Neurology RSS : Gourt

Exercise Engagement as a Moderator of the Effects of APOE Genotype on Amyloid Deposition [Original Contribution]

Objective APOE 4 status has been associated with greater cortical amyloid deposition, whereas exercise has been associated with less in cognitively normal adults. The primary objective here was to examine whether physical exercise moderates the association between APOE genotype and amyloid deposition in cognitively normal adults. Design APOE genotyping data and answers to a questionnaire on physical exercise engagement over the last decade were obtained in conjunction with cerebrospinal fluid (CSF) samples and amyloid imaging with carbon 11–labeled Pittsburgh Compound B ([11C]PiB) positron emission tomography. Participants were classified as either low or high exercisers based on exercise guidelines of the American Heart Association. Setting Knight Alzheimer's Disease Research Center at Washington University, St Louis, Missouri. Participants A total of 201 cognitively normal adults (135 of whom were women) aged 45 to 88 years were recruited from the Knight Alzheimer’s Disease Research Center. Samples of CSF were collected from 165 participants. Amyloid imaging was performed for 163 participants. Results APOE 4 carriers evidenced higher [11C]PiB binding (P < .001) and lower CSF Aβ42 levels (P < .001) than did noncarriers. Our previous findings of higher [11C]PiB binding (P = .005) and lower CSF Aβ42 levels (P = .009) in more sedentary individuals were replicated. Most importantly, we observed a novel interaction between APOE status and exercise engagement for [11C]PiB binding (P = .008) such that a more sedentary lifestyle was significantly associated with higher [11C]PiB binding for 4 carriers (P = .013) but not for noncarriers (P = .20). All findings remained significant after controlling for age; sex; educational level; body mass index; the presence or history of hypertension, diabetes mellitus, heart problems, or depression; and the interval between assessments. Conclusion Collectively, these results suggest that cognitively normal sedentary APOE 4–positive individuals may be at augmented risk for cerebral amyloid deposition.

A Unique Manifestation of Pupillary Fatigue in Autoimmune Autonomic Ganglionopathy [Observation]

Objective To demonstrate a unique abnormality of the pupillary light reflex in patients with autoimmune autonomic ganglionopathy (AAG). Design Case series. Setting Autonomic clinics at 2 university hospitals (University of Texas Southwestern Medical Center and Beth Israel Deaconess Medical Center). Participants Seven patients with antibody-positive AAG. Interventions All patients with AAG underwent either monocular or binocular infrared pupillometry using a standard 2-second light stimulus at a defined intensity. Findings were compared with those from healthy control subjects and patients with other autonomic disorders. The light stimulus used in this study was selected to eliminate the normal phenomenon of pupil escape. Main Outcome Measures The time to onset of redilation as well as other indices of pupillary constriction to light stimulus. Results Patients with AAG exhibited premature pupillary redilation (mean [SD], 1.02 [0.20] seconds) compared with healthy control subjects (mean [SD], 2.24 [0.10] seconds) and other patients with autonomic disorders (mean [SD], 2.30 [0.12] seconds) (P < .001). In healthy control subjects and patients with other autonomic disorders, pupillary redilation always followed the termination of the light stimulus; in patients with AAG, redilation consistently occurred during the light stimulus. In 1 patient, serial repetitive light stimulation further decreased the time to onset of redilation. Conclusions Premature redilation of the pupil is a unique physiological feature seen only in patients with AAG. This phenomenon appears to be a manifestation of pupillary fatigue, a clinical correlate of defective synaptic transmission at the level of autonomic ganglia in antibody-positive AAG.

Human Metapneumovirus in the Cerebrospinal Fluid of a Patient With Acute Encephalitis [Observation]

Objective To report, to our knowledge, the first case of detection of human metapneumovirus in the cerebrospinal fluid of a patient during acute encephalitis. Design Case report. Setting University hospital. Patient A 10-year-old girl with acute encephalitis. Results Human metapneumovirus was detected in cerebrospinal fluid and nasal-wash specimens during the initial phase of mild encephalitis. Abrupt clinical deterioration was associated with the presence of multiple areas of demyelination and cortical abnormalities. Demyelinated areas improved after immunomodulatory therapy, but cortical lesions spread in both hemispheres. Surprisingly, clinical worsening occurred when the virus became undetectable in cerebrospinal fluid. Conclusions The detection of human metapneumovirus in cerebrospinal fluid strongly suggests its causative role in acute encephalitis. The evolution of the clinical and radiological features provided insight into the pathogenesis of human metapneumovirus encephalitis.

Contributions of the Framingham Heart Study to Stroke and Dementia Epidemiologic Research at 60 Years [Neurological Review]

The Framingham Heart Study, the longest-running prospective epidemiologic study in history, was initiated in 1948 in response to the rising toll of coronary heart disease and hypertension. During the ensuing decades, the study of other diseases, notably stroke and dementia, was added. In 1971, 5124 offspring of the original cohort of 5209 men and women were added, and a third generation of 4095 men and women were added in 2002. The 3-generation structure was used to relate a host of risk factors measured in mid and late life to the subsequent development of stroke, dementia, and cognitive decline. It has also facilitated studies of family occurrence of disease over generations particularly for genomic research. Dementia and Alzheimer disease research has proceeded from the determination of risk factors for at least moderately severe Alzheimer disease in the first generation to mild cognitive impairment and mild Alzheimer disease in the offspring and to studies of the third generation for detection of pre–mild cognitive impairment and indicators of cognitive decline in mid life. These research efforts have been facilitated by genome-wide association studies, biomarkers, and multiple measures of subclinical vascular disease. The tempo of decline has been documented by serial quantitative measures of brain structure on magnetic resonance imaging and cognitive performance by neuropsychological testing. Clinical correlation with systematic neuropathological examinations of more than 150 brains has provided important confirmation of cerebrovascular and brain tissue indices of disease. Identification of persons at heightened risk for stroke, mild cognitive impairment, Alzheimer disease, and cognitive decline years prior to disease onset may facilitate delay in disease onset and prevention.

Biomarkers for Insulin Resistance and Inflammation and the Risk for All-Cause Dementia and Alzheimer Disease: Results From the Framingham Heart Study [Original Contribution]

Objective To investigate the contribution of biomarkers of glucose homeostasis (adiponectin, glucose, glycated albumin, and insulin levels) and inflammation (high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A2 levels) to the risk of developing Alzheimer disease (AD) and all-cause dementia. Design Prospective cohort study. Setting Dementia-free Framingham Heart Study participants had sera measured for these biomarkers at the 19th biennial examination (1985-1988) and were followed up prospectively for the development of AD and all-cause dementia. Participants Eight hundred forty (541 women, median age of 76 years) subjects participated in the study. Main Outcome Measures We used sex-pooled and sex-specific multivariable Cox proportional hazards models adjusted for age, education, body mass index, recent change in weight, APOE 4 allele status, and plasma docosahexaenoic acid levels to determine association of these biomarkers with the development of all-cause dementia and AD. Results Over a mean follow-up period of 13 years, 159 persons developed dementia (including 125 with AD). After adjustment for other risk factors, only adiponectin in women was associated with an increased risk of all-cause dementia (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.00-1.66; P = .054) and AD (HR, 1.33; 95% CI, 1.00-1.76; P = .050) per 1-SD increase in adiponectin level. Women with baseline adiponectin values more than the median had a higher risk of all-cause dementia (HR, 1.63; 95% CI, 1.03-2.56; P = .04) and AD (HR, 1.87; 95% CI, 1.13-3.10; P = .01) as compared with those with values less than the median. Conclusion In women, increased plasma adiponectin levels are an independent risk factor for the development of both all-cause dementia and AD.

Predictors of Survival in Patients With Parkinson Disease [Original Contribution]

Objective To determine the life expectancy of patients with Parkinson disease (PD) in the United States and identify demographic, geographic, and clinical factors that influence survival. Design Retrospective cohort study of 138 000 Medicare beneficiaries with incident PD who were identified in 2002 and followed up through 2008. Main Outcome Measures Confounder-adjusted 6-year risk of death as influenced by 3 groups of factors: (1) race, sex, and age at diagnosis; (2) geography and environmental factors; and (3) clinical conditions. We examined hospitalization diagnoses in patients with terminal PD and compared PD mortality with that of other common diseases. Results Thirty-five percent of patients with PD lived more than 6 years. Sex and race significantly predicted survival; patients who were female (HR [hazard ratio], 0.74; 95% CI, 0.73-0.75), Hispanic (HR, 0.72; 95% CI, 0.65-0.80), or Asian (HR, 0.86; 95% CI, 0.82-0.91) had a lower adjusted risk of death than white men. Dementia, diagnosed in 69.6% of cases and most often in African American patients (78.2%) and women (71.5%), was associated with a greater likelihood of death (HR, 1.72; 95% CI, 1.69-1.75). Parkinson disease mortality was greater than that of many common life-threatening diseases. Patients with terminal PD were hospitalized frequently for cardiovascular disease (18.5%) and infection (20.9%) but rarely for PD (1.0%). Regional survival rates were similar but patients with PD living in urban high industrial metal emission areas had a slightly higher adjusted risk of death (HR, 1.19; 95% CI, 1.10-1.29). Conclusions Demographic and clinical factors impact PD survival. Dementia is highly prevalent in patients with PD and is associated with a significant increase in mortality. More research is needed to understand whether environmental exposures influence PD course or survival.

Addressing Diffuse Glioma as a Systemic Brain Disease With Single-Cell Analysis [Observation]

Objective To analyze infiltration patterns of IDH1 mutant diffuse gliomas into the brain by identification of single tumor cells applying an antibody specific to mutant IDH1 R132H protein. Design Immunohistochemical analysis. Setting University hospital. Patients Whole-brain and hemisphere sections of 4 patients diagnosed with diffuse glioma. Results Tumor cells were identified in areas that appeared inconspicuous macroscopically and at histological analysis with respect to cellularity, cellular pleomorphism, or mitotic activity in all cases. Conclusion Detection of single tumor cells throughout the brain demonstrates diffuse glioma to represent systemic brain disease.

Antibodies to Low Density Lipoprotein Receptor-Related Protein 4 in Seronegative Myasthenia Gravis [Editorial]

Use of Acetazolamide in Sulfonamide-Allergic Patients With Neurologic Channelopathies [Observation]

Objective To report the safe and successful use of the carbonic anhydrase inhibitor acetazolamide for treatment of patients with episodic ataxia and periodic paralysis who had been denied treatment because of a history of severe allergic reactions to antibiotic sulfonamides. Design Case reports. Setting University of Rochester Medical Center, Rochester, New York. Patients A 61-year-old man with late-onset episodic ataxia, an 83-year-old woman with mutation-positive Andersen-Tawil syndrome, and a 21-year-old woman with mutation-positive episodic ataxia 2, all of whom had a history of severe skin rash with the use of sulfonamides for treatment of infection. Results The 3 patients had been considered for carbonic anhydrase inhibitor treatment but a pharmacist had refused to fill a prescription for acetazolamide for 1 patient and the other 2 patients were denied treatment because of the allergy history. All 3 patients were prescribed acetazolamide and had no adverse reaction. Two patients improved substantially and are continuing treatment. A review of the pharmacology literature suggests that cross-reactivity between antibiotic and nonantibiotic carbonic anhydrase inhibitors is unlikely. Moreover, a review of case reports does not suggest cross-reactivity. Previous reports in the ophthalmology literature also indicate that acetazolamide can be administered to patients with a history of antibiotic sulfonamide allergic reaction. Conclusions These 3 cases confirm that the carbonic anhydrase inhibitor acetazolamide can be given to patients with a history of allergic skin rash with antibiotic sulfonamide.

Autoantibodies to Lipoprotein-Related Protein 4 in Patients With Double-Seronegative Myasthenia Gravis [Original Contribution]

Objectives To determine whether patients with myasthenia gravis (MG) have serum antibodies to lipoprotein-related protein 4 (LRP4), a newly identified receptor for agrin that is essential for neuromuscular junction formation, and to establish whether such antibodies contribute to MG pathogenesis. Design Serum samples from patients with MG with known status of serum antibodies to the acetylcholine receptor (AChR) and muscle-specific kinase (MuSK) and serum samples from control subjects (healthy individuals and individuals with other diseases) were tested for antibodies to LRP4. Serum samples with such antibodies were tested to determine whether they had the ability to inhibit 2 different functions of LRP4 at the neuromuscular junction. Setting Serum samples were collected at the Hellenic Pasteur Institute and Wayne State University. Samples were tested for LRP4 autoantibodies at Georgia Health Sciences University. Other immunoreactivities of the samples were tested at the Hellenic Pasteur Institute, Athens, Greece, or processed through University Laboratories of the Detroit Medical Center, Michigan. Patients The study included 217 patients with MG, 76 patients with other neurologic or psychiatric diseases, and 45 healthy control subjects. Results Anti-LRP4 antibodies were detected in 11 of 120 patients with MG without detectable anti-AChR or anti-MuSK antibodies (double seronegative) and in 1 of 36 patients without anti-AChR antibodies but with anti-MuSK antibodies, but they were not detected in any of the 61 patients with anti-AChR antibodies. No healthy control subjects and only 2 of the 76 control patients with neurologic disease had anti-LRP4 antibodies. Serum samples from patients with MG with anti-LRP4 antibodies were able to inhibit the LRP4-agrin interaction and/or alter AChR clustering in muscle cells. Conclusions Anti-LRP4 antibodies were detected in the serum of approximately 9.2% of patients with double-seronegative MG. This frequency is intermediate compared with 2 recent studies showing anti-LRP4 antibodies in 2% and 50% of patients with double-seronegative MG from different geographic locations. Together, these observations indicate that LRP4 is another autoantigen in patients with MG, and anti-LRP4 autoantibodies may be pathogenic through different immunopathogenic processes.

Autoimmune Autonomic Ganglionopathy With Reversible Cognitive Impairment [Original Contribution]

Background Autoimmune autonomic ganglionopathy (AAG) is a rare disorder of antibody-mediated impaired transmission across the autonomic ganglia resulting in severe autonomic failure. Some patients with AAG report cognitive impairment of unclear etiology despite treatment of autonomic symptoms. Objective To investigate the relationship between orthostatic hypotension, antibody titers, and cognitive impairment in patients with AAG. Design Prospective cohort. Setting Academic medical center. Participants Three patients with AAG underwent neuropsychological testing before and after cycles of plasma exchange in both the seated and standing positions. Main Outcome Measures Patients' responses to neuropsychological tests were measured by percentage change from baseline in the seated and standing positions before and after plasma exchange to determine the effects of orthostatic hypotension and antibody titers on cognition. Results Orthostatic hypotension and elevated antibody titer were associated independently with neuropsychological impairment (P < .05), particularly in domains of executive function, sustained attention, and working memory. Cognitive dysfunction improved, even in the seated normotensive position, after plasmapheresis and consequent reduction in antibody levels. Conclusion Reversible cognitive impairment is independently associated with both orthostatic hypotension and elevated nicotinic acetylcholine receptor autoantibodies, thereby expanding the clinical spectrum of autonomic ganglionopathy and, in so doing, providing an additional treatable cause of cognitive impairment.

Molecular Pathophysiology and Disease-Modifying Therapies for Spinal and Bulbar Muscular Atrophy [Neurological Review]

Spinal and bulbar muscular atrophy (SBMA), or Kennedy disease, is an adult-onset lower motor neuron disease characterized by slowly progressive muscle weakness and atrophy. The disease is caused by the expansion of a trinucleotide CAG repeat encoding a polyglutamine tract within the first exon of the androgen receptor (AR) gene. During the 2 decades since the discovery of the AR gene mutation in SBMA, basic and clinical research have deepened our understanding of the disease phenotype and pathophysiology. Spinal and bulbar muscular atrophy exclusively affects men, whereas women homozygous for the AR mutation do not fully develop the disease. The ligand-dependent nuclear accumulation of pathogenic AR protein is central to the pathogenesis, although additional steps, eg, DNA binding and interdomain interactions of AR, are required for toxicity. Downstream molecular events, eg, transcriptional dysregulation, axonal transport disruption, and mitochondrial dysfunction, are implicated in the neurodegeneration in SBMA. Pathogenic AR-induced myopathy also contributes to the degeneration of motor neurons. Several potential therapies, including hormonal manipulation, have emerged from animal studies, some of which have been tested in clinical trials.

Acute Severe Animal Model of Anti-Muscle-Specific Kinase Myasthenia: Combined Postsynaptic and Presynaptic Changes [Original Contribution]

Objectives To determine the pathogenesis of anti–muscle-specific kinase (MuSK) myasthenia, a newly described severe form of myasthenia gravis associated with MuSK antibodies characterized by focal muscle weakness and wasting and absence of acetylcholine receptor antibodies, and to determine whether antibodies to MuSK, a crucial protein in the formation of the neuromuscular junction (NMJ) during development, can induce disease in the mature NMJ. Design, Setting, and Participants Lewis rats were immunized with a single injection of a newly discovered splicing variant of MuSK, MuSK 60, which has been demonstrated to be expressed primarily in the mature NMJ. Animals were assessed clinically, serologically, and by repetitive stimulation of the median nerve. Muscle tissue was examined immunohistochemically and by electron microscopy. Results Animals immunized with 100 μg of MuSK 60 developed severe progressive weakness starting at day 16, with 100% mortality by day 27. The weakness was associated with high MuSK antibody titers, weight loss, axial muscle wasting, and decrementing compound muscle action potentials. Light and electron microscopy demonstrated fragmented NMJs with varying degrees of postsynaptic muscle end plate destruction along with abnormal nerve terminals, lack of registration between end plates and nerve terminals, local axon sprouting, and extrajunctional dispersion of cholinesterase activity. Conclusions These findings support the role of MuSK antibodies in the human disease, demonstrate the role of MuSK not only in the development of the NMJ but also in the maintenance of the mature synapse, and demonstrate involvement of this disease in both presynaptic and postsynaptic components of the NMJ.

Symptoms and Signs of Posterior Circulation Ischemia in the New England Medical Center Posterior Circulation Registry [Original Contribution]

Objective To evaluate the frequencies of symptoms and signs in patients with posterior circulation ischemia in a large case series of prospectively collected patients. Design Case series. Setting Outpatient and inpatient setting at the New England Medical Center, a tertiary care referral center in Boston, Massachusetts. Patients Consecutive sample of 407 adult patients who had stroke and/or transient ischemic attacks in the posterior circulation within 6 months of study inclusion. All patients were examined by senior stroke neurologists. All patients had either computed tomography or magnetic resonance imaging of the brain as well as vascular imaging of the head and neck. The study included 256 men (63%) and 151 women (37%). Main Outcome Measures Frequencies of posterior circulation ischemic symptoms and signs. These outcome measures were planned before data collection began. Correlations between symptoms and signs with separate vascular territories of the posterior circulation were then analyzed. Results The most frequent posterior circulation symptoms were dizziness (47%), unilateral limb weakness (41%), dysarthria (31%), headache (28%), and nausea or vomiting (27%). The most frequent signs were unilateral limb weakness (38%), gait ataxia (31%), unilateral limb ataxia (30%), dysarthria (28%), and nystagmus (24%). Logistic regression analysis reveals that the clinical features dysphagia (P = .004; 95% CI, 1.8-24.4), nausea or vomiting (P = .002; 95% CI, 1.6-8.2), dizziness (P = .047; 95% CI, 1.0-5.4), and Horner syndrome (P = .001; 95% CI, 2.4-26.6) were positively correlated with the proximal vascular territory. Unilateral limb weakness (P = .001; 95% CI, 1.7-8.7) and cranial nerve VII deficits (P = .02; 95% CI, 1.1-5.3) were positively correlated with the middle territory. Limb sensory deficit (P = .001; 95% CI, 1.8-7.8), lethargy (P = .001; 95% CI, 2.3-12.4), and visual field loss (P = .001; 95% CI, 5.3-23.9) were positively correlated with the distal territory. Conclusions We report the most frequent symptoms and signs in the largest published registry, the New England Medical Center Posterior Circulation Registry, of patients with posterior circulation ischemia who had complete neurological examinations and extensive cerebrovascular imaging. Knowledge of the vascular territory involved aids in the diagnosis of the causative vascular lesion and stroke mechanism.

Clinical Significance of Rare Copy Number Variations in Epilepsy: A Case-Control Survey Using Microarray-Based Comparative Genomic Hybridization [Original Contribution]

Objective To perform an extensive search for genomic rearrangements by microarray-based comparative genomic hybridization in patients with epilepsy. Design Prospective cohort study. Setting Epilepsy centers in Italy. Patients Two hundred seventy-nine patients with unexplained epilepsy, 265 individuals with nonsyndromic mental retardation but no epilepsy, and 246 healthy control subjects were screened by microarray-based comparative genomic hybridization. Main Outcomes Measures Identification of copy number variations (CNVs) and gene enrichment. Results Rare CNVs occurred in 26 patients (9.3%) and 16 healthy control subjects (6.5%) (P = .26). The CNVs identified in patients were larger (P = .03) and showed higher gene content (P = .02) than those in control subjects. The CNVs larger than 1 megabase (P = .002) and including more than 10 genes (P = .005) occurred more frequently in patients than in control subjects. Nine patients (34.6%) among those harboring rare CNVs showed rearrangements associated with emerging microdeletion or microduplication syndromes. Mental retardation and neuropsychiatric features were associated with rare CNVs (P = .004), whereas epilepsy type was not. The CNV rate in patients with epilepsy and mental retardation or neuropsychiatric features is not different from that observed in patients with mental retardation only. Moreover, significant enrichment of genes involved in ion transport was observed within CNVs identified in patients with epilepsy. Conclusions Patients with epilepsy show a significantly increased burden of large, rare, gene-rich CNVs, particularly when associated with mental retardation and neuropsychiatric features. The limited overlap between CNVs observed in the epilepsy group and those observed in the group with mental retardation only as well as the involvement of specific (ion channel) genes indicate a specific association between the identified CNVs and epilepsy. Screening for CNVs should be performed for diagnostic purposes preferentially in patients with epilepsy and mental retardation or neuropsychiatric features.

Low Serum Vitamin D Levels and Recurrent Inflammatory Spinal Cord Disease [Original Contribution]

Background Low 25-hydroxyvitamin D levels have been associated with a higher risk of developing multiple sclerosis and increased relapse rates in patients with multiple sclerosis. As a sterol hormone involved in multiple immunologic pathways, vitamin D may play a role in preventing monophasic immune-mediated central nervous system attacks from developing into recurrent disease. Objective To investigate the association between low serum vitamin D levels and recurrent spinal cord disease. Design, Setting, and Patients We performed a retrospective analysis at Johns Hopkins Transverse Myelitis Center, Baltimore, Maryland, evaluating 25-hydroxyvitamin D levels in 77 patients with monophasic and recurrent inflammatory diseases of the spinal cord. Main Outcome Measure Levels of 25-hydroxyvitamin D. Results Vitamin D levels are significantly lower in patients who developed recurrent spinal cord disease, adjusting for season, age, sex, and race. Conclusions This study provides a basis for a prospective trial of measuring 25-hydroxyvitamin D levels in these patient populations and assessing the influence of vitamin D supplementation on the frequency of relapses in those with recurrent inflammatory spinal cord disease.

Classification of Cause of Motor Weakness in Traumatic Brain Injury Using Diffusion Tensor Imaging [Original Contribution]

Background Many studies have attempted to elucidate the causes of motor weakness in patients with traumatic brain injury (TBI). Most of these studies have focused on the specific cause of motor weakness. However, little is known about the classification and elucidation of the causes of motor weakness in consecutive patients with TBI. Objective To attempt to classify with diffusion tensor imaging the causes of motor weakness in patients with TBI by conducting an analysis of the injury mechanism of the corticospinal tract (CST). Design Retrospective study. Setting Rehabilitation department of a university hospital. Patients We recruited 41 consecutive patients who showed motor weakness among patients with TBI admitted for rehabilitation. Main Outcome Measures We classified the causes of weakness according to the injury mechanism of the CST on diffusion tensor imaging. Results Injury mechanisms of the CST were classified as follows, in order: diffuse axonal injury, 24 patients (58.5%); traumatic intracerebral hemorrhage, 9 patients (21.9%); transtentorial herniation, 6 patients (14.6%); and focal cortical contusion, 4 patients (9.8%). In patients with diffuse axonal injury, the mean number of lesions composing CST injury was 3.6 (range, 2-6) and CST injury locations were as follows: the pons (61%), the cerebral peduncle (50%), the medulla (40%), the posterior limb of the internal capsule (17%), and the corona radiata (13%). Conclusion We found that diffusion tensor imaging was useful in elucidation and classification of the causes of motor weakness resulting from CST injury in patients with TBI.

The Evolution of Academic Neurology: New Information Will Bring New Meaning [Special Article]

The Evaluation of Distal Symmetric Polyneuropathy: A Physician Survey of Clinical Practice [Original Contribution]

Objective To define current clinical practice for evaluating distal symmetric polyneuropathy. Design Using a modified Dillman method, we sent surveys to 600 internists, 600 neurologists, and 45 neuromuscular specialists selected from the American Medical Association Physician Masterfile. Survey questions pertained to which tests providers would order in the following 3 scenarios: (1) the initial evaluation of distal symmetric polyneuropathy, (2) the use of additional tests if the initial evaluation was unrevealing, and (3) patients with diabetes. The t test was used to compare the number of tests ordered by physician type, and the 2 test was used to compare proportions of tests ordered. Setting National survey of physicians. Participants Internists, neurologists, and neuromuscular specialists. Results The response rate was 35%. Overall, many tests were ordered for the full evaluation of distal symmetric polyneuropathy (mean [SD], 16.5 [7.2] tests), and there was substantial variation within and between provider types. Internists ordered fewer tests (mean [SD], 14.5 [6.1] tests) than did neurologists (mean [SD], 17.5 [7.9] tests) (P < .001). Regarding the glucose tolerance test, substantial differences were found between physician types, with neurologists and neuromuscular specialists ordering this test more frequently (28.6% and 72.3%, respectively) and internists ordering it less frequently (4.1%). A brain and/or spine magnetic resonance imaging scan was ordered by 19.8% of internists and 12.9% of neurologists. Conclusions From the supporting evidence, current practice intent on evaluating distal symmetric polyneuropathy is highly variable and differs widely. For this disorder of the peripheral nerves, a high-yield test such as the glucose tolerance test is rarely used, whereas magnetic resonance imaging is likely overused. Research that defines the optimal evaluation of distal symmetric polyneuropathy has the potential to result in more efficient care.

Optimizing the Hachinski Ischemic Scale [Special Article]

Background Vascular causes and factors remain the most significant preventable component of cognitive disorders of elderly individuals. The Hachinski Ischemic Score (HIS) is the questionnaire most commonly used for diagnosis of vascular dementia. Objective To consolidate and further validate the HIS. Design The Canadian Study for Health and Aging was used for this study. It was a cohort study conducted in 3 waves in 1991, 1996-1997, and 2001-2002. The HIS containing 13 items was subjected to correspondence analysis to identify its optimal scaling of item scores and minimal set of items while maximizing the explainable variance. Setting A community-based cohort study. Patients For this analysis, we used 2968 of 3054 well-characterized and well-diagnosed cases with complete HIS data (86 cases had ≥1 item missing) from Canadian Study for Health and Aging phases 2 (1996-1997; n = 2431) and 3 (2001-2002; n = 623). Results Two optimized HIS versions were identified that classify patients with vascular dementia vs those with nonvascular dementia as well as or more accurately than the original HIS instrument. Assuming the HIS instrument measures only a single dimension, correspondence analysis identified the 7 most discriminative HIS items. Binary scoring (0, 1) of these items led to a 7-item HIS model that classified as well as the original 13-item HIS instrument. By merging highly similar HIS items and applying correspondence analysis, a 5-item composite HIS model was created that measures 2 meaningful dimensions of information and classified vascular vs nonvascular dementia better than the original HIS instrument. Each HIS version developed has specific advantages and disadvantages in terms of simplicity, scoring, generalizability, and accuracy. Conclusion Depending on the specific setting, 2 reduced HIS versions consisting of 5 composite-question items or 7 single-question items classify as well as or better than the original HIS instrument.

Mechanism of Amyloid Removal in Patients With Alzheimer Disease Treated With Gantenerumab [Original Contribution]

Background Gantenerumab is a fully human anti-Aβ monoclonal antibody in clinical development for the treatment of Alzheimer disease (AD). Objectives To investigate whether treatment with gantenerumab leads to a measurable reduction in the level of Aβ amyloid in the brain and to elucidate the mechanism of amyloid reduction. Design A multicenter, randomized, double-blind, placebo-controlled, ascending-dose positron emission tomographic study. Additionally, ex vivo studies of human brain slices from an independent sample of patients who had AD were performed. Setting Three university medical centers. Patients Patients with mild-to-moderate AD. Intervention Two consecutive cohorts of patients received 2 to 7 infusions of intravenous gantenerumab (60 or 200 mg) or placebo every 4 weeks. Brain slices from patients who had AD were coincubated with gantenerumab at increasing concentrations and with human microglial cells. Main Outcome Measures Percent change in the ratio of regional carbon 11–labeled Pittsburgh Compound B retention in vivo and semiquantitative assessment of gantenerumab-induced phagocytosis ex vivo. Results Sixteen patients with end-of-treatment positron emission tomographic scans were included in the analysis. The mean (95% CI) percent change from baseline difference relative to placebo (n = 4) in cortical brain amyloid level was –15.6% (95% CI, –42.7 to 11.6) for the 60-mg group (n = 6) and –35.7% (95% CI, –63.5 to –7.9) for the 200-mg group (n = 6). Two patients in the 200-mg group showed transient and focal areas of inflammation or vasogenic edema on magnetic resonance imaging scans at sites with the highest level of amyloid reduction. Gantenerumab induced phagocytosis of human amyloid in a dose-dependent manner ex vivo. Conclusion Gantenerumab treatment resulted in a dose-dependent reduction in brain amyloid level, possibly through an effector cell–mediated mechanism of action.

Association Between Immediate Initiation of Intramuscular Interferon Beta-1a at the Time of a Clinically Isolated Syndrome and Long-term Outcomes: A 10-Year Follow-up of the Controlled High-Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurological Surveillance [Original Contribution]

Objective To determine whether immediate initiation of treatment at the time of a clinically isolated syndrome in patients at high risk for clinically definite multiple sclerosis alters disease course over 10 years. Design Prospective follow-up study. Setting Twenty-four Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) sites in the United States and Canada. Participants A total of 81 patients originally randomly assigned to receive intramuscular interferon beta-1a (the immediate-treatment group) and 74 patients originally randomly assigned to receive placebo (the delayed-treatment group). All patients were from CHAMPS. Intervention For the immediate-treatment group, treatment was initiated within a month after the onset of a clinically isolated syndrome, and for the delayed-treatment group, treatment was initiated a median of 30 months (interquartile range, 24-35 months) after CHAMPS randomization. Main Outcome Measures Rate of developing clinically definite multiple sclerosis, annualized relapse rate, disease course classification, disability measures, and magnetic resonance imaging measures. Results The immediate-treatment group showed a lower 10-year rate of clinically definite multiple sclerosis (unadjusted hazard ratio, 0.64 [95% CI, 0.48-0.87]; P = .004) and a lower annualized relapse rate between years 5 and 10 (P = .03). There was no differential effect on disability, magnetic resonance imaging T2-weighted lesions, or the proportion of patients developing progressive disease at 10 years. Few patients reached the Expanded Disability Status Scale milestone scores of 4.0 or greater (9% of patients) or 6.0 or greater (6% of patients). Conclusions Immediate initiation of intramuscular interferon beta-1a at the time of a clinically isolated syndrome in high-risk patients reduces relapse rates over 10 years but does not improve disability outcomes compared with a control group that also initiated therapy relatively early in the disease course. Trial Registration clinicaltrials.gov Identifier: NCT00179478

Archetypal and New Families With Alexander Disease and Novel Mutations in GFAP [Original Contribution]

Objective To describe genetic analyses of the 2 most thoroughly studied, historically seminal multigenerational families with Alexander disease described prior to the identification of GFAP as the related gene, as well as 1 newly discovered family. Design Clinical histories were obtained and DNA was analyzed from blood, cheek epithelial cells, or fixed paraffin-embedded surgical samples. Subjects Affected and unaffected adult members of 3 families and affected children were included. Main Outcome Measures Mutations in GFAP and behavior of mutant protein in cellular transfection assays. Results Family A contains 4 siblings in whom we found a novel p.Ser247Pro mutation that was paternally inherited. The phenotypes of these siblings include 1 unaffected adult, 1 individual with juvenile-onset disease, and 2 individuals with adult-onset disease. Family B spans 4 generations, including the first described patient with adult-onset disease originally reported in 1968. Analysis of members of the later generations revealed a novel p.Asp417Ala mutation. Family C contains 3 generations. We detected a novel p.Gln426Leu mutation that, to our knowledge, is the farthest C-terminal mutation known. Conclusions These families display clear evidence of variable phenotypes but do not support recessive inheritance. While germline mosaicism cannot be excluded for 1 family (A), we propose that for genetic counseling purposes the risk of germline mosaicism should be described as less than 1%.

Brain Excitability in Stroke: The Yin and Yang of Stroke Progression [Clinical Implications of Basic Neuroscience Research]

There is no current medical therapy for stroke recovery. Principles of physiological plasticity have been identified during recovery in both animal models and human stroke. Stroke produces a loss of physiological brain maps in adjacent peri-infarct cortex and then a remapping of motor and sensory functions in this region. This remapping of function in peri-infarct cortex correlates closely with recovery. Recent studies have shown that the stroke produces abnormal conditions of excitability in neuronal circuits adjacent to the infarct that may be the substrate for this process of brain remapping and recovery. Stroke causes a hypoexcitability in peri-infarct motor cortex that stems from increased tonic -aminobutyric acid activity onto neurons. Drugs that reverse this -aminobutyric acid signaling promote recovery after stroke. Stroke also increases the sensitivity of glutamate receptor signaling in peri-infarct cortex well after the stroke event, and stimulating α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate glutamate receptors in peri-infarct cortex promotes recovery after stroke. Both blocking tonic -aminobutyric acid currents and stimulating α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors promote recovery after stroke when initiated at quite a delay, more than 3 to 5 days after the infarct. These changes in the excitability of neuronal circuits in peri-infarct cortex after stroke may underlie the process of remapping motor and sensory function after stroke and may identify new therapeutic targets to promote stroke recovery.

Identifying Subtle Cortical Gyral Abnormalities as a Predictor of Focal Cortical Dysplasia and a Cure For Epilepsy [Observation]

Objectives To highlight a case series of 3 cases of focal cortical dysplasia that were unrecognized for many years though the patients were seen by various neurologists and received the appropriate neuroimaging studies, and to retrospectively characterize the clinical elements, neuroimaging, electroencephalography, and pathologic findings in these cases. Design Retrospective descriptive study. Setting Tertiary urban and suburban neurology and epilepsy outpatient and inpatient clinic settings and hospitals. Patients We analyze retrospectively 3 patients in whom magnetic resonance images were previously deemed as normal, who, in fact, exhibited subtle gyral abnormalities and who underwent focal surgical resections of these regions after invasive electroencephalography monitoring or electrocorticography and were cured of their epilepsy. Main Outcome Measures Clinical semiology and neuroimaging findings. Results Focal cortical dysplasias may present with subtle gyral abnormalities. These gyral abnormalities may guide invasive electroencephalography or electrocorticography and may delineate seizure onsets with precision. Resection of these areas in 3 such patients resulted in excellent surgical outcomes. Conclusions Subtle gyral abnormalities may be associated with intractable epilepsy and seizure onsets. Focal resection after appropriate evaluations in selected patients may be curative. The magnetic resonance imaging features of focal cortical dysplasia can be subtle and require a high index of suspicion based on ictal semiology and clinical presentation.

About This Journal [About This Journal]

Reviewers Who Completed a Review During 2011 [Annual Reviewers List]

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

Statin Use and Intracerebral Hemorrhage: Evidence for Safety in Recurrent Stroke Prevention? [Editorial]

Online First All the Time and More Continuing Medical Education Credit Too! [Editorial]

Outcome Measures Used in Pediatric Stroke Studies: A Systematic Review [Neurological Review]

Because no gold-standard outcome measure or measures exist to allow comparison of pediatric stroke study outcomes in clinical trials, we designed a systematic review of the literature to survey the current use of pediatric stroke outcome measures. Studies that used at least 1 standardized measure to assess the outcome of children with ischemic or hemorrhagic stroke, from full-term newborn to age 18 years, were included. Although 34 studies were included, an additional 36 studies could not be included because ad hoc, author-generated outcome measures were used. Excluding those measures in neuropsychological batteries, 38 unique outcome measures were used. The Wechsler Intelligence Scales, Pediatric Stroke Outcome Measure, and Bayley Scales of Infant Development were among the most used, but 79% of outcome measures were used by no more than 2 studies. Although many measures used have been validated for use in children with other medical conditions or for adults with stroke, only 1 measure has been specifically validated for use in pediatric ischemic stroke. To maximize comparability of future clinical trial results, agreement regarding a preferred pediatric stroke outcome scale or battery of measures is paramount; these measures should be reliable, responsive to change, and specifically validated for use in children with stroke.

Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment: A Pilot Clinical Trial [Clinical Trials]

Objective To examine the effects of intranasal insulin administration on cognition, function, cerebral glucose metabolism, and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease (AD). Design Randomized, double-blind, placebo-controlled trial. Setting Clinical research unit of a Veterans Affairs medical center. Participants The intent-to-treat sample consisted of 104 adults with amnestic mild cognitive impairment (n = 64) or mild to moderate AD (n = 40). Intervention Participants received placebo (n = 30), 20 IU of insulin (n = 36), or 40 IU of insulin (n = 38) for 4 months, administered with a nasal drug delivery device (Kurve Technology, Bothell, Washington). Main Outcome Measures Primary measures consisted of delayed story recall score and the Dementia Severity Rating Scale score, and secondary measures included the Alzheimer Disease's Assessment Scale–cognitive subscale (ADAS-cog) score and the Alzheimer's Disease Cooperative Study–activities of daily living (ADCS-ADL) scale. A subset of participants underwent lumbar puncture (n = 23) and positron emission tomography with fludeoxyglucose F 18 (n = 40) before and after treatment. Results Outcome measures were analyzed using repeated-measures analysis of covariance. Treatment with 20 IU of insulin improved delayed memory (P < .05), and both doses of insulin (20 and 40 IU) preserved caregiver-rated functional ability (P < .01). Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD (P < .05). Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group, but, in exploratory analyses, changes in memory and function were associated with changes in the Aβ42 level and in the tau protein–to–Aβ42 ratio in cerebrospinal fluid. Placebo-assigned participants showed decreased fludeoxyglucose F 18 uptake in the parietotemporal, frontal, precuneus, and cuneus regions and insulin-minimized progression. No treatment-related severe adverse events occurred. Conclusions These results support longer trials of intranasal insulin therapy for patients with amnestic mild cognitive impairment and patients with AD. Trial Registration clinicaltrials.gov Identifier: NCT00438568

Statins and Intracerebral Hemorrhage: A Retrospective Cohort Study [Original Contribution]

Background A recent post hoc analysis of a large randomized trial in patients with cerebrovascular disease suggested that statins may increase the risk of intracerebral hemorrhage (ICH). Objective To examine the association between statins and ICH in patients with recent ischemic stroke in a population-based setting. Design Retrospective propensity-matched cohort study with accrual from July 1, 1994, to March 31, 2008. Setting Ontario, Canada. Participants A total of 17 872 patients aged 66 years and older who initiated statin therapy following acute ischemic stroke and were followed for a median of 4.2 years (interquartile range, 2.4-5.0 years). To enhance causal inference, we conducted several tests of specificity to exclude healthy user bias in this sample. Main Outcome Measure Hospitalization or emergency department visit for ICH defined using validated diagnosis coding. Results Overall, 213 episodes of ICH occurred. In the primary analysis comparing statin users with nonusers, we found no association between statins and ICH (hazard ratio = 0.87; 95% confidence interval, 0.65-1.17). Subgroup and dose-response analyses yielded similar results. In tests of specificity, statin therapy was not associated with bone mineral density testing, vitamin D or B12 screening, gastrointestinal endoscopy, or elective knee arthroplasty, suggesting that results were not due to healthy user bias or differences in quality of care. Conclusion Statin exposure following ischemic stroke was not associated with ICH.

Assessing Response to Stroke Thrombolysis: Validation of 24-Hour Multimodal Magnetic Resonance Imaging [Original Contribution]

Background Imaging is used as a surrogate for clinical outcome in early-phase stroke trials. Assessment of infarct growth earlier than the standard 90 days used for clinical end points may be equally accurate and more practical. Objective To compare assessment of the effect of reperfusion therapies using 24-hour vs day 90 magnetic resonance imaging. Design Infarct volume was assessed on diffusion-weighted imaging (DWI) at baseline and 24 hours after stroke onset and on fluid-attenuated inversion recovery images at day 90. The DWI and fluid-attenuated inversion recovery lesions were manually outlined by 2 independent raters, and the volumes were averaged. Interrater consistency was assessed using the median difference in lesion volume between raters. Setting Referral center. Patients Imaging data were available for 83 patients; 77 of these patients received thrombolysis. Main Outcome Measures Infarct volume at 24 hours and 90 days. Results The 24-hour DWI infarct volume had a strong linear correlation with day 90 fluid-attenuated inversion recovery infarct volume (r = 0.98, 95% confidence interval, 0.97-0.99). Recanalization had a significant effect on infarct evolution between baseline and 24 hours but not between 24 hours and day 90. Infarct growth from baseline was significantly reduced by recanalization, whether assessed at 24 hours or day 90. Infarct volume at either time point predicted functional outcome independent of age and baseline stroke severity. Interrater agreement was better for DWI than fluid-attenuated inversion recovery (1.4 mL [8%] vs 1.8 mL [17%]; P = .002). Conclusions Assessment of final infarct volume using DWI at 24 hours captures the effect of reperfusion therapies on infarct growth and predicts functional outcome similarly to imaging at day 90. This has the potential to reduce loss to follow-up in trials and may add early prognostic information in clinical practice.

Effects of Age and Amyloid Deposition on A{beta} Dynamics in the Human Central Nervous System [Original Contribution]

Background The amyloid hypothesis predicts that increased production or decreased clearance of β-amyloid (Aβ) leads to amyloidosis, which ultimately culminates in Alzheimer disease (AD). Objective To investigate whether dynamic changes in Aβ levels in the human central nervous system may be altered by aging or by the pathology of AD and thus contribute to the risk of AD. Design Repeated-measures case-control study. Setting Washington University School of Medicine in St Louis, Missouri. Participants Participants with amyloid deposition, participants without amyloid deposition, and younger normal control participants. Main Outcome Measures In this study, hourly cerebrospinal fluid (CSF) Aβ concentrations were compared with age, status of amyloid deposition, electroencephalography, and video recording data. Results Linear increases were observed over time in the Aβ levels in CSF samples obtained from the younger normal control participants and the older participants without amyloid deposition, but not from the older participants with amyloid deposition. Significant circadian patterns were observed in the Aβ levels in CSF samples obtained from the younger control participants; however, circadian amplitudes decreased in both older participants without amyloid deposition and older participants with amyloid deposition. Aβ diurnal concentrations were correlated with the amount of sleep but not with the various activities that the participants participated in while awake. Conclusions A reduction in the linear increase in the Aβ levels in CSF samples that is associated with amyloid deposition and a decreased CSF Aβ diurnal pattern associated with increasing age disrupt the normal physiology of Aβ dynamics and may contribute to AD.

Autosomal Recessive Causes Likely in Early-Onset Alzheimer Disease [Original Contribution]

Objectives To determine the genetic contribution to non–autosomal dominant early-onset Alzheimer disease (EOAD) (onset age ≤60 years) cases and identify the likely mechanism of inheritance in those cases. Design A liability threshold model of disease was used to estimate heritability of EOAD and late-onset Alzheimer disease (AD) using concordance for AD among parent-offspring pairs. Setting The Uniform Data Set, whose participants were collected from 32 US Alzheimer's Disease Centers, maintained by the National Alzheimer's Coordinating Center. Participants Individuals with probable AD and detailed parental history (n = 5370). Main Outcome Measures The concordance among relatives and heritability of EOAD and late-onset AD. Results For late-onset AD (n = 4302), we found sex-specific parent-offspring concordance that ranged from approximately 10% to 30%, resulting in a heritability of 69.8% (95% confidence interval, 64.6%-75.0%), and equal heritability for both sexes regardless of parental sex. For EOAD (n = 702), we found that the parent-offspring concordance was 10% or less and concordance among siblings was 21.6%. Early-onset AD heritability was 92% to 100% for all likely values of EOAD prevalence. Conclusions We confirm late-onset AD is a highly polygenic disease. By contrast, the data for EOAD suggest it is an almost entirely genetically based disease, and the patterns of observed concordance for parent-offspring pairs and among siblings lead us to reject the hypotheses that EOAD is a purely dominant, mitochondrial, X-linked, or polygenic disorder. The most likely explanation of the data is that approximately 90% of EOAD cases are due to autosomal recessive causes.

Diffusion Tensor Imaging in Acute Optic Neuropathies: Predictor of Clinical Outcomes [Original Contribution]

Objective To evaluate directional diffusivities within the optic nerve in a first event of acute optic neuritis to determine whether decreased axial diffusivity (AD) would predict 6-month visual outcome and optic nerve integrity measures. Design Cohort study. Setting Academic multiple sclerosis center. Patients Referred sample of 25 individuals who presented within 31 days after acute visual symptoms consistent with optic neuritis. Visits were scheduled at baseline, 2 weeks, and 1, 3, 6, and 12 months. Main Outcome Measures Visual acuity, contrast sensitivity, visual evoked potentials (VEPs), and thickness of the retinal nerve fiber layer (RNFL). Results An incomplete 6-month visual recovery was associated with a lower baseline AD (1.50 µm2/ms [95% confidence interval {CI}, 1.36-1.64 µm2/ms for incomplete recovery vs 1.75 µm2/ms [95% CI, 1.67-1.83 µm2/ms] for complete recovery). Odds of complete recovery decreased by 53% (95% CI, 27%-70%) for every 0.1-unit decrease in baseline AD. A lower baseline AD correlated with worse 6-month visual outcomes in visual acuity (r = 0.40, P = .03), contrast sensitivity (r = 0.41, P = .02), VEP amplitude (r = 0.55, P < .01), VEP latency (r = –0.38, P = .04), and RNFL thickness (r = 0.53, P = .02). Radial diffusivity increased between months 1 and 3 to become higher in those with incomplete recovery at 12 months than in those with complete recovery (1.45 µm2/ms [95% CI, 1.31-1.59 µm2/ms] vs 1.19 µm2/ms [95% CI, 1.10-1.28 µm2/ms]). Conclusions Decreased AD in acute optic neuritis was associated with a worse 6-month visual outcome and correlated with VEP and RNFL measures of axon and myelin injury. Axial diffusivity may serve as a marker of axon injury in acute white matter injury.

11C-PiB Imaging of Human Immunodeficiency Virus-Associated Neurocognitive Disorder [Original Contribution]

Objective To evaluate whether the amyloid-binding agent carbon 11–labeled Pittsburgh Compound B (11C-PiB) could differentiate Alzheimer disease (AD) from human immunodeficiency virus (HIV)–associated neurocognitive disorder (HAND) in middle-aged HIV-positive participants. Design 11C-PiB scanning, clinical assessment, and cerebrospinal fluid (CSF) analysis were performed. Both 2 and t tests assessed differences in clinical and demographic variables between HIV-positive participants and community-living individuals observed at the Knight Alzheimer’s Disease Research Center (ADRC). Analysis of variance assessed for regional differences in amyloid-β protein 1-42 (Aβ42) using 11C-PiB. Setting An ADRC and HIV clinic. Participants Sixteen HIV-positive participants (11 cognitively normal and 5 with HAND) and 19 ADRC participants (8 cognitively normal and 11 with symptomatic AD). Main Outcome Measures Mean and regional 11C-PiB binding potentials. Results Participants with symptomatic AD were older (P < .001), had lower CSF Aβ42 levels (P < .001), and had higher CSF tau levels (P < .001) than other groups. Regardless of degree of impairment, HIV-positive participants did not have increased 11C-PiB levels. Mean and regional binding potentials were elevated for symptomatic AD participants (P < .001). Conclusions Middle-aged HIV-positive participants, even with HAND, do not exhibit increased 11C-PiB levels, whereas symptomatic AD individuals have increased fibrillar Aβ42 deposition in cortical and subcortical regions. Observed dissimilarities between HAND and AD may reflect differences in Aβ42 metabolism. 11C-PiB may provide a diagnostic biomarker for distinguishing symptomatic AD from HAND in middle-aged HIV-positive participants. Future cross-sectional and longitudinal studies are required to assess the utility of 11C-PiB in older individuals with HAND.

Daclizumab Use in Patients With Pediatric Multiple Sclerosis [Original Contribution]

Background Daclizumab, a humanized monoclonal antibody specific for the interleukin 2 receptor α chain, reduces clinical and magnetic resonance imaging disease activity in patients with adult-onset multiple sclerosis (MS) as monotherapy or add-on therapy with interferon. Objective To report the use of daclizumab in pediatric-onset MS. Design Case series. Setting Two comprehensive pediatric MS centers. Patients Seven patients with pediatric-onset MS with clinical and magnetic resonance imaging disease activity despite first-line disease-modifying therapy. Intervention Intravenous daclizumab, 1 mg/kg monthly. Main Outcome Measures Annualized relapse rates, Expanded Disability Status Scale scores, contrast-enhancing lesions, and adverse effects. Results Treatment with daclizumab, primarily combined with interferon, was associated with reductions in annualized relapse rates and contrast-enhancing lesions and with reduction or stabilization of Expanded Disability Status Scale scores in each patient. However, 4 patients had relapses and new contrast-enhancing lesions during daclizumab treatment. No significant adverse effects occurred. Conclusion Daclizumab may be a safe and at least partially effective treatment option for patients with pediatric-onset MS with disease activity despite first-line disease-modifying therapy.

Impact of Inflammation on Brain Volume in Multiple Sclerosis [Original Contribution]

Objective To study changes in brain volume measured monthly in patients treated for relapsing multiple sclerosis due to loss of tissue and the appearance of inflammation. Design and Patients The results from T2/fluid-attenuated inversion recovery axial images from 13 consecutive monthly 3-T brain magnetic resonance imaging tests conducted on 74 patients diagnosed with relapsing multiple sclerosis in the BECOME study were used to calculate whole brain volumes using automated software analysis tools. The patients had been randomized to receive treatment with interferon beta-1b or glatiramer acetate. Ongoing inflammation was studied by counting the number of combined active lesions and measuring the volume of gadolinium enhancement. A mixed-effects model was used to analyze brain volumes over time. Results There was a significant decrease in brain volume over time but there was no difference in its rate of change by age, sex, frequency of ongoing inflammation, multiple sclerosis type, or randomized treatment assignment. The mean rate of brain volume change per month from multivariable models was –1.1 cm3 (95% CI, –1.5 to –0.6) and during times of magnetic resonance imaging activity, it increased transiently by an average of 1.2 cm3/lesion (95% CI, 0.7 to 1.7) and 7.1 cm3/1 cm3 of gadolinium volume. In a model with both measures, combined active lesions were independent predictors of brain volume but gadolinium volume was not. Conclusion Two major changes in brain volume occur in patients with relapsing multiple sclerosis, a steady decrease likely due to tissue loss with overlapping transient increases due to the appearance of inflammation.

Large, Nonplateauing Relationship Between Clinical Disability and Cerebral White Matter Lesion Load in Patients With Multiple Sclerosis [Original Contribution]

Objective To better characterize the relationship between cerebral white matter lesion load (CWM-LL) and clinical disability by (1) covering the entire range of the Kurtzke Expanded Disability Status Scale (EDSS), (2) minimizing nonbiological sources of variability, and (3) increasing pathologic specificity by studying CWM lesions that are hypointense on T1-weighted magnetic resonance imaging. Design Cross-sectional, retrospective study. Setting Hospital-based multiple sclerosis (MS) clinic. Patients A total of 110 patients with untreated MS were recruited and studied from June 1, 1997, through June 30, 2003. Main Outcome Measures Cube-rooted CWM-LL and EDSS-measured clinical disability scores. Results We found a large, nonplateauing relationship between cube-rooted CWM-LL and concurrent EDSS scores, more so for T1-hypointense than T2-hyperintense lesions (r = 0.619 vs 0.548). Correlations between the EDSS scores and CWM-LL diminished when, as typically done in clinical trials, only those patients with EDSS scores of 0 to 6.0 were studied (n = 92; r = 0.523 for T1-hypointense lesions and r = 0.457 for T2-hyperintense lesions); more important, a series of boot-strapped correlations suggested that this decrease was not simply due to smaller sample size, and these relationships remained even after correcting for disease duration. Conclusion A large, nonplateauing relationship exists between CWM-LL and EDSS-measured clinical disability when patients with MS are studied to examine the entire range of disability, minimize nonbiological sources of variability, and increase pathologic specificity.

Proteomic Changes in Cerebrospinal Fluid of Presymptomatic and Affected Persons Carrying Familial Alzheimer Disease Mutations [Original Contribution]

Objective To identify cerebrospinal fluid (CSF) protein changes in persons who will develop familial Alzheimer disease (FAD) due to PSEN1 and APP mutations, using unbiased proteomics. Design We compared proteomic profiles of CSF from individuals with FAD who were mutation carriers (MCs) and related noncarriers (NCs). Abundant proteins were depleted and samples were analyzed using liquid chromatography–electrospray ionization–mass spectrometry on a high-resolution time-of-flight instrument. Tryptic peptides were identified by tandem mass spectrometry. Proteins differing in concentration between the MCs and NCs were identified. Setting A tertiary dementia referral center and a proteomic biomarker discovery laboratory. Participants Fourteen FAD MCs (mean age, 34.2 years; 10 are asymptomatic, 12 have presenilin-1 [PSEN1 ] gene mutations, and 2 have amyloid precursor protein [APP ] gene mutations) and 5 related NCs (mean age, 37.6 years). Results Fifty-six proteins were identified, represented by multiple tryptic peptides showing significant differences between MCs and NCs (46 upregulated and 10 downregulated); 40 of these proteins differed when the analysis was restricted to asymptomatic individuals. Fourteen proteins have been reported in prior proteomic studies in late-onset AD, including amyloid precursor protein, transferrin, α1β-glycoprotein, complement components, afamin precursor, spondin 1, plasminogen, hemopexin, and neuronal pentraxin receptor. Many other proteins were unique to our study, including calsyntenin 3, AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) 4 glutamate receptor, CD99 antigen, di- N-acetyl-chitobiase, and secreted phosphoprotein 1. Conclusions We found much overlap in CSF protein changes between individuals with presymptomatic and symptomatic FAD and those with late-onset AD. Our results are consistent with inflammation and synaptic loss early in FAD and suggest new presymptomatic biomarkers of potential usefulness in drug development.

Association of Sequence Alterations in the Putative Promoter of RAB7L1 With a Reduced Parkinson Disease Risk [Original Contribution]

Objective To examine whether PARK16, which was recently identified as a protective locus for Parkinson disease (PD) in Asian, white, and South American populations, is also associated with PD in the genetically homogeneous Ashkenazi Jewish population. Design Case-control study. Setting A medical center affiliated with a university. Subjects Five single-nucleotide polymorphisms (SNPs) located between RAB7L1 and SLC41A1 were analyzed in 720 patients with PD and 642 controls, all of Ashkenazi Jewish origin. Main Outcome Measures Haplotypes were defined and risk estimates were determined for each SNP and haplotype. Bioinformatic analysis defined the putative promoter region of RAB7L1 and the transcription factor binding sites that are potentially affected by 2 of the tested SNPs. Results All tested SNPs were significantly associated with PD (odds ratios = 0.64-0.76; P = .0002-.014). Two of them, rs1572931 and rs823144, were localized to the putative promoter region of RAB7L1 and their sequence variations altered the predicted transcription factor binding sites of CdxA, p300, GATA-1, Sp1, and c-Ets-1. Only 0.4% of patients were homozygous for the protective rs1572931 genotype (T/T), compared with 3.0% among controls (P = 5 x 10–5). This SNP was included in a haplotype that reduced the risk for PD by 10- to 12-fold (P = .002-.01) in all patients with PD and in a subgroup of patients who do not carry the Ashkenazi founder mutations in the GBA or LRRK2 genes. Conclusions Our data demonstrate that specific SNP variations and haplotypes in the PARK16 locus are associated with reduced risk for PD in Ashkenazim. Although it is possible that alterations in the putative promoter of RAB7L1 are associated with this effect, the role of other genes in this locus cannot be ruled out.

Fulminant Postpartum Cerebral Vasoconstriction Syndrome [Original Contribution]

Objective To raise awareness of the potentially adverse consequences of postpartum cerebral vasoconstriction, which is typically considered benign and self-limiting, by describing 4 fulminantly fatal cases. Design Retrospective case series. Setting Tertiary referral center. Patients Four postpartum women aged 15 to 33 years developed acute neurologic deficits 1 to 8 days after uncomplicated deliveries. One had a history of migraine headaches and 2 had histories of spontaneous abortion. Two of the patients had uneventful pregnancies and 2 had preeclampsia, 1 of whom had acute hepatic failure. Presenting symptoms included severe headache (n = 3), focal deficit (n = 1), seizure (n = 1), and encephalopathy (n = 1). Initial brain imaging results demonstrated cortical ischemia and global edema in 2 patients, lobar hemorrhage in 1, and normal findings in 1. All had rapid clinical deterioration from hours to days with multiterritorial infarctions and global brain edema on imaging. All had angiographic findings of diffuse, severe, segmental multifocal arterial narrowings. Interventions Aggressive treatment was attempted with most patients including intravenous magnesium sulfate, corticosteroids, calcium channel blockers, balloon angioplasty, vasopressors, and osmotic agents. Two patients underwent serial angiography, with results showing severe, recurrent proximal vasoconstriction involving all major intracranial vessels. Results All patients had fulminant, accelerating courses leading to their deaths within 8 to 24 days after delivery. Conclusions Postpartum vasoconstriction can be fatal, with rapid progression of vasoconstriction, ischemia, and brain edema. Clinicians need to be aware of the potential consequences of this condition. Postpartum women with acute neurologic symptoms require prompt investigation with noninvasive cerebrovascular imaging and close monitoring for possible secondary deterioration.

To Sleep, Perchance to Delay Dementia [From JAMA]

Association Between Paroxysmal Tonic Spasms and Neuromyelitis Optica [Observation]

Objective To determine the frequency of the association between tonic spasms and neuromyelitis optica (NMO) at our center. Design An institutional review board–approved retrospective study of clinical, serological, and radiographic characteristics of patients with NMO. Setting Multiple sclerosis center. Patients Patients with NMO treated at our center between 1990 and 2008. Main Outcome Measure Records were examined for documentation of tonic spasms. Results Of 110 patients with International Classification of Diseases code 341, 57 patients met diagnostic criteria for NMO. Of these, 8 patients (14%) had documented typical tonic spasms (median age at onset, 39.5 years; range, 13.8-54.2 years). Of those patients, 4 were African American, 3 were Hispanic, and 1 was white. Only 1 was male. The NMO-IgG antibody was found in 1 of 6 patients tested. Tonic spasms appeared after a mean of 24.6 months (range, 0-91 months). In 2 of 57 patients meeting NMO criteria, tonic spasms accompanied their initial episodes. Seven of 8 patients who had tonic spasms responded to treatment with carbamazepine within 1 week. Conclusion Tonic spasms are associated with NMO more commonly than with multiple sclerosis and may be a presenting sign in both diseases.

Novel Hypomyelinating Leukoencephalopathy Affecting Early Myelinating Structures [Observation]

Objective To describe 4 children with a novel hypomyelinating leukoencephalopathy, defined by a distinct pattern of magnetic resonance imaging (MRI) abnormalities. Design In our ongoing study on leukoencephalopathies of unknown origin, MRIs of patients are rated in a standardized manner. Patients are grouped according to their MRI abnormalities. The clinical and laboratory data are retrospectively reviewed. Subjects The MRIs of approximately 3000 patients with a leukoencephalopathy of unknown origin were initially evaluated. Four unrelated patients (all male, aged 1.8-7.4 years) displayed similar MRI alterations. Results Patients displayed mild T2 hyperintensity of the medulla oblongata, caudal part of the pons, hilus of the dentate nucleus, peridentate white matter, subcortical cerebellar white matter, optic radiation, and frontoparietal periventricular white matter. The posterior limb of the internal capsule showed alternating T2 hyperintense-hypointense-hyperintense stripes in 3 patients. The T1-weighted images showed hyperintensity, isointensity, or mild hypointensity of T2 hyperintense structures. The thalamus had a neonatal appearance with a mildly hyperintense signal except for a darker lateral part. Clinically, patients presented with nystagmus between ages 6 and 20 months. Over time, cerebellar ataxia and mild spasticity developed. All achieved unsupported walking. Cognition and language were normal. Known causes of hypomyelination were excluded. Conclusions The patients share a striking pattern of MRI abnormalities and have a similar clinical picture, suggesting that they have the same disorder. The hypomyelination in this disorder specifically occurs in structures that normally myelinate early. We hypothesize that the disease is caused by a defect in a gene involved in early myelination.

Severe Hypercalcemia Following Vitamin D Supplementation in a Patient With Multiple Sclerosis: A Note of Caution [Observation]

Objective To describe a patient with multiple sclerosis (MS) who developed severe hypercalcemia, attributed to the additive effect of 5500 IU of cholecalciferol and 2020 mg of calcium daily. Design Case report. Setting University hospital. Patient A 58-year-old woman with MS and osteoporosis presenting with acute-onset tremors and confusion. Main Outcome Measures Serum calcium and 25-hydroxyvitamin D levels. Results The patient's corrected serum calcium level was 15.2 mg/dL (reference range, 8.7-10.1 mg/dL; to convert to millimoles per liter, multiply by 0.25), and her 25-hydroxyvitamin D level was 103 ng/mL (to convert to nanomoles per liter, multiply by 2.496). The results of extensive laboratory tests to rule out hyperparathyroidism, malignant neoplasms, and other causes of hypercalcemia were unrevealing. Conclusions It is common practice to prescribe high-dose cholecalciferol to MS patients for its possible role in immunomodulation and relapse-rate reduction. Nevertheless, cholecalciferol may increase serum calcium, and there seems to be an additive effect when patients simultaneously use calcium supplements. This case underscores the need for physicians to be attentive to the possibility of hypercalcemia in patients treated with both high-dose cholecalciferol and calcium.

Topiramate Effect in Opsoclonus-Myoclonus-Ataxia Syndrome [Images in Neurology]

Multiple Cranial Neuropathies Evolving Over a Decade From Occult Perineural Basal Cell Carcinoma [Images in Neurology]

Central Nervous System Epidermoid Cyst Rupture [Images in Neurology]

Paradoxical Worsening of Brain Tuberculomas During Treatment [Images in Neurology]

Neurology: A Clinician's Approach [Book Reviews]

Laboratory Diagnosis in Neurology [Book Reviews]

Varicella-Zoster Virus Expression in the Cerebral Arteries of Diabetic Subjects [Research Letters]

Methodological Issues With the Risk of Relapse Study in Patients With Multiple Sclerosis After Yellow Fever Vaccination [Correspondence]

Methodological Issues With the Risk of Relapse Study in Patients With Multiple Sclerosis After Yellow Fever Vaccination--Reply [Correspondence]

Daytime Polysomnography Recording in LIG1 -Related Limbic Encephalitis [Correspondence]

Daytime Polysomnography Recording in LIG1 -Related Limbic Encephalitis--Reply [Correspondence]

About This Journal [About This Journal]

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

Clinical Pathologic Conference [Editorial]

No Endovascular Innovation Without Evaluation in Chronic Cerebrospinal Venous Insufficiency: A Call for the IDEAL Model [Editorial]

Magnetic Resonance Techniques in Multiple Sclerosis: The Present and the Future [Neurological Review]

Magnetic resonance imaging (MRI) is sensitive to focal multiple sclerosis (MS) lesions. For this reason, conventional MRI measures of the burden of disease derived from dual-echo, fluid-attenuated inversion recovery and postcontrast T1-weighted sequences are regularly used to monitor disease course in patients with confirmed MS and have been included in the diagnostic workup of patients in whom MS is suspected. Other quantitative magnetic resonance (MR)–based techniques with a higher pathological specificity (including magnetization transfer–MRI, diffusion tensor–MRI, and proton MR spectroscopy) have been extensively applied to measure disease burden within focal visible lesions and in the normal-appearing white matter and gray matter of MS patients at different stages of the disease. These methods, combined with functional imaging techniques, are progressively improving our understanding of the factors associated with MS evolution. More recently, the application of new imaging modalities capable of measuring pathological processes related to the disease that have been neglected in the past (eg, iron deposition and perfusion abnormalities) and the advent of high- and ultrahigh-field magnets have provided further insight into the pathobiological features of MS. After a brief summary of the main results obtained from the established and emerging MR methods, this review discusses the steps needed before the latter become suitable for widespread use in the MS research community.

No Cerebral or Cervical Venous Insufficiency in US Veterans With Multiple Sclerosis [Original Contribution]

Objective To determine if chronic cerebral venous insufficiency exists in patients with multiple sclerosis (MS) using ultrasonography and 4-dimensional color Doppler ultrasonography examination and unverified criteria proposed by Zamboni et al. Design Patients with MS and clinically isolated syndrome were matched by age and sex with subjects with migraine or no neurological disease. All subjects underwent gray-scale, color, and spectral Doppler ultrasonography examination of the internal jugular veins (IJVs), vertebral veins, and deep cerebral veins for stenosis, absence of signal, and reflux. Setting Academic MS center. Patients All patients with MS fulfilled revised McDonald criteria for the diagnosis of MS. Patients with clinically isolated syndrome exhibited a typical transient focal neurological deficit and had magnetic resonance imaging lesions typical of MS. Control subjects were recruited from the VA migraine clinic or staff. Main Outcome Measures Five parameters of venous outflow used by Zamboni et al were examined: (1) IJV or vertebral vein reflux, (2) deep cerebral vein reflux, (3) IJV stenosis, (4) absence of flow in IJVs or vertebral veins, and (5) change in cross-sectional area of the IJV with postural change. Results There was no significant difference in the number and type of venous outflow abnormalities in patients with MS compared with controls. Conclusion This study does not support the theory that chronic cerebral venous insufficiency exists in MS.

Evidence for Ordering of Alzheimer Disease Biomarkers [Original Contribution]

Objective To empirically assess the concept that Alzheimer disease (AD) biomarkers significantly depart from normality in a temporally ordered manner. Design Validation sample. Setting Multisite, referral centers. Participants A total of 401 elderly participants in the Alzheimer's Disease Neuroimaging Initiative who were cognitively normal, who had mild cognitive impairment, or who had AD dementia. We compared the proportions of 3 AD biomarker values (the Aβ42 level in cerebrospinal fluid [CSF], the total tau level in CSF, and the hippocampal volume adjusted for intracranial volume [hereafter referred to as the adjusted hippocampal volume]) that were abnormal as cognitive impairment worsened. Cut points demarcating normal vs abnormal for each biomarker were established by maximizing diagnostic accuracy in independent autopsy samples. Main Outcome Measures Three AD biomarkers (ie, the CSF Aβ42 level, the CSF total tau level, and the adjusted hippocampal volume). Results Within each clinical group of the entire sample (n = 401), the CSF Aβ42 level was abnormal more often than was the CSF total tau level or the adjusted hippocampal volume. Among the 298 participants with both baseline and 12-month data, the proportion of participants with an abnormal Aβ42 level did not change from baseline to 12 months in any group. The proportion of participants with an abnormal total tau level increased from baseline to 12 months in cognitively normal participants (P = .05) but not in participants with mild cognitive impairment or AD dementia. For 209 participants with an abnormal CSF Aβ42 level at baseline, the percentage with an abnormal adjusted hippocampal volume but normal CSF total tau level increased from baseline to 12 months in participants with mild cognitive impairment. No change in the percentage of MCI participants with an abnormal total tau level was seen between baseline and 12 months. Conclusions A reduction in the CSF Aβ42 level denotes a pathophysiological process that significantly departs from normality (ie, becomes dynamic) early, whereas the CSF total tau level and the adjusted hippocampal volume are biomarkers of downstream pathophysiological processes. The CSF total tau level becomes dynamic before the adjusted hippocampal volume, but the hippocampal volume is more dynamic in the clinically symptomatic mild cognitive impairment and AD dementia phases of the disease than is the CSF total tau level.

Thrombolytic Treatment of Patients With Acute Ischemic Stroke Related to Underlying Arterial Dissection in the United States [Original Contribution]

Objective To determine the outcomes related to thrombolytic treatment of an acute ischemic stroke secondary to an arterial dissection in a large national cohort. Design Retrospective database study. Setting Nationwide Inpatient Sample data files from 2005 to 2008. Patients We determined the frequency of underlying arterial dissection among patients with acute ischemic stroke treated with thrombolytic treatment and associated in-hospital outcomes. Main Outcome Measures All the in-hospital outcomes were analyzed after adjusting for potential confounders using multivariate analysis. Results Of the 47 899 patients with ischemic stroke who received thrombolytic treatment, 488 (1%) had an underlying dissection. The intracranial hemorrhage rates did not differ between patients with ischemic stroke with or without underlying dissection who received thrombolytic treatment (6.9% vs 6.4%). After adjusting for age, sex, hypertension, diabetes mellitus, renal failure, congestive heart failure, and hospital teaching status, presence of dissection was associated with higher rates of moderate disability (odds ratio, 2.8; 95% confidence interval, 1.7-4.6; P < .001) at discharge. The interaction terms between dissection and thrombolytic treatment among all patients with ischemic stroke for predicting in-hospital mortality (P = .84) and minimal disability (P = .13) were not statistically significant. Conclusions The adjusted rate of favorable outcomes is lower among patients with ischemic stroke with underlying arterial dissection following thrombolytic treatment compared with those without underlying dissections. However, the observed lower rates are not influenced by thrombolytic treatment.

Neurological Injury in Adults Treated With Extracorporeal Membrane Oxygenation [Original Contribution]

Background Extracorporeal membrane oxygenation (ECMO) may be urgently used as a last resort form of life support when all other treatment options for potentially reversible cardiopulmonary injury have failed. Objective To examine the range and frequency of neurological injury in ECMO-treated adults. Design Retrospective clinicopathological cohort study. Setting Mayo Clinic, Rochester, Minnesota. Patients A prospectively collected registry of all patients 15 years or older treated with ECMO for 12 or more hours from January 2002 to April 2010. Intervention Patients were analyzed for potential risk factors for neurological events and death using logistic regression and Cox proportional hazards models. Main Outcome Measures Neurological diagnosis and/or death. Results A total of 87 adults were treated (35 female [40%]; median age, 54 years [interquartile range, 31]; mean duration of ECMO, 91 hours [interquartile range, 100]; overall survival >7 days after ECMO, 52%). Neurological events occurred in 42 patients who received ECMO (50%; 95% confidence interval [CI], 39%-61%). Diagnoses included subarachnoid hemorrhage, ischemic watershed infarctions, hypoxic-ischemic encephalopathy, unexplained coma, and brain death. Death in patients who received ECMO who did not require antecedent cardiopulmonary resuscitation was associated with increased age (odds ratio, 1.24 per decade; 95% CI, 1.03-1.50; P = .02) and lower minimum arterial oxygen pressure (odds ratio, 0.79; 95% CI, 0.68-0.92; P = .03). Although stroke was rarely diagnosed clinically, 9 of 10 brains studied at autopsy demonstrated hypoxic-ischemic and hemorrhagic lesions of vascular origin. Conclusion Severe neurological sequelae occur frequently in adult ECMO-treated patients with otherwise reversible cardiopulmonary injury (conservative estimate, 50%) and include a range of potentially fatal neurological diagnoses that may be due to the precipitating event and/or ECMO treatment.

Ten-Year Outcome of Subthalamic Stimulation in Parkinson Disease: A Blinded Evaluation [Original Contribution]

Objective To assess the 10-year motor outcome of deep brain stimulation of the subthalamic nucleus (STN-DBS) in patients with Parkinson disease (PD). Design Patients with PD with bilateral STN-DBS were assessed according to the Core Assessment Program for Surgical Interventional Therapies in Parkinson's Disease protocol and videotaped at baseline and 1, 5, and 10 years after surgery. An independent rater blinded to stimulation and medication condition scored the 10-year video assessments. Setting Movement Disorders Centre, Toronto Western Hospital, University Health Network, University of Toronto. Patients Eighteen patients with advanced PD and 10-year follow-up of STN-DBS. Intervention Bilateral STN-DBS surgery. Main Outcome Measures The primary outcome was the change in blinded Unified Parkinson's Disease Rating Scale (UPDRS) motor scores/subscores between the no medication/stimulation condition vs the no medication/no stimulation condition at 10 years. Secondary outcomes were the changes in blinded UPDRS motor scores between the medication/no stimulation and medication/stimulation conditions, UPDRS II scores, UPDRS IV dyskinesia and motor fluctuations scores, and anti-PD medication dose (levodopa equivalent daily dose) at different points. Results In the 18 patients available for follow-up at 10 years, STN-DBS still significantly improved the UPDRS total motor score (P = .007) and resting and action tremor (P < .01 and P = .02, respectively) and bradykinesia (P = .01) subscores. The UPDRS II scores in the medication and no medication conditions, UPDRS IV dyskinesia and motor fluctuations scores, and the levodopa equivalent daily dose were also significantly reduced compared with baseline. Axial signs showed the most progressive decline in stimulation and levodopa response over the years. Conclusion This class III study provides evidence that stimulation-induced motor improvement was sustained overall at 10 years, although part of the initial benefit wore off mainly because of progressive loss of benefit on axial signs over time.

Myasthenia Gravis-Associated Neuromyelitis Optica-Like Disease: An Immunological Link Between the Central Nervous System and Muscle? [Original Contribution]

Background Although overt involvement of the central nervous system (CNS) in myasthenia gravis (MG) is considered rare, hyperreflexia is a common and yet unexplained finding. Aquaporin 4 (AQP4), the target autoantigen in neuromyelitis optica, is expressed both in the CNS and in the neuromuscular junction. Objectives To evaluate the prevalence of even mild CNS involvement in patients with MG and to identify features indicative of neuromyelitis optica–like disease. Design Cohort study. Setting Outpatient clinic. Patients A cohort of 164 patients with MG. Methods In 24 patients with MG, signs of CNS involvement were detected; 15 of these patients had at least 1 additional paraclinical indication of neuromyelitis optica–like disease (presence of antibodies against AQP4, pathological visual evoked potentials, or white matter lesions detected on brain and/or spinal magnetic resonance imaging scans) and fulfilled the inclusion and exclusion criteria for our study. Results Of the 15 patients who had at least 1 additional paraclinical indication of neuromyelitis optica–like disease, 14 had abnormal visual evoked potentials, and in 6 of 9 patients in whom magnetic resonance imaging was performed, there was evidence of lesions in the white matter of the brain and/or spinal cord. Anti-AQP4 antibodies were detected in 7 patients (out of the 14 tested). Thymic enlargement (hyperplasia or thymoma) was more frequent in patients with MG who had signs of CNS involvement than in patients with MG who did not. Conclusions The incidence of CNS involvement in MG is higher than previously reported and is expressed predominantly as a pyramidal syndrome accompanied by optical tract involvement (frequently subclinical). These features bear some resemblance to neuromyelitis optica spectrum disease, supported also by the presence of anti-AQP4 antibodies in 7 of the 14 patients tested. This association may represent a new nosological entity or may indicate that an autoimmune process targeting AQP4 is an integral part of the immunopathogenetic mechanisms in MG.

Neurodegeneration Across Stages of Cognitive Decline in Parkinson Disease [Original Contribution]

Objective To assess regions and patterns of brain atrophy in patients with Parkinson disease (PD) with normal cognition (PD-NC), mild cognitive impairment (PD-MCI), and dementia-level cognitive deficits (PDD). Design Images were quantified using a region-of-interest approach and voxel-based morphometry analysis. We used a high-dimensional pattern classification approach to delineate brain regions that collectively formed the Spatial Pattern of Abnormalities for Recognition of PDD. Setting The Parkinson's Disease and Movement Disorders Center at the University of Pennsylvania. Subjects Eighty-four PD patients (61 PD-NC, 12 PD-MCI, and 11 PDD) and 23 healthy control subjects (HCs) underwent magnetic resonance imaging of the brain. Results The PD-NC patients did not demonstrate significant brain atrophy compared with HCs. Compared with PD-NC patients, PD-MCI patients had hippocampal atrophy (β = –0.37; P = .001), and PDD patients demonstrated hippocampal (β = –0.32; P = .004) and additional medial temporal lobe atrophy (β = –0.36; P = .003). The PD-MCI patients had a different pattern of atrophy compared with PD-NC patients (P = .04) and a similar pattern to that of PDD patients (P = .81), characterized by hippocampal, prefrontal cortex gray and white matter, occipital lobe gray and white matter, and parietal lobe white matter atrophy. In nondemented PD patients, there was a correlation between memory-encoding performance and hippocampal volume. Conclusions Hippocampal atrophy is a biomarker of initial cognitive decline in PD, including impaired memory encoding and storage, suggesting heterogeneity in the neural substrate of memory impairment. Use of a pattern classification approach may allow identification of diffuse regions of cortical gray and white matter atrophy early in the course of cognitive decline.

A Comprehensive Genetic Association Study of Alzheimer Disease in African Americans [Original Contribution]

Objectives To evaluate the association of genetic variation with late-onset Alzheimer disease (AD) in African Americans, including genes implicated in recent genome-wide association studies of whites. Design We analyzed a genome-wide set of 2.5 million imputed markers to evaluate the genetic basis of AD in an African American population. Subjects Five hundred thirteen well-characterized African American AD cases and 496 cognitively normal African American control subjects. Setting Data were collected from multiple sites as part of the Multi-Institutional Research on Alzheimer Genetic Epidemiology (MIRAGE) Study and the Henry Ford Health System as part of the Genetic and Environmental Risk Factors for Alzheimer Disease Among African Americans (GenerAAtions) Study. Results Several significant single-nucleotide polymorphisms (SNPs) were observed in the region of the apolipoprotein E gene (APOE). After adjusting for the confounding effects of APOE genotype, one of these SNPs, rs6859 in PVRL2, remained significantly associated with AD (P = .0087). Association was also observed with SNPs in CLU, PICALM, BIN1, EPHA1, MS4A, ABCA7, and CD33, although the effect direction for some SNPs and the most significant SNPs differed from findings in data sets consisting of whites. Finally, using the African American genome-wide association study data set as a discovery sample, we obtained suggestive evidence of association with SNPs for several novel candidate genes. Conclusions Some genes contribute to AD pathogenesis in both white and African American cohorts, although it is unclear whether the causal variants are the same. A larger African American sample will be needed to confirm novel gene associations, which may be population specific.

The APOE {varepsilon}2 Allele Increases the Risk of Earlier Age at Onset in Machado-Joseph Disease [Original Contribution]

Objective To investigate a modulating effect of the apolipoprotein E (APOE) polymorphism on age at onset of Machado-Joseph disease (MJD). Design We collected blood samples from 192 patients with MJD and typed the APOE polymorphism. Patients The 192 patients with MJD included 59 from the Azores, 73 from mainland Portugal, and 60 from Brazil. Setting Academic research center. Results Cases with the 2/3 genotype had an earlier onset compared with those with the 3/3 or the 3/4 genotype. In this series of patients, the presence of an APOE 2 allele implies a decrease of nearly 5 years in the age at onset. When combining several other predictors in a general linear model, namely, the presence/absence of the APOE 2 allele, with the size of the (CAG)n in expanded alleles, the model was significantly improved and the explanation of onset variance was raised from 59.8% to 66.5%. Furthermore, the presence of the 2 allele was associated with an onset before age 39 years (odds ratio, 5.00; 95% CI, 1.18-21.14). Conclusion The polymorphism at the APOE gene plays a role as a genetic modifier of MJD phenotype.

Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Affecting an African American Man: Identification of a Novel 15-Base Pair NOTCH3 Duplication [Observation]

Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the best characterized genetic cause of vascular dementia and stroke and has been extensively reported in European and Asian populations. Objective To report the pathological and genetic analysis of CADASIL in an African American man with a 15–base pair NOTCH3 duplication. Design Case report. Setting University hospital. Patient A 78-year-old man with dementia, recurrent strokes, a family history of similar neurological disease, and white matter abnormalities seen on brain magnetic resonance imaging. Main Outcome Measures Brain pathology and genetic analysis of NOTCH3. Results The patient's brain showed widespread arteriopathy in large and small arteries. Using electron microscopy, granular osmiophilic material typical of CADASIL was identified abutting the plasma membrane of smooth muscle cells. Brain extracts contained elevated NOTCH3 protein levels. Sequencing of the NOTCH3 gene revealed a novel 15–base pair heterozygous duplication in exon 7, which is predicted to direct expression of a protein that contains 5 extra amino acids, including a cysteine residue. Conclusions To our knowledge, this is the first reported pathological and genetic analysis of an African American patient with CADASIL. The mutation in NOTCH3 is the longest duplication within this gene yet reported.

Propylthiouracil-Induced Lupus, Antiphospholipid Syndrome, and Stroke in a Patient With Graves Hyperthyroidism [Observation]

Objective To describe a case of propylthiouracil-induced lupus, complicated with antiphospholipid syndrome and acute ischemic stroke. Design Case report. Setting Academic medical center. Patient A 27-year-old man with a diagnosis of Graves disease developed multiple ischemic strokes 2 weeks after starting treatment with propylthiouracil. Thyrotoxicosis and abnormal hypercoagulable and rheumatological profiles were remarkable, with prolonged partial thromboplastin time, elevated anticardiolipin antibody level, and positive antinuclear antibody, lupus anticoagulant, Sjögren antibody, and anti–double-stranded DNA antibody test results, which were more than 8-fold greater than normal values. No clinical manifestations of systemic lupus erythematosus were present. Intervention Discontinuation of propylthiouracil and treatment with radioactive iodine. Results Hyperthyroidism resolved and anti–double-stranded DNA antibodies returned to normal levels. Eventually, antiphospholipid syndrome was diagnosed. He was treated with oral anticoagulation and remained asymptomatic for 1 year of follow-up. Conclusion In this young man with Graves hyperthyroidism, treatment with propylthiouracil was associated with transient autoimmune reactions suggestive of drug-induced lupus, antiphospholipid syndrome, and acute ischemic stroke.

Paraneoplastic Syndrome of Inappropriate Antidiuretic Hormone Mimicking Limbic Encephalitis [Observation]

Objective To compare the features of paraneoplastic syndrome of inappropriate antidiuretic hormone with those of limbic encephalitis. Design Case study. Setting Academic medical center. Patient A 46-year-old woman with progressive memory impairment, hyponatremia, and seizures. Interventions Magnetic resonance imaging of the brain, fluoro-2-deoxyglucose positron emission tomography of the body, and immunohistochemical analysis of a resected tumor. Results Though the patient presented with clinical features of classic limbic encephalitis, magnetic resonance imaging, electroencephalogram, and cerebrospinal fluid analysis findings were unremarkable. Her chronic hyponatremia was ultimately found to be due to ectopic secretion of antidiuretic hormone by a neuroendocrine tumor with Merkel cell carcinoma phenotype. Conclusions Patients presenting with memory impairment, seizures, and hyponatremia should undergo a thorough workup for occult malignancy. In addition to considering classic immune-mediated paraneoplastic limbic encephalitis, the ectopic secretion of antidiuretic hormone should be included in the differential diagnosis.

Quantitative and Qualitative Analysis of Ambulatory Electroencephalography During Mild Traumatic Brain Injury [Observation]

Objectives To characterize the neurophysiological changes in a patient with mild traumatic brain injury (mTBI) and to compare these changes with a small cohort of patients with neurocardiogenic syncope, an analogous cause of transient neurological dysfunction. Design Case report and quantitative analysis of a small electroencephalography (EEG) cohort. Setting University-affiliated teaching hospital. Patients A 64-year-old man with mTBI recorded on ambulatory EEG. The comparison group was 4 patients with spontaneous neurocardiogenic syncope during continuous video EEG recording. Intervention Quantitative and qualitative analysis of EEG. Main Outcome Measures Changes in quantitative EEG measurements between the patient with mTBI and the comparison group. Results In the patient with mTBI, there was an abrupt decrease in high-frequency (beta) power and alpha-delta ratio immediately after the injury and a corresponding increase in lower-frequency (alpha, theta, delta) power. The change in beta power resolved within 5 minutes of the injury, but the increases in low-frequency power persisted up to 20 minutes after the injury before resolving. Similar but smaller changes were seen in the patients with syncope, but these changes resolved within 5 minutes, with no intermediate or long-term changes. Conclusions The quantitative EEG changes in mTBI are initially similar to those in syncope, suggesting acute transient cortical dysfunction. However, there are longer-lasting increases in low-frequency power during mTBI, suggesting ongoing disruption of cortical-thalamic circuits.

Exercise-Associated Numbness and Tingling in the Legs [Clinical Pathologic Conference]

A 52-year-old physically active man with a medical history of coronary artery disease, hypertension, and hyperlipidemia presented with numbness and tingling in the legs. His symptoms were intermittent initially, triggered by running or playing soccer and relieved by rest. Symptoms progressed during 1 year. The numbness became more constant, and he developed leg pain radiating from the popliteal fossa to the heel bilaterally (pain was more severe in the left leg compared with the right leg). Recently, he had noted some constipation as well as difficulty in initiating urination.

Recurrent Embolic Stroke Due to Nonbacterial Thrombotic Endocarditis Followed by Transesophageal Echocardiography [Images in Neurology]

Growing Posterior Fossa Arachnoid Cyst Causing Tonsillar Herniation and Hydrocephalus [Images in Neurology]

Radiation-Induced Myelopathy: Treatment With Bevacizumab [Images in Neurology]

Angioplasty for Symptomatic Middle Cerebral Artery Stenosis and a Perioperative Evaluation Using High-Resolution Magnetic Resonance Imaging at 3 T [Images in Neurology]

Ultrastructural Mitochondrial Abnormalities in Patients With Sporadic Amyotrophic Lateral Sclerosis [Research Letters]

Central Nervous System Problems With Eosinophilia [Correspondence]

Central Nervous System Problems With Eosinophilia--Reply [Correspondence]

Reversible Cerebral Vasoconstriction Syndrome and Hemorrhagic Events: Who Precedes Whom? [Correspondence]

Reversible Cerebral Vasoconstriction Syndrome and Hemorrhagic Events: Who Precedes Whom?--Reply [Correspondence]

Parkinson Disease and Vitamin D: An Interplay Between Genes and the Environment? [Correspondence]

About This Journal [About This Journal]

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

Amyloid Imaging: Liberal or Conservative? Let the Data Decide [Editorial]

Chronic Cerebrospinal Venous Insufficiency and Multiple Sclerosis [Neurological Review]

Chronic cerebrospinal venous insufficiency has recently been proposed to be etiologic to multiple sclerosis. Independent investigation into this theory during the past 2 years has not succeeded in verifying this relationship. A critical analysis of the scientific methods used in the original studies of chronic cerebrospinal venous insufficiency in multiple sclerosis reveals several methodological problems with regard to potential bias and confounding. The current evidence calls into question whether chronic cerebrospinal venous insufficiency in multiple sclerosis exists at all.

Cholesterol Level and Statin Use in Alzheimer Disease: II. Review of Human Trials and Recommendations [Neurological Review]

Substantial evidence has accumulated in support of the hypothesis that elevated cholesterol levels increase the risk of developing Alzheimer disease (AD). As a result, much work has investigated the potential use of lipid-lowering agents, particularly statins, as preventive or therapeutic agents for AD. Although epidemiology and preclinical statin research (described in part I of this review) have generally supported an adverse role of high cholesterol levels regarding AD, human studies of statins (reviewed herein) show highly variable outcomes, making it difficult to draw firm conclusions. We identify several confounding factors among the human studies, including differing blood-brain barrier permeabilities among statins, the stage in AD at which statins were administered, and the drugs' pleiotropic metabolic effects, all of which contribute to the substantial variability observed to date. We recommend that future human studies of this important therapeutic topic (1) take the blood-brain barrier permeabilities of statins into account when analyzing results, (2) include specific analyses of the effects on low- and high-density lipoprotein cholesterol, and, most important, (3) conduct statin treatment trials solely in patients with mild AD, who have the best chance for disease modification.

Coping With Death and Dying on a Neurology Inpatient Service: Death Rounds as an Educational Initiative for Residents [Special Article]

Background Residents in neurology may feel unprepared to care for dying patients. We developed Death Rounds to provide emotional support and end-of-life care teaching for residents caring for dying patients on the inpatient neurology service. Death Rounds are monthly 1-hour clinical case discussions where residents identify issues through shared experiences. Objective To survey neurology residents' perceptions of Death Rounds with respect to end-of-life care teaching and emotional support. Design, Setting, and Participants We conducted an electronic survey of all (n = 26) neurology residents and recent residency graduates at the University of Washington 2 years after instituting monthly Death Rounds. Main Outcome Measure The survey consisted of 10 questions examining residents' perceptions of the extent to which Death Rounds provided emotional support and end-of-life care teaching. We dichotomized responses to statements about Death Rounds as agree or disagree. Results All 26 residents responded to the survey and attended at least 1 Death Rounds session. More than half of residents attended more than 3 sessions. Residents agreed that Death Rounds helped them cope with dying patients (17 residents [65%]), delivered closure for the team (16 residents [61%]), and provided emotional support, more for the team (18 residents [69%]) than the individual (10 residents [38%]). Most residents felt that Death Rounds provided useful teaching about end-of-life care (18 residents [69%]), and they were satisfied overall with Death Rounds (16 residents [61%]). Conclusions Death Rounds afford an opportunity for physicians-in-training to process as a group their feelings, intense emotions, and insecurities while learning from the dying process. In our inpatient neurology service, most residents found it a rewarding and valuable experience.

Association Between In Vivo Fluorine 18-Labeled Flutemetamol Amyloid Positron Emission Tomography Imaging and In Vivo Cerebral Cortical Histopathology [Original Contribution]

Objective To determine the correspondence of in vivo quantitative estimates of brain uptake of fluorine 18–labeled flutemetamol with immunohistochemical estimates of amyloid levels in patients who underwent previous biopsy. Design Cross-sectional study of 18F-flutemetamol positron emission tomography (PET) findings in patients with prior cortical biopsy specimen stained for the presence or absence of amyloid plaques. Setting University hospital. Patients Seven patients who previously had a prior right frontal cortical biopsy at the site of ventriculoperitoneal placement for presumed normal pressure hydrocephalus were recruited. Inclusion criteria included an adequate biopsy specimen for detection and quantification of β-amyloid pathology and age older than 50 years. Intervention All patients underwent an 18F-flutemetamol PET scan. Main Outcome Measures Quantitative measures of 18F-flutemetamol uptake (standardized uptake value ratio, a ratio of mean target cortex activity divided by that in a cerebellar reference region) were made at a location contralateral to the biopsy site and compared with estimates of amyloid load based on immunohistochemical and histological staining. Results There was complete agreement between visual reads of 18F-flutemetamol PET scans (3 blinded readers with majority rule) and histology. A regression model, including time from biopsy as a covariate, demonstrated a significant relationship (P = .01) between 18F-flutemetamol uptake and percentage of area of amyloid measured by a monoclonal antibody raised against amyloid (NAB228). Similar results were found with the amyloid-specific monoclonal antibody 4G8 and Thioflavin S. Conclusion To our knowledge, these data are the first to demonstrate the concordance of 18F-flutemetamol PET imaging with histopathology, supporting its sensitivity to detect amyloid and potential use in the study and detection of Alzheimer disease.

Using Positron Emission Tomography and Florbetapir F 18 to Image Cortical Amyloid in Patients With Mild Cognitive Impairment or Dementia Due to Alzheimer Disease [Original Contribution]

Objectives To characterize quantitative florbetapir F 18 (hereafter referred to as simply florbetapir) positron emission tomographic (PET) measurements of fibrillar β-amyloid (Aβ) burden in a large clinical cohort of participants with probable Alzheimer disease (AD) or mild cognitive impairment (MCI) and older healthy controls (OHCs). Design Cerebral–to–whole-cerebellar florbetapir standard uptake value ratios (SUVRs) were computed. Mean cortical SUVRs were compared. A threshold of SUVRs greater than or equal to 1.17 was used to reflect pathological levels of amyloid associated with AD based on separate antemortem PET and postmortem neuropathology data from 19 end-of-life patients. Similarly, a threshold of SUVRs greater than 1.08 was used to signify the presence of any identifiable Aβ because this was the upper limit from a separate set of 46 individuals 18 to 40 years of age who did not carry apolipoprotein E (APOE) 4. Setting Multiple research imaging centers. Participants A total of 68 participants with probable AD, 60 participants with MCI, and 82 OHCs who were 55 years of age or older. Main Outcome Measure Florbetapir-PET activity. Results All of the participants (ie, those with probable AD or MCI and those who were OHCs) differed significantly in mean (SD) cortical florbetapir SUVRs (1.39 [0.24], 1.17 [0.27], and 1.05 [0.16], respectively; P < 1.0 x 10–7), in percentage meeting levels of amyloid associated with AD by SUVR criteria (80.9%, 40.0%, and 20.7%, respectively; P < 1.0 x 10–7), and in percentage meeting SUVR criteria for the presence of any identifiable Aβ (85.3%, 46.6%, and 28.1%, respectively; P < 1.0 x 10–7). Among OHCs, the percentage of florbetapir positivity increased linearly by age decile (P = .05). For the 54 OHCs with available APOE genotypes, APOE 4 carriers had a higher mean (SD) cortical SUVR than did noncarriers (1.14 [0.2] vs 1.03 [0.16]; P = .048). Conclusions The findings of our analysis confirm the ability of florbetapir-PET SUVRs to characterize amyloid levels in clinically probable AD, MCI, and OHC groups using continuous and binary measures of fibrillar Aβ burden. It introduces criteria to determine whether an image is associated with an intermediate-to-high likelihood of pathologic AD or with having any identifiable cortical amyloid level above that seen in low-risk young controls.

Repeated Treatment With Rituximab Based on the Assessment of Peripheral Circulating Memory B Cells in Patients With Relapsing Neuromyelitis Optica Over 2 Years [Original Contribution]

Objective To evaluate the efficacy and safety of repeated rituximab treatment based on the assessment of peripheral circulating memory B cells over 24 months in patients with relapsing neuromyelitis optica (NMO). Design Prospective open-label study. Setting Institutional referral center for multiple sclerosis. Patients Thirty patients with relapsing NMO or NMO spectrum disorder. Intervention Treatment protocol of rituximab consisted of an induction therapy (375 mg/m2 once weekly for 4 weeks or 1000 mg infused twice, with a 2-week interval between the infusions) followed by maintenance therapy. The maintenance therapy was repeated treatment with rituximab (375 mg/m2, once) whenever the frequency of reemerging CD27+ memory B cells was more than 0.05% in peripheral blood mononuclear cells by flow cytometric analysis. Main Outcome Measures Annualized relapse rate, disability (Expanded Disability Status Scale score), anti–aquaporin 4 antibody level, and safety of rituximab treatment. Results Of 30 patients, 28 showed a marked reduction in relapse rate while taking rituximab over 24 months. The relapse rate was reduced significantly, by 88%, and 70% of patients became relapse-free over 24 months. Disability either improved or stabilized in 97% of patients. Anti–aquaporin 4 antibody levels declined significantly following treatment with rituximab, consistent with the clinical response and the effect on CD27+ memory B cells. Repeated treatment with rituximab was generally well tolerated, and no clinically relevant adverse event leading to discontinuation of treatment was observed. Conclusion Repeated treatment with rituximab appeared to produce consistent and sustained efficacy over 24 months with good tolerability in patients with NMO.

Interferon Beta-1b for the Treatment of Primary Progressive Multiple Sclerosis: Five-Year Clinical Trial Follow-up [Original Contribution]

Objectives To investigate, during the 5-year period without treatment after termination of a 2-year clinical trial of interferon beta-1b for the treatment of primary progressive multiple sclerosis, differences in the evolution of clinical variables and magnetic resonance imaging results between trial arms and to investigate correlations between in-trial changes in Multiple Sclerosis Functional Composite (MSFC) score and magnetic resonance imaging variables and Expanded Disability Status Scale (EDSS) score evolution. Design Five-year clinical trial follow-up. Setting Clinical Neuroimmunology Unit, Multiple Sclerosis Centre of Catalonia, Autonomous University of Barcelona, Spain. Patients Seventy-three patients received interferon beta-1b or placebo during the trial. Main Outcome Measures After 5 years without treatment, the EDSS and MSFC measures were scored for 63 and 59 patients, respectively. Neuropsychological and magnetic resonance imaging assessments were performed for 59 and 50 patients, respectively. Results After 5 years without treatment, the interferon beta-1b group had better 9-Hole Peg Test (P = .02) and Word List Generation Test (P < .001) scores, and their magnetization transfer ratio measures in the normal-appearing white matter were significantly higher (P = .02, P = .009, and P = .03 for the mean, peak location, and peak height magnetic transfer ratios, respectively). During the entire study period (from trial baseline to assessment at 5 years without treatment), the placebo group showed a greater decrease in brain parenchymal fraction (P = .004). The in-trial increase of lesions correlated with the worsening of the EDSS score during the 5-year period without treatment (P = .004). Conclusions Modest but beneficial effects of interferon beta-1b on clinical variables and brain atrophy development were observed 5 years after trial termination. Moreover, in-trial lesion activity correlated with EDSS progression after trial termination. Therefore, we provide evidence to consider immunomodulation as a sensible approach to treat primary progressive multiple sclerosis.

Natalizumab and Impedance of the Homing of CD34+ Hematopoietic Progenitors [Original Contribution]

Background Treatment with natalizumab, an antibody blocking the α4-integrin, is associated with increased numbers of circulating CD34+ cells in the peripheral blood of patients with multiple sclerosis. Objective To determine whether natalizumab mobilizes CD34+ cells from or inhibits homing to the bone marrow (BM). Design Fifty-two patients with relapsing-remitting multiple sclerosis treated with natalizumab were included. Flow cytometric analyses; polymerase chain reaction assays for JC (John Cunningham) virus DNA detection; and adhesion, migration, and apoptosis assays of immunomagnetically enriched peripheral blood and BM CD34+ cells were conducted. A comparison was made with CD34+ cells from granulocyte colony-stimulating factor–mobilized peripheral blood or steady-state BM of age- and sex-matched healthy donors. Results We found adhesion and migration of peripheral blood–derived CD34+ cells to be reduced. In BM aspirates from natalizumab-treated patients, the cellularity, the proportion, and the adhesive capacity of CD34+ cells were normal. The JC virus was undetectable. Conclusions Natalizumab mediates an increase in circulating CD34+ cells by interfering with homing to the BM. Thus, CD34+ cells appear unlikely to represent a source mobilizing JC virus out of the BM in patients treated with natalizumab.

Brain Involvement in Neuromyelitis Optica Spectrum Disorders [Original Contribution]

Background Neuromyelitis optica spectrum disorders (NMOSDs) are severe inflammatory demyelinating disorders of the central nervous system. Brain involvement is increasingly recognized. Objective To study brain involvement in NMOSDs among Hong Kong Chinese patients. Design Retrospective study of patients with NMOSDs. Setting Tertiary medical center in Hong Kong. Patients Thirty-four Hong Kong Chinese patients with NMOSDs of 2 years or longer were recruited. Interventions Brain and spinal cord magnetic resonance imaging was performed during NMOSD attacks and was repeated yearly for the first 3 years. Main Outcome Measures We evaluated clinical features of NMOSDs associated with brain involvement and brain lesions on magnetic resonance imaging. Results Among 34 patients with NMOSDs of 2 years or longer, 20 (59%) had brain involvement. The mean age at onset among these 20 patients was 45.6 years (age range, 19-67 years); 18 were women. Eleven patients (32% of all the patients with NMOSDs) had clinical manifestation of brain involvement, 19 patients (56%) had brain abnormalities on magnetic resonance imaging consistent with inflammatory demyelination, and 2 patients (6%) fulfilled criteria for multiple sclerosis. Clinical manifestation of brain involvement included the following: trigeminal neuralgia; vomiting, vertigo, ataxia, dysphagia, and tetraparesis from lesions around the third and fourth ventricles and aqueduct; homonymous hemianopia, aphasia, hemiparesis, and cognitive impairment from extensive hemispheric white matter lesions; and ataxia, diplopia, hiccups, facial sensory loss, internuclear ophthalmoplegia, hemisensory loss, and hemiparesis from other lesions in the midbrain, pons, cerebellar peduncles, and medulla. Eight patients (24%) developed brainstem encephalitis clinically, and brainstem encephalitis was the initial clinical manifestation in 6 patients (18%). Brain abnormalities on magnetic resonance imaging were detected in brainstem in 15 patients (44%), hemispheric periventricular white matter in 7 patients (21%), deep white matter in 7 patients (21%), corpus callosum in 4 patients (12%), subcortical white matter in 3 patients (9%), thalamus in 2 patients (6%), hypothalamus in 1 patient (3%), basal ganglia in 1 patient (3%), internal capsule in 1 patient (3%), periaqueductal gray matter in 1 patient (3%), and around the third and fourth ventricles in 1 patient (3%); large confluent lesions were detected in 2 patients (6%). Conclusion Brain involvement manifesting clinically as brainstem encephalitis is common among Hong Kong Chinese patients with NMOSDs.

SQSTM1 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis [Original Contribution]

Background The SQSTM1 gene encodes p62, a major pathologic protein involved in neurodegeneration. Objective To examine whether SQSTM1 mutations contribute to familial and sporadic amyotrophic lateral sclerosis (ALS). Design Case-control study. Setting Academic research. Patients A cohort of 546 patients with familial (n = 340) or sporadic (n = 206) ALS seen at a major academic referral center were screened for SQSTM1 mutations. Main Outcome Measures We evaluated the distribution of missense, deletion, silent, and intronic variants in SQSTM1 among our cohort of patients with ALS. In silico analysis of variants was performed to predict alterations in p62 structure and function. Results We identified 10 novel SQSTM1 mutations (9 heterozygous missense and 1 deletion) in 15 patients (6 with familial ALS and 9 with sporadic ALS). Predictive in silico analysis classified 8 of 9 missense variants as pathogenic. Conclusions Using candidate gene identification based on prior biological knowledge and the functional prediction of rare variants, we identified several novel SQSTM1 mutations in patients with ALS. Our findings provide evidence of a direct genetic role for p62 in ALS pathogenesis and suggest that regulation of protein degradation pathways may represent an important therapeutic target in motor neuron degeneration.

Incorrect Positioning in Novel POLG Splice Site Mutation and Optic Atrophy [Correction]

Prefrontal Cortex and Executive Function Impairments in Primary Breast Cancer [Original Contribution]

Objectives To examine differences in prefrontal-executive function between breast cancer (BC) survivors with and without a history of chemotherapy treatment compared with healthy control women and to determine the associations between prefrontal cortex deficits and behavioral impairments, as well as certain demographic and disease variables. Design Observational study. Setting University-based research facility. Participants Twenty-five women with BC who had received chemotherapy, 19 women with BC who had not received chemotherapy, and 18 healthy female controls, all matched for age and other demographic variables. Results Women with BC demonstrated significantly reduced activation in the left middle dorsolateral prefrontal cortex and premotor cortex compared with healthy controls. The chemotherapy group also demonstrated significantly reduced left caudal lateral prefrontal cortex activation and increased perseverative errors and reduced processing speed compared with the other 2 groups. Reduced left caudal lateral prefrontal cortex activation was significantly correlated with higher disease severity and elevated subjective executive dysfunction in the chemotherapy-treated women. Older age and lower educational level were associated with increased executive function impairment in the chemotherapy group. Conclusions These findings provide further evidence of neurological impairment associated with primary BC irrespective of treatment history. The left caudal lateral prefrontal region may be particularly vulnerable to the effects of chemotherapy and/or disease severity and may represent a novel biomarker of subjective executive dysfunction in chemotherapy-treated women. Furthermore, negative effects of chemotherapy on brain function may be exacerbated by such factors as increased age and lower educational level.

Relationship Between Chronic Atrial Fibrillation and Worse Outcomes in Stroke Patients After Intravenous Thrombolysis [Original Contribution]

Background It is unclear whether stroke patients with atrial fibrillation (AF) are prone to adverse outcomes following treatment with intravenous recombinant tissue plasminogen activator, and whether the burden of AF affects these outcomes. Objective To investigate the contribution of AF (whether it be a first-detected episode of AF or chronic AF) to stroke outcomes in patients treated with intravenous recombinant tissue plasminogen activator. Design Retrospective study. Setting Academic hospital. Patients Consecutive patients with acute ischemic stroke who received intravenous recombinant tissue plasminogen activator within 3 hours from symptom onset were included. Vascular risk factors, stroke characteristics, and outcome measures were compared between patients with and without AF. Main Outcome Measures Symptomatic intracranial hemorrhage and poor functional recovery (modified Rankin Scale score of >2). Results Of the 214 patients who were studied (mean [SD] age, 74 [14] years, with 50% of patients being men), 21 had a first-detected episode of AF, and 55 had chronic AF. The incidence of symptomatic intracranial hemorrhage was significantly higher in patients with chronic AF than in patients without AF (16% vs 5%), and the incidence of poor functional recovery was significantly higher in patients with chronic AF than in patients without AF (62% vs 44%). The increase in risk of symptomatic intracranial hemorrhage (but not in poor functional recovery) among patients with chronic AF remained significant after adjusting for age and baseline National Institutes of Health Stroke Scale score (odds ratio, 2.95 [95% CI, 1.12-9.30]). Patients with chronic AF who developed a symptomatic intracranial hemorrhage had a longer duration of AF than those who did not (59 vs 23 months), and patients with chronic AF who had a poor functional recovery had a longer duration of AF than those who did not (36 vs 16 months) (P < .05). By contrast, there were no differences in outcomes between patients with a first-detected episode of AF and those without AF, and between patients with paroxysmal AF and those with persistent or permanent AF. Conclusions Patients with chronic AF have worse stroke outcomes than do patients without AF, and the risk for worse outcomes was greater in patients with a longer duration of AF.

Clusterin as an Alzheimer Biomarker [From JAMA]

Positron Emission Tomography and Neuropathologic Estimates of Fibrillar Amyloid-{beta} in a Patient With Down Syndrome and Alzheimer Disease [Observation]

Background Down syndrome appears to be associated with a virtually certain risk of fibrillar amyloid-β (Aβ) pathology by the age of 40 and a very high risk of dementia at older ages. The positron emission tomography (PET) ligand florbetapir F18 has been shown to characterize fibrillar Aβ in the living human brain and to provide a close correlation with subsequent Aβ neuropathology in individuals proximate to and after the end of life. The extent to which the most frequently used PET ligands can be used to detect fibrillar Aβ in patients with Down syndrome remains to be determined. Objectives To characterize PET estimates of fibrillar Aβ burden in a Down syndrome patient very close to the end of life and to compare them with neuropathologic assessment made after his death. Design/Methods With the family's informed consent, florbetapir PET was used to study a 55-year-old Down syndrome patient with Alzheimer disease near the end of life; his brain was donated for neuropathologic assessment when he died 14 days later. Visual ratings of cerebral florbetapir uptake were performed by trained readers who were masked to the patient's diagnosis as part of a larger study, and an automated algorithm was used to characterize regional-to-cerebellar standard uptake value ratios in 6 cerebral regions of interest. Neuropathologic assessments were performed masked to the patient's diagnosis or PET measurements. Results Visual ratings and automated analyses of the PET image revealed a heavy fibrillar Aβ burden in cortical, striatal, and thalamic regions, similar to that reported for patients with late-onset Alzheimer disease. This matched neuropathologic findings of frequent neuritic and diffuse plaques, as well as frequent amyloid angiopathy, except for neuropathologically demonstrated frequent cerebellar diffuse plaques and amyloid angiopathy that were not detected by the PET scan. Conclusions Florbetapir PET can be used to detect increased cerebral-to-cerebellar fibrillar Aβ burden in a Down syndrome patient with Alzheimer disease, even in the presence of frequent amyloid angiopathy and diffuse plaques in the cerebellum. Additional studies are needed to determine the extent to which PET could be used to detect and to track fibrillar Aβ and to evaluate investigational Aβ-modifying treatments in the presymptomatic and symptomatic stages of Alzheimer disease.

New Type of Cortical Neuroplasticity After Nerve Repair in Brachial Plexus Lesions [Observation]

Background In brachial plexus avulsion, a recent technique connects the ending of the disrupted musculocutaneous nerve to the side of the intact phrenic nerve to regain elbow flexion. This requires the phrenic nerve to perform a new double function: independent control of breathing and elbow flexion. Neuroplastic changes associated with acquisition of double nerve functions have not yet been investigated. Objective To evaluate neuroplastic changes associated with acquisition of double nerve functions in a monofunctional nerve (phrenic nerve). Design Clinical and functional magnetic resonance imaging investigations during arm movements, forced inspiration, and motor control tasks. Setting Investigations at the Medical University of Vienna, Vienna, Austria. Participants Three healthy control subjects, 2 patients with phrenic nerve end-to-side coaptation, and 1 control patient with C7 end-to-end coaptation (same clinical presentation but phrenic nerve unchanged). Results Clinical documentation showed that both patients with phrenic nerve end-to-side coaptation were able to control the diaphragm and the biceps independently via the same phrenic nerve. In contrast to all controls, both patients with phrenic nerve end-to-side coaptation activated the cortical diaphragm areas with flexion of the diseased arm. Conclusion Our functional magnetic resonance imaging data indicate that the patient's cortical diaphragm areas reorganize in such a way that independent control of breathing and elbow flexion is possible with the same neuronal population.

Whipple Limbic Encephalitis [Observation]

Objective To describe a relapse of Whipple disease revealed by isolated limbic encephalitis with no other signs of systemic involvement. Design Case report. Setting University Hospital of Strasbourg, Strasbourg, France. Patient A 41-year-old patient. Main Outcome Measures Cognitive functions and results of cerebrospinal fluid analysis and brain magnetic resonance imaging. Results A 41-year-old patient was hospitalized for headache associated with anterograde amnesia and temporospatial disorientation. Whipple disease with systemic manifestations was diagnosed 4 years previously and insufficiently treated. The neuropsychological evaluation showed impaired episodic memory and executive functions. Analysis of the cerebrospinal fluid showed increased lymphocytes and a positive Tropheryma whipplei polymerase chain reaction result. Cerebral magnetic resonance imaging revealed a typical pattern of limbic encephalitis with an intense signal in the amygdalae and hippocampi. The outcome under antibiotic treatment was marked by partial improvement of the cognitive disorders, disappearance of the positive T whipplei polymerase chain reaction result in cerebrospinal fluid, and a clear decrease of inflammation on brain magnetic resonance imaging. Conclusions Whipple disease can present as limbic encephalitis. Few cases have been previously described in the literature. Such diagnosis is of importance because of the specific treatment.

Ring Sign on Diffusion-Weighted Imaging [Images in Neurology]

Pontine Ring-Enhancing Glioblastoma Multiforme-Like Fungal Abscess [Images in Neurology]

Unilateral Tongue Atrophy and Fasciculation [Images in Neurology]

Niedermeyer's Electroencephalography, Basic Principles, Clinical Applications, and Related Fields, 6th ed [Book Reviews]

Progenitor Cell Therapy for Neurological Injury [Book Reviews]

Limitations of NIS Database in Evaluation of Epilepsy Surgery Morbidity and Mortality [Correspondence]

Limitations of NIS Database in Evaluation of Epilepsy Surgery Morbidity and Mortality--Reply [Correspondence]

About This Journal [About This Journal]

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

Treat Alzheimer Disease Before It Is Symptomatic [Editorial]

Cholesterol Level and Statin Use in Alzheimer Disease: I. Review of Epidemiological and Preclinical Studies [Neurological Review]

During the last 2 decades, evidence has accumulated that a high cholesterol level may increase the risk of developing Alzheimer disease (AD). With the global use of statins to treat hypercholesterolemia, this finding has led to the anticipation that statins could prove useful in treating or preventing AD. However, the results of work on this topic are inconsistent: some studies find beneficial effects, but other studies do not. In this first segment of a 2-part review, we examine the complex preclinical and clinical literature on cholesterol level and AD. First, we review epidemiological research on cholesterol level and the risk of AD and discuss the relevance of discrepancies among studies with regard to participants' age and clinical status. Second, we assess studies correlating cholesterol level with neuropathological AD type. The potential molecular mechanisms for the apparent adverse effects of cholesterol on the development of AD are then discussed. Third, we review preclinical studies of statin use and AD. Therefore, this first part of our review provides the background and rationale for investigating statins as potential therapeutic agents in patients with AD, the subject of the second part.

Error in Notation in: Association of Low Ejection Fraction With Impaired Verbal Memory in Older Patients With Heart Failure [Correction]

Risk of Stroke and Cardiovascular Events After Ischemic Stroke or Transient Ischemic Attack in Patients With Type 2 Diabetes or Metabolic Syndrome: Secondary Analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial [Clinical Trials]

Objective To perform a secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, which tested the effect of treatment with atorvastatin in reducing stroke in subjects with a recent stroke or transient ischemic attack, to explore the effects of treatment in subjects with type 2 diabetes mellitus or metabolic syndrome (MetS). Methods The 4731 subjects enrolled in the SPARCL trial were classified as having type 2 diabetes mellitus at enrollment (n = 794), MetS retrospectively (n = 642), or neither diabetes nor MetS (n = 3295, the reference group) based on data collected at baseline. Cox regression models were used to determine whether the effect of treatment on the primary end point (combined risk of nonfatal and fatal stroke) and secondary end points (major coronary events, major cardiovascular events, any coronary heart disease event, and any revascularization procedure) varied based on the presence of type 2 diabetes mellitus or MetS. Results Subjects with type 2 diabetes mellitus had increased risks of stroke (hazard ratio [HR] = 1.62; 95% confidence interval [CI], 1.33-1.98; P < .001), major cardiovascular events (HR = 1.66; 95% CI, 1.39-1.97; P < .001), and revascularization procedures (HR = 2.39; 95% CI, 1.78-3.19; P < .001) compared with the reference group. Subjects with MetS were not at increased risk for stroke (P = .78) or major cardiovascular events (P = .38) but more frequently had revascularization procedures (HR = 1.78; 95% CI, 1.26-2.5; P = .001). There were no treatment x subgroup interactions for the SPARCL primary end point (P = .47). Conclusions The SPARCL subjects with type 2 diabetes were at higher risk for recurrent stroke and cardiovascular events. This exploratory analysis found no difference in the effect of statin treatment in reducing these events in subjects with or without type 2 diabetes or MetS. Trial Registration clinicaltrials.gov Identifier: NCT00147602

Evidence and the Effective Clinical Neurologist: The 2009 H. Houston Merritt Lecture [Special Article]

Longitudinal Change of Biomarkers in Cognitive Decline [Original Contribution]

Objective To delineate the trajectories of Aβ42 level in cerebrospinal fluid (CSF), fludeoxyglucose F18 (FDG) uptake using positron emission tomography, and hippocampal volume using magnetic resonance imaging and their relative associations with cognitive change at different stages in aging and Alzheimer disease (AD). Design Cohort study. Setting The 59 study sites for the Alzheimer's Disease Neuroimaging Initiative. Participants A total of 819 participants 55 to 90 years of age with normal cognition, mild cognitive impairment, and AD who were followed up during the period from 2005 to 2007. Main Outcome Measures Rates of change in level of Aβ42 in CSF, FDG uptake, hippocampal volume, and the Alzheimer Disease's Assessment Scale–cognitive subscale score during up to 36 months of follow-up by diagnostic group as well as prediction of cognitive change by each biomarker. Results Reductions in the level of Aβ42 in CSF were numerically greater in participants with normal cognition than in participants with mild cognitive impairment or AD; whereas both glucose metabolic decline and hippocampal atrophy were significantly slower in participants with normal cognition than in participants with mild cognitive impairment or AD. Positive APOE4 status accelerated hippocampal atrophic changes in participants with mild cognitive impairment or AD, but did not modify rates of change in level of Aβ42 in CSF or FDG uptake. The Alzheimer Disease's Assessment Scale–cognitive subscale scores were related only to the baseline level of Aβ42 in CSF and the baseline FDG uptake in participants with normal cognition, which were about equally associated with change in FDG uptake and hippocampal volume in participants with mild cognitive impairment and best modeled by change in FDG uptake in participants with AD. Conclusion Trajectories of Aβ42 level in CSF, FDG uptake, and hippocampal volume vary across different cognitive stages. The longitudinal patterns support a hypothetical sequence of AD pathology in which amyloid deposition is an early event before hypometabolism or hippocampal atrophy, suggesting that biomarker prediction for cognitive change is stage dependent.

Yellow Fever Vaccination and Increased Relapse Rate in Travelers With Multiple Sclerosis [Original Contribution]

Objective To investigate the effect of yellow fever (YF) immunization on the subsequent multiple sclerosis (MS) relapse risk. Design Self-controlled case series study. Setting An MS outpatient clinic. Patients Seven patients with clinical relapsing-remitting MS traveling to endemic YF areas who received the YF 17D-204 vaccine were studied. Intervention The YF 17D-204 vaccine. Main Outcome Measure Number of relapses. Secondary outcomes included the number of new lesions on magnetic resonance imaging and peripheral mononuclear cell cytokine and chemokine production. Results The annual exacerbation rate during risk periods following immunization was 8.57, while the relapse rate outside the risk period was only 0.67 (rate ratio = 12.778; P < .001). Three months after immunization, patients showed a significant increase in new or enlarging T2-weighted lesions and gadolinium-enhancing lesions compared with 12 months prior to vaccination and 9 months after immunization (both P < .001). Moreover, blood myelin basic protein and myelin oligodendrocyte glycoprotein responses showed significant increases in interferon –induced protein 10 kDa–, interferon –, interleukin 1α–, interleukin 1β–, and tumor necrosis factor–secreting cell numbers as well as complement component C1qB production after YF vaccination in patients with MS compared with unvaccinated patients with MS, patients with MS vaccinated against influenza, and healthy control subjects (P = .01 and P < .001, respectively). Conclusion For patients with MS traveling to endemic YF areas, vaccination should be recommended on the basis of carefully weighing the risk of exacerbation against the likelihood of exposure to the YF virus.

Fetal Effects of Anticonvulsant Polytherapies: Different Risks From Different Drug Combinations [Original Contribution]

Objective To determine the frequency of malformations among infants born to women who had taken lamotrigine or carbamazepine as part of polytherapy during the first trimester of pregnancy. Design A cohort of women enrolled during pregnancy in the North American AED (Antiepileptic Drug) Pregnancy Registry between February 1, 1997, and June 1, 2010. Information on AED use and demographic characteristics was collected in 3 telephone interviews. Setting United States and Canada. Patients A total of 6857 pregnant women taking an AED for any reason. Main Outcome Measures Major congenital malformations were identified at birth and through the first 12 weeks after delivery. Diagnoses were based on the mother's report and confirmed by medical records. The risks of malformations were compared between polytherapy and monotherapy groups, using exact odds ratios (ORs) and 95% confidence intervals (CIs). Results The risk of malformations was 1.9% among infants exposed to lamotrigine as monotherapy (n = 1441). Among the infants exposed to lamotrigine as polytherapy (n = 505), the risks were 9.1% for lamotrigine plus valproate sodium (OR, 5.0; 95% CI, 1.5-14.0) and 2.9% for lamotrigine plus any other AEDs (1.5; 0.7-3.0). The risk of malformations was 2.9% for the infants exposed to carbamazepine monotherapy (n = 1012). For the infants exposed to carbamazepine as polytherapy (n = 365), the risks were 15.4% for carbamazepine plus valproate (OR, 6.2; 95% CI, 2.0-16.5) and 2.5% for carbamazepine plus any other AEDs (0.8; 0.3-1.9). Confounding by factors such as periconceptional vitamin use, cigarette smoking, alcohol use, and chronic maternal diseases did not explain the results. Conclusions The risk of malformations among infants exposed to lamotrigine and carbamazepine as polytherapy was higher than the corresponding monotherapies only when the polytherapy includes valproate. These findings suggest that counseling for fetal risks from AED polytherapy should be based on the specific drugs included.

Purkinje Cell Cytoplasmic Autoantibody Type 1 Accompaniments: The Cerebellum and Beyond [Original Contribution]

Objective To investigate the full extent of Purkinje cell cytoplasmic autoantibody type 1 autoimmunity (classically associated with paraneoplastic cerebellar degeneration) from clinical, immunohistochemical, and neuropathological perspectives. Design Case series. Setting Mayo Clinics, 3 sites (Minnesota, Arizona, and Florida). Patients Of 133 138 patients tested over a 21-year period, 83 (0.06%) were identified as seropositive for Purkinje cell cytoplasmic autoantibody type 1 IgG. Main Outcome Measures The frequency of cerebellar and noncerebellar disorders and the clinical outcomes (neurological and oncological) of the patients. Results All patients were women. At initial presentation, 64 patients (77%) had a cerebellar disorder, and 19 patients (23%) had an extracerebellar disorder. Over the clinical course, neurological symptoms and signs were multifocal in 50 patients (60%), and they involved the cerebellum (89% of patients), the pyramidal tract (30%), the brainstem (13%), and the spinal anterior horn cells or peripheral nerve (10%; frequently upper limb predominant); 11% of patients did not develop cerebellar ataxia. Serological and neuropathological findings were observed in the cerebellum, the brainstem, the spinal cord, the anterior horn, and the dorsal root ganglion that paralleled the diversity of clinical signs. After a median follow-up of 18 months, 1 or more carcinomas had been detected in 88% of patients: ovarian epithelial cancer (53%), breast cancer (22%), fallopian tubal cancer (11%), primary peritoneal cancer (5%), metastases of unknown primary cancer (4%), and other cancers (4%). Sustained improvement was reported in 15% of patients following oncological or immunological therapies. Voltage-gated calcium channel antibodies coexisted in 23 patients (28%). Conclusions Purkinje cell cytoplasmic autoantibody type 1 autoimmunity most commonly affects the cerebellum, but the spectrum of neurological symptoms and presentations is broad. Neurological outcomes are usually poor, even when cancer remission is achieved.

A Controlled Study of Medial Arterial Calcification of Legs: Implications for Diabetic Polyneuropathy [Original Contribution]

Background Diabetes mellitus (DM) is associated with an increased prevalence of peripheral arterial disease and medial arterial calcification (MAC), possibly related to prevalence and severity of diabetic polyneuropathy (DPN). Objective To assess the prevalence, risk covariates, and implication of MAC in a controlled study of healthy subjects and patients with DM. Design Masked evaluation of radiographs. Setting Olmsted County, Minnesota. Patients Ambulatory volunteers with DM from the Rochester Diabetic Neuropathy Study cohort (n = 260) and matched healthy subjects from the Rochester Diabetic Neuropathy Study–Healthy Subject cohort (n = 221). Methods Patients and controls underwent standard radiographs of distal legs and feet from January 1, 1995, through December 31, 2002. The radiographs were independently read by masked, experienced radiologists for vessel calcification. Medial arterial calcification prevalence, risk covariates, correlation with peripheral arterial disease, and implication for distal, length-dependent sensorimotor polyneuropathy (DSPN) were studied. Results Of 481 study participants, MAC was found in 66 (13.7%): 55 of 260 (21.2%) in patients with DM and 11 of 221 (5.0%) in healthy subjects (P < .001). Interrater agreement of MAC was 94.1% ( coefficient of 0.7). Medial arterial calcification was significantly associated with DSPN (P < .001). In stepwise logistic regression analysis, the significant risk covariates for MAC were advancing age, male sex, DM, and stage of microvessel disease (retinopathy). Conclusions Medial arterial calcification of legs was approximately 4 times as prevalent in population-representative ambulatory persons with DM as in healthy subjects. Advancing age, male sex, DM, and retinopathy were the significant risk covariates for MAC of legs. Medial arterial calcification of legs, although significantly associated with DSPN, was not a useful surrogate marker of DSPN. Also, MAC was not shown to be a risk covariate for late worsening of DSPN, although other lines of evidence suggest that peripheral arterial disease may worsen DSPN.

Large Kindred Evaluation of Mitofusin 2 Novel Mutation, Extremes of Neurologic Presentations, and Preserved Nerve Mitochondria [Original Contribution]

Background Mitofusin 2 (MFN2) is a mitochondrial membrane protein mediating mitochondrial fusion and function. Mutated MFN2 is responsible for Charcot-Marie-Tooth type 2A2. In small kindreds, specific MFN2 mutations have been reported to associate with severity of axonal neuropathy, optic atrophy, and involvement of the central nervous system. The results of the nerve biopsy specimens suggested that the mitochondria are structurally abnormal in patients with MFN2 mutations. Objective To study a newly identified MFN2 mutation, Leu146Phe, and the associated phenotypes in a large kindred. Patients An American kindred of Northern European and Cherokee American Indian descent. Results Genetic analysis revealed a novel GTPase domain MFN2 mutation Leu146Phe that associated with clinical status of 15 studied persons (10 affected and 5 unaffected) and not found in 800 control persons. Clinical manifestations were markedly different. In 1 affected person, optic atrophy and brain magnetic resonance imaging abnormalities led to multiple sclerosis diagnosis and interferon β-1a treatment when neuropathy was initially unrecognized. Age of onset ranged from 1 to 45 years. In some affected family members, severe and rapid-onset motor sensory neuropathy led to early loss of ambulation, whereas other family members experienced minimal neuropathic sensory symptoms. Despite histologically significant loss of nerve fibers, the mitochondria were not distinguishable from diseased sural nerve biopsy specimens and healthy controls. Conclusions Novel MFN2 mutation Leu146Phe causes Charcot-Marie-Tooth type 2A2. Intrafamilial clinical phenotype variability is emphasized and has important implications in genetic counseling. The clinical phenotype may mimic multiple sclerosis when optic atrophy and the characteristic brain lesions of MFN2 on magnetic resonance imaging are present and neuropathy is mild or unrecognized. The predicted molecular pathogenesis may occur without evident histological abnormalities of mitochondria in nerve.

Continuous Epileptiform Discharges in Patients Treated With Cefepime or Meropenem [Original Contribution]

Objective To test the hypothesis that treatment with cefepime hydrochloride leads to higher incidence of periodic epileptiform discharges compared with treatment with other β-lactams. Design Data from hospital pharmacy databases of patients treated with cefepime or meropenem during a 42-month period (from January 1, 2007, through June 30, 2010) were retrospectively crossed with data from the electroencephalography database for the same period. Setting Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium. Patients Patients who underwent electroencephalographic testing while taking cefepime or meropenem were selected. Only electroencephalographic tests performed during the antibiotic treatment period were considered. Matches were compared with nurses' medication records to ensure that the antibiotic considered was effectively given. Main Outcome Measure Proportions of patients with continuous epileptiform discharges in the 2 groups were compared using the Fisher exact test. Results A total of 1120 patients were treated with cefepime and 1572 patients with meropenem. Electroencephalographic testing was performed during treatment in 59 patients treated with cefepime and 80 treated with meropenem (5.26% vs 5.08%, P = .85). Continuous epileptiform discharges were present in 14 patients in the cefepime group and 3 in the meropenem group (1.25% vs 0.19%, P < .001). Blood creatinine concentration was elevated in 5 of the 17 patients (range, 1.5-4.2 mg/dL; reference range, 0.7-1.2 mg/dL), and liver enzyme levels were elevated in 5 patients. No patient had major electrolyte disturbances. Conclusions Our study showed a prevalence of electroencephalographic test results with continuous epileptiform discharges in 14 of 1120 patients receiving cefepime (1.25%) but only 3 of 1572 patients receiving meropenem (0.19%). Contrary to the results of previous case series, these electroencephalographic patterns occurred, in most cases, in patients with normal renal function. These results suggest that cefepime may be an independent risk factor for periodic epileptiform discharges, which are associated with worse outcomes. This finding could provide a partial explanation for the higher mortality rates reported in patients treated with cefepime compared with other β-lactams.

Serum N -acetylaspartate Level in Amyotrophic Lateral Sclerosis [Original Contribution]

Background N -acetylaspartate (NAA) level is a biomarker of functional integrity and vitality in neurons. In vivo multisection proton (1H)–magnetic resonance spectroscopy studies indicate that NAA level decreases in specific cortical brain areas of patients with amyotrophic lateral sclerosis (ALS). Objective To study NAA level in serum samples as a possible biomarker of ALS. Design Serum NAA assay by liquid chromatography–mass spectrometry in a case-control series. Setting Department of Neurological and Psychiatric Sciences, Policlinico, University of Bari, Bari, Italy. Patients One hundred twelve consecutive patients with ALS and 51 age- and sex-matched healthy control subjects. Main Outcome Measures General estimating equations tested associations between serum NAA level and clinical variables in patients with ALS. Results Serum NAA level was significantly higher in ALS cases than in controls. Multivariate logistic regression analysis showed a direct association between serum NAA level and the presence of ALS. After stratifying serum NAA level based on the median value (0.171 mmol/L), the age- and sex-adjusted odds ratio for ALS was 19.97 (95% confidence interval, 7.18-55.55) (P < .001). N -acetylaspartate level did not differ across ALS clinical phenotypes. Riluzole treatment did not affect NAA level. A significant correlation was found between serum NAA level and ALS progression rate. Conclusions High serum NAA level was found in patients with ALS, which may relate to greater excretion of NAA into the blood circulation following increased release of this metabolite from damaged neurons. The correlation between serum NAA level and disease progression rate suggests that it may be a useful biomarker of ALS.

Role of Family History for Alzheimer Biomarker Abnormalities in the Adult Children Study [Original Contribution]

Objective To assess whether family history (FH) of Alzheimer disease (AD) alone influences AD biomarker abnormalities. Design Adult Children Study. Setting Washington University's Charles F. and Joanne Knight Alzheimer's Disease Research Center. Participants A total of 269 cognitively normal middle- to older-aged individuals with and without an FH for AD. Main Outcome Measures Clinical and cognitive measures, magnetic resonance imaging–based brain volumes, diffusion tensor imaging–based white matter microstructure, cerebrospinal fluid biomarkers, and molecular imaging of cerebral fibrillar amyloid with positron emission tomography using the [11C] benzothiazole tracer, Pittsburgh compound B. Results A positive FH for AD was associated with an age-related decrease of cerebrospinal fluid Aβ42; the 4 allele of apolipoprotein E (APOE4) did not alter this effect. Age-adjusted cerebrospinal fluid Aβ42 was decreased for individuals with APOE4 compared with the level for those without, and the decrease was larger for individuals with a positive FH compared with the decrease for those without. The variation of cerebrospinal fluid tau and Pittsburgh compound B mean cortical binding potential increased by age. For individuals younger than 55, an age-related increase in mean cortical binding potential was associated with APOE4 but not FH. For individuals older than 55, a positive FH and a positive APOE4 implied the fastest age-related increase in mean cortical binding potential. A positive FH was associated with decreased fractional anisotropy from diffusion tensor imaging in the genu and splenium of the corpus callosum. Conclusion Independent of APOE4, FH is associated with age-related change of several cerebrospinal fluid, Pittsburgh compound B, and diffusion tensor imaging biomarkers in cognitively normal middle- to older-aged individuals, suggesting that non- APOE susceptibility genes for AD influence AD biomarkers.

Failure to Take Antiepileptic Drugs as Prescribed: A Socioeconomic Issue After All [From JAMA]

Status Epilepticus-Induced Hyperemia and Brain Tissue Hypoxia After Cardiac Arrest [Observation]

Objective To report changes of cerebral blood flow and metabolism associated with status epilepticus after cardiac arrest. Design Case report. Setting Neurological intensive care unit in a university hospital. Patient An 85-year-old man resuscitated from out-of-hospital cardiac arrest underwent brain multimodality monitoring and treatment with therapeutic hypothermia. Main Outcome Measures Changes of cerebral blood flow and metabolism. Results Repetitive electrographic seizure activity detected at the start of monitoring was associated with dramatic reductions in brain tissue oxygen tension and striking surges in cerebral blood flow and brain temperature. Intravenous lorazepam and levetiracetam administration resulted in immediate cessation of the seizures and these associated derangements. The lactate to pyruvate ratio was initially elevated and trended down after administration of anticonvulsants. Conclusion Brain multimodality monitoring is a feasible method for evaluating secondary brain injury associated with seizure activity after cardiac arrest.

Postvaccination Miller Fisher Syndrome [Observation]

Background Although postvaccination Guillain-Barré syndrome is commonly reported, there have only been 2 previously reported cases of postvaccination Miller Fisher syndrome, and none in association with the novel influenza A(H1N1) vaccine. Objective To describe a case of Miller Fisher syndrome following receipt of the seasonal influenza and novel influenza A(H1N1) vaccine. Design Case report and literature review. Setting Vancouver General Hospital. Patient A 77-year-old Chinese woman. Results The patient presented with ophthalmoplegia, ataxia, areflexia, and a sensory neuropathy within 2 weeks of immunization. Findings of parainfectious evaluation were unremarkable. Treatment with 2 courses of intravenous immunoglobulin led to clinical improvement. Her presentation and natural history of disease were similar to the 2 previously published cases. Conclusions We present the third case of postvaccination Miller Fisher syndrome in the literature and the first associated with the novel influenza A(H1N1) vaccine.

Chorea-Acanthocytosis Genotype in the Original Critchley Kentucky Neuroacanthocytosis Kindred [Observation]

Objective To determine the molecular nature of the neurological disease in the seminal family reported by Critchley et al in the 1960s, characterized by a hyperkinetic movement disorder and the appearance of acanthocytosis on peripheral blood smear. The eponym Levine-Critchley syndrome, subsequently termed neuroacanthocytosis, has been applied to symptomatically similar, but genetically distinct, disorders, resulting in clinical and diagnostic confusion. Design DNA analysis. Setting Molecular biology research laboratories. Participants First- and second-degree relatives of the original Critchley et al proband from Kentucky. Main Outcome Measures Mutations in the VPS13A gene. Results A mutation was identified in the VPS13A gene, responsible for autosomal recessive chorea-acanthocytosis. Haplotype reconstruction suggested that this mutation was homozygous in the proband. Conclusion These findings strongly support the diagnosis of chorea-acanthocytosis as the disorder described in the original report.

Idiopathic Superficial Siderosis [Images in Neurology]

Addition of Magnetic Resonance Imaging to Computed Tomography and Sensitivity to Blood in Pituitary Apoplexy [Images in Neurology]

Brain Fludeoxyglucose F 18 Positron Emission Tomography Hypometabolism in Magnetic Resonance Imaging-Negative X-Linked Adrenoleukodystrophy [Images in Neurology]

Postoperative Varicella-Zoster Virus Myelopathy and Dissemination [Images in Neurology]

Neurologic Emergencies, 3rd ed [Book Reviews]

Electrophysiologic Recording Techniques [Book Reviews]

Microbleeds and Lacunar Infarcts in the Rotterdam Scan Study [Correspondence]

Microbleeds and Lacunar Infarcts in the Rotterdam Scan Study--Reply [Correspondence]

Patient With Unilateral White Matter Involvement Does Not Have Krabbe Disease [Correspondence]

Neurology jobs

All Neurology jobs for Tue Jan 31 2012

Neurology jobs in "Neurologist needed in KY. Choose partnership, employed or solo practice!" - KY

Job 921826 Exceptional opportunity for a Neurologist to choose the practice you prefer. Join a group with quick partnership, become a hospital employee or start a solo practice with hospital assistance.

Neurology jobs in "Neurologist needed with opportunity for Sleep Medicine MD in NE Louisiana" - LA

Job 94198 BC/BE Neurologist needed to replace leaving physician. This is a hospital-employed position, but willing to discuss hospital-sponsored option if desired. There is a Sleep Lab available and

Neurology jobs in "Busy" - KY

Job 92859 Great practice opportunity in High Tech Hospital B/E or B/C Neurology Join excellent department bursting with patients Shared call 1:4 with Academic affiliation 11 Primary Care hospitalists

Neurology jobs in "Excellent practice opportunity for a Neurology physician in North Dakota" - ND

Job 918780 Prestigious Multi specialty group is seeking a Neurology Doctor Modern facility with the latest in diagnostics equipment , tests, and services Academic Hub Strong support staff Excellent location

Neurology jobs in "Neurology opportunity in Southern Utah with a sleep component available" - UT

Job 94108 MSG seeking aggresive Neurologist to keep up with demand in Southern Utah Waiting patient base Very nice and modern facility Close to Las Vegas Excellent family community Competitive wages

Neurology jobs in "Gen. Neurologist job excellent compensation with hospital in Oklahoma," - OK

Job 918408 Group adding to Neurology physician services, General Neurology joining 2 others on staff now - EMG, EEG. Will employ with a very strong compensation and complete benefit package. Full service

Neurology jobs in "General Neurologist and choose between employed or a private practice" - WA

Job 922017 Practice near Seattle! A very busy practice seeks a general neurologist with two employment options. You can join a private practice or be employed by the hospital. Either way, there is a

Neurology jobs in "Southern Alabama is seeking a Neurologist for a ready made practice" - AL

Job 921297 Ready made Neurology practice awaits in Alabama Be a solo physician or choose to be employed by the hospital Sleep component available 6 week waiting list to see a neurologist Very nice income

Neurology jobs in "Immediate Need for General Neurologist in a Thriving Alabama City!" - AL

Job 921618 Immediate need for additional Neurologist due to strong community need. Walk into a waiting patient base and be busy immediately. This hospital has an excellent reputation, a reasonable call

Neurology jobs in "Hardworking Neurologist needed for a growing group close to Boston" - MA

Job 94299 Neurology in Massachusetts B/C or B/E Neurology Shared call 1:4 Multi-specialty Group Boston suburb Join 3 established Neurologists Academic affiliation possible Partnership track Malpractice

Neurology jobs in "Exceptional Neurology Opportunity with Excellent Quality of Life!" - MI

Job 921736 Excellent employed opportunity that offers great compensation AND an exceptional quality of life! Call 1:4, with hospitalist program in place. Huge community need, waiting patient base and

Neurology jobs in "Neurologist needed with opportunity for Sleep Medicine MD in Utah" - UT

Job 94203 BC/BE Neurologist needed to join 2 other Neurologists. Eventual plans are to hire 2 Neurologists, for a total of four. This is a hospital-employed position, but willing to discuss hospital-sponsored

Neurology jobs in "Neurologist needed with opportunity for Sleep Medicine MD in Utah" - UT

Job 94204 BC/BE Neurologist needed to join 2 other Neurologists. Eventual plans are to hire 2 Neurologists, for a total of four. This is a hospital-employed position, but willing to discuss hospital-sponsored

Neurology jobs in "Neurologist needed with opportunity for Sleep Medicine MD in Utah" - UT

Job 94205 BC/BE Neurologist needed to join 1 other Neurologist. Eventual plans are to hire 2 Neurologists, for a total of three. This is a hospital-employed position, but willing to discuss hospital-sponsored

Neurology jobs in "General Neurologist wanted for a four day work week in Wisconsin" - WI

Job 921447 Board Certified or Board Eligible Neurologist wanted to join existing Neurologist. Enjoy a great lifestyle in this outpatient practice with a four day work week. Wisconsin has a very favorable

Neurology jobs in "Solo Neurology opportunity - J1 or H1 Visa sponsorship in Maine" - ME

Job 94206 Join premier Multi-Specialty group as a Solo Neurologist. BC/BE Neurologist Will support J1/H1B Visas Employed opportunity Great place to live and practice Neurology Enjoy all four seasons

Neurology jobs in "Neurology opportunity close to Lexington, KY and Cincinnati, OH" - KY

Job 94154 Your choice of practice models in a growing Kentucky community Be employed or go solo Nice family area Overwhelming demands will keep you busy from day one Competitive MGMA wages Full benefits

Neurology jobs in "Pacific" - WA

Job 919493 Bread and Butter Neurology opportunity in Washington Excellent location and a nice place to raise a family Modern facility Build the practice your way Very close to Seattle Very attractive

Neurology jobs in "Neurology for solo or Employed opportunity in Southern Alabama" - AL

Job 94126 Neurology for solo or Employed opportunity in Southern Alabama Busy, waiting patient base Your choice of practice models Call schedule is 10 days a week Competitive wages/income guarantee Attractive

Neurology jobs in "Neurologist needed for an outstanding opportunity in Oregon" - OR

Job 94394 Live and practice in one of the most beautiful areas in Oregon Share excellent call of 1:4 with huge referrals Practice general Neurology with easy lifestyle Admit at only one local nearby

Neurology jobs in "Employed Neurology opportunity in Kentucky, close to OH, WV" - KY

Job 94262 Employed Neurology opportunity in Kentucky, close to OH, WV Large stable group Favorable call schedule Excellent family friendly community Competitive wages Full benefits Incentive and bonus

Neurology jobs in "Hospital sponsored Search for Neurology in Southern Georgia" - GA

Job 918042 BC Neurologist needed to perform EMG's and interpret EMG, EEG and ENG's Hospital sponsored Search Call schedule of 1:3 Sleep study interest welcomed and pain management is an option Driving

Neurology jobs in "Neurology opportunity with waiting patient base in Indiana" - IN

Job 92371 Neurology opportunity with partnership Replace a physician who just relocated Hospital sponsored search Waiting patient base Low cost of living Excellent school systems Family Friendly location

Neurology jobs in "Exciting Neurology practice opportunity in the Southeast!" - SC

Job 921597 Hospital employed opportunity with easy access to Atlantic Ocean Board Certified or Board Eligible Neurology General Neurology or Subspecialty - Fellowships including Stroke welcome , not

Neurology jobs in "Memphis" - TN

Job 94344 Employed Neurology opportunity near Memphis and Nashville Growing group needs another neurologist Very attractive call schedule No state income tax in TN and there is a low cost of living There

Neurology jobs in "General Neurology with emphasis on stroke in Metro Idaho" - ID

Job 94608 General Neurology with emphasis on stroke in Metro Idaho. Possible academic affiliation. Medical Directorship possible. Employed opportunity Employed position, hospital based 1:4 call schedule

Neurology jobs in "Excellent Neurology Earnings Position in East Texas Town" - TX

Job 922008 Join a new startup group in East Texas! High Earning Potential! This position will be joining a hospital employed group in a safe, low cost of living area. Manageable work schedule without

Neurology jobs in "Single Specialty Neurology Group is Growing in Illinois" - IL

Job 921971 Partnership track in the Midwest B/E or B/C in Neurology Join three Neurologists for manageable call of 1:4/1:5 Quality of life in the friendly Midwest Easy access to Chicago College town

Neurology jobs in "Beautiful NW Washington State Metro Needs a Neurologist" - WA

Job 921815 Exceptional Coastal Washington location, with lush green rolling mountains and all the outdoor attractions you could enjoy. Short drive to Seattle or Vancouver, Canada. Hurry, this position

Neurology jobs in "General Neurologists needed due to great demand in area" - PA

Job 917775 General Neurology Opportunity in Eastern Pennsylvania - will be hospital employee or join a group. Work within 700+ bed facility. Level 1 trauma center with 28 bed emergency care - 10 bed

Neurology jobs in "Wonderful General Neurology position in New York State" - NY

Job 921587 Immediate opening for a Neurologist in a truly unique set up. Waiting patient base for the incoming physician with terrific starting salary and production bonuses. Enjoy light call at 1:3.

Neurology jobs in "Tampa" - FL

Job 94257 Practice Neurology on Florida's Gulf Coast Join the most stable Multi Specialty Group in the area Easy Call schedule Partnership in two years. Also eligible for a real estate buy in as well

Neurology jobs in "Employed Neurology opportunity in Metro North Dakota" - ND

Job 94400 Employed Neurology opportunity in Metro North Dakota Waiting Patient base Excellent call schedule of 1:5 Rehab expertise welcomed Visa Candidates are welcomed Call Tom Kennedy at 801-930-3383

Neurology jobs in "Neurology Partnership, NJ, close to Philadelphia, PA" - NJ

Job 92837 Step into ready made 26 year old Multi Specialty practice of Neurologists with excellent compensation in New Jersey close to Philadelphia. There is an income guarantee and partnership agreement

Neurology jobs in "100% Inpatient Neurology Opportunity in Metro Texas!" - TX

Job 92662 100% Inpatient Neurologist needed in Metro Texas. Highly sought after location, traditional Monday through Friday schedule. Call shared with partners for 1:3 or 1:4 schedule. Employed position

Neurology jobs in "100% Inpatient Neurology Opportunity in Metro Texas!" - TX

Job 92546 100% Inpatient Neurologist needed in Metro Texas. Highly sought after location, traditional Monday through Friday schedule. Call shared with partners for 1:3 or 1:4 schedule. Employed position

Neurology jobs in "Warm weather year round and Award winning hospital" - TX

Job 92718 Be part of a winning team in Texas B/C or B/E Neurology for Texas Fellowship trained or general neurologists Shared call of 1:4 State of the art facilities with certified stroke center Admit

Neurology jobs in "Wonderful Neurology position awaits in metro Ohio" - OH

Job 921824 Private practice is busy and looking to expand services B/E or B/C Neurologist needed Metro location in Ohio Covering only one hospital Largely outpatient need Employed position with great

Neurology jobs in "Great Neurology opportunity in beautiful Kentucky" - KY

Job 94465 Join other Neurologists in this excellent location with fantastic office setting There is a very attractive and generous sign on bonus Excellent patient base awaits incoming Physician Group

Neurology jobs in "Join a Highly Reputable Organization in Wisconsin" - WI

Job 921209 Share a terrific call of 1:5 or better with other specialists in this great practice Bring your skills and join this highly reputable organization in Wisconsin Have fun practicing Neurology

Neurology jobs in "Single Specialty Practice is adding a Neurologist" - NV

Job 92522 Outpatient practice in Metro area B/C or B/E Neurology General Neurology Growing Single Specialty Group Shared call for quality of life 100% outpatient EMG proficiency preferred Brand new Sleep

Neurology jobs in New York

All Neurology jobs in New York for Tue Jan 31 2012

Neurology jobs in "Practice Neurology in outdoor recreation heaven" - AR

Job 921398 Join one other Neurologist in this hospital based opportunity. The hospital is a level 3 trauma center and serves as the main hub to a service area of 275k. Visa candidates are welcome.

Neurology jobs in "Beautiful area of Arizona seeking a Neurologist" - AZ

Job 9110228 Traditional practice with hospital support in Southwest- EEG- EMG Full hospital support for solo start up General Neurology with any sub specialty interest welcome (except sleep medicine)

Neurology jobs in "Excellent Neurology opportunity in Pennsylvania" - PA

Job 917987 Join this highly respected and well known group in the Keystone State of Pennsylvania Because of the wealth of this group, you will receive wonderful competitive base income Huge earning

Neurology jobs in "Neurologist Needed in WV -Exceptional Position" - WV

Job 921966 Hospital is seeking a Neurologist to replace one who is leaving the community. Existing patient base with extensive referral network. The incoming Neurologist can be an employee of the hospital

Neurology jobs in "Outstanding Neurology job awaits you in Nevada" - NV

Job 918964 Be part of an organization with huge rewards for a great Neurologist Receive wonderfully competitive base salary or income guarantee Control what you make as earning potential is huge and

Neurology jobs in "Neurology opportunity in a large Arizona City" - AZ

Job 9110001 Neurologist needed for a well established Group in Arizona Well established Single specialty Group continues to grow and needs your services Excellent location with easy access to a major

Neurology jobs in "Neurointensivist needed 2 hours from Chicago" - IL

Job 921104 Neurointensivist program Be the first neurointensivist in community Great support staff Potentially lead to a lead Medical Director role Will be starting program in the summer of 2011 Fellows

Neurology jobs in "Excellent Neurology opportunity in Tennessee" - TN

Job 92681 Join this great organization with huge patient base There is an amazing base competitive base income Very lavished bonuses and incentives Incredible earning potential Huge referral base from

Neurology jobs in "Excellent Neurology opportunity in Wisconsin" - WI

Job 9110441 A highly respected organization in Wisconsin is looking for a Neulrologist Enjoy a fun working environment with great referral base There is a huge income potential with incentives Area

Neurology jobs in "Midwest Neurology opportunity with 1:5 call" - MI

Job 921907 Join a winning team in great Midwest town B/C or B/E Neurology Join a Neurology team of 4, who is adding a 5th due to growth Shared call of 1:6 and quality of life Can do some sleep medicine

Neurology jobs in "Neurologist to join four others in Missouri" - MO

Job 94370 Neurologist to become a Partner from day one of your employment Receive a greatly competitive base salary with this group Fantastic Call schedule of 1 in 4 or better There is NO buy in to this