Archives of Neurology recent issues

Archives of Neurology publishes peer-reviewed original contributions of interest to clinicians. It provides practicing physicians with access to the latest information from leading centers of neurological research. It is published monthly.

Symptomatic Intracerebral Hemorrhage Among Eligible Warfarin-Treated Patients Receiving Intravenous Tissue Plasminogen Activator for Acute Ischemic Stroke [Original Contribution]

Objective  To determine whether warfarin-treated patients with an international normalized ratio less than 1.7 who receive intravenous tissue plasminogen activator for acute ischemic stroke are at increased risk for symptomatic intracerebral hemorrhage.

Design  Retrospective study.

Setting  Academic hospital.

Patients  Consecutive patients with acute ischemic stroke who are treated with intravenous tissue plasminogen activator.

Main Outcome Measure  Symptomatic intracerebral hemorrhage.

Results  One hundred seven patients were included (mean age, 69.2 years; 43.9% men; median National Institutes of Health Stroke Scale score, 14; median onset-to-treatment time, 140 minutes; baseline warfarin use, 12.1%). The median international normalized ratio was 1.04 (range, 0.82-1.61). The overall rate of symptomatic intracerebral hemorrhage was 6.5%, but it was nearly 10-fold higher among patients taking warfarin compared with those not taking warfarin at baseline (30.8% vs 3.2%, respectively; P = .004). Baseline warfarin use remained strongly associated with symptomatic intracerebral hemorrhage (P = .004) after adjusting for relevant covariates, including age, atrial fibrillation, National Institutes of Health Stroke Scale score, and international normalized ratio.

Conclusions  Despite an international normalized ratio less than 1.7, warfarin-treated patients are more likely than those not taking warfarin to experience symptomatic intracerebral hemorrhage following treatment with intravenous tissue plasminogen activator. Larger studies in this subgroup are warranted.

Published online March 8, 2010 (doi:10.1001/archneurol.2010.25).

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Clinical Effect of Neutralizing Antibodies to Interferon Beta That Persist Long After Cessation of Therapy for Multiple Sclerosis [Original Contribution]

Objectives  To confirm that neutralizing antibodies (NAb) to interferon beta can persist after therapy withdrawal and to evaluate whether persisting NAb are associated with a worse clinical disease course in multiple sclerosis (MS).

Design  Retrospective study.

Setting  Tertiary referral center in the Netherlands.

Patients  A total of 71 patients with relapsing-remitting multiple sclerosis treated with interferon beta in the past.

Main Outcome Measures  Persisting NAb after therapy withdrawal were tested using the cytopathic effect assay. Patients with and without persisting NAb were compared on several outcomes: the change in annualized relapse rate from prior to interferon beta treatment initiation to after cessation of treatment, time to sustained disability on the Kurtzke Expanded Disability Status Scale, and the use of disease-modifying treatments after cessation of treatment with interferon beta.

Results  Seventeen of 71 patients (24%) tested NAb positive after a median interval of 25 months (interquartile range, 10-51 months) after interferon beta treatment cessation. Eleven of these 17 patients (15%) were high-titer NAb positive (>150 10-fold reduction units per mL). Persisting NAb were associated with an increase in the annualized relapse rate (P = .04) and a reduction in time to reach a sustained Expanded Disability Status Scale score of 6.0, ie, the need for unilateral assistance to walk 100 m (P = .02). Moreover, NAb-positive patients were treated with second-line therapy significantly more often, especially mitoxantrone (P = .006).

Conclusion  Anti–interferon beta NAb can persist after interferon beta treatment withdrawal and are associated with overt clinical disease activity. This is made apparent by an increase in relapse rate and faster disability progression and is supported by the observed need for more aggressive therapy after interferon beta treatment cessation. Prospective studies are warranted to confirm these results.

Published online February 8, 2010 (doi: 10.1001/archneurol.2010.21).

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About This Journal [About This Journal]

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

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Cancer of the Nervous System: 2010 [Editorial]

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New Insights Into Susceptibility to Glioma [Neurological Review]

The study of inherited susceptibility to cancer has been one of the most informative areas of research in the past decade. Most of the cancer genetics studies have been focused on the common tumors such as breast and colorectal cancers. As the allelic architecture of these tumors is unraveled, research attention is turning to other rare cancers such as glioma, which are also likely to have a major genetic component as the basis of their development. In this brief review we discuss emerging data on glioma whole genome–association searches to identify risk loci. Two glioma genome-wide association studies have so far been reported. Our group identified 5 risk loci for glioma susceptibility (TERT rs2736100, CCDC26 rs4295627, CDKN2A/CDKN2B rs4977756, RTEL1 rs6010620, and PHLDB1 rs498872). Wrensch and colleagues provided further evidence to 2 risk loci (CDKN2B rs1412829 and RTEL1 rs6010620) for GBM and anaplastic astrocytoma. Although these data provide the strongest evidence to date for the role of common low-risk variants in the etiology of glioma, the single-nucleotide polymorphisms identified alone are unlikely to be candidates for causality. Identifying the causal variant at each specific locus and its biological impact now poses a significant challenge, contingent on a combination of fine mapping and functional analyses. Finally, we hope that a greater understanding of the biological basis of the disease will lead to the development of novel therapeutic interventions.

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Recent Advances in Therapy for Glioblastoma [Neurological Review]

Glioblastoma is the most common primary malignant brain tumor in adults and is a challenging disease to treat. The current standard of care includes maximal safe surgical resection, followed by a combination of radiation and chemotherapy with temozolomide. Despite that, recurrence is quite common, and so we continue to search for more effective treatments both for initial therapy and at the time of recurrence. This article will review recent advances in therapy for glioblastoma, including surgery, radiotherapy, cytotoxic chemotherapies, molecularly targeted agents, and immunotherapy; the role of antiangiogenic agents in the treatment of glioblastoma is discussed in a separate article in this issue of the Archives.

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Bevacizumab for Malignant Gliomas [Neurological Review]

Malignant gliomas are the most common and aggressive primary brain tumors in adults. Despite optimal treatment with surgery, radiotherapy, and temozolomide, tumor recurrences are frequent and patients with malignant gliomas continue to have poor prognoses. Malignant gliomas are often highly vascularized, and significant advances have been made in the last few decades in our understanding of the mechanisms of tumor angiogenesis. Recently, bevacizumab, an antibody against vascular endothelial growth factor, has demonstrated significant activity in recurrent glioblastomas, resulting in US Food and Drug Administration approval and raising the prospect for other antiangiogenic drugs now entering clinical trials.

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Primary Central Nervous System Lymphoma [Neurological Review]

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Myelopathies in Patients With Cancer [Neurological Review]

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New Strategies in the Management of Leptomeningeal Metastases [Neurological Review]

The management of patients with leptomeningeal metastases (LM) is multifaceted and complex. Even with an aggressive approach, therapeutic outcomes are uniformly disappointing. This is because of the relentless growth of the central nervous system (CNS) and/or the systemic cancers, or their lethal complications. Advances in the understanding of the homing of cancer cells to the CNS, and of cancer metastasis in general, and more effective anticancer drugs that are adequately delivered to the CNS and cerebrospinal fluid (CSF) are needed to improve outcomes for patients with LM. These advances may lead to better treatments for this disease and, ultimately, its prevention.

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A Phase 1 Trial of ABT-510 Concurrent With Standard Chemoradiation for Patients With Newly Diagnosed Glioblastoma [Clinical Trials]

Objective  To determine the maximum tolerated dose of ABT-510, a thrombospondin-1 mimetic drug with antiangiogenic properties, when used concurrently with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma.

Design  Phase 1 dose-escalation clinical trial.

Setting  Comprehensive Cancer Center, University of Alabama at Birmingham.

Patients  A total of 23 patients with newly diagnosed, histologically verified glioblastoma enrolled between April 2005 and January 2007.

Interventions  Four cohorts of 3 patients each received subcutaneous ABT-510 injection at doses of 20, 50, 100, or 200 mg/d. The maximum cohort was expanded to 14 patients to obtain additional safety and gene expression data. The treatment plan included 10 weeks of induction phase (temozolomide and radiotherapy with ABT-510 for 6 weeks plus ABT-510 monotherapy for 4 weeks) followed by a maintenance phase of ABT-510 and monthly temozolomide.

Main Outcome Measures  Patients were monitored with brain magnetic resonance imaging and laboratory testing for dose-limiting toxicities, defined as grades 3 or 4 nonhematological toxicities and grade 4 hematological toxicities. Therapy was discontinued if 14 maintenance cycles were completed, disease progression occurred, or if the patient requested withdrawal. Disease progression, survival statistics, and gene expression arrays were analyzed.

Results  There were no grade 3 or 4 dose-limiting toxicity events that appeared related to ABT-510 for the dose range of 20 to 200 mg/d. A maximum tolerated dose was not defined. Most adverse events were mild, and injection-site reactions. The median time to tumor progression was 45.9 weeks, and the median overall survival time was 64.4 weeks. Gene expression analysis using TaqMan low-density arrays identified angiogenic genes that were differentially expressed in the brains of controls compared with patients with newly diagnosed glioblastoma, and identified FGF-1 and TIE-1 as being downregulated in patients who had better clinical outcomes.

Conclusions  ABT-510, at subcutaneous doses up to 200 mg/d, is tolerated well with concurrent temozolomide and radiotherapy in patients with newly diagnosed glioblastoma, and low-density arrays provide a useful method of exploring gene expression profiles.

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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).

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Paraneoplastic Neurologic Syndrome in the PNS Euronetwork Database: A European Study From 20 Centers [Original Contribution]

Background  Paraneoplastic neurologic syndrome (PNS) represents the remote effects of cancer on the nervous system. Diagnostic criteria for the syndrome were published by the PNS Euronetwork and form the basis of a database to collect standardized clinical data from patients with PNS.

Objectives  To analyze various types of PNS, frequent tumor and antibody associations, clinical characteristics of individual syndromes, and possible therapeutic and prognostic strategies.

Design  Prospective case series and database study.

Setting  Twenty European centers.

Patients  Patients were recruited from January 1, 2000, to December 31, 2008.

Main Outcome Measures  Based on diagnostic criteria published by the PNS Euronetwork consortium, clinical characteristics of classic PNS and several other less well-characterized syndromes associated with cancer were assessed.

Results  Data from 979 patients were analyzed, representing the largest PNS investigation to date. The findings elucidate the clinical evolution of paraneoplastic cerebellar syndrome according to the onconeural antibodies present, the heterogeneity and prognosis of dysautonomic disorders, and the clinical variability of paraneoplastic limbic encephalitis.

Conclusion  The study results confirm that PNS influences oncologic patient survival. Tumors are the main cause of death, but some types of PNS (such as dysautonomia) have a poorer prognosis than malignant neoplasms.

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Morphological Characteristics of Brain Tumors Causing Seizures [Original Contribution]

Objective  To quantify size and localization differences between tumors presenting with seizures vs nonseizure neurological symptoms.

Design  Retrospective imaging survey. We performed magnetic resonance imaging–based morphometric analysis and nonparametric mapping in patients with brain tumors.

Setting  University-affiliated teaching hospital.

Patients or Other Participants  One hundred twenty-four patients with newly diagnosed supratentorial glial tumors.

Main Outcome Measures  Volumetric and mapping methods were used to evaluate differences in size and location of the tumors in patients who presented with seizures as compared with patients who presented with other symptoms.

Results  In high-grade gliomas, tumors presenting with seizures were smaller than tumors presenting with other neurological symptoms, whereas in low-grade gliomas, tumors presenting with seizures were larger. Tumor location maps revealed that in high-grade gliomas, deep-seated tumors in the pericallosal regions were more likely to present with nonseizure neurological symptoms. In low-grade gliomas, tumors of the temporal lobe as well as the insular region were more likely to present with seizures.

Conclusions  The influence of size and location of the tumors on their propensity to cause seizures varies with the grade of the tumor. In high-grade gliomas, rapidly growing tumors, particularly those situated in deeper structures, present with non–seizure-related symptoms. In low-grade gliomas, lesions in the temporal lobe or the insula grow large without other symptoms and eventually cause seizures. Quantitative image analysis allows for the mapping of regions in each group that are more or less susceptible to seizures.

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Efficacy and Safety of Levetiracetam in Patients With Glioma: A Clinical Prospective Study [Original Contribution]

Objective  To evaluate the efficacy and safety of levetiracetam in the management of epilepsy in patients with glioma.

Design  A prospective study in hospitalized patients with a new diagnosis of glioma.

Setting  Department of Neurological Sciences and Visions, Spedali Civili of Brescia.

Patients  From March 1, 2006, until January 1, 2009, 176 consecutive patients (101 men and 75 women) with a first diagnosis of glioma were enrolled in the study. All patients with a diagnosis of epilepsy were treated with levetiracetam.

Main Outcome Measures  Clinical, histological, and magnetic resonance imaging findings were analyzed.

Results  Age at the diagnosis of glioma ranged from 22 to 79 years (mean [SD], 57 [15] years; median, 59 years). Duration of the disease ranged from 27 days to 21/2 years (mean [SD], 13.7 [7.8] months; median, 13 months). Eighty-two patients received levetiracetam because of a diagnosis of epilepsy. At the last evaluation (May 1, 2009), 75 of 82 patients (91%) treated with levetiracetam were seizure free; in 2 of these patients, levetiracetam was withdrawn because of intolerable adverse effects. Prompt and long-lasting control of seizures was obtained in 49 of 82 patients (60%) with a dose of levetiracetam that ranged from 1500 to 3000 mg/d, and 9 (11%) of the treated patients needed an increase of levetiracetam dosage to 4000 mg/d to become seizure free. No laboratory abnormalities were observed in patients with concomitant chemotherapy.

Conclusion  The results of this study provide good evidence that levetiracetam is efficacious and safe in patients with epilepsy due to glioma.

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Increased Melanoma Risk in Parkinson Disease: A Prospective Clinicopathological Study [Original Contribution]

Objective  To evaluate the possible association of Parkinson disease (PD) and melanoma in North America.

Design, Setting, and Patients  Thirty-one centers enrolled patients with idiopathic PD. At visit 1, a neurologist obtained a medical history. At visit 2, a dermatologist recorded melanoma risk factors, performed a whole-body examination, and performed a biopsy of lesions suggestive of melanoma for evaluation by a central dermatopathology laboratory. We compared overall prevalence of melanoma with prevalence calculated from the US Surveillance Epidemiology and End Results (SEER) cancer database and the American Academy of Dermatology skin cancer screening programs.

Results  A total of 2106 patients (mean [SD] age, 68.6 [10.6] years; duration of PD, 7.1 [5.7] years) completed the study. Most (84.8%) had received levodopa. Dermatology examinations revealed 346 pigmented lesions; dermatopathological findings confirmed 20 in situ melanomas (0.9%) and 4 invasive melanomas (0.2%). In addition, histories revealed 68 prior melanomas (3.2%). Prevalence (5-year limited duration) of invasive malignant melanoma in the US cohort of patients with PD (n = 1692) was 2.24-fold higher (95% confidence interval, 1.21-4.17) than expected in age- and sex-matched populations in the US SEER database. Age- or sex-adjusted relative risk of any melanoma for US patients was more than 7 times that expected from confirmed cases in American Academy of Dermatology skin cancer screening programs.

Conclusions  Melanoma prevalence appears to be higher in patients with PD than in the general population. Despite difficulties in comparing other databases with this study population, the study supports increased melanoma screening in patients with PD.

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Malignant Astrocytomas: A System Disease [From JAMA]

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Giant Plexiform Neurofibroma in Neurofibromatosis Type 1 [Images in Neurology]

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Spinal Epidural Metastasis [Images in Neurology]

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Intramedullary Spinal Metastasis From Breast Cancer [Images in Neurology]

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Papilledema as the Sole Magnetic Resonance Imaging Finding in Leptomeningeal Metastasis [Images in Neurology]

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Chemotherapy-Associated Peripheral Sensory Neuropathy Assessed Using In Vivo Corneal Confocal Microscopy [Images in Neurology]

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FDG-PET a Pivotal Imaging Modality for Diagnosis of Stroke-Onset Intravascular Lymphoma [Images in Neurology]

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Diffuse Brain Stem Glioma [Images in Neurology]

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Evaluation of O-(2-[18F]-Fluoroethyl)-L-Tyrosine in the Diagnosis of Glioblastoma [Observation]

Objective  To assess the feasibility of synthesis of O-(2-[¹⁸F]-fluoroethyl)-l-tyrosine (FET), a new positron emission tomographic (PET) tracer described in several studies but not yet considered standard in management of glioma, in routine practice and to determine FET uptake in a homogeneous group of patients with suspected high-grade glioma.

Design  Prospective nonrandomized trial.

Patients  Twelve patients with suspicion of high-grade glioma.

Results  The mean (SD) FET uptake ratio was 3.15 (0.72) for the 12 patients and 3.16 (0.75) for the 11 patients with glioblastoma.

Conclusion  The initial results are promising and indicate that FET PET is a valuable and applicable tool for the imaging of high-grade glioma.

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Janeway Lesions, Osler Nodes, or Neither? [Correspondence]

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Janeway Lesions, Osler Nodes, or Neither?--Reply [Correspondence]

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About This Journal [About This Journal]

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

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Progress on Progranulin [Editorial]

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Error in Figure in: Cellular Mechanisms of Central Nervous System Repair by Natural Autoreactive Monoclonal Antibodies [Correction]

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Inherited Metabolic Disorders and Stroke Part 2: Homocystinuria, Organic Acidurias, and Urea Cycle Disorders [Neurological Review]

Several inherited metabolic disorders have been associated with stroke particularly in newborns, children, and young adults. In part 1, we discussed the genetics, stroke pathophysiology, clinical presentation, diagnosis, and treatment of Fabry disease and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. In part 2, we overview homocystinuria, organic acidurias, and urea cycle disorders.

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A Randomized, Placebo-Controlled Trial of Latrepirdine in Huntington Disease [Clinical Trials]

Objectives  To evaluate the safety and tolerability of latrepirdine in Huntington disease (HD) and explore its effects on cognition, behavior, and motor symptoms.

Design  Double-blind, randomized, placebo-controlled trial.

Setting  Multicenter outpatient trial.

Participants  Ninety-one participants with mild to moderate HD enrolled at 17 US and UK centers from July 18, 2007, through July 16, 2008.

Intervention  Latrepirdine, 20 mg 3 times daily (n = 46), or matching placebo (n = 45) for a 90-day treatment period.

Main Outcome Measures  The primary outcome variable was tolerability, defined as the ability to complete the study at the assigned drug dosage. Secondary outcome variables included score changes from baseline to day 90 on the Unified Huntington's Disease Rating Scale (UHDRS), the Mini-Mental State Examination (MMSE), and the Alzheimer Disease Assessment Scale–cognitive subscale (ADAS-cog).

Results  Latrepirdine was well tolerated (87% of the patients given latrepirdine completed the study vs 82% in the placebo group), and adverse event rates were comparable in the 2 groups (70% in the latrepirdine group and 80% in the placebo group). Treatment with latrepirdine resulted in improved mean MMSE scores compared with stable performance in the placebo group (treatment effect, 0.97 points; 95% confidence interval, 0.10-1.85; P = .03). No significant treatment effects were seen on the UHDRS or the ADAS-cog.

Conclusions  Short-term administration of latrepirdine is well tolerated in patients with HD and may have a beneficial effect on cognition. Further investigation of latrepirdine is warranted in this population with HD.

Trial Registration  clinicaltrials.gov Identifier: NCT00497159

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The Spectrum of Mutations in Progranulin: A Collaborative Study Screening 545 Cases of Neurodegeneration [Original Contribution]

Background  Mutation in the progranulin gene (GRN) can cause frontotemporal dementia (FTD). However, it is unclear whether some rare FTD-related GRN variants are pathogenic and whether neurodegenerative disorders other than FTD can also be caused by GRN mutations.

Objectives  To delineate the range of clinical presentations associated with GRN mutations and to define pathogenic candidacy of rare GRN variants.

Design  Case-control study.

Setting  Clinical and neuropathology dementia research studies at 8 academic centers.

Participants  Four hundred thirty-four patients with FTD, including primary progressive aphasia, semantic dementia, FTD/amyotrophic lateral sclerosis (ALS), FTD/motor neuron disease, corticobasal syndrome/corticobasal degeneration, progressive supranuclear palsy, Pick disease, dementia lacking distinctive histopathology, and pathologically confirmed cases of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U); and 111 non-FTD cases (controls) in which TDP-43 deposits were a prominent neuropathological feature, including subjects with ALS, Guam ALS and/or parkinsonism dementia complex, Guam dementia, Alzheimer disease, multiple system atrophy, and argyrophilic grain disease.

Main Outcome Measures  Variants detected on sequencing of all 13 GRN exons and at least 80 base pairs of flanking introns, and their pathogenic candidacy determined by in silico and ex vivo splicing assays.

Results  We identified 58 genetic variants that included 26 previously unknown changes. Twenty-four variants appeared to be pathogenic, including 8 novel mutations. The frequency of GRN mutations was 6.9% (30 of 434) of all FTD-spectrum cases, 21.4% (9 of 42) of cases with a pathological diagnosis of FTLD-U, 16.0% (28 of 175) of FTD-spectrum cases with a family history of a similar neurodegenerative disease, and 56.2% (9 of 16) of cases of FTLD-U with a family history.

Conclusions  Pathogenic mutations were found only in FTD-spectrum cases and not in other related neurodegenerative diseases. Haploinsufficiency of GRN is the predominant mechanism leading to FTD.

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Alzheimer Disease-like Phenotype Associated With the c.154delA Mutation in Progranulin [Original Contribution]

Objective  To characterize a kindred with a familial neurodegenerative disorder associated with a mutation in progranulin (PGRN), with emphasis on the unique clinical features in this kindred.

Design  Antemortem and postmortem characterization of a kindred with a familial neurodegenerative disorder.

Setting  Multispecialty group academic medical center.

Patients  Affected members of a kindred with dementia with or without parkinsonism associated with a unique mutation in PGRN.

Main Outcome Measure  Genotype-phenotype correlation.

Results  Of 10 affected individuals identified, 6 presented with early amnestic symptoms which resulted in initial diagnoses of Alzheimer disease or amnestic mild cognitive impairment. Some individuals presented with features characteristic of frontotemporal dementia. Mean age at onset was substantially younger in generation III (75.8 years; range, 69-80 years) than in generation II (60.7 years; range, 55-66 years). The pattern of cerebral atrophy varied widely in the affected individuals. Neuropathologic features in 6 individuals included frontotemporal lobar degeneration with ubiquitin-positive neuronal cytoplasmic and intranuclear inclusions (FTLD-U with NII). PGRN analysis revealed a single base pair deletion in exon 2 (c.154delA), which caused a frameshift (p.Thr52HisfsX2) and, therefore, creation of a premature termination codon and a likely null allele.

Conclusions  In this large kindred, most affected individuals had clinical presentations that resembled Alzheimer disease or amnestic mild cognitive impairment associated with a mutation in PGRN and underlying FTLD-U with NII neuropathologic abnormalities. This finding is in distinct contrast to previously reported kindreds, in which clinical presentations have typically been within the spectrum of FTLD. The basis for the large difference in age at onset between generations requires further study.

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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).

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Hypertension, Executive Dysfunction, and Progression to Dementia: The Canadian Study of Health and Aging [Original Contribution]

Background  Midlife hypertension has long been established as a risk factor for dementia, but the role of late-life hypertension remains unclear.

Objective  To investigate the role of hypertension in cognitive deterioration among older subjects with cognitive impairment, no dementia.

Design  The Canadian Study of Health and Aging was conducted in 3 waves (1991, 1995-1996, and 2001-2002).

Setting  Community-based cohort study.

Patients  We studied 990 subjects with a mean (SD) age of 83.06 (6.97) years having cognitive impairment, no dementia who were followed up for 5 years in the Canadian Study of Health and Aging.

Main Outcome Measures  Determination of cognitive dysfunction and association between hypertension and cognitive deterioration.

Results  No difference in the rate of progression to dementia based on the presence of hypertension was found between subjects with memory dysfunction alone or in combination with executive dysfunction. However, among subjects with executive dysfunction alone, 57.7% having hypertension progressed to dementia compared with 28.0% having normotension (P = .02).

Conclusions  Hypertension predicts progression to dementia in older subjects with executive dysfunction but not memory dysfunction. Control of hypertension could prevent progression to dementia in one-third of the subjects with cognitive impairment, no dementia.

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Prospective Study of Endogenous Circulating Estradiol and Risk of Stroke in Older Women [Original Contribution]

Objective  To test the hypothesis that circulating endogenous estradiol is associated with stroke risk in older postmenopausal women. Stroke incidence increases after menopause, when endogenous estrogen levels fall, yet exogenous estrogen increases strokes in older postmenopausal women. The relation between endogenous estrogen and stroke is unclear.

Design  Prospective case-control study.

Setting  Study of Osteoporotic Fractures.

Patients or Other Participants  Women at least age 65 years (99% follow-up) who were not taking estrogen at baseline.

Main Outcome Measures  Free estradiol index (FEI) was calculated by dividing total estradiol by sex hormone–binding globulin concentrations measured in banked baseline serum. Using logistic regression, odds ratios were estimated for a first-ever atherothrombotic stroke associated with endogenous FEI in 196 women who had a subsequent validated stroke (median follow-up, 8 years) compared with 219 randomly selected women who did not. Potential mediators were assessed in multivariable models.

Results  The age-adjusted odds of atherothrombotic stroke increased with increasing FEI quartiles (P_trend = .007). Women in the highest FEI quartile had an age-adjusted 2.31-fold (odds ratio, 2.31; 95% confidence interval, 1.28-4.17) higher odds than women in the lowest quartile. Women with greater central adiposity had a suggestively stronger association (P = .08). Atherogenic dyslipidemia, type 2 diabetes mellitus, and C-reactive protein level were potential mediators of this relation.

Conclusions  Endogenous estradiol level is an indicator of stroke risk in older postmenopausal women, especially in those with greater central adiposity. Potential mediators, including atherogenic dyslipidemia, insulin resistance, and inflammation, might underlie this association. Whether estradiol, independent of atherogenic adiposity, influences such mediators and stroke risk needs to be determined. Estrogen-altering agents might be harmful or beneficial depending on endogenous estradiol levels, especially in women with greater central adiposity.

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Autoantibody-Mediated Dysfunction of Sympathetic Neurons in Guillain-Barre Syndrome [Original Contribution]

Objective  To investigate a pathologic immune response to autonomic nerve fibers in Guillain-Barré syndrome (GBS).

Design  We compared the effects of purified IgG from patients with GBS, multiple sclerosis, and chronic inflammatory demyelinating polyneuropathy on transmitter synthesis and synaptic transmission in an in vitro model of sympathetic neurons and cardiomyocytes.

Subjects  Three patients with GBS, 2 with chronic inflammatory demyelinating polyradiculoneuropathy, and 2 with relapsing-remitting multiple sclerosis.

Results  Incubation of sympathetic neurons with GBS-IgG resulted in an upregulation of tyrosine hydroxylase and caused a relative increase of noradrenaline levels. In cocultures of sympathetic neurons and cardiomyocytes, GBS-IgG altered the synaptic transmission, as assessed by changes in the average cardiomyocyte beat rate. These effects could be neutralized by preincubation of sympathetic neurons with intravenous immunoglobulins.

Conclusion  Our findings indicate that in GBS, circulating antibodies directed against sympathetic neurons may contribute to autonomic dysfunction via functionally relevant changes in the noradrenaline synthesis.

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Ventilatory and Cardiovascular Responses to Hypercapnia and Hypoxia in Multiple-System Atrophy [Original Contribution]

Background  Loss of medullary sympathoexcitatory neurons may contribute to baroreflex failure, leading to orthostatic hypotension in multiple-system atrophy (MSA). The cardiovascular responses to chemoreflex activation in MSA have not been explored to date.

Objectives  To determine whether ventilatory and cardiovascular responses to hypercapnia and hypoxia during wakefulness are systematically impaired in MSA.

Design  Case-control study.

Setting  Mayo Clinic, Rochester, Minnesota.

Patients  Sixteen patients with probable MSA (cases) and 14 age-matched control subjects (controls).

Main Outcome Measures  Minute ventilation, blood pressure, and heart rate responses to hypercapnia and hypoxia during wakefulness. Hypercapnia was induced by a rebreathing technique and was limited to a maximal expiratory partial pressure of carbon dioxide of 65 mm Hg. Hypoxia was induced by a stepwise increase in inspiratory partial pressure of nitrogen and was limited to a minimal arterial oxygen saturation of 80%. Ventilatory responses were assessed as slopes of the regression line relating minute ventilation to changes in arterial oxygen saturation and partial pressure of carbon dioxide.

Results  In cases, ventilatory responses to hypercapnia and hypoxia were preserved, despite the presence of severe autonomic failure, while cardiovascular responses to these stimuli were impaired. Among cases, hypercapnia elicited a less robust increase in arterial pressure than among controls, and hypoxia elicited a depressor response rather than the normal pressor responses (P < .001 for both).

Conclusions  Ventilatory responses to hypercapnia and hypoxia during wakefulness may be preserved in patients with MSA, despite the presence of autonomic failure and impaired cardiovascular responses to these stimuli. A critical number of chemosensitive medullary neurons may need to be lost before development of impaired automatic ventilation during wakefulness in MSA, whereas earlier loss of medullary sympathoexcitatory neurons may contribute to the impaired cardiovascular responses in these patients.

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Correlation of Longitudinal Cerebrospinal Fluid Biomarkers With Cognitive Decline in Healthy Older Adults [Original Contribution]

Background  Abnormal cerebrospinal fluid (CSF) biomarker levels predict development of Alzheimer disease with good accuracy and are thought to precede cognitive deterioration.

Objective  To investigate whether changes in CSF biomarker levels over time in healthy older adults are associated with a concurrent decline in cognitive performance.

Design  Retrospective analysis of longitudinal CSF biomarker levels and clinical data.

Setting  A combined academic dementia disorder research center and dementia clinic.

Participants  Thirty-seven cognitively healthy older volunteers (mean age, 73 years).

Main Outcome Measures  Longitudinal CSF total tau protein, hyperphosphorylated tau protein 181, and β-amyloid_1-42 protein levels and cognitive assessments at baseline and at follow-up 4 years later.

Results  Low levels of CSF β-amyloid_1-42 protein at follow-up were associated with decreased delayed word recall score on the Alzheimer Disease Assessment Scale–cognitive subscale (r_s = –0.437, P < .01) and with slower results on A Quick Test of Cognitive Speed (r_s = –0.540, P < .001). Individuals with a decrease during the 4-year study of 15% or more in CSF β-amyloid_1-42 protein level performed worse on the Alzheimer Disease Assessment Scale–cognitive subscale delayed word recall (z = –2.18, P < .05) and A Quick Test of Cognitive Speed (z = –2.35, P < .05) at follow-up. An increase over time of 20% or more in CSF hyperphosphorylated tau protein 181 level correlated with slower results on A Quick Test of Cognitive Speed at follow-up (z = –2.13, P < .05). Furthermore, the presence of the APOE-4 (OMIM 107741) allele was associated with a greater longitudinal decrease in CSF β-amyloid_1-42 protein level (² = 10.47, P < .05) and with a higher CSF total tau protein level at follow-up (² = 8.83, P < .05). No correlation existed between baseline CSF biomarker levels and baseline or follow-up cognitive scores.

Conclusions  In this group of healthy older adults, changes in CSF biomarker levels previously associated with Alzheimer disease correlated with a decline in cognitive functions. Changes in CSF biomarker levels may identify early neurodegenerative processes of Alzheimer disease.

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FUS Mutations in Familial Amyotrophic Lateral Sclerosis in the Netherlands [Original Contribution]

Objectives  To assess the frequency of FUS mutations in 52 probands with familial amyotrophic lateral sclerosis (FALS) and to provide careful documentation of clinical characteristics.

Design  FUS mutation analysis was performed using capillary sequencing on all coding regions of the gene in a cohort of patients with FALS. The clinical characteristics of patients carrying FUS mutations were described in detail.

Setting  Three university hospitals in the Netherlands (referral centers for neuromuscular diseases).

Patients  Fifty-two probands from unrelated pedigrees with FALS.

Main Outcome Measure  FUS mutations.

Results  We identified 3 mutations in 4 of 52 probands. We observed 2 previously identified mutations (p.Arg521Cys and p.Arg521His) and 1 novel mutation (p.Ser462Phe). In addition, a p.Gln210His polymorphism was identified in 1 proband and 3 healthy control subjects. Phenotypic analysis demonstrated that patients may lack upper motor neuron signs, which was confirmed at autopsy, and disease survival was short (<36 months for 8 of 10 patients).

Conclusions  We discovered FUS mutations in Dutch patients with FALS and the occurrence of benign variations in the gene. Therefore, caution is warranted when interpreting results in a clinical setting. Although the phenotype associated with FUS mutations is variable, most patients predominantly demonstrate loss of lower motor neurons and have short disease survival.

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Scoliosis Surgery in Children With Neuromuscular Disease: Findings From the US National Inpatient Sample, 1997 to 2003 [Original Contribution]

Background  Scoliosis is a frequent complication of pediatric neuromuscular disease (NMD). Scoliosis surgery in children with NMD is thought to carry greater morbidity and mortality.

Objectives  To study demographics, comorbidities, outcomes, and hospitalization expenditures among children with NMD undergoing scoliosis surgery.

Design  Using the Kids Inpatient Database, a large all-payer US database of hospital discharges among children and adults younger than 20 years, we studied children undergoing scoliosis surgery between January 1, 1997, and December 31, 2003. Continuous variables were compared by t test, and categorical variables were compared by Pearson product moment correlation ² test.

Setting  National database of pediatric hospital discharges.

Patients  Children with and without NMD.

Main Outcome Measures  Demographics, hospital length of stay, and in-hospital mortality associated with scoliosis surgery.

Results  Of 17 780 reported hospitalizations owing to scoliosis surgery, 437 children (2.5%) had NMD. Compared with children undergoing scoliosis surgery for other indications, children with NMD were more likely to be younger (12.4 vs 14.2 years), male (73.5% vs 38.3%), and insured by Medicaid (35.6% vs 20.3%). Comorbidities that were more common among children with NMD included pulmonary complications (lung disease not classified, pulmonary collapse, pulmonary insufficiency, chronic respiratory failure, and ventilator requirement) and cardiovascular complications (cardiomyopathy, hypotension, and tachycardia). Scoliosis surgery in children with NMD was associated with increased hospital length of stay (10.3 vs 7.7 days) and hospitalization expenditures ($80 251 vs $62 154), and higher in-hospital mortality (1.6% vs 0.2%).

Conclusion  Children with NMD have increased hospital length of stay and higher in-hospital mortality associated with scoliosis surgery, highlighting the need for further study of measures that could reduce complications and improve outcomes in this population.

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Intraparenchymal Hemorrhage in a Patient With Osteogenesis Imperfecta and Plasminogen Activator Inhibitor-1 Deficiency [Observation]

Background  Osteogenesis imperfecta is associated with susceptibility to connective tissue damage, including intracranial but usually extra-axial hemorrhage. Plasminogen activator inhibitor-1 deficiency is a rare fibrinolytic cause of systemic bleeding diathesis.

Objective  To describe a case of a brainstem intraparenchymal hemorrhage associated with connective tissue and coagulation disorders.

Design  Case report.

Setting  Academic medical center.

Patient  A 36-year-old woman with a history of osteogenesis imperfecta presented to the emergency department after an argument, during which she developed left ear pain and right eye esotropia followed by quadriparesis and somnolence. Neuroimaging showed a tegmental mesencephalic hemorrhage.

Main Outcome Measures  Results of computerized tomography, magnetic resonance angiography, and parenchymal imaging; and serum hematologic markers.

Results  No underlying vascular abnormality or mass lesion was found. Among coagulopathic serum markers, only plasminogen activator inhibitor-1 activity level was abnormally low.

Conclusion  Intraparenchymal hemorrhage may occur in the setting of a fibrinolytic inhibitory deficiency and osteogenesis imperfecta.

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A Novel POLG Gene Mutation in 4 Children With Alpers-like Hepatocerebral Syndromes [Observation]

Objective  To describe a novel POLG missense mutation (c.3218C>T; p.P1073L) that, in association with 2 previously described mutations, caused an Alpers-like hepatocerebral syndrome in 4 children.

Design  Genotype-phenotype correlation.

Setting  Tertiary care universities.

Patients  Four children, 2 related and 2 unrelated, with the novel p.P1073L mutation (all patients) and either the p.A467T (2 patients), p.G848S (1 patient), or p.W748S (1 patient) mutation presented with psychomotor delay, encephalopathy, and liver failure.

Interventions  Detailed clinical and laboratory examinations including brain magnetic resonance imaging, muscle biopsy, measurement of mitochondrial DNA, and sequencing of the POLG gene.

Main Outcome Measures  Definition of clinical variability.

Results  All 4 patients had psychomotor delay, seizures, and liver disease. Three patients had severe gastrointestinal dysmotility, which may be associated with the new p.P1073L mutation.

Conclusions  The heterozygous presence of the novel p.P1073L mutation in trans with another recessive POLG mutation causes a hepatocerebral disorder identical or very similar to Alpers syndrome. This adds to the already striking clinical heterogeneity of POLG mutations. In the Belgian patients, the familial occurrence without consanguinity is related to the high frequency of the recessive p.A467T and p.W748S mutations in northwestern Europe and reveals a pitfall for diagnosis and genetic counseling.

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Acute Bilateral Basal Ganglia Lesions and Chorea in a Diabetic-Uremic Patient on Dialysis [Images in Neurology]

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A Very Small but Very Symptomatic Vertebral Artery Dissection [Images in Neurology]

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Anti-N-methyl-D-aspartate Receptor Encephalitis: Characteristic Behavioral And Movement Disorder [Images in Neurology]

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Stroke: An American Academy of Neurology Press Quality of Life Guide [Book Reviews]

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Blueprints Neurology, 3rd ed [Book Reviews]

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About This Journal [About This Journal]

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

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

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

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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.

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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

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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).

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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

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

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

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

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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.

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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.

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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.

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

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

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

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About This Journal [About This Journal]

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

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Natural Oxidant Balance in Parkinson Disease [Editorial]

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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.

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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.

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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).

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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

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

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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.

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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.

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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.

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Shivering in Coma [Images in Neurology]

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

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Progressive Myopathy With Multiple Symmetric Lipomatosis [Images in Neurology]

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

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

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Breastfeeding and Multiple Sclerosis [Correspondence]

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

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

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Worlds Best Pharmacy

The name says it all. This is the best online pharmacy on the web. The index page is set to show the most polular ED products, while the menu and quicksearch allow to find products in other categories.

worlds-best-pharmacy.com

Indian Meds

A most recent indian-themed, ethnic site. Includes generic and original (brand) products. al our standard navigational tools and support options are available. This site converts nicely on general pharmaceutical traffic as it has products for vurtually any need.

indianmeds.org

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