Morphological and molecular comparison of HIV-associated and sporadic inclusion body myositis.

OBJECTIVE: The molecular characteristics of sporadic inclusion body myositis (sIBM) have been intensively studied, and specific patterns on the cellular, protein and RNA level have emerged. However, these characteristics have not been studied in the context of HIV-associated IBM (HIV-IBM). In this study, we compared clinical, histopathological, and transcriptomic patterns of sIBM and HIV-IBM. METHODS: In this cross-sectional study, we compared patients with HIV-IBM and sIBM based on clinical and morphological features as well as gene expression levels of specific T-cell markers in skeletal muscle biopsy samples. Non-disease individuals served as controls (NDC). Cell counts for immunohistochemistry and gene expression profiles for quantitative PCR were used as primary outcomes. RESULTS: 14 muscle biopsy samples (7 HIV-IBM, 7 sIBM) of patients and 6 biopsy samples from NDC were included. Clinically, HIV-IBM patients showed a significantly lower age of onset and a shorter period between symptom onset and muscle biopsy. Histomorphologically, HIV-IBM patients showed no KLRG1+ or CD57+ cells, while the number of PD1+ cells did not differ significantly between the two groups. All markers were shown to be significantly upregulated at gene expression level with no significant difference between the IBM subgroups. CONCLUSION: Despite HIV-IBM and sIBM sharing important clinical, histopathological, and transcriptomic signatures, the presence of KLRG1+ cells discriminated sIBM from HIV-IBM. This may be explained by longer disease duration and subsequent T-cell stimulation in sIBM. Thus, the presence of TEMRA cells is characteristic for sIBM, but not a prerequisite for the development of IBM in HIV+ patients.

[Neurological complications of hepatitis C infections]. / Neurologische Komplikationen der Hepatitis-C-Infektion.

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.

Simplification of combination antiretroviral therapy (cART) and the brain-a real-life experience.

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.

HIV-1-associated neurocognitive disorder: epidemiology, pathogenesis, diagnosis, and treatment.

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.

[Update HIV and neurology]. / Update HIV und Neurologie.

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.

Increases in CSF dopamine in HIV patients are due to the dopamine transporter 10/10-repeat allele which is more frequent in HIV-infected individuals.

Dysfunction of dopaminergic neurotransmission has been implicated in HIV infection. We showed previously increased dopamine (DA) levels in CSF of therapy-naïve 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.

Clinical improvement precedes lesion size regression in a severe case of acute disseminated encephalomyelitis.

Here, we present a case of a severe acute disseminated encephalomyelitis (ADEM) of a 42-year-old male patient. The diagnosis was established after brain biopsy and due to acutely evolving encephalopathy occurring in the context of atypical Mycoplasma pneumoniae (MP). We analysed the prominent MRI white matter lesions using a three-dimensional algorithm as cutting-edge technique to study morphological abnormalities and correlated them to the clinical condition of the patient. We found a discrepancy between the lesion size and the clinical deficits of the patient, actually the clinical improvement antedated the regression of the white matter lesions.

Early microstructural white matter changes in patients with HIV: a diffusion tensor imaging study.

BACKGROUND: Previous studies have reported white matter (WM) brain alterations in asymptomatic patients with human immunodeficiency virus (HIV). METHODS: We compared diffusion tensor imaging (DTI) derived WM fractional anisotropy (FA) between HIV-patients with and without mild macroscopic brain lesions determined using standard magnetic resonance imaging (MRI). We furthermore investigated whether WM alterations co-occurred with neurocognitive deficits and depression. We performed structural MRI and DTI for 19 patients and 19 age-matched healthy controls. Regionally-specific WM integrity was investigated using voxel-based statistics of whole-brain FA maps and region-of-interest analysis. Each patient underwent laboratory and neuropsychological tests. RESULTS: Structural MRI revealed no lesions in twelve (HIV-MRN) and unspecific mild macrostructural lesions in seven patients (HIV-MRL). Both analyses revealed widespread FA-alterations in all patients. Patients with HIV-MRL had FA-alterations primarily adjacent to the observed lesions and, whilst reduced in extent, patients with HIV-MRN also exhibited FA-alterations in similar regions. Patients with evidence of depression showed FA-increase in the ventral tegmental area, pallidum and nucleus accumbens in both hemispheres, and patients with evidence of HIV-associated neurocognitive disorder showed widespread FA-reduction. CONCLUSION: These results show that patients with HIV-MRN have evidence of FA-alterations in similar regions that are lesioned in HIV-MRL patients, suggesting common neuropathological processes. Furthermore, they suggest a biological rather than a reactive origin of depression in HIV-patients.

Cytokine levels in CSF and neuropsychological performance in HIV patients.

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.

Late-stage neurosyphilis presenting with severe neuropsychiatric deficits: diagnosis, therapy, and course of three patients.

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.

Subclinical reactivation of varicella zoster virus in all stages of HIV infection.

Analysis of 200 paired serum and cerebrospinal fluid (CSF) samples from 180 HIV-positive individuals, 136 of whom had AIDS, revealed intrathecal synthesis of antibodies specific for varicella zoster virus (VZV) in 28 (16%) individuals, measles virus in 15 (8%), herpes simplex virus-1 (HSV-1) in 1 (0.6%), and HSV-2 in none. Of the 28 subjects with a positive VZV antibody specificity index, only 1 had zoster rash at the time of serum and CSF sampling; of the total 180 HIV-positive subjects, 146 (81%) had no history of zoster. Based on an estimated 33.4 million HIV-positive individuals worldwide, subclinical reactivation of VZV in even less than 16% of HIV-positive people suggests the possibility that millions of people have active VZV infection of the central nervous system. In cases of VZV vasculopathy, myelopathy and even zoster sine herpete, the CSF is often positive for anti-VZV antibody, but negative for VZV DNA. To rule out VZV infection of the nervous system, CSF must be tested for VZV DNA and anti-VZV IgG and IgM antibody.

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.

Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases.

BACKGROUND: Treatment of multiple sclerosis with natalizumab is complicated by rare occurrence of progressive multifocal leukoencephalopathy (PML). Between July, 2006, and November, 2009, there were 28 cases of confirmed PML in patients with multiple sclerosis treated with natalizumab. Assessment of these clinical cases will help to inform future therapeutic judgments and improve the outcomes for patients. RECENT DEVELOPMENTS: The risk of PML increases with duration of exposure to natalizumab over the first 3 years of treatment. No new cases occurred during the first two years of natalizumab marketing but, by the end of November, 2009, 28 cases had been confirmed, of which eight were fatal. The median treatment duration to onset of symptoms was 25 months (range 6-80 months). The presenting symptoms most commonly included changes in cognition, personality, and motor performance, but several cases had seizures as the first clinical event. Although PML has developed in patients without any previous use of disease-modifying therapies for multiple sclerosis, previous therapy with immunosuppressants might increase risk. Clinical diagnosis by use of MRI and detection of JC virus in the CSF was established in all but one case. Management of PML has routinely used plasma exchange (PLEX) or immunoabsorption to hasten clearance of natalizumab and shorten the period in which natalizumab remains active (usually several months). Exacerbation of symptoms and enlargement of lesions on MRI have occurred within a few days to a few weeks after PLEX, indicative of immune reconstitution inflammatory syndrome (IRIS). This syndrome seems to be more common and more severe in patients with natalizumab-associated PML than it is in patients with HIV-associated PML. WHERE NEXT?: Diagnosis of natalizumab-associated PML requires optimised clinical vigilance, reliable and sensitive PCR testing of the JC virus, and broadened criteria for recognition of PML lesions by use of MRI, including contrast enhancement. Optimising the management of IRIS reactions will be needed to improve outcomes. Predictive markers for patients at risk for PML must be sought. It is crucial to monitor the risk incurred during use of natalizumab beyond 3 years.

Measurement of soluble inflammatory mediators in cerebrospinal fluid of human immunodeficiency virus-positive patients at distinct stages of infection by solid-phase protein array.

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.

Severe aseptic leucoencephalopathy as immune reconstitution inflammatory syndrome in Caucasian and African patients.

Immune reconstitution inflammatory syndrome (IRIS) after HAART may become manifest in form of aseptic severe leucoencephalopathy. All HIV-1-positive patients in this case series had widespread laboratory tests and follow-up MRI in order to investigate the course and the underlying pathophysiology of IRIS-associated leucoencephalopathy. All patients were treated with corticosteroids, in spite of additional immunosuppression. Three patients were successfully treated with corticosteroids and survived up to now, one died. A neuropathological examination was performed showing massive aseptic intraparenchymal and perivascular invasion of cytotoxic CD8 cells. It is assumed that IRIS-associated leucoencephalopathy is based on other preconditions in Africans and Caucasians.

Cidofovir in combination with HAART and survival in AIDS-associated progressive multifocal leukoencephalopathy.

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.

Viral load determines the B-cell response in the cerebrospinal fluid during human immunodeficiency virus infection.

OBJECTIVE: Human immunodeficiency virus (HIV) infection of the central nervous system (CNS) is frequently associated with intrathecal immunoglobulin synthesis and cerebrospinal fluid (CSF) pleocytosis, but little is known about the B-cell response in the CSF of these patients. In this study, we investigated the relation between virus load and the frequency and phenotype of B cells in the CSF of HIV-infected patients. METHODS: The distribution of T cells, B cells, short-lived plasmablasts, and long-lived plasma cells was analyzed by flow cytometry in CSF and peripheral blood of 33 patients with HIV infection compared with 12 patients with noninfectious CNS diseases. HIV RNA copy number in CSF and serum was quantified by kinetic polymerase chain reaction. RESULTS: B-cell and plasmablast levels were increased in the CSF of HIV-infected patients compared with patients with noninfectious CNS diseases. Whereas CSF B cells were found at similar frequency during early and late stages of HIV infection, plasmablasts were more prevalent in the CSF during early infection. Plasmablasts in the CSF correlated with intrathecal IgG synthesis and even stronger with HIV RNA copy numbers in CSF, in particular, in untreated, early HIV-infected individuals. Initiation of antiviral treatment in therapy-naive patients strongly decreased HIV copy numbers and plasmablasts in CSF. INTERPRETATION: Our findings demonstrate that HIV infection of the CNS triggers an early profound B-cell response, with plasmablasts serving as the main virus-related B-cell subset in the CSF.