Load In Cerebrospinal Fluid Research Articles

Brain biopsy and pathological diagnosis for drug-associated progressive multifocal leukoencephalopathy (PML) with inflammatory reactions.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by JC virus (JCV) infection. Although recognized as an AIDS complication in the 1980s, PML has emerged as a serious adverse event of immunosuppressive therapies since 2005, particularly disease-modifying drugs (DMDs) for multiple sclerosis (MS). PML can also occur in patients with collagenous diseases receiving steroid therapy or with age-related immunosuppression. In some cases, the etiology of immunosuppression remains unclear. These cases often present with early manifestations of PML, which, while common, are less well recognized, as PML was identified at more advanced stages in AIDS-related cases. Early diagnosis poses difficulty due to unfamiliar magnetic resonance (MR) images and low viral loads in cerebrospinal fluid (CSF), and brain biopsy may be conducted. This review summarizes the PML pathology identified through biopsy. Early cytopathological changes of JCV-infected cells, with the importance of dot-shaped inclusions associated with promyelocytic leukemia nuclear bodies (PML-NBs), are described. The variability of host immune responses, including PML immune reconstitution inflammatory syndrome (PML-IRIS), is addressed. The potential role of immune checkpoint inhibitors (ICIs), such as pembrolizumab, is also explored. Understanding the pathology of early PML helps to optimize diagnostic strategies and therapeutic interventions, ultimately improving prognosis.

Cerebrospinal Fluid Viral Escape on Highly Active Antiretroviral Therapy: Analysis from Single Tertiary Care Centre.

HIV-infected individuals receiving regular antiretroviral therapy (ART) can present with a high viral load in cerebrospinal fluid (CSF) at times when it is suppressed in blood. This study presents data of HIV-infected patients who had undetectable or low plasma viral load in blood but presented with neurological signs and symptoms and were diagnosed to have CSF HIV viral escape. Records were reviewed for clinical manifestations, details of opportunistic or coinfection, and HIV viral copies in plasma and CSF at time of diagnosis of CSF escape. A total of 10,200 HIV-infected individuals were registered in HIV care till December 31, 2021. Nineteen individuals (14 virologically confirmed and 5 clinically) were diagnosed with high viral copies in CSF from June 2014 to December 2021. Mean age was 41.5 ± 9.2 (median, 39.5; range, 30-62) years. Average duration of antiretroviral treatment received at the time of diagnosis of CSF escape was 10.1 years. Median plasma HIV-viral copies were 2,469.8 (undetectable to 29,418) and in CSF were 12,773.7 (n = 14, range, 1,340-48,530) copies/mL. HIV viral copies in CSF were significantly higher than in plasma at the time of presentation (p = .003). ART regimen switch was done after identification of HIV CSF escape. Seventeen patients were alive with a regular follow-up of average 35 (range 7-66) months. All had documented clinical improvement with reversal of neurological impairment after ART switch. There was one death and one lost to follow-up. Early identification and timely intervention in CSF viral escape could revert severe neurological impairment and improves treatment outcome.

Bacterial load in cerebrospinal fluid predicts unfavourable outcome in pneumococcal meningitis: a prospective nationwide cohort study

ObjectivesThe objective of this study was to determine the role of cerebrospinal fluid (CSF) bacterial load in adults with pneumococcal meningitis. MethodsWe quantified bacterial load in CSF samples from the diagnostic lumbar puncture of adults with community-acquired pneumococcal meningitis. We also measured CSF concentrations of complement component 5a (C5a), and determined associations between bacterial load, clinical characteristics, C5a and unfavourable outcome (Glasgow Outcome Scale score <5). ResultsBacterial load was quantified in 152 CSF samples. Median age of these patients was 61 years (interquartile range [IQR] 51–68), and 69 of 152 (45%) were female. Median CSF bacterial load was 1.6 × 104 DNA copies/mL (IQR 3.4 × 103–1.2 × 105), and did not correlate with CSF white cell count nor with CSF protein concentrations. Median CSF C5a concentration was 35.8 mg/L (IQR 15.9–105.6), and was moderately correlated with CSF bacterial loads (Spearman's rho = 0.42; p < 0001). High bacterial loads were associated with development of complications, such as circulatory shock (OR per logarithmic increase: 2.4, 95% CI: 2.0–2.9; p < 0.001) and cerebrovascular complications [OR: 1.9, 95% CI: 1.6–2.3; p < 0.001]). High bacterial loads were also associated with unfavourable outcome (OR: 2.8, 95% CI: 2.4–3.3; p < 0.001) and death (OR: 3.1, 95% CI: 2.6–3.8; p < 0.001). In a multivariable regression model including age, immunocompromised state, extrameningeal infection focus, admission Glasgow Coma Scale score and CSF C5a concentration, CSF bacterial load remained an independent predictor of unfavourable outcome (adjusted OR: 2.5, 95% CI: 1.6–3.9; p < 0.001). DiscussionHigh CSF bacterial load predicts the development of complications and unfavourable outcome in adults with pneumococcal meningitis.

Evaluation of enterovirus concentration, species identification, and cerebrospinal fluid parameters in patients of different ages with aseptic meningitis in São Paulo, Brazil.

Human enteroviruses (EV) are the most common cause of aseptic meningitis worldwide. Data on EV viral load in cerebrospinal fluid (CSF) and related epidemiological studies are scarce in Brazil. This study investigated the influence of EV viral load on CSF parameters, as well as identifying the involved species. CSF samples were collected in 2018-2019 from 140 individuals at The Hospital das Clínicas, São Paulo. The EV viral load was determined usingreal-time quantitative polymerase chain reaction,while EV species were identified by5'UTR region sequencing.Median viral load was 5.72 log10 copies/mL and did not differ by subjects'age and EV species. Pleocytosis was observed in 94.3% of cases, with the highest white blood cell (WBC) counts in younger individuals. Viral load and WBC count were correlated in children (p = 0.0172). Elevated lactate levels were observed in 60% of cases and correlated with the viral load in preteen-teenagers (p = 0.0120) and adults (p = 0.0184). Most individuals had normal total protein levels (70.7%), with higher in preteen-teenagers and adults (p < 0.0001). By sequencing, 8.2% were identified as EV species A and 91.8% as species B. Age-specific variations in CSF characteristics suggest distinct inflammatory responses in each group.

BLOOD AND CEREBROSPINAL FLUID HIV LOAD INPATIENTS WITH HIV-ASSOCIATED NEUROLOGICAL DISORDERS

Relevance. The issues of replication and concentration of the human immunodeficiency virus (HIV) in various tissues and body fluids remain insufficiently studied. Solving this problem is hindered by the lack of simple, cheap and accessible methods for quantitative determination of HIV in various tissue samples.&#x0D; Objective is to establish a relationship between the presence of HIV-associated damage of the central nervous system (CNS), the number of CD4+ lymphocytes in the blood, and the level of HIV load in blood plasma and cerebrospinal fluid. The difference between the level of HIV viral load in different tissues and biological fluids may reflect the formation of several independent reservoirs of HIV replication in the human body.&#x0D; Materials and methods. 87 patients with HIV infection with clinical signs of central nervous system damage who had no experience of taking antiretroviral drugs (ARVP) were examined. Paired samples of blood and cerebrospinal fluid were analyzed to determine the level of viral load in both biological fluids, as well as the number of CD4+ lymphocytes in the blood.&#x0D; Results. It was established that the patient's presence of clinical signs of CNS damage was reliably correlated with the level of HIV load in the cerebrospinal fluid (logistic regression, P&lt;0.001) and was not associated with the content of CD4+ lymphocytes or the level of HIV load in the blood (logistic regression, P &gt;0.05).&#x0D; The level of HIV load in the cerebrospinal fluid (CSF) was on average 1.5 lg RNA copies/ml higher (P&lt;0.001) in patients with neurological disorders despite the fact that the mean CD4+-lymphocyte count and HIV load in blood in both groups of patients did not differ. The difference between the HIV load in blood and cerebrospinal fluid of patients with neurological disorders was only 0.8 lg RNA copies/ml.&#x0D; Despite the similar indicators of the content of CD4+ lymphocytes and the amount of HIV in the blood, in HIV-infected patients with clinical signs of CNS damage, the level of HIV load in CSF is 1.5 lg RNA copies/ml higher, compared with patients without symptoms of CNS dysfunction (P &lt;0.001). The difference between HIV load in blood and cerebrospinal fluid in the presence of neurocognitive disorders was reduced to 0.7 lg RNA copies/ml compared to 1.8 lg RNA copies/ml in the group of individuals without signs of CNS damage. The presence of HIV-associated damage to the central nervous system is not statistically related to the content of CD4+ lymphocytes or the level of HIV load in the blood.&#x0D; Statistical analysis showed that a CSF HIV load equal to or greater than 4.00 lg RNA copies/mL (10,000 RNA copies/mL) indicated a significant likelihood of HIV-associated CNS involvement in patients (P&lt;0.001) .&#x0D; Conclusion. The method of determining the level of HIV load in cerebrospinal fluid samples can be used to optimize the diagnostic algorithm of HIV-associated lesions of the central nervous system, differential diagnosis with neurocognitive disorders of non-infectious etiology. The threshold for making a clinical decision is the level of HIV load in the CSF sample, which is equal to or exceeds 4.00 lg RNA copies/ml, which indicates a significant probability of the presence of an HIV-associated lesion of the CNS in the patient.

Efficacy assessment of a novel endolysin PlyAZ3aT for the treatment of ceftriaxone-resistant pneumococcal meningitis in an infant rat model.

Treatment failure in pneumococcal meningitis due to antibiotic resistance is an increasing clinical challenge and alternatives to antibiotics warrant investigation. Phage-derived endolysins efficiently kill gram-positive bacteria including multi-drug resistant strains, making them attractive therapeutic candidates. The current study assessed the therapeutic potential of the novel endolysin PlyAZ3aT in an infant rat model of ceftriaxone-resistant pneumococcal meningitis. Efficacy of PlyAZ3aT was assessed in a randomized, blinded and controlled experimental study in infant Wistar rats. Meningitis was induced by intracisternal infection with 5 x 107 CFU/ml of a ceftriaxone-resistant clinical strain of S. pneumoniae, serotype 19A. Seventeen hours post infection (hpi), animals were randomized into 3 treatment groups and received either (i) placebo (phosphate buffered saline [PBS], n = 8), (ii) 50 mg/kg vancomycin (n = 10) or (iii) 400 mg/kg PlyAZ3aT (n = 8) via intraperitoneal injection. Treatments were repeated after 12 h. Survival at 42 hpi was the primary outcome; bacterial loads in cerebrospinal fluid (CSF) and blood were secondary outcomes. Additionally, pharmacokinetics of PlyAZ3aT in serum and CSF was assessed. PlyAZ3aT did not improve survival compared to PBS, while survival for vancomycin treated animals was 70% which is a significant improvement when compared to PBS or PlyAZ3aT (p<0.05 each). PlyAZ3aT was not able to control the infection, reflected by the inability to reduce bacterial loads in the CSF, whereas Vancomycin sterilized the CSF and within 25 h. Pharmacokinetic studies indicated that PlyAZ3aT did not cross the blood brain barrier (BBB). In support, PlyAZ3aT showed a peak concentration of 785 μg/ml in serum 2 h after intraperitoneal injection but could not be detected in CSF. In experimental pneumococcal meningitis, PlyAZ3aT failed to cure the infection due to an inability to reach the CSF. Optimization of the galenic formulation e.g. using liposomes might enable crossing of the BBB and improve treatment efficacy.

Adoptive Transfer of JC Virus-Specific T Lymphocytes for the Treatment of Progressive Multifocal Leukoencephalopathy.

ObjectiveProgressive multifocal leukoencephalopathy (PML) is still burdened by high mortality in a subset of patients, such as those affected by hematological malignancies. The aim of this study was to analyze the safety and carry out preliminary evaluation of the efficacy of polyomavirus JC (JCPyV)‐specific T cell therapy in a cohort of hematological patients with PML.MethodsBetween 2014 and 2019, 9 patients with a diagnosis of “definite PML” according to the 2013 consensus who were showing progressive clinical deterioration received JCPyV‐specific T cells. Cell lines were expanded from autologous or allogenic peripheral blood mononuclear cells by stimulation with JCPyV antigen‐derived peptides.ResultsNone of the patients experienced treatment‐related adverse events. In the evaluable patients, an increase in the frequency of circulating JCPyV‐specific lymphocytes was observed, with a decrease or clearance of JCPyV viral load in cerebrospinal fluid. In responsive patients, transient appearance of punctate areas of contrast enhancement within, or close to, PML lesions was observed, which was interpreted as a sign of immune control and which regressed spontaneously without the need for steroid treatment. Six of 9 patients achieved PML control, with 5 alive and in good clinical condition at their last follow‐up.InterpretationAmong other novel treatments, T cell therapy is emerging as a viable treatment option in patients with PML, particularly for those not amenable to restoration of specific immunity. Neurologists should be encouraged to refer PML patients to specialized centers to allow access to this treatment strategy. ANN NEUROL 2021;89:769–779

Improved diagnosis of viral encephalitis in adult and pediatric hematological patients using viral metagenomics.

Metagenomic sequencing is a powerful technique that enables detection of the full spectrum of pathogens present in any specimen in a single test. Hence, metagenomics is increasingly being applied for detection of viruses in clinical cases with suspected infections of unknown etiology and a large number of relevant potential causes. This is typically the case in patients presenting with encephalitis, in particular when immunity is impaired by underlying disorders. In this study, viral metagenomics has been applied to a cohort of hematological patients with encephalitis of unknown origin. Because viral loads in cerebrospinal fluid of patients with encephalitis are generally low, the technical performance of a metagenomic sequencing protocol with viral enrichment by capture probes targeting all known vertebrate viral sequences was studied. Subsequently, the optimized viral metagenomics protocol was applied to a cohort of hematological patients with encephalitis of unknown origin. Viral enrichment by capture probes increased the viral sequence read count of metagenomics on cerebrospinal fluid samples 100 - 10.000 fold, compared to unenriched metagenomic sequencing. In five out of 41 (12%) hematological patients with encephalitis, a virus was detected by viral metagenomics which had not been detected by current routine diagnostics. BK polyomavirus, hepatitis E virus, human herpes virus-6 and Epstein Barr virus were identified by this unbiased metagenomic approach. This study demonstrated that hematological patients with encephalitis of unknown origin may benefit from early viral metagenomics testing as a single step approach.

Human immunodeficiency virus-associated vacuolar encephalomyelopathy with granulomatous-lymphocytic interstitial lung disease improved after antiretroviral therapy: a case report

BackgroundVacuolar encephalomyelopathy, a disregarded diagnosis lately, was a major neurological disease in the terminal stages of human immunodeficiency virus (HIV)-1 infection in the pre-antiretroviral therapy (ART) era. Granulomatous-lymphocytic interstitial lung disease (GLILD) was classically identified as a non-infectious complication of common variable immunodeficiency; however, it is now being recognized in other immunodeficiency disorders. Here, we report the first case of GLILD accompanied by vacuolar encephalomyelopathy in a newly diagnosed HIV-infected man.Case presentationA 40-year-old Japanese man presented with chronic dry cough and progressing paraplegia. Radiological examination revealed diffuse pulmonary abnormalities in bilateral lungs, focal demyelinating lesions of the spinal cord, and white matter lesions in the brain. He was diagnosed with GLILD based on marked lymphocytosis detecting in bronchoalveolar lavage, and transbronchial-biopsy proven T-cellular interstitial lung disease with granulomas. Microbiological examinations did not reveal an etiologic agent. The patient was also diagnosed with HIV-associated vacuolar encephalomyelopathy on the basis of an elevated HIV viral load in cerebrospinal fluid. After initiating ART, the brain lesions and paraplegia improved significantly, and interstitial abnormalities of the lungs and cough disappeared.ConclusionThis report highlights that even in the post-ART era in developed countries with advanced healthcare services, HIV-associated vacuolar encephalomyelopathy should be considered in the differential diagnosis of a progressive neurological disorder during the first visit. Furthermore, GLILD may represent an HIV-associated pulmonary manifestation that can be treated by ART.

Detection of varicella-zoster virus from cerebrospinal fluid using advanced fragment analysis in a child with encephalitis: a case report

BackgroundVaricella zoster virus (VZV) encephalitis is an infectious inflammatory disease of brain that can cause irreversible mental damage without timely treatment. In fact, many viruses can cause encephalitis, and the viral loads in cerebrospinal fluid (CSF) in the early stage of the disease are usually too low to be detected. Here we report a case of VZV encephalitis diagnosed by advanced fragment analysis (AFA), which could potentially to contribute to early diagnosis of VZV central nervous system (CNS) infections with a small volume of CSF samples.Case presentationA 10-year-old boy was admitted to the hospital with obvious neurological symptoms of headache, dizziness and vomiting for one day. Physical examination showed left facial paralysis. Complete blood count (CBC) test only showed an unspecific inflammation, and the culture of cerebrospinal fluid and microscopic staining examination were all negative. AFA was performed to screen the common 18 encephalitis related pathogens in CSF. Obvious VZV DNA fragments were observed by capillary electrophoresis at 160 nt, suggesting the existence of VZV CNS infection in children. The results were consistence with real-time quantitative PCR and concomitant symptoms in the acute stage of the disease.ConclusionsWe report a case of acute VZV encephalitis in a child without obvious skin manifestations, which was rapidly diagnosed by AFA. Overall, we would recommend the use of AFA analysis as the rapid screening system for the identification and differentiation of encephalitis pathogens in children.

P59 Acute varicella zoster encephalitis? Don’t forget the treatment!

ObjectivesEducate physicians on the need for monitoring of Aciclivir levels in renal failure.DesignRetrospective case report.Subjects59 year old woman presented with acute psychosis following recent herpes zoster treated with oral Aciclovir.MethodsData collection from; original casenotes, electronic laboratory records, electronic picture archiving and communication system (PACS).ResultsLumbar puncture showed raised protein (0.92 g/L), CSF:serum glucose ratio(0.9), 36 WBCs/cmm(72% polymorphs) and detection of VZV DNA. MRI brain only revealed intracranial-hypotension secondary to lumbar puncture. Despite absence of VZV DNA on surveillance lumbar puncture, she remained minimally responsive. Aciclovir levels were significantly elevated post-dose at 32.7 mg/L (cutoff 10.8 mg/L) and a sedation hold revealed temporal correlation of pre-dose levels (6.4 mg/L) with improvement of GCS, strongly implicating Aciclovir as causative agent. Rapid resolution of encephalopathy occurred upon cessation with no residual neurological compromise.ConclusionsAciclovir neurotoxicity mimics zoster-related encephalitis and VZV DNA is commonly detected in cerebrospinal fluid of patient’s with herpes zoster (Rudzek et al. 2007). Our case highlights the need for vigilance of Aciclovir-neurotoxicity in renal failure patients.ReferenceRudzek D, Piskunova N, Zampachova E. High variability in viral load in cerebrospinal fluid from patients with herpes simplex and varicella-zoster infections of the central nervous system. Clinical Microbiology and Infection2007;13(12):1217–1219.

Pretreatment Cerebrospinal Fluid Bacterial Load Correlates With Inflammatory Response and Predicts Neurological Events During Tuberculous Meningitis Treatment.

The Mycobacterium tuberculosis load in the brain of individuals with tuberculous meningitis (TBM) may reflect the host's ability to control the pathogen, determine disease severity, and determine treatment outcomes. We used the GeneXpert assay to measure the pretreatment M. tuberculosis load in cerebrospinal fluid (CSF) specimens from 692 adults with TBM. We sought to understand the relationship between CSF bacterial load and inflammation, and their respective impact on disease severity and treatment outcomes. A 10-fold higher M. tuberculosis load was associated with increased disease severity (odds ratio, 1.59; P = .001 for the comparison between grade 1 and grade 3 severity), CSF neutrophil count (r = 0.364 and P < .0001), and cytokine concentrations (r = 0.438 and P < .0001). A high M. tuberculosis load predicted new neurological events after starting treatment (P = .005, by multinomial logistic regression) but not death. Patients who died had an attenuated inflammatory response at the start of treatment, with reduced cytokine concentrations as compared to survivors. In contrast, patients with high pretreatment CSF bacterial loads, cytokine concentrations, and neutrophil counts were more likely to subsequently experience neurological events. The pretreatment GeneXpert-determined M. tuberculosis load may be a useful predictor of neurological complications occurring during TBM treatment. Given the evidence for the divergent pathogenesis of TBM-associated neurological complications and deaths, therapeutic strategies to reduce them may need reassessment.

HTLV-1 proviral load in cerebrospinal fluid may not be a good marker to differentiate asymptomatic carriers with high proviral load in blood from HAM/TSP patients.

An elevated human T cell leukemia virus type 1 (HTLV-1) proviral load (PVL) is an important risk factor for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), although there is a considerable frequency of asymptomatic carriers (AC) with high PVL in blood. Our objective was to evaluate whether PVL quantified in cerebrospinal fluid (CSF) is helpful to distinguish AC from HAM when AC have high PVL in blood (ACH). ACH (n = 7) were characterized to have high PVL in blood by quantification of samples collected over time (mean 7years). HAM patients (n = 14) also had analyzed blood samples collected at different times (mean 9years). Comparing paired CSF and blood samples of each individual, CSF PVL mean was 4.7-fold higher than blood PVL in the ACH group and 10.8-fold in the HAM group. CSF PVL was significantly greater than blood PVL in the HAM group (p = 0.004), but not in the ACH group. Important to highlight, CSF PVL was not significantly different between the ACH and the HAM groups. These results suggested that significantly higher PVL in CSF than in blood is a hallmark of HAM/TSP patients, but this is also true for asymptomatic carriers with high PVL in blood, thus reducing its usefulness as a marker for HAM/TSP. A greater number of ACH should be analyzed, but whether they will eventually develop HAM/TSP or why they have not developed the disease are still questions to be clarified. Longitudinal studies are necessary to answer these questions.

Relationship of Human Immunodeficiency Virus Viral Load in Cerebrospinal Fluid and Plasma in Patients Co-infected With Cryptococcal Meningitis.

We measured human immunodeficiency virus (HIV) ribonucleic acid (RNA) in paired cerebrospinal fluid (CSF) and plasma samples in a prospective study of 91 HIV-infected, antiretroviral therapy-naive patients with cryptococcal meningitis. Cerebrospinal fluid HIV RNA was lower than in plasma (median 4.7 vs 5.2 log10 copies/mL, P < .0001) and positively correlated with plasma HIV RNA, peripheral CD4+ T-cell percentage, and CSF CXCL10. Plasma/CSF ratio of HIV RNA ranged widely from 0.2 to 265.5 with a median of 2.6. Cerebrospinal fluid quantitative cryptococcal culture positively correlated with CSF CCL2 and CCL3. CSF-plasma viral discordance was not associated with cryptococcal-associated immune reconstitution inflammatory syndrome.

Cytomegalovirus Polyradiculopathy in the Modern Age of Human Immunodeficiency Virus Therapies

Abstract Cytomegalovirus (CMV) polyradiculopathy in human immunodeficiency virus–infected patients is an increasingly rare disease given the widespread availability of effective antiretroviral therapy. Here, we describe a case of CMV polyradiculopathy in a man following the initiation of antiretrovirals. The patient presented with a 2-week history of rapidly progressing bilateral lower extremity weakness resulting in paraplegia; he was diagnosed with CMV polyradiculopathy based on cerebrospinal fluid and magnetic resonance imaging findings. Treatment with ganciclovir, foscarnet, and antiretroviral therapy resulted in rapid reduction of CMV viral load in cerebrospinal fluid and halting of disease progression. Six months after presentation, the patient continues to show improvement in lower extremity strength and has regained the ability to ambulate without assistance for short distances.

Diagnostic challenges in vacuolar myelopathy: a didactic case report.

Because of the diagnostic complexity and potential pitfalls in interpreting test results, HIV-vacuolar myelopathy (HIVM) is far more often diagnosed postmortem than in vivo. In the era of highly active antiretroviral therapy (HAART), the topic of neuro-AIDS has become increasingly important. This case report covers some of the diagnostic problems encountered in vacuolar myelopathy based on magnetic resonance imaging (MRI) fiber-tracking pictures of the spine in a patient with HIVM, including a 1-year follow-up. A 49-year-old man felt progressive weakness, and difficulties while walking, and he suffered from incomplete voiding. A week before admission, follicles appeared on the right side of his neck and shoulder. His medical history included a chronic HIV infection treated with HAART and a B-cell lymphoma in complete remission after chemotherapy. The initial exam revealed thoracic hyposensitivity level distal to dermatome Th9, spastic paraparesis of the lower limbs and herpes zoster infection in dermatome C3/C4. A lesion of the thoracic myelon could be ruled out in the MRI scan, chemotherapy-induced polyneuropathy was stable, and no acute opportunistic infection of the CNS was found. HIV load in cerebrospinal fluid (CSF) was markedly elevated. An HIV-associated vacuolar myelopathy was diagnosed, revealing the HIV itself as etiology. A negative or unspecific MRI scan excludes possible other causes, but by no means rules out HIV-related myelopathy. Furthermore, peripheral and central viral load should always be assessed to avoid missing a possible 'CSF HIV-escape'.

Enhanced antagonism of BST-2 by a neurovirulent SIV envelope.

Current antiretroviral therapy (ART) is not sufficient to completely suppress disease progression in the CNS, as indicated by the rising incidence of HIV-1-associated neurocognitive disorders (HAND) among infected individuals on ART. It is not clear why some HIV-1-infected patients develop HAND, despite effective repression of viral replication in the circulation. SIV-infected nonhuman primate models are widely used to dissect the mechanisms of viral pathogenesis in the CNS. Here, we identified 4 amino acid substitutions in the cytoplasmic tail of viral envelope glycoprotein gp41 of the neurovirulent virus SIVsm804E that enhance replication in macrophages and associate with enhanced antagonism of the host restriction factor BM stromal cell antigen 2 (BST-2). Rhesus macaques were inoculated with a variant of the parental virus SIVsmE543-3 that had been engineered to contain the 4 amino acid substitutions present in gp41 of SIVsm804E. Compared with WT virus-infected controls, animals infected with mutant virus exhibited higher viral load in cerebrospinal fluid. Together, these results are consistent with a potential role for BST-2 in the CNS microenvironment and suggest that BST-2 antagonists may serve as a possible target for countermeasures against HAND.

Relevance of retrovirus quantification in cerebrospinal fluid for neurologic diagnosis.

Different human retroviruses, such as Human Immunodeficiency Virus (HIV) and Human T-cell Lymphotropic Virus (HTLV), can cause neurologic infection. However, a definitive diagnosis may be hampered by several factors. Quantification of the viral or proviral load in cerebrospinal fluid (CSF) may be helpful in the diagnosis of nervous system disorders due to retroviral infection and may influence the treatment approach. The present work discusses retrovirus infection and neurologic impairment, as well as the usefulness of the determination of the HIV and HTLV proviral or viral load in cerebrospinal fluid in cases of neurologic disorder, in light of recent advances in this field. This study also discusses the different molecular techniques for quantifying the proviral load (real-time quantitative PCR, droplet digital PCR, and semi-nested real-time reverse transcription PCR) that are currently available.

Central Nervous System Antiretroviral High Penetration Therapy

The use of highly effective antiretroviral therapy penetration into the central nervous system has indicators for input that can eradicate the viral load in cerebrospinal fluid, thereby helping to prevent the virus compartmentalization in CNS and hence probably preventing perpetuation of these cognitive disorders associated with HIV virus. However, more studies are necessary in order to demonstrate the real pathophysiological mechanisms associated with these effects and to prove that the side effects associated with the use of these medications are harmless than the benefits achieved on the neurocognitive disorders.

A label-free electrical impedimetric biosensor for the specific detection of Alzheimer's amyloid-beta oligomers

Alzheimer's disease (AD) is the most common form of dementia, with over 37 million sufferers worldwide and a global cost of over $600 billion. There is currently no cure for AD and no reliable method of diagnosis other than post-mortem brain examination. The development of a point-of-care test for AD is an urgent requirement in order to provide earlier diagnosis and, thus, useful therapeutic intervention. Here, we present a novel, label-free impedimetric biosensor for the specific detection of amyloid-beta oligomers (AβO), which are the primary neurotoxic species in AD. AβO have been proposed as the best biomarker for AD and levels of AβO in the blood have been found to correlate with cerebrospinal fluid load. The biorecognition element of our biosensor is a fragment of the cellular prion protein (PrPC, residues 95–110), a highly expressed synaptic protein which mediates the neuronal binding and toxicity of AβO. During the layer-by-layer sensor construction, biotinylated PrPC (95–110) was attached via a biotin/NeutrAvidin bridge to polymer-functionalised gold screen-printed electrodes. Electrochemical impedance spectroscopy (EIS), cyclic voltammetry and scanning electron microscopy were used to validate biosensor assembly and functionality. EIS was employed for biosensor interrogation in the presence of Aβ oligomers or monomers. The biosensor was specific for the detection of synthetic AβO and gave a linear response, without significant detection of monomeric Aβ, down to an equivalent AβO concentration of ~0.5pM. The biosensor was also able to detect natural, cell-derived AβO present in conditioned medium. The eventual commercialisation of this biosensor system could allow for the early diagnosis and disease monitoring of AD.