Showing papers in "JAMA Neurology in 2000"

Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors.

Abstract: Context Increasing evidence suggests that cholesterol plays a role in the pathophysiology of Alzheimer disease (AD). For instance, an elevated serum cholesterol level has been shown to be a risk factor for AD. Objective To determine whether patients taking 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), which are a group of medicines that inhibit the synthesis of cholesterol, have a lower prevalence of probable AD. Design The experiment uses a cross-sectional analysis comparing the prevalence of probable AD in 3 groups of patients from hospital records: the entire population, patients receiving 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (hereafter referred to as the statins), and patients receiving medications used to treat hypertension or cardiovascular disease. Patients The subjects studied were those included in the computer databases of 3 different hospitals for the years October 1, 1996, through August 31, 1998. Main Outcome Measures Diagnosis of probable AD. Results We find that the prevalence of probable AD in the cohort taking statins during the study interval is 60% to 73% ( P Conclusions There is a lower prevalence of diagnosed probable AD in patients taking 2 different 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors—lovastatin and pravastatin. While one cannot infer causative mechanisms based on these data, this study reveals an interesting association in the data, which warrants further study.

Seizures after stroke: a prospective multicenter study.

Abstract: Background Studies of seizures after stroke have largely been retrospective, with small patient numbers and limited statistical analysis. Much of the doctrine about seizures after stroke is not evidenced based. Objective To determine the incidence, outcome, and risk factors for seizures after stroke. Design International, multicenter, prospective, analytic inception cohort study conducted for 34 months. Patients and Setting There were 2021 consecutive patients with acute stroke admitted to university teaching hospitals with established stroke units. After exclusion of 124 patients with previous epilepsy or without computed tomographic diagnosis, 1897 were available for analysis. Mean follow-up was 9 months. Main Outcome Measures Occurrence of 1 or more seizures after stroke, stroke disability, and death after stroke. Results Seizures occurred in 168 (8.9%) of 1897 patients with stroke (28 [10.6%] of 265 with hemorrhagic and 140 [8.6%] of 1632 with ischemic stroke). On Kaplan-Meier survival analysis, patients with hemorrhagic stroke were at significantly greater risk of seizures ( P = .002), with an almost 2-fold increase in risk of seizure after stroke (hazard ratio [HR], 1.85; 95% confidence interval [CI], 1.26-2.73; P = .002). On multivariate analysis, risk factors for seizures after ischemic stroke were cortical location of infarction (HR, 2.09; 95% CI, 1.19-3.68; P P P P Conclusions Seizures occur more commonly with hemorrhagic stroke than with ischemic stroke. Only a small minority later develop epilepsy. Patients with a disabling cortical infarct or a cortical hemorrhage are more likely to have seizures after stroke; those with late-onset seizures are at greater risk of epilepsy.

The Preclinical Phase of Alzheimer Disease: A 22-Year Prospective Study of the Framingham Cohort

Abstract: Objectives To relate performance on tests of cognitive ability to the subsequent development of probable Alzheimer disease (pAD) and to identify the pattern of earliest changes in cognitive functioning associated with a diagnosis of pAD. Design From May 1975 to November 1979, a screening neuropsychological battery was administered to Framingham Study participants. They were followed up prospectively for 22 years and examined at least every 2 years for the development of pAD. Setting A community-based center for epidemiological research. Participants Subjects were 1076 participants of the Framingham Study aged 65 to 94 years who were free of dementia and stroke at baseline (initial) neuropsychological testing. Main Outcome Measure Presence or absence of pAD during a 22-year surveillance period was related to test performance at initial neuropsychological testing. Results Lower scores for measures of new learning, recall, retention, and abstract reasoning obtained during a dementia-free period were associated with the development of pAD. Lower scores for measures of abstract reasoning and retention predicted pAD after a dementia-free period of 10 years. Conclusions The "preclinical phase" of detectable lowering of cognitive functioning precedes the appearance of pAD by many years. Measures of retention of information and abstract reasoning are among the strongest predictors of pAD when the interval between initial assessment and the development of pAD is long.

Plasma and cerebrospinal fluid Levels of amyloid β proteins 1-40 and 1-42 in Alzheimer disease

Abstract: Background In brains with AD, Aβ is a major component of diffuse plaques Previous reports showed that CSF Aβ42 levels were lower in patients with AD than in controls Although studies showed higher plasma Aβ42 levels in familial AD, a recent report has indicated that plasma Aβ42 levels were similar in a sporadic AD group and controls However, no information is published on plasma Aβ40 and Aβ42 levels in relation to Apo E genotype or severity of dementia in sporadic AD Objective To examine plasma and cerebrospinal fluid (CSF) levels of amyloid β protein 1-40 (Aβ40) and 1-42 (Aβ42) levels in patients with probable Alzheimer disease (AD) and elderly nondemented control subjects in relation to the apolipoprotein E (Apo E) genotype and dementia severity Setting Two university medical centers Patients and Methods Levels of Aβ40 and Aβ42 were measured in plasma from 78 patients with AD and 61 controls and in CSF from 36 patients with AD and 29 controls by means of a sandwich enzyme-linked immunosorbent assay Results Mean plasma Aβ40 levels were higher in the AD group than in controls ( P = 005), but there was substantial overlap; Aβ42 levels were similar between the groups Levels of Aβ40 and Aβ42 showed no association with sex or Mini-Mental State Examination scores There was a significant relationship between age and Aβ40 level in controls but not in the AD group Levels of Aβ40 were higher in patients with AD with the Apo E ϵ4 allele than in controls ( P P Conclusions Although mean plasma Aβ40 levels are elevated in sporadic AD and influenced by Apo E genotype, measurement of plasma Aβ40 levels is not useful to support the clinical diagnosis of AD Lower levels of CSF Aβ42 in the AD group are consistent with previous studies

Region-specific neurotrophin imbalances in Alzheimer disease: decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas.

Abstract: Background Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4/5 (NT-4/5) are members of the neurotrophin gene family that support the survival of specific neuronal populations, including those that are affected by neurodegeneration in Alzheimer disease (AD). Objective To determine whether neurotrophin protein levels are altered in the AD-affected brain compared with control brains. Methods We quantitated protein levels of NGF, BDNF, NT-3, and NT-4/5, and calculated neurotrophin/NT-3 ratios in AD-affected postmortem hippocampus, frontal and parietal cortex, and cerebellum, and compared them with age-matched control tissue (patients with AD/controls: hippocampus, 9/9 cases; frontal cortex, 19/9; parietal cortex, 8/5; and cerebellum, 5/7, respectively). We applied highly sensitive and specific enzyme-linked immunosorbent assays in rapid-autopsy–derived brain tissue (mean±SD postmortem interval, 2.57±1.75 h, n=71) to minimize postmortem proteolytic activity. Results Levels of BDNF were significantly reduced in hippocampus and parietal cortex ( P P P P P P Conclusion Decreased levels of BDNF may constitute a lack of trophic support and, thus, may contribute to the degeneration of specific neuronal populations in the AD-affected brain, including the basal forebrain cholinergic system.

The global burden of disease study: implications for neurology.

Abstract: Because of the epidemiological transition, the global burden of illness has changed. Several factors have contributed to this change, including improvements in maternal and child health, increasing age of populations, and newly recognized disorders of the nervous system. It is now evident that neurologic disorders have emerged as priority health problems worldwide. This is reflected in the Global Burden of Disease Study, jointly published by the World Health Organization and other groups. The proportionate share of the total global burden of disease resulting from neuropsychiatric disorders is projected to rise to 14.7% by 2020. Although neurologic and psychiatric disorders comprise only 1.4% of all deaths, they account for a remarkable 28% of all years of life lived with a disability. This study provides compelling evidence that one cannot assess the neurologic health status of a population by examining mortality statistics alone. Health ministries worldwide must prioritize neurologic disorders, and neurologists must be prepared to provide care for increased numbers of people individually and in population groups.

Using serial registered brain magnetic resonance imaging to measure disease progression in Alzheimer disease - Power calculations and estimates of sample size to detect treatment effects

Abstract: Objective To evaluate the rate of brain atrophy calculated from serial magnetic resonance imaging (MRI) registration as a surrogate marker of disease progression for use in clinical trials in Alzheimer disease (AD). Methods Eighteen patients with mild to moderate AD and 18 age-matched normal controls underwent 2 MRI brain scans separated by a 12-month interval. Each individual's later scan was registered to their first scan, and the volume of cerebral tissue loss calculated directly from the registered and subtracted MRI scan pairs. The mean and SD of the rate of brain volume changes were used to estimate the sample sizes that would be needed in a clinical trial with a drug anticipated to modify disease progression by varying degrees. Comparable sample size estimates were performed with data for other methods of monitoring rates of brain atrophy, extracted from published papers. Results The mean (SD) rate of brain atrophy for the patients with AD was 2.37% (1.11%) per year, while in the control group it was 0.41% (0.47%) per year. Based on these figures, to have 90% power to detect a drug effect equivalent to a 20% reduction in the rate of atrophy, 207 patients would be needed in each treatment arm. This assumes a 1-year placebo-controlled trial with a 10% patient dropout rate, and that 10% of scan pairs are unusable. Conclusion Registration of serial MRI volume images provides a powerful method of quantification of brain atrophy that can be used to monitor progression of AD in clinical trials.

Predicting Conversion to Alzheimer Disease Using Standardized Clinical Information

Abstract: Objective To identify aspects of a standardized clinical assessment that can predict which individuals within the category of "questionable" Alzheimer disease (AD) have a high likelihood of converting to AD over time. Design Detailed semistructured interviews were performed at baseline and annually for 3 years. Setting University-based gerontology research program. Patients The patient population consisted of 165 individuals 65 years and older: 42 of the participants had a Clinical Dementia Rating (CDR) of normal cognition (CDR rating, 0.0) and 123 had a rating of questionable AD (CDR rating, 0.5). After 3 years of follow-up, 23 of the 123 subjects with questionable AD were diagnosed with probable AD. Main Outcome Measures The interview was used to generate a summary measure based on the sum of 6 CDR categories, known as the Total Box Score. The responses to 32 selected questions from the interview also were examined. Results Likelihood of progression to AD during the follow-up period was strongly related to the Total Box Score. For example, more than 50% of individuals with a Total Box Score of 2.0 or higher at baseline developed AD during the follow-up interval, whereas about 10% of individuals with a Total Box Score of 1.0 or lower developed AD during this same period. Selected questions from the standardized clinical interview also were highly predictive of subsequent conversion to AD among the study population. Eight selected questions from the clinical interview at baseline, combined with the CDR Total Box Score, identified 88.6% of such individuals accurately (questionable group, 82/91; converter group, 19/23). Conclusions A standardized clinical assessment can be used to identify the subgroup of individuals within the category of questionable AD who have a high likelihood of converting to AD over time. Subjects who met the criteria for questionable AD had a variety of trajectories during a 3-year follow-up, suggesting that diverse factors may influence the functional changes observed in this population.

The course of cognitive impairment in preclinical Alzheimer disease: three- and 6-year follow-up of a population-based sample.

Abstract: Objectives To examine the ability of the total score and individual items from the Mini-Mental State Examination in predicting the development of Alzheimer disease (AD) across a 3- and 6-year period in a population-based sample, and to describe the longitudinal changes in these measures across the same follow-up periods. Design Prospective follow-up of a community-based cohort, with 3 times of testing across a 6-year period. At each time of measurement, participants were clinically examined by physicians to identify demented and nondemented participants according to Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition , criteria. Participants The study population consisted of all participants who were nondemented at the first follow-up and participated in the second follow-up examination. Among those, 459 remained nondemented and 73 developed AD during the second follow-up period. Results Baseline differences in the total Mini-Mental State Examination score and the delayed memory item were seen 6 years before eventual dementia diagnosis ( P P >.10). However, the incident AD group exhibited precipitous declines in 8 of the 10 subscales between time 2 and time 3, the point at which they were clinically diagnosed ( P P Conclusions The diagnosis of AD is preceded by a long preclinical phase in which deficits in memory performance are most common. These deficits remain relatively stable up until the time that a dementia diagnosis can be rendered.

Clinical features of amyotrophic lateral sclerosis according to the El Escorial and Airlie House diagnostic criteria: A population-based study.

Abstract: Background The El Escorial and the revised Airlie House diagnostic criteria for amyotrophic lateral sclerosis (ALS) classify patients into categories reflecting different levels of diagnostic certainty. We conducted a prospective, population-based study of the natural course of ALS in the Republic of Ireland during a 6-year period to examine the utility of these ALS diagnostic criteria. Methods Using data from the Irish ALS Register, we studied the clinical features of all patients diagnosed as having ALS in Ireland throughout their illness. Results Between 1993 and 1998, 388 patients were diagnosed as having ALS. Forty percent of patients reported bulbar-onset symptoms. Disease progression occurred over time: at last follow-up, 75% of all patients had bulbar signs, compared with 59% at diagnosis. When the El Escorial criteria were applied, more than half of patients (218 [56%]) had definite or probable ALS at diagnosis. Of the 165 possible and suspected ALS cases at diagnosis (trial ineligible), 110 (67%) were trial eligible at last follow-up. Of the 254 patients who had died, 229 (90%) had definite or probable ALS, whereas 25 patients (10%) remained trial ineligible at death. El Escorial category at diagnosis was not a significant prognostic indicator. Use of the Airlie House criteria had no effect on the median time from symptom onset to trial eligibility (12.9 vs 12.8 months). Conclusions The El Escorial and Airlie House diagnostic criteria are excessively restrictive. Furthermore, levels of diagnostic certainty cannot be used as prognostic indicators.

Cognitive impairment and the brain dopaminergic system in Parkinson disease: [18F]fluorodopa positron emission tomographic study.

Abstract: Objective To investigate the role of the brain dopaminergic system in cognitive impairment in patients with Parkinson disease (PD). Design We studied 28 patients with PD and 16 age-matched healthy control subjects using [ 18 F]fluorodopa (fluorodopa F 18) positron emission tomography. Patients with PD showed a variable degree of cognitive impairment, which was assessed using the Mini-Mental State Examination and detailed neuropsychologic assessment, including tests sensitive for frontal lobe function. Results [ 18 F]Fluorodopa uptake was reduced in the putamen (to 36% of the control mean; P P P 18 F]fluorodopa uptake values. The influx constant ( K i occ ) in the caudate nucleus had a negative association with performance in the attention-demanding Stroop interference task, especially with the interference time. The K i occ in the frontal cortex had a positive correlation with performance in the digit span (backwards), verbal fluency, and verbal immediate recall tests. Thus, the better the patient performed in tasks demanding immediate and working memory and executive strategies, the better the [ 18 F]fluorodopa uptake in the frontal cortex. In the putamen, no significant correlation was seen between the K i occ value and any of the cognitive tests. The severity of the motor symptoms of PD and [ 18 F]fluorodopa uptake showed a negative correlation in the putamen ( r = −0.38; P = .04), and in the caudate nucleus a similar trend was seen ( r = −0.36; P = .06). Conclusions Reduced [ 18 F]fluorodopa uptake in PD in the caudate nucleus (and frontal cortex) is related to impairment in neuropsychologic tests measuring verbal fluency, working memory, and attentional functioning reflecting frontal lobe function. This indicates that dysfunction of the dopamine system has an impact on the cognitive impairment of patients with PD. However, our results do not exclude the possibility of more generalized cognitive impairment in PD, the pathophysiology of which is probably different and more generalized.

Apolipoprotein E polymorphism and Alzheimer disease: The Indo-US Cross-National Dementia Study.

Abstract: Background The APOE*E4 allele of the gene for apolipoprotein E ( APOE ) has been reported as a risk factor for Alzheimer disease (AD) to varying degrees in different ethnic groups. Objective To compare APOE*E4 -AD epidemiological associations in India and the United States in a cross-national epidemiological study. Design Case-control design within 2 cohort studies, using standardized cognitive screening and clinical evaluation to identify AD and other dementias and polymerase chain reaction to identify APOE genotyping. Participants Rural community samples, aged 55 years or older (n=4450) in Ballabgarh, India, and 70 years or older (n=886) in the Monongahela Valley region of southwestern Pennsylvania. Main Outcome Measures Criteria of the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association for probable and possible AD and Clinical Dementia Rating (CDR) scale for dementia staging. Results Frequency of APOE*E4 was significantly lower ( P APOE*E4 vs noncarriers were 3.4 (1.2-9.3) and 2.3 (1.3-4.0) in the Indian and US samples, respectively, and not significantly different between cohorts ( P =.20). Conclusion This first report of APOE*E4 and AD from the Indian subcontinent shows very low prevalence of AD in Ballabgarh, India, but association of APOE*E4 with AD at similar strength in Indian and US samples.

Assessing financial capacity in patients with Alzheimer disease: A conceptual model and prototype instrument.

Abstract: Objective To investigate financial capacity in patients with Alzheimer disease (AD) using a new theoretical model and prototype psychometric instrument. Design Cross-sectional comparisons of older control subjects (n=23) and patients with mild (n=30) and moderate AD (n=20). Main Outcome Measures Financial capacity was measured using the Financial Capacity Instrument, a prototype psychometric instrument that tests financial capacity using 14 tasks of financial ability comprising 6 clinically relevant domains of financial activity: basic monetary skills, financial conceptual knowledge, cash transactions, checkbook management, bank statement management, and financial judgment. Results The Financial Capacity Instrument tasks and domains showed adequate to excellent internal, interrater, and test-retest reliabilities. At the task level, patients with mild AD performed equivalently with controls on simple tasks such as counting coins/currency and conducting a 1-item grocery purchase, but significantly below controls on more complex tasks such as using a checkbook/register and understanding and using a bank statement. At the domain level, patients with mild AD performed significantly below controls on all domains except basic monetary skills. Patients with moderate AD performed significantly below controls and patients with mild AD on all tasks and domains. Regarding capacity status outcomes (capable, marginally capable, incapable) on domains, patients with mild AD had high proportions of marginally capable or incapable outcomes (range, 47%-87%), particularly on difficult domains like bank statement management (domain 5) and financial judgment (domain 6), but variability in individual outcomes. Patients with moderate AD had almost exclusively incapable outcomes across the 6 domains (range, 90%-100%). Conclusions Financial capacity is already significantly impaired in mild AD. Patients with mild AD demonstrate deficits in more complex financial abilities and impairment in most financial activities. Patients with moderate AD demonstrate severe impairment of all financial abilities and activities. The Financial Capacity Instrument has promise as an instrument for assessing domain-level financial activities and task-specific financial abilities in patients with dementia.

Clinical Criteria for the Diagnosis of Vascular Dementia: A Multicenter Study of Comparability and Interrater Reliability

Abstract: Background Several clinical criteria have been developed to standardize the diagnosis of vascular dementia (VaD). Significant differences in patient classification have been reported, depending on the criteria used. Few studies have examined interrater reliability. Objective To assess the concordance in classification and interrater reliability for the following 4 clinical definitions of VaD: the Hachinski Ischemic Score (HIS), the Alzheimer Disease Diagnostic and Treatment Centers (ADDTC), National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN), and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ( DSM-IV ). Methods Structured diagnostic checklists were developed for 4 criteria for VaD, 2 criteria for Alzheimer disease (AD), and 4 criteria for dementia. Twenty-five case vignettes, representing a spectrum of cognitive impairment and subtypes of dementia, were prepared in a standardized clinical format. Concordance in case classification using different criteria and interrater reliability among 7 ADDTCs given a specific set of criteria was assessed using the κ statistic. Results The frequency of a diagnosis of VaD was highest using the modified HIS or DSM-IV criteria, intermediate using the original HIS and ADDTC criteria, and lowest using the NINDS-AIREN criteria. Scores for interrater reliability ranged from κ = 0.30 (ADDTC) to κ = 0.61 (original HIS). Conclusions Clinical criteria for VaD are not interchangeable. Depending on the criteria selected, the reported prevalence of VaD will vary significantly. The traditional HIS has higher interrater reliability than the newer criteria for VaD. Prospective longitudinal studies with clinical-pathological correlation are needed to compare validity.

The Insula and Cerebrogenic Sudden Death

Abstract: Sudden death is an "electrical accident" caused by fatal cardiac arrhythmias. While brain-heart control has physiological advantages, cerebrogenic sudden death and nonfatal cardiovascular disturbances can complicate stroke of all types, seizures and epilepsy, head injury, other neurological conditions, neurosurgical procedures, and intense emotional states. Cerebrogenic cardiovascular and autonomic disturbances include electrocardiographic changes, elevation of cardiac enzymes, cardiac arrhythmias, disturbances of blood pressure regulation, and cerebrogenic pulmonary edema. Evidence from experimental studies and clinical observations indicates a crucial role of the insula in cerebrogenic cardiovascular disturbances and sudden death. Future studies should focus on identification of at-risk patients, confirmation of a vulnerable period of cerebrogenic sudden death in those with different neurological conditions and intense emotional states, and clarification of the neurochemical mediators.

Pompe's Disease

Abstract: Over the past 25 years, the widespread application of genetic and biochemical techniques has revolutionized the way physicians, particularly neurologists, characterize and even name diseases. Pompe's disease, or glycogen storage disease type II, provides an excellent illustration of how an understanding of the molecular basis of a disease alters fundamental elements of clinical nosology and therapy.

The Evolution of Diagnosis in Early Parkinson Disease

Abstract: Context Since there is no diagnostic biological marker for Parkinson disease (PD), the diagnosis is based on the results of clinical assessment. The accuracy of diagnosis improves with time and repeated assessments. Studies that require only inclusion of early cases of PD present a diagnostic challenge. Previous studies concluded that initial diagnoses of PD made by general neurologists were incorrect in 24% to 35% of the cases when patients were examined at autopsy. Experts in movement disorders are expected to have greater accuracy of initial diagnosis of PD. Objective To determine the evolution of clinical diagnosis in patients with early PD made initially by experts in PD. Design Eight hundred patients with mild parkinsonian symptoms (Hoehn and Yahr stage 1 or 2) who received a diagnosis of PD less than 5 years before the beginning of the study were included in the original Deprenyl and Tocopherol Antioxidative Therapy for Parkinson's Disease study. These patients were followed up prospectively with repeated clinical assessments. The following clinical criteria were used to reassess the initial diagnosis: investigator's confidence in the diagnosis of PD, presence of atypical clinical features, findings of imaging studies, response to levodopa, and results of autopsy examinations. Results The mean ± SD duration of illness in the 800 cases at enrollment was 2.2 ± 1.3 years, and the mean ± SD Hoehn and Yahr stage was 1.6 ± 0.5. The mean ± SD follow-up was 6.0 ± 1.4 years (range, 0.2-7.6 years). In 5 cases, PD was not confirmed at autopsy, and in 15 patients, the results of imaging studies indicated the presence of other pathological conditions. Of the 550 cases treated with levodopa, 49 (8.9%) had little or no improvement; 6 of these cases overlap with either autopsy or imaging study exclusion criteria. Two other cases had at least 4 of the 6 atypical clinical features arguing against the diagnosis of PD. Thus, of the 800 patients, 65 (8.1%) did not have PD according to the study criteria. Compared with those patients with the final diagnosis of PD, in the diagnoses of 60 patients without autopsy, the duration of symptoms (mean ± SD, 7.2 ± 2.0 years vs 8.3 ± 1.9 years; P P Conclusions We found that 65 (8.1%) of patients initially diagnosed as having PD were later found to have an alternate diagnosis based on multifactorial clinical diagnostic criteria. This alternate diagnosis indicated that experts in PD changed their diagnoses infrequently during the 7.6-year follow-up.

Homocysteine and neurologic disease.

Abstract: Over the last 10 years, there has been an explosion of interest in homocysteine, a sulfur-containing amino acid that occupies a central location in the metabolic pathways of thiol compounds. This interest is primarily because of the realization that hyperhomocysteinemia is an important risk factor for vascular disease, including stroke, independent of long-recognized factors such as hyperlipidemia, hypertension, diabetes mellitus, and smoking. Since elevated homocysteine levels can often be normalized by supplementing the diet with folic acid (folate), pyridoxine hydrochloride (vitamin B(6)), and cyanocobalamin (vitamin B(12)), these observations raise the exciting possibility that this inexpensive and well-tolerated therapy may be effective in decreasing the incidence of vascular disease. In addition to its association with cerebrovascular disease, homocysteine may play a role in neurodegenerative disorders, even if only as a marker of functional vitamin B(12) deficiency. Homocysteine is also important to neurologists since most anticonvulsants raise homocysteine levels, an effect that may explain the teratogenic effects of these drugs. Practical knowledge concerning some details of homocysteine metabolism, the diagnosis of hyperhomocysteinemia, and the use of polyvitamin therapy to lower homocysteine levels will be increasingly important in the treatment of patients with neurologic disease. Arch Neurol. 2000;57:1422-1428

Subthalamic stimulation in Parkinson disease: a multidisciplinary approach.

Abstract: Background High-frequency stimulation of the subthalamic nucleus constitutes a therapeutic advance for severely disabled patients with Parkinson disease. Objective To evaluate the efficacy and safety of continuous bilateral high-frequency stimulation of the subthalamic nucleus in patients with Parkinson disease. Design A prospective study of patients with Parkinson disease treated at a university hospital. Patients and Methods Electrodes were implanted bilaterally in the subthalamic nucleus of 23 consecutive patients with Parkinson disease who responded well to levodopa but had severe motor complications. There were 16 men and 7 women (mean ± SEM age, 53 ± 2 years) who had a mean ± SEM disease duration of 14.7 ± 1.0 years. Targets were determined by 3-dimensional magnetic resonance imaging, combined with intraoperative electrophysiologic recordings and stimulation. Results Six months after surgery, motor disability, levodopa-induced motor fluctuations, dyskinesias, and the daily dose of levodopa equivalent decreased significantly by 67%, 78%, 77%, and 61%, respectively, compared with the preoperative state. No significant morbidity was observed, except transient depression in 4 patients. Conclusions The beneficial effects of subthalamic stimulation depend on (1) the criteria used for patient selection, (2) the precision with which the subthalamic nucleus is targeted (dependent on the 3-dimensional magnetic resonance imaging and the intraoperative electrophysiologic and clinical assessments), and (3) the long-term postoperative adjustment of stimulation variables.

A quantitative study of water diffusion in multiple sclerosis lesions and normal-appearing white matter using echo-planar imaging.

Abstract: Objectives We used an optimized echo-planar pulse sequence for isotropically weighted diffusion imaging (1) to measure mean diffusivity ( D ) in lesions and normal-appearing white matter (NAWM) in the entire brain from patients with mildly disabling relapsing-remitting multiple sclerosis (MS), (2) to compare the D of NAWM from patients with that of white matter from normal controls, (3) to evaluate whether lesions classified on the basis of their appearance on enhanced T1-weighted scans have different D , and (4) to investigate the relationship between diffusion changes in lesions and NAWM. Methods Dual-echo and diffusion-weighted scans were obtained from 35 patients with relapsing-remitting MS and 24 sex- and age-matched normal controls. Postcontrast T1-weighted images were also obtained from the patients. After creating D maps and image coregistration, D values were measured for MS lesions larger than 5 mm and for 22 NAWM areas from each subject. Results All NAWM areas studied had significantly higher D in patients than in controls. A total of 173 lesions were identified on the dual-echo scans from patients. The average D for these lesions was significantly higher than that of NAWM. Twenty-two lesions were enhancing and 60 were classified as T1-hypointense. No significant difference in D values was found between enhancing and nonenhancing lesions, while the average D of T1-hypointense lesions was significantly higher than the average D of T1-isointense lesions. There was no significant correlation between the average D in lesions and NAWM. Conclusions This study shows that diffusion-weighted imaging is able to identify MS lesions with severe tissue disruption. It also shows that widespread increased diffusion can be measured in the NAWM from patients with MS, and suggests that such changes are, at least partially, independent of larger abnormalities.

Amyotrophic Lateral Sclerosis Mimic Syndromes A Population-Based Study

Abstract: Background The Irish ALS Register is a population-based register of the epidemiological characteristics of amyotrophic lateral sclerosis (ALS) in the republic of Ireland. Objective To describe the clinical and demographic details of those patients included in the Irish ALS Register who were incorrectly diagnosed as having ALS (patients who were ultimately rediagnosed as having an "ALS mimic syndrome"). Methods The medical records of each patient referred to the register are routinely reviewed and, where possible, patients are examined by our group during their illness. Results Between January 1, 1993, and December 31, 1997, 32 patients (representing 7.3% of 437 referrals) were rediagnosed as having a condition other than ALS. The median age at onset for these 32 patients was 56.0 years (range, 19.5-85.8 years) for men and 53.5 years (range, 39.5-70.4 years) for women. Twenty-nine patients (91%) presented with symptoms referable to the limbs, and the remainder presented with symptoms involving the bulbar musculature. Multifocal motor neuropathy was the most common condition mistaken for ALS, accounting for 7 cases (22%), followed closely by Kennedy disease (4 cases [13%]). Factors leading to diagnostic revision included evolution of atypical symptoms, results of specific investigations, and failure of symptoms to progress. Twenty-seven (84%) of the patients with an ALS mimic syndrome fulfilled the El Escorial criteria for either "suspected" or "possible" ALS, 4 (13%) met the criteria for probable ALS, and 1 (3%) had definite ALS. Conclusions The application of the El Escorial diagnostic criteria may facilitate early recognition of non-ALS cases. Misdiagnosis of ALS remains a common clinical problem despite the increased availability of investigations and a greater awareness among neurologists of potential diagnostic pitfalls.

Levodopa Withdrawal After Bilateral Subthalamic Nucleus Stimulation in Advanced Parkinson Disease

Abstract: Context Subthalamic nucleus (STN) stimulation may be effective in ameliorating parkinsonian symptoms even to the extent to permit levodopa withdrawal. Objectives To analyze the efficacy of STN stimulation in patients with Parkinson disease (PD) and to determine if levodopa may be withdrawn after surgery. Design Before-after trial. Setting Referral center, hospitalized care. Patients Fifteen patients with advanced PD. Interventions Microelectrode-guided bilateral STN high-frequency stimulation. Outcome Measures Before surgery patients were evaluated in off-medication and on-medication conditions. Dopaminergic drug dosages were reduced after surgery, aiming for complete withdrawal. Six months after surgery, patients were reeavaluated in off- and on-medication conditions, with the stimulation turned on and off. Results Total Unified Parkinson's Disease Rating Scale (UPDRS) motor score in the off-medication condition improved by 65.9%; and axial symptoms, bradykinesia, rigidity, and tremor improved by 65.8%, 60.4%, 66.1%, and 81.1%, respectively. UPDRS part II scores were reduced by 71.8% and Schwab and England scores improved by 45.3%. Levodopa was withdrawn in 8 patients and the overall levodopa dose was reduced 80.4%. "Off" time was reduced 89.7% and the severity of dyskinesias decreased 80.6% after surgery. All results reached significance (P Conclusions Bilateral STN stimulation safely improves all parkinsonian symptoms, decreases or eliminates the need for levodopa, and ameliorates motor fluctuations and dyskinesias. Complete withdrawal of levodopa is feasible with this technique and the overall motor effect of STN stimulation is quantitatively comparable to that obtained with levodopa.

Magnetic Resonance Imaging in the Clinical Diagnosis of Creutzfeldt-Jakob Disease

Abstract: Objective: To evaluate the diagnostic usefulness of magnetic resonance imaging (MRI) in the clinical diagnosis of Creutzfeldt-Jakob disease (CJD). Background: Creutzfeldt-Jakob disease is a rare neurodegenerative disease that belongs to the group of human spongiform encephalopathies and usually affects elderly people. It is clinically characterized by rapidly progressive dementia and development of neurological symptoms, such as myoclonus or ataxia. Until now, neuroradiologic investigations have only played a minor role in establishing the clinical diagnosis of CJD, and they are often performed to exclude differential diagnoses. Setting: A university hospital, base of the German National Creutzfeldt-Jakob Disease Surveillance Study. Methods and Patients: In this study, MRIs from suspected cases of CJD were examined by one investigator blinded to the diagnosis. Patients were classified according to the established clinical and neuropathological criteria. Results: Bilateral symmetric, high signal intensities on T2-weighted MRIs were present in the basal ganglia of 109 (67%) of 162 patients with CJD. In the control group, which consisted of non-CJD dementia patients, these abnormalities on T2-weighted MRIs were found in 4 (7%) of 58 patients. This corresponds to a high specificity in the differential diagnosis of CJD. Conclusion: These results indicate that MRI is a useful and valuable tool with reasonable sensitivity (67%) and high specificity (93%) and should be considered as an additional cornerstone in the clinical diagnosis of CJD.

Visuoperceptual impairment in dementia with Lewy bodies.

Abstract: Background In dementia with Lewy bodies (DLB), vision-related cognitive and behavioral symptoms are common, and involvement of the occipital visual cortices has been demonstrated in functional neuroimaging studies. Objectives To delineate visuoperceptual disturbance in patients with DLB in comparison with that in patients with Alzheimer disease and to explore the relationship between visuoperceptual disturbance and the vision-related cognitive and behavioral symptoms. Design Case-control study. Setting Research-oriented hospital. Patients Twenty-four patients with probable DLB (based on criteria of the Consortium on DLB International Workshop) and 48 patients with probable Alzheimer disease (based on criteria of the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association) who were matched to those with DLB 2:1 by age, sex, education, and Mini-Mental State Examination score. Main Outcome Measures Four test items to examine visuoperceptual functions, including the object size discrimination, form discrimination, overlapping figure identification, and visual counting tasks. Results Compared with patients with probable Alzheimer disease, patients with probable DLB scored significantly lower on all the visuoperceptive tasks ( P P P =.01) than those without them (n=6), and patients with television misidentifications (n=5) scored significantly lower on the size discrimination ( P P =.01), and visual counting ( P =.007) than those without them (n=19). Conclusions Visual perception is defective in probable DLB. The defective visual perception plays a role in development of visual hallucinations, delusional misidentifications, visual agnosias, and visuoconstructive disability charcteristic of DLB.

Reduction of rapid eye movement sleep by diurnal and nocturnal seizures in temporal lobe epilepsy.

Abstract: Background: Patients with brief, complex partial seizures frequently suffer from tiredness and decreased productivity that continue well beyond the postictal period. A possible explanation is that seizures, even when occurring during the day, disrupt sleep the following night. Objective: To determine the effect of temporal lobe complex partial seizures on sleep structure and daytime drowsiness. Methods: Patients with temporal lobe epilepsy were admitted for video-electroencephalography monitoring. Allnight polysomnography was recorded under the following 3 conditions: seizure free, seizure during the day before the recording, and seizure during the recording. Percentage of time in each sleep stage, sleep efficiency, and time to first and second rapid eye movement (REM) period were compared for seizure vs control conditions. Daytime drowsiness was also measured, using a modified maintenance of wakefulness test and 2 subjective drowsiness tests. Results: Daytime seizures reduced REM from 18% ± 1% to 12% ± 2% (P = .003). Night seizures reduced REM from 16% ±1 % to 6.8% ±2 % ( P ,.001). Night seizures also significantly reduced stages 2 and 4 while increasing stage 1 sleep. Night seizures, but not day seizures, significantly reduced sleep efficiency, increased time to first REM period, and increased drowsiness as measured by the maintenance of wakefulness test. Conclusions: Temporal lobe complex partial seizures decrease REM sleep, particularly when occurring during sleep but also when occurring on the previous day. This may, in part, be responsible for the prolonged impairment of functioning that some patients report following seizures. Arch Neurol. 2000;57:363-368

National Institutes of Health consensus conference: tuberous sclerosis complex.

Abstract: I n July 1998, the National Institutes of Health sponsored a consensus conference of international experts to review the literature on tuberous sclerosis complex (TSC). First described in the 1800s, this multiorgan disease has wide-ranging effects on the body, including the brain, kidneys, eyes, and heart. Tuberous sclerosis affects an estimated 40000 Americans and approximately 2 million people worldwide. The panel provided recommendations on revised diagnostic criteria and surveillance protocols for affected individuals. Areas for future research were highlighted.

Botulinum toxin in the treatment of tics.

Abstract: Objective To evaluate the safety and efficacy of botulinum toxin A (BTX) injections in the treatment of tics in patients with Tourette syndrome (TS). Background BTX is an effective treatment for an increasing number of conditions characterized by abnormal muscle contractions. BTX may improve not only the motor component of tics, but also premonitory sensations that precede tics. Methods Thirty-five patients (30 male, 5 female) were treated with BTX in the sites of their most problematic tics. Response to BTX was based on a 0 to 4 clinical rating scale (0, no improvement, to 4, marked improvement in both severity and function). Questionnaires were administered to evaluate patients' impressions of overall efficacy and degree of benefit with premonitory sensations. Results Mean duration of tics prior to initial injection was 15.3 years (range, 1-62 years) and mean duration of follow-up was 21.2 months (range, 1.5-84 months). The mean peak effect response in 35 patients treated in 115 sessions was 2.8 (range, 0-4); the mean duration of benefit was 14.4 weeks (maximum, 45 weeks); and the mean latency to onset of benefit was 3.8 days (maximum, 10 days). Twenty-one (84%) of 25 patients with premonitory sensations derived marked relief of these symptoms (mean benefit, 70.6%). Total mean dose was 502.1 U (range, 15-3550 U); mean number of visits, 3.3 (range, 1-16); and mean dose per visit, 119.9 U (range, 15-273 U). Sites of injections were as follows: cervical or upper thoracic area (17), upper face (14), lower face (7), vocal cords (4), upper back and/or shoulder (3), scalp (1), forearm (1), leg (1) and rectus abdominis (1). Complications included neck weakness (4), dysphagia (2), ptosis (2), nausea (1), hypophonia (1), fatigue (1), and generalized weakness (1), which were all mild and transient. Conclusions Botulinum toxin A injections are an effective and well-tolerated treatment of tics. In addition to improving the motor component of tics, BTX also provides relief of premonitory sensations.

Phantom limbs and neural plasticity.

Abstract: The study of phantom limbs has received tremendous impetus from recent studies linking changes in cortical topography with perceptual experience. Systematic psychophysical testing and functional imaging studies on patients with phantom limbs provide 2 unique opportunities. First, they allow us to demonstrate neural plasticity in the adult human brain. Second, by tracking perceptual changes (such as referred sensations) and changes in cortical topography in individual patients, we can begin to explore how the activity of sensory maps gives rise to conscious experience. Finally, phantom limbs also allow us to explore intersensory effects and the manner in which the brain constructs and updates a "body image" throughout life.

Safety of discontinuation of anticoagulation in patients with intracranial hemorrhage at high thromboembolic risk.

Abstract: Background Limited data are available to guide the management of anticoagulation in patients with intracranial hemorrhage (ICH) at high thromboembolic risk. Objective To review the management of anticoagulation in patients with ICH at high thromboembolic risk. Patients and Methods We reviewed the management of anticoagulation in 141 patients who have a high risk of ischemic stroke and have ICH while taking warfarin. The 30-day risk of ischemic stroke while not taking anticoagulation treatment was determined using Kaplan-Meier survival estimates. Results The indications for anticoagulation were a prosthetic heart valve (52 patients [group 1]), atrial fibrillation and cardioembolic stroke (53 patients [group 2]), and a recurrent transient ischemic attack or an ischemic stroke (36 patients [group 3]). A prior ischemic stroke occurred in 14 (27%) of group 1 patients and in 23 (43%) of group 2 patients. Death occurred in 43% of the 141 patients. The median time not taking warfarin in this cohort was 10 days. Three patients had an ischemic stroke within 30 days of warfarin therapy discontinuation. Using Kaplan-Meier survival estimates, the probability of having an ischemic stroke at 30 days following warfarin therapy cessation in groups 1, 2, and 3 was 2.9% (95% confidence interval, 0%-8.0%), 2.6% (95% confidence interval, 0%-7.6%), and 4.8% (95% confidence interval, 0%-13.6%), respectively. In the 35 patients who had warfarin therapy restarted, none had recurrence of ICH during the same hospitalization. Conclusions Discontinuation of warfarin therapy for 1 to 2 weeks has a comparatively low probability of embolic events in patients at high embolic risk. This should be taken into consideration when deciding whether to continue or discontinue anticoagulation in these patients at high embolic risk. Early recurrence of ICH is exceedingly uncommon.