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ObjectiveMost suicidality literature in Huntington disease (HD) is based on natural history studies or retrospective reviews, but reports on risk factors from clinical trials are limited.MethodsWe analyzed 609 participants from 2CARE, a randomized, double-blind, placebo-controlled clinical trial with up to 5 years of follow-up, for risk factors related to suicidality. The primary outcome variable was the time from randomization until the first occurrence of either suicidal ideation or attempt. We also considered time from randomization until the first suicide attempt as a secondary outcome variable.ResultsDepression, anxiety, bipolar disorder, antidepressant or anxiolytic use, and prior suicide attempt at baseline were associated with time to ideation or attempt. Baseline employment status, marital status, CAG repeat length, tetrabenazine use, and treatment assignment (coenzyme Q10 or placebo) were not associated with suicidality. Time-dependent variables from the Unified Huntington's Disease Rating Scale Behavioral Assessment were associated with time to suicidal ideation or attempt, driven mainly by items related to depressed mood, low self-esteem/guilt, anxiety, suicidal thoughts, irritability, and compulsions. Variables associated with time to suicide attempt alone were generally similar.ConclusionThese data suggest psychiatric comorbidities in HD are predictive of suicidal behavior while participating in clinical trials, reinforcing the importance of clinical surveillance and treatment towards lessening risk during participation and perhaps beyond. Designing a composite algorithm for early prediction of suicide attempts in HD may be of value, particularly given anticipated trials aimed at disease modification are likely to be long-term.Clinicaltrials.gov identifierNCT00608881.

Objective: Subtle signs and symptoms of Huntington disease (HD) are often present before impairments reach a point where the neurologic disease is manifest and a diagnosis must be considered. The objective is to examine the prognostic significance of these early clinical signs and symptoms regarding time until unequivocal clinical HD diagnosis. Methods: We analyzed longitudinal data from 218 at-risk but healthy participants in the Huntington Study Group database who had either normal motor examination results or minimal soft motor signs at first observation. This group was followed periodically in HD clinics for up to 4.5 years. We used survival analysis to examine predictors of time until HD diagnosis. Results: Diagnostic prediction was significantly improved using specific, nonredundant items from the Unified Huntington9s Disease Rating Scale. When a movement disorder specialist initially had a global impression of “soft signs” present, cumulative relative risk of diagnosis was 4.68 times greater at 1.5 years of follow-up and 3.58 at 3 years. A neuropsychological test pattern with psychomotor speed 1 SD worse than a semantic knowledge measure increased cumulative risk by 1.99 times at 1.5 years and 1.81 at 3 years. Finally, reports of various subjective HD symptoms increased 3-year relative risk by 2.6 to 3.4. Conclusions: Findings demonstrate that neuropsychological performance and both the clinician rating and the patient subjective perception of motor difficulties contribute nonredundantly to a prediction of Huntington disease diagnosis. These findings may have implications for prognostic assessment of persons at risk and eventually assist with early interventions.

Objective: To determine if future studies of coenzyme Q10 and GPI-1485 in Parkinson disease (PD) may be warranted. Methods: We conducted a randomized, double-blind, calibrated futility clinical trial of coenzyme Q10 and GPI-1485 in early untreated PD using placebo data from the DATATOP study to establish the futility threshold. Results: The primary outcome measure (change in total Unified Parkinson's Disease Rating Scale scores over 1 year) did not meet the prespecified criteria for futility for either agent. Secondary analyses using calibration controls and other more recent placebo data question the appropriateness of the predetermined definition of futility, and suggest that a more restrictive threshold may be needed. Conclusions: Coenzyme Q10 and GPI-1485 may warrant further study in Parkinson disease, although the data are inconsistent. Additional factors (cost, availability of other agents, more recent data on placebo outcomes, other ongoing trials) should also be considered in the selection of agents for Phase III studies. NEUROLOGY 2007;68:20-28

Despite advances in understanding the pathogenesis of Parkinson's disease (PD), treatments that favorably influence the course of illness have remained elusive. In order to identify potentially neuroprotective interventions, improved clinical trial designs are needed. Researchers have to carefully consider what type of PD patients, how to measure the impact of putative neuroprotective agents, how to choose which interventions to study and what sequence of clinical trial designs is most appropriate. The possible use of futility studies to rapidly identify strongly ineffective agents and the use of delayed start designs to identify disease modifying interventions may both be important advances. Improved clinical trial design along with continued new insights into PD pathogenesis will likely lead to the identification of agents which can favorably influence the course of this disease.

To evaluate whether baseline levels of plasma and CSF HIV RNA, tumor necrosis factor alpha (TNFalpha), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-2 (MMP-2), or macrophage colony stimulating factor (M-CSF) are predictors of incident HIV-associated dementia (HIVD) in a cohort with advanced HIV infection.A total of 203 nondemented subjects with CD4 lymphocyte counts less than 200/muL, or300/microL but with cognitive impairment, underwent semiannual neurologic, cognitive, functional, and laboratory assessments. HIVD and minor cognitive motor disorder (MCMD) were defined using American Academy of Neurology criteria. The cumulative incidence of HIVD was estimated using Kaplan-Meier curves. Cox proportional hazards regression models were used to examine the associations between biologic variables and time to HIVD, adjusting for age, sex, years of education, duration of HIV infection, type of antiretroviral use, premorbid IQ score, and presence of MCMD.After a median follow-up time of 20.7 months, 74 (36%) subjects reached the HIVD endpoint. The dementia was mild in 70% of cases. The cumulative incidence of HIVD was 20% at 1 year and 33% at 2 years. Highly active antiretroviral therapy (HAART) was used by 73% of subjects at baseline. A plasma HIV RNA level was undetectable in 23% of subjects and a CSF HIV RNA level was undetectable in 48% of subjects. In adjusted analyses, neither plasma nor CSF HIV RNA levels (log10) were associated with time to HIVD; log10 levels of plasma TNFalpha (HR 3.07, p = 0.03) and CSF MCP-1 (HR = 3.36, p = 0.06) tended to be associated with time to HIVD.The lack of association between baseline plasma and CSF HIV RNA levels and incident dementia suggests highly active antiretroviral therapy may be affecting CNS viral dynamics, leading to lower HIV RNA levels, and therefore weakening the utility of baseline HIV RNA levels as predictors of HIV-associated dementia.

Objective: To determine the inter-rater reliability of a modification of the Memorial Sloan-Kettering (MSK) Staging for HIV-associated cognitive impairment. Methods: Data were abstracted on neurologic, neuropsychological, and functional status on 100 individuals participating at four sites in the Northeast AIDS Dementia (NEAD) Consortium cohort study, a longitudinal study of predictors of cognitive impairment in HIV-infected individuals. Neuropsychological performance was defined 1) based on the neuropsychologist’s global impression and 2) solely based on neuropsychological test scores. Raters at each site used the abstracted data to assign an MSK stage to each subject blind to any identifying information. Inter-rater reliability was assessed using kappa statistics. Agreement between computer-generated ratings and site-generated ratings was also assessed. Results: Kappa statistics for pair-wise agreement among the sites regarding MSK stage ranged from 0.70–0.91, representing good to excellent agreement between sites. Agreement between computer-generated ratings and site-generated ratings was in the good to excellent range (0.62–0.79). Conclusions: The authors have modified the MSK rating scale and developed a reliable instrument that can be used in multicenter studies. This instrument will be useful in staging HIV-dementia in future longitudinal studies and will be valuable in increasing accuracy of clinicopathologic studies.

Background: CPI-1189 is a compound with antioxidant properties that blocks tumor necrosis factor-α (TNFα) effects in animal models. It has neuroprotective properties in model systems for HIV-associated neurotoxicity and thus is a candidate for neuroprotective therapy in humans with HIV-associated CNS disease. Objective: To assess the tolerability and safety of CPI-1189 in treating HIV-associated cognitive–motor impairment. Methods: Sixty-four subjects with mild to moderate HIV-associated cognitive–motor impairment were randomized to receive either placebo or 50 or 100 mg daily of CPI-1189 in addition to optimal HIV therapy. Subjects were followed prospectively in a double-masked study for 10 weeks. The primary assessment was tolerability and safety of the compound. Secondary objectives examined neuropsychological and functional change associated with this treatment. Results: The study compound was well tolerated, with 91% of CPI-1189-treated subjects and 76% of placebo-treated subjects completing the trial. Skin rash was seen equally in placebo and active arms, but the only study withdrawals due to skin rash occurred in CPI-1189-treated subjects (n = 2). One subject developed a cataract on drug (100 mg/day). CD4 lymphocyte counts and plasma HIV viral load remained stable in all groups throughout the trial. No significant treatment effects were observed on the change in composite Z -scores for eight neuropsychologic measures (NPZ-8). The Grooved Pegboard Test (nondominant) showed improved performance with CPI-1189 at 100 mg/day ( p = 0.01), but no other neuropsychometric or functional measures demonstrated significant improvement. Conclusions: CPI-1189 was well tolerated in HIV subjects with cognitive–motor disorder. This study was not powered to conclusively determine efficacy and showed no consistent treatment-associated improvement in cognitive or functional measures.

Objective: To assess the incidence of and risk factors for distal sensory polyneuropathy (DSP) in a cohort of HIV-infected subjects.Methods: We followed 272 subjects semiannually for up to 30 months. DSP was diagnosed if subjects had decreased or absent ankle jerks, decreased or absent vibratory perception at the toes, or decreased pinprick or temperature in a stocking distribution. Subjects were further classified at each visit as having asymptomatic DSP (ADSP) (signs only) or symptomatic DSP (SDSP) if, in addition to the neurologic signs, paresthesias or pain was reported.Results: At baseline, 45% of the subjects did not meet criteria for DSP, 20% met criteria for ADSP, and 35% met criteria for SDSP. Dideoxynucleoside therapy was used by 23% of the patients, and this treatment was independent of their neuropathy status. In longitudinal univariate analyses, history of AIDS diagnoses (hazard ratio [HR] = 1.89; p = 0.02) and lower CD4 cell count (HR = 0.69; p = 0.0006) were risk factors for incident DSP (ADSP or SDSP). However, for incident SDSP only, in addition to history of AIDS diagnoses, mood and neurologic (other than DSP) and functional abnormalities were significant risk factors. Functional abnormalities remained a significant risk factor in a multiple regression analysis. The presence of ADSP and the use of dideoxynucleosides at baseline were not significant risk factors for incident SDSP. The Kaplan–Meier estimate of the 1-year incidence of SDSP was 36%.Conclusion: Subjects with moderate-to-severe immunosuppression from HIV infection commonly have SDSP. However, sex, use of dideoxynucleosides, and presence of ADSP were not significant risk factors for SDSP.

Cognitive and functional outcomes are of primary interest in the design of efficacy trials in HIV-associated cognitive impairment. In a longitudinal cohort study, weak associations were found between measures of cognitive performance and commonly used measures of daily functioning (mostly self-report measures) in HIV-infected individuals. Modifications of current functional scales or new functional instruments are needed to assess the clinical relevance of cognitive changes in clinical trials of HIV-associated cognitive impairment.

Neurology invites the help of reviewers from over 25 countries. Neurology received nearly 3,000 manuscripts in 2000, up 15% from last year. Over 90% of submitted papers were sent out for peer review. At least two reviewers consider each paper and over 25% have three or more reviewers. Revised papers are usually re-reviewed at least once prior to acceptance. Many receive additional re-reviews. Neurology depends upon the dedication and commitment of our ad hoc reviewers. The average time from manuscript submission to initial decision has been decreased to less than 3 weeks. Expedited papers are usually peer reviewed within 14 days. Our reviewers are expert and experienced. When we ask for the assistance of a new reviewer we always obtain at least two reviews from established experts. The busiest, most senior leaders in clinical neuroscience are among our best and most timely reviewers. The rewards for reviewers include the following: the knowledge that they are contributing to good science, the opportunity to gain perspective on their field, and especially for young people, the improvement of their own ability to effectively write and present scientific results. The reviewer is usually a superior scientist and a capable mentor. Our reviewers work anonymously. Neither the authors nor the other reviewers know their identity. The editors do know and respect this anonymity—but have gratitude and admiration for our reviewers’ generosity and commitment to shaping and mentoring our field. Listed below are the reviewers who completed reviews in the 6 months between April 2000 and October 2000. Those with an asterisk reviewed five or more papers, and those with two asterisks reviewed 10 or more—and some of them have reviewed 20, 30, or more. The Editors thank the following reviewers who contributed their time and expertise to the success of Neurology. Abou–Chebl, Alex Abou–Khalil, Bassel …

Background: Painful sensory neuropathy is a common complication of HIV infection. Based on prior uncontrolled observations, we hypothesized that amitriptyline or mexiletine would improve the pain symptoms. Method: A randomized, double-blind, 10-week trial of 145 patients assigned equally to amitriptyline, mexiletine, or matching placebo. The primary outcome measure was the change in pain intensity between baseline and the final visit. Results: The improvement in amitriptyline group (0.31 ± 0.31 units [mean ± SD]) and mexiletine group (0.23 ± 0.41) was not significantly different from placebo (0.20 ± 0.30). Both interventions were generally well tolerated. Conclusions: Neither amitriptyline nor mexiletine provide significant pain relief in patients with HIV-associated painful sensory neuropathy.

Objective: The objective of the study was to determine the effects of short-term levodopa administration on motor, cognitive, and psychiatric aspects of Parkinson9s disease (PD). Background: The effects of levodopa on mental processes in PD are controversial. Opinions range from the claim that levodopa improves cognition to the opposite view that levodopa causes or exacerbates dementia, delusions, and hallucinations. Of the 800 idiopathic PD patients enrolled in the original DATATOP study, 387 reached the end point of functional disabilities sufficiently severe to require levodopa treatment. There were 263 men and 124 women who were comparable with regard to age, symptom duration of PD, and measures of PD severity. We compared test scores on motor performance, cognitive function, and psychiatric status before levodopa and again within 6 months after initiation of levodopa therapy. Results: Levodopa administration improved all motor functions significantly. The improvement was significantly greater in women than in men. Levodopa administration did not worsen scores on any cognitive tests, and there were quantitatively small but significant improvements in tests of frontal lobe function. Levodopa exerted only minor effects on psychiatric measures. There were small but significant decreases in scores for depression, and increases in vivid dreams and hallucinations. Conclusions: Levodopa administration for up to 6 months in dosages sufficient to improve motor function has only small effects on cognitive function and psychiatric status in mild to moderate PD patients. We conclude that motor symptoms in early PD, which result from dopamine depletion, are dissociable from cognitive functions and psychiatric status, which may be more dependent on nondopaminergic mechanisms.

Based on published prevalence studies, we used two different methodologies to project the number of individuals with Parkinson disease (PD) in Western Europe's 5 most and the world's 10 most populous nations. The number of individuals with PD over age 50 in these countries was between 4.1 and 4.6 million in 2005 and will double to between 8.7 and 9.3 million by 2030.

The cause of Parkinson disease (PD) remains unknown. Progress has been made on the genetic front with the identification of specific gene mutations (e.g., α-synuclein) associated with familial Parkinson syndromes. Because of their clinical heterogeneity there remains debate as to whether these genetic syndromes are representative of what has been considered classical PD. The identification of mutations in the parkin and LRRK2 genes in both familial and sporadic PD1,2 suggest that genetic mutations may be more common than previously estimated. Despite these advances, at least 80% of PD cases do not have a clear genetic or familial basis. The knowledge that different genetic mutations can produce the PD phenotype suggests that perhaps there is no single clinical entity PD, but rather that PD is an amalgamation of many different conditions that simply have a greater or lesser degree of phenotypic overlap. However, most clinicians and scientists still endorse the classical concept of idiopathic PD. See also pages 2021 and 2033 For the condition generally referred to as idiopathic PD and characterized by asymmetric onset of rest tremor, bradykinesia and rigidity, responsiveness to dopaminergic treatment, and the classic pathology of nigral degeneration with Lewy bodies, the cause remains unknown. Because genetic causes appear identifiable in only a minority of cases, there has been an extensive search for potential environmental causes. This search has been fueled by the identification of individuals who developed parkinsonism following exposure to MPTP through injection drug use and epidemiologic links between PD and environmental exposure to agricultural chemicals. Another environmental topic of recent interest has been the potential relationship between occupational welding fume exposure and PD. Welding fume is the cloud of smoke that is produced when welding metals. This fume, like cigarette smoke, is a combination of many different chemicals in a complex interaction. The …

Background: For early phase trials of novel interventions—such as gene transfer for Parkinson disease (PD)—whose focus is primarily on safety and tolerability, it is important that participants have a realistic understanding of the goals of such research. Recently, some have expressed concern that patients with PD may have unrealistic expectations.Methods: The authors examined why patients with PD might volunteer for invasive early phase research by interviewing 92 patients with PD and comparing those who would (n = 46) and those who would not (n = 46) participate in a hypothetical phase I gene-transfer study.Results: The two groups' demographic, clinical, functional, and quality of life measures, as well as their understanding of the research protocol, were similar. The groups did not differ on their perception of potential for personal benefit nor on the level of likelihood of benefit they saw as a precondition for volunteering. However, those willing to participate tended to perceive lower probability of risk, were tolerant of greater probability of risk, and were more optimistic about the phase I study's potential benefits to society. They also appeared more decisive and action-oriented than the unwilling group.Conclusions: It is likely that the decision whether to participate in early phase PD gene transfer studies will depend mostly on patients' attitudes regarding risk, optimism about science, and an action orientation, rather than on their clinical, functional, or demographic characteristics.

Many agents are being considered for treatment of Parkinson disease (PD). Given the large number of agents and the limited resources to evaluate new agents, it is essential to reduce the likelihood of advancing ineffective agents into large, long-term Phase III trials. Futility design methodology addresses this goal. The authors describe how a single-arm Phase II futility study uses a short-term outcome to compare a treatment group response to a predetermined hypothesized or historically based control response. The authors present advantages and limitations of futility designs along with examples derived from the data archive of a large Phase III efficacy study of treatments to delay PD progression, the Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism (DATATOP) trial. Using the same control progression rate and treatment effect assumptions used to power the original DATATOP trial, the authors calculated the number of subjects needed to conduct two 12-month futility studies. DATATOP was designed to enroll 800 patients. Using data on 124 consecutive subjects randomized into each of the DATATOP treatment groups, the authors identified tocopherol as futile and deprenyl as worthy of further study. Using Phase II information, DATATOP could have been simplified from a 2 × 2 factorial design to a comparison of deprenyl vs placebo. While not testing efficacy, futility designs provide a strategy for discarding treatments unlikely to be effective in Phase III. A limitation is the dependence on historical data or hypothesized outcomes for untreated controls. Futility studies may decrease the time to identify treatments unworthy of further pursuit and reduce subjects’ exposure to futile treatments.

Background: HIV infection is associated with a painful distal sensory polyneuropathy (DSP) that can severely limit the quality of life of affected subjects. The pathogenesis of DSP is unknown, although both HIV proteins and products of immune activation triggered by HIV infection have been implicated. Objective: To assess the association between baseline markers of immune activation and HIV RNA levels (viral load) and time to symptomatic DSP (SDSP). Methods: A cohort of 376 subjects, most receiving highly active antiretroviral therapy (HAART), were followed semiannually for up to 48 months. Blood and CSF levels of HIV viral load, monocyte chemotactic protein-1, macrophage colony-stimulating factor (M-CSF), matrix metalloproteinase-2, and tumor necrosis factor-α were measured in addition to CD4 lymphocyte cell count. Results: In subjects without SDSP at baseline (62.5% of the cohort), among the virologic and immunologic markers, only baseline CSF M-CSF levels were associated with time to SDSP (hazard ratio = 2.97, p = 0.05). The Kaplan–Meier estimate of the 1-year incidence of SDSP was 21%, a 15% decrease from that observed in the Dana cohort, a pre-HAART cohort enrolled with the same inclusion/exclusion criteria. Conclusion: Highly active retroviral therapy (HAART) has changed the natural history of HIV-associated symptomatic distal sensory polyneuropathy (SDSP), which may explain, in contrast with studies from the pre-HAART era, the lack of association between SDSP and baseline HIV viral load and CD4 cell count.

To determine whether motor, behavioral, or psychiatric symptoms in Huntington disease (HD) predict skilled nursing facility (SNF) placement.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 chi2 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.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, p0.0001); were more likely to have obsessions, compulsions, delusions, and auditory hallucinations; and had more aggressive, disruptive (p0.0001), 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.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.

Current federal regulations allow a legally authorized representative (LAR) to give permission on behalf of another person to participate in research, but defer to the states to define LAR. Since most states have not addressed the issue, most researchers and Institutional Review Boards currently operate in a gray area of law and ethics when it comes to proxy consent for adult research. Despite decades of discussion, a consensus remains elusive.1 But what we are learning about the decisionally impaired may help inform future policy. The article by Guerrera et al. in this issue of Neurology 2 (although their focus is on treatment consent) adds to the growing body of neuropsychological studies on decision-making capacity3 by showing that, even across various instruments for assessing decisional abilities, there may be informative neuropsychological underpinnings to each ability. We are also learning that the abilities of persons with dementia challenge the stereotypes often assumed in policy discussions. For example, …

Clinical research and practice in neurology are rapidly changing with the development and introduction of new therapies. Within the past 3 years, specific treatments have been introduced for disorders that were previously considered untreatable, including ischemic stroke, amyotrophic lateral sclerosis, multiple sclerosis, and Alzheimer's disease. In addition, a flood of new therapeutic agents, some representing novel pharmacologic classes, are being introduced for the treatment of epilepsy and Parkinson's disease. After years of slow discovery of therapeutic agents, this veritable deluge of therapeutic options may be overwhelming for clinicians. Moreover, there is a vast array of other interventions currently in development that will complement the compounds that are already marketed. Neurology has always sought to publish information on new treatments; however, we intend to take additional steps to make experimental therapeutics a major focus of the journal. The development and reporting of new treatments will have a critical impact on the lives of our patients, the practice of neurology, and the planning of future basic and clinical research. To make Neurology as useful as possible to authors and clinicians, we will expedite publication of important clinical trials (see preceding editorial) and publish well-designed and conducted clinical trials regardless of the outcome of the study. Journals have sometimes had a bias toward publishing "positive" (regarding therapeutic benefit) studies while relegating "negative" studies to appear as abstracts or to less available venues. "Positive" studies with methodologic deficiencies have been prominently published, while "negative" studies with more methodologic rigor have not. We will focus on publishing more rigorously designed studies, specifically those using a control group, randomization, and a method of blinding, instead of publishing studies with weaker designs. Uncontrolled, nonrandomized, unblinded studies will be considered for publicationas Brief Communications or Clinical/Scientific Notes but will rarely be appropriate for publication as full-length articles. Such …

In an ideal world, clinicians would decide on the relative merits of treatments based on high-quality evidence from randomized, double-blind, controlled clinical trials. The need for such evidence is particularly acute when there are several treatments available but no trials comparing efficacy. In this issue of Neurology , two randomized clinical trials report the relative benefits of different strategies of MS treatment with parenteral interferons. Although both interferon β-1a and interferon β-1b have been shown to delay the progression of disability in relapsing-remitting MS, there remains uncertainty about the relative benefits of the products available, as well as the optimal dosage, route, and frequency of administration of those products. The study by Clanet et al.1 was a randomized, double-blind, parallel group trial of two dosages of interferon β-1a. The participants were followed for a minimum of 3 years and the primary outcome variable was the time from randomization until a sustained increase of 1 or more points on …

The level of concern about conflicts of interest in medical literature is at an all-time high. A recent Neurology editorial1 and American Academy of Neurology (AAN) position statement2 focus on financial conflicts of interest in the patient care setting, in academic institutions, and for members of AAN committees and AAN office holders. Equally important conflicts of interest pertain to the publishing of Neurology . A conflict of interest exists when an individual (e.g., an author, reviewer, or editor) must make a judgment concerning a primary interest (publishing high-quality research), but is unduly influenced by secondary interests (such as financial gain or personal relationship to an author or others).3 In Thompson's view of conflict-of-interest situations,3 the secondary interest is usually legitimate and may be a necessary and desirable part of the life of the professional who must make such judgments. Thus, the secondary interests only become an issue when they are given sufficient weight to perhaps inappropriately influence judgment, whether or not the judgment is altered. Because a conflict of interest may impair the integrity of judgment, or cause reasonable persons to believe that the judgment has been improperly influenced,3-4 conflict-of-interest situations are usually regulated to prevent this actual or perceived impairment of judgment. The two main features of regulation are disclosure that a conflict of interest exists and prohibition or avoidance of certain conflicts of interest. The decision to prohibit certain conflicts of interest is based on the likelihood that professional judgment will be influenced, or appear to be influenced, and that this …

HIV infection of the CNS probably occurs shortly after initial systemic infection, although in most individuals productive CNS infection develops only after immunosuppression. HIV-associated dementia (HAD) is a predominantly subcortical dementia that occurs in 15 to 20% of individuals with HIV infection. HAD is a chronic encephalitis with active HIV replication predominantly targeting macrophages and microglia. Macrophages are activated and evidence of immune activation correlates with the severity of neurologic disease. Despite the prevalence of HAD and the rapid pace of antiretroviral drug development leading to Food and Drug Administration (FDA) approval of 16 agents in the United States since 1987, only three placebo-controlled trials of antiretroviral therapy for HIV-associated cognitive impairment have been completed—two studying zidovudine monotherapy1,2 and the third and most recent, the addition of abacavir to standard antiretroviral regime.3 The relative dearth of controlled trials for HAD represents, in part, the successful validation of plasma viral load as an efficient and reliable surrogate marker of drug efficacy for systemic infection and the lack of such a surrogate marker for CNS infection. The FDA now approves new antiretrovirals on the basis of changes in plasma viral load. Mounting complex clinical trials where the outcome may be changes …

The authors conducted a pilot randomized, double-blind, placebo-controlled clinical trial of the transdermal administration of selegiline in HIV+ patients to obtain preliminary data to assess its safety, tolerability, and impact on HIV-associated cognitive impairment. Both selegiline and placebo were well tolerated with few adverse events. Improvements favoring the selegiline group were suggested on single tests of verbal memory and motor/psychomotor performance, warranting a larger study.

Objective: To assess the safety and tolerability of lexipafant in HIV-associated cognitive impairment. Background: Cognitive impairment is the most common neurologic complication of advanced HIV-1 infection. There is evidence that a variety of inflammatory mediators, including platelet-activating factor (PAF), may contribute to neuronal injury. We hypothesized that lexipafant, a PAF antagonist, might improve cognitive dysfunction in HIV-infected people. Methods: We conducted a randomized, double-blind, placebo-controlled clinical trial to assess the safety and tolerability of lexipafant 500 mg/day. The primary outcome measure for tolerability was the ability to complete the study on the originally assigned dosage of medication. Thirty patients with cognitive impairment were enrolled. Results: Lexipafant was safe and well tolerated. Ninety-three percent in the placebo group and 88% in the lexipafant group completed the study at the originally assigned dosage. Trends toward improvement were seen in neuropsychological performance, especially verbal memory, in the lexipafant treatment group. Conclusions: This study shows that lexipafant, the first PAF antagonist used in HIV-associated cognitive impairment, is a safe and well tolerated compound. The observed trends toward improvement in neuropsychological test scores warrant the pursuit of a larger and longer efficacy trial to assess the impact of lexipafant on cognitive performance.

Movement Disorders: Neurologic Principles and Practice by Ray L. Watts and William C. Koller , 779 pp., ill., New York, NY, McGraw-Hill Corporation, 1997, $125.00 Watts and Koller have produced a comprehensive textbook on movement disorders suitable for general neurologists as well as subspecialists in movement disorders. Although the volume has contributions from over 80 authors, there is a clear effort to provide consistency in terminology and writing style. Despite this effort there is some unevenness of the chapters. The …