Alexander P. Auchus

Outbreak of Nipah-virus infection among abattoir workers in Singapore

BACKGROUND In March 1999, an outbreak of encephalitis and pneumonia occurred in workers at an abattoir in Singapore. We describe the clinical presentation and the results of investigations in these patients. METHODS Clinical and laboratory data were collected by systemic review of the case records. Serum and cerebrospinal fluid (CSF) samples were tested for IgM antibodies to Nipah virus with an IgM capture ELISA. Reverse-transcriptase PCR was done on the CSF and tissue samples from one patient who died. FINDINGS Eleven patients were confirmed to have acute Nipah-virus infection based on raised IgM in serum. Nipah virus was identified by reverse transcriptase PCR in the CSF and tissue of the patient who died. The patients were all men, with a median age of 44 years. The commonest presenting symptoms were fever, headache, and drowsiness. Eight patients presented with signs of encephalitis (decreased level of consciousness or focal neurological signs). Three patients presented with atypical pneumonia, but one later developed hallucinations and had evidence of encephalitis on CSF examination. Abnormal laboratory findings included a low lymphocyte count (nine patients), low platelet count, low serum sodium, and high aspartate aminostransferase concentration (each observed in five patients). The CSF protein was high in eight patients and white-blood-cell count was high in seven. Chest radiography showed mild interstitial shadowing in eight patients. Magnetic resonance imaging (MRI) showed focal areas of increased signal intensity in the cortical white marker in all eight patients who were scanned. The nine patients with encephalitis received empirical treatment with intravenous aciclovir and eight survived. INTERPRETATION Infection with Nipah virus caused an encephalitis illness with characteristic focal areas of increased intensity seen on MRI. Lung involvement was also common, and the disease may present as an atypical pneumonia.

Treatment of agitation in AD A randomized, placebo-controlled clinical trial

Background: Treatment of agitation is a crucial problem in the care of patients with AD. Although antipsychotic and antidepressant medications and behavior management techniques (BMT) have each been used to treat agitation, clinical trials of these treatments have been characterized by small sample sizes and uncontrolled treatment designs. Objective: To compare haloperidol, trazodone, and BMT with placebo in the treatment of agitation in AD outpatients. Methods: A total of 149 patients with AD and their caregivers participated in a randomized, placebo-controlled, multicenter trial. Blind assessment was conducted at baseline and after 16 weeks of treatment. The three active treatments were haloperidol, trazodone, and BMT. The Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change was the primary outcome measure. Secondary outcomes included patient agitation, cognition, and function, and caregiver burden. Results: Thirty-four percent of subjects improved relative to baseline. No significant differences on outcome were obtained between haloperidol (mean dose, 1.8 mg/d), trazodone (mean dose, 200 mg/d), BMT, or placebo. Significantly fewer adverse events of bradykinesia and parkinsonian gait were evident in the BMT arm. No other significant difference in adverse events was seen. Symptoms did not respond differentially to the different treatments. Conclusions: Comparable modest reductions in agitation occurred in patients receiving haloperidol, trazodone, BMT, and placebo. More effective pharmacologic, nonpharmacologic, and combination treatments are needed.

Predictors of nursing home placement in Huntington disease

Objective: To determine whether motor, behavioral, or psychiatric symptoms in Huntington disease (HD) predict skilled nursing facility (SNF) placement. Methods: Subjects were participants in the Huntington Study Group’s Unified Huntington Disease Rating Scale Database (Rochester, NY) between January 1994 and September 1999. Specific motor, psychiatric, and behavioral variables in subjects residing at home and in SNF were analyzed using χ2 and Student’s t-tests. For a subset of subjects for whom longitudinal data existed, a Cox proportional hazards model controlling for age, sex, and disease duration was used. Results: Among 4,809 subjects enrolled, 3,070 had clinically definite HD. Of these, 228 (7.4%) resided in SNF. The SNF residents’ average age was 52 years, average disease duration was 8.6 years, and they were predominantly women (63%). The SNF residents had worse motor function (chorea, bradykinesia, gait abnormality, and imbalance, p < 0.0001); were more likely to have obsessions, compulsions, delusions, and auditory hallucinations; and had more aggressive, disruptive (p < 0.0001), and irritable behaviors (p = 0.0012). For 1,559 subjects, longitudinal data existed (average length of follow-up, 1.9 years), and 87 (5%) moved from home to SNF. In the Cox model, bradykinesia (HR 1.965, 95% CI 1.083 to 3.564), impaired gait (HR 3.004, 95% CI 1.353 to 6.668), and impaired tandem walking (HR 2.546, 95% CI 1.460 to 4.439) were predictive of SNF placement. Conclusions: Institutionalized patients with HD are more motorically, psychiatrically, and behaviorally impaired than their counterparts living at home. However, motor variables alone predicted institutionalization. Treatment strategies that delay the progression of motor dysfunction in HD may postpone the need for institutionalization.

Correction of Positron Emission Tomography Data for Cerebral Atrophy

Because positron emission tomography (PET) provides measurements per unit volume of intracranial contents, these measurements may be affected by the inclusion of metabolically inactive CSF spaces in the volume in which they are made. Thus, PET measurements of CBF and metabolism may be artifactually lowered in normal aging and dementia, which are both associated with significant brain atrophy. We describe a method to correct global PET data, averaged over several tomographic slices, for cerebral atrophy by using measurements of CSF space volume obtained with quantitative x-ray computed tomography. The importance of making such a correction is demonstrated using PET measurements of CBF and oxygen metabolism obtained in normal young, normal elderly, and demented subjects.

Diffusion Tensor Imaging of Normal Appearing White Matter and Its Correlation with Cognitive Functioning in Mild Cognitive Impairment and Alzheimer's Disease

Abstract:  Diffusion tensor imaging (DTI) was used to examine the microstructural integrity of normal appearing white matter (NAWM) in subjects with mild cognitive impairment (MCI) and Alzheimers disease (AD). Significant frontal, temporal, and parietal white matter diffusion tensor changes were demonstrated in MCI and AD compared with normal controls. These changes were correlated with cognitive functioning, and are consistent with a hypothesized loss of axonal processes in affected regions.

Recurrent jaw dislocation after botulinum toxin treatment for sialorrhoea in amyotrophic lateral sclerosis

Botulinum toxin (BTX) has been used successfully to treat various movement disorders, and is increasingly used for many other medical conditions. Sialorrhoea is a disabling symptom in many neurological patients including those with Parkinsons disease, stroke and amyotrophic lateral sclerosis (ALS). BTX has recently been shown to be effective for treating sialorrhoea. We report an ALS patient who developed recurrent jaw dislocation following BTX treatment for sialorrhoea to highlight the observation that intraparotid BTX may be complicated by jaw dislocations in some at-risk ALS patients. Clinicians using BTX to treat sialorrhoea in ALS need to be aware of this potentially serious complication.

Severity of CIND and MCI predict incidence of dementia in an ischemic stroke cohort

Background: The utility of poststroke cognitive status, namely dementia, cognitive impairment no dementia (CIND), mild cognitive impairment (MCI), and no cognitive impairment (NCI), in predicting dementia has been previously examined. However, no studies to date have compared the ability of subtypes of MCI and CIND to predict dementia in a poststroke population. Methods: A cohort of ischemic stroke patients underwent neuropsychological assessment annually for up to 5 years. Dementia was defined using the DSM-IV criteria. Univariate and multivariable Cox proportional regression was performed to determine the ability of MCI subtypes, CIND severity, and individual domains of impairment to predict dementia. Results: A total of 362 patients without dementia were followed up for a mean of 3.4 years (17% drop out), with 24 developing incident dementia. Older age, previous and recurrent stroke, and CIND and MCI subtypes were significant predictors of dementia. In multivariable analysis controlling for treatment allocation, patients who were older, had previous or recurrent stroke, and had either CIND moderate or multiple domain MCI with amnestic component were at elevated risk for dementia. In multivariable domain analysis, recurrent strokes, age, and previous strokes, verbal memory, and visual memory were significant predictors of dementia. Receiver operating characteristic curve analysis showed that CIND moderate (area under the curve: 0.893) and multiple domain MCI with amnestic component (area under the curve: 0.832) were significant predictors of conversion to dementia. All other classifications of cognitive impairment had areas under the curve less than 0.7. Conclusion: Stroke patients with cognitive impairment no dementia (CIND) moderate are at higher risk of developing dementia, while CIND mild patients are not at increased risk of developing dementia.

The Prognostic Effects of Poststroke Cognitive Impairment No Dementia and Domain-Specific Cognitive Impairments in Nondisabled Ischemic Stroke Patients

Background and Purpose— There is some evidence that poststroke dementia, cognitive impairment no dementia (CIND), and mild cognitive impairment predict for poor outcomes such as dementia, death, and institutionalization. However, few studies have examined the prognostic value of CIND, CIND severity, and domain impairments in a poststroke cohort. Methods— A cohort of ischemic stroke patients with baseline cognitive assessments 3 months poststroke were followed up annually for outcomes of dependency, vascular events, and death for up to 5 years. Univariate and multivariate Cox proportional regression was performed to determine the ability CIND, CIND severity, and domain impairments to predict dependency, vascular outcomes, and death. Results— Four-hundred nineteen patients without dementia (mean age 60±11 years, 32% female) were followed for a mean of 3.2 years. Older age, diabetes, more severe strokes, CIND-mild, and CIND-moderate were independently predictive of dependency. There were no independent predictors of recurrent vascular events. Older age, diabetes, and CIND-moderate were independently predictive of death. In analyses of individual cognitive domains, impairments in visuomotor speed were independently predictive of dependency. Conclusions— In poststroke patients, CIND predicts dependency and death, while CIND severity discriminates patients with poor survival. Impairments in visuomotor speed independently predict dependency. Clinical Trial Registration— URL: http://clinicaltrials.gov. Unique Identifier: NCT00161070.

Improving Detection of Dementia in Asian Patients with Low Education: Combining the Mini-Mental State Examination and the Informant Questionnaire on Cognitive Decline in the Elderly

Background/Aims: Previous work combining the Mini-Mental State Examination (MMSE) and Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) has been conducted in western populations. We ascertained, in an Asian population, (1) the best method of combining the tests, (2) the effects of educational level, and (3) the effect of different dementia etiologies. Methods: Data from 576 patients were analyzed (407 nondemented controls, 87 Alzheimer’s disease and 82 vascular dementiapatients). Sensitivity, specificity and AUC values were obtained using three methods, the ‘And’ rule, the ‘Or’ rule, and the ‘weighted sum’ method. Results: The ‘weighted sum’ rule had statistically superior AUC and specificity results, while the ‘Or’ rule had the best sensitivity results. The IQCODE outperformed the MMSE in all analyses. Patients with no education benefited more from combined tests. There was no difference between Alzheimer’s disease and vascular dementia populations in the predictive value of any of the combined methods. Conclusion: We recommend that the IQCODE be used to supplement the MMSE whenever available and that the ‘weighted sum’ method be used to combine the MMSE and the IQCODE, particularly in populations with low education. As the study population selected may not be representative of the general population, further studies are required before generalization to nonclinical samples.

Quantitative light microscopic demonstration of increased pallidal and striatal met5-enkephalin-like immunoreactivity in rats following chronic treatment with haloperidol but not with clozapine: Implications for the pathogenesis of neuroleptic-induced movement disorders

Acute and late onset movement disorders frequently complicate the treatment of psychosis with typical neuroleptic drugs like haloperidol, but not with atypical neuroleptic drugs like clozapine. Although the neural mechanisms underlying neuroleptic-induced movement disorders remain unknown, alterations in basal ganglia function are likely involved. A potential role for the endogenous opiate peptides in neuroleptic-induced movement disorders is suggested by the immunocytochemical localization of met5-enkephalin (ME) in the striatopallidal projection pathway, and by the increased levels of ME measured by radioimmunoassay in the rat caudate-putamen nuclei (CPN) following haloperidol treatment. We sought to determine whether met5-enkephalin-like immunoreactivity (MELI) in terminal fields within globus pallidus and in perikarya in CPN was differentially altered in rats chronically treated with haloperidol or clozapine. Acrolein-fixed forebrain sections were collected from cohorts of adult rats receiving 21-day oral administration of haloperidol, clozapine, or water. Sections from the three treatment groups were collectively processed for immunocytochemical labeling using varying dilutions of ME antiserum and the avidin-biotin peroxidase method. In globus pallidus, densitometry measures revealed significantly increased levels of immunoperoxidase labeling for ME in haloperidol-treated, but not in clozapine-treated animals. In CPN, optical densitometry as well as cell counting measurements also showed a significant increase in MELI only in the haloperidol-treated group. These results support the concept that alterations in endogenous opiate peptides in basal ganglia may contribute to movement disorders seen in patients receiving typical neuroleptic drugs.(ABSTRACT TRUNCATED AT 250 WORDS)