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.

GBP was more effective than placebo in reducing pain and sleep interference in patients with HIV-SN.

Deposition of phosphorylated SNCA (also known as α-synuclein) in cutaneous nerve fibres has been shown pre- and post-mortem in Parkinson's disease. Thus far, no pre-mortem studies investigating the presence of phosphorylated SNCA in skin sympathetic nerve fibres of multiple system atrophy, another synucleinopathy, have been conducted. In this in vivo study, skin from the ventral forearm of 10 patients with multiple system atrophy and 10 with Parkinson's disease, together with six control subjects with essential tremor, were examined by immunohistochemistry. Phosphorylated SNCA deposits in skin sympathetic nerve fibres and dermal nerve fibre density were assessed. All patients with Parkinson's disease expressed phosphorylated SNCA in sympathetic skin nerve fibres, correlating with an age-independent denervation of autonomic skin elements. In contrast, no phosphorylated SNCA was found in autonomic skin nerve fibres of patients with multiple system atrophy and essential tremor control subjects. These findings support that phosphorylated SNCA deposition is causative for nerve fibre degeneration in Parkinson's disease. Moreover, pre-mortem investigation of phosphorylated SNCA in cutaneous nerve fibres may prove a relevant and easily conductible diagnostic procedure to differentiate Parkinson's disease from multiple system atrophy.

Lyme disease (LD) is caused by Borrelia burgdorferi and displays different stages, including localized, early disseminated, and persistent infection, all of which are associated with profound inflammatory reactions in the host. Induction of proinflammatory cytokines by B. burgdorferi is mainly mediated by outer surface proteins interacting with TLR-2/TLR-1 heterodimers. In this study, we show that TNF-α induction by Borrelia lysate was impaired in heterozygous TLR-2 knockout mice, while reactivity to lipoteichoic acid, another TLR-2 ligand signaling via TLR-2/TLR-6 heterodimers, was unaffected. Blood from individuals heterozygous for the TLR-2 polymorphism Arg753Gln was tested for cytokine release upon stimulation with Borrelia lysate, and induction of TNF-α and IFN-γ was significantly lower as compared with individuals not exhibiting this variation. Overexpression of TLR-2 carrying the Arg753Gln polymorphism in HEK 293 cells led to a significantly stronger impairment of activation by TLR-2/TLR-1 ligands as compared with TLR-2/TLR-6 ligands. To study whether heterozygosity for the Arg753Gln variant of TLR-2 influenced susceptibility for LD, we analyzed 155 patients for this polymorphism. The Arg753Gln variant occurs at a significantly lower frequency in LD patients as compared with matched controls (5.8 vs 13.5%, odds ratio 0.393, 95% confidence interval 0.17–0.89, p = 0.033), with an even more pronounced difference when late stage disease was observed (2.3 vs 12.5%, odds ratio 0.163, 95% confidence interval 0.04–0.76, p = 0.018). These data suggest that Arg753Gln may protect from the development of late stage LD due to a reduced signaling via TLR-2/TLR-1.

• Focal destruction of the optic radiation is detectable by 7 T MRI. • Focal optic radiation damage is common in MS. • Optic radiation damage is associated with RNFL thinning, detectable by OCT. • Optic radiation damage is associated with delayed VEP and visual dysfunction. • RNFL thickness in non-optic neuritis eyes correlates with optic radiation demyelination.

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BackgroundAlthough common and often disabling in multiple sclerosis (MS), visual dysfunction is currently not adequately accounted for in both clinical routine and MS trials. Sloan low contrast letter acuity (SLCLA) is a standardised chart-based measure of visual function particular at low contrast and has been suggested as additional visual component to the Multiple Sclerosis Functional Composite (MSFC). Here, we evaluate the relations between SLCLA, retinal integrity, MSFC, and quality of life (QoL) in MS patients.MethodsCross-sectional analysis of retinal nerve fibre layer (RNFL) thickness, MSFC, SLCLA (2.5% and 1.25% contrast levels), visual evoked potentials, and QoL (Short Form (SF) 36, National Eye Institute Visual Functioning Questionnaire (NEIVFQ)) using baseline data of 92 MS patients from an ongoing prospective longitudinal trial. Relations between RNFL thickness or P100 latency and SLCLA were analysed using generalised estimating equations (GEE) accounting for intra-individual inter-eye dependencies and corrected for age, gender, and history of optic neuritis. Pearson’s correlations were used to assess relations between SLCLA, MSFC, and QoL.ResultsSLCLA reflected RNFL thickness (p = 0.021) and P100 latency (p = 0.004) and predicted vision-related QoL, reflected by the NEIVFQ39 subscores “general vision” and “near activities” (p < 0.008 for both). SLCLA did not predict general QoL reflected by SF36. Implementing SLCLA into MSFC, thus creating a four-dimensional MSFC4, captured aspects of disability reflected by the NEIVFQ39 subscores “general vision” (r = 0.42, p < 0.0001) and “near activity” (r = 0.3, p = 0.014) which were not captured by standard MSFC3.ConclusionsSLCLA at 2.5% and 1.25% contrast levels correlates with retinal morphology and P100 latency and predicts some aspects of vision-related QoL in MS. More importantly, using a prospective cross-sectional approach we provide evidence that extending the MSFC by SLCLA as an additional visual component increases the performance of MSFC to capture MS-related disability. Longitudinal data on the relation between SLCLA, MSFC, and QoL will be available in the near future.

Human immunodeficiency virus-associated distal-symmetric neuropathy (HIV-DSP) is the most common neurological complication of HIV infection. The pathophysiology of HIV-DSP is poorly understood and no treatment is available for this entity. The dorsal root ganglia (DRG) are the principal sites of neuronal damage and are associated with reactive mononuclear phagocytes as well as HIV-infected macrophages. To determine the role of HIV-infected macrophages in the pathogenesis of HIV-DSP, we developed a technique for culturing human DRG's. When the dissociated DRG neurons were exposed to supernatants from macrophages infected with CXCR4 or CCR5 tropic HIV-1 strains axonal retraction was observed without neuronal cell death but there was mitochondrial dysfunction in the neuronal cell body. Even though CXCR4 and CCR5 were expressed on the DRG neurons, the effects were independent of these receptors. Antioxidants rescued the neuronal cell body but not the axon from the toxic effects of the culture supernatants. Further, peripheral nerves of HIV-infected patients obtained at autopsy did not show evidence of increased oxidative stress. These observations suggest a differential effect on the axon and cell body. Different mechanisms of injury may be operative in these two structures.