Gabriele Arendt

Immune surveillance in multiple sclerosis patients treated with natalizumab.

Our objective was to test whether natalizumab, an antibody against very late activating antigen (VLA)‐4, interferes with central nervous system immune surveillance as assessed by leukocyte cell numbers and cellular phenotypes in cerebrospinal fluid (CSF) and peripheral blood.

HIV dementia: the role of the basal ganglia and dopaminergic systems.

The clinical features of human immunodefiency virus (HIV) dementia exhibit the hallmarks of a subcortical dementia. These features include psychomotor slowing, apathy, bradykinesia and altered posture and gait similar to those observed in advanced Parkinsons disease. The dementia has the hallmarks attributed to subcortical dementia. The exquisite sensitivity of many of these patients to dopamine receptor blockade suggested a profound and, perhaps, selective abnormality of striatal dopaminergic systems. Additional investigations, electrophysiological, pathological, virological, metabolic and radiological studies, indicate that the basal ganglia are a major target of HIV infection. In this review, we describe the evidence for involvement of basal ganglia and, in particular, the dopaminergic systems, in HIV dementia. We also suggest novel therapeutic strategies that may be beneficial in the treatment of this disorder.

A placebo-controlled trial of gabapentin for painful HIV-associated sensory neuropathies

Abstract.Background:Painful HIV-associated sensory neuropathies (HIV-SN) are a common complication of HIV infection. The pathogenesis is unknown and the treatment very limited. Gabapentin (GBP) is effective in painful diabetic neuropathy and postherpetic neuralgia and its effectiveness on painful HIV-SN has been reported anecdotally.Design:Multicenter, prospective, randomised, double-blind, placebo-controlled study.Methods:Patients were followed for a 1-week screening, a 4-week double-blind and a 2-week open treatment phase. GBP was initiated at 400 mg/d, titrated over 2 weeks to 1200 mg/d, and then either maintained at this level or—if not beneficial—titrated to 2400 mg/d. After 4 weeks the medication was unblinded and the patient had the choice to begin, to maintain or to increase GBP to 3600 mg/d. The primary outcome measure was an improvement in median pain on the Visual Analogue Scale (VAS) from the screening week compared to the 4th treatment week. A secondary efficacy measure was the median sleep score (VAS).Results:15 patients received GBP and 11 placebo. In each group one patient dropped out during the doubleblind phase. Median pain (GBP 5.1; placebo 4.7) and sleep score (GBP 4.5; placebo 5.6) did not differ between both groups at baseline. In the GBP-group there was a significant decrease of the pain to 2.85 (–44.1 %) as well as of the sleep VAS to 2.3 (–48.9 %). No significant decrease in the pain (median VAS=3.3, –29.8 %) as well as in the sleep score (median VAS=4.95, –11.6 %) was observed in the placebo-group. GBP was generally well tolerated. The most frequent side effect was somnolence reported in 80% of GBP-treated patients.Conclusions:GBP was more effective than placebo in reducing pain and sleep interference in patients with HIV-SN.

Motor dysfunction in HIV-infected patients without clinically detectable central-nervous deficit

SummaryMotor tests were performed in 50 HIV-infected patients in all stages according to the current CDC classification, but without any clinically evident central nervous system deficit, and the results compared with an age-matched control group. Patients were excluded from the study if there was alcohol or drug abuse, fever and/or opportunistic cerebral infection. The parameters tested were postural tremor of the outstretched hands, most rapid voluntary alternating index finger movements (MRAM) and rise time of most rapid index finger extensions (MRC). Whereas tremor peak frequencies did not differ significantly in the patients and controls, MRAM and rise times of MRCs showed significant slowing in the patient group. Morphologically, the motor test performance of the HIV-infected patients was similar to that of patients with manifest basal ganglia disease (Parkinsons, Huntingtons and Wilsons diseases). MRI scans of all patients were normal. It is concluded that in HIV-infected patients there is a very early subclinical central nervous system affection, especially of the basal ganglia, which is detectable with appropriate, quantitative motor function tests. These functional abnormalities precede the structural alterations in the MRI scans.

Neuropsychiatric side effects of efavirenz therapy

The non-nucleoside analogue inhibitor of the reverse transcriptase, efavirenz (EFV), has become commonly used in highly active antiretroviral combination therapy in the treatment of HIV infection. Although being effective in suppressing plasma viral load, neuropsychiatric side effects have been reported in individuals treated with EFV. There are early complications, such as acute psychosis resembling reactions to LSD intake, as well as nightmares occurring for several days up to 4 weeks after the start of therapy. Although LSD-like psychosis provokes the necessity of therapy discontinuation, the nightmares, as well as irritability and concentration problems in daily life, disappear after several weeks of treatment. Late complications are depressive episodes that must be carefully differentiated from pre-existing psychiatric disease and virus-induced brain damage. This review describes neuropsychiatric symptoms provoked by EFV, differential-diagnostic procedures and treatment options, and provides pros and cons for EFV use in clinical practice with respect to drug safety.

Motor analysis predicts progression in HIV-associated brain disease

One hundred HIV-positive individuals without clinically evident central nervous system (CNS) deficits entered this follow-up study and were examined clinically and with a well-defined motor test battery every 3 months over 2 years or until they decreased. They underwent magnetic resonance tomography once a year. None received any form of therapy at onset of the study. Three groups were analyzed: (A) patients without electrophysiologically detectable motor impairment (n = 23), (B) patients with electrophysiologically detectable motor impairment but no virostatic medication (n = 33), and (C) patients with motor deficits undergoing AZT treatment (n = 44) after study onset. Group A patients, although slightly deteriorating over time, had the best clinical and electrophysiological outcome compared to the other groups, whereas group B patients deteriorated markedly in both clinical and electrophysiological tests, even though the majority did not develop cerebral complications during the observation period. Those group C patients belonging to early CDC stages (II and III) improved electrophysiologically under AZT therapy, while 76% of the patients in more advanced stages (CDC IVA-D) died of cerebral AIDS manifestations. Four patients of this group, being alive at the end of the study, were completely demented. It is suggested that early detectable motor impairment predicts future cerebral involvement in AIDS. Late onset of virostatic treatment did not influence the clinical outcome.

Cognitive impairment in HIV infection is associated with MRI and CSF pattern of neurodegeneration.

Biomarkers as indicators for the progression of human immunodeficiency virus (HIV)‐associated neurocognitive disorders (HAND) remain still elusive. We performed a cross‐sectional study to analyze the correlation between cognitive impairment, abnormalities in magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) markers of neurodegeneration in HIV‐infected patients.

Therapeutic effects of nonnucleoside reverse transcriptase inhibitors on the central nervous system in HIV-1-infected patients.

Summary: Psychomotor slowing predicts the development of HIV‐1‐associated dementia, AIDS, and death independent of immune status. We retrospectively selected all patients who showed pathologic psychomotor slowing as a sign of central nervous system (CNS) dysfunction before the onset of therapy and who were then treated with nonnucleoside reverse‐transcriptase inhibitors—either efavirenz (EFV) (n = 65 patients) or nevirapine (NVP) (n = 39 patients), each given in combination with two nucleoside analogues (NAs). Patients who were treated only with two NAs (n = 66) served as controls. Patients were observed for 6 months. Both EFV and NVP combinations improved CNS function as determined by electrophysiologic motor tests. The therapeutic effects of EFV and NVP did not depend on the type of NA added. Although results did not reach significance, NVP combinations were more effective than EFV combinations or therapy regimens with NAs alone in patients who were naive to all antiretroviral therapy. EFV and NVP combinations were equally effective in patients pretreated with highly active antiretroviral therapy, including protease inhibitors.

Association of human polyomavirus JC with peripheral blood of immunoimpaired and healthy individuals

JC virus (JCV) infection is regularly asymptomatic in healthy individuals. In contrast, in immunocompromised individuals, highly activated virus replication may lead to PML. Peripheral blood cells (PBCs) are found to habor JCV DNA in healthy and diseased individuals and it is discussed that they might be responsible for dissemination of the virus to the central nervous system (CNS) during persistence. To better understand the role of JCV DNA in PBCs for persistent infection and pathogenesis, the authors characterized the extent of JCV infection in Ficoll-gradient purified blood cells (peripheral blood mononuclear cells [PBMCs]) of healthy and human immunodeficiency virus type 1 (HIV-1)-infected individuals. Virus activation in PBMCs from healthy JCV-infected individuals was found at a rate of 0% to 38% at low polymerase chain reaction (PCR) sensitivity. In progressive multifocal leukoencephalopathy (PML) patients, a stronger signal was found, indicating increased virus activation. JCV DNA was regularly detected in T and B lymphocytes and in monocytes at low levels. However, granulocytes were shown to be the predominant reservoir of JCV DNA harboring high copy numbers. Although the overall distribution of viral genomes holds true for the population studied, in the individual, a markedly changed pattern of distribution can be found.

CD34+ progenitor cells mobilized by natalizumab are not a relevant reservoir for JC virus

Background: Progressive multifocal leukoencephalopathy (PML) is associated with natalizumab treatment in patients with multiple sclerosis (MS). It has been hypothesized that natalizumab mobilizes JC virus (JCV)-infected haematopoietic progenitor cells mediating viraemia and subsequently this disease. Objective: The objective of this study was to investigate peripheral haematopoietic progenitor cells for evidence of JCV DNA in MS patients treated with natalizumab. Methods: We assessed JCV and cytomegalovirus (CMV) DNA in magnetically separated CD34+ haematopoietic progenitor cells, peripheral blood mononuclear cells and plasma of 67 natalizumab-treated patients with MS and six PML patients. Results: Viral DNA was not detectable in CD34+ haematopoietic progenitor or peripheral blood mononuclear cells from any sample. Two plasma samples from patients with MS while undergoing natalizumab treatment were JCV-positive. In one case clinically manifest PML developed 8 months thereafter. Conclusions: Our findings do not support the hypothesis that natalizumab mobilizes JC virus-infected CD34+ cells from the bone marrow mediating JC viraemia. Notably, JC viraemia was detected in one patient with MS prior to developing clinical PML. This warrants further study.