Katrin Hahn

Heterozygous Arg753Gln Polymorphism of Human TLR-2 Impairs Immune Activation by Borrelia burgdorferi and Protects from Late Stage Lyme Disease

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.

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

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

Phosphorylated α-synuclein in skin nerve fibres differentiates Parkinson’s disease from multiple system atrophy

Deposition of phosphorylated SNCA (also known as α-synuclein) in cutaneous nerve fibres has been shown pre- and post-mortem in Parkinsons 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 Parkinsons 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 Parkinsons 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 Parkinsons disease. Moreover, pre-mortem investigation of phosphorylated SNCA in cutaneous nerve fibres may prove a relevant and easily conductible diagnostic procedure to differentiate Parkinsons disease from multiple system atrophy.

Relations of low contrast visual acuity, quality of life and multiple sclerosis functional composite: a cross-sectional analysis

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.

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.

Validation of the International HIV Dementia Scale as a Screening Tool for HIV-Associated Neurocognitive Disorders in a German-Speaking HIV Outpatient Clinic.

Background HIV-associated neurocognitive disorders (HAND) are widely present among people living with HIV. Especially its milder forms, asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND), remain highly prevalent worldwide. Diagnosing these conditions is subject to a time and resource consuming neuropsychological assessment. Selecting patients at a higher risk of cognitive impairment by using a simple but effective screening tool helps to organise access to further neuropsychological diagnosis. The International HIV Dementia Scale (IHDS) has until now been a well-established screening tool in African and American countries, however these populations’ demographics defer significantly from ours, so using the same parameters could be ineffective. Objectives To calculate the prevalence of this condition among people attending an HIV outpatient clinic in Berlin and to validate the use of the IHDS as a screening tool for HAND in a German-speaking population. Methods We screened 480 HIV-infected patients using the IHDS, 89% of them were on a stable antiretroviral treatment. Ninety of them completed a standardised neuropsychological battery of tests and a specific cognitive complaints questionnaire. The same procedure was applied to a control group of 30 HIV-negative participants. HAND diagnosis was established according to the Frascati criteria. Results The overall prevalence of HAND in our cohort was 43% (20% ANI, 17% MND and 6% HIV-associated dementia). The optimal cut-off on the IHDS for detecting HAND cases was set at 11 and achieved both a sensitivity and a specificity of 80%. When specifically screening for the more severe form of HAND, HIV-associated dementia, a cut-off value of 10 offered an increase in both sensitivity (94%) and specificity (86%). The Youden Index for diagnostic accuracy was 0.6 and 0.8, respectively. Conclusions The prevalence of HAND was comparable to the reported by recent studies performed in countries with a similar economic development. The study confirms the IHDS to be a useful HAND screening tool in primary care settings and establishes new recommendations for its use in German-speaking countries.

HIV Associated Neuropathies

Human immunodeficiency virus (HIV)-associated polyneuropathy has become the most common neurological complication of HIV infection and is one of the main risk factors for development of a neuropathy worldwide. Therefore HIV should always be considered as an underlying cause in patients with neuropathy. Many types of peripheral neuropathies are seen in HIV infection depending on the stage of infection. The inflammatory demyelinating neuropathies both acute (Guillain-Barre syndrome, GBS) and chronic (chronic inflammatory demyelinating neuropathy, CIDP) occur mainly at the time of seroconversion or early in the course of the disease while syndromes associated with opportunistic infections like CMV (i.e. polyradiculoneuropathy) occur in the late phase of HIV infection and are related to the loss of immune function. Distal symmetrical polyneuropathy (DSP) is the most common neuropathy in HIV-infected patients. We review the clinical manifestations, epidemiology, clinical diagnostics, pathophysiology and management strategies for HIV-associated polyneuropathies.

Effect of interferon-free therapy on cognition in HCV and HCV/HIV infection: A pilot study

Approval of direct-acting antivirals against the hepatitis C virus (HCV) has dramatically changed the management of HCV infection due to high cure rates and a favorable safety profile. Their influence on neurologic aspects is notably relevant, as studies demonstrated active HCV replication within the CNS1 and alterations in cerebral metabolism consistent with neuroinflammatory conditions.2 These findings may be causative for cognitive deficits in HCV-infected patients.3 Similar impairment has been demonstrated in patients coinfected with HIV, with a prevalence as high as 60%.4 Therefore, these patients may particularly benefit from HCV eradication. To date, studies addressing the issue of reversibility of cognitive deficits after HCV therapy are based on interferon treatment, which itself can cause continuing cognitive impairment.5 The important question whether these deficits are indeed reversible after HCV eradication remains unsolved to date.

Progressive Facial Asymmetry due to Trigeminal Motor Neuropathy

to the left due to paresis of the left pterygoid muscle. The corneal refl ex was positive on both sides. All other neurological systems were regular. In particular, there were no sensory disturbances and no signs of polyneuropathy. Electromyography did not detect pathological spontaneous activity (most probably due to massive atrophy and chronicity of the process), but showed a single unit interference pattern during maximal voluntary contraction in the left masseter muscle and motor unit action potentials with amplitudes of 4 mV. Myopathic changes were absent. Other laboratory parameters were regular, e.g., C-reactive protein, creatine kinase, myoglobin, and blood cell count. A brain magnetic resonance imaging (MRI) scan did not detect any pathology, in particular no lesion of the pons or the mandibular trigeminal nerve branch. However, pronounced left-sided masseteric atrophy was clearly depictable on MRI images ( fi g. 1 ). Altogether, there was massive atrophy and paresis of the left jaw muscles without any sensory facial disturbances, indicating pure motor trigeminal neuropathy. Electromyography confi rmed chronic denervation of the left masseter muscle. Lumbar puncture was declined. Dear Sir, Facial asymmetry often occurs because of unilateral facial nerve paresis. Here, we report on a HIV-positive patient with progressive facial asymmetry due to unilateral motor trigeminal neuropathy.

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.