 25-hydroxyvitamin D [25(OH)D] levels) are associated with risk of first demyelinating events (FDEs) and to evaluate the contribution of these factors to the latitudinal gradient in FDE incidence in Australia. Methods: This was a multicenter incident case-control study. Cases (n = 216) were aged 18–59 years with a FDE and resident within one of 4 Australian centers (from latitudes 27°S to 43°S), from November 1, 2003, to December 31, 2006. Controls (n = 395) were matched to cases on age, sex, and study region, without CNS demyelination. Exposures measured included self-reported sun exposure by life stage, objective measures of skin phenotype and actinic damage, and vitamin D status. Results: Higher levels of past, recent, and accumulated leisure-time sun exposure were each associated with reduced risk of FDE, e.g., accumulated leisure-time sun exposure (age 6 years to current), adjusted odds ratio (AOR) = 0.70 (95% confidence interval [CI] 0.53–0.94) for each ultraviolet (UV) dose increment of 1,000 kJ/m 2 (range 508–6,397 kJ/m 2 ). Higher actinic skin damage (AOR = 0.39 [95% CI 0.17–0.92], highest grade vs the lowest) and higher serum vitamin D status (AOR = 0.93 [95% CI 0.86–1.00] per 10 nmol/L increase in 25(OH)D) were independently associated with decreased FDE risk. Differences in leisure-time sun exposure, serum 25(OH)D level, and skin type additively accounted for a 32.4% increase in FDE incidence from the low to high latitude regions. Conclusions: Sun exposure and vitamin D status may have independent roles in the risk of CNS demyelination. Both will need to be evaluated in clinical trials for multiple sclerosis prevention.

Glucose tolerance status and risk of dementia in the community: The Hisayama Study

Abstract: Objective: We investigated the association between glucose tolerance status defined by a 75-g oral glucose tolerance test (OGTT) and the development of dementia. Methods: A total of 1,017 community-dwelling dementia-free subjects aged ≥60 years who underwent the OGTT were followed up for 15 years. Outcome measure was clinically diagnosed dementia. Results: The age- and sex-adjusted incidence of all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD) were significantly higher in subjects with diabetes than in those with normal glucose tolerance. These associations remained robust even after adjustment for confounding factors for all-cause dementia and AD, but not for VaD (all-cause dementia: adjusted hazard ratio [HR] = 1.74, 95% confidence interval [CI] = 1.19 to 2.53, p = 0.004; AD: adjusted HR = 2.05, 95% CI = 1.18 to 3.57, p = 0.01; VaD: adjusted HR = 1.82, 95% CI = 0.89 to 3.71, p = 0.09). Moreover, the risks of developing all-cause dementia, AD, and VaD significantly increased with elevated 2-hour postload glucose (PG) levels even after adjustment for covariates, but no such associations were observed for fasting plasma glucose (FPG) levels: compared with those with 2-hour PG levels of Conclusions: Our findings suggest that diabetes is a significant risk factor for all-cause dementia, AD, and probably VaD. Moreover, 2-hour PG levels, but not FPG levels, are closely associated with increased risk of all-cause dementia, AD, and VaD.

Vascular risk factors promote conversion from mild cognitive impairment to Alzheimer disease

Abstract: Objective: Growing evidence suggests that vascular risk factors (VRF) contribute to cognitive decline. The aim of this study was to investigate the impact of VRF on the conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD) dementia. Methods: A total of 837 subjects with MCI were enrolled at baseline and followed up annually for 5 years. The incidence of AD dementia was investigated. A mixed random effects regression model was used to analyze the association between VRF and the progression of MCI assessed with Mini-Mental State Examination and instrumental Activities of Daily Living. Cox proportional hazard models were used to identify the association between VRF and dementia conversion, and to examine whether treatment of VRF can prevent dementia conversion. Results: At the end of the follow-up, 298 subjects converted to AD dementia, while 352 remained MCI. Subjects with VRF had a faster progression in cognition and function relative to subjects without. VRF including hypertension, diabetes, cerebrovascular diseases, and hypercholesterolemia increased the risk of dementia conversion. Those subjects with MCI in whom all VRF were treated had a lower risk of dementia than those who had some VRF treated. Treatment of individual VRF including hypertension, diabetes, and hypercholesterolemia was associated with the reduced risk of AD conversion. Conclusion: VRF increased the risk of incident AD dementia. Treatment of VRF was associated with a reduced risk of incident AD dementia. Although our findings are observational, they suggest active intervention for VRF might reduce progression in MCI to AD dementia.

Diffusion-weighted MRI hyperintensity patterns differentiate CJD from other rapid dementias

Abstract: Background: Diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) MRI have high sensitivity and specificity for Creutzfeldt-Jakob disease (CJD). No studies, however, have demonstrated how MRI can distinguish CJD from nonprion causes of rapidly progressive dementia (npRPD). We sought to determine the diagnostic accuracy of MRI for CJD compared to a cohort of npRPD subjects. Methods: Two neuroradiologists blinded to diagnosis assessed DWI and FLAIR images in 90 patients with npRPD (n = 29) or prion disease (sporadic CJD [sCJD], n = 48, or genetic prion disease [familial CJD, n = 6, and Gerstmann-Straussler-Scheinker, n = 7]). Thirty-one gray matter regions per hemisphere were assessed for abnormal hyperintensities. The likelihood of CJD was assessed using our previously published criteria. Results: Gray matter hyperintensities (DWI > FLAIR) were found in all sCJD cases, with certain regions preferentially involved, but never only in limbic regions, and rarely in the precentral gyrus. In all sCJD cases with basal ganglia or thalamic DWI hyperintensities, there was associated restricted diffusion (apparent diffusion coefficient [ADC] map). This restricted diffusion, however, was not seen in any npRPD cases, in whom isolated limbic hyperintensities (FLAIR > DWI) were common. One reader9s sensitivity and specificity for sCJD was 94% and 100%, respectively, the other9s was 92% and 72%. After consensus review, the readers9 combined MRI sensitivity and specificity for sCJD was 96% and 93%, respectively. Familial CJD had overlapping MRI features with sCJD. Conclusions: The pattern of FLAIR/DWI hyperintensity and restricted diffusion can differentiate sCJD from other RPDs with a high sensitivity and specificity. MRI with DWI and ADC should be included in sCJD diagnostic criteria. New sCJD MRI criteria are proposed.

Age-related changes in the default mode network are more advanced in Alzheimer disease

Abstract: Objective: To investigate age-related default mode network (DMN) connectivity in a large cognitively normal elderly cohort and in patients with Alzheimer disease (AD) compared with age-, gender-, and education-matched controls. Methods: We analyzed task-free–fMRI data with both independent component analysis and seed-based analysis to identify anterior and posterior DMNs. We investigated age-related changes in connectivity in a sample of 341 cognitively normal subjects. We then compared 28 patients with AD with 56 cognitively normal noncarriers of the APOE ϵ4 allele matched for age, education, and gender. Results: The anterior DMN shows age-associated increases and decreases in fontal lobe connectivity, whereas the posterior DMN shows mainly age-associated declines in connectivity throughout. Relative to matched cognitively normal controls, subjects with AD display an accelerated pattern of the age-associated changes described above, except that the declines in frontal lobe connectivity did not reach statistical significance. These changes survive atrophy correction and are correlated with cognitive performance. Conclusions: The results of this study indicate that the DMN abnormalities observed in patients with AD represent an accelerated aging pattern of connectivity compared with matched controls.

Risk factors, inpatient care, and outcomes of pneumonia after ischemic stroke

Abstract: Objectives: Pneumonia is the most common medical complication after stroke. Although several risk factors have been reported, the role of common comorbidities in the development of pneumonia is not well established. Moreover, there is discrepancy in the literature regarding the impact of pneumonia on stroke outcomes. Methods: This is a multicenter retrospective cohort study including consecutive patients with ischemic stroke admitted to Regional Stroke Centers participating in the Registry of Canadian Stroke Network in July 2003–March 2007. Pneumonia was defined as a complication that occurred within the first 30 days of the stroke and was confirmed radiographically. The main outcome measure was adjusted 30-day mortality. Secondary outcomes were adjusted 7- and 365-day mortality, institutionalization, length of stay, and modified Rankin score on discharge. We also assessed the impact of organized stroke care on pneumonia development and mortality. Results: Overall, 8,251 patients were included in the study. Stroke-associated pneumonia was observed in 587 patients (7.1*). Pneumonia increased 30-day (odds ratio [OR] 2.2 [95% confidence interval (CI) 1.8–2.7]) and 1-year mortality (OR 3.0 [95% CI 2.5–3.7]), but not 7-day mortality. Pneumonia was associated with poor functional outcome. Higher access to organized inpatient care resulted in a reduction of 30-day mortality (OR 0.50 [95% CI 0.41–0.61]). Older age, male sex, stroke severity, dysphagia, chronic obstructive pulmonary disease, coronary artery disease, nonlacunar ischemic stroke, and preadmission dependency were independent predictors of pneumonia. Conclusions: Development of pneumonia after stroke was associated with mortality at 30 days and 1 year, longer length of stay, and dependency at discharge. Patients who received more inpatient stroke services had reduced mortality after pneumonia.

Evidence-based guideline update: Plasmapheresis in neurologic disorders Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology

Abstract: Objective: To reassess the role of plasmapheresis in the treatment of neurologic disorders. Methods: We evaluated the available evidence based on a structured literature review for relevant articles from 1995 through September 2009. In addition, due to revision of the definitions of classification of evidence since the publication of the previous American Academy of Neurology assessment in 1996, the evidence cited in that manuscript was reviewed and reclassified. Results and Recommendations: Plasmapheresis is established as effective and should be offered in severe acute inflammatory demyelinating polyneuropathy (AIDP)/Guillain-Barresyndrome (GBS) and in the short-term management of chronic inflammatory demyelinating polyneuropathy (Class I studies, Level A). Plasmapheresis is established as ineffective and should not be offered for chronic or secondary progressive multiple sclerosis (MS) (Class I studies, Level A). Plasma- pheresis is probably effective and should be considered for mild AIDP/GBS, as second-line treat- ment of steroid-resistant exacerbations in relapsing forms of MS, and for neuropathy associated with immunoglobulin A or immunoglobulin G gammopathy, based on at least one Class I or 2 Class II studies (Level B). Plasmapheresis is probably not effective and should not be considered for neuropathy associated with immunoglobulin M gammopathy, based on one Class I study (Level B). Plasmapheresis is possibly effective and may be considered for acute fulminant demyelinating CNS disease (Level C). There is insufficient evidence to support or refute the use of plasmaphere- sis for myasthenia gravis, pediatric autoimmune neuropsychiatric disorders associated with streptococcus infection, and Sydenham chorea (Class III evidence, Level U). Neurology ® 2011;76:

Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults

Abstract: Objective: Since Alzheimer disease (AD) neuropathology is thought to develop years before dementia, it may be possible to detect subtle AD-related atrophy in preclinical AD. Here we hypothesized that the “disease signature” of AD-related cortical thinning, previously identified in patients with mild AD dementia, would be useful as a biomarker to detect anatomic abnormalities consistent with AD in cognitively normal (CN) adults who develop AD dementia after longitudinal follow-up. Methods: We studied 2 independent samples of adults who were CN when scanned. In sample 1, 8 individuals developing AD dementia (CN-AD converters) after an average of 11.1 years were compared to 25 individuals who remained CN (CN-stable). In sample 2, 7 CN-AD converters (average follow-up 7.1 years) were compared to 25 CN-stable individuals. Results: AD-signature cortical thinning in CN-AD converters in both samples was remarkably similar, about 0.2 mm ( p d effect sizes for these differences were very large (>1). Of the 11 CN individuals with baseline low AD-signature thickness (≥1 SD below cohort mean), 55% developed AD dementia over nearly the next decade, while none of the 9 high AD-signature thickness individuals (≥1 SD above mean) developed dementia. This marker predicted time to diagnosis of dementia (hazard ratio = 3.4, p Conclusions: By focusing on cortical regions known to be affected in AD dementia, subtle but reliable atrophy is identifiable in asymptomatic individuals nearly a decade before dementia, making this measure a potentially important imaging biomarker of early neurodegeneration.

Use of ibuprofen and risk of Parkinson disease

Abstract: Background: Neuroinflammation may contribute to the pathogenesis of Parkinson disease (PD). Use of nonsteroidal anti-inflammatory drugs (NSAID) in general, and possibly ibuprofen in particular, has been shown to be related to lower PD risk in previous epidemiologic studies. Methods: We prospectively examined whether use of ibuprofen or other NSAIDs is associated with lower PD risk among 136,197 participants in the Nurses9 Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) free of PD at baseline (1998 for NHS and 2000 for HPFS). NSAIDs use was assessed via questionnaire. Results were combined in a meta-analysis with those of published prospective investigations. Results: We identified 291 incident PD cases during 6 years of follow-up. Users of ibuprofen had a significantly lower PD risk than nonusers (relative risk [RR], adjusted for age, smoking, caffeine, and other covariates = 0.62; 95% confidence interval [CI] 0.42–0.93; p = 0.02). There was a dose–response relationship between tablets of ibuprofen taken per week and PD risk ( p trend = 0.01). In contrast, PD risk was not significantly related to use of aspirin (RR = 0.99; 95% CI 0.78–1.26), other NSAIDs (RR = 1.26; 95% CI 0.86–1.84), or acetaminophen (RR = 0.86; 95% CI 0.62–1.18). Similar results were obtained in the meta-analyses: the pooled RR was 0.73 (95% CI 0.63–0.85; p Conclusions: The association between use of ibuprofen and lower PD risks, not shared by other NSAIDs or acetaminophen, suggests ibuprofen should be further investigated as a potential neuroprotective agent against PD.

Executive dysfunction is a negative prognostic indicator in patients with ALS without dementia.

Abstract: Background: The prognostic implications of cognitive impairment in amyotrophic lateral sclerosis (ALS) are not established. Objectives: To investigate the survival effect of the comorbid frontotemporal dementia (FTD) and to determine whether, in the absence of dementia, impairment in different cognitive domains affects outcome. Methods: A prospective population-based study of incident cases of ALS in the Republic of Ireland included home-based neuropsychological assessments using age-, sex-, and education-matched controls. Four cognitive domains were evaluated: executive function, memory, language, and visuospatial skills. Results: Mean age of the participants (n = 139) was 63.3 years; 61.2% were male and 35.3% had bulbar-onset ALS. Factors associated with shorter survival included age more than 60, severe disability at baseline, shorter delay to diagnosis, and early respiratory involvement. Comorbid FTD was associated with significantly shorter survival time (hazard ratio [HR] 2.67, 95% confidence interval [CI] 1.04–6.85, p = 0.041). In patients with ALS without dementia, the presence of executive dysfunction was significantly associated with shorter survival. This was confirmed in a multivariate model that included age, delay to diagnosis, disease severity at baseline, education, and respiratory status (HR 3.44, 95% CI 1.45–8.18, p = 0.005). In the absence of executive dysfunction, single or multi-domain impairment in other cognitive domains had no significant effect on survival. Conclusion: Comorbid frontotemporal dementia is a negative prognostic indicator. In patients with ALS without dementia, executive dysfunction, but not impairment in other cognitive domains, is an important negative prognostic indicator.

Factors influencing in-hospital mortality and morbidity in patients treated on a stroke unit

Abstract: Objective: To determine the extent that demographics, clinical characteristics, comorbidities, and complications contribute to the risk of in-hospital mortality and morbidity in acute stroke. Methods: Data of consecutive patients admitted to 14 stroke units cooperating within the Berlin Stroke Register were analyzed. The association of demographics, clinical characteristics, comorbidities, and complications with the risk of in-hospital death and poor outcome at discharge was assessed, and independent attributable risks were calculated, applying average sequential attributable fractions. Results: In a 3-year period, 16,518 consecutive patients with ischemic or hemorrhagic stroke were documented. In-hospital mortality was 5.4%, and 45.7% had a poor outcome (modifed Rankin Scale score ≥3). In patients with length of stay (LOS) ≤7 days, 37.5% of in-hospital deaths were attributed to stroke severity, 23.1% to sociodemographics (age and prestroke disability), and 28.9% to increased intracranial pressure (iICP) and other complications. In those with LOS >7 days, age and stroke severity accounted for 44.1%, whereas pneumonia (12.2%), other complications (12.6%), and iICP (8.3%) contributed to one-third of in-hospital deaths. For poor outcome, attributable risks were similar for prestroke disability, stroke severity, pneumonia, and other complications regardless of the patient9s LOS. Conclusions: Approximately two-thirds of early death and poor outcome in acute stroke is attributed to nonmodifiable predictors, whereas main modifiable factors are early complications such as iICP, pneumonia, or other complications, on which stroke unit treatment should focus to further improve the prognosis of acute stroke.

Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome

Abstract: Objective: To report the metabotropic glutamate receptor 5 (mGluR5) as the autoantigen of antibodies from 2 patients with Hodgkin lymphoma (HL) and limbic encephalopathy (Ophelia syndrome). Methods: Immunohistochemistry with brain tissue and cultures of rat hippocampal neurons were used to demonstrate antibodies. Immunoprecipitation, mass spectrometry, and mGluR5 -null mice served to identify the antigen. HEK293 cells transfected with mGluR5 or mGluR1 were used to determine immunologic crossreactivity. Results: Both patients developed symptoms consistent with limbic encephalopathy; one had MRI findings typical of this disorder and the other had more extensive radiologic involvement, including parietal and occipital cortex. Patients9 sera had antibodies that predominantly reacted with the neuropil of hippocampus and cell surface of live hippocampal neurons. Immunoprecipitation from cultured neurons and mass spectrometry demonstrated that the antigen was mGluR5, a receptor involved in processes of learning and memory. The reactivity of patients9 sera was abrogated in brain of mGluR5 -null mice, further confirming the antibody specificity. Studies with a large number of controls including 2 patients with cerebellar ataxia and mGluR1 antibodies showed that mGluR5 was only identified by sera of the 2 patients with the Ophelia syndrome, and that despite the homology of this receptor with mGluR1 each autoantigen was specific for a distinct syndrome. Conclusions: Antibodies to mGluR5 should be considered in patients with symptoms of limbic encephalitis and HL (Ophelia syndrome). Recognition of this disorder is important because it can affect young individuals and is reversible.

A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease

Abstract: Background: Lowering cholesterol is associated with reduced CNS amyloid deposition and increased dietary cholesterol increases amyloid accumulation in animal studies. Epidemiologic data suggest that use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may decrease the risk of Alzheimer disease (AD) and a single-site trial suggested possible benefit in cognition with statin treatment in AD, supporting the hypothesis that statin therapy is useful in the treatment of AD. Objective: To determine if the lipid-lowering agent simvastatin slows the progression of symptoms in AD. Methods: This randomized, double-blind, placebo-controlled trial of simvastatin was conducted in individuals with mild to moderate AD and normal lipid levels. Participants were randomly assigned to receive simvastatin, 20 mg/day, for 6 weeks then 40 mg per day for the remainder of 18 months or identical placebo. The primary outcome was the rate of change in the Alzheimer’s Disease Assessment Scale–cognitive portion (ADAS-Cog). Secondary outcomes measured clinical global change, cognition, function, and behavior. Results: A total of 406 individuals were randomized: 204 to simvastatin and 202 to placebo. Simvastatin lowered lipid levels but had no effect on change in ADAS-Cog score or the secondary outcome measures. There was no evidence of increased adverse events with simvastatin treatment. Conclusion: Simvastatin had no benefit on the progression of symptoms in individuals with mild to moderate AD despite significant lowering of cholesterol. Classification of evidence: This study provides Class I evidence that simvastatin 40 mg/day does not slow decline on the ADAS-Cog. Neurology ® 2011;77:556–563

Neuromyelitis optica unique area postrema lesions: Nausea, vomiting, and pathogenic implications

Abstract: Objective: To characterize the neuropathologic features of neuromyelitis optica (NMO) at the medullary floor of the fourth ventricle and area postrema. Aquaporin-4 (AQP4) autoimmunity targets this region, resulting in intractable nausea associated with vomiting or hiccups in NMO. Methods: This neuropathologic study was performed on archival brainstem tissue from 15 patients with NMO, 5 patients with multiple sclerosis (MS), and 8 neurologically normal subjects. Logistic regression was used to evaluate whether the presence of lesions at this level increased the odds of a patient with NMO having an episode of nausea/vomiting. Results: Six patients with NMO (40%), but no patients with MS or normal controls, exhibited unilateral or bilateral lesions involving the area postrema and the medullary floor of the fourth ventricle. These lesions were characterized by tissue rarefaction, blood vessel thickening, no obvious neuronal or axonal pathology, and preservation of myelin in the subependymal medullary tegmentum. AQP4 immunoreactivity was lost or markedly reduced in all 6 cases, with moderate to marked perivascular and parenchymal lymphocytic inflammatory infiltrates, prominent microglial activation, and in 3 cases, eosinophils. Complement deposition in astrocytes, macrophages, and/or perivascularly, and a prominent astroglial reaction were also present. The odds of nausea/vomiting being documented clinically was 16-fold greater in NMO cases with area postrema lesions (95% confidence interval 1.43–437, p = 0.02). Conclusions: These neuropathologic findings suggest the area postrema may be a selective target of the disease process in NMO, and are compatible with clinical reports of nausea and vomiting preceding episodes of optic neuritis and transverse myelitis or being the heralding symptom of NMO.

Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis

Abstract: Objective: To study the longitudinal dynamics of anti–myelin oligodendrocyte glycoprotein (MOG) autoantibodies in childhood demyelinating diseases. Methods: We addressed the kinetics of anti-MOG immunoglobulins in a prospective study comprising 77 pediatric patients. This was supplemented by a cross-sectional study analyzing 126 pediatric patients with acute demyelination and 62 adult patients with multiple sclerosis (MS). MOG-transfected cells were used for detection of antibodies by flow cytometry. Results: Twenty-five children who were anti-MOG immunoglobulin (Ig) positive at disease onset were followed for up to 5 years. Anti-MOG antibodies rapidly and continuously declined in all 16 monophasic patients with acute disseminated encephalomyelitis and in one patient with clinically isolated syndrome. In contrast, in 6 of 8 patients (75%) eventually diagnosed with childhood MS, the antibodies to MOG persisted with fluctuations showing a second increase during an observation period of up to 5 years. Antibodies to MOG were mainly IgG 1 and their binding was largely blocked by pathogenic anti-MOG antibodies derived from a spontaneous animal model of autoimmune encephalitis. The cross-sectional part of our study elaborated that anti-MOG Ig was present in about 25% of children with acute demyelination, but in none of the pediatric or adult controls. Sera from 4/62 (6%) adult patients with MS had anti-MOG IgG at low levels. Conclusions: The persistence or disappearance of antibodies to MOG may have prognostic relevance for acute childhood demyelination.

Amyloid vs FDG-PET in the differential diagnosis of AD and FTLD

Abstract: Objective: To compare the diagnostic performance of PET with the amyloid ligand Pittsburgh compound B (PiB-PET) to fluorodeoxyglucose (FDG-PET) in discriminating between Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD). Methods: Patients meeting clinical criteria for AD (n 62) and FTLD (n 45) underwent PiB and FDG-PET. PiB scans were classified as positive or negative by 2 visual raters blinded to clinical diagnosis, and using a quantitative threshold derived from controls (n 25). FDG scans were visually rated as consistent with AD or FTLD, and quantitatively classified based on the region of lowest metabolism relative to controls. Results: PiB visual reads had a higher sensitivity for AD (89.5% average between raters) than FDG visual reads (77.5%) with similar specificity (PiB 83%, FDG 84%). When scans were classified quantitatively, PiB had higher sensitivity (89% vs 73%) while FDG had higher specificity (83% vs 98%). On receiver operating characteristic analysis, areas under the curve for PiB (0.888) and FDG (0.910) were similar. Interrater agreement was higher for PiB ( 0.96) than FDG ( 0.72), as was agreement between visual and quantitative classification (PiB 0.88– 0.92; FDG 0.64–0.68). In patients with known histopathology, overall classification accuracy (2 visual and 1 quantitative classification per patient) was 97% for PiB (n 12 patients) and 87% for FDG (n 10). Conclusions: PiB and FDG showed similar accuracy in discriminating AD and FTLD. PiB was more sensitive when interpreted qualitatively or quantitatively. FDG was more specific, but only when scans were classified quantitatively. PiB slightly outperformed FDG in patients with known histopathology. Neurology ® 2011;77:2034–2042

Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis

Abstract: Background: Due to a heightened risk of progressive multifocal leukoencephalopathy (PML) with increased natalizumab exposure, some physicians interrupt treatment of patients with multiple sclerosis (MS) despite a lack of data regarding the safety of treatment interruption, the rate and severity of MS disease activity return after treatment interruption, or alternative treatment strategies. Objectives: To determine the effects of natalizumab treatment interruption on clinical and MRI measures of disease activity in relapsing patients with MS. Methods: Clinical relapses and gadolinium-enhanced (Gd+) lesions were analyzed over an 8-month period in patients from the AFFIRM, SENTINEL, and GLANCE studies of natalizumab, and their respective safety extension studies, following the voluntary suspension of natalizumab dosing that occurred in February 2005. Results: Relapses were analyzed in 1,866 patients, and Gd+ lesions were analyzed in 341 patients. Annualized relapse rates and Gd+ lesions both increased shortly after natalizumab interruption and peaked between 4 and 7 months. A consistent return of disease activity was observed regardless of overall natalizumab exposure, whether or not patients received alternative MS therapies, and in patients with highly active MS disease. A rebound of relapse or Gd+ lesion activity, beyond placebo-treated levels from the clinical studies, was not observed in any of the analyses conducted. Conclusions: Following interruption of natalizumab treatment, MS disease activity returned in a pattern that was consistent with known pharmacokinetic and pharmacodynamic properties of natalizumab, and did not show evidence of rebound.

The King-Devick test as a determinant of head trauma and concussion in boxers and MMA fighters

Abstract: Objective: Sports-related concussion has received increasing attention as a cause of short- and long-term neurologic symptoms among athletes. The King-Devick (K-D) test is based on measurement of the speed of rapid number naming (reading aloud single-digit numbers from 3 test cards), and captures impairment of eye movements, attention, language, and other correlates of suboptimal brain function. We investigated the K-D test as a potential rapid sideline screening for concussion in a cohort of boxers and mixed martial arts fighters. Methods: The K-D test was administered prefight and postfight. The Military Acute Concussion Evaluation (MACE) was administered as a more comprehensive but longer test for concussion. Differences in postfight K-D scores and changes in scores from prefight to postfight were compared for athletes with head trauma during the fight vs those without. Results: Postfight K-D scores (n = 39 participants) were significantly higher (worse) for those with head trauma during the match (59.1 ± 7.4 vs 41.0 ± 6.7 seconds, p r s = −0.79, p = 0.0001) and greater worsening of scores ( r s = 0.90, p Conclusions: The K-D test is an accurate and reliable method for identifying athletes with head trauma, and is a strong candidate rapid sideline screening test for concussion.