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Modern antiretroviral combination therapy (cART) has transformed HIV from a life-threatening infection into a chronic disease. However, the life-long treatment has side effects that frequently have a negative impact on patients' quality of life. Thus, there are some efforts to "simplify" therapy, i.e. apply regimens with three or fewer antiretroviral substances. However, neurologists are relatively sceptical towards this cART "simplification", because the capacity of simplified regimens to access the cerebrospinal fluid (CSF) might be too weak to effectively suppress viral load in this compartment. Thus, data of a big Neuro-AIDS cohort of 4992 HIV-positive patients consecutively recruited over three decades were retrospectively analysed in terms of neurocognitive performance of patients switched to simplified therapy regimens. To test whether simplified drug regimens result in new neuropsychological deficits or the worsening of pre-existing ones in HIV+ patients. Three groups of HIV+ patients were switched from triple therapy to three different two drug regimens (n = 177 to lamivudine/PI, n = 37 to INI/PI, and n = 303 to dual PI); three other groups of patients put from one to an alternative triple combination (n = 290 ABC/3TC/PI, n = 244 TDF/FTC/PI, and n = 158 TDF/FTC/NNRTI) for whatever reason served as controls. All patients were followed up over 4 years maximum. Every patient group improved immunologically and virologically after the switch. However, patients who switched to INI/PI combinations remained stable in neuropsychological tests, while a considerable percentage of patients who switched to other treatments demonstrated a decline. Remarkably, a high percentage of the patients switched to "simplified drug regimens" was not well-controlled virologically before the switch. HIV-positive patients with simplified therapy regimens show some benefit in terms of systemic infection surrogate markers (CD4 ± cell count and plasma viral load); however, neurocognitive deficits do not improve, but remain stable in most cases.

Chronic hepatitis C virus (HCV) infection is a highly prevalent systemic disease, which can cause a variety of neurological complications. The HCV-associated symptoms can be differentiated into central and peripheral nervous systems as well as the musculature. Important pathomechanisms are HCV-associated autoimmunity (e.g. mixed cryoglobulinemia with polyneuropathy) and direct neurotoxic effects of the virus (e.g. HCV-associated cognitive deficits). Distal symmetric polyneuropathies, small fiber neuropathies and cognitive deficits are the most prevalent neurological manifestations. Furthermore, HCV infection is a risk factor for ischemic and hemorrhagic stroke as well as Parkinson's disease. As HCV infection has become a permanently curable disease in90% of patients, early identification and antiviral treatment of HCV positive patients is of utmost importance.Die chronische Hepatitis-C-Virus(HCV)-Infektion ist eine hochprävalente Systemerkrankung, die verschiedene neurologische Komplikationen verursachen kann. Es lassen sich HCV-assoziierte Symptome im zentralen und peripheren Nervensystem sowie der Muskulatur unterscheiden. Wichtige Pathomechanismen sind die HCV-assoziierte Autoimmunität (z. B. gemischte Kryoglobulinämie mit Polyneuropathie) und direkte Neurotoxizität (z. B. bei HCV-assoziierten kognitiven Defiziten). Die häufigsten neurologischen Komplikationen sind distal-symmetrische Polyneuropathien, Small-fiber-Neuropathien und kognitive Defizite. Die HCV-Infektion stellt außerdem einen Risikofaktor für ischämische und hämorrhagische Schlaganfälle sowie den Morbus Parkinson dar. Die frühe Identifikation und antivirale Behandlung HCV-positiver Patienten steht im Zentrum der Behandlung. Durch neue antivirale Therapien können90 % der Patienten dauerhaft von der HCV-Infektion geheilt werden.

Chronic hepatitis C virus (HCV) infection is a highly prevalent systemic disease, which can cause a variety of neurological complications. The HCV-associated symptoms can be differentiated into central and peripheral nervous systems as well as the musculature. Important pathomechanisms are HCV-associated autoimmunity (e.g. mixed cryoglobulinemia with polyneuropathy) and direct neurotoxic effects of the virus (e.g. HCV-associated cognitive deficits). Distal symmetric polyneuropathies, small fiber neuropathies and cognitive deficits are the most prevalent neurological manifestations. Furthermore, HCV infection is a risk factor for ischemic and hemorrhagic stroke as well as Parkinson's disease. As HCV infection has become a permanently curable disease in >90% of patients, early identification and antiviral treatment of HCV positive patients is of utmost importance., Die chronische Hepatitis-C-Virus(HCV)-Infektion ist eine hochprävalente Systemerkrankung, die verschiedene neurologische Komplikationen verursachen kann. Es lassen sich HCV-assoziierte Symptome im zentralen und peripheren Nervensystem sowie der Muskulatur unterscheiden. Wichtige Pathomechanismen sind die HCV-assoziierte Autoimmunität (z. B. gemischte Kryoglobulinämie mit Polyneuropathie) und direkte Neurotoxizität (z. B. bei HCV-assoziierten kognitiven Defiziten). Die häufigsten neurologischen Komplikationen sind distal-symmetrische Polyneuropathien, Small-fiber-Neuropathien und kognitive Defizite. Die HCV-Infektion stellt außerdem einen Risikofaktor für ischämische und hämorrhagische Schlaganfälle sowie den Morbus Parkinson dar. Die frühe Identifikation und antivirale Behandlung HCV-positiver Patienten steht im Zentrum der Behandlung. Durch neue antivirale Therapien können >90 % der Patienten dauerhaft von der HCV-Infektion geheilt werden.

Die HIV-Infektion ist eine durch das humane Immundefizienzvirus (HIV) hervorgerufene Krankheit, die seit Anfang der 80er-Jahre des vorigen Jahrhunderts bekannt ist, seit 1984 durch Antikorpertests diagnostiziert werden kann und seit 1996, als die modernen hochaktiven antiretroviralen Kombinationstherapien (HAART) eingefuhrt wurden, zu einer behandelbaren chronischen Erkrankung geworden ist. Seit 2005 bezeichnet man die Therapie als cART („combination antiretroviral therapy“). UN-AIDS veroffentlichte 2014 die Zielvorgabe, dass bis 2020 90 % aller HIV-Infektionen weltweit diagnostiziert und 90 % antiretroviral behandelt sein sollen, davon ebenfalls 90 % erfolgreich (Viruslast im Blut unterhalb der Nachweisgrenze), eine Forderung, die in Deutschland nahezu umgesetzt ist.

Das Zika-Virus ist ein Arbovirus aus der Familie der Flaviviren, welches durch die Stechmucke Aedes aegyptii ubertragen wird, aber auch durch die Asiatische Tigermucke Aedes albopticus. Die bisher groste beobachtete Zika-Virus-Epidemie findet momentan in Nord- und Sudamerika, in der Karibik, im Suden der USA und in Sudostasien statt. Meistens verlauft die Infektion als unspezifische, akute, fiebrige Erkrankung. Neurologische Manifestationen bestehen in der Hauptsache in einer Mikrozephalie bei Neugeborenen und einem Guillain-Barre-Syndrom, aber auch andere, seltenere Manifestationen sind in der Zwischenzeit bekannt geworden, wie eine Meningoenzephalitis und eine Myelitis. Es liegt daher nahe, dass das Zika-Virus, ahnlich wie andere Flaviviren, neuropathogene Eigenschaften aufweist. Insbesondere der drastische Anstieg der Mikrozephaliefalle in Brasilien hat grose Forschungsaktivitaten induziert. Das Virus wird perinatal ubertragen und kann im Fruchtwasser, in der Plazenta und im Gehirngewebe des Neugeborenen nachgewiesen werden. Eine Impfung oder eine kausale Therapie existierten bislang nicht. Der signifikante Anstieg des durch das Zika-Virus induzierten Guillain-Barre-Syndroms wurde schon wahrend fruherer Ausbruche beobachtet. In der Zwischenzeit haben sich wissenschaftlich klare Verbindungen zwischen einer Zika-Virus-Infektion und diesen neurologischen Manifestationen gezeigt. Durch Langzeitstudien und Tiermodelle kann erreicht werden, die Pathomechanismen dieser Erkrankung besser zu verstehen.

ZusammenfassungOpportunistische Infektionen des zentralen Nervensystems (ZNS) mit infolge einer iatrogenen Immunsuppression auftretenden Virus-, Parasiten-, Pilz- oder Bakterien-induzierten Erkrankungen sind bei der steigenden Zahl an Patienten mit Organtransplantationen oder immunmodulierenden Therapien von großer medizinischer Bedeutung. Hauptsächliche Anwender dieser modernen Behandlungsformen sind neben der Transplantationsmedizin die Dermatologie (Interferone, Rituximab, Fingolimod u. a.), Hämato-/Onkologie (Rituximab u. a.), Neurologie (Beta-Interferon, Glatirameracetat, Natalizumab, Rituximab, Teriflunomid, Fingolimod, Alemtuzumab, Daclizumab u. a.) und Rheumatologie (Rituximab u. a.).Das Keimspektrum bei iatrogener Immunsuppression in Europa umfasst in der Hauptsache Viren der Herpesgruppe sowie insbesondere bei immunmodulatorisch behandelten Patienten das JC-Virus (JCV); an Pilzerregern sind Aspergillus fumigatus, Candida albicans und Cryptococcus neoformans von Bedeutung. Eine wichtige parasitäre Infektion ist die mit Toxoplasma gondii (T. g.). Typische bakterielle Infektionen des iatrogen immunkompromittierten Patienten werden durch Nocardia asteroides, Listeria monocytogenes und Mycobacterium tuberculosis hervorgerufen.Es werden typische diagnostische Konstellationen und Therapien vorgestellt.

Opportunistic infections of the central nervous system (CNS) with bacteria, parasites, fungi or viruses due to iatrogenic immunosuppression are of immense importance because of rising numbers of organ transplantations and immunomodulating treatments. Besides transplantation medicine, the most frequently involved medical subspecialties are dermatology (interferons, rituximab, fingolimod, among others), hematology/oncology (rituximab, among others), neurology (beta-interferon, glatiramer acetate, natalizumab, rituximab, teriflunomide, fingolimod, alemtuzumab, daclizumab, among others) and rheumatology (rituximab).In Europe, typical infections affecting the immunocompromised host are due to herpes viruses and, especially in immunomodulated patients, JC virus (JCV); frequently occurring fungi are Aspergillus fumigatus, Candida albicans and Cryptococcus neoformans. An important parasite is Toxoplasma gondii (TG). Typical bacterial infections of the immunocompromised patient are caused by Nocardia asteroides, Listeria monocytogenes and Mycobacterium tuberculosis.Modern diagnostic and therapeutic procedures will be described.

Unter der modernen antiretroviralen Kombinationstherapie (cART) haben sich Diagnostik und Therapie HIV-assoziierter Erkrankungen des Nervensystems verbessert. Nachdem man zur Kenntnis nehmen musste, dass auch bei effektiver Suppression der Viruslast im Blut neurokognitive Defizite sowie Erkrankungen des peripheren Nerven und Muskels auftreten konnen, wurden Screeningmethoden, diagnostische Schritte und Monitoringmethoden etabliert.

The modern antiretroviral treatment of human immunodeficiency virus (HIV-1) infection has considerably lowered the incidence of opportunistic infections. With the exception of the most severe dementia manifestations, the incidence and prevalence of HIV-associated neurocognitive disorders (HAND) have not decreased, and HAND continues to be relevant in daily clinical practice. Now, HAND occurs in earlier stages of HIV infection, and the clinical course differs from that before the widespread use of combination antiretroviral treatment (cART). The predominant clinical feature is a subcortical dementia with deficits in the domains concentration, attention, and memory. Motor signs such as gait disturbance and impaired manual dexterity have become less prominent. Prior to the advent of cART, the cerebral dysfunction could at least partially be explained by the viral load and by virus-associated histopathological findings. In subjects where cART has led to undetectable or at least very low viral load, the pathogenic virus-brain interaction is less direct, and an array of poorly understood immunological and probably toxic phenomena are discussed. This paper gives an overview of the current concepts in the field of HAND and provides suggestions for the diagnostic and therapeutic management.

Die Fortschritte der antiretroviralen Therapie haben die HIV-Infektion zu einer chronischen Krankheit gemacht. Der Ubersichtsartikel fasst zusammen, was ein Leben mit HIV aus neurologischer Sicht uber Jahrzehnte hinweg fur die Betroffenen bedeutet. Neben klinischen und pathophysiologischen Aspekten des HIV-assoziierten kognitiven Defizits (HAND) werden auch periphere HIV-Manifestationen beleuchtet. Der Artikel berucksichtigt Komorbiditaten wie die in der Inzidenz ansteigende Neurolues, sowie die Hepatitis C, da beide durch ihr Interaktionsspektrum mit dem HI-Virus insbesondere fur den Neurologen von grosem Interesse sind.

Trotz sehr effektiver Behandlungsoptionen fur die systemische HIV-Infektion sind Neuro-Aids und die HIV-assoziierte neurokognitive Storung ein klinisches und alltagsrelevantes Problem. Man unterscheidet 3 Stufen, das HIV-assoziierte, neuropsychologische Defizit (ANPD), das milde, HIV-assoziierte neurokognitive Defizit (MNCD) und die HIV-assoziierte Demenz (HAD). Die Behandlungsmoglichkeiten HIV-assoziierter neuro-kognitiver Storungen umfasst die antiretrovirale Therapie (cART), die den CPE-Score zur Penetration der Medikamente ins ZNS berucksichtigen sollte. Es ist sinnvoll, bei Auftreten multiresistenter Virusvarianten im Blut auch im Liquor entsprechende Untersuchungen durchzufuhren. Im peripheren Nervensystems treten neben der klassischen, distal-symmetrischen, HIV-assoziierten Polyneuropathie immunogen vermittelte Neuropathien oder Myopathien auf (CIDP, AIDP). Durch die antiretrovirale Therapie (cART) verursachte Polyneuropathien sind differenzialdiagnostisch zu berucksichtigen. Erworbene mitochondrial toxische Myopathien treten haufiger auf, da nun eine cART durchaus uber 10 – 20 Jahre durchgefuhrt wird. Bei Patienten mit schweren depressiven Episoden zeigte sich eine 6-mal hohere Wahrscheinlichkeit, die Einnahme der cART mindestens einmal zu vergessen. Depressive Episoden sind oft ein Grund fur mangelhafte Adharenz, korrelieren mit einer hoheren Viruslast und sind dringend zu behandeln. In den letzten Jahren kam es infolge der verbesserten cART zu einem Ruckgang der opportunistischen Infektionen (OI) des ZNS. Die haufigsten OI stellen die progressive multifokale Leukoenzephalopathie (PML), die Toxoplasma-Enzephalitis und die Kryptokokken-Meningitis dar. Bei rasch progredientem Verlauf einer OI muss an ein Immunrekonstitutionssyndrom (IRIS) gedacht werden. Es gibt momentan keine sichere Methode, z. B. die Verschlechterung einer PML durch den naturlichen Krankheitsverlauf von der Verschlechterung durch ein IRIS zu unterscheiden. Infolge der deutlich zunehmenden Lebenserwartung treten Komorbiditaten mehr in den Vordergrund. Zu den viralen Biomarkern fur die Krankheitsaktivitat im ZNS zahlen Neopterin als Marker der Makrophagenaktivierung, das Neurofilament-Leichtprotein und das Gesamt-Tau-Protein.

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.

Dysfunction of dopaminergic neurotransmission has been implicated in HIV infection. We showed previously increased dopamine (DA) levels in CSF of therapy-naive HIV patients and an inverse correlation between CSF DA and CD4 counts in the periphery, suggesting adverse effects of high levels of DA on HIV infection. In the current study including a total of 167 HIV-positive and negative donors from Germany and South Africa (SA), we investigated the mechanistic background for the increase of CSF DA in HIV individuals. Interestingly, we found that the DAT 10/10-repeat allele is present more frequently within HIV individuals than in uninfected subjects. Logistic regression analysis adjusted for gender and ethnicity showed an odds ratio for HIV infection in DAT 10/10 allele carriers of 3.93 (95 % CI 1.72–8.96; p = 0.001, Fishers exact test). 42.6 % HIV-infected patients harbored the DAT 10/10 allele compared to only 10.5 % uninfected DAT 10/10 carriers in SA (odds ratio 6.31), whereas 68.1 versus 40.9 %, respectively, in Germany (odds ratio 3.08). Subjects homozygous for the 10-repeat allele had higher amounts of CSF DA and reduced DAT mRNA expression but similar disease severity compared with those carrying other DAT genotypes. These intriguing and novel findings show the mutual interaction between DA and HIV, suggesting caution in the interpretation of CNS DA alterations in HIV infection solely as a secondary phenomenon to the virus and open the door for larger studies investigating consequences of the DAT functional polymorphism on HIV epidemiology and progression of disease.

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.

HIV-associated dementia and its precursors are frequently observed complications of HIV infection, even in the presence of combination antiretroviral treatment (cART). The development, surveillance and treatment of this condition are still not completely understood. Cytokines, as immunological transmitters, may be one key to gaining a deeper understanding of the disease. A total of 33 HIV-positive male patients were evaluated by neuropsychological testing, lumbar and venous puncture, neuroimaging and neurological examination. The cytokine content in the CSF (cerebrospinal fluid) was examined by a solid-phase protein array. The Digit-Symbol Test, contraction time analysis, Rey-Osterrieth Figure and Grooved-Pegboard Test showed inferior results in the presence of an inflammatory CSF environment, whereas neuroprotective or anti-inflammatory conditions were correlated to better results in contraction time analysis. Higher CSF levels of cytokines were independently correlated with the duration of HIV infection. The study showed a correlation of cytokine levels in the CSF of HIV patients with test results of their neuropsychological functioning. The effect was pronounced with regard to the more complex executive tasks. Determining CSF cytokine levels may be a useful supplement to the assessment of HIV patients and contribute helpful information to predict neurocognitive performance. Therapeutic strategies to ameliorate a negative impact of an altered cytokine milieu may aid in slowing the evolution of neurocognitive dysfunction.

With modern antiretroviral drug regimens, HIV-infected people are living longer and HIV has transformed into a chronic illness. The review summarizes pathophysiological as well as clinical aspects of a chronic infection from a neurological point of view including neurocognitive impairment, depression, neuropathies and myopathies. It also draws attention to comorbidities such as syphilis and hepatitis C. They are of particular neurological interest because of the interaction of the pathogens.

Neurosyphilis is an infectious disease that has reappeared over the past two decades. It is caused by Treponema pallidum subspecies pallidum that can affect the central nervous system (CNS) during any stage of the disease. Besides early CNS involvement predominantly presenting with symptoms of meningitis, a parenchymal affection of the brain leading to severe neuropsychiatric symptoms particularly emerges at later stages, but is rarely seen nowadays due to early antibiotic treatment. Together with the clinical findings, a characteristic combination of serological and cerebrospinal fluid (CSF) abnormalities leads to the diagnosis of neurosyphilis and is required to assess its activity. However, particularly at later stages of disease and after antibiotic treatment, serological and CSF abnormalities may become ambiguous and, therefore, difficult to interpret. This can be accompanied by persisting or fluctuating neuropsychological deficits. To this day, no well-controlled clinical data exists concerning the treatment of late-stage neurosyphilis, neither on type, optimal dosage, duration, and long-term efficacy of antibiotic therapy. Therefore, treatment and follow-up of late-stage neurosyphilis are challenging tasks. Here, we present three cases of neurosyphilis with severe neuropsychiatric symptoms in non-immunocompromised patients and a review of the recent literature.

The article describes the immune reconstitution inflammatory syndrome in HIV-positive patients as a phenomenon detected in recent years as a consequence of HAART initiation in patients with a severely compromised immune system and rapid improvement under HAART. Pathophysiology, clinical presentation and therapeutic options are discussed.

The objective of this study was to evaluate immune cytokine expression in cerebrospinal fluid (CSF) of patients with human immunodeficiency virus-1 (HIV-1)-associated dementia (HAD) using a novel cytokine array assay. HIV-1 induces a condition resembling classical subcortical dementia, known as HAD. The immune mechanisms contributing to HAD have not been elucidated. Cytokine expression in CSF was determined by solid-phase protein array in 33 neurologically asymptomatic HIV-positive male patients and were compared to levels in non-HIV controls and patients with HAD. Neurological examinations and lumbar and venous punctures were conducted in all patients and controls. Interleukin (IL)-1, IL-4, and IL-10, were up-regulated in all treated acquired immunodeficiency syndrome (AIDS) patients independent of neurological status compared to controls. In contrast, interferon gamma (IFN-gamma), IL-1alpha, IL-15, and tumor necrosis factor alpha (TNF-alpha) were highly expressed in patients with HAD compared to undemented HIV-positive patients. These results show that solid-phase protein array can detect immunological changes in patients infected with HIV. Cytokine expression levels differ in different disease stages and in patients on different treatment paradigms. Pending further validation on a larger number of patients, this method may be a useful tool in CSF diagnostics and the longitudinal evaluation of patient with HAD.

Wir stellen die Hypothese auf, dass sich ein „immune reconstitution inflammatory syndrome“ (IRIS) des Zentralnervensystems (ZNS) nach hochaktiver antiretroviraler Therapie (HAART) bei HIV1-positiven Patienten als schwere aseptische Leukenzephalopathie manifestieren kann und somit eine Steroidtherapie Erfolg versprechend ist. Wir zeigen eine Fallserie immunsupprimierter AIDS-Patienten, die nach HAART ein IRIS des ZNS entwickelten. Bei allen Patienten erfolgte eine ausgiebige infektiologische und radiologische Verlaufsdiagnostik, um Verlauf und zugrunde liegende Pathophysiologie zu verstehen. Eine Patientin starb und es erfolgte eine neuropathologische Aufarbeitung. Kein opportunistischer Erreger konnte vor oder wahrend der hochaktiven antiretroviralen Therapie nachgewiesen werden. Drei der 4 Patienten konnten erfolgreich mit Methylprednisolon behandelt werden, wobei die HAART nie unterbrochen wurde. Die einzige afrikanische Patientin starb an einem Hirnodem. Unter HAART konnen HIV1-positive Patienten einen aseptischen Subtyp des IRIS entwickeln, der in vielen Fallen erfolgreich mit Kortikosteroiden behandelt werden kann. Dieser Subtyp ist bisher nicht publiziert worden. Moglicherweise hat IRIS bei Afrikanern eine hohere Inzidenz und zeigt ein schlechteres Outcome als bei Kaukasier.

Highly active antiretroviral therapy [HAART] has increased the mean survival time in the AIDS stage by up to more than 10 years. Five different groups of antiretroviral medications are known, of which integrase and entry inhibitors represent the latest and most modern substances. The long survival time in the AIDS stage means that side effects and interactions become of greater relevance and have to be differentiated from the symptoms of Neuro-AIDS as such. Side effects of HAART tend to affect the central and peripheral nervous system as well as the muscles. Neurotoxicity of HAART components varies considerably and depends on the substance involved. They are to be considered with the choice of HAART as a treatment, and a corresponding combination of medication must be carefully discussed by the doctor and patient in those cases in which side effects on the nervous system by antiretroviral agents are already present. There are special cases, however, in which the associated side-effects are to be accepted and endured if no other combination of medications is possible-e.g. as a result of resistance development. Knowledge of HAART side effects and interactions with antiepileptics, antidepressants and analgetics are essential for the treatment of patients with Neuro-AIDS.

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.

Objectives - We compared clinical long-term course and outcome in all AIDS patients admitted to our outpatient department from January, 1989 to June, 1998 with toxoplasma encephalitis (TE) as first AIDS-defining infection (n=106) and in 106 patients with Pneumocystis carinii pneumonia (PCP) as first AIDS-defining disease. Material and methods -The 2 groups were matched with respect to age, sex, risk group, degree of immunodeficiency as measured by CD4 cell counts and duration of HIV-1-positivity. TE was diagnosed radiologically and by response to treatment. Results - Forty-three TE patients surviving the first TE symptoms >14 months developed dementive symptoms, leucoencephalopathy in imaging procedures and died from dementia. In contrast only 5 patients surviving PCP for an equally long period showed dementive symptoms. Conclusion - Cerebral infections like toxoplasma encephalitis (TE) may negatively influence HIV-1-activity so far latent in the brain.

Twenty-three patients with Wilson's disease (WD) treated with D-penicillamine underwent clinical examination, as well as laboratory and motor testing. The clinical findings were scored. Laboratory tests included determination of the caeruloplasmin level, the free serum copper level, 24 h urinary copper excretion, liver enzymes and in 10 patients liver copper content of a liver biopsy. Laboratory tests and clinical scores were correlated. To quantify impairment of voluntary movements in WD fastest possible isometric index finger extensions and fastest alternating finger movements were analysed. Eleven patients presented with abnormally slow and 15 with abnormally irregular voluntary movements. Slowness of alternating movements correlated with the clinical score. The clinical score also correlated with the duration of symptoms prior to onset of therapy. Motor testing turned out to be sensitive enough to monitor improvement of neurological symptoms after onset of therapy. Comparison with motor testing in other basal ganglia diseases and cerebellar patients showed differences to patients with Parkinson's and Huntington's disease and similarities to patients suffering from AIDS-related dementia. In a small number of WD-patients similar results as in patients with a degenerative cerebellar disease were found.

330 females and 274 males out of a population of 700 students with a mean age of 23.3 (19-64) years completed a questionnaire handed out by their teachers with consisted of 26 questions concerning sexual practice and knowledge about AIDS. 285 students were studying natural sciences 134 arts and 185 medicine. There were significant differences between the sexes (p

Progressive multifocal leukoencephalopathy is a demyelinating disease with a high mortality caused by the JC virus and occurs in about 5% of HIV-infected patients. Highly active anti-retroviral therapy (HAART) has a proven efficacy in prolonging the survival of patients with AIDS-associated PML, but there are differing opinions about adding cidofovir to the treatment of PML. To investigate the benefit of HAART combined with cidofovir, we retrospectively analysed the survival of 33 patients with AIDS-associated PML proven by PCR in CSF, biopsy or at autopsy. Additionally, we also analysed 37 patients with probable PML. Seventeen (51.5%) of the patients with confirmed PML were treated with HAART and 14 (42.4%) with cidofovir in any combination. Of these patients, 13 (39.4%) were treated with HAART and cidofovir in combination, four (12.1%) patients received only HAART without cidofovir and one (3%) patient received only cidofovir without HAART. Fifteen patients did not receive HAART or cidofovir. The cumulative survival was significantly longer in patients with HAART than in patients without HAART (p = 0.006), independent whether cidofovir was given or not. In comparison with single therapy with HAART, the combination of HAART and cidofovir showed no significant increase in survival (p = 0.435). Therefore, a benefit for cidofovir in addition to HAART in the treatment of PML in HIV-infected patients could not be proven.

Cytokines are important mediators of the immune system, which is attacked and permanently disturbed after infection with HIV-1. Since specific immune reactions against HIV are present in the blood as well as in the CNS, both are involved in infection. Immune dysfunction in the CNS may be largely responsible for the development of neuropsychological symptoms in the course of HIV infection and in end-stage HIV-associated dementia (HAD). As potent and easily accessible indicators of immune function, cytokines were identified early in HIV-research as potential surveillance markers. Despite long-term research on cytokines and their diagnostic value in HAD and its precursors, results are, to date, contradictory. Future studies have to be focused on cytokine networks, infection stage, treatment status, autoimmunity, genetic and environmental factors, and they should also use recent genome- and proteome-research techniques.

In 1991, the AIDS Task Force of the American Academy of Neurology published nomenclature and research case definitions to guide the diagnosis of neurologic manifestations of HIV-1 infection. Now, 16 years later, the National Institute of Mental Health and the National Institute of Neurological Diseases and Stroke have charged a working group to critically review the adequacy and utility of these definitional criteria and to identify aspects that require updating. This report represents a majority view, and unanimity was not reached on all points. It reviews our collective experience with HIV-associated neurocognitive disorders (HAND), particularly since the advent of highly active antiretroviral treatment, and their definitional criteria; discusses the impact of comorbidities; and suggests inclusion of the term asymptomatic neurocognitive impairment to categorize individuals with subclinical impairment. An algorithm is proposed to assist in standardized diagnostic classification of HAND.

The objectives of this study is to clarify whether there are phases critical for the infection of the central nervous system (CNS) as defined by active viral replication in the cerebrospinal fluid (CSF) in human immunodeficiency virus (HIV) infection. One hundred and nine HIV-1-positive homo- and bisexual patients in early and late disease stages with or without highly active antiretroviral therapy (HAART) were included in the cross-sectional, diagnostic (phase I) multicenter study. No patients had any overt neurological deficits; all underwent venous and lumbar puncture as well as neuropsychological testing. In untreated early-stage patients, cerebrospinal fluid (CSF) viral load correlated with inflammatory parameters, but not significantly with neuropsychological abnormalities. CSF viral load and inflammatory reactions were suppressed in HAART-treated early-stage patients. In HAART-treated late-stage patients, there was a weak correlation between CSF viral load and CSF cell count as well as a moderate correlation with immune activation markers and with distinct cerebral deficits independent of CSF viral load. Seventeen of the 109 patients had higher CSF than plasma viral loads and marked inflammatory reactions and immune activation. In patients with greater plasma than CSF viral loads, the factors contributing to cerebral deficits still need to be identified. The results suggest not only that there is an early "set point" for CSF/central nervous system (CNS) infection, but also that there is a subgroup of patients in whom intrathecal viral replication correlates with cerebral deficits. Lumbar puncture should be performed in all positive patients to identify members of this subgroup and to ascertain what characteristic factors they have in common in order to improve therapy.

Objective 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. Methods Cell numbers and cellular phenotypes in CSF and peripheral blood were analyzed in multiple sclerosis (MS) patients treated with natalizumab, untreated MS patients, and patients with other neurological disease (OND). JC virus DNA in the CSF and peripheral blood was quantified by kinetic polymerase chain reaction. Results CSF leukocyte counts, CD4+ and CD8+ T cells, CD19+ B cells, and CD138+ plasma cells were significantly lower in natalizumab-treated MS patients compared with OND patients and untreated MS patients. JC virus DNA was not detected in CSF or peripheral blood from natalizumab-treated patients. Six months after cessation of natalizumab therapy, low lymphocyte counts in the CSF persisted. The patient with the highest total leukocyte and CD4+ and CD8+T-cell counts in the CSF experienced a clinical relapse. Interpretation These data suggest that natalizumab treatment results in a prolonged decrease of lymphocytes in the CSF and are consistent with the hypothesis that natalizumab impairs immune surveillance of the central nervous system. Ann Neurol 2006;59:743–747

At the beginning of the AIDS pandemic, affective disorders (such as depressed mood) were seen in a considerable number of HIV-1-infected individuals. These disorders were a result of the poor physical condition of the patients, brain involvement by the virus (e.g. encephalopathy) or a reaction to disadvantageous living conditions (losing friends, jobs, etc.). In the era of highly active antiretroviral therapy (HAART), mental illness related to physical weakness is declining, as is the incidence of HIV-1-associated encephalopathy. However, depressed mood and fatigue caused by efavirenz (a standard component of HAART) is becoming increasingly important, particularly in individuals who are infected long-term with HIV-1. Whatever the cause of affective disorders, their presence has been shown to negatively influence adherence to HAART and HIV-1 disease progression. Specialist knowledge of HIV-1 infection, and HAART and its psychiatric complications (particularly in subgroups of patients such as drug abusers and older people), is needed to care adequately for patients. Furthermore, prospective studies are needed to more fully differentiate between the various aetiologies of affective disorders seen in individuals living with HIV/AIDS and to determine their incidence and prevalence. Such information is important to ensure that affective disorders are recognised and adequately treated, which will in turn improve the efficacy of HAART.

The authors examined the correlation between Human Immunodeficiency Virus (HIV) Dementia Scale (HDS) and psychomotor tests, evaluating basal ganglia function in 266 HIV-seropositive, Caucasian, homosexual men. Fifty-five HIV-positive, patients with mild dementia (HDS scoreor =10) showed significant slowing of most rapid alternating movements (MRAM) and significantly prolonged contraction times compared to 211 HIV-positive nondemented patients (HDS score10). Motor performance correlated significantly with the time-dependent HDS subscores for psychomotor speed and construction and HDS sum score. In contrast to contraction times and MRAM, HDS scores also showed significant correlations to age, premorbid and actual intelligence, and duration of HIV seropositivity.

We compared CSF HIV viral load in 33 asymptomatic HIV seropositive patients, 11 patients with incipient minor motor deficits (MMD), 11 patients with sustained MMD, and 16 patients with HIV-associated dementia. Patients with incipient MMD showed significantly higher CSF viral load than asymptomatic patients. Demented patients also had higher CSF viral loads than asymptomatic patients. This phenomenon is independent of antiretroviral therapy. Thus, correlation of viral load with time suggests a multiphasic course of HIV-associated CNS disease.

Background: Both HIV and hepatitis C virus (HCV) may enter the central nervous system and cause cognitive and/or motor dysfunction. There are limited data on cognition and no data on motor performance in HIV/HCV-coinfected patients. Objective: To provide data on cognition and motor performance in HIV/HCV infected patients. Methods: We compared 43 HIV-seropositive but HCV-seronegative patients, 43 HIV/HCV-coinfected patients, and 44 HIV-negative but HCV-positive patients, all of whom went through neuropsychologic testing and electrophysiologic assessment of basal ganglia-mediated motor function. Results: No significant differences could be found among the groups with regard to premorbid verbal and actual nonverbal intelligence, attention, and memory; the HIV dementia scale; and all somatic and most psychiatric complaints. Affective disorders were less frequent in HIV-negative but HCV-positive patients. This group also scored lower for depression. For all 3 groups, significant pathologic slowing of most rapid alternating movements (right hand) compared with those of HIV/HCV-negative controls as well as significantly prolonged contraction times (both hands) could be diagnosed. Simple reaction times were significantly prolonged only in HIV/HCV-coinfected patients. Conclusions: Although clinically asymptomatic, both HIV-positive and HCV-positive patients may show affective disturbances and significant psychomotor slowing. A potential predictive value for the further course of infection, which is well established in HIV-positive patients, remains to be investigated in HCV-positive or HIV/HCV-coinfected patients.

Objectives – To find out about potential involvement of the peripheral and autonomic nervous system in Wilson's disease (WD). Material and methods – Seventeen patients with laboratory proven WD were examined with quantitative sensory testing (QST) (thermal, pain and vibratory sensation), pupillometric evaluation and electrophysiological testing of basal ganglia motor function [frequency of most rapid alternating movements (MRAM), reaction time (RT), contraction time (CT)]. Results were compared with those obtained in 20 healthy controls. Results – After correction for multiple comparisons, patients with WD showed significantly higher thresholds for warm sensation [sural and peroneal nerve, thermal sensory limen (TSL), unpaired t-test]. Individual results were pathological in eight (peroneal) and nine (sural nerve) patients, respectively. Pupil function was not altered. Patients with WD showed significant slowing of MRAM and prolongation of RT and CT. There was no significant correlation between RT and QST results. Conclusions – These findings are compatible with a potential involvement of unmyelinated warm-specific C fibers in WD, independent from predominant basal ganglia motor dysfunction.

Lyme borreliosis is a multi-organ infection caused by spirochetes of the Borrelia burgdorferi sensu lato group with its species B burgdorferi sensu stricto, Borrelia garinii, and Borrelia afzelii, which are transmitted by ticks of the species Ixodes. Laboratory testing of Lyme borreliosis includes culture, antibody detection using ELISA with whole extracts or recombinant chimeric borrelia proteins, immunoblot, and PCR with different levels of sensitivity and specificity for each test. Common skin manifestations of Lyme borreliosis include erythema migrans, lymphocytoma, and acrodermatitis chronica atrophicans. The last two conditions are usually caused by B garinii and B afzelii, respectively, which are seen more frequently in Europe than in America. Late extracutaneous manifestations of Lyme borreliosis are characterised by carditis, neuroborreliosis, and arthritis. We present evidence-based treatment recommendations for Lyme borreliosis and review the prevention of Lyme borreliosis, including the Lyme vaccines.

Objective: To find out whether HIV-associated subclinical psychomotor slowing is present in HIV-infected children despite effective highly active antiretroviral therapy (HAART). Patients and Methods: An electrophysiological motor test battery shown to sensitively describe HIV-associated CNS disease in adults (tremor peak frequency []TPF], most rapid alternating movements [MRAM], reaction time [RT] and contraction time [CT]) was performed in 17 HIV seropositive (+) right-handed children. Results were compared to 16 HIV seronegative (-) children. Results: HIV (-) children showed slower frequencies (TPF, MRAM) and longer RTand CT than (-) adults. They showed a significant correlation (p = 0.0263) between RT (right = dominant hand) and age. HIV (+) children showed significant prolongations of RT (right hand) and CT (both hands) compared to HIV (-) children. RT right hand did not accelerate with age in HIV (+) children. CT were significantly prolonged in 10 children with detectable HIV plasma viral burden and normal in 7 children with no detectable HIV plasma viral load. There was no correlation between CT and CD 4 cell counts. Conclusions: Despite effective HAART, electrophysiological motor testing in HIV (+) children reveals significant subclinical CNS dysfunction, especially in children with insufficient viral load suppression.

PURPOSE: To investigate whether advanced magnetic resonance (MR) imaging techniques such as diffusion-weighted (DW) and perfusion-weighted (PW) MR imaging and hydrogen 1 (1H) MR spectroscopy can depict functional and pathophysiologic mechanisms in patients who have minor motor deficits (MMDs) associated with human immunodeficiency virus 1 (HIV-1). MATERIALS AND METHODS: Thirty-two patients with results seropositive for HIV-1 and different degrees of HIV-1–related MMD underwent conventional brain MR imaging, as well as DW and PW MR imaging and 1H MR spectroscopy of the basal ganglia. PW MR imaging data were computed pixel by pixel for creation of time-to-peak, relative regional cerebral blood volume, and bolus amplitude parameter maps. In addition, quantitative regional cerebral blood flow (rCBF) maps were calculated with respect to the arterial input function by using the singular value decomposition algorithm. For 1H MR spectrocopy, a stimulated echo acquisition mode 20, or STEAM 20, sequence was used. S...

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 harbor 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.

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.

The 10th International Conference on Neuroscience of HIV Infection was held conjointly with the 4th International Symposium on NeuroVirology. This review summarizes a number of important topics addressed at the conference including clinical aspects of HIV-1 associated dementia and peripheral nervous system pathology and their epidemiology in the era of highly active antiretroviral therapy. The neuropathogenesis was discussed with a special focus on different cellular compartments involved, viral and non-viral factors, immune activation, and alterations of the blood-brain barrier, animal models and their relevance for understanding HIV dementia. New aspects of antiretroviral therapy as well as immunization were covered. Neuroradiological approaches including new MR techniques and neuropsychological tests were presented. Viral opportunistic infections (e.g., JCV infection resulting in progressive multifocal leukoencephalopathy) as well as coinfection with hepatitis C represented a further topic.

The alpha chemokine receptor CXCR4 is used as the major coreceptor for the cell entry of T-cell-tropic human immunodeficiency virus-1 (HIV-1) isolates. Activation of this coreceptor by its natural ligand SDF1alpha is associated with an intracellular Ca(2+) increase. Because the HIV-1 glycoprotein 120 (gp120) is shedded from the surface of HIV-1-infected cells and is regarded as an injurious molecule in the pathogenesis of HIV-1-associated encephalopathy (HIVE), we investigated the effects of gp120 on the intracellular Ca(2+) regulation of astrocytes and neurons. After 5 days in vitro (DIV), SDF1alpha (50 nM) elicited a pertussis toxin-sensitive intracellular Ca(2+) increase due to Ca(2+) release from internal stores that was reduced by a blocking monoclonal antibody against the CXCR4 receptor in astrocytes and neurons. Parallel with the development of the SDF1alpha response, cells became sensitive to direct application of gp120 (1.25 microg/ml), which, similarly to SDF1alpha, elicited a transient intracellular Ca(2+) increase. However, short-term incubation with gp120 for 60 to 120 min induced a reduction of glutamate- or ATP-evoked intracellular Ca(2+) responses only in astrocytes and not in neurons, although functional CXCR4 receptors were expressed in both cell types. Therefore, our data strongly suggest that the CXCR4 receptor-mediated intracellular signaling pathway of gp120 differs in astrocytes and neurons.