Journals 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]