Neurology RSS : Gourt

Missouri Hospital Needs Inpatient Call Coverage Starting Next Year. :: Missouri :: CompHealth Inc

Job 0840799-0194 Requires: EEG About 9-12 patients per day 100% Inpatient We offer competitive pay that may include incentives and bonuses We coordinate and pay for your travel, housing, and transportation

Neurology - Epilepsy Temp to Perm Opportunity in Pennsylvania :: Pennsylvania :: CompHealth Inc

Job 0053655-0359 This is an excellent opportunity to join a well-established hospital employed practice. Beautiful and family friendly community, one of the nations lowest crime rates, diversified economic

Fantastic position open in Virginia for a General Neurologist :: Virginia :: CompHealth Inc

Job 9110855 Fantastic position open in Virginia for a General Neurologist. There is room to grow into subspecialty training, so please don't hesitate to contact. The group is willing to look at now physicians,

Neurology Job Located in Northeastern Pennsylvania! :: Pennsylvania :: CompHealth Inc

Job 0067867-0702 A well respected healthcare group is searching for someone to provide neurology coverage for the month of March. Must be Board Certified, BLS Monday - Friday 8-5 Bread & butter position

Government Neurology Job in Fayetteville, Arkansas. :: Arkansas :: CompHealth Inc

Job 1243059-0114 Any State License Outpatient, some Inpatient & Consults: Nerve Conduction and EMG's are a must! BLS, ACLS, and NPI required Board Certified/Board Eligible Monday - Friday 8:00am -

Neurology with Partnership opportunity in Florida :: Florida :: CompHealth Inc

Job 9111115 Join three other Neurologists in a very lucrative practice Become a partner in this magnificent facility You will be rewarded with a very competitive salary Once a partner, earning potential

Choose between Traditional and Neuro-Hospitalist :: Florida :: CompHealth Inc

Job 9111023 General Neurology , Neurophysiology, Neuromuscular B/C or B/E Neurology Join 4 Neurologists and 1 Neurosurgeon General Neurology, EEG, EMG Choose between Neuro-Hospitalist or traditional

Neurologist needed in Ohio for Locums to Perm :: Ohio :: CompHealth Inc

Job 0289982-0015 Beautiful area with great patient population looking for a locums to permanent physician Full-time or Part-time position available 100% outpatient with occassional consult Approximately

Neurologist needed for non clinical position :: Illinois :: CompHealth Inc

Job 92112 Monitoring surgical procedures in an office environment work Mon.-Fri. with no clinical duties Monitor electroneurogiadnostic testing off site Full support staff of 12 technicians and administrators

Part-Time Neurology Need in Arizona :: Arizona :: CompHealth Inc

Job 0137229-0039 Mostly inpatient, could have some outpatient work EMG, NCV, EEG Approximately 10 days per month AZ lic required, quick turn around time We offer competitive pay that may include incentives

Board Certified Neurologist needed! :: Wisconsin :: CompHealth Inc

Job 0258538-0113 Come work in Wisconsin from 11/19-12/06/2009, 7am to 7am. Call schedule is required and you will have approxitmatley 1-2 # of phone calls per night & 1-2 consults per night. Required:

Neurology Permanent Option in NE :: Nebraska :: CompHealth Inc

Job 0068958-0041 Looking for a locums to perm type hire 50% Inpatient & 50% Outpatient Serious permanent candidates only. We offer competitive pay that may include incentives and bonuses We coordinate

Partnership near the Big Apple :: New Jersey :: CompHealth Inc

Job 9110816 Private Practice- General Neurology B/C or B/E Neurology General Neurology , Neurophysiology, Epilepsy or Sleep Shared call 1:4/1:5 Join a thriving single specialty group Admit to 2 hospitals

Vacation coverage in Delaware :: Delaware :: CompHealth Inc

Job 0079814-0055 Dec 18 to Jan 3 BC/BE within 3 years of training program 100% inpatient, 100% adult Monday-Sunday TPA, EEG, EMG, NCV, evoked potentials We offer competitive pay that may include incentives

Long Term Locum in Delaware :: Delaware :: CompHealth Inc

Job 0078437-0091 Great opportunity 12/14 Start date for 4-6 months 24/7 call BC or BE within 3 years of program EEG, EMG, NCV, brain death exam required ER and Stroke call required 100% inpatient coverage,

Locums to Perm in Delaware :: Delaware :: CompHealth Inc

Job 0078437-0092 4-6 months of locums start end of Dec or beginning of Jan. Option to go perm after that time EMG/NCV, EEG 24/7 call, stroke & ER plus consults 100% inpatient and adult We offer competitive

Neurology in the Southeast :: Mississippi :: CompHealth Inc

Job 9110873 Year round golf and swimming B/E or B/C Neurology Choose between solo or employed 3 Busy Neurologists in Service area Call is 1:3 Sleep interest a plus Easy access to Memphis Fishing, boating,

Outdoor paradise :: West Virginia :: CompHealth Inc

Job 9110658 Neurology and shared call B/C or B/E Neurology Choose between solo or join a single specialty group 1 Neurosurgeon and 3 Neurologists in town Busy ER and new Multimillion dollar medical

Neurologist :: Pennsylvania :: CompHealth Inc

Job 9111049 Neurologist needed near PIttsburgh, PA General Neurology with support for sub specialty interest Optional employment model Favorable payer mix No ER call Service only 1 hospital Full hospital

Neurologist :: Ohio :: CompHealth Inc

Job 9111032 General Neuro, + Sleep More than 60% Sleep Inherit full patient base 6 bed sleep lab Service 1 hospital Employed position On call 10 nights per month Great support staff 4 weeks vacation

Infectious Burden and Risk of Stroke: The Northern Manhattan Study [Original Contribution]

Objective To determine the association between a composite measure of serological test results for common infections (Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, and herpes simplex virus 1 and 2) and stroke risk in a prospective cohort study.Design Prospective cohort followed up longitudinally for median 8 years.Setting Northern Manhattan Study.Patients Randomly selected stroke-free participants from a multiethnic urban community.Main Outcome Measure Incident stroke and other vascular events.Results All 5 infectious serological results were available from baseline samples in 1625 participants (mean [SD] age, 68.4 [10.1] years; 64.9% women). Cox proportional hazards models were used to estimate associations of each positive serological test result with stroke. Individual parameter estimates were then combined into a weighted index of infectious burden and used to calculate hazard ratios and confidence intervals for association with risk of stroke and other outcomes, adjusted for risk factors. Each individual infection was positively, though not significantly, associated with stroke risk after adjusting for other risk factors. The infectious burden index was associated with an increased risk of all strokes (adjusted hazard ratio per standard deviation, 1.39; 95% confidence interval, 1.02-1.90) after adjusting for demographics and risk factors. Results were similar after excluding those with coronary disease (adjusted hazard ratio, 1.50; 95% confidence interval, 1.05-2.13) and adjusting for inflammatory biomarkers.Conclusions A quantitative weighted index of infectious burden was associated with risk of first stroke in this cohort. Future studies are needed to confirm these findings and to further define optimal measures of infectious burden as a stroke risk factor.Published online November 9, 2009 (doi:10.1001/archneurol.2009.271).

Urate as a Predictor of the Rate of Clinical Decline in Parkinson Disease [Original Contribution]

Background The risk of Parkinson disease (PD) and its rate of progression may decline with increasing concentration of blood urate, a major antioxidant.Objective To determine whether serum and cerebrospinal fluid concentrations of urate predict clinical progression in patients with PD.Design, Setting, and Participants Eight hundred subjects with early PD enrolled in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial. The pretreatment urate concentration was measured in serum for 774 subjects and in cerebrospinal fluid for 713 subjects.Main Outcome Measures Treatment-, age-, and sex-adjusted hazard ratios (HRs) for clinical disability requiring levodopa therapy, the prespecified primary end point of the original DATATOP trial.Results The HR of progressing to the primary end point decreased with increasing serum urate concentrations (HR for highest vs lowest quintile = 0.64; 95% confidence interval [CI], 0.44-0.94; HR for a 1-SD increase = 0.82; 95% CI, 0.73-0.93). In analyses stratified by -tocopherol treatment (2000 IU/d), a decrease in the HR for the primary end point was seen only among subjects not treated with -tocopherol (HR for a 1-SD increase = 0.75; 95% CI, 0.62-0.89; vs HR for those treated = 0.90; 95% CI, 0.75-1.08). Results were similar for the rate of change in the Unified Parkinson's Disease Rating Scale score. Cerebrospinal fluid urate concentration was also inversely related to both the primary end point (HR for highest vs lowest quintile = 0.65; 95% CI, 0.44-0.96; HR for a 1-SD increase = 0.89; 95% CI, 0.79-1.02) and the rate of change in the Unified Parkinson's Disease Rating Scale score. As with serum urate concentration, these associations were present only among subjects not treated with -tocopherol.Conclusions Higher serum and cerebrospinal fluid urate concentrations at baseline were associated with slower rates of clinical decline. The findings strengthen the link between urate concentration and PD and the rationale for considering central nervous system urate concentration elevation as a potential strategy to slow PD progression.Published online October 12, 2009 (doi:10.1001/archneurol.2009.247).

About This Journal [About This Journal]

This Month in Archives of Neurology [This Month in Archives of Neurology]

Herzmyasthenie: Myasthenia of the Heart [Editorial]

Cellular Prion Protein Mediates the Toxicity of {beta}-Amyloid Oligomers: Implications for Alzheimer Disease [Clinical Implications of Basic Neuroscience Research]

Alzheimer disease (AD) is the most common cause of age-related dementia, affecting more than 25 million people worldwide. The accumulation of insoluble β-amyloid (Aβ) plaques in the brain has long been considered central to the pathogenesis of AD. However, recent evidence suggests that soluble oligomeric assemblies of Aβ may be of greater importance. β-Amyloid oligomers have been found to be potent synaptotoxins, but the mechanism by which they exert their action has remained elusive. Herein, we review the recently published finding that cellular prion protein (PrPc) is a high-affinity receptor for Aβ oligomers, mediating their toxic effects on synaptic plasticity. We further discuss the relationship between AD and PrPc and the potential clinical implications. Cellular prion protein may provide a novel target for therapeutic intervention in AD.

Vocal Cord Dysfunction in Amyotrophic Lateral Sclerosis: Four Cases and a Review of the Literature [Neurological Review]

We describe 4 patients with amyotrophic lateral sclerosis (ALS) and glottic narrowing due to vocal cord dysfunction, and review the literature found using the following search terms: amyotrophic lateral sclerosis, motor neuron disease, stridor, laryngospasm, vocal cord abductor paresis, and hoarseness. Neurological literature rarely reports vocal cord dysfunction in ALS, in contrast to otolaryngology literature (4%-30% of patients with ALS). Both infranuclear and supranuclear mechanisms may play a role. Vocal cord dysfunction can occur at any stage of disease and may account for sudden death in ALS. Treatment of severe cases includes acute airway management and tracheotomy.

Autoimmune Targets of Heart and Skeletal Muscles in Myasthenia Gravis [Original Contribution]

Objective To investigate the clinical, histological, and immunological features of patients with myasthenia gravis (MG) who also developed myocarditis and/or myositis. Design Observational and retrospective case series. Setting Keio University, Hanamaki General Hospital, Kanazawa University, Nagasaki University, and Juntendo University. Patients A cohort of 8 patients with MG with clinically defined inflammatory myopathies. Interventions Clinical and histological features were described. Serological analyses included MG-related antistriational autoantibodies (those to titin, ryanodine receptor, muscular voltage-gated potassium channel Kv1.4) and myositis-specific autoantibodies. Results Of 924 patients with MG, 8 (0.9%) had inflammatory myopathies. The mean (SD) onset age of MG was 55.3 (10.3) years. All patients showed severe symptoms with bulbar involvement; 5 patients had myasthenic crisis and 4 had invasive thymoma. Myocarditis was found in 3 patients and myositis in 6. Myocarditis, developing 13 to 211 months after the MG onset, was characterized by heart failure and arrhythmias. Myositis, developing before or at the same time as MG, affected limb and paraspinal muscles. Histological findings of skeletal muscles showed CD8+ lymphocyte infiltration. Seven patients had 1 of these antistriational autoantibodies but not myositis-specific autoantibodies. Immunomodulatory therapy was required for all patients and was effective for both MG and inflammatory myopathies, although 1 patient died. Conclusions Heart and skeletal muscles are autoimmune targets in some patients with MG. This autoimmunity has a broad clinical spectrum with antistriational autoantibodies. Published online September 14, 2009 (doi:10.1001/archneurol.2009.229).

Association of Muscle Strength With the Risk of Alzheimer Disease and the Rate of Cognitive Decline in Community-Dwelling Older Persons [Original Contribution]

Background Loss of muscle strength is common and is associated with various adverse health outcomes in old age, but few studies have examined the association of muscle strength with the risk of Alzheimer disease (AD) or mild cognitive impairment (MCI). Objective To test the hypothesis that muscle strength is associated with incident AD and MCI. Design Prospective observational cohort study. Setting Retirement communities across the Chicago, Illinois, metropolitan area. Participants More than 900 community-based older persons without dementia at the baseline evaluation and in whom strength was measured in 9 muscle groups in arms and legs, and in the axial muscles and summarized into a composite measure of muscle strength. Main Outcome Measures Incident AD and MCI and the rate of change in global cognitive function. Results During a mean follow-up of 3.6 years, 138 persons developed AD. In a proportional hazards model adjusted for age, sex, and education status, each 1-U increase in muscle strength at baseline was associated with about a 43% decrease in the risk of AD (hazard ratio, 0.57; 95% confidence interval, 0.41-0.79). The association of muscle strength with AD persisted after adjustment for several covariates, including body mass index, physical activity, pulmonary function, vascular risk factors, vascular diseases, and apolipoprotein E4 status. In a mixed-effects model adjusted for age, sex, education status, and baseline level of global cognition, increased muscle strength was associated with a slower rate of decline in global cognitive function (P < .001). Muscle strength was associated with a decreased risk of MCI, the precursor to AD (hazard ratio, 0.67; 95% confidence interval, 0.54-0.84). Conclusion These findings suggest a link between muscle strength, AD, and cognitive decline in older persons.

Magnetic Resonance Imaging Predictors of Conversion to Multiple Sclerosis in the BENEFIT Study [Original Contribution]

Background Several studies have confirmed the predictive value of baseline and follow-up magnetic resonance (MR) imaging variables for conversion to clinically definite multiple sclerosis (CDMS), depending on the population, follow-up duration, and treatment intervention. However, the timing of follow-up imaging and the effect of treatment intervention on the predictive value of baseline MR imaging variables require further elucidation. Objectives To assess the prognostic value of baseline MR imaging variables for conversion to CDMS over 3 years and whether this was affected by treatment intervention and (2) to assess the increased risk for conversion posed by dissemination in time on follow-up MR imaging. Design Cohort study. Setting Multicenter randomized clinical trial. Patients Four hundred sixty-eight patients with a clinically isolated syndrome who had an initial clinical demyelinating event within the past 60 days who received early treatment (3 years of interferon beta-1b) or delayed treatment (placebo first, followed by ≥1 year of interferon beta-1b). Intervention Magnetic resonance imaging. Main Outcome Measure Time to CDMS. Results The overall conversion rate to CDMS was 42%. Barkhof criteria with the strongest prognostic value were the presence at baseline of at least 9 T2-weighted lesions (hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.15-2.33; P = .006) and at least 3 periventricular lesions (1.66; 1.14-2.41; P = .009). No specific advantage was noted in using a fixed cutoff of at least 3 Barkhof criteria (HR, 1.31; 95% CI, 0.95-1.79; P = .10). The prognostic value of all MR imaging criteria was unaffected by treatment intervention (P ≥ .20 for all). Dissemination in time resulted in increased risk for CDMS only in patients without dissemination in space at baseline and was most informative at the 9-month MR imaging (HR, 2.72; 95% CI, 1.26-5.87; P = .01). Conclusions The modified Barkhof criteria showed moderate predictive value for conversion to CDMS, although all patients had received interferon beta-1b therapy for at least 1 year. The predictive value was unaffected by treatment intervention. Follow-up MR imaging was most informative after 9 months in patients without dissemination in space at baseline.

Clinical Features in Early Parkinson Disease and Survival [Original Contribution]

Objective To examine the association between demographic and clinical features in early Parkinson disease (PD) and length of survival in a multiethnic population. Design Clinical features within 2 years of diagnosis were determined for an inception cohort established during 1994-1995. Vital status was determined through December 31, 2005. Predictor variables included age at diagnosis, sex, race/ethnicity, as well as clinical subtype (modified tremor dominant, postural instability gait difficulty), symmetry, cognitive impairment, depression, dysphagia, and hallucinations. Cox proportional hazards regression analysis was used to identify factors associated with shorter survival. Setting Kaiser Permanente Medical Care Program, northern California. Patients Five hundred seventy-three men and women with newly diagnosed PD. Results Three hundred fifty-two participants in the PD cohort (61.4%) had died in the follow-up period. Older age at diagnosis (hazard ratio [HR], 1.1; 95% confidence interval [CI], 1.09-1.12), modified postural instability gait difficulty subtype (HR, 1.8; 95% CI, 1.3-2.7), symmetry of motor signs (HR, 2.0; 95% CI, 1.1-3.7), mild (HR, 1.7; 95% CI, 1.3-2.2) and severe (HR, 2.7; 95% CI, 1.9-3.9) cognitive impairment, dysphagia (HR, 1.4; 95% CI, 1.1-1.9), and hallucinations (HR, 2.1; 95% CI, 1.3-3.2) were associated with increased all-cause mortality, after adjusting for age, sex, and race/ethnicity. None of the other factors altered mortality risk. In an empirical predictive analysis, most previous significant predictors remained associated with shorter survival. Conclusions Both motor and nonmotor features in early PD predict increased mortality risk, particularly postural instability gait difficulty, cognitive impairment, and hallucinations. These predictors may be useful in clinical practice and when designing clinical trials.

Survival Profiles of Patients With Frontotemporal Dementia and Motor Neuron Disease [Original Contribution]

Background Frontotemporal dementia and amyotrophic lateral sclerosis are neurodegenerative diseases associated with TAR DNA-binding protein 43– and ubiquitin-immunoreactive pathologic lesions. Objective To determine whether survival is influenced by symptom of onset in patients with frontotemporal dementia and amyotrophic lateral sclerosis. Design, Setting, and Patients Retrospective review of patients with both cognitive impairment and motor neuron disease consecutively evaluated at 4 academic medical centers in 2 countries. Main Outcome Measures Clinical phenotypes and survival patterns of patients. Results A total of 87 patients were identified, including 60 who developed cognitive symptoms first, 19 who developed motor symptoms first, and 8 who had simultaneous onset of cognitive and motor symptoms. Among the 59 deceased patients, we identified 2 distinct subgroups of patients according to survival. Long-term survivors had cognitive onset and delayed emergence of motor symptoms after a long monosymptomatic phase and had significantly longer survival than the typical survivors (mean, 67.5 months vs 28.2 months, respectively; P < .001). Typical survivors can have simultaneous or discrete onset of cognitive and motor symptoms, and the simultaneous-onset patients had shorter survival (mean, 19.2 months) than those with distinct cognitive or motor onset (mean, 28.6 months) (P = .005). Conclusions Distinct patterns of survival profiles exist in patients with frontotemporal dementia and motor neuron disease, and overall survival may depend on the relative timing of the emergence of secondary symptoms.

Macular Volume Determined by Optical Coherence Tomography as a Measure of Neuronal Loss in Multiple Sclerosis [Original Contribution]

Background Inner (area adjacent to the fovea) and outer regions of the macula differ with respect to relative thicknesses of the ganglion cell layer (neurons) vs retinal nerve fiber layer (RNFL; axons). Objective To determine how inner vs outer macular volumes relate to peripapillary RNFL thickness and visual function in multiple sclerosis (MS) and to examine how these patterns differ among eyes with vs without a history of acute optic neuritis (ON). Design Study using cross-sectional optical coherence tomography. Setting Three academic tertiary care MS centers. Participants Patients with MS, diagnosed by standard criteria, and disease-free control participants. Main Outcome Measures Optical coherence tomography was used to measure macular volumes and RNFL thickness. Visual function was assessed using low-contrast letter acuity and high-contrast visual acuity (Early Treatment Diabetic Retinopathy Study charts). Results Among eyes of patients with MS (n = 1058 eyes of 530 patients), reduced macular volumes were associated with peripapillary RNFL thinning; 10-µm differences in RNFL thickness (9.6% of thickness in control participants without disease) corresponded to 0.20-mm3 reductions in total macular volume (2.9% of volume in control participants without disease, P < .001). This relation was similar for eyes of MS patients with and without a history of ON. Although peripapillary RNFL thinning was more strongly associated with decrements in outer compared with inner macular volumes, correlations with inner macular volume were significant (r = 0.58, P < .001) and of slightly greater magnitude for eyes of MS patients with a history of ON vs eyes of MS patients without a history of ON (r = 0.61 vs r = 0.50). Lower (worse) visual function scores were associated with reduced total, inner, and outer macular volumes. However, accounting for peripapillary RNFL thickness, the relation between vision and inner macular volume remained significant and unchanged in magnitude, suggesting that this region contains retinal structures separate from RNFL axons that are important to vision. Conclusions Analogous to studies of gray matter in MS, these data provide evidence that reductions of volume in the macula (approximately 34% neuronal cells by average thickness) accompany RNFL axonal loss. Peripapillary RNFL thinning and inner macular volume loss are less strongly linked in eyes of MS patients without a history of ON than in eyes of MS patients with a history of ON, suggesting alternative mechanisms for neuronal cell loss. Longitudinal studies with segmentation of retinal layers will further explore the relation and timing of ganglion cell degeneration and RNFL thinning in MS.

Optical Coherence Tomography in Clinically Isolated Syndrome: No Evidence of Subclinical Retinal Axonal Loss [Original Contribution]

Background Optical coherence tomography has emerged as a new tool for quantifying axonal loss in multiple sclerosis (MS). A reduction in retinal nerve fiber layer (RNFL) thickness is correlated with Expanded Disability Status Scale score and brain atrophy. Objective To investigate RNFL and macular volume measurements using optical coherence tomography in the clinically isolated syndrome population. Design Prospective case series. Settings Neurologic clinics at the university hospitals of Lille and Strasbourg (France). Participants Fifty-six consecutive patients with clinically isolated syndrome (18 with optic neuritis and 38 without optic neuritis) and 32 control subjects. Main Outcome Measures Macular volume and RNFL thickness. Results Mean (SD) overall RNFL thickness (98.98 [10.26] µm) and macular volume (6.86 [0.32] µm3) in the clinically isolated syndrome population were not significantly different compared with the controls (98.71 [9.08] µm and 6.92 [0.38] µm3, respectively). No link was noted between atrophy of the RNFL or macula and conversion to MS at 6 months. Conclusions Optical coherence tomography does not reveal retinal axonal loss at the earliest clinical stage of MS and does not predict conversion to MS at 6 months.

Effects of Family History and Apolipoprotein E {varepsilon}4 Status on Cognitive Decline in the Absence of Alzheimer Dementia: The Cache County Study [Original Contribution]

Objective To evaluate the influences of a family history of Alzheimer dementia (FHxAD) and the apolipoprotein E 4 genotype (APOE 4) on cognitive decline. Design, Setting, and Participants Residents of Cache County, Utah, aged 65 years or older, were invited to participate. At baseline, 2957 participants provided DNA for genotyping of APOE and a detailed FHxAD. They also completed the Modified Mini-Mental State Examination. Cognitive status was reexamined after 3 and 7 years. We used mixed-effects models to examine the association among FHxAD, APOE 4, and cognitive trajectories. Main Outcome Measure Modified Mini-Mental State Examination score trajectories over time. Results Compared with participants who did not have APOE 4 or an FHxAD, those with APOE 4 scored lower on the Modified Mini-Mental State Examination at baseline (–0.70 points; 95% confidence interval [CI], –1.15 to –0.24). Participants with an FHxAD and APOE 4 differed less, if at all, in baseline score (–0.46 points; 95% CI, –1.09 to 0.16) but declined faster during the 7-year study (–9.75 points [95% CI, –10.82 to –8.67] vs –2.91 points [95% CI, –3.37 to –2.44]). After exclusion of participants who developed prodromal AD or incident dementia, the group with an FHxAD and APOE 4 declined much less during the 7-year study (–1.54; 95% CI, –2.59 to –0.50). Conclusions Much of the association among FHxAD, APOE 4, and cognitive decline may be attributed to undetected incipient (latent) disease. In the absence of latent disease, the 2 factors do not appear individually to be associated with cognitive decline, although they may be additive.

Error in Figure in: Depletion of B Lymphocytes From Cerebral Perivascular Spaces by Rituximab [Correction]

Linking Hippocampal Structure and Function to Memory Performance in an Aging Population [Original Contribution]

Background Hippocampal atrophy and reductions in basal cerebral blood volume (CBV), a hemodynamic correlate of brain function, occur with cognitive impairment in Alzheimer disease, but whether these are early or late changes remains unclear. Magnetic resonance imaging is used to assess structure and function in the hippocampal formation. Objective To estimate differences in the associations of hippocampal and entorhinal cortex volumes and CBV with memory function in the early and late stages of cognitive impairment by relating these measures to memory function in persons with and without dementia who underwent detailed brain imaging and neuropsychological assessment. Design Multivariate regression analyses were used to relate entorhinal cortex volume, entorhinal cortex CBV, hippocampal volume, and hippocampal CBV to measurements of memory performance. The same measures were related to language function as a reference cognitive domain. Setting Community-based cohort. Participants Two hundred thirty-one elderly Medicare recipients (aged ≥65 years) residing in northern Manhattan, New York. Main Outcome Measures Values for entorhinal cortex volume, hippocampal volume, entorhinal cortex CBV, and hippocampal CBV and their relation to memory performance. Results No association was noted between entorhinal cortex volume or hippocampal CBV and memory. Decreased hippocampal volume was strongly associated with worse performance in total recall, and lower entorhinal cortex CBV was associated with lower performance in delayed recall. Excluding persons with Alzheimer disease, the association of entorhinal cortex CBV with memory measures was stronger, whereas the association between hippocampal volume and total recall became nonsignificant. Conclusions In the early stages of Alzheimer disease or in persons without dementia with worse memory ability, functional and metabolic hippocampal hypofunction contributes to memory impairment, whereas in the later stages, functional and structural changes play a role.

Differences in Brain Volume, Hippocampal Volume, Cerebrovascular Risk Factors, and Apolipoprotein E4 Among Mild Cognitive Impairment Subtypes [Original Contribution]

Objectives To evaluate demographics, magnetic resonance imaging (MRI) measures, and vascular risk among mild cognitive impairment (MCI) subtypes. Design Cross-sectional study. Setting Both clinics and the community. Participants A total of 153 subjects with MCI, 218 cognitively normal older individuals (controls), and 68 patients with Alzheimer disease. Main Outcome Measures Classification of subjects with MCI according to current subtype diagnostic convention based on neuropsychological performance, estimates of vascular risk based on medical history, research MRI unless there was a specific contraindication, and apolipoprotein E genotype. Results Of the 153 subjects with MCI, 65 were diagnosed with amnestic single-domain, 46 with amnestic multiple-domain, 27 with nonamnestic single-domain, and 15 with nonamnestic multiple-domain MCI. Analyses of control, MCI, and Alzheimer disease cases revealed significant differences in brain and hippocampal volumes between each group. Post hoc analyses of MRI measures among the MCI subtypes found that patients with amnestic single-domain MCI had significantly less brain atrophy and that hippocampal volume differed significantly from controls for the 2 amnestic forms of MCI. Apolipoprotein E genotype prevalence was significantly greater in the amnestic and nonamnestic subtypes of MCI. Conversely, the nonamnestic subtypes were more likely to have increased vascular risk and to be African American. Conclusions Amnestic forms of MCI appear to have demographic, genetic, and MRI findings suggestive of Alzheimer disease pathology, whereas the nonamnestic forms of MCI have findings suggestive of vascular disease. Importantly, however, all subjects with MCI showed evidence of brain injury, and the biological differences among subtypes are relatively subtle beyond the memory vs nonmemory groupings.

Lipid Profile Components and Risk of Ischemic Stroke: The Northern Manhattan Study (NOMAS) [Original Contribution]

Objective To explore the relationship between lipid profile components and incident ischemic stroke in a stroke-free prospective cohort. Design Population-based prospective cohort study. Setting Northern Manhattan, New York. Patients Stroke-free community residents. Intervention As part of the Northern Manhattan Study, baseline fasting blood samples were collected on stroke-free community residents followed up for a mean of 7.5 years. Main Outcome Measures Cox proportional hazard models were used to calculate hazard ratios and 95% confidence intervals for lipid profile components and ischemic stroke after adjusting for demographic and risk factors. In secondary analyses, we used repeated lipid measures over 5 years from a 10% sample of the population to calculate the change per year of each of the lipid parameters and to impute time-dependent lipid parameters for the full cohort. Results After excluding those with a history of myocardial infarction, 2940 participants were available for analysis. Baseline high-density lipoprotein cholesterol, triglyceride, and total cholesterol levels were not associated with risk of ischemic stroke. Low-density lipoprotein cholesterol (LDL-C) and non–high-density lipoprotein cholesterol levels were associated with a paradoxical reduction in risk of stroke. There was an interaction with use of cholesterol-lowering medication on follow-up, such that LDL-C level was only associated with a reduction in stroke risk among those taking medications. An LDL-C level greater than 130 mg/dL as a time-dependent covariate showed an increased risk of ischemic stroke (adjusted hazard ratio, 3.81; 95% confidence interval, 1.53-9.51). Conclusions Baseline lipid panel components were not associated with an increased stroke risk in this cohort. Treatment with cholesterol-lowering medications and changes in LDL-C level over time may have attenuated the risk in this population, and lipid measurements at several points may be a better marker of stroke risk.

Error in Author Affiliation in: Diffusion Abnormalities in the Primary Sensorimotor Pathways in Writer's Cramp [Correction]

Multifocal Paraneoplastic Cortical Encephalitis Associated With Myasthenia Gravis and Thymoma [Observation]

Objectives To report a case of multifocal cortical encephalitis associated with thymoma and to establish an association of this thymoma-related paraneoplastic syndrome with voltage-gated potassium channel antibodies. Design Case report. Setting University hospital. Patient A 43-year-old woman with a history of seropositive myasthenia gravis and successfully treated invasive thymoma. Four years after thymectomy, she presented with seizure and rapidly progressive confusion and aphasia. Myasthenia gravis remained in pharmacological remission. Magnetic resonance imaging of the brain showed innumerable cortically based signal abnormalities as well as extensive left mesial temporal lobe abnormality with minimal enhancement. Results Chest computed tomography showed abnormal pleural thickening of the left lung, which proved to be recurrent metastatic thymoma. Results of serological evaluation were positive for acetylcholine receptor, striational, and voltage-gated potassium channel antibodies. She showed partial improvement in response to immunotherapy and chemotherapy but ultimately died 2 months later of tumor complications. Conclusions Thymoma and myasthenia gravis may be associated with other autoimmune neurological disorders including paraneoplastic encephalitis. This second case of thymoma-associated multifocal cortical encephalitis demonstrates that autoimmune encephalitis can extend to cortical regions outside the limbic system. Autoimmune encephalitis should be considered in the differential diagnosis of patients with myasthenia gravis or thymoma who develop new cognitive symptoms.

Childhood Chorea With Cerebral Hypotrophy: A Treatable GLUT1 Energy Failure Syndrome [Observation]

Objective To expand the spectrum of glucose transporter type 1 deficiency syndromes with a novel clinical and radiological phenotype not associated with microcephaly. Design Case report. Setting Two academic medical centers. Patient A 7-year-old patient followed up for 4 years. Results The patient exhibited a predominant syndrome of chorea and mental retardation associated with a combination of paroxysmal ataxia, dysarthria, dystonia and aggravated intellectual disability induced by fasting or exertion. She harbored a sporadic, heterozygous amino acid insertion in the GLUT1 transporter (insY292) that, in all likelihood, impaired blood-brain glucose flux. Her brain configuration appeared hypotrophic via magnetic resonance imaging, particularly over the occipital lobes. A ketogenic diet resulted in brain growth that accompanied a favorable symptomatic outcome. Conclusions To date, glucose transporter type 1 deficiency syndrome includes several epileptic and movement disorder phenotypes caused by the clinical expressivity of the prominent cortical, basal ganglia, and cerebellar abnormalities found in the disease, but hypomorphic or novel variants are probably yet to be discovered.

The Value of Specifying Brand-name Antiepileptic Drugs [Controversies in Neurology]

Generic Anticonvulsant Use in Children: Do We Have Evidence to Recommend Brand Formulations? [Controversies in Neurology]

The Cost of Gullibility [Controversies in Neurology]

Deep Venous Anomaly: Caput Medusa in the Brain [Images in Neurology]

Intramedullary Spinal Cord Metastasis [Images in Neurology]

Fornix Injury in a Patient With Diffuse Axonal Injury [Images in Neurology]

Treating Tourette Syndrome and Tic Disorders: A Guide for Practitioners [Book Reviews]

Are Neurology Residents Prepared to Deal With Dying Patients? [Research Letters]

What Is Really New in Progressive Muscle Atrophy? [Correspondence]

What Is Really New in Progressive Muscle Atrophy?--Reply [Correspondence]

About This Journal [About This Journal]

This Month in Archives of Neurology [This Month in Archives of Neurology]

Immunotherapy for Multiple Sclerosis: The Curious Case of Interferon Beta [Editorial]

Physiologic Alterations in Ataxia: Channeling Changes Into Novel Therapies [Neurological Review]

The ataxias constitute a heterogeneous group of diseases in which cerebellar dysfunction typically underlies the major neurologic manifestations. It is increasingly clear that ataxia can result directly from mutations in ion channels or from perturbations in ion channel physiology in the absence of a primary channel defect. Neuronal dysfunction stemming from perturbed channel activity likely explains some motor deficits in episodic and degenerative ataxias. Understanding these pathophysiologic changes may reveal novel therapeutic targets for symptomatic treatment of ataxia.

Essential Tremors: A Family of Neurodegenerative Disorders? [Neurological Review]

Essential tremor (ET) is the most common pathologic tremor in humans. The traditional view of ET, as a monosymptomatic condition, is being replaced by an appreciation of the spectrum of clinical features, with both motor and nonmotor elements. These features are not distributed homogeneously across patients. In addition, postmortem studies are now demonstrating distinct structural changes in ET. There is growing evidence that ET may be a family of diseases rather than a single entity. Furthermore, this aging-associated, progressive disorder is associated with neuronal loss and postmortem changes that occur in traditional neurodegenerative disorders.

Promising Strategies for the Prevention of Dementia [Neurological Review]

The incidence and prevalence of dementia are expected to increase several-fold in the coming decades. Given that the current pharmaceutical treatment of dementia can only modestly improve symptoms, risk factor modification remains the cornerstone for dementia prevention. Some of the most promising strategies for the prevention of dementia include vascular risk factor control, cognitive activity, physical activity, social engagement, diet, and recognition of depression. In observational studies, vascular risk factors—including diabetes, hypertension, dyslipidemia, and obesity—are fairly consistently associated with increased risk of dementia. In addition, people with depression are at high risk for cognitive impairment. Population studies have reported that intake of antioxidants or polyunsaturated fatty acids may be associated with a reduced incidence of dementia, and it has been reported that people who are cognitively, socially, and physically active have a reduced risk of cognitive impairment. However, results from randomized trials of risk factor modification have been mixed. Most promising, interventions of cognitive and physical activity improve cognitive performance and slow cognitive decline. Future studies should continue to examine the implication of risk factor modification in controlled trials, with particular focus on whether several simultaneous interventions may have additive or multiplicative effects.

Enhancement of Chemokine Expression by Interferon Beta Therapy in Patients With Multiple Sclerosis [Original Contribution]

Background Interferon beta has been approved for the treatment of multiple sclerosis (MS). It is believed that immunomodulatory rather than antiviral activity of interferon beta is responsible for disease amelioration. The impact of interferon beta on the chemoattraction of immune cells has not been fully addressed. Objective To address the influence of interferon beta on the expression of chemokines and their receptors in a standardized setting. Design The expression of 14 chemokines and 14 chemokine receptor genes was determined by quantitative real-time polymerase chain reaction from fresh blood samples. Setting Outpatient units in Germany. Patients Untreated and interferon beta–treated patients with MS who tested positive and negative for neutralizing antibodies (NABs) were recruited from August 24, 2006, through December 15, 2006, for the initial study and from March 12, 2007, through April 2, 2007, for the validation study. Main Outcome Measures Gene expression and serum chemokine protein levels. Results CCL1, CCL2, CCL7, CXCL10, CXCL11, and CCR1 gene expression was strongly upregulated in interferon beta–treated, NAB-negative MS patients. In contrast, gene expression in interferon beta–treated, NAB-positive MS patients did not differ from untreated control donor individuals. Antibody titers inversely correlated with chemokine and chemokine receptor gene expression. Accordingly, serum chemokine protein levels of interferon beta–treated, NAB-negative MS patients were significantly higher than in untreated or interferon beta–treated, NAB-positive MS patients. Conclusions We demonstrate that interferon beta strongly upregulates a set of chemokines and CCR1 in peripheral immune cells. The peripheral upregulation of these chemokines may reduce the chemoattraction of immune cells to the central nervous system and thus add to the therapeutic effects of interferon beta. Published online August 10, 2009 (doi:10.1001/archneurol.2009.138).

Prediction by Modeling That Epilepsy May Be Caused by Very Small Functional Changes in Ion Channels [Original Contribution]

Objective To use computer simulation to perform a "genetic sensitivity" analysis to predict which genes are best positioned to increase risk as well as to predict functionally how variants in these genes might increase network excitability. Methods A previously published, biophysically realistic model of the dentate gyrus that included mossy fiber sprouting between granule cells was used to model putative environmental changes associated with temporal lobe epilepsy. Properties of voltage-gated ion channels, either 1 at a time or in combinations, were varied systematically to determine their effect on network excitability. Results We found that the network is most sensitive to changes in steady-state voltage dependence of activation and relatively insensitive to changes in inactivation. Changes in sodium channels had the greatest effect on excitability, followed by changes in fast-delayed rectifier potassium channels and then N-type calcium channels. We also investigated the effects of simultaneous small changes in several ion channels, modeling a complex genetic background expected for common epilepsies. A combination of 2 or 3 simultaneous voltage shifts in steady-state activation as small as 2 mV could produce large changes in network excitability. Conclusion Statistical power calculations indicate that changes this small are effectively undetectable with current experimental practices, thus posing new challenges for the functional analysis and validation of epilepsy genes.

Seizure Relapse and Development of Drug Resistance Following Long-term Seizure Remission [Original Contribution]

Objective To quantify and identify predictive risk factors for seizure relapse and development of drug resistance in patients who achieved long-term (>1 year) antiepileptic drug–induced seizure remission. Design Prospective cohort study. Setting Epilepsy Center, Rambam Medical Center. Patients Two hundred fifty-six consecutive patients who entered long-term (>1 year) antiepileptic drug–induced seizure remission were followed up prospectively for 2 years or more. Main Outcome Measures Seizure relapse and development of drug-resistant epilepsy. Results Five years after entering seizure remission, 40.2% of patients experienced seizure relapse and 25.3% of patients developed drug-resistant epilepsy. The Kaplan-Meier curves could be fitted by monoexponential functions, with a maximal seizure relapse rate of 43.6%, maximal drug-resistance rate of 27.4%, and half-decay constant of 21.5 months for both curves. Treatment history served as a significant independent prognostic risk factor for both seizure relapse and development of drug resistance. The preremission seizure frequency and duration of epilepsy were also identified as significant prognostic risk factors in the univariant analysis but failed to reach statistical significance in the multivariate analysis. Conclusion Seizure relapse commonly occurs in patients following long-term seizure remission. Treatment history and duration of epilepsy are predictive risk factors for both seizure relapse and development of drug resistance.

Codistribution of Amyloid {beta} Plaques and Spongiform Degeneration in Familial Creutzfeldt-Jakob Disease With the E200K-129M Haplotype [Original Contribution]

Background Dominantly inherited Creutzfeldt-Jakob disease (CJD) represents 5% to 15% of all CJD cases. The E200K mutation in the prion protein (PrP) gene (PRNP) is the most frequent cause of familial CJD. Coexistent amyloid β (Aβ) plaques have been reported in some transmissible spongiform encephalopathies but to date have not been reported in familial CJD with the E200K mutation. Objective To characterize a family with CJD in which Aβ plaques codistribute with spongiform degeneration. Design Clinicopathologic and molecular study of a family with CJD with the E200K-129M haplotype. Setting Alzheimer disease research center. Participants Two generations of a family. Main Outcome Measures Clinical, biochemical, and neuropathologic observations in 2 generations of a family. Results In this kindred, 3 autopsied cases showed pathologic changes typical for the E200K-129M haplotype, including spongiform degeneration, gliosis, neuronal loss, and PrP deposition. Moreover, 2 of these cases (ages 57 and 63 years) showed numerous Aβ plaques codistributed with spongiform degeneration. APOE genotyping in 2 cases revealed that Aβ plaques were present in the APOE 4 carrier but not in the APOE 4 noncarrier. Two additional cases exhibited incomplete penetrance, as they had no clinical evidence of CJD at death after age 80 years but had affected siblings and children. Conclusions To our knowledge, this is the first description of Aβ plaques in familial CJD with the E200K mutation. The codistribution of plaques and CJD-associated changes suggests that PrP plays a central role in Aβ formation and that Aβ pathology and prion disease likely in fluence each other. The kindred described herein provides support that PrPE200K may result in increased Aβ deposition.

Ten-Year Change in Plasma Amyloid {beta} Levels and Late-Life Cognitive Decline [Original Contribution]

Background Plasma levels of amyloid β peptide (Aβ) are potential biomarkers of early cognitive impairment and decline and of Alzheimer disease risk. Objective To relate midlife plasma Aβ measures and 10-year change in plasma Aβ measures since midlife to late-life cognitive decline. Design Prospective study of a population-based sample. Setting Academic research. Participants Plasma Aβ40 and Aβ42 levels were measured in 481 Nurses' Health Study participants in late midlife (mean age, 63.6 years) and again 10 years later (mean age, 74.6 years). Cognitive testing also began 10 years after the initial blood draw. Participants completed 3 repeated telephone-based assessments (mean span, 4.1 years). Multivariable linear mixed-effects models were used to estimate relations of midlife plasma Aβ40 to Aβ42 ratios and Aβ42 levels to late-life cognitive decline, as well as relations of 10-year change in Aβ40 to Aβ42 ratios and Aβ42 levels to cognitive decline. Main Outcome Measures The 3 primary outcomes were the Telephone Interview for Cognitive Status (TICS) findings, a global score averaging the results of all tests (TICS, immediate and delayed verbal recall, category fluency, and attention), and a verbal memory score averaging the results of 4 tests of verbal recall. Results Higher midlife plasma Aβ40 to Aβ42 ratios were associated with worse late-life decline on the global score (P = .04 for trend). Furthermore, increase in Aβ40 to Aβ42 ratios since midlife predicted greater decline in the global score (P = .03 for trend) and in the TICS (P = .02 for trend). There was no association of cognitive decline with midlife plasma Aβ42 levels alone or with change in Aβ42 levels since midlife. Conclusion In this large community-dwelling sample, higher plasma Aβ40 to Aβ42 ratios in late midlife and increases in Aβ40 to Aβ42 ratios 10 years later were significantly associated with greater decline in global cognition at late life.

Longitudinal Study of the Transition From Healthy Aging to Alzheimer Disease [Original Contribution]

Background Detection of the earliest cognitive changes signifying Alzheimer disease is difficult. Objective To model the cognitive decline in preclinical Alzheimer disease. Design Longitudinal archival study comparing individuals who became demented during follow-up and people who remained nondemented on each of 4 cognitive factors: global, verbal memory, visuospatial, and working memory. Setting Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, Missouri. Participants One hundred thirty-four individuals who became demented during follow-up and 310 who remained nondemented. Main Outcome Measures Inflection point in longitudinal cognitive performance. Results The best-fitting model for each of the 4 factors in the stable group was linear, with a very slight downward trend on all but the Visuospatial factor. In contrast, a piecewise model with accelerated slope after a sharp inflection point provided the best fit for the group that progressed. The optimal inflection point for all 4 factors was prior to diagnosis of dementia: Global, 2 years; Verbal and Working Memory, 1 year; and Visuospatial, 3 years. These results were also obtained when data were limited to the subset (n = 44) with autopsy-confirmed Alzheimer disease. Conclusions There is a sharp inflection point followed by accelerating decline in multiple domains of cognition, not just memory, in the preclinical period in Alzheimer disease when there is insufficient cognitive decline to warrant clinical diagnosis using conventional criteria. Early change was seen in tests of visuospatial ability, most of which were speeded. Research into early detection of cognitive disorders using only episodic memory tasks may not be sensitive to all of the early manifestations of disease.

Implication of Sex and SORL1 Variants in Italian Patients With Alzheimer Disease [Original Contribution]

Objective To investigate the association of genetic variants in sortilin-related receptor (SORL1), which has been proposed as an important genetic contributor to late-onset Alzheimer disease (LOAD). Design We analyzed 13 SORL1 single-nucleotide polymorphisms (SNPs) and the relative haplotypes in a case-control association study. Participants The sample included 708 Italian subjects: 251 unrelated, sporadic patients with LOAD, 99 sporadic patients with early-onset Alzheimer disease (AD), and 358 healthy controls. Main Outcome Measures We analyzed the 13 SNPs in the SORL1 gene that had been studied in previous reports using case-control methods and included sex, apolipoprotein E (APOE) genotype, and age at AD onset as covariates. Results The SNPs 4 (rs661057), 7 (rs12364988), and 10 (rs641120) were significantly associated with LOAD compared with controls. We found an association between these 3 variants and sex, suggesting that SORL1 may possibly affect LOAD through a female-specific mechanism. Of interest, the association of these SNPs with LOAD was confined to APOE 4 noncarriers. Several haplotypic associations at the 5' end of SORL1 were found, including the previously associated CGC haplotype at SNPs 8 through 10. Conclusions Our results confirm the association of SORL1 with AD and show a possible effect of female sex, suggesting that this gene may be a promising susceptibility factor for LOAD. Further studies to detect pathogenic variants and further elucidate the effect of SORL1 on the development of AD are necessary.

Association of Intronic Variants of the BTBD9 Gene With Tourette Syndrome [Original Contribution]

Objective To test the association between Tourette syndrome (TS) and genetic variants in genomic loci MEIS1, MAP2K5/LBXCOR1, and BTBD9, for which genome-wide association studies in restless legs syndrome and periodic limb movements during sleep revealed common risk variants. Design Case-control association study. Setting Movement disorder clinic in Montreal. Subjects We typed 14 single-nucleotide polymorphisms spanning the 3 genomic loci in 298 TS trios, 322 TS cases (including 298 probands from the cohort of TS trios), and 290 control subjects. Main Outcome Measures Clinical diagnosis of TS, obsessive-compulsive disorder, and attention-deficit disorder. Results The study provided 3 single-nucleotide polymorphisms within BTBD9 associated with TS (2 = 8.02 [P = .005] for rs9357271), with the risk alleles for restless legs syndrome and periodic limb movements during sleep overrepresented in the TS cohort. We stratified our group of patients with TS according to presence or absence of obsessive-compulsive disorder and/or attention-deficit disorder and found that variants in BTBD9 were strongly associated with TS without obsessive-compulsive disorder (2 = 12.95 [P < .001] for rs9357271). Furthermore, allele frequency of rs9357271 inversely correlated with severity of obsessive-compulsive disorder as measured by the Yale-Brown Obsessive Compulsive Scale score. Conclusion Variants in BTBD9 that predispose to restless legs syndrome and periodic limb movements during sleep are also associated with TS, particularly TS without obsessive-compulsive disorder.

Error in Table in: Progress and Challenges in RNA Interference Therapy for Huntington Disease [Correction]

Association of Ideomotor Apraxia With Frontal Gray Matter Volume Loss in Corticobasal Syndrome [Original Contribution]

Objective To determine the brain areas associated with specific components of ideomotor apraxia (IMA) in corticobasal syndrome (CBS). Design Case-control and cross-sectional study. Participants Forty-eight patients with CBS and 14 control subjects. Intervention Administration of the Test of Oral and Limb Apraxia. Main Outcome Measures Differences between patients with CBS and healthy controls and associations between areas of gray matter volume and IMA determined by voxel-based morphometry in patients with CBS. Results Overall, IMA was associated with decreased gray matter volume in the left supplemental motor area, premotor cortex, and caudate nucleus of patients with CBS. The overall degree of apraxia was independent of the side of motor impairment. Praxis to imitation (vs command) was particularly impaired in the patients with CBS. Patients demonstrated equal impairment in transitive and intransitive praxis. Conclusions In patients with CBS, IMA is associated with left posterior frontal cortical and subcortical volume loss. Despite showing left frontal volume loss associated with IMA, patients with CBS have particularly impaired imitation of gestures. These findings suggest either that the IMA of CBS affects a route of praxis that bypasses motor engrams or that motor engrams are affected but that they exist in areas other than the inferior parietal cortex.

Sensations Evoked in Patients With Amputation From Watching an Individual Whose Corresponding Intact Limb Is Being Touched [Observation]

Background After amputation of a limb, the majority of patients experience phantom sensations, such as phantom pain. Such patients provide an opportunity for the exploration of the perceptual correlates of recently discovered "mirror neurons," which fire not only when individuals move their own limb but when they watch the movements of the corresponding limb of another person. Similar neurons exist in the secondary somatosensory cortex for touch: they fire when the individual is touched or simply watches another person be touched. While these neurons cannot by themselves discriminate between the two, the mind is aware of the difference between feeling and watching; one does not confuse empathy with actual experience. Objective To investigate whether patients with amputation experience the sensations of another person in their own phantom limb during the mere observation of someone else being touched, owing to removal of the inhibition of the mirror neuron system that would have occurred had the limb been intact. Design Case report. Setting University campus, academic setting. Patients Four patients with upper-limb amputation. Main Outcome Measures The subjective reports of patients. Results We report that 4 individuals with arm amputation, the mere watching of the intact hand of another being touched evokes vivid, precisely localized sensations in their own phantom hands. Conclusions We suggest these evoked sensations are owing to removal of neural signals from the hand that would have ordinarily inhibited the response of the mirror neurons and prevented their activity from reaching the threshold of conscious awareness.

Polymyoclonus, Laryngospasm, and Cerebellar Ataxia Associated With Adenocarcinoma and Multiple Neural Cation Channel Autoantibodies [Observation]

Objective To describe and provide audiovisual documentation of a syndrome of polymyoclonus, laryngospasm, and cerebellar ataxia associated with adenocarcinoma and multiple neural cation channel autoantibodies. Design Case report with video. Setting University hospitals. Patient A 69-year-old woman presented with subacute onset of whole-body tremulousness and laryngospasm attributed to gastroesophageal reflux. Results Further evaluation revealed polymyoclonus, cerebellar ataxia, and laryngospasm suspicious of an underlying malignant neoplasm. Surface electromyography of multiple limb muscles confirmed the presence of polymyoclonus. The patient was seropositive for P/Q-type voltage-gated calcium channel antibody; subsequently, whole-body fluorine 18 fluorodeoxyglucose positron emission tomography and cervical lymph node biopsy revealed widespread metastatic adenocarcinoma. Follow-up serologic evaluation revealed calcium channel antibodies (P/Q type and N type) and potassium channel antibody. Conclusions We highlight the importance of recognizing polymyoclonus. To our knowledge, this is also the first description of a syndrome of polymyoclonus, laryngospasm, and ataxia associated with adenocarcinoma and these cation channel antibodies.

Stroke Incidentally Identified Using Improved Positron Emission Tomography for Microglial Activation [Images in Neurology]

Neurocysticercosis: Still Life in the Brain [Images in Neurology]

Multiple Brain Abscesses Associated With Tongue Piercing [Images in Neurology]

A Giant Spinal Cord Cavity [Images in Neurology]

Headache and Facial Pain: What Do I Do Now? [Book Reviews]

Humoral Pattern II Multiple Sclerosis Pathology Not Associated With Neuromyelitis Optica IgG [Research Letters]

Notice of Incomplete Referencing [Correspondence]

Notice of Incomplete Referencing--Reply [Correspondence]

Unreported Financial Disclosure [Correspondence]

Unreported Financial Disclosure--Reply [Correspondence]

About This Journal [About This Journal]

This Month in Archives of Neurology [This Month in Archives of Neurology]

Error in Byline in: The Natural History of Recurrent Optic Neuritis [Correction]

Translating What Is Known About Neurological Complications of Coronary Artery Bypass Graft Surgery Into Action [Editorial]

Emerging Viral Infections of the Central Nervous System: Part 2 [Neurological Review]

The first part of this review ended with a discussion of new niches for known viruses as illustrated by viral central nervous system (CNS) disease associated with organ transplant and the syndrome of human herpesvirus 6–associated posttransplant acute limbic encephalitis. In this part, we begin with a continuation of this theme, reviewing the association of JC virus–associated progressive multifocal leukoencephalopathy (PML) with novel immunomodulatory agents. This part then continues with emerging viral infections associated with importation of infected animals (monkeypox virus), then spread of vectors and enhanced vector competence (chikungunya virus [CHIK]), and novel viruses causing CNS infections including Nipah and Hendra viruses and bat lyssaviruses (BLV).

Preventive Antibiotics for Infections in Acute Stroke: A Systematic Review and Meta-analysis [Neurological Review]

Objective To provide a systematic overview and meta-analysis of randomized clinical trials evaluating preventive antibiotics in patients with acute stroke. Data Sources The MEDLINE (1966-February 2009) and Cochrane databases and reference lists of retrieved articles. Study Selection Randomized controlled trials on preventive antibiotic treatment in stroke. For inclusion, at least case fatality or infection rate had to be recorded. Data Extraction Each study was scored for methodological key issues and appraised by the Jadad scale. We extracted the data using a predetermined protocol and included all patients who were randomized or who started therapy in an intent-to-treat analysis. Data Synthesis We identified 4 randomized clinical trials including 426 patients; 94% had ischemic stroke. Study interventions were fluoroquinolones in 2 and tetracycline or a combination of β-lactam antibiotic with β-lactamase inhibitor in 1. Therapy was started within 24 hours of stroke onset. Duration of therapy varied between 3 and 5 days. The methodological quality ranged from 2 to 5 on the Jadad scale, and studies were subject to potential bias. The proportion of patients with infection was significantly smaller in the antibiotic group than in the placebo/control group (32 of 136 [23.5%] vs 53 of 139 [38.1%] patients). The pooled odds ratio for infection was 0.44 (95% confidence interval, 0.23-0.86). Ten of 210 patients (4.8%) in the antibiotic group died, compared with 13 of 216 (6.0%) in the placebo/control group. The pooled odds ratio for mortality was 0.63 (95% confidence interval, 0.22-1.78). No major harm or toxicity was reported. Conclusions In adults with acute stroke, preventive antibiotics reduced the risk of infection, but did not reduce mortality. The observed effect warrants evaluation of preventive antibiotics in large stroke trials.

Robotic Devices as Therapeutic and Diagnostic Tools for Stroke Recovery [Neurological Review]

The understanding that recovery of brain function after stroke is imperfect has prompted decades of effort to engender speedier and better recovery through environmental manipulation. Clinical evidence has shown that the performance plateau exhibited by patients with chronic stroke, usually signaling an end of standard rehabilitation, might represent a period of consolidation rather than a performance optimum. These results highlight the difficulty of translating pertinent neurological data into pragmatic changes in clinical programs. This opinion piece focuses on upper limb impairment reduction after robotic training. We propose that robotic devices be considered as novel tools that might be used alone or in combination with novel pharmacology and other bioengineered devices. Additionally, robotic devices can measure motor performance objectively and will contribute to a detailed phenotype of stroke recovery.

Strokes After Cardiac Surgery and Relationship to Carotid Stenosis [Original Contribution]

Objective To critically examine the role of significant carotid stenosis in the pathogenesis of postoperative stroke following cardiac operations. Design Retrospective cohort study. Setting Single tertiary care hospital. Participants A total of 4335 patients undergoing coronary artery bypass grafting, aortic valve replacement, or both. Main Outcome Measures Incidence, subtype, and arterial distribution of stroke. Results Clinically definite stroke was detected in 1.8% of patients undergoing cardiac operations during the same admission. Only 5.3% of these strokes were of the large-vessel type, and most strokes (76.3%) occurred without significant carotid stenosis. In 60.0% of cases, strokes identified via computed tomographic head scans were not confined to a single carotid artery territory. According to clinical data, in 94.7% of patients, stroke occurred without direct correlation to significant carotid stenosis. Undergoing combined carotid and cardiac operations increases the risk of postoperative stroke compared with patients with a similar degree of carotid stenosis but who underwent cardiac surgery alone (15.1% vs 0%; P = .004). Conclusions There is no direct causal relationship between significant carotid stenosis and postoperative stroke in patients undergoing cardiac operations. Combining carotid and cardiac procedures is neither necessary nor effective in reducing postoperative stroke in patients with asymptomatic carotid stenosis.

Determinants of the Timing of Symptomatic Treatment in Early Parkinson Disease: The National Institutes of Health Exploratory Trials in Parkinson Disease (NET-PD) Experience [Original Contribution]

Objective To assess the predictive value of baseline measures of impairment, disability, and quality of life for the timing of initiation of symptomatic treatment in early Parkinson disease (PD). Design Inception cohort analysis. Setting Ambulatory population from multiple sites in the United States and Canada. Participants Four hundred thirteen patients with early, untreated PD who participated in 2 double-blind trials that assessed the potential of experimental drugs to serve as disease-modifying agents in PD. Intervention Participants were randomized into treatment groups: creatine (n = 67), minocycline (n = 66), coenzyme Q10 (n = 71), GPI-1485 (n = 71), and placebo (n = 138). Main Outcome Measure Time between baseline assessment and need for the initiation of symptomatic treatment for PD. The following baseline variables were assessed for their relation to the main outcome measure, while adjusting for possible treatment effect: sex; age; level of education; race/ethnicity; disease duration; occupational status; and Unified Parkinson Disease Rating Scale (UPDRS), Medical Outcomes Study Short Form Survey, Modified Rankin Scale, Schwab and England Activities of Daily Living Scale, Total Functional Capacity Scale, 39-item Parkinson Disease Questionnaire, and Geriatric Depression Scale scores. Variables reaching statistical threshold in univariate analyses ( = .15) were entered into a multivariable Cox proportional hazards regression model using time to symptomatic treatment as the dependent variable. Results Approximately half (48.5%) of the participants reached end point within 12 months. Higher baseline impairment and disability, as determined by UPDRS III (motor section), UPDRS II (activities of daily living section, participant rating), and Modified Rankin Scale scores and level of education were independently associated with an earlier need for symptomatic treatment. Conclusions In early PD, greater impairment and disability and higher level of education are independently associated with an earlier need for symptomatic treatment. Published online July 13, 2009 (doi:10.1001/archneurol.2009.159).

Occupation and Risk of Parkinsonism: A Multicenter Case-Control Study [Original Contribution]

Background We examined risk of parkinsonism in occupations (agriculture, education, health care, welding, and mining) and toxicant exposures (solvents and pesticides) putatively associated with parkinsonism. Objective To investigate occupations, specific job tasks, or exposures and risk of parkinsonism and clinical subtypes. Design Case-control. Setting Eight movement disorders centers in North America. Participants Inclusion criteria were parkinsonism (≥2 cardinal signs), diagnosis within 8 years of recruitment (to minimize survival bias), and ability to participate in detailed telephone interviews. Control subjects were primarily nonblood relatives or acquaintances of patients. Main Outcome Measures This multicenter case-control study compared lifelong occupational and job task histories to determine associations with parkinsonism and certain clinical subtypes (postural instability and gait difficulty and age at diagnosis ≤50 years). Results Findings in 519 cases and 511 controls were analyzed. Work in agriculture, education, health care, or welding was not associated with increased risk of parkinsonism. Unexpected increased risks associated with legal, construction and extraction, or religious occupations were not maintained after adjustment for duration. Risk of parkinsonism increased with pesticide use (odds ratio, 1.90; 95% confidence interval, 1.12-3.21), use of any of 8 pesticides mechanistically associated with experimental parkinsonism (2.20; 1.02-4.75), and use of 2,4-dichlorophenoxyacetic acid (2.59; 1.03-6.48). None of the specific occupations, job tasks, or task-related exposures were associated with younger age at diagnosis (≤50 years). Ever working in business and finance, legal occupations, construction and extraction, or transportation and material moving was associated with postural instability and gait difficulty subtype of parkinsonism. Tobacco use was inversely associated with parkinsonism risk. Conclusion The association of disease risk with pesticides support a toxicant-induced cause of parkinsonism.

Comparison of Risk Factor Profiles in Incidental Lewy Body Disease and Parkinson Disease [Original Contribution]

Objective To explore whether associations of potential risk factors for incidental Lewy body disease (iLBD) are similar to those for Parkinson disease (PD). Design Brain autopsy study (1988-2004) of subjects without evidence of neurodegenerative disease or tremor who were evaluated by at least 1 physician within 1 year of death. Researchers analyzed incidental Lewy pathology blinded to clinical abstraction. Setting Olmsted County, Minnesota. Subjects Residents of Olmsted County and the immediate vicinity aged older than 60 years. Main Outcome Measures Whether risk factors previously associated with PD in Olmsted County are also associated with iLBD. Results Of 235 subjects, 34 had iLBD (14.5%). The overall risk factor profiles for iLBD and PD were fairly similar between the 2 sets of odds ratio (OR) estimates, with 11 of 16 ORs in the same direction. Prior Olmsted County studies documented 7 risk factors with statistically significant associations with PD; for physician occupation and caffeine intake, the ORs for iLBD were in the same direction and statistically significant, whereas for education, head injury, and number of children, they were in the same direction but not significant; they were in the opposite direction but not statistically significant for depression and anxiety. Incidental Lewy body disease was not associated with various end-of-life conditions or causes of death, though these patients were slightly older and more likely cachectic. Conclusions Based on this exploratory study, iLBD and PD appear to have similar risk factor profiles. Thus, at least some cases of iLBD could represent preclinical PD, arrested PD, or a partial syndrome due to a lesser burden of causative factors. Incidental Lewy body disease is not explained by nonspecific end-of-life brain insults.

Extrapyramidal Signs Before and After Diagnosis of Incident Alzheimer Disease in a Prospective Population Study [Original Contribution]

Background Extrapyramidal signs (EPSs) are commonly accepted as a feature of Alzheimer disease (AD) and may influence both the profile of impairment and prognosis. Objective To examine rates of occurrence and risk factors for all types of EPSs and to describe the impact of EPSs over time on the clinical course of AD. Design Longitudinal study. Setting The Washington Heights Hamilton Heights Inwood Columbia Aging Project. Patients A total of 388 patients with incident AD (mean age, 79 years; 71.4% female). Main Outcome Measures Extrapyramidal signs rated by means of a standardized portion of the Unified Parkinson's Disease Rating Scale; prevalence and incidence rates and cumulative risk for non–drug-induced EPSs; and rates of change in EPSs over time, taking into account potential covariates. Results Extrapyramidal signs were detected in 12.3% of patients at first evaluation and 22.6% at last evaluation. In a multivariate-adjusted generalized estimating equation model of change, total EPS score increased at an annual rate of 1.3%. Women (relative risk [RR], 1.57; P = .03), older patients (RR, 1.03; P = .02), and those with EPSs at baseline (RR, 2.07; P = .001) had greater rates of cognitive decline. Conclusions Extrapyramidal signs occur frequently and progress significantly in AD. Patients with incident AD and concomitant EPSs have a greater rate of cognitive decline than do patients with incident AD but without EPSs.

Treatment of Neuromyelitis Optica With Mycophenolate Mofetil: Retrospective Analysis of 24 Patients [Original Contribution]

Background Neuromyelitis optica (NMO) is the first inflammatory autoimmune demyelinating disease of the central nervous system for which a specific antigenic target has been identified; the marker autoantibody NMO-IgG specifically recognizes the astrocytic water channel aquaporin 4. Current evidence strongly suggests that NMO-IgG may be pathogenic. Since disability accrues incrementally related to attacks, attack prevention with immunosuppressive therapy is the mainstay of preventing disability. Objective To evaluate the efficacy and safety of mycophenolate mofetil therapy in NMO spectrum disorders. Design Retrospective case series with prospective telephone follow-up. Setting Mayo Clinic Health System. Patients Twenty-four patients with NMO spectrum disorders (7 treatment-naive). Intervention Mycophenolate mofetil (median dose of 2000 mg per day). Main Outcome Measures Annualized relapse rates and disability (Expanded Disability Status Scale). Results At a median follow-up of 28 months (range, 18-89 months), 19 patients (79%) were continuing treatment. The median duration of treatment was 27 months (range, 1-89 months). The median annualized posttreatment relapse rate was lower than the pretreatment rate (0.09; range, 0-1.5; and 1.3; range, 0.23-11.8, respectively; P < .001). Disability stabilized or decreased in 22 of 24 patients (91%). One patient died of disease complications during follow-up. Six patients (25%) noted adverse effects during treatment with mycophenolate. Conclusion Mycophenolate is associated with reduction in relapse frequency and stable or reduced disability in patients with NMO spectrum disorders.

Diagnosis of Neuromyelitis Spectrum Disorders: Comparative Sensitivities and Specificities of Immunohistochemical and Immunoprecipitation Assays [Original Contribution]

Objective To compare the sensitivity and specificity of immunofluorescence (IF) and immunoprecipitation (IP) assays using green fluorescent protein–tagged aquaporin-4 (AQP4) in 6335 patients for whom serological evaluation was requested on a service basis. Design Case-control study. Setting Mayo Clinic Neuroimmunology Laboratory (Rochester, Minnesota) and Departments of Neurology (Rochester, Minnesota; Scottsdale, Arizona; and Jacksonville, Florida). Patients Group 1, 835 Mayo Clinic patients, 100 with a neuromyelitis optica (NMO) spectrum disorder diagnosis and 735 without NMO spectrum disorder; group 2, 5500 non–Mayo Clinic patients. Main Outcome Measure Sensitivity and specificity of each assay for NMO or NMO spectrum disorder, individually and combined. Results In group 1, the sensitivity rates for NMO were IF, 58%; IP, 33%; and combined assays, 63%. The sensitivity rates for relapsing longitudinally extensive transverse myelitis were IF, 29%; IP, 6%; and combined assays, 29%. The specificity rates for NMO and relapsing longitudinally extensive transverse myelitis were IF, 99.6%; IP, 99.3%; and combined assays, 99.2%. In group 2, NMO-IgG was detected by IF in 498 of 5500 patients (9.1%) and by IP in 331 patients (6.0%); 76 of the 331 patients seropositive by IP (23%) were negative by IF. Clinical information was available for 124 patients (including 16 of those seropositive by IP only); 123 had a definite NMO spectrum disorder and 1 was at risk for NMO (monophasic optic neuritis). Conclusions In this large, clinical practice-based study, NMO-IgG detected by IF or IP was highly specific for NMO spectrum disorders. The IP assay was significantly less sensitive than IF. Combined testing improved sensitivity by 5%.

Multiple Sclerosis With Predominant, Severe Cognitive Impairment [Original Contribution]

Objective To describe the characteristics of multiple sclerosis (MS) presenting with severe cognitive impairment as its primary disabling manifestation. Design Retrospective case series. Setting Tertiary referral center. Patients Patients were identified through the Mayo Clinic data retrieval system (1996-2008) with definite MS (McDonald criteria) and severe cognitive impairment as their primary neurological symptom without accompanying significant MS-related impairment or alternative diagnosis for cognitive dysfunction. Twenty-three patients meeting inclusion criteria were compared regarding demographics, clinical course, and radiological features. Main Outcome Measures Demographic, clinical, and radiological characteristics of the disease. Results Twelve patients were men. The median age of the first clinical symptom suggestive of central nervous system demyelination was 33 years, and severe MS-related cognitive impairment developed at a median age of 39 years. Cognitive impairment could be dichotomized as subacute fulminant (n = 9) or chronic progressive (n = 14) in presentation, which corresponded to subsequent relapsing or progressive MS courses. Study patients commonly exhibited psychiatric (65%), mild cerebellar (57%), and cortical symptoms and signs (eg, seizure, aphasia, apraxia) (39%). Fourteen of 21 (67%), where documented, smoked cigarettes. Brain magnetic resonance imaging demonstrated diffuse cerebral atrophy in 16 and gadolinium-enhancing lesions in 11. Asymptomatic spinal cord magnetic resonance imaging lesions were present in 12 of 16 patients (75%). Immunomodulatory therapies were generally ineffective in improving these patients. Conclusions We describe patients with MS whose clinical phenotype is characterized by severe cognitive dysfunction and prominent cortical and psychiatric signs presenting as a subacute fulminant or chronic progressive clinical course. Cigarette smokers may be overrepresented in this phenotype.

Cortical Lesions and Atrophy Associated With Cognitive Impairment in Relapsing-Remitting Multiple Sclerosis [Original Contribution]

Background Neuropsychological deficits in patients with multiple sclerosis (MS) have been shown to be associated with the major pathological substrates of the disease, ie, inflammatory demyelination and neurodegeneration. Double inversion recovery sequences allow cortical lesions (CLs) to be detected in the brain of patients with MS. Modern postprocessing techniques allow cortical atrophy to be assessed reliably. Objective To investigate the contribution of cortical gray matter lesions and tissue loss to cognitive impairment in patients with relapsing-remitting MS. Design Cross-sectional survey. Setting Referral, hospital-based MS clinic. Patients Seventy patients with relapsing-remitting MS. Main Outcome Measures Neuropsychological performance was tested using the Rao Brief Repeatable Battery of Neuropsychological Tests, version A. Patients who scored 2 SDs below the mean normative values on at least 1 test of the Rao Brief Repeatable Battery of Neuropsychological Tests, version A, were considered to be cognitively impaired. A composite cognitive score (the cognitive impairment index) was computed. T2 hyperintense white matter lesion volume, contrast-enhancing lesion number, CL number and volume, normalized brain volume, and normalized neocortical gray matter volume were also assessed. Results Twenty-four patients with relapsing-remitting MS (34.3%) were classified as cognitively impaired. T2 hyperintense white matter lesion volume and contrast-enhancing lesion number were not different between cognitively impaired and cognitively unimpaired patients. Cognitively impaired patients had a higher CL number (P = .01) and volume (P < .001) and decreased normalized brain volume (P = .02) and normalized neocortical gray matter volume (P = .002) when compared with cognitively unimpaired patients. Multivariate analysis revealed that age (β = 0.228; P = .02), CL volume (β = 0.452; P < .001), and normalized neocortical gray matter volume (β = 0.349; P < .001) were independent predictors of the cognitive impairment index (r2 = 0.55; F = 23.903; P < .001). Conclusion The burden of CLs and tissue loss are among the major structural changes associated with cognitive impairment in relapsing-remitting MS.

Progression of Mild Cognitive Impairment to Dementia in Clinic- vs Community-Based Cohorts [Original Contribution]

Background Mild cognitive impairment is increasingly recognized as an important public health problem associated with increased risk of developing dementia. Annual conversion rates, however, vary across different studies with clinic samples showing higher rates of conversion than community-based samples. Objectives To establish whether the rates of conversion from mild cognitive impairment to dementia differed according to recruitment source and, if so, to investigate factors that might explain this discrepancy. Design Rates and predictors of conversion were examined in a prospective longitudinal study at a single center. Setting Among the participants, 46% were recruited from a clinical setting and 54% were recruited directly through community outreach. Participants One hundred eleven individuals with mild cognitive impairment were followed up longitudinally for an average of 2.4 years (range, 0.5-4.0 years). Main Outcome Measures Conversion from mild cognitive impairment to dementia. Results During the follow-up period, 28 individuals progressed to dementia with a mean (SD) time to conversion of 2.19 (0.72) years. The clinic sample had an annual conversion rate of 13%, whereas the community sample had an annual conversion rate of 3%. In a Cox proportional hazards model, clinic recruitment source alone was associated with an increased hazard of incident dementia (hazard ratio = 3.50; 95% confidence interval, 1.31-9.18; P = .01). When other variables were added to the model, only baseline functional impairment as measured by the Clinical Dementia Rating Scale (and no demographic, cognitive, or neuroimaging variables or mild cognitive impairment subtype) accounted for the differences in conversion rates across the 2 cohorts. Conclusions These findings add to the growing literature to suggest that the degree of functional impairment at baseline is an important predictor of conversion to dementia and may help explain differences in findings between epidemiological and clinic-based studies.

Disparate Diseases Due to Copycat Copy Number Variations [From the Archives]

Nineteen Episodes of Recurrent Myelitis in a Woman With Neuromyelitis Optica and Systemic Lupus Erythematosus [Observation]

Objectives To describe the case of a patient with systemic lupus erythematosus (SLE) and neuromyelitis optica (NMO) who experienced 19 recurrent attacks of myelitis. Design Case report. Setting An outpatient neurorheumatology clinic at the Johns Hopkins Hospital devoted to care of patients with neurological manifestation of rheumatic diseases. Patient A woman with NMO and SLE. Intervention Rituximab therapy. Main Outcome Measures Clinical and neuroimaging features of relapsing disease. Results Recurrent and increasingly severe myelitis attacks still occurred after treatment with rituximab. Conclusions It may be progressively more difficult to prevent relapses and commensurate disability in patients with later stages of relapsing NMO. Recognition of NMO as a distinct diagnostic entity in patients with SLE and other rheumatic diseases is crucial, in that institution of earlier targeted immunosuppressant treatment may be more effective than later targeted immunosuppression. The cellular arm of the immune system may be recruited by pathogenic B cells and may explain why relapses may occur after treatment with B cell–depleting therapy.

Prediction of Neuromyelitis Optica Attack Severity by Quantitation of Complement-Mediated Injury to Aquaporin-4-Expressing Cells [Observation]

Background Recent reports support a pathogenic role in neuromyelitis optica (NMO) for the aquaporin-4 (AQP4)–specific autoantibody (NMO-IgG). Neuromyelitis optica is an inflammatory demyelinating central nervous system disease, usually relapsing, that causes variable degrees of attack-related disability. The NMO-IgG binds in vitro to the extracellular domain of AQP4, activates complement, and causes astrocyte lesioning. Objective To compare the prognostic utility of NMO-IgG titer and quantitative measures of complement-mediated injury to AQP4-expressing cells in NMO attacks. Design, Setting, and Participants A retrospective clinical-serological correlative study at Mayo Clinic's Neuroimmunology Laboratory was undertaken. Over an 18-month period, we identified NMO-IgG–seropositive patients in whom sufficient serum and adequate clinical information pertaining to NMO attacks (6 severe, 6 mild) were available to analyze clinical-serological correlations. Sera from 9 patients with multiple sclerosis and 9 healthy subjects (all NMO-IgG seronegative) served as controls. Complement activation was measured by quantifying the number of green fluorescent protein–AQP4–transfected HEK 293 cells permeable to the viability dye propidium iodide after exposure to patient serum and active complement. Main Outcome Measures Attack severity (mild or severe), percentage of AQP4-transfected cells lesioned, and NMO-IgG titer. Results The median percentage of AQP4-transfected cells lesioned by complement in the presence of serum from patients with NMO was 14% for patients with mild attacks and 54% for patients with severe attacks (P = .005). Median complement activation values for sera from healthy subjects and patients with multiple sclerosis were 8% and 12%, respectively. Patients with mild NMO attacks and patients with severe NMO attacks did not differ significantly with respect to NMO-IgG titer (P = .089). Conclusions A laboratory measure of complement-mediated cell injury may serve as a prognostic biomarker in NMO. Larger prospective studies are required to validate this observation.

Repeated Embolic Stroke From an Infected Aortic Arch Graft With Transesophageal Echocardiography-Documented Mobile Vegetation [Images in Neurology]

Cerebral Fat Embolism: Susceptibility-Weighted Magnetic Resonance Imaging [Images in Neurology]

Air Embolism With Pneumocephalus [Images in Neurology]

Multifocal Stroke From Tumor Emboli [Images in Neurology]

Changing Aspects in Stroke Surgery: Aneurysms, Dissections, Moyamoya Angiopathy, and EC-IC Bypass [Book Reviews]

Neurotropic Viral Infections [Book Reviews]

Would You Save This Patient's Eye or His Brain? [Correspondence]

Thrombolysis in Acute Ischemic Stroke With Vitreous Hemorrhage [Correspondence]

Thrombolysis in Acute Ischemic Stroke With Vitreous Hemorrhage--Reply [Correspondence]

In Vivo Confocal Microscopy of Corneal Stromal Nerves in Patients With Peripheral Neuropathy [Correspondence]

In Vivo Confocal Microscopy of Corneal Stromal Nerves in Patients With Peripheral Neuropathy--Reply [Correspondence]

About This Journal [About This Journal]

This Month in Archives of Neurology [This Month in Archives of Neurology]

Drilling for Energy in Mitochondrial Disease [Editorial]

Progress and Challenges in RNA Interference Therapy for Huntington Disease [Neurological Review]

Huntington disease is an incurable, dominant neurodegenerative disorder caused by polyglutamine repeat expansion in the huntingtin protein. Reducing mutant huntingtin expression may offer a treatment for Huntington disease. RNA interference has emerged as a powerful method to silence dominant disease genes. As such, it is being developed as a prospective Huntington disease therapy. Here I discuss the current progress and important remaining challenges of RNA interference therapy for Huntington disease.

Emerging Viral Infections of the Central Nervous System: Part 1 [Neurological Review]

In this 2-part review, I will focus on emerging virus infections of the central nervous system (CNS). Part 1 will introduce the basic features of emerging infections, including their definition, epidemiology, and the frequency of CNS involvement. Important mechanisms of emergence will be reviewed, including viruses spreading into new host ranges as exemplified by West Nile virus (WNV), Japanese encephalitis (JE) virus, Toscana virus, and enterovirus 71 (EV71). Emerging infections also result from opportunistic spread of viruses into known niches, often resulting from attenuated host resistance to infection. This process is exemplified by transplant-associated cases of viral CNS infection caused by WNV, rabies virus, lymphocytic choriomeningitis, and lymphocytic choriomeningitis–like viruses and by the syndrome of human herpesvirus 6 (HHV6)–associated posttransplantation acute limbic encephalitis. The second part of this review begins with a discussion of JC virus and the occurrence of progressive multifocal leukoencephalopathy in association with novel immunomodulatory therapies and then continues with an overview of the risk of infection introduced by imported animals (eg, monkeypox virus) and examples of emerging diseases caused by enhanced competence of viruses for vectors and the spread of vectors (eg, chikungunya virus) and then concludes with examples of novel viruses causing CNS infection as exemplified by Nipah and Hendra viruses and bat lyssaviruses.

Human NARP Mitochondrial Mutation Metabolism Corrected With {alpha}-Ketoglutarate/Aspartate: A Potential New Therapy [Original Contribution]

Objective To verify whether enhanced substrate-level phosphorylation increases viability and adenosine 5'-triphosphate (ATP) content of cells with neuropathy, ataxia, and retinitis pigmentosa/maternally inherited Leigh syndrome (NARP/MILS) mitochondrial DNA mutations and ATP synthase dysfunction. Design We used cell lines "poisoned" with oligomycin, the specific inhibitor of ATP synthase, and "natural" models, including transmitochondrial human cell lines (cybrids) harboring 2 different pathogenic mutations associated with the NARP/MILS phenotypes. Main Outcome Measures Cell survival, morphology, and ATP content. Results When normal human fibroblasts cultured in glucose-free medium were forced to increase energy consumption by exposure to the ionophore gramicidin or were energy challenged by oligomycin inhibition, their survival at 72 hours was 5%, but this increased to 70% when the medium was supplemented with -ketoglutarate/aspartate to boost mitochondrial substrate-level phosphorylation. Homoplasmic cybrids harboring the 8993T->G NARP mutation were also protected from death (75% vs 15% survival at 72 hours) by the supplemented medium and their ATP content was similar to controls. Conclusions These results show that ATP synthase–deficient cells can be rescued by increasing mitochondrial substrate-level phosphorylation and suggest potential dietary or pharmacological therapeutic approaches based on the supplementation of -ketoglutarate/aspartate to patients with impaired ATP synthase activity.

Exclusive Breastfeeding and the Risk of Postpartum Relapses in Women With Multiple Sclerosis [Original Contribution]

Objective To determine if exclusive breastfeeding protects against postpartum relapses of multiple sclerosis (MS) and, if so, whether this protection is related to prolonged lactational amenorrhea. Design We conducted structured interviews to assess clinical, menstrual, and breastfeeding history during each trimester and 2, 4, 6, 9, and 12 months postpartum and collected neurological examination findings from the treating physicians of women with MS. Hazards ratios (HRs) were adjusted for measures of disease severity and age. Setting Kaiser Permanente Northern California and Stanford University. Participants We prospectively enrolled 32 pregnant women with MS and 29 age-matched, pregnant controls. Main Outcome Measure Postpartum relapse. Results Of the 52% of women with MS who did not breastfeed or began regular supplemental feedings within 2 months postpartum, 87% had a postpartum relapse, compared with 36% of the women with MS who breastfed exclusively for at least 2 months postpartum (unadjusted HR, 5.0; 95% confidence interval, 1.7-14.2; P = .003; adjusted HR, 7.1; 95% confidence interval, 2.1-24.3; P = .002). Sixty percent reported that the primary reason for foregoing exclusive breastfeeding was to resume MS therapies. Women who breastfed exclusively had a later return of menses (P = .001) than women who did not, and lactational amenorrhea was associated with a reduced risk of postpartum relapses (P = .01). Conclusions Our findings suggest that exclusive breastfeeding and concomitant suppression of menses significantly reduce the risk of postpartum relapses in MS. Our findings call into question the benefit of foregoing breastfeeding to start MS therapies and should be confirmed in a larger study. Published online June 8, 2009 (doi:10.1001/archneurol.2009.132).

Neuromyelitis Optica IgG Serostatus in Fulminant Central Nervous System Inflammatory Demyelinating Disease [Original Contribution]

Background The aquaporin-4–specific serum autoantibody neuromyelitis optica (NMO) IgG is a validated biomarker distinguishing NMO spectrum disorders from multiple sclerosis (MS). Because fulminant attacks are more common in NMO spectrum disorders than in MS, some investigators suggest that NMO IgG may be a marker of destructive demyelination rather than a disease-specific biomarker. To our knowledge, this study is the first to compare NMO IgG serostatus among patients with fulminant central nervous system inflammatory demyelinating disease (CNS IDD). Objective To determine whether NMO IgG distinguishes patients with NMO spectrum disorders from those with other fulminant corticosteroid-refractory CNS IDD. Design Descriptive historical cohort. Setting Neuroimmunology laboratory and neurology practice, Mayo Clinic College of Medicine, Rochester, Minnesota. Patients Serum samples from 74 patients who underwent plasmapheresis between February 24, 1993, and November 22, 2007, for a corticosteroid-refractory CNS IDD were tested for NMO IgG by indirect immunofluorescence assay. Main Outcome Measures Two blinded observers scored serum samples tested at 1:120 dilution. Clinical data were obtained by medical record review. Results Preplasmapheresis serum samples were available from 74 patients (ratio of women to men, 2:5); the mean interval between blood draw and plasmapheresis was 13 days. At the time of plasmapheresis, the mean age of patients was 46 years (age range, 7-80 years); the mean Expanded Disability Status Scale score was 7.0 (score range, 3.5-9.5 [10.0 is death]). Diagnoses included MS (18 patients with definite and 11 patients with probable), longitudinally extensive transverse myelitis involving at least 3 vertebral segments (20 patients), NMO (14 patients), transverse myelitis involving fewer than 3 vertebral segments (8 patients), optic neuritis (2 patients), and acute disseminated encephalomyelitis (1 patient). Neuromyelitis optica IgG was detected in 20 patients (27%) (10 with longitudinally extensive transverse myelitis, 9 with NMO, and 1 with recurrent optic neuritis) and was not detected in any patient with MS, short transverse myelitis, monophasic optic neuritis, or acute disseminated encephalomyelitis. Conclusion Neuromyelitis optica IgG is a specific biomarker for NMO spectrum disorders and is not simply a marker of destructive CNS IDD.

Difference in Disease Burden and Activity in Pediatric Patients on Brain Magnetic Resonance Imaging at Time of Multiple Sclerosis Onset vs Adults [Original Contribution]

Objective To compare initial brain magnetic resonance imaging (MRI) characteristics of children and adults at multiple sclerosis (MS) onset. Design Retrospective analysis of features of first brain MRI available at MS onset in patients with pediatric-onset and adult-onset MS. Setting A pediatric and an adult MS center. Patients Patients with pediatric-onset <18 years) and adult-onset (≥18 years) MS. Main Outcome Measures We evaluated initial and second (when available) brain MRI scans obtained at the time of first MS symptoms for lesions that were T2-bright, ovoid and well defined, large (≥1cm), or enhancing. Results We identified 41 patients with pediatric-onset MS and 35 patients with adult-onset MS. Children had a higher number of total T2- (median, 21 vs 6; P < .001) and large T2-bright areas (median, 4 vs 0; P < .001) than adults. Children more frequently had T2-bright foci in the posterior fossa (68.3% vs 31.4%; P = .001) and enhancing lesions (68.4% vs 21.2%; P < .001) than adults. On the second brain MRI, children had more new T2-bright (median, 2.5 vs 0; P < .001) and gadolinium-enhancing foci (P < .001) than adults. Except for corpus callosum involvement, race/ethnicity was not strongly associated with disease burden or lesion location on the first scan, although other associations cannot be excluded because of the width of the confidence intervals. Conclusion While it is unknown whether the higher disease burden, posterior fossa involvement, and rate of new lesions in pediatric-onset MS are explained by age alone, these characteristics have been associated with worse disability progression in adults.

Genome-wide Scan of 500 000 Single-Nucleotide Polymorphisms Among Responders and Nonresponders to Interferon Beta Therapy in Multiple Sclerosis [Original Contribution]

Background Interferon beta is 1 of 2 first-line treatments for relapsing-remitting multiple sclerosis (MS). However, not all patients respond to interferon beta therapy, and to date there is a lack of surrogate markers that reliably correlate with responsiveness to interferon beta therapy in MS. Objective To identify allelic variants that influence response to interferon beta therapy in patients with MS. Design Genome-wide scan. Setting Academic research. Patients Two hundred patients having relapsing-remitting MS treated with interferon beta and having a follow-up period of at least 2 years were classified as responders or nonresponders to treatment based on stringent clinical criteria. Main Outcome Measures In the first phase of the study, a pooling-based genome-wide association study of 428 867 single-nucleotide polymorphisms (SNPs) was performed in 53 responders and 53 nonresponders to interferon beta therapy. After applying several selection criteria, 383 SNPs were individually genotyped in an independent validation cohort of 49 responders and 45 nonresponders to interferon beta therapy using a different genotyping platform. Results Eighteen SNPs had uncorrected P < .05 associated with interferon beta responder status in the validation cohort. Of these, 7 SNPs were located in genes that code for alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid–type glutamate receptor GRIA3, type 1 interferon–related proteins ADAR and IFNAR2, cell cycle–dependent protein CIT, zinc finger proteins ZFAT and ZFHX4, and guanosine triphosphatase–activating protein STARD13. Conclusions This study supports an underlying polygenic response to interferon beta treatment in MS and highlights the importance of the glutamatergic system in patient response to interferon beta therapy.

Affect of Seizures During Gestation on Pregnancy Outcomes in Women With Epilepsy [Original Contribution]

Objective To assess whether seizures in women with epilepsy during pregnancy contribute to adverse pregnancy outcomes. Design A retrospective cross-sectional study. Setting Taiwan. Patients This study linked 2 nationwide population-based data sets: Taiwan's birth certificate registry and the Taiwan National Health Insurance Research Data set. A total of 1016 women with epilepsy were selected who had single births from 2001 to 2003 and who had been diagnosed with epilepsy within 2 years prior to their index delivery, together with 8128 matched women without chronic disease as a comparison cohort. Women with epilepsy were further stratified into 2 groups for analysis: women who did and did not have seizures during pregnancy. Main Outcome Measures Low-birth-weight infants, preterm delivery, and infants who are small for gestational age (SGA). Results Compared with women without epilepsy, epileptic seizures during pregnancy were independently associated with a 1.36-fold (95% confidence interval [CI], 1.01-1.88), 1.63-fold (95% CI, 1.21-2.19), and 1.37-fold (95% CI, 1.09-1.70) increased risk of low-birth-weight infants, preterm delivery, and SGA, respectively, after adjusting for family income and parental and infant characteristics. Further, the risk of SGA increased significantly (odds ratio, 1.34; 95% CI, 1.01-1.84) for women with seizures during pregnancy compared with women with epilepsy who did not have seizures during pregnancy. Conclusion We suggest preventing seizures during pregnancy as an essential step to reduce risk of adverse pregnancy outcomes.

Prognostic Implications of Periodic Epileptiform Discharges [Original Contribution]

Background Periodic epileptiform discharges (PEDs) are an abnormal finding on electroencephalograms (EEGs), the significance of which is uncertain. Objective To investigate long-term outcome in patients with PEDs. Design We retrospectively analyzed the outcomes of patients who had PEDs diagnosed during a 7-year period. We abstracted and tabulated clinical parameters from the time of EEG, imaging findings, EEG measurements, and subsequent clinical outcome from medical records. We used descriptive, inferential, and logistic regression analysis to determine the factors associated with clinical outcomes in patients with PEDs. We divided PEDs into the following subgroups: periodic lateralized epileptiform discharges (PLEDs), generalized PEDs, and bilateral PEDs and analyzed these subgroups individually. Setting University-affiliated teaching hospital. Subjects One hundred sixty-two patients with PEDs. Results We obtained complete clinical, neuroimaging, neurophysiologic, and long-term outcome data in 118 patients. In the subgroup of patients with PLEDs, absence of seizures at onset (odds ratio, 0.21 per point; 95% confidence interval, 0.04-0.97) and an acute etiology for the PLEDs (odds ratio, 0.14 per point; 95% confidence interval, 0.03-0.72) were associated with death. A nonneoplastic cause for PLEDs was associated with independent functionality (odds ratio, 0.45 per point; 95% confidence interval, 0.3-0.67). Conclusion In patients with PLEDs, the absence of clinical seizures at the time of detection and presumed acute etiology are associated with death, whereas a nonneoplastic etiology was associated with a good clinical outcome.

Seizures in Alzheimer Disease: Who, When, and How Common? [Original Contribution]

Background Transient symptoms in Alzheimer disease (AD) are frequent and include seizures, syncope, and episodes of inattention or confusion. The incidence of seizures in AD and predictors of which patients with AD might be more predisposed to them is based primarily on retrospective studies and is not well established. Objective To determine the incidence and predictors of new-onset unprovoked seizures. Design Prospective cohort study. Setting Three academic centers. Patients Four hundred fifty-three patients with probable AD observed prospectively from mild disease stages since 1992. Main Outcome Measure Informant interviews every 6 months included questions about whether the patient had a seizure (convulsion, fainting, or "funny" spell) and whether diagnosis or treatment for epilepsy or seizure was made. Two epileptologists independently retrospectively reviewed all available medical records for 52 patients with positive responses to either of these questions, and using a specific checklist form, events were diagnosed as to whether they were unprovoked seizures (intrarater concordance, = 0.67). Diagnosis of unprovoked seizures constituted the event in survival analyses. Potential predictors included sex, age, race/ethnicity, educational achievement, duration of illness, baseline cognition and function, depression, medical comorbidities, and time-dependent use of cholinesterase inhibitors and neuroleptic agents, apolipoprotein E genotype, and previous electroencephalographic findings. Results Over the course of 3518 visit-assessments (per patient: mean, 7.8; maximum, 27), 7 patients (1.5%) developed seizures. Younger age was associated with higher risk (hazard ratio, 1.23; 95% confidence interval, 1.08-1.41; P = .003 for each additional year of age) of seizure incidence. No other predictor was significant. The overall incidence of seizures was low (418 per 100 000 person-years of observation) although significantly higher than expected for idiopathic unprovoked seizures in similar age ranges of the general population (hazard ratio, 8.06; 95% confidence interval, 3.23-16.61). Conclusions Unprovoked seizures are uncommon in AD, but they do occur more frequently than in the general population. Younger age is a risk factor for seizures in AD.

Damage to the Optic Radiation in Multiple Sclerosis Is Associated With Retinal Injury and Visual Disability [Original Contribution]

Objective To determine whether damage to the optic radiation (OR) in multiple sclerosis (MS) is associated with optic nerve injury and visual dysfunction. Design Case-control study. Setting Referral center. Participants Ninety referred patients with MS and 29 healthy volunteers. Main Outcome Measures Magnetic resonance imaging indices along the OR were reconstructed with diffusion tensor tractography. Retinal nerve fiber layer thickness and visual acuity at high and low contrast were measured in a subset of the MS group (n = 36). Results All tested magnetic resonance imaging indices (fractional anisotropy [FA]; mean, parallel, and perpendicular [] diffusivity; T2 relaxation time; and magnetization transfer ratio) were significantly abnormal in patients with MS. Mean retinal nerve fiber layer thickness was significantly correlated with FA (r = 0.55; P < .001) and (r = –0.37; P = .001). The retinal nerve fiber layer thickness in the nasal retinal quadrant was also specifically correlated with FA and in the synaptically connected contralateral OR. In individuals with less severely damaged optic nerves (mean retinal nerve fiber layer thickness >80 µm), letter acuity scores at 2.5% contrast were correlated with OR-specific FA (r = 0.55; P = .004), (r = –0.40; P = .04), and magnetization transfer ratio (r = 0.54; P = .01), as well as the fraction of OR volume made up of lesions (r = –0.69; P < .001). Conclusions Fractional anisotropy and are potentially useful quantitative magnetic resonance imaging biomarkers of OR-specific damage in MS. Such damage is associated with retinal injury and visual disability.

LIS1-Related Isolated Lissencephaly: Spectrum of Mutations and Relationships With Malformation Severity [Original Contribution]

Objective With the largest data set of patients with LIS1-related lissencephaly, the major cause of posteriorly predominant lissencephaly related to either LIS1 mutation or intragenic deletion, described so far, we aimed to refine the spectrum of neurological and radiological features and to assess relationships with the genotype. Design Retrospective study. Subjects A total of 63 patients with posteriorly predominant lissencephaly. Interventions Of the 63 patients, 40 were found to carry either LIS1 point mutations (77.5%) or small genomic deletions (20%), and 1 carried a somatic nonsense mutation. On the basis of the severity of neuromotor impairment, epilepsy, and radiological findings, correlations with the location and type of mutation were examined. Results Most patients with LIS1 mutations demonstrated posterior agyria (grade 3a, 55.3%) with thin corpus callosum (50%) and prominent perivascular spaces (67.4%). By contrast, patients without LIS1 mutations tended to have less severe lissencephaly (grade 4a, 41.6%) and no additional brain abnormalities. The degree of neuromotor impairment was in accordance with the severity of lissencephaly, with a high incidence of tetraplegia (61.1%). Conversely, the severity of epilepsy was not determined with the same reliability because 82.9% had early onset of seizures and 48.7% had seizures more often than daily. In addition, neither the mutation type nor the location of the mutation were found to predict the severity of LIS1-related lissencephaly. Conclusion Our results confirm the homogeneity profile of patients with LIS1-related lissencephaly who demonstrate in a large proportion Dobyns lissencephaly grade 3a, and the absence of correlation with LIS1 mutations.

Depletion of B Lymphocytes From Cerebral Perivascular Spaces by Rituximab [Observation]

Background Rituximab is a recombinant chimeric monoclonal antibody against CD20, a molecule expressed on cells of the B-cell lineage. A phase 2 clinical trial recently provided strong evidence of the beneficial effects of rituximab in patients with relapsing-remitting multiple sclerosis. We and other investigators previously demonstrated that rituximab therapy depletes B lymphocytes from peripheral blood and cerebrospinal fluid of patients with relapsing-remitting multiple sclerosis. Objective To determine the effect of rituximab on the presence of B cells in cerebral perivascular spaces. Design, Setting, and Patients Case report from a tertiary academic medical center. Cerebral white matter from autopsy material of a patient with gastrointestinal mantle-cell lymphoma who developed progressive multifocal leukoencephalopathy following rituximab therapy was evaluated by immunohistochemistry. Location-matched brain sections of patients with multiple sclerosis not treated with rituximab, patients without central nervous system disease, and patients with progressive multifocal leukoencephalopathy not associated with rituximab were used as controls. Main Outcome Measures Assessment of the number of B lymphocytes in cerebral perivascular spaces in a patient with gastrointestinal mantle-cell lymphoma treated with rituximab, patients with multiple sclerosis, patients with progressive multifocal leukoencephalopathy not associated with rituximab, and healthy control subjects. Results We were unable to detect B cells in cerebral perivascular spaces of the patient who developed progressive multifocal leukoencephalopathy following rituximab therapy 8 months after her last dose. In contrast, B cells were detectable in all control brain tissues. Conclusions To our knowledge, this is the first report to show B-lymphocyte depletion from brain tissue following rituximab therapy. A reduction in B-cell numbers may be an important contributing factor in the pathogenesis of central nervous system infections.

Atypical Progressive Multifocal Leukoencephalopathy Associated With an Unusual JC Polyomavirus Mutation [Observation]

Objective To report the clinical and radiologic features in a patient with myelofibrosis who developed atypical progressive multifocal leukoencephalopathy. Design Case report. Setting Tertiary referral center. Patient A 72-year-old man with myelofibrosis and mild leukopenia experienced progressive limb weakness and dysarthria. Results Imaging revealed almost complete sparing of the white matter with isolated involvement of the brainstem and deep gray matter. Postmortem examination led to definitive diagnosis of progressive multifocal leukoencephalopathy and demonstrated an unusual miliary pattern of disease rather than the typical confluent involvement. Genetic analysis revealed a mutation in the transcription control region of the JC polyomavirus, prompting speculation about the pathogenesis of progressive multifocal leukoencephalopathy. Conclusions Leukopenia may render patients effectively immunosuppressed. The differential diagnosis should include progressive multifocal leukoencephalopathy even in patients with atypical clinical and radiologic features.

Acute and Bilateral Blindness Due to Optic Neuropathy Associated With Copper Deficiency [Observation]

Background Acquired copper deficiency in adults is associated with a subacute to chronic progressive myeloneuropathy and optic neuropathy. Objective To describe an individual after gastric bypass surgery who developed a chronic progressive myeloneuropathy, an acute optic neuropathy, along with anemia and leukopenia. Design Case report. Setting Academic center. Patient A 55-year-old woman, following gastric bypass surgery 22 years earlier, developed progressive numbness, weakness, and sphincter disturbance over 6 years. She awoke one morning with bilateral blindness. Examination findings showed evidence of severe myelopathy and peripheral neuropathy. Main Outcome Measures Magnetic resonance imaging, optical coherence tomography, electrophysiologic studies, nerve and muscle biopsy specimens, and vision testing. Results Over 1 year of follow-up, copper infusion therapy seemed to stabilize the progressive myeloneuropathy and improved leukopenia and anemia. It had no effect on the optic neuropathy. Optic nerve tissue injury was observed on magnetic resonance diffusion tensor imaging and on optical coherence tomography. Conclusions Copper deficiency should be considered in cases of atypical optic neuropathy. Serum copper levels should be monitored in patients with a compatible neurologic syndrome who have undergone gastric bypass surgery. Although visual acuity did not improve after copper infusion in our patient, prompt recognition of copper deficiency may prevent further deterioration.

Mitochondrial Neurogastrointestinal Encephalopathy Due to Mutations in RRM2B [Observation]

Background Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a progressive neurodegenerative disorder associated with thymidine phosphorylase deficiency resulting in high levels of plasma thymidine and a characteristic clinical phenotype. Objective To investigate the molecular basis of MNGIE in a patient with a normal plasma thymidine level. Design Clinical, neurophysiological, and histopathological examinations as well as molecular and genetic analyses. Setting Nerve and muscle center and genetic clinic. Patient A 42-year-old woman with clinical findings strongly suggestive for MNGIE. Main Outcome Measures Clinical description of the disease and its novel genetic cause. Results Identification of mitochondrial DNA depletion in muscle samples (approximately 12% of the control mean content) prompted us to look for other causes of our patient's condition. Sequencing of genes associated with mitochondrial DNA depletion—POLG, PEO1, ANT1, SUCLG1, and SUCLA2—did not reveal deleterious mutations. Results of sequencing and array comparative genomic hybridization of the mitochondrial DNA for point mutations and deletions in blood and muscle were negative. Sequencing of RRM2B, a gene encoding cytosolic p53-inducible ribonucleoside reductase small subunit (RIR2B), revealed 2 pathogenic mutations, c.329G>A (p.R110H) and c.362G>A (p.R121H). These mutations are predicted to affect the docking interface of the RIR2B homodimer and likely result in impaired enzyme activity. Conclusions This study expands the clinical spectrum of impaired RIR2B function, challenges the notion of locus homogeneity of MNGIE, and sheds light on the pathogenesis of conditions involved in the homeostasis of the mitochondrial nucleotide pool. Our findings suggest that patients with MNGIE who have normal thymidine levels should be tested for RRM2B mutations.

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Joseph Babinski: A Biography [Book Reviews]

Identification of Creutzfeldt-Jakob Disease Variants [Correspondence]

Identification of Creutzfeldt-Jakob Disease Variants--Reply [Correspondence]