Neurology RSS : Gourt

Coastal Georgia :: Georgia :: Medical Search Consultants

HOSPITAL EMPLOYEE OR INCOME GUARANTEE -This is an excellent opportunity for a BE/BC Neurologist to establish a new solo practice, either hospital-employed or income guarantee, in this coastal Georgia

Not Disclosed :: Montana :: Locum Medical Group

A facility in the largest metropolitan area of Montana seeks to hire a Board Certified or Board Eligible Neurologist. Candidates need not to be licensed to practice medicine in Montana to be considered

Not Disclosed :: New York :: Locum Medical Group

A growing facility in upstate New York is in need of a permanent Neurologist to join their team. The hours are flexible and there is no call for this position. Residents and fellows are welcome to apply.

Not Disclosed :: South Carolina :: Locum Medical Group

An established multispecialty group near Myrtle Beach (North of Charleston) is in need of a Neurologist to join a group of 1 other Neurologist and 3 Rheumatologists on a permanent basis. This practice

Not Disclosed :: Texas :: Locum Medical Group

A hospital in southern Texas is seeking a permanent Neurologist for a solo hospital start-up practice. The physician will receive full financial support in starting a private practice including income

Not Disclosed :: Texas :: Locum Medical Group

A Board Certified Neurologist is needed to establish a hospital affiliated solo practice in beautiful southern Texas. Primary care physicians will refer patients to this physician for consults and procedures.

Not Disclosed :: Nevada :: Locum Medical Group

A hospital supported practice located in Northeastern Nevada is looking for a permanent neurologist. This position has a great income guarantee and paid overhead along with being a W2 position. Other

Not Disclosed :: Utah :: Locum Medical Group

Our client, located in Eastern Utah, is looking for a Neurologist to join their community and establish a solo practice. This position is offered as either an income guarantee or as a salaried hospital

Philadelphia :: Pennsylvania :: New England Physician Recruitment Center

Neurologist Pennsylvania Fellowship trained in Vascular Neuro, Neuro Hospitalist or Critical Care Neuro. Competitive salary; 22 dys vacation; Call 1:3 for stroke and 1:8 for routine; over 1000 admissions

Poughkeepsie :: New York :: New England Physician Recruitment Center

Mid-Hudson/Poughkeepsie Area Seeking a Stroke/Critical Care Neurologist $250k-$300k base Single specialty neurology group with 7 members seeks BC/BE neurologists with fellowship training in Stroke

N. Dartmouth :: Massachusetts :: New England Physician Recruitment Center

Neurologist-minutes to Boston and Providence. Salary and Compensation very, very competitive. Ideal Coastal Southern Massachusetts location. Outstanding opportunity for BC/BE Neurologist (who is also

Middletown :: New York :: New England Physician Recruitment Center

Join group practice Simply the the best private group in New York. Exceeds MGMA standards and partners do incredibly well. TOP Salaries and Incentives- New Yorks finest group top money-interviewing

Middletown :: New York :: New England Physician Recruitment Center

Neurology Middletown region NewYork- about 1 hour to NYC- join group of 8 expanding their services and have recently moved into another modern office building....group is a premier physician owned

Manchester :: New Hampshire :: New England Physician Recruitment Center

Dartmouth system- New Hampshire- Less than one hour to Boston- Tax free-top school systems adult Neurologist A 120,000 square foot outpatient facility, Dartmouth-Hitchcock, includes an array of

Rochester :: New Hampshire :: New England Physician Recruitment Center

Neurology- new facility- beautiful. Southeastern New Hampshire-Minutes to the Seacoast and minutes to the White Mountans, Ocean, and some of the best schools and Universities in the Country .This 88

Manhattan :: New York :: New England Physician Recruitment Center

Mid-Town Manhattan Private Practice Seeking a Neurologist or PM&R Busy Mid-town Manhattan Private Neurology group is seeking a Neurologist with an interest in performing EMGs. Fellowship training is

Atlanta :: Georgia :: Medical Search Consultants

This is an excellent opportunity for a BE/BC Neurologist to join a well-established hospital-employed group. This is a new addition to the group required by continued expansion in this highly-desirable

Boston :: Massachusetts :: New England Physician Recruitment Center

North of Boston Seeking Stroke and Epilepsy Neurologist 2 year Partnership Adult neurology group practice located 25 miles north of Boston is dedicated to providing quality medical care for patients

Albany :: New York :: New England Physician Recruitment Center

Neurologist New York, Albany region -650 bed tertiary care center - Fellowship trained in movement disorders. Assistant or associate professor level. Busy outpatient practice and active clinical trial

Nashua :: New Hampshire :: New England Physician Recruitment Center

Group Neurology need Affiliated with major New Hampshire Medical Center, group is located about 40 minutes to Boston and is the second largest multi-specialty group in New Hampshire. The group includes

Positron Emission Tomography- Computed Tomography in Paraneoplastic Neurologic Disorders: Systematic Analysis and Review [Original Contribution]

Objective To evaluate the cancer detection rate of whole-body positron emission tomography–computed tomography (PET-CT) in a paraneoplastic neurologic context.Design Retrospective medical record review.Setting Mayo Clinic, Rochester, Minnesota.Patients Fifty-six consecutive patients with clinically suspected paraneoplastic neurologic disorders who underwent PET-CT after negative standard evaluations, including CT.Main Outcome Measure Rate of cancer detection.Results Abnormalities suggestive of cancer were detected using PET-CT in 22 patients (39%); 10 patients (18%) had cancer confirmed histologically. Cancers detected (limited stage in 9 of 10 patients and extratruncal in 4) were as follows: 2 thyroid papillary cell carcinomas, 3 solitary lymph nodes with unknown primary (2 adenocarcinomas and 1 small cell carcinoma), 1 tonsil squamous cell carcinoma, 3 lung carcinomas (1 adenocarcinoma, 1 small cell, and 1 squamous cell), and 1 colon adenocarcinoma. Detection of a well-characterized neuronal nuclear or cytoplasmic paraneoplastic autoantibody was associated with a successful PET-CT–directed cancer search (P < .001). Detection of limited-stage cancer facilitated early initiation of oncologic treatments and immunotherapy; cancer remission was reported in 7 patients, and sustained improvements in neurologic symptoms were reported in 5 (median follow-up, 11 months; range, 2-48 months). Combined data from 2 previous studies using conventional PET alone (123 patients) revealed that 28% of patients had a PET abnormality suggestive of cancer and that 12% had a cancer diagnosis.Conclusion In a paraneoplastic neurologic context, PET-CT improves the detection of cancers when other screening test results are negative, particularly in the setting of seropositivity for a neuronal nuclear or cytoplasmic autoantibody marker of cancer.Published online January 11, 2010 (doi:10.1001/archneurol.2009.336).

Effects of Intensive Medical Therapy on Microemboli and Cardiovascular Risk in Asymptomatic Carotid Stenosis [Original Contribution]

Objective To assess the effect of more intensive medical therapy on the rate of transcranial Doppler (TCD) microemboli and cardiovascular events in patients with asymptomatic carotid stenosis (ACS).Design A prospective study.Setting A teaching hospital.Patients Four hundred sixty-eight patients with ACS greater than 60% by Doppler peak velocity.Main Outcome Measures We compared (1) the proportion of ACS patients who had microemboli on TCD, (2) cardiovascular events, (3) rate of carotid plaque progression, and (4) baseline medical therapy, before and since 2003.Results Among 468 ACS patients, 199 were enrolled between January 1, 2000, and December 31, 2002; and 269 were enrolled between January 1, 2003, and July 30, 2007. Microemboli were present in 12.6% before 2003 and 3.7% since 2003 (P < .001). The decline in microemboli coincided with better control of plasma lipids and slower progression of carotid total plaque area. Since 2003, there have been significantly fewer cardiovascular events among patients with ACS: 17.6% had stroke, death, myocardial infarction, or carotid endarterectomy for symptoms before 2003, vs 5.6% since 2003 (P < .001). The rate of carotid plaque progression in the first year of follow-up has declined from 69 mm2 (SD, 96 mm2) to 23 mm2 (SD, 86 mm2) (P < .001).Conclusions Cardiovascular events and microemboli on TCD have markedly declined with more intensive medical therapy. Less than 5% of patients with ACS now stand to benefit from revascularization; patients with ACS should receive intensive medical therapy and should only be considered for revascularization if they have microemboli on TCD.Published online December 14, 2009 (doi:10.1001/archneurol.2009.289).

About This Journal [About This Journal]

Reviewers Who Completed a Review During 2009 [Annual Reviewers List]

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

Do Multiple Chronic Infections Increase the Risk of Stroke?: The Infectious Burden Concept [Editorial]

Inherited Metabolic Disorders and Stroke Part 1: Fabry Disease and Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Strokelike Episodes [Neurological Review]

Inherited metabolic disorders are single-gene genetic diseases associated with multiorgan damage. Some of these conditions increase the risk of stroke through a variety of mechanisms, and there is evidence that early recognition and initiation of appropriate treatment may improve prognosis. In this 2-part review we provide an update of the genetics, stroke pathophysiology, clinical manifestations, diagnosis, and treatment of metabolic disorders associated with stroke. In part 1, we concentrate on Fabry disease and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. In part 2 we will review homocystinuria, organic acidurias, and urea cycle disorders.

Effects of a Dopamine Agonist on the Pharmacodynamics of Levodopa in Parkinson Disease [Clinical Trials]

Background Treatment of Parkinson disease commonly includes levodopa and dopamine agonists; however, the interaction of these 2 drugs is poorly understood. Objective To examine the effects of a dopamine agonist on the motor response to levodopa. Design Double-blind, randomized, placebo-controlled, crossover clinical trial. Setting Ambulatory academic referral center. Patients Thirteen patients with idiopathic Parkinson disease taking levodopa and experiencing motor fluctuations and dyskinesia. Interventions Eligible individuals were randomly assigned to receive pramipexole dihydrochloride or placebo for 4 weeks followed by a 2-hour intravenous levodopa infusion on consecutive days at 2 rates and with blinded assessments. They were then crossed over to the alternate oral therapy for 4 weeks followed by levodopa infusion and reassessment. Main Outcome Measures Change in finger-tapping speed, measured using the area under the curve (AUC) for finger taps per minute across time; peak finger-tapping speed; duration of response; time to "ON" (defined as a 10% increase in finger-tapping speed above baseline); walking speed; and dyskinesia AUC. Results Pramipexole with levodopa infusion increased finger-tapping speed beyond the change in baseline by a mean (SE) of 170 (47.2) per minute x minutes (P = .006) and more than doubled the AUC for finger-tapping speed. Pramipexole increased peak finger-tapping speed by a mean (SE) of 18 (8.5) taps per minute (P = .02) and improved mean (SE) walking speed (15.9 [0.70] vs 18.9 [0.70] seconds, P = .004). Pramipexole prolonged duration of response after levodopa infusion and shortened time to ON. Pramipexole increased mean (SE) baseline dyskinesia scores (26.0 [5.85] vs 12.1 [5.85] points, P = .05) and peak dyskinesia scores with levodopa infusion. Conclusions Pramipexole augmented the motor response to levodopa beyond a simple additive effect and increased the severity of levodopa-induced dyskinesia. When considering a combination of these therapies, an appropriate balance should be maintained regarding gain of motor function vs worsening of dyskinesia. Trial Registration clinicaltrials.gov Identifier: NCT00666653

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).

Hospital Care for Patients Experiencing Weekend vs Weekday Stroke: A Comparison of Quality and Aggressiveness of Care [Original Contribution]

Background We examined the quality and aggressiveness of care for the treatment of acute ischemic stroke (AIS) on weekends vs weekdays. Acute ischemic stroke is a leading cause of death and disability in the United States, and aggressive treatment must be provided within 3 hours for optimal patient outcomes. Because of this short treatment window for the administration of tissue plasminogen activator, patients need around-the-clock access to high-quality and aggressive care. Objective To determine whether there is a difference in the quality or aggressiveness of care for patients experiencing AIS on weekends vs weekdays. Design Retrospective study. Setting Academic research. Patients We conducted a retrospective study of patients with AIS in Virginia. Two logistic regression analyses assessed the relationship between weekend admission and quality and aggressiveness of care, while controlling for appropriate patient-level and hospital-level control variables. A propensity score stratification approach controlled for selection bias. Main Outcome Measures Treatment with tissue plasminogen activator and in-hospital mortality. Results Patients with AIS admitted on weekends are more likely to receive tissue plasminogen activator than those admitted on weekdays (P < .05). No statistically significant difference was noted in patient mortality based on day of admission (P ≥ .05). We detected no difference in the likelihood to seek hospital care on weekends between patients with AIS vs patients with hemorrhagic stroke. Conclusions Patients experiencing AIS are more likely to receive tissue plasminogen activator on weekends than on weekdays. Patients experiencing AIS who are admitted on weekends are no more likely to die than those who are admitted on weekdays. Further research is necessary to understand differences in weekend vs weekday care.

Strong Independent Correlation of Proteinuria With Cerebral Microbleeds in Patients With Stroke and Transient Ischemic Attack [Original Contribution]

Objective To assess the association of proteinuria with the frequency and number of cerebral microbleeds (CMB), a harbinger of future hemorrhagic stroke. Design Cross-sectional analysis. Patients Patients with consecutive ischemic stroke and transient ischemic attack admitted to a university hospital during a 22-month period. Interventions Presence and number of CMB were evaluated using gradient-echo T2*-weighted magnetic resonance imaging. Multivariable models were generated to determine the contribution of proteinuria to the frequency and number of CMB after adjusting for confounders. Results Of 236 patients (mean age, 70 years; 53% female), 72 (31%) had CMB present on gradient-echo imaging and 89 (38%) had evidence of proteinuria. In multivariable analyses with presence of CMB as the outcome, higher urinary protein (odds ratio [OR], 2.33; 95% confidence interval [CI], 1.10-4.95), being female (OR, 2.29; 95% CI, 1.19-4.49), history of atrial fibrillation (OR, 2.49; 95% CI, 1.14-5.44), elevated serum homocysteine (OR, 1.19; 95% CI, 1.09-1.29), and small-vessel disease subtype (OR, 2.95 95% CI, 1.43-6.10) were all significantly associated with presence of CMB. Logistic regression analysis by number of CMB showed similar findings. Conclusions Proteinuria is strongly associated with both the frequency and number of CMB in patients with recent cerebral ischemia. Urinary protein excretion may be a CMB risk marker or potential therapeutic target for mitigating the untoward clinical sequela of CMB.

Interferon-{gamma}-Producing T Cells, Pregnancy, and Postpartum Relapses of Multiple Sclerosis [Original Contribution]

Objective To determine whether fluctuations in functional T-cell subsets can explain why multiple sclerosis (MS) relapses decline during pregnancy and increase in the postpartum period. Design Case-control study. Setting Kaiser Permanente Northern California and Stanford University. Participants Twenty-six pregnant women with MS and 24 age-matched, pregnant controls. Intervention We prospectively followed up the pregnant women with MS and the age-matched, pregnant controls; conducted structured interviews; and collected peripheral blood mononuclear cells during each trimester and 2, 4, 6, 9, and 12 months post partum. Main Outcome Measures Sixteen functional cell types, including interferon- (IFN-)– and tumor necrosis factor–producing T-cell subsets, were measured using multicolor flow cytometry. Since these cell types may also fluctuate with pregnancy, lactational amenorrhea, or MS treatment, the data were analyzed taking into account these factors. Results Fifteen women with MS (58%) had relapses during the postpartum year. CD4+IFN-–producing cells fluctuated with MS relapses, declining during pregnancy in women with MS (P < .001) and continuing to decline after parturition in women with relapses (P = .001), yet rising or remaining stable in women with nonrelapsing MS or healthy pregnant women. Lactational amenorrhea was associated with a rise in CD4+IFN-–producing cells in women with MS (P = .009). In contrast, CD4+ tumor necrosis factor–producing cells decreased during lactational amenorrhea in all groups of women and, once this was taken into account, obscured any relationship to MS relapses. CD8+IFN-–producing cells were elevated in women with MS throughout the study (P < .001) but did not fluctuate with relapses. Conclusions Our findings suggest that a decline in circulating CD4+IFN-–producing cells leads to postpartum MS relapses. Our findings also suggest that the decline in these cells may begin during late pregnancy and that lactational amenorrhea induced by exclusive breastfeeding may be able to interrupt this process.

Dopamine Agonist Withdrawal Syndrome in Parkinson Disease [Original Contribution]

Objectives To report and characterize a dopamine agonist (DA) withdrawal syndrome (DAWS) in Parkinson disease. Design Retrospective cohort study. Setting Outpatient tertiary movement disorders clinic. Patients A cohort of 93 nondemented patients with Parkinson disease enrolled in a prospective study of nonmotor and motor disease manifestations. Main Outcome Measure The presence of DAWS, defined as a severe, stereotyped cluster of physical and psychological symptoms that correlate with DA withdrawal in a dose-dependent manner, cause clinically significant distress or social/occupational dysfunction, are refractory to levodopa and other Parkinson disease medications, and cannot be accounted for by other clinical factors. Results Of 40 subjects treated with a DA, 26 underwent subsequent DA taper. Of these 26 subjects, 5 (19%) developed DAWS and 21 (81%) did not. All subjects with DAWS had baseline DA-related impulse control disorders. Symptoms of DAWS resembled those of other drug withdrawal syndromes and included anxiety, panic attacks, agoraphobia, depression, dysphoria, diaphoresis, fatigue, pain, orthostatic hypotension, and drug cravings. Subjects with DAWS as compared with those without DAWS had higher baseline DA use (mean [SD], 420 [170] vs 230 [180] DA levodopa equivalent daily doses [DA-LEDD], respectively; P = .04) and higher cumulative DA exposure (mean [SD], 1800 [1200] vs 700 [900] DA-LEDD-years, respectively; P = .03). Subjects with DAWS also had considerably lower Unified Parkinson's Disease Rating Scale motor scores than those without DAWS (mean [SD], 21 [5] vs 31 [10], respectively; P = .007), despite comparable disease duration (mean [SD], 7.3 [7] vs 6.3 [4] years, respectively; P = .77) and similar total dopaminergic medication use (mean [SD], 830 [450] vs 640 [610] total LEDD, respectively; P = .52) in the 2 groups. Conclusions Dopamine agonists have a stereotyped withdrawal syndrome that can lead to profound disability in a subset of patients. Physicians should monitor patients closely when tapering these medications.

The Clinically Important Difference on the Unified Parkinson's Disease Rating Scale [Original Contribution]

Objective To determine the estimates of minimal, moderate, and large clinically important differences (CIDs) for the Unified Parkinson's Disease Rating Scale (UPDRS). Design Cross-sectional analysis of the CIDs for UPDRS total and motor scores was performed on patients with Parkinson disease (PD) using distribution- and anchor-based approaches based on the following 3 external standards: disability (10% on the Schwab and England Activities of Daily Living Scale), disease stage (1 stage on the Hoehn and Yahr Scale), and quality of life (1 SD on the 12-Item Short Form Health Survey). Setting University of Maryland Parkinson Disease and Movement Disorders Center, Patients Six hundred fifty-three patients with PD. Results A minimal CID was 2.3 to 2.7 points on the UPDRS motor score and 4.1 to 4.5 on the UPDRS total score. A moderate CID was 4.5 to 6.7 points on the UPDRS motor score and 8.5 to 10.3 on the UPDRS total score. A large CID was 10.7 to 10.8 points on the UPDRS motor score and 16.4 to 17.8 on the UPDRS total score. Conclusions Concordance among multiple approaches of analysis based on subjective and objective data show that reasonable estimates for the CID on the UPDRS motor score are 2.5 points for minimal, 5.2 for moderate, and 10.8 for large CIDs. Estimates for the UPDRS total score are 4.3 points for minimal, 9.1 for moderate, and 17.1 for large CIDs. These estimates will assist in determining clinically meaningful changes in PD progression and response to therapeutic interventions.

Effects of Aerobic Exercise on Mild Cognitive Impairment: A Controlled Trial [Original Contribution]

Objectives To examine the effects of aerobic exercise on cognition and other biomarkers associated with Alzheimer disease pathology for older adults with mild cognitive impairment, and assess the role of sex as a predictor of response. Design Six-month, randomized, controlled, clinical trial. Setting Veterans Affairs Puget Sound Health Care System clinical research unit. Participants Thirty-three adults (17 women) with amnestic mild cognitive impairment ranging in age from 55 to 85 years (mean age, 70 years). Intervention Participants were randomized either to a high-intensity aerobic exercise or stretching control group. The aerobic group exercised under the supervision of a fitness trainer at 75% to 85% of heart rate reserve for 45 to 60 min/d, 4 d/wk for 6 months. The control group carried out supervised stretching activities according to the same schedule but maintained their heart rate at or below 50% of their heart rate reserve. Before and after the study, glucometabolic and treadmill tests were performed and fat distribution was assessed using dual-energy x-ray absorptiometry. At baseline, month 3, and month 6, blood was collected for assay and cognitive tests were administered. Main Outcome Measures Performance measures on Symbol-Digit Modalities, Verbal Fluency, Stroop, Trails B, Task Switching, Story Recall, and List Learning. Fasting plasma levels of insulin, cortisol, brain-derived neurotrophic factor, insulinlike growth factor-I, and β-amyloids 40 and 42. Results Six months of high-intensity aerobic exercise had sex-specific effects on cognition, glucose metabolism, and hypothalamic-pituitary-adrenal axis and trophic activity despite comparable gains in cardiorespiratory fitness and body fat reduction. For women, aerobic exercise improved performance on multiple tests of executive function, increased glucose disposal during the metabolic clamp, and reduced fasting plasma levels of insulin, cortisol, and brain-derived neurotrophic factor. For men, aerobic exercise increased plasma levels of insulinlike growth factor I and had a favorable effect only on Trails B performance. Conclusions This study provides support, using rigorous controlled methodology, for a potent nonpharmacologic intervention that improves executive control processes for older women at high risk of cognitive decline. Moreover, our results suggest that a sex bias in cognitive response may relate to sex-based differences in glucometabolic and hypothalamic-pituitary-adrenal axis responses to aerobic exercise.

Physical Exercise, Aging, and Mild Cognitive Impairment: A Population-Based Study [Original Contribution]

Background Physical exercise is associated with decreased risk of dementia and Alzheimer disease. Objective To investigate whether physical exercise is associated with decreased risk of mild cognitive impairment (MCI). Design Population-based case-control study. Setting The Mayo Clinic Study of Aging, an ongoing population-based cohort study in Olmsted County, Minnesota. Participants A total of 1324 subjects without dementia who completed a Physical Exercise Questionnaire. Main Outcome Measures An expert consensus panel classified each subject as having normal cognition or MCI based on published criteria. Results We compared the frequency of physical exercise among 198 subjects with MCI with that among 1126 subjects with normal cognition and adjusted the analyses for age, sex, years of education, medical comorbidity, and depression. The odds ratios for any frequency of moderate exercise were 0.61 (95% confidence interval, 0.43-0.88; P = .008) for midlife (age range, 50-65 years) and 0.68 (95% confidence interval, 0.49-0.93; P = .02) for late life. The findings were consistent among men and women. Light exercise and vigorous exercise were not significantly associated with decreased risk of MCI. Conclusion In this population-based case-control study, any frequency of moderate exercise performed in midlife or late life was associated with a reduced odds of having MCI.

Association of C-Reactive Protein With Cognitive Impairment [Original Contribution]

Background High-sensitivity C-reactive protein (hsCRP) is a biomarker of cardiovascular risk that is suggested to be a biomarker for cognitive impairment. Objective To explore the association between hsCRP and cognitive impairment. Design Cross-sectional analysis of a population-based community aging study. Setting Northern Manhattan, New York, New York. Other Participants One thousand three hundred thirty-one participants from a longitudinal study of aging without dementia and with available hsCRP and neuropsychological testing data at baseline. Main Outcome Measures Four cognitive scores (memory, visuospatial, executive, and language impairment) derived from a neuropsychological battery. Cognitive impairment was defined by scores below 1.5 SDs of demographically corrected means. Results Participants in the highest hsCRP tertile had higher adjusted odds of impaired memory (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.0-2.1; P = .03) than participants in the lowest tertile. Subjects in the highest hsCRP tertile also had greater odds of visuospatial impairment (OR, 1.6; 95% CI, 1.0-2.3; P = .03). Higher hsCRP was not associated with executive or language impairment. Persons with at least 1 APOE 4 allele and hsCRP in the highest tertile had the greatest odds of impaired memory (OR, 2.7; 95% CI, 1.6-4.4). Conclusions High hsCRP may be a marker of memory and visuospatial impairment in the elderly. The role of APOE 4 requires further exploration.

APOE {varepsilon}4 Genotype and Longitudinal Changes in Cerebral Blood Flow in Normal Aging [Original Contribution]

Objective To study differences in longitudinal changes in regional cerebral blood flow (rCBF) between apolipoprotein E (APOE) 4 carriers and noncarriers in nondemented older adults from the Baltimore Longitudinal Study of Aging using positron emission tomography in order to determine whether there are regionally specific longitudinal changes in rCBF in APOE 4 carriers that might be related to its well-established role as a genetic risk factor for Alzheimer disease. Design, Setting, and Participants Using oxygen 15 ([15O])–labeled water positron emission tomography and voxel-based analysis, we compared changes in rCBF over an 8-year period between 29 nondemented APOE 4 carriers and 65 noncarriers older than 55 years. Serial neuropsychological data were collected for all participants. Results Widespread differences were observed in longitudinal change in rCBF between 4 carriers and noncarriers. The predominant pattern was greater rCBF decline in 4 carriers. These differences were observed in the frontal, parietal, and temporal cortices. The affected brain regions were those especially vulnerable to pathological changes in Alzheimer disease. Both 4 carriers and noncarriers remained free of clinical diagnoses of dementia or mild cognitive impairment during the course of the study. Conclusions Our findings suggest that APOE 4–mediated risk for Alzheimer disease is associated with widespread decline in rCBF over time that precedes the onset of dementia. Accelerated rates of decline in brain function in APOE 4 carriers may contribute to an increased risk for Alzheimer disease and a younger age at onset.

Donepezil Treatment and Changes in Hippocampal Structure in Very Mild Alzheimer Disease [Original Contribution]

Objective To compare longitudinal changes in the hippocampal structure in subjects with very mild dementia of the Alzheimer type (DAT) treated with donepezil hydrochloride, untreated subjects with very mild DAT, and controls without dementia. Design MPRAGE sequences were collected approximately 2 years apart on two 1.5-T magnetic resonance imaging systems, yielding 2 cohorts. Large-deformation high-dimensional brain mapping was used to compute deformation of hippocampal subfields. Setting A dementia clinic at Washington University School of Medicine. Patients or Other Participants Subjects came from 2 sources: 18 untreated subjects with DAT and 26 controls were drawn from a previous longitudinal study; 18 treated subjects with DAT were studied prospectively, and 44 controls were drawn from a longitudinal study from the same period. Intervention Patients were prescribed donepezil by their physician. Main Outcome Measures Hippocampal volume loss and surface deformation. Results There was no significant cohort effect at baseline; therefore, the 2 groups of control subjects were combined. The potential confounding effect of cohort/scanner was dealt with by including it as a covariate in statistical tests. There was no significant group effect in the rate of change of hippocampal volume or subfield deformation. Further exploration showed that compared with the untreated subjects with DAT, the treated subjects with DAT did not differ in the rate of change in any of the hippocampal measures. They also did not differ from the controls, while the untreated subjects with DAT differed from the controls in the rates of change of hippocampal volume and CA1 and subiculum subfield deformations. Conclusions Treatment with donepezil did not alter the progression of hippocampal deformation in subjects with DAT in this study. Small sample size may have contributed to this outcome.

Lost in Translation: Epidemiology, Risk, and Alzheimer Disease [Commentary in Neurology]

Diagnosis of Facial Nerve Schwannoma by Magnetic Resonance Imaging Enhancement of the Geniculate Ganglion [Images in Neurology]

Levodopa-Induced Dyskinesias in Spinocerebellar Ataxia Type 2 [Images in Neurology]

Ataxic Hemiparesis: The Benefit of Acute Multiparametric Magnetic Resonance Imaging [Images in Neurology]

Opsoclonus-Myoclonus Syndrome in Anti-N-Methyl-D-Aspartate Receptor Encephalitis [Observation]

Background Anti–N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis has been recently reported as autoimmune/paraneoplastic encephalitis, affecting mostly young females. Objective To describe opsoclonus-myoclonus syndrome in association with anti-NMDAR antibodies. Design Case report. Setting Geneva University Hospital. Patient A 23-year-old woman with opsoclonus-myoclonus syndrome. Results Two weeks after an episode of gastroenteritis, the patient developed symptoms of depression associated with psychomotor slowing, progressive gait instability, and opsoclonus-myoclonus. Cerebrospinal fluid examination showed mild lymphocytic pleocytosis and intrathecal IgG synthesis with oligoclonal bands. The patient's condition worsened rapidly to an akinetic mutism, followed by a period of agitation, delirium, and hallucinations. These gradually subsided; however, a frontal behavior and executive dysfunction persisted 5 months after symptom presentation. No tumor was found. Anti-NMDAR antibodies were found in the cerebrospinal fluid. Conclusions Opsoclonus-myoclonus may occur in patients with anti-NMDAR encephalitis. Prompt diagnosis of this disorder is important because after tumor removal and immunomodulatory therapies it has a relatively good prognosis.

The Stripe of Primary Lateral Sclerosis: Focal Primary Motor Cortex Hypometabolism Seen on Fluorodeoxyglucose F18 Positron Emission Tomography [Observation]

Background Primary lateral sclerosis (PLS) is a progressive upper motor neuron neurodegenerative condition. The diagnosis is made using clinical history, objective neurological assessment, and exclusion of other neurodegenerative disorders. Objective To evaluate the role of fluorodeoxyglucose F18 positron emission tomography and 3-dimensional stereotactic surface projection in the diagnosis of PLS. Design Case series. Setting Outpatient neurology clinic. Patients Three cases of probable PLS. Intervention Fluorodeoxyglucose F18 positron emission tomography in 3 patients with PLS. Results Three patients (2 male and 1 female; mean age, 65 years) were identified with a clinical diagnosis of PLS. Fluorodeoxyglucose F18 positron emission tomography demonstrated varying degrees of primary motor cortex hypometabolism. Conclusion Fluorodeoxyglucose F18 positron emission tomography and 3-dimensional stereotactic surface projection provide a useful diagnostic method to support a clinical diagnosis of PLS.

Biotin-Responsive Basal Ganglia Disease in Ethnic Europeans With Novel SLC19A3 Mutations [Observation]

Objective To report the first 2 European cases of biotin-responsive basal ganglia disease and novel SLC19A3 mutations. Design Case reports. Setting University hospital. Patients A 33-year-old man and his 29-year-old sister, both of Portuguese ancestry, presented with recurrent episodes of encephalopathy. Between episodes patients exhibited generalized dystonia, epilepsy, and bilateral hyperintensities of the caudate and putamen. Main Outcome Measures Clinical and radiologic findings. Results Administration of high doses of biotin or of a combination of biotin and thiamine during encephalopathies resulted in spectacular clinical and radiologic improvement in both patients. Sequencing of the SLC19A3 disclosed 2 novel mutations, both of which created premature stop codons in the protein sequence of hTHTR2. Conclusion This study demonstrates that biotin-responsive basal ganglia disease is a panethnic condition. A therapeutic trial with high doses of biotin and thiamine seems mandatory in every unexplained encephalopathy with bilateral lesions of putamen and caudate nuclei.

Ideal Management of Diabetes Mellitus and Dementia: Walking a Tightrope Between Hyperglycemia and Hypoglycemia [From JAMA]

Raymond Adams: A Life of Mind and Muscle [Book Reviews]

Neurology: PreTest Self-Assessment and Review, 7th ed [Book Reviews]

About This Journal [About This Journal]

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

Natural Oxidant Balance in Parkinson Disease [Editorial]

Mild Cognitive Impairment: Ten Years Later [Neurological Review]

In the past 10 years, there has been a virtual explosion in the literature concerning the construct of mild cognitive impairment. The interest in this topic demonstrates the increasing emphasis on the identification of the earliest features of cognitive disorders such as Alzheimer disease and other dementias. Mild cognitive impairment represents the earliest clinical features of these conditions and, hence, has become a focus of clinical, epidemiologic, neuroimaging, biomarker, neuropathological, disease mechanism, and clinical trials research. This review summarizes the progress that has been made while also recognizing the challenges that remain.

Cellular Mechanisms of Central Nervous System Repair by Natural Autoreactive Monoclonal Antibodies [Neurological Review]

Natural autoreactive monoclonal IgM antibodies have demonstrated potential as therapeutic agents for central nervous system (CNS) disease. These antibodies bind surface antigens on specific CNS cells, activating intracellular repair-promoting signals. IgM antibodies that bind to surface antigens on oligodendrocytes enhanced remyelination in animal models of multiple sclerosis. IgM antibodies that bind to neurons stimulate neurite outgrowth and prevent neuron apoptosis. The neuron-binding IgM antibodies may have utility in CNS axon- or neuron-damaging diseases, such as amyotrophic lateral sclerosis, stroke, spinal cord injury, or secondary progressive multiple sclerosis. Recombinant remyelination-promoting IgM antibodies have been generated for formal toxicology studies and, after Food and Drug Administration approval, a phase 1 clinical trial. Natural autoreactive monoclonal antibodies directed against CNS cells represent novel therapeutic molecules to induce repair of the nervous system.

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).

Pittsburgh Compound B Imaging and Prediction of Progression From Cognitive Normality to Symptomatic Alzheimer Disease [Original Contribution]

Objective To determine whether preclinical Alzheimer disease (AD), as detected by the amyloid-imaging agent Pittsburgh Compound B (PiB) in cognitively normal older adults, is associated with risk of symptomatic AD. Design A longitudinal cohort study of cognitively normal older adults assessed with positron emission tomography (PET) to determine the mean cortical binding potential for PiB and followed up with annual clinical and cognitive assessments for progression to very mild dementia of the Alzheimer type (DAT). Setting The Alzheimer's Disease Research Center, Washington University, St Louis, Missouri. Participants One hundred fifty-nine participants with a mean age of 71.5 years with a Clinical Dementia Rating (CDR) of 0 on a PET PiB scan at baseline. Main Outcome Measure Progression from CDR 0 to CDR 0.5 status (very mild dementia). Results Twenty-three participants progressed to CDR 0.5 at follow-up assessment (range, 1-5 assessments after PET PiB). Of these, 9 also were diagnosed with DAT. Higher mean cortical binding potential values for PiB (hazard ratio, 4.85; 95% confidence interval, 1.22-19.01; P = .02) and age (hazard ratio, 1.14; 95% confidence interval, 1.02-1.28; P = .03) predicted progression to CDR 0.5 DAT. The CDR 0.5 DAT group showed decline in 3 cognitive domains (episodic memory, semantic memory, and visuospatial performance) and had volume loss in the parahippocampal gyrus (includes entorhinal cortex) compared with individuals who remained at CDR 0. Conclusion Preclinical AD as detected by PET PiB is not benign, as it is associated with progression to symptomatic AD.

Cognitive Decline and Brain Volume Loss as Signatures of Cerebral Amyloid-{beta} Peptide Deposition Identified With Pittsburgh Compound B: Cognitive Decline Associated With A{beta} Deposition [Original Contribution]

Objective To examine the relation of amyloid-β peptide (Aβ) levels in the cerebral cortex with structural brain integrity and cognitive performance in cognitively healthy older people. Design Longitudinal study from May 22, 1985, through October 15, 2008. Setting Washington University Alzheimer Disease Research Center. Participants A total of 135 individuals aged 65 to 88 years with a Clinical Dementia Rating of 0. Main Outcome Measures The relations between mean cortical carbon 11 (11C)–labeled Pittsburgh compound B (PiB) binding potential values, proportional to the density of fibrillar Aβ binding sites in the brain, concurrent regional brain volumes as assessed by magnetic resonance imaging, and both concurrent and longitudinal cognitive performance in multiple domains. Results Elevated cerebral Aβ levels, in some cases comparable to those seen in individuals with Alzheimer disease, were observed in 29 participants, who also had smaller regional volumes in the hippocampus, temporal neocortex, anterior cingulate, and posterior cingulate. Concurrent cognitive performance was unrelated to Aβ levels but was related to regional brain volumes with the exception of the caudate. Longitudinal cognitive decline in episodic and working memory and visuospatial ability was associated with elevated Aβ levels and decreased hippocampal volume. Conclusion The in vivo measure of cerebral amyloidosis known as [11C]PiB is associated with cross-sectional regionally specific brain atrophy and longitudinal cognitive decline in multiple cognitive domains that occur before the clinical diagnosis of Alzheimer disease. These findings contribute to the understanding of the cognitive and structural consequences of Aβ levels in cognitively healthy older adults.

Transactive Response DNA-Binding Protein 43 Burden in Familial Alzheimer Disease and Down Syndrome [Original Contribution]

Objective To assess the transactive response DNA-binding protein 43 (TDP-43) burden in familial forms of Alzheimer disease (FAD) and Down syndrome (DS) to determine whether TDP-43 inclusions are also present. Design Using standard immunohistochemical techniques, we examined brain tissue samples from 42 subjects with FAD and 14 with DS. Results We found pathological TDP-43 aggregates in 14.0% of participants (6 of 42 and 2 of 14 participants with FAD and DS, respectively). In both FAD and DS, TDP-43 immunoreactivity did not colocalize with neurofibrillary tangles. Occasionally participants with FAD or DS had TDP-43–positive neuropil threads or dots. Overall, the amygdala was most commonly affected, followed by the hippocampus, with no TDP-43 pathology in neocortical regions. A similar distribution of TDP-43 inclusions is seen in sporadic Alzheimer disease, but it differs from that seen in amyotrophic lateral sclerosis and frontotemporal dementia. Conclusions Transactive response DNA-binding protein 43 pathology occurs in FAD and DS, similar to that observed in sporadic Alzheimer disease. Thus, pathological TDP-43 may contribute the cognitive impairments in familial and sporadic forms of Alzheimer disease.

Characteristics and Surgical Outcomes of Patients With Refractory Magnetic Resonance Imaging-Negative Epilepsies [Original Contribution]

Objective To explore several characteristics of patients with pharmacoresistant epilepsy without distinct lesions on magnetic resonance images (MRI–), who account for a relevant proportion of presurgical patient cohorts. Design Retrospective case series. Setting University epilepsy center. Patients A cohort of 1200 patients who had comprehensive presurgical assessment from January 1, 2000, through December 31, 2006. Main Outcome Measures Frequency of MRI– patients in the total presurgical cohort, seizure-free outcome rates in patients who had surgery and those who did not, outcome predictors, and spatial properties of epileptogenic areas in MRI– patients with epilepsy. All MRI– patients were retrospectively analyzed. Presurgical MRIs were reevaluated for subtle cortical dysplasias by postprocessing and visual reassessment. Results One-hundred ninety MRI– patients were identified (16% of all presurgical candidates); 29 (15%) had surgery. Eleven (38%) became seizure free (including those with auras only; 45%). Surgical therapy was more frequently offered to MRI+ patients (76%; P < .001), and their outcome was also superior (66% seizure-free; P = .001). The seizure-free rate of 16% in MRI– patients who did not have surgery was, however, inferior to that of the MRI– patients who did (P = .008). Nine MRI– patients who had surgery had distinct histopathological lesions, 8 of which turned out to be retrospectively detectable on presurgical MRI. Seven of the MRI– but histopathologically lesional patients became seizure free compared with only 4 of 20 patients without histopathological lesions (P = .003). Three-fifths of the histopathologically nonlesional patients had multifocal or extensive epileptogenic areas. Conclusions Patients with epilepsy who are MRI– can be successfully treated with surgery. Improved sensitivity of MRI will improve the outcomes of presurgically studied patients. Surgical failures in patients without histopathological lesions mostly result from extensive epileptogenic areas.

Status Epilepticus Associated With Subtentorial Posterior Fossa Lesions [Original Contribution]

Background Nonconvulsive status epilepticus (SE) is a frequent complication in critically ill patients in the intensive care unit. While seizures have been reported in association with subtentorial posterior fossa lesions, the frequency of occurrence of SE among these patients is not known. Objectives To examine prevalence, clinical features, potential risk factors, and outcome of SE among patients presenting with subtentorial posterior fossa lesions. Design Retrospective review of our hospital database was conducted to identify patients with posterior fossa lesions complicated by SE over 1 year between April 1, 2007, and May 1, 2008. Setting Tertiary care setting. Patients Patients with subtentorial posterior fossa lesions admitted to the hospital for neurological or neurosurgical care. Main Outcome Measures Prevalence of SE, potential risk factors, and eventual neurological outcome. Results Over 1 year, 13 of 501 patients (2.6%) admitted to the hospital with posterior fossa lesions had SE. Some patients had risk factors for SE such as sepsis, use of particular drugs, or intracranial bleeding, while others had no other clear identifiable cause. Conclusions Status epilepticus can be a potential complication in patients with posterior fossa cranial lesions and can be seen in up to 2.6% of such patients. Most have unfavorable outcome.

Functional and Cognitive Outcome in Prolonged Refractory Status Epilepticus [Original Contribution]

Objective To determine the functional and cognitive outcomes of patients with prolonged refractory status epilepticus (PRSE) lasting 7 or more days despite the use of anesthetic agents for seizure suppression. Design Retrospective analysis. Setting St Mary's Hospital, Mayo Clinic, Rochester, Minnesota. Participants Fourteen patients with PRSE. Intervention Hospital follow-up interview. Main Outcome Measures Survival rate of PRSE and functional and cognitive outcome of surviving patients based on the modified Rankin Scale (mRS) and Telephone Interview for Cognitive Status (TICS). Results Forty-three percent of patients (6 of 14) died during hospitalization for PRSE, and 57% (8 of 14) had died by the last follow-up. Of the 6 surviving patients, 4 showed improvement and 2 showed no change in mRS score (median mRS change, –1; range, 0 to –3). Owing to preexisting cognitive deficits, 1 patient could not complete the TICS. The 5 remaining patients scored a median of 34 on the TICS (range, 30-37; reference TICS score, ≥31; maximum TICS score, 41). Age, sex, PRSE duration, and etiology were not associated with chance of survival. Conclusions Despite the high mortality rate, survival with meaningful functional and cognitive recovery is possible after PRSE. Prolonged duration of status epilepticus alone should not be considered a reason to discontinue treatment.

Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Type 2 Caused by Mitofusin 2 Mutations [Original Contribution]

Background Mutations in the gene encoding mitofusin 2 (MFN2) cause Charcot-Marie-Tooth disease type 2 (CMT2), with heterogeneity concerning severity and associated clinical features. Objective To describe MFN2 mutations and associated phenotypes in patients with hereditary motor and sensory neuropathy (HMSN). Design Direct sequencing of the MFN2 gene and clinical investigations of patients with MFN2 mutations. Setting Molecular genetics laboratory of a university hospital and the Limoges National Referral Center for Rare Peripheral Neuropathies. Patients One hundred fifty index patients with HMSN and a median motor nerve conduction velocity of 25 m/s or greater and without mutations in the genes encoding connexin 32 and myelin protein zero. Main Outcome Measures Results of genetic analyses and phenotypic observations. Results Twenty different missense mutations were identified in 20 index patients. Mutation frequency was 19 of 107 (17.8%) in patients with CMT2 and 1 of 43 (2.3%) in patients with a median motor nerve conduction velocity less than 38 m/s. Four patients had proven de novo mutations, 8 families had autosomal dominant inheritance, and 3 had autosomal recessive inheritance. The remaining 5 patients were sporadic cases with heterozygous mutations. Phenotypes varied from mild forms to early-onset severe forms. Additional features were encountered in 8 patients (32%). Six patients underwent sural nerve biopsy: electronic microscopy showed prominent mitochondrial abnormalities on longitudinal sections. Conclusions MFN2 mutations are a frequent cause of CMT2, with variable severity and either dominant or recessive inheritance. MFN2 gene testing must be a first-line analysis in axonal HMSN irrespective of the mode of inheritance or the severity of the peripheral neuropathy.

Motor Phenotype of LRRK2 G2019S Carriers in Early-Onset Parkinson Disease [Original Contribution]

Objective To determine the motor phenotype of LRRK2 G2019S mutation carriers. LRRK2 mutation carriers were previously reported to manifest the tremor dominant motor phenotype, which has been associated with slower motor progression and less cognitive impairment compared with the postural instability and gait difficulty (PIGD) phenotype. Design Cross-sectional observational study. Setting Thirteen movement disorders centers. Participants Nine hundred twenty-five early-onset Parkinson disease cases defined as age at onset younger than 51 years. Main Outcome Measures LRRK2 mutation status and Parkinson disease motor phenotype: tremor dominant or PIGD. Demographic information, family history of Parkinson disease, and the Unified Parkinson's Disease Rating Scale score were collected on all participants. DNA samples were genotyped for LRRK2 mutations (G2019S, I2020T, R1441C, and Y1699C). Logistic regression was used to examine associations of G2019S mutation status with motor phenotype adjusting for disease duration, Ashkenazi Jewish ancestry, levodopa dose, and family history of Parkinson disease. Results Thirty-four cases (3.7%) (14 previously reported) were G2019S carriers. No other mutations were found. Carriers were more likely to be Ashkenazi Jewish (55.9% vs 11.9%; P < .001) but did not significantly differ in any other demographic or disease characteristics. Carriers had a lower tremor score (P = .03) and were more likely to have a PIGD phenotype (92.3% vs 58.9%; P = .003). The association of the G2019S mutation with PIGD phenotype remained after controlling for disease duration and Ashkenazi Jewish ancestry (odds ratio, 17.7; P < .001). Conclusion Early-onset Parkinson disease G2019S LRRK2 carriers are more likely to manifest the PIGD phenotype, which may have implications for disease course.

Heterogeneity in Infarct Patterns and Clinical Outcomes Following Internal Carotid Artery Occlusion [Original Contribution]

Objective To investigate whether the extent of infarction and clinical outcomes after internal carotid artery (ICA) occlusion depends on the additional occlusion of the middle cerebral artery (MCA). Design Using statistical parametric mapping, we compared infarct patterns in stroke patients. Setting A tertiary care hospital. Patients Patients with coexistent ICA and MCA occlusion (n = 25), isolated ICA occlusion (n = 20), and isolated MCA occlusion (n = 40). Main Outcome Measure Modified Rankin scale score. The independent effect of infarct type on clinical outcome was estimated using logistic regression, adjusting for age and sex. Results The mean age was 62.6 years (standard deviation [SD], 15.5 years) in patients with ICA and MCA occlusion, 64.3 years (SD, 12.9 years) in patients with isolated ICA occlusion, and 67.4 years (SD, 14.2 years) in patients with isolated MCA occlusion. Infarct patterns, volume (P = .13), and the proportion of patients with poor outcomes (P = .5) were similar between those with ICA and MCA occlusions and those with isolated MCA occlusion. Compared with the other 2 groups, those with isolated ICA occlusion were less likely to have infarction of the insula (P < .001) and superior temporal lobe (P < .001) and had smaller infarct volume and lower modified Rankin scale scores (all P < .05). Compared with those with isolated ICA occlusion, the risk of poor clinical outcome was greater in those with coexistent ICA and MCA occlusion (P = .02) and those with isolated MCA occlusion (P = .06) independent of age and sex. Comments Patients with ICA occlusion but without coexistent MCA occlusion have different infarct patterns, less extensive infarcts, and better clinical outcomes than those with coexistent MCA occlusion or MCA occlusion alone. It may not be warranted to exclude such patients from acute stroke trials.

HLA-DRB1*1501 and Spinal Cord Magnetic Resonance Imaging Lesions in Multiple Sclerosis [Original Contribution]

Background Multiple sclerosis (MS) is a heterogeneous neurologic disease with extensive variation with respect to the most affected central nervous system region (brain vs spinal cord). Objective To test the hypothesis that this variation in lesion location (brain vs spinal cord) might be (partially) genetically determined. Design Candidate gene study. Setting Academic research. Patients Patients were selected for the availability of DNA material, clinical variables, and brain and spinal cord magnetic resonance images (evaluating T2-weighted lesion load in the brain and the number of spinal cord lesions). Main Outcome Measures For genotyping, we used a DNA chip containing a set of genes mentioned in previous publications noting their relation to different phenotypes of MS. We assessed the association between brain and spinal cord abnormalities and the genotypes of the patients. Results One hundred fifty patients were included in the analysis. Five single-nucleotide polymorphisms within the major histocompatibility complex region were associated with the number of focal abnormalities in the spinal cord. The most significant was rs3135388 (surrogate marker for the HLA-DRB1*1501 allele). Carriers of HLA-DRB1*1501 had a median of 4 spinal cord lesions compared with 2 lesions for noncarriers (P < .001). No significant association was noted between the single-nucleotide polymorphisms and T2-weighted lesion load in the brain. Conclusions Carriership of HLA-DRB1*1501 (via rs3135388) was associated with the extent of focal abnormalities in the spinal cord. Spinal cord lesions might be an explanation for increased MS disease severity in patients carrying HLA-DRB1*1501.

High Striatal Amyloid {beta}-Peptide Deposition Across Different Autosomal Alzheimer Disease Mutation Types [Original Contribution]

Background Supported by compelling genetic data regarding early-onset familial Alzheimer disease (AD), the amyloid β-peptide (Aβ)–centric theory holds that Aβ is involved in the pathogenesis of sporadic AD. Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes lead to increased Aβ levels before symptoms arise. Objectives To evaluate the pattern of Pittsburgh Compound B (PiB) retention in subjects with different autosomal dominant mutations associated with familial AD vs that in healthy age-matched control subjects and subjects with probable sporadic AD, to correlate Aβ burden as measured by PiB with available clinical and cognitive data, and to compare the regional brain patterns of PiB retention and fluorodeoxyglucose F 18 (FDG) uptake. Design Correlation analysis of positron emission tomography (PET) imaging studies. Setting Academic research. Participants Seven PSEN1 mutation carriers and 1 APP mutation carrier underwent PiB and FDG PET imaging. Amyloid β-peptide burden and FDG uptake were established using standardized uptake values normalized to pons. Main Outcome Measure Primary outcomes were PET results, which were compared with those of a well-characterized cohort of 30 healthy control subjects and 30 subjects with probable sporadic AD. Results All mutation carriers had high PiB retention in the striatum, with some also having cortical PiB retention in ventrofrontal and posterior cingulate/precuneus areas. The striatal pattern of PiB retention was similar in the PSEN1 and APP mutation carriers. Neither striatal nor cortical Aβ burden was related to cognitive status. Conclusions Consistent with previous studies, the pattern of Aβ deposition in familial AD differs from that in sporadic AD, with higher striatal and somewhat lower cortical PiB retention in familial AD. The pattern and degree of Aβ deposition were not associated with mutation type nor cognitive status.

Quantitative Template for Subtyping Primary Progressive Aphasia [Original Contribution]

Background The syndrome of primary progressive aphasia (PPA) is diagnosed when a gradual failure of word usage or comprehension emerges as the principal feature of a neurodegenerative disease. Objective To provide a quantitative algorithm for classifying PPA into agrammatic (PPA-G), semantic (PPA-S), and logopenic (PPA-L) variants, each of which is known to have a different probability of association with Alzheimer disease vs frontotemporal lobar degeneration. Design Prospective study. Setting University medical center. Patients Sixteen consecutively enrolled patients with PPA who underwent neuropsychological testing and magnetic resonance imaging recruited nationally in the United States as part of a longitudinal study. Results A 2-dimensional template that reflects performance on tests of syntax (Northwestern Anagram Test) and lexical semantics (Peabody Picture Vocabulary Test—Fourth Edition) classified all 16 patients in concordance with a clinical diagnosis that had been made before the administration of quantitative tests. All 3 PPA subtypes had distinctly asymmetrical atrophy of the left perisylvian language network. Each subtype also had distinctive peak atrophy sites: PPA-G in the inferior frontal gyrus (Broca area), PPA-S in the anterior temporal lobe, and PPA-L in Brodmann area 37. Conclusions Once an accurate root diagnosis of PPA is made, subtyping can be quantitatively guided using a 2-dimensional template based on orthogonal tasks of grammatical competence and word comprehension. Although the choice of tasks and the precise cutoff levels may need to be adjusted to fit linguistic and educational backgrounds, these 16 patients demonstrate the feasibility of using a simple algorithm for clinicoanatomical classification in PPA. Prospective studies will show whether this subtyping can improve clinical prediction of the underlying neuropathologic condition.

Cerebrospinal Fluid {beta}-Amyloid 42, Tau, and P-tau: Confirmation Now Realization [From JAMA]

Surgery Is the Best Option for Intractable Unilateral Mesial Temporal Epilepsy [From JAMA]

Absence of Pittsburgh Compound B Detection of Cerebral Amyloid {beta} in a Patient With Clinical, Cognitive, and Cerebrospinal Fluid Markers of Alzheimer Disease: A Case Report [Observation]

Background To date, there have been no reports of individuals who have been characterized longitudinally using clinical and cognitive measures and who transitioned from cognitive normality to early symptomatic Alzheimer disease (AD) during a period when both cerebrospinal fluid (CSF) markers and Pittsburgh Compound B (PiB) amyloid imaging were obtained. Objective To determine the temporal relationships of clinical, cognitive, CSF, and PiB amyloid imaging markers of AD. Design Case report. Setting Alzheimer disease research center. Participant Longitudinally assessed 85-year-old man in a memory and aging study who was cognitively normal at his initial and next 3 annual assessments. Main Outcome Measures Serial clinical and psychometric assessments over 6 years in addition to PiB imaging with positron emission tomography (PET) and CSF biomarker assays before autopsy. Results Decline in measures of episodic memory and, to a lesser degree, working memory began at about age 88 years. PiB PET amyloid imaging was negative at age 881/2 years, but at age 891/2 years there was reduced amyloid β 42 and elevated levels of tau in the CSF. Beginning at age 89 years, very mild cognitive and functional decline reported by his collateral source resulted in a diagnosis of very mild dementia of the Alzheimer type. After death at age 91 years, the autopsy revealed foci of frequent neocortical diffuse amyloid β plaques sufficient to fulfill Khachaturian neuropathologic criteria for definite AD, but other neuropathologic criteria for AD were not met because only sparse neuritic plaques and neurofibrillary tangles were present. Postmortem biochemical analysis of the cerebral tissue confirmed that PiB PET binding was below the level needed for in vivo detection. Conclusion Clinical, cognitive, and CSF markers consistent with AD may precede detection of cerebral amyloid β using amyloid imaging agents such as PiB that primarily label fibrillar amyloid β plaques.

Symptomatic Narcolepsy in Patients With Neuromyelitis Optica and Multiple Sclerosis: New Neurochemical and Immunological Implications [Observation]

Objective To characterize factors that contribute to symptomatic narcolepsy and excessive daytime sleepiness in neuromyelitis optica and multiple sclerosis. Setting Japanese university hospitals. Design Case study. Patients Seven Japanese patients whose initial diagnoses were multiple sclerosis and who were exhibiting excessive daytime sleepiness. Main Outcome Measures Lesions on magnetic resonance imaging, cerebrospinal fluid hypocretin-1 levels, and serum anti–aquaporin 4 (AQP4) antibody titer. Results Bilateral and symmetrical hypothalamic lesions associated with marked or moderate hypocretin deficiency were found in all 7 cases. Four of these patients met the International Classification of Sleep Disorders 2 narcolepsy criteria. Three patients, including 2 patients with narcolepsy, were seropositive for anti-AQP4 antibody and diagnosed as having neuromyelitis optica–related disorder. Conclusion Since AQP4 is highly expressed in the hypothalamic periventricular regions, an immune attack on AQP4 may be partially responsible for the bilateral and hypothalamic lesions and hypocretin deficiency in narcolepsy/excessive daytime sleepiness associated with autoimmune demyelinating diseases.

Subdural Fluid Collections in Patients With Infantile Neuronal Ceroid Lipofuscinosis [Observation]

Objective To describe subdural fluid collections on magnetic resonance imaging as part of the natural history of infantile neuronal ceroid lipofuscinosis. Design Case series. Setting Program on Developmental Endocrinology and Genetics, The Clinical Center, National Institutes of Health, Bethesda, Maryland. Patients Patients with infantile neuronal ceroid lipofuscinosis with subdural fluid collections. Main Outcome Measure Neurodegeneration on magnetic resonance imaging. Results During an ongoing bench-to-bedside clinical investigation, magnetic resonance imaging examinations led to the incidental discovery of subdural fluid collections in 4 of 9 patients with infantile neuronal ceroid lipofuscinosis. No particular event (such as trauma) or change in symptoms was linked to this finding, which was already in the chronic phase when discovered. Of the 4 patients, 1 was followed up for 7 years, 2 for 4 years, and 1 for 2.5 years. Over time, these collections remained stable or decreased in size. Conclusion Recognition that subdural fluid collections are part of the infantile neuronal ceroid lipofuscinosis disease process may obviate the necessity of additional workup as well as therapeutic interventions in these chronically sick children.

Shivering in Coma [Images in Neurology]

Lateral Medullary Syndrome and Ipsilateral Hemiplegia (Opalski Syndrome) Due to Left Vertebral Artery Dissection [Images in Neurology]

Progressive Myopathy With Multiple Symmetric Lipomatosis [Images in Neurology]

HIV and the Brain: New Challenges in the Modern Era [Book Reviews]

Adams and Victor's Principles of Neurology, 9th ed [Book Reviews]

Breastfeeding and Multiple Sclerosis [Correspondence]

Protective Effect of Breastfeeding in Postpartum Relapse Rate of Mothers With Multiple Sclerosis [Correspondence]

Protective Effect of Breastfeeding in Postpartum Relapse Rate of Mothers With Multiple Sclerosis--Reply [Correspondence]

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]