A phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection. AIDS Clinical Trials Group Team 291.

Objective: To evaluate the safety and efficacy of recombinant human nerve growth factor (rhNGF) in HIV-associated sensory neuropathy (SN) within a multicenter, placebo-controlled, randomized trial (ACTG 291).

Background: SN affects 30% of individuals with AIDS, is worsened by neurotoxic antiretrovirals, and its treatment is often ineffective. NGF is trophic for small sensory neurons and stimulates the regeneration of damaged nerve fibers.

Human immunodeficiency virus-associated dementia.

HIV-associated dementia will eventually develop in 15-20% of individuals with advanced HIV disease. It has become one of the leading causes of dementia in the young, with 10,000 new cases annually in the USA. The clinical syndrome includes progressive development of psychomotor slowing and memory impairment, eventually with brain atrophy and neurol loss.

Incidence of neuropathy in HIV-infected patients on monotherapy versus those on combination therapy with didanosine, stavudine and hydroxyurea.

Background: Sensory neuropathy is a common adverse effect of the nucleoside analogue anti-retroviral drugs didanosine (ddl) and stauvudine (d4T). These drugs are increasingly being used in combination, and it is not currently known whether the incidence of neuropathy is higher with combination compared to individual drug use. It is also not known if hydroxyurea, used to potentiate the antiviral efficacy of these drugs, may also increase the risk of neuropathy.

Transdermal selegiline in HIV-associated cognitive impairment: pilot, placebo-controlled study.

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.

Progressive multifocal leukoencephalopathy in AIDS: are there any MR findings useful to patient management and predictive of patient survival? AIDS Clinical Trials Group, 243 Team.

Background And Purpose: While MR findings in progressive multifocal leukoencephalopathy (PML) have been described previously, usually in retrospective studies with limited sample size, what has not been well addressed is whether any are predictive of longer survival. Our participation in a large prospective clinical trial of AIDS patients with biopsy-proved PML and MR correlation allowed us to test our hypothesis that certain MR features could be found favorable to patient survival.

Methods: The patient cohort derived from a randomized multicenter clinical trial of cytosine arabinoside for PML.

Epidermal nerve fiber density and sural nerve morphometry in peripheral neuropathies.

Objective: To study intraepidermal nerve fiber (IENF) density in distal leg skin biopsies, sural nerve morphometry, electrophysiology, and clinical features in patients with peripheral neuropathies.

Methods: We studied 26 patients with neuropathic complaints who had undergone clinical evaluation, nerve conduction studies, distal leg skin biopsy, and sural nerve biopsy. We quantified densities of IENF and of myelinated and unmyelinated fibers in the sural nerve.

A decision guideline for emergency department utilization of noncontrast head computed tomography in HIV-infected patients.

Objective: To determine which neurologic signs or symptoms are predictive of new focal lesions on head CT in HIV-infected patients.

Methods: Prospective study with convenience sample enrollment of HIV-infected patients who presented to a large inner-city university-based ED over an 11-month period. Patients were assessed using a standardized neurologic evaluation to ascertain whether they had developed new or changed neurologic signs or symptoms.

Cerebrospinal fluid levels of MMP-2, 7, and 9 are elevated in association with human immunodeficiency virus dementia.

Pathological evidence suggests that alterations of the blood-brain barrier (BBB) may occur in association with human immunodeficiency virus (HIV) dementia (HIVD). Increased BBB permeability could contribute to the development of dementia by facilitating the entry of activated and infected monocytes, as well as potentially toxic serum proteins, into the central nervous system. One mechanism by which BBB permeability may be altered is through increased activity of select matrix metalloproteinases (MMPs).

Randomized trial of the platelet-activating factor antagonist lexipafant in HIV-associated cognitive impairment. Neurological AIDS Research Consortium.

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.

Epidermal innervation: changes with aging, topographic location, and in sensory neuropathy.

In previous work we demonstrated little effect of aging on the density and spatial pattern of epidermal innervation, however, this was restricted to two sites proximal and distal in the leg. To expand on these observations, we used punch skin biopsy in ten healthy controls to examine the variation in intra-epidermal nerve fiber (IENF) density at multiple specific sites in the leg. There was a consistent gradient in IENF from proximal to distal sites in all subjects, but minimal effect of age was noted.

Combination antiretroviral therapy improves psychomotor speed performance in HIV-seropositive homosexual men. Multicenter AIDS Cohort Study (MACS).

Background: Combination antiretroviral therapy including protease inhibitors (combo+PI) is effective in suppressing systemic viral load in HIV infection, but its impact on HIV-associated cognitive impairment is unclear.

Objective: To determine whether psychomotor speed, a sensitive measure of impairment in HIV dementia, improves with combo+PI compared with other antiretroviral treatments.

Methods: A total of 411 HIV-seropositive (HIV+) homosexual men (with longitudinal neuropsychological testing) in the Multicenter AIDS Cohort Study and, in a separate analysis, 282 HIV+ homosexual men with psychomotor slowing at baseline were classified by treatment into four groups: antiretroviral naive (no antiretroviral medication treatment), monotherapy, combination antiretroviral therapy without protease inhibitors (combo-noPI), and combo+PI.

HIV-associated primary CNS lymorbidity and utility of brain biopsy.

Introduction: Human immunodeficiency virus (HIV) infection is associated with several central nervous system (CNS) infections and neoplasms. These opportunistic processes generally occur with advanced immunosuppression, but if an accurate diagnosis is made, effective treatment can frequently be initiated.

Methods: In an attempt to assess the safety, diagnostic yield, and utility of stereotactic brain biopsy in the clinical management of suspected HIV-associated primary CNS lymphoma, we retrospectively studied the performance of biopsy in HIV-seropositive patients presenting with focal intracranial lesions.

Quantitative analysis of epidermal innervation in Fabry disease.

Objective: To use skin biopsy specimens to quantitate the cutaneous innervation density of Fabry patients who had preserved renal function.

Background: The small fiber neuropathy of Fabry disease is difficult to detect and quantitate by conventional methods. Because this neuropathy is a common characteristic of Fabry disease, quantitating changes in this parameter would be helpful in demonstrating the effectiveness of enzyme or gene replacement therapy.

Rate and severity of HIV-associated dementia (HAD): correlations with Gp41 and iNOS.

Background: Fifteen to thirty percent of AIDS patients develop some type of neurologic disorder during the course of their illness and the vast majority of these neurologic disorders will be HIV-associated dementia (HAD). These patients can exhibit varying degrees of severity and rates of progression of HAD. Neuropathologic variables that are associated with the rate of progression of HAD are not known.

HAART improves prognosis in HIV-associated progressive multifocal leukoencephalopathy.

Introduction of highly active antiretroviral therapy (HAART) has been associated with many changes in the complications of human immunodeficiency virus (HIV) infection. A cohort of 25 HIV patients with progressive multifocal leukoencephalopathy (PML) treated with HAART experienced a median survival of >46 weeks. This is an improvement in prognosis compared with recent historic experience and correlated with HIV RNA viral load reductions.

Plasma viral load and CD4 lymphocytes predict HIV-associated dementia and sensory neuropathy.

Objective: To determine the predictive value of plasma HIV RNA and CD4 lymphocytes for HIV-associated dementia and sensory neuropathy.

Methods: A total of 1,604 AIDS-free HIV seropositive men from the Multicenter AIDS Cohort Study were followed over a 10-year period (1985 to 1995). HIV-associated dementia and sensory neuropathy were diagnosed according to standard definitions.

Epidermal nerve fiber density: normative reference range and diagnostic efficiency.

Background: The sensitivity of neuron-specific antibodies permit the identification of the small unmyelinated nerve fibers within the skin.

Objectives: To develop a reference range of epidermal nerve fiber density in humans, and to evaluate their diagnostic efficiency for sensory neuropathies.

Methods: Ninety-eight normal controls (age range, 13-82 years) were examined with both directed neurologic examinations and quantitative sensory testing.

Beta-chemokines MCP-1 and RANTES are selectively increased in cerebrospinal fluid of patients with human immunodeficiency virus-associated dementia.

Human immunodeficiency virus-associated dementia (HAD) is associated with increased numbers of activated central nervous system (CNS) macrophages. Chemokines, which regulate infiltration of macrophages, were measured in the cerebrospinal fluid (CSF) of human immunodeficiency virus (HIV)-negative and HIV-positive individuals with and without neurological disease. Monocyte chemotactic protein (MCP)-1 and RANTES (but not MCP-3), macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, or interleukin-8 (IL-8) was higher in HAD.

Neuropathological alterations in diabetic truncal neuropathy: evaluation by skin biopsy.

Objectives: To describe the neuropathological features in skin biopsies from patients with diabetic truncal neuropathy.

Methods: Three patients with diabetic truncal neuropathy underwent skin biopsies from both symptomatic and asymptomatic regions of the chest and trunk. After local anaesthesia, biopsies were performed using a 3 mm diameter punch device (Acupunch).

Neuronal death induced by brain-derived human immunodeficiency virus type 1 envelope genes differs between demented and nondemented AIDS patients.

Human immunodeficiency virus type 1 (HIV-1) infection of the brain results in viral replication primarily in macrophages and microglia. Despite frequent detection of viral genome and proteins in the brains of AIDS patients with and without HIV dementia, only 20% of AIDS patients become demented. To investigate the role of viral envelope gene variation in the occurrence of dementia, we examined regions of variability in the viral envelope gene isolated from brains of AIDS patients.

Brain-derived HIV-1 tat sequences from AIDS patients with dementia show increased molecular heterogeneity.

HIV-1 infection results in a dementing illness affecting 20% of patients with AIDS. Several HIV-1 genes have been implicated in the pathogenesis of HIV-induced neurological disease. To search for distinct HIV-1 sequences associated with the development of dementia, brain-derived tat, env, and pol sequences were examined from AIDS patients defined pre-mortem as demented (HIV-D)[n=5] or non-demented (HIV-ND)[n=5].

A phase I/II trial of nimodipine for HIV-related neurologic complications.

Background: Few effective treatments are available for AIDS dementia complex (ADC) and HIV-associated neuropathy. However, recent in vitro studies indicate that nimodipine, a voltage-dependent calcium channel antagonist, can prevent HIV-related neuronal injury and may provide a novel form of treatment for these disorders.

Methods: To determine the safety and possible efficacy of this agent, 41 patients with mild to severe ADC, including 19 patients with neuropathy, were entered into the AIDS Clinical Trial Group multicenter, phase-I and phase-II study.

Small-fiber sensory neuropathies: clinical course and neuropathology of idiopathic cases.

We describe the clinical features, natural history, and neuropathology of 32 patients presenting with "burning feet," for whom no specific cause was identified. All had neuropathic pain in the feet and morphological abnormalities of cutaneous innervation in skin obtained using punch biopsy. Most (29) had an abnormal sensory examination.

Survival prolongation in HIV-associated progressive multifocal leukoencephalopathy treated with alpha-interferon: an observational study.

Unlabelled: A retrospective chart review was conducted to determine the effect of alpha-Interferon (alpha-IFN) on disease progression, symptom palliation, and survival in HIV-associated Progressive Multifocal Leukoencephalopathy (PML).

Methods: Subjects were HIV seropositive patients diagnosed with PML at the Johns Hopkins Hospital between 1985 and July of 1986. Diagnostic criteria for PML included both clinical symptomatology and histologic or radiographic confirmation.