[Zika virus infection and the nervous system]. / Zika-Virus-Infektion und das Nervensystem.

Zika virus is an arbovirus from the family of flaviviruses, which is transmitted by the mosquito Aedes aegyptii and also by the Asian mosquito Aedes albopticus. The largest observed Zika virus epidemic is currently taking place in North and South America, in the Caribbean, southern USA and Southeast Asia. In most cases the infection is an unspecific, acute, febrile disease. Neurological manifestations consist mainly of microcephaly in newborns and Guillain-Barré syndrome but other rare manifestations have also become known in the meantime, such as meningoencephalitis and myelitis. Therefore, the Zika virus, similar to other flaviviruses, has neuropathogenic properties. In particular, the drastic increase in microcephaly cases in Brazil has induced great research activities. The virus is transmitted perinatally and can be detected in the amniotic fluid, placenta and brain tissue of the newborn. Vaccination or a causal therapy does not yet exist. The significant increase in Guillain-Barré syndrome induced by the Zika virus was observed during earlier outbreaks. In the meantime, scientifically clear connections between a Zika virus infection and these neurological manifestations have been shown. Long-term studies and animal models should be used for a better understanding of the pathomechanisms of this disease.

The dopamine-related polymorphisms BDNF, COMT, DRD2, DRD3, and DRD4 are not linked with changes in CSF dopamine levels and frequency of HIV infection.

We showed previously that higher levels in CSF dopamine in HIV patients are associated with the presence of the dopamine transporter (DAT) 10/10-repeat allele which was also detected more frequently in HIV-infected individuals compared to uninfected subjects. In the current study, we investigated further whether other genetic dopamine (DA)-related polymorphisms may be related with changes in CSF DA levels and frequency of HIV infection in HIV-infected subjects. Specifically, we studied genetic polymorphisms of brain-derived neurotrophic factor, catechol-O-methyltransferase, and dopamine receptors DRD2, DRD3, and DRD4 genetic polymorphisms in uninfected and HIV-infected people in two different ethnical groups, a German cohort (Caucasian, 72 individuals with HIV infection and 22 individuals without HIV infection) and a South African cohort (Xhosan, 54 individuals with HIV infection and 19 individuals without HIV infection). We correlated the polymorphisms with CSF DA levels, HIV dementia score, CD4+ T cell counts, and HIV viral load. None of the investigated DA-related polymorphisms was associated with altered CSF DA levels, CD4+ T cell count, viral load, and HIV dementia score. The respective allele frequencies were equally distributed between HIV-infected patients and controls. Our findings do not show any influence of the studied genetic polymorphisms on CSF DA levels and HIV infection. This is in contrast to what we found previously for the DAT 3'UTR VNTR and highlights the specific role of the DAT VNTR in HIV infection and disease.

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

BACKGROUND AND PURPOSE: 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. METHODS: We enrolled 94 patients (82 men and 12 women; mean age 45 ± 10 years) with HIV infection, but without opportunistic infections of the CNS. All patients underwent MRI and CSF analysis. The global pattern of white matter signal intensity abnormalities, the index of atrophy, the severity of periventricular white matter abnormalities, and the severity of basal ganglia signal changes were analyzed. We measured CSF markers of neurodegeneration (total tau, phospho-tau, beta-amyloid). The findings of this evaluation were correlated with demographic and infection parameters of the patients in blood and CSF. RESULTS: We found a highly significant correlation between the severity of global brain atrophy, basal ganglia signal changes, and cognitive impairment in HIV-infected patients. Furthermore, cognitive impairment was significantly correlated with total tau, but not with phospho-tau or A-beta-amyloid in CSF analysis. CONCLUSIONS: Our results confirm the significant correlation between MRI changes and cognitive impairment in HIV infection. Furthermore, we could show that global brain atrophy and signal changes in basal ganglia are the typical MRI pattern in HAND. The correlation between cognitive impairment and total tau, but not phospho-tau, supports the hypothesis that HAND are not a subtype of Alzheimer's dementia.

[Neuro-AIDS in the cART era]. / Neuro-AIDS in der cART-Ära.

After the introduction of antiretroviral combination therapy for the treatment of HIV infection in 1996 (highly active antiretroviral therapy = HAART, nowadays called combination antiretroviral therapy = cART), a steady decline in infection associated complications had been expected, especially with respect to central and peripheral nervous system manifestations. Until the beginning of the new millenium this hope came in fact true, but since then there has been a slow, but constant rise in the prevalence, and later on also in the incidence of directly virus-associated neurological complications in HIV infected patients. HIV-associated diseases that neurologists might see in their routine work include HIV-associated dementia (HAD) and its precursor stages, HIV-associated myelopathy, HIV-associated polyneuropathies and myopathies as well as the opportunistic brain infections and immune reconstitution phenomena (IRIS). This article describes practical diagnostic procedures according to the guidelines of the German Neurological Society and the respective therapeutic options.

Impact of earlier HAART initiation on the immune status and clinical course of treated patients on the basis of cohort data of the German Competence Network for HIV/AIDS.

PURPOSE: Hitherto, studies on highly active antiretroviral therapy (HAART) initiation have shown partly inconsistent results. Our study investigated the clinical course and course of immune status after HAART initiation at CD4-cell-count/µl of treated patients between 250 and 349 (group 1), compared to 350-449 (group 2), on the basis of the cohort of the Competence Network for HIV/AIDS (KompNet cohort). METHODS: Patients had to be HAART-naïve. Medication had to start at the earliest in 1996, being at least triple combination therapy. The primary endpoints of death, first AIDS-defining illness and first drop of CD4-cell-count/µl below 200 were evaluated as censored event times between the initiation of HAART (t (0)) and the date of the first event/date of last observation. Probabilities of event-free intervals since t (0) were calculated by Kaplan-Meier estimation, compared by logrank tests. The results were adjusted for confounders using Cox regression. Additionally, incidences were estimated. RESULTS: A total of 822 patients met the inclusion criteria (group 1: 526, group 2: 296), covering 4,133 patient years (py) overall. In group 1, 0.64 death cases/100 py were found, with the corresponding vale being 0.17 in group 2. In group 1, 1.38 AIDS-defining events/100 py occurred, whereas it was 0.78 in group 2. In group 1, 2.64 events of first drop of CD4-cell-count/µl below 200 occurred per 100 py, compared to 0.77 in group 2. Kaplan-Meier estimations showed borderline significant differences regarding death (p = 0.063), no differences regarding first AIDS-defining illness (p = 0.148) and distinct differences regarding the first drop of CD4-cell-count/µl below 200 (p = 0.0004). CONCLUSIONS: The results gave a strong hint for a therapy initiation at higher CD4-cell-count/µl regarding the outcome of death in treated patients. A distinct benefit was shown regarding the first decline of CD4-cell-count/µl below 200.

Increased dopaminergic neurotransmission in therapy-naïve asymptomatic HIV patients is not associated with adaptive changes at the dopaminergic synapses.

Central dopaminergic (DA) systems are affected during human immunodeficiency virus (HIV) infection. So far, it is believed that they degenerate with progression of HIV disease because deterioration of DA systems is evident in advanced stages of infection. In this manuscript we found that (a) DA levels are increased and DA turnover is decreased in CSF of therapy-naïve HIV patients in asymptomatic infection, (b) DA increase does not modulate the availability of DA transporters and D2-receptors, (c) DA correlates inversely with CD4+ numbers in blood. These findings show activation of central DA systems without development of adaptive responses at DA synapses in asymptomatic HIV infection. It is probable that DA deterioration in advanced stages of HIV infection may derive from increased DA availability in early infection, resulting in DA neurotoxicity. Our findings provide a clue to the synergism between DA medication or drugs of abuse and HIV infection to exacerbate and accelerate HIV neuropsychiatric disease, a central issue in the neurobiology of HIV.

HIV or HIV-therapy? Causal attributions of symptoms and their impact on treatment decisions among women and men with HIV.

OBJECTIVES: Among people with HIV, we examined symptom attribution to HIV or HIV-therapy, awareness of potential side effects and discontinuation of treatment, as well as sex/gender differences. METHODS: HIV-patients (N=168, 46% female) completed a comprehensive symptom checklist (attributing each endorsed symptom to HIV, HIV-therapy, or other causes), reported reasons for treatment discontinuations and potential ART-related laboratory abnormalities. RESULTS: Main symptom areas were fatigue/sleep/energy, depression/mood, lipodystrophy, and gastrointestinal, dermatological, and neurological problems. Top HIV-attributed symptoms were lack of stamina/energy in both genders, night sweats, depression, mood swings in women; and fatigue, lethargy, difficulties concentrating in men. Women attributed symptoms less frequently to HIV than men, particularly fatigue (p<.01). Top treatment-attributed symptoms were lipodystrophy and gastrointestinal problems in both genders. Symptom attribution to HIV-therapy did not differ between genders. Over the past six months, 22% switched/interrupted ART due to side effects. In women, side effect-related treatment decisions were more complex, involving more side effects and substances. Remarkably, women took predominantly protease inhibitor-sparing regimens (p=.05). Both genders reported only 15% of potential ART-related laboratory abnormalities but more than 50% had laboratory abnormalities. Notably, women had fewer elevated renal parameters (p<.01). CONCLUSIONS: Men may attribute symptoms more often to HIV and maintain a treatment-regimen despite side effects, whereas women may be more prudent in avoiding treatment side effects. Lacking awareness of laboratory abnormalities in both genders potentially indicates gaps in physician-patient communication. Gender differences in causal attributions of symptoms/side effects may influence treatment decisions.

[Highly active antiretroviral therapy of neuro-AIDS. Side effects on the nervous system and interactions]. / Hochaktive antiretrovirale Therapie bei Neuro-AIDS. Nebenwirkungen auf das Nervensystem und Interaktionen.

Highly active antiretroviral therapy (HAART) has increased the mean survival time in the AIDS stage to sometimes more than 10 years. Five different groups of antiretroviral medications are known, of which integrase inhibitors and CCR5 antagonists represent the newest and most modern substances. The long AIDS survival time implies that side effects and interactions become relatively more important and must be differentiated from the symptoms of HIV itself. Side effects of HAART concern the central and peripheral nervous system and the muscles. The neurotoxicity of the components in HAART varies considerably and depends on the substance itself. Knowledge of side effects and interactions of HAART with antiepileptics, antidepressants, and analgetics are essential for the treatment of patients with neuro-AIDS.

[Severe aseptic leucoencephalopathy. Manifested as immune reconstitution inflammatory syndrome in Caucasian and African patients]. / Schwere Leukenzephalopathie. Manifestationsform des aseptischen Immune-reconstitution-inflammatory-Syndroms bei Kaukasiern und Afrikanern.

BACKGROUND: We hypothesize that CNS immune reconstitution inflammatory syndrome (IRIS) after highly active antiretroviral therapy (HAART) in HIV-1-positive patients may become manifest without any opportunistic infection as an aseptic leucoencephalopathy. This opens a window of opportunity for successful treatment with corticosteroids. DESIGN: We describe a case series of immunocompromised HIV-1-positive patients who were started on HAART. All of them had clinical laboratory follow-up tests and cerebral MRI in order to investigate the course and the underlying pathophysiology of this aseptic form of IRIS. One African patient died and we performed a neuropathological examination. RESULTS: No infectious agent was detected before and during HAART. Three of four immunocompromised patients were successfully treated with corticosteroids while HAART was never interrupted and have survived up to now. One African patient died within 2 days despite intensive care due to cerebral oedema. CONCLUSIONS: Starting HAART, HIV-1-positive patients may develop an aseptic type of IRIS of the CNS without any detectable opportunistic infection, a finding that has not yet been published. This makes them susceptible for successful treatment with corticosteroids. Perhaps IRIS has a higher incidence in African patients and the patients have a poorer outcome than Caucasians.

Recommendations for the classification of HIV associated neuromanifestations in the German DRG system.

HIV associated neuromanifestations are of growing importance in the in-patient treatment of HIV infected patients. In Germany, all in-patients have to be coded according to the ICD-10 classification and the German DRG-system. We present recommendations how to code the different primary and secondary neuromanifestations of HIV infection. These recommendations are based on the commentary of the German DRG procedures and are aimed to establish uniform coding of neuromanifestations.

[Neurological manifestations of the HIV infection]. / Immer häufiger und in immer mehr klinischen Erscheinungsformen. Neurologische Manifestationen der HIV-Infektion.

As a result of improved therapeutic possibilities with highly active antiretroviral therapy (HAART), an increasing prevalence of neurological complications of the HIV infection is observed. In particular, some authors now also describe a "morphogenesis" of the HIV-1-related encephalopathy. The current state of knowledge should be taken into account in the diagnostics and therapy of HIV-1-related encephalopathy, depression, progressive multifocal leukencephalopathy and polyneuropathy.

Therapeutic effects of nucleoside analogues on psychomotor slowing in HIV infection.

OBJECTIVE: Since psychomotor slowing predicts the development of HIV-1-associated dementia, AIDS and death independently of the immune status, there is urgent need for a neurological therapeutic rationale. METHODS: The therapeutic efficacy of nucleoside analogues with different abilities to penetrate into the cerebrospinal fluid was assessed in 410 HIV-1-seropositive patients using the results of detailed fine motor tests, which detect minor motor deficits. Patients were selected who showed pathological psychomotor slowing as signs of central nervous system (CNS) dysfunction before therapy onset and who were then treated only with nucleoside analogues for at least 6 months. RESULTS: Both zidovudine and didanosine improve CNS function to an equal degree when given as monotherapy. Adding a second nucleoside analogue (didanosine, lamivudine, zalcitabine) to zidovudine does not further improve psychomotor performance. However, adding a second nucleoside after a period of zidovudine monotherapy does result in a second but less remarkable therapeutic effect. Combinations containing stavudine are as effective as those including zidovudine when given as first antiretroviral treatment. Furthermore, stavudine effectively improves motor performance even after pretreatment with zidovudine.

Soluble cerebrospinal fluid factors induce Ca2+ dysregulation in rat cultured cortical astrocytes in HIV-1-associated dementia complex.

OBJECTIVES: To investigate the effect of cerebrospinal fluid (CSF) of HIV-1-seropositive patients with and without HIV-1-associated dementia complex (HADC) on the intracellular Ca2+ regulation of cultured cortical astrocytes. DESIGN: In a blinded study the effects of CSF samples from HADC patients and from HIV-1-seropositive but not demented patients on intracellular Ca2+ regulation of cultured cortical astrocytes were investigated. Astrocytes were chosen because they contribute to both electrophysiological and immunological processes within the brain. METHODS: Astrocytes were incubated in CSF samples for 1 h, loaded with the Ca2+ indicator dye Fura-2 and intracellular Ca2+ responses upon glutamate application were measured. RESULTS: CSF samples from 10 out of 11 HADC patients induced a significant reduction of the intracellular Ca2+ increase upon glutamate application. On the contrary, seven out of 10 CSF samples from HIV-1-seropositive patients without HADC as well as 10 out of 10 CSF samples from HIV-1-seronegative controls did not affect the intracellular Ca2+ response. CONCLUSIONS: Our data strongly confirm the hypothesis that CSF samples of HADC patients contain soluble factors which interfere with the function of astrocytes. These factors may include HIV-1 proteins, locally released cytokines or neurotoxins.

Control of posture in patients with neurologically asymptomatic HIV infection and patients with beginning HIV-1-related encephalopathy.

OBJECTIVE: Stance control measurements (sway velocity, sway area, and postural reflexes) were performed in 36 patients with neurologically asymptomatic human immunodeficiency virus infection (HIV) and in 10 patients with beginning HIV type 1 (HIV-1)-related encephalopathy. All recordings were performed using a movable platform system. OBSERVATIONS: Static posturography and postural reflexes revealed pathologic results in patients with beginning HIV-1-related encephalopathy and in about 25% of patients with nonsymptomatic HIV infection in comparison with age- and sex-matched control subjects. CONCLUSIONS: Postural control is well preserved in early HIV infection; thus, it is not an appropriate measure for detecting subclinical deficits, but disturbances of postural control seem to be one of the first neurological abnormalities in patients with beginning HIV-1-related encephalopathy.

Potential time course of human immunodeficiency virus type 1-associated minor motor deficits: electrophysiologic and positron emission tomography findings.

BACKGROUND: We tested whether metabolic abnormalities in the prefrontal-striatal circuitry as demonstrated by positron emission tomography (PET) were present in patients seropositive for human immunodeficiency virus type 1 (HIV-1) with HIV-1-associated minor motor deficits as demonstrated by quantitative motor testing. PATIENTS: We examined 19 HIV-1-positive patients, covering the range from normal results of quantitative motor testing to clearly pathologic psychomotor slowing indicative of HIV-1-associated minor motor deficits. None fulfilled the clinical criteria for HIV-1-associated dementia. Results were compared with those of 15 healthy volunteers. METHODS: All subjects underwent clinical examination, routine magnetic resonance (MR) imaging, and electrophysiologic motor testing at the time of PET. RESULTS: Seven HIV-1-positive patients showed significant hypermetabolism in the basal ganglia. Nine patients showed a significant frontomesial hypometabolism. CONCLUSIONS: The data of our cross-sectional study strongly suggest a characteristic time course in the development of HIV-1-associated minor motor deficits. Hypermetabolism in the basal ganglia is associated initially with normal motor performance. Moderate motor slowing appears at a later stage when basal ganglia hypermetabolism drops toward hypometabolism. More severe functional deficits and highly pathologic motor slowing become manifest when hypometabolism is most widespread in the basal ganglia. This stage leads to dementia.

Basal ganglia metabolite abnormalities in minor motor disorders associated with human immunodeficiency virus type 1.

BACKGROUND: Minor motor disorders (MMDs) associated with human immunodeficiency virus type 1 (HIV-1) predict HIV-1 dementia and death. Little is known about the time course and neuropathologic mechanisms of HIV-1 MMDs. OBJECTIVE: To investigate the relationship between HIV-1 MMDs, as assessed by psychomotor speed, and metabolic alterations in the basal ganglia, as detected by proton magnetic resonance spectroscopy. PATIENTS AND METHODS: A total of 32 HIV-1-seropositive patients (10 with no MMD, 8 with incipient MMD, and 14 with sustained MMD, assessed through electrophysiologic testing of psychomotor speed including contraction times; 29 treated with highly active antiretroviral therapy) and 14 HIV-1-seronegative control subjects were examined for cerebral metabolite abnormalities in the basal ganglia by means of magnetic resonance spectroscopy. RESULTS: The 3 patient groups showed significantly different ratios of myoinositol/creatine (P =.02) in the basal ganglia. Whereas patients with no MMD or incipient MMD showed normal ratios, patients with sustained MMD showed higher values for myoinositol/creatine as a sign of glial proliferation. No differences in N-acetyl compounds, indicative of neuronal loss, were found. CONCLUSION: Whereas metabolic alterations in the basal ganglia were not detected in patients with incipient HIV-1 MMD, patients with sustained HIV-1 MMD did have significantly altered metabolic spectra indicative of glial proliferation.

Improvement of motor performance of HIV-positive patients under AZT therapy.

We performed motor tests (most rapid alternating movements [MRAMs] of index fingers and most rapid contractions [MRCs] of voluntary isometric index finger extensions) in HIV-positive patients with (group 1) and without (group 2) AZT treatment over a 6-month period. Whereas MRAMs remained uninfluenced, MRCs showed a clear improvement in the treated group and a decline in the nontreated group, according to the T helper cell counts. MRCs were not only a sensitive test procedure for detecting subclinical lesions in HIV-positive patients, but also a reliable therapy control measurement.

Serum and cerebrospinal fluid levels of soluble intercellular adhesion molecule 1 (sICAM-1) in patients with HIV-1 associated neurological diseases.

We measured levels of soluble intercellular adhesion molecule 1 (sICAM-1) in paired serum and CSF samples of 110 HIV-1-positive patients with and without neurological symptoms and 40 HIV-negative non-immune neurological controls, and in sera of 26 asymptomatic HIV-1-positive patients. Serum sICAM-1 levels in asymptomatic HIV-1-positive patients were significantly increased in comparison to HIV-negative controls. Moreover, they were significantly higher in HIV-1-positive patients with AIDS-defining diseases than in the asymptomatic HIV-1-positive group. In subgroups of patients with neurological disease, the highest serum values were found in HIV encephalopathy. CSF levels of sICAM-1 were elevated only in HIV-1-positive patients with neurological disease mainly due to passive diffusion through a defective blood-brain barrier. An sICAM-1 index was calculated as a measure for intrathecal production of sICAM-1 but showed no significant differences between patients with and without neurological involvement. However, increased levels of the sICAM-1 index were found in some patients with opportunistic CNS infection of bacterial or fungal origin. Serum and CSF levels of sICAM-1 correlated with neopterin levels, a marker of interferon-gamma-mediated macrophage activation and CSF sICAM-1 levels were inversely correlated to numbers of CD4+ T cells. Elevated serum sICAM-1 levels already in asymptomatic HIV-1-positive individuals add to the evidence for an early immune activation in HIV infection. With the further increase of serum and CSF s-ICAM-1 in patients with AIDS-defining diseases sICAM-1 could serve as a new surrogate marker similar to neopterin.

Antiretroviral therapy regimens for neuro-AIDS.

In the era of highly active antiretroviral therapy (HAART) the central nervous system (CNS) becomes increasingly important as a sanctuary site for the human immunodeficiency virus (HIV-1). HIV-1-associated brain disease is subdivided into the minor cognitive/motor disorder, the minor cognitive/motor complex and the AIDS dementia complex, all of which are predictive for patients' deaths. CNS effective therapy therefore influences the prognosis of each individual patient. Thus, there is urgent need both for prophylactic and therapeutic strategies preventing or treating HIV-1-associated CNS disease. HAART consisting of two nucleoside analogues (NAs), one or two protease inhibitors (PIs) and/or one non-nucleoside inhibitor of the reverse transcriptase (NNRTI) has a neuroprophylactic value with regard to the manifestation of HIV-I associated CNS disease. With regard to therapeutic effects, the NAs zidovudine and stavudine penetrate into the cerebrospinal fluid and positively influence HIV-1-associated brain disease. Adding a second NA has no additional therapeutic effect. NNRTIs (nevirapine and efavirenz) are also CNS effective. However, there is a subgroup of non-responders, who obviously need other forms of therapeutic interventions. The very few existing studies point out that patients with high plasma viral loads and neurological abnormalities should be treated with a combination of two NAs and one NNRTI. The value of PIs for CNS protection remains to be evaluated.

TNFalpha reduces glutamate induced intracellular Ca(2+) increase in cultured cortical astrocytes.

The proinflammatory cytokine TNFalpha is locally released during various inflammatory CNS diseases and high cerebrospinal fluid (CSF) titers of TNFalpha were found in meningitis patients. We know from previous studies that TNFalpha also depolarizes astrocytes by reducing their inwardly rectifying K+ currents. We have now investigated the effect of TNFalpha on the glutamate induced intracellular Ca2+ increase in astrocytes, a process which seems to be involved in glial mediated modulation of neuronal synaptic transmisssion. Incubation with TNFalpha (50-1000 U/ml for 60 min) reduces the glutamate induced intracellular Ca2+ increase in astrocytes but not in neurons and this seems to be a phenomenon secondary to the TNFalpha induced depolarization. While other proinflammatory cytokines (interleukin 1beta, IL-2, IL-6) did not interfere with the astrocytic glutamate response, incubation in CSF from septic meningitis patients (CSF-SM) also reduced the glutamate induced intracellular Ca2+ increase. The application of a neutralizing anti-TNFalpha antibody to the CSF-SM prior to cell incubation partially restored the glutamate response. Our data suggest that inflammatory molecules such as TNFalpha impair astrocytes' response to glutamate and this may indirectly affect neuronal synaptic transmission.