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Shoulder complaints are a very prevalent condition and a significant cause of morbidity and disability. Most patients with shoulder complaints are primarily seen by general physicians. The guideline, as developed by the Dutch College of General Physicians (NHG) in 2019, formulates a basic algorithm to start early conservative management of shoulder complaints. This article describes several causes of shoulder complaints more extensively and offers possible tools to obtain a more precise diagnosis. With a better knowledge of the multiple causes of shoulder complaints, most shoulder complaints can be adequately managed by general physicians, thus preventing unnecessary referrals.

Background: Despite successful antiretroviral therapy, people living with human immunodeficiency virus (PLWH) experience higher rates of age-related morbidity, including abnormal brain structure, brain function, and cognitive impairment. This has raised concerns that PLWH may experience accelerated aging-related brain pathology., Methods: We performed a multicenter longitudinal study of 134 virologically suppressed PLWH (median age, 56.0 years) and 79 demographically similar human immunodeficiency virus (HIV)-negative controls (median age, 57.2 years). To measure cognitive performance and brain pathology, we conducted detailed neuropsychological assessments and multimodality neuroimaging (T1-weighted, T2-weighted, diffusion magnetic resonance imaging [MRI], resting-state functional MRI, spectroscopy, arterial spin labeling) at baseline and at 2 years. Group differences in rates of change were assessed using linear mixed effects models., Results: One hundred twenty-three PLWH and 78 HIV-negative controls completed longitudinal assessments (median interval, 1.97 years). There were no differences between PLWH and HIV-negative controls in age, sex, years of education, smoking or alcohol use. At baseline, PLWH had poorer global cognitive performance (P < .01), lower gray matter volume (P = .04), higher white matter hyperintensity load (P = .02), abnormal white matter microstructure (P < .005), and greater brain-predicted age difference (P = .01). Longitudinally, there were no significant differences in rates of change in any neuroimaging measure between PLWH and HIV-negative controls (P > .1). Cognitive performance was longitudinally stable in both groups., Conclusions: We found no evidence that middle-aged PLWH, when receiving successful treatment, are at increased risk of accelerated aging-related brain changes or cognitive decline over 2 years.

Background: Brain structural abnormalities have been reported in persons living with human immunodeficiency virus (HIV; PLWH) who are receiving suppressive combination antiretroviral therapy (cART), but their pathophysiology remains unclear., Methods: We investigated factors associated with brain tissue volumes and white matter microstructure (fractional anisotropy) in 134 PLWH receiving suppressive cART and 79 comparable HIV-negative controls, aged ≥45 years, from the Comorbidity in Relation to AIDS cohort, using multimodal neuroimaging and cerebrospinal fluid biomarkers., Results: Compared with controls, PLWH had lower gray matter volumes (-13.7 mL; 95% confidence interval, -25.1 to -2.2) and fractional anisotropy (-0.0073; 95% confidence interval, -.012 to -.0024), with the largest differences observed in those with prior clinical AIDS. Hypertension and the soluble CD14 concentration in cerebrospinal fluid were associated with lower fractional anisotropy. These associations were independent of HIV serostatus (Pinteraction = .32 and Pinteraction = .59, respectively) and did not explain the greater abnormalities in brain structure in relation to HIV infection., Conclusions: The presence of lower gray matter volumes and more white matter microstructural abnormalities in well-treated PLWH partly reflect a combination of historical effects of AIDS, as well as the more general influence of systemic factors, such as hypertension and ongoing neuroinflammation. Additional mechanisms explaining the accentuation of brain structure abnormalities in treated HIV infection remain to be identified., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Long-term comorbidities such as cognitive impairment remain prevalent in otherwise effectively treated people living with human immunodeficiency virus (HIV). We investigate the relationship between cognitive impairment and brain structure in successfully treated patients using multimodal neuroimaging from the Comorbidity in Relation to AIDS (COBRA) cohort., Methods: Cognitive function, brain tissue volumes, and white matter microstructure were assessed in 134 HIV-infected patients and 79 controls. All patients had suppressed plasma HIV RNA at cohort entry. In addition to comprehensive voxelwise analyses of volumetric and diffusion tensor imaging, we used an unsupervised machine learning approach to combine cognitive, diffusion, and volumetric data, taking advantage of the complementary information they provide., Results: Compared to the highly comparable control group, cognitive function was impaired in 4 of the 6 cognitive domains tested (median global T-scores: 50.8 vs 54.2; P < .001). Patients had lower gray but not white matter volumes, observed principally in regions where structure generally did not correlate with cognitive function. Widespread abnormalities in white matter microstructure were also seen, including reduced fractional anisotropy with increased mean and radial diffusivity. In contrast to the gray matter, these diffusion abnormalities correlated with cognitive function. Multivariate neuroimaging analysis identified a neuroimaging phenotype associated with poorer cognitive function, HIV infection, and systemic immune activation., Conclusions: Cognitive impairment, lower gray matter volume, and white matter microstructural abnormalities were evident in HIV-infected individuals despite fully suppressive antiretroviral therapy. White matter abnormalities appear to be a particularly important determinant of cognitive dysfunction seen in well-treated HIV-infected individuals., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com)

Objective: To establish whether HIV disease is associated with abnormal levels of age-related brain atrophy, by estimating apparent brain age using neuroimaging and exploring whether these estimates related to HIV status, age, cognitive performance, and HIV-related clinical parameters., Methods: A large sample of virologically suppressed HIV-positive adults (n = 162, age 45-82 years) and highly comparable HIV-negative controls (n = 105) were recruited as part of the Comorbidity in Relation to AIDS (COBRA) collaboration. Using T1-weighted MRI scans, a machine-learning model of healthy brain aging was defined in an independent cohort (n = 2,001, aged 18-90 years). Neuroimaging data from HIV-positive and HIV-negative individuals were then used to estimate brain-predicted age; then brain-predicted age difference (brain-PAD = brain-predicted brain age - chronological age) scores were calculated. Neuropsychological and clinical assessments were also carried out., Results: HIV-positive individuals had greater brain-PAD score (mean ± SD 2.15 ± 7.79 years) compared to HIV-negative individuals (-0.87 ± 8.40 years; b = 3.48, p < 0.01). Increased brain-PAD score was associated with decreased performance in multiple cognitive domains (information processing speed, executive function, memory) and general cognitive performance across all participants. Brain-PAD score was not associated with age, duration of HIV infection, or other HIV-related measures., Conclusion: Increased apparent brain aging, predicted using neuroimaging, was observed in HIV-positive adults, despite effective viral suppression. Furthermore, the magnitude of increased apparent brain aging related to cognitive deficits. However, predicted brain age difference did not correlate with chronological age or duration of HIV infection, suggesting that HIV disease may accentuate rather than accelerate brain aging., (Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To assess if HIV-infected patients on long-term successful combination antiretroviral therapy show cerebral blood flow (CBF) alterations in comparison with HIV-uninfected, otherwise similar controls. To explore whether such alterations are associated with HIV-associated cognitive impairment and to explore potential determinants of CBF alterations in HIV., Design: Cross-sectional comparison of CBF in an observational cohort study., Methods: Clinical, cognitive and MRI data of 100 middle-aged aviremic HIV-infected men on combination antiretroviral therapy and 69 HIV-uninfected controls were collected and compared. From pseudocontinuous arterial spin labeling MRI data, CBF-maps were calculated. The associations of mean gray matter CBF with clinical and cognitive parameters were explored in regression models, followed by a spatial delineation in a voxel-based analysis., Results: CBF was decreased in HIV-infected patients compared with HIV-uninfected controls (P = 0.02), adjusted for age, ecstasy use and waist circumference. Spatially distinct and independent effects of total gray matter volume and HIV-serostatus on CBF were found. Within the HIV-infected group, decreased CBF was associated with increased triglyceride levels (P = 0.005) and prior clinical AIDS (P = 0.03). No association between CBF and cognitive impairment was found., Conclusion: Decreased CBF was observed among HIV-infected patients, which was associated with both vascular risk factors as well as with measures of past immune deficiency. These results provide support for increased vascular disease in HIV-infected patients as represented by hemodynamic alteration, but without overt cognitive consequences within the current cohort of patients on long-term successful treatment.

Objectives: The objective of this study was to assess whether HIV-infected patients on long-term successful combination antiretroviral therapy (cART) have more extensive white matter hyperintensities (WMH) of presumed vascular origin compared with uninfected controls and whether these intensities are associated with cognitive impairment. Furthermore, we explored potential determinants of increased WMH load long-term suppressed HIV infection., Design: A cross-sectional comparison of WMH in an observational cohort., Methods: Clinical, cognitive, and MRI data were collected from 103 middle-aged, aviremic HIV-infected men on cART, and 70 HIV-uninfected, otherwise similar controls. In the MRI data, WMH load was quantified by automated approaches and qualitatively reviewed by an experienced neuroradiologist using the Fazekas scale., Results: HIV-infected men had an increased WMH load. Among HIV-infected patients, increased WMH load was independently associated with older age, higher DBP, higher D-dimer levels, and longer time spent with a CD4 cell count below 500 cells/μl. HIV-associated cognitive deficits were associated with increased WMH load., Conclusions: WMH are more extensive and associated with cognitive deficits in middle-aged, aviremic cART-treated HIV-infected men. The extent of WMH load was associated with both cardiovascular risk factors and past immune deficiency. As cognitive impairment in these same patients is also associated with these risk factors, this may suggest that in the setting of HIV, WMH, and cognitive deficits share a common cause. This supports the importance of optimizing cardiovascular risk management, and early, effective treatment of HIV infection.

Objective: The spectrum of risk factors for HIV-associated cognitive impairment is likely very broad and includes not only HIV/antiretroviral therapy-specific factors but also other comorbid conditions. The purpose of this current study was to explore possible determinants for decreased cognitive performance., Design and Methods: Neuropsychological assessment was performed on 103 HIV-1-infected men with suppressed viraemia on combination antiretroviral therapy for at least 12 months and 74 HIV-uninfected highly similar male controls, all aged at least 45 years. Cognitive impairment and cognitive performance were determined by multivariate normative comparison (MNC). Determinants of decreased cognitive performance and cognitive impairment were investigated by linear and logistic regression analysis, respectively., Results: Cognitive impairment as diagnosed by MNC was found in 17% of HIV-1-infected men. Determinants for decreased cognitive performance by MNC as a continuous variable included cannabis use, history of prior cardiovascular disease, impaired renal function, diabetes mellitus type 2, having an above normal waist-to-hip ratio, presence of depressive symptoms, and lower nadir CD4⁺ cell count. Determinants for cognitive impairment, as dichotomized by MNC, included cannabis use, prior cardiovascular disease, impaired renal function, and diabetes mellitus type 2., Conclusion: Decreased cognitive performance probably results from a multifactorial process, including not only HIV-associated factors, such as having experienced more severe immune deficiency, but also cardiovascular/metabolic factors, cannabis use, and depressive symptoms.

Objective: Cognitive impairment is highly prevalent in HIV-1-infected (HIV+) patients, despite adequate suppression of viral replication by combination antiretroviral therapy (cART). Cerebral white matter structure alterations are often associated with cognitive impairment and have commonly been reported in the natural course of HIV infection. However, the existence of these alterations in adequately treated HIV+ patients remains unknown, as well as its possible association with cognitive impairment., Design: We used diffusion tensor imaging (DTI) to investigate whether white matter structure alterations exist in HIV+ patients with sustained suppressed viral replication on cART, and if such alterations are related to HIV-associated cognitive deficits., Methods: We compared 100 aviraemic HIV+ men on cART with 70 HIV-uninfected, otherwise comparable men. Clinical and neuropsychological assessments were performed. From DTI data, white matter fractional anisotropy and mean diffusion were calculated. Subsequently, tract-based spatial statistics (TBSS) was performed, with and without masking out white matter lesions., Results: HIV+ patients showed diffuse white matter structure alterations as compared with HIV-uninfected controls, observed as widespread decreased fractional anisotropy and an increased mean diffusion. These white matter structure alterations were associated with the number of years spent with a CD4 cell count below 500 cells/μl, but not with HIV-associated cognitive deficits., Conclusion: Cerebral white matter structure alterations are found in middle-aged HIV+ men with sustained suppression of viraemia on cART, and may result from periods with immune deficiency when viral toxicity and host-inflammatory responses were at their peak. These white matter structure alterations were not associated with the observed subtle HIV-associated cognitive deficits., Video Abstract: .

Objective: The objective of this study is to assess whether multivariate normative comparison (MNC) improves detection of HIV-1-associated neurocognitive disorder (HAND) as compared with Frascati and Gisslén criteria., Methods: One-hundred and three HIV-1-infected men with suppressed viremia on combination antiretroviral therapy (cART) for at least 12 months and 74 HIV-uninfected male controls (comparable regarding age, ethnicity, sexual orientation, premorbid intelligence and educational level), aged at least 45 years, underwent neuropsychological assessment covering six cognitive domains (fluency, attention, information processing speed, executive function, memory, and motor function). Frascati and Gisslén criteria were applied to detect HAND. Next, MNC was performed to compare the cognitive scores of each HIV-positive individual against the cognitive scores of the control group., Results: HIV-infected men showed significantly worse performance on the cognitive domains of attention, information processing speed and executive function compared with HIV-uninfected controls. HAND by Frascati criteria was highly prevalent in HIV-infected [48%; 95% confidence interval (95% CI) 38-58] but nearly equally so in HIV-uninfected men (36%; 95% CI 26-48), confirming the low specificity of this method. Applying Gisslén criteria, HAND-prevalence was reduced to 5% (95% CI 1-9) in HIV-infected men and to 1% (95% CI 1-3) among HIV-uninfected controls, indicating better specificity but reduced sensitivity. MNC identified cognitive impairment in 17% (95% CI 10-24) of HIV-infected men and in 5% (95% CI 0-10) of the control group (P = 0.02, one-tailed), showing an optimal balance between sensitivity and specificity., Conclusion: Prevalence of cognitive impairment in HIV-1-infected men with suppressed viremia on cART estimated by MNC was much higher than that estimated by Gisslén criteria, while the false positive rate was greatly reduced compared with the Frascati criteria., Video Abstract: :

Background: Infection with HIV-1 may result in severe cognitive and motor impairment, referred to as HIV-1-associated dementia (HAD). While its prevalence has dropped significantly in the era of combination antiretroviral therapy, milder neurocognitive disorders persist with a high prevalence. To identify additional therapeutic targets for treating HIV-associated neurocognitive disorders, several candidate gene polymorphisms have been evaluated, but few have been replicated across multiple studies., Methods: We here tested 7 candidate gene polymorphisms for association with HAD in a case-control study consisting of 86 HAD cases and 246 non-HAD AIDS patients as controls. Since infected monocytes and macrophages are thought to play an important role in the infection of the brain, 5 recently identified single nucleotide polymorphisms (SNPs) affecting HIV-1 replication in macrophages in vitro were also tested., Results: The CCR5 wt/Δ32 genotype was only associated with HAD in individuals who developed AIDS prior to 1991, in agreement with the observed fading effect of this genotype on viral load set point. A significant difference in genotype distribution among all cases and controls irrespective of year of AIDS diagnosis was found only for a SNP in candidate gene PREP1 (p = 1.2 × 10(-5)). Prep1 has recently been identified as a transcription factor preferentially binding the -2,518 G allele in the promoter of the gene encoding MCP-1, a protein with a well established role in the etiology of HAD., Conclusion: These results support previous findings suggesting an important role for MCP-1 in the onset of HIV-1-associated neurocognitive disorders.

Here, we describe a newly diagnosed HIV-1-infected patient, in whom shortly after the initiation of a darunavir-based regimen, the HIV-1 virus exclusively mutated in the cerebrospinal fluid (CSF), leading to an increase in CSF HIV-1 RNA load and neurological complaints., (© 2011 International Medical Press)

Introduction: Tight glycemic control (TGC) after ischemic stroke may improve clinical outcome but previous studies failed to establish TGC, principally because of postprandial glucose surges. The aim of the present study was to investigate if safe, effective and feasible TGC can be achieved with continuous tube feeding and a computerized treatment protocol., Methods: We subjected ten acute ischemic stroke patients with admission hyperglycemia (glucose >7.0 mmol/l (126.0 mg/dl)) to continuous tube feeding and a computerized intensive protocol with insulin adjustments every 1-2 h. Two groups of regularly fed patients from a previous study with a similar design served as controls. These groups comprised hyperglycemic patients treated according to an intermediate protocol with insulin adjustments at standard intervals (N = 13), and normoglycemic controls treated according to standard care (N = 15). The primary outcome was the percentage of time within target (4.4-6.1 mmol/l (79.2-109.8 mg/dl)). Secondary outcome was the number of patients with hypoglycemic episodes (glucose <3.0 mmol/l (54.0 mg/dl))., Results: Median time within target was 55% in the continuously fed intensive group compared to 19% in the regularly fed intermediate group, and 58% in normoglycemic controls. Hypoglycemic episodes occurred in 20% of patients in the continuously fed group-lowest glucose level 2.4 mmol/l (43.2 mg/dl). In contrast, in the regularly fed group, this was 31%-lowest glucose level 1.6 mmol/l (28.8 mg/dl)., Conclusions: TGC after acute ischemic stroke is feasible with continuous tube feeding and a computerized intensive treatment protocol. Although glycemic control is associated with hypoglycemia, no severe hypoglycemia occurred in the continuous tube feeding group.

Acute bacterial meningitis (ABM) is a potentially life-threatening neurological emergency. An agreed protocol for early, evidence-based and effective management of community-acquired ABM is essential for best possible outcome. A literature search of peer-reviewed articles on ABM was used to collect data on the management of ABM in older children and adults. Based on the strength of published evidence, a consensus guideline was developed for initial management, investigations, antibiotics and supportive therapy of community-acquired ABM. Patients with ABM should be rapidly hospitalized and assessed for consideration of lumbar puncture (LP) if clinically safe. Ideally, patients should have fast-track brain imaging before LP, but initiation of antibiotic therapy should not be delayed beyond 3 h after first contact of patient with health service. In every case, blood sample must be sent for culture before initiating antibiotic therapy. Laboratory examination of cerebrospinal fluid is the most definitive investigation for ABM and whenever possible, the choice of antibiotics, and the duration of therapy, should be guided by the microbiological diagnosis. Parenteral therapy with a third-generation cephalosporin is the initial antibiotics of choice in the absence of penicillin allergy and bacterial resistance; amoxicillin should be used in addition if meningitis because of Listeria monocytogenes is suspected. Vancomycin is the preferred antibiotic for penicillin-resistant pneumococcal meningitis. Dexamethasone should be administered both in adults and in children with or shortly before the first dose of antibiotic in suspected cases of Streptococcus pneumoniae and H. Influenzae meningitis. In patients presenting with rapidly evolving petechial skin rash, antibiotic therapy must be initiated immediately on suspicion of Neisseria meningitidis infection with parenteral benzyl penicillin in the absence of known history of penicillin allergy.

Bell's palsy accounts for two-thirds ofall acute facial palsies. Presumed reactivation of the herpes simplex virus and concurrent swelling of the facial nerve prompted the use of antivirals in combination with corticosteroids, although evidence supporting the effectiveness of this approach was weak. A recently published randomized placebo-controlled clinical trial assessed the effectiveness of adding valacyclovir to prednisolone; another larger primary-care-based study compared treatment with prednisolone, acyclovir or both with placebo. In patients with severe or complete facial palsy, the addition of valacyclovir improved the chance of complete recovery, but as this study was single-blinded, results should be interpreted with caution. Early treatment with prednisolone (25 mg twice daily for to days) significantly improved the chance of complete recovery at 3 and 9 months. Acyclovir, given alone or in addition to prednisolone, did not show any benefit.

3 patients with liver failure developed hepatic encephalopathy. 2 patients, men aged 60 and 72 years, had chronic liver disease and presented with episodes of confusion. They recovered after being treated with lactulose. The third patient, a 37-year-old woman, became comatose shortly after the onset of acute liver failure due to acute autoimmune hepatitis. She died before a suitable donor liver became available. Hepatic encephalopathy is a syndrome of potential reversible neurological symptoms. Especially in the early stages of the condition, hepatic encephalopathy can be difficult to diagnose. Patients may present with mild cognitive impairment or episodes characterized by neurological symptoms. Hepatic encephalopathy is a clinical diagnosis. The pathophysiologic mechanism is only partly understood but toxicity of ammonia on the central nervous system seems to be of major importance. Raised ammonia concentrations or EEG findings consistent with metabolic encephalopathy may support but are not essential to the diagnosis. Episodes of hepatic encephalopathy are often elicited by an underlying disease such as infection or gastro-intestinal bleeding. It is important to recognize hepatic encephalopathy in its early stages because adequate treatment of the condition and any underlying disease reduces morbidity and mortality.

Bell's palsy is the most frequent type of peripheral facial paresis. Its cause is unknown. The prognosis is good in 85% of patients. Based on theories about its pathogenesis, antivirals and corticosteroids have been tried. In 6 studies with antivirals and 9 with corticosteroids (most ofthe studies were methodologically flawed), the efficacy of these treatments was not demonstrated.

The spectrum of neurological complications of HIV-infection has remained unchanged through the years, but its epidemiology changed remarkably as a result of the introduction of highly active antiretroviral therapy (HAART). Guidelines for the diagnosis and treatment of cerebral toxoplasmosis, cryptococcal meningitis, progressive multifocal leukoencephalopathy, CMV encephalitis, CMV polyradiculomyelitis, tuberculous meningitis, primary CNS lymphoma, HIV dementia, HIV myelopathy and HIV polyneuropathy are given with a grading of evidence and recommendations.

Recent developments in antiretroviral therapeutics are summarized. The seven groups of antiretroviral drugs are briefly described, focussing on mechanism of action and new compounds. Updated recommendations of the International AIDS Society are reviewed.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with unknown pathogenesis. Loss of motor neurons leads to progressive weakness and, finally, respiratory failure with a mean survival of 3 years. A possible causal role of a retroviral infection has recently been suggested by studies of 7 HIV-infected patients who developed a rapid progressive ALS-like disorder as the first manifestation of their HIV-infection. All patients stabilised or improved with antiretroviral therapy. Other research groups have published on the detection of enterovirus RNA in the spinal cords of ALS-patients, also suggesting a viral aetiology of the disease. The results of these neuro-virological studies warrant further research into the possible role of viral infections as a cause of ALS, as well as clinical trials with anti-retroviral and anti-enteroviral drugs in ALS.

Objective: To examine the association between Kaposi's sarcoma (KS), human herpes virus 8 (HHV8) and AIDS dementia complex (ADC)., Design: A total of 599 HIV-1 infected homosexual men participated in a prospective cohort study (Amsterdam, 1984-1996)., Methods: The risk for ADC in patients with prior KS or HHV8 infection was estimated using the Cox proportional hazards method with adjustments for antiretroviral medication and low CD4 cell counts., Results: Of the 599 participants, 290 (48.4%) had HHV8 antibodies, 99 (16.5%) had KS and 30 (5.0%) had ADC. ADC was diagnosed in 5.2% of participants with KS and 5.0% of those without KS, and in 4.8% of HHV8 seropositive compared to 5.2% seronegative individuals and thus was not associated with KS or HHV8 infection. Using a time-dependent Cox proportional hazards analysis with the date of KS as risk factor, the risk for ADC was 2.7 [95% confidence interval (CI), 0.92-7.96; P = 0.07) and when only definite ADC was considered it was 3.5 (95% CI, 1.00-12.26;P = 0.05). After adjusting for decreases in CD4 cell count and use of medication, the hazards ratio for participants with KS to develop ADC was 2.0 (95% CI, 0.66-5.77; P = 0.23) and 2.6 (95% CI, 0.73-9.12; P = 0.14), respectively. HHV8 seropositivity, adjusted for the same variables, showed a risk for ADC of 0.85 (95% CI, 0.41-1.77;P = 0.66) and for definite ADC 0.69 (95% CI, 0.27-1.73; P = 0.42). The expected neuroprotective effects of antiretroviral medication were observed., Conclusions: KS or HHV8 does not significantly influence the risk for developing ADC in a group with a uniform risk for developing KS therefore we recommend caution in searching for a KS-associated or HHV8-derived therapy for ADC.

Objective: (1) To evaluate a clinical guideline for the diagnostic investigation of patients presenting with signs and symptoms (present for longer than 6 weeks) suggesting a chronic polyneuropathy. (2) To investigate the contribution of electrophysiological studies to a focused search for aetiology in these patients., Methods: A chart review was carried out of a consecutive group of outpatients in 1993-7 at a university department of neurology, with signs and symptoms suggesting a polyneuropathy in whom the diagnostic investigation had been carried out according to a recently introduced guideline. Diagnostic tests were performed and final diagnoses were made., Results: Unnecessary investigations were carried out in 108 (51%) of 213 patients and too few tests in 23 (11%) of these patients. In 82 (48%) of the 172 patients who fulfilled the inclusion criteria neurophysiological tests did not contribute to the final diagnosis. Neurophysiological criteria for demyelination were fulfilled in only 13 (8%) of the 172 patients., Conclusion: In patients presenting with signs and symptoms of chronic polyneuropathy the number of tests in the diagnostic investigation can be considerably reduced. In patients with signs and symptoms of polyneuropathy, providing the clinical phenotype is typical, in the presence of diabetes mellitus, renal failure, HIV infection, alcoholism, or use of potentially neurotoxic drugs further investigations are non-contributory. The significance of electrophysiological studies in the investigation of patients with polyneuropathy is rather to separate sensorimotor neuropathies from pure sensory neuropathies than to distinguish between demyelinating and axonal neuropathies.

An axonal sensory neuropathy is a frequent complication in the course of HIV infection; more than 30% of all HIV-infected individuals will develop a polyneuropathy. Low CD4 cell counts and high HIV RNA loads increase the risk. This neuropathy causes pain, paresthesias and burning sensations and/or numbness in the feet, which sometimes occurs in the hands as well. Neurological examination reveals sensory deficits in a stocking and glove distribution and depressed or absent ankle reflexes, without severe paresis. The cause of the sensory neuropathy is unknown. Either the HIV infection or certain other infections, for example cytomegalovirus, may play a role in the pathogenesis; vasculitis may be a process associated with this. Some antiretroviral drugs within the nucleoside analogue group cause a neuropathy but the pathogenesis of this remains unclear. Amitriptyline, tramadol and carbamazepine can be used for symptomatic treatment. The efficacy of lamotrigine and gabapentin has yet to be confirmed.

In 6 patients with primary human immunodeficiency virus type 1 (HIV-1) infection, concentrations of HIV-1 RNA and beta(2)-microglobulin were monitored in cerebrospinal fluid (CSF) and in plasma during antiretroviral therapy. Four patients had neurological symptoms. At baseline, the CSF of 5 patients had detectable levels of HIV-1 RNA (median, 3.68 log(10) copies/mL; range, <2.60-5.67 log(10) copies/mL), and the CSF of 3 patients had elevated levels of beta(2)-microglobulin. After 8 weeks of treatment, the median concentrations of HIV-1 RNA in CSF had decreased to <2.60 log(10) copies/mL (range, <1.60-3.00 log(10) copies/mL; P=.04) and in plasma to 3.07 log(10) copies/mL (range, 2.57-3.79 log(10) copies/mL; P=.03). Median concentration of beta(2)-microglobulin in CSF had decreased to 1.2 mg/L (range, 0.9-1.7 mg/L; P=.06) and, in plasma, to 1.7 mg/L (range, 1.1-2.2 mg/L; P=.03). After 48 weeks, HIV-1 RNA concentrations in 1 patient were still 1.97 log(10) copies/mL in CSF and 1.51 log(10) copies/mL in plasma, although beta(2)-microglobulin concentrations in CSF and plasma had normalized after 8 weeks.

Objective: To assess the durability of the antiretroviral effect in plasma and cerebrospinal fluid (CSF) of antiviral therapy intensification, produced by the addition of indinavir from week 12 onwards to the original regimen of zidovudine/lamivudine or stavudine/lamivudine, after 72 weeks of follow-up using an ultrasensitive HIV-1 RNA assay. To assess CSF concentrations of indinavir at week 48., Design: In a prospectively, randomized, open, single-centre study, antiretroviral-naive patients (CD4 cell count > or =200 cells/microl and a plasma HIV-1 RNA level 10,000 copies/ml) were assigned to a combination of zidovudine/lamivudine or stavudine/lamivudine. Indinavir could be added to the double nucleoside analogue regimen from week 12 or thereafter in case the plasma HIV RNA level was insufficiently suppressed (>500 copies/ml)., Results: Forty-seven patients were enrolled (23 stavudine/lamivudine and 24 zidovudine/lamivudine), of whom 33 completed a follow-up of 72 weeks. Indinavir was added in 89% (42/47) of the patients. Only one discontinuation occurred due to virological failure. At week 72, the median plasma HIV-1 RNA levels in the zidovudine/lamivudine group had decreased from 4.80 log10 copies/ml to <500 copies/ml in 100% of patients and <50 copies/ml in 86.6% of the patients. In the stavudine/lamivudine group the plasma HIV-1 RNA decreased from 4.98 log10 copies/ml at baseline to <500 copies/ml in 100% of patients and <50 copies/ml in 66.7% of the patients. On an intent-to-treat basis these figures were 54.2 and 52.2% for zidovudine/lamivudine and stavudine/lamivudine, respectively, for the 50 copies/ml assay. The median CD4 cell count increased from 315 cells/microl, with 150 cells/microl in the zidovudine/lamivudine arm, and from 290 cells/microl, with 310 cells/microl in the stavudine/lamivudine arm (P=0.0001). However, the percentage of CD4 cells did not differ in each group. In the zidovudine/lamivudine group 9/10 and 5/5, and in the stavudine/lamivudine group 11/11 and 6/6 had a CSF HIV-1 RNA level <50 copies/ml at week 12 and 48, respectively. The CSF indinavir concentration ranged from 50 to 170 ng/ml., Conclusion: The long-term HIV-1 suppression observed in this study is remarkable, as adding a single antiretroviral agent to a failing regimen goes against current notions of adequate therapy.

Only limited data on cerebrospinal fluid (CSF) HIV-1 RNA responses and markers of local inflammation in CSF during antiretroviral therapy are available. HIV-RNA, soluble tumor necrosis factor (TNF)-receptor (sTNFr)-II, monocyte chemoattractant protein (MCP)-1, and interferon-gamma-inducible protein (IP)-10 were measured in the peripheral blood and CSF of 26 antiretroviral-naive HIV-1-positive patients, who were treated with ritonavir (RTV)/saquinavir (SQV) (n = 5), RTV/SQV/stavudine (d4T; n = 8) or zidovudine (AZT)/lamivudine (3TC)/abacavir/nevirapine/indinavir (n = 13). After 8 to 12 weeks of treatment, CSF HIV-RNA dropped to <400 copies/ml in 1 of 5 patients in the RTV/SQV group, 8 of 8 patients in the RTV/SQV/d4T group, and 9 of 10 patients in the five-drug group. CSF sTNFr-II and IP-10 levels increased in patients with detectable CSF HIV-RNA. However, increases in CSF chemokine and sTNFr-II concentrations were also observed in some patients with good CSF HIV-RNA responses. Moreover, CSF MCP-1 concentrations increased in the whole population after 2 months of treatment. Ongoing residual HIV replication in the central nervous system, which cannot be detected with CSF HIV-RNA measurements, may account for this phenomenon.

Objective: To assess the HIV-1-RNA response and drug concentrations in cerebrospinal fluid (CSF) and serum during treatment with saquinavir (SQV)/ritonavir (RTV) or SQV/RTV plus stavudine (d4T) in HIV-1 -infected patients., Design: A multicentre, open-label, randomized controlled trial., Methods: A total of 208 protease inhibitor (PI) and d4T-naive, HIV-1-infected patients were treated with RTV 400 mg twice daily and SQV 400 mg twice daily with or without d4T 40 mg twice daily. Intensification with reverse transcriptase inhibitors was allowed if serum HIV RNA remained above 400 copies/ml after 12 weeks. In 27 volunteers, CSF and serum HIV RNA were measured at baseline, weeks 12 and 48, using the Roche Amplicor and the ultrasensitive assay. In 22 patients, serum and CSF drug concentrations were determined at week 12., Results: The median baseline serum and CSF HIV-RNA concentrations were 4.81 and 3.21 log10 copies/ml, respectively. A difference in the proportion of patients with a CSF HIV-RNA level below the limit of quantification (< LLQ) after 12 weeks was found: four out of 14 (RTV/SQV) versus 12 out of 13 (RTV/SQV/d4T) (P = 0.001). The same results were found using the ultrasensitive assay. Patients with a baseline HIV-RNA level < LLQ in CSF remained < LLQ, regardless of the treatment regimen. Treatment with RTV/SQV alone was the only independent predictor of a CSF HIV-RNA level > LLQ at week 12 in logistic regression analysis (P = 0.005). CSF RTV and SQV concentrations were < LLQ in most patients., Conclusion: RTV/SQV alone cannot suppress detectable CSF HIV-1-RNA levels to < LLQ after 12 weeks of treatment in the majority of patients. CSF drug concentrations of RTV and SQV < LLQ may explain the suboptimal antiretroviral effect in the CSF.

Objective: Penetration of antiretroviral drugs into anatomical HIV-1 reservoirs such as the male genital tract and the central nervous system is important. Data on indinavir (IDV) concentrations in seminal plasma are lacking and IDV concentrations in cerebrospinal fluid are at best borderline., Design: Thirteen patients were treated with zidovudine (or stavudine), lamivudine, abacavir, nevirapine and IDV (1000 mg three times daily). When nevirapine led to low IDV concentrations, IDV was changed into the combination IDV/ritonavir (RTV) 800/100 mg twice daily to improve the pharmacokinetic profile of IDV., Methods: A serum pharmacokinetic profile, a semen sample and a cerebrospinal fluid sample were collected at weeks 8, 24, 48 and 72., Results: Addition of RTV increased the median IDV trough concentration in serum from 65 to 336 ng/ml (P = 0.005). Median IDV concentration in seminal plasma increased from 141 to 1634 ng/ml (P = 0.002) (n = 9) and in cerebrospinal fluid from 39 (n = 12) to 104 (n = 7) ng/ml (P < 0.001). In six patients with samples collected both before and after the addition of RTV, the IDV concentration in seminal plasma increased 8.2 times [95% confidence interval (CI) 5.2-11.6], and in cerebrospinal fluid 2.4 times (95% CI 1.8-3.9)., Conclusions: IDV penetrates well into the male genital tract. The addition of low-dose RTV not only increases IDV concentrations in serum but also in seminal plasma and cerebrospinal fluid, thereby probably improving the potency of the regimen in these anatomical HIV reservoirs. Higher serum trough levels alone can not sufficiently explain the observed increases in seminal plasma and cerebrospinal fluid concentrations. Inhibition of P-glycoprotein-mediated transport by RTV might be an additional mechanism.

The neurological complications of Epstein-Barr virus infection include viral meningitis, encephalitis and neuromuscular complications. The introduction of cerebrospinal fluid polymerase chain reaction for Epstein-Barr virus DNA has improved diagnosis of these conditions and of primary central nervous system lymphoma in acquired immune deficiency syndrome, and has enabled cerebrospinal fluid monitoring of therapy. Prognosis remains good for most Epstein-Barr virus-related neurological complications; for primary central nervous system lymphoma in acquired immune deficiency syndrome the prognosis is still poor.

We assessed survival in AIDS-related progressive multifocal leukoencephalopathy (PML) and the effect of cytarabine and antiretroviral therapy in a retrospective analysis of a series of consecutive 35 patients with AIDS-related PML in an academic AIDS referral center over 15 years. Treatment regimens consisted of highly active antiretroviral treatment (HAART), intravenous cytarabine, or both. Median survival after diagnosis in the overall series was 88 days. Patients with low CD4 cell count tended to have shorter survival. Seven patients (20%) had prolonged survival (> 1 year). Cytarabine did not affect survival. Seven patients were treated with HAART, which did not significantly improve survival. We conclude that the prognosis of AIDS-related PML is still poor, with a median survival of 3 months.

CSF levels of beta2-microglobulin (b2m), monocyte chemotactic protein-1 (MCP-1), soluble tumor necrosis factor receptors (sTNFRs), and HIV-1 RNA were determined in 16 neurologically asymptomatic HIV-1 infected patients before and 12 weeks after treatment with lamivudine plus zidovudine or stavudine. b2m levels were significantly higher in patients (1.7 mg/l) compared with controls (0.8 mg/l) (P < 0.001), and decreased to 1.1 mg/l during treatment (P = 0.001). MCP-1 levels were low, and did not change during treatment. Levels of sTNFR type I were elevated in patients (0.92 ng/ml) compared to controls (0.30 ng/ml) (P = 0.03), but did not change during treatment. Levels of sTNFR type II were below the limit of detection in most patients and controls. In conclusion, CSF levels of b2m and HIV-I RNA, but not sTNFRs or MCP-1, are candidate surrogate markers of treatment efficacy in early CNS infection.

Heterozygosity for a 32-bp deletion in the CCR5 gene (CCR5 Delta32), which encodes the coreceptor for macrophage-tropic non-syncytium-inducing (NSI) human immunodeficiency virus type 1 (HIV-1) variants, results in a lower CCR5 expression and reduced NSI HIV-1 replication. Because infection of macrophages and microglial cells by NSI HIV-1 is considered to be instrumental for the development of AIDS dementia complex (ADC), we studied whether the CCR5 Delta32 heterozygous genotype correlated with a reduced frequency of ADC. Two (4.1%) of 49 patients with ADC versus 27 (14. 5%) of 186 AIDS patients without ADC were heterozygous for CCR5 Delta32 (P=.05). In contrast, a point mutation in the first transmembrane domain of CCR2 (CCR2 64I) did not show this protective effect (P=.57). The reduced prevalence of the CCR5 Delta32 allele among patients with ADC may indicate a reduced or absent reservoir of macrophage-tropic NSI HIV-1 in the brain of CCR5 Delta32 heterozygotes.

Although neurotrophic factors are currently considered as treatment for neurodegenerative diseases, little is still known about their presence in the central nervous system under pathological conditions. We investigated the expression of the neurotrophic molecules NGF, bFGF, BDNF and IGF-1 in brain tissue of patients suffering from AIDS dementia complex. In contrast to IGF-1 and BDNF, NGF and bFGF mRNA levels were significantly elevated. Strong NGF immunoreactivity was found in perivascular areas and was colocalized with infiltrating macrophages, whereas intense bFGF staining was found in cells with characteristic astrocytic morphology. These data suggest that the induction of NGF and bFGF alone appears to be insufficient as a compensatory mechanism to prevent ADC.

Oxidative stress is suggested to be involved in several neurodegenerative diseases. One mechanism of oxidative damage is mediated by peroxynitrite, a neurotoxic reaction product of superoxide anion and nitric oxide. Expression of two cytokines and two key enzymes that are indicative of the presence of reactive oxygen intermediates and peroxynitrite was investigated in brain tissue of AIDS patients with and without AIDS dementia complex and HIV-seronegative controls. RNA expression of IL-1beta, IL-10, inducible nitric oxide synthase, and superoxide dismutase (SOD) was found to be significantly higher in demented compared with nondemented patients. Immunohistochemical analysis showed that SOD was expressed in CD68-positive microglial cells while inducible nitric oxide synthase was detected in glial fibrillary acidic protein (GFAP)-positive astrocytes and in equal amounts in microglial cells. Approximately 70% of the HIV p24-Ag-positive macrophages did express SOD, suggesting a direct HIV-induced intracellular event. HIV-1 infection of macrophages resulted in both increased superoxide anion production and elevated SOD mRNA levels, compared with uninfected macrophages. Finally, we show that nitrotyrosine, the footprint of peroxynitrite, was found more intense and frequent in brain sections of demented patients compared with nondemented patients. These results indicate that, as a result of simultaneous production of superoxide anion and nitric oxide, peroxynitrite may contribute to the neuropathogenesis of HIV-1 infection.

Objectives: To determine the occurrence and cellular localization of inducible nitric oxide synthase (iNOS), NOS activity and its association with cell death in brains of AIDS and AIDS dementia complex (ADC) patients., Design and Methods: Post-mortem cerebral cortex tissue of eight AIDS patients, eight ADC patients and eight control subjects was processed for iNOS immunocytochemistry, NADPH-diaphorase activity staining as an index of NOS activity, and in situ end-labelling to detect cell death., Results: iNOS-positive cells were present in the white matter of 14 out of 16 AIDS and ADC patients, whereas two out of eight control subjects showed iNOS-positive cells. iNOS immunoreactivity was exclusively localized in activated macrophages and microglial cells that both showed NADPH-diaphorase activity. In addition, NADPH-diaphorase activity, not related to iNOS immunoreactivity, was observed in astrocytes in both white and grey matter of AIDS and ADC patients. All AIDS and ADC patients, and only one control subject showed characteristic features of apoptotic cell death., Conclusions: Different forms of NOS are present in microglial cells and astrocytes of AIDS and ADC patients but are largely absent in control subjects. Although more NOS-expressing cells occur in ADC than in AIDS patients, apoptotic cell death was found in both patient groups to the same extent. We postulate that NO production in brains of AIDS patients results in cumulative cortical cell loss, which becomes neurologically evident at later stages of disease and is expressed as ADC.

Two patients, a woman aged 65 years and a man aged 56 years, with cancer, presented with pain in one leg as the first manifestation of metastases. The woman had tumour plexopathy of the lumbosacral plexus caused by an os sacrum metastasis of a thyroid carcinoma; she received radiotherapy but died a short time later. The man had lumbosacral epidural metastases of a colon carcinoma, compressing lumbosacral roots; with radiotherapy he survived the first year. Back pain with radiating pain is a frequent symptom in patients with cancer. Spinal epidural metastases, spinal and paraspinal metastases without epidural extension, tumour plexopathy and leptomeningeal metastases are the commonest causes. Early diagnosis (by MRI or spinal fluid examination) is important; with progressive weakness or sphincter disturbances the prognosis worsens.

Background: Treatment and prevention of HIV-1-related central-nervous-system disease may be dependent on penetration of antiretroviral drugs into the central nervous system. Few data are available about cerebrospinal-fluid penetration and concomitant changes of HIV-1-RNA concentrations during treatment with antiretroviral agents. We investigated these effects in HIV-1-infected people., Methods: 28 antiretroviral-naive individuals with CD4 cell counts of 200/microL or more and plasma HIV-1-RNA concentrations of 10,000 or more copies/mL who were free of neurological symptoms were randomly assigned lamivudine plus either stavudine (n = 17) or zidovudine (n = 11). We did lumbar punctures on 28 individuals before and 22 individuals after 12 weeks of treatment to assess HIV-1-RNA and drug concentrations in cerebrospinal fluid., Findings: All 28 individuals had detectable HIV-1-RNA concentrations in the cerebrospinal fluid (median 4.64 log10 copies/mL and 4.20 log10 copies/mL in the lamivudine plus zidovudine and lamivudine plus stavudine groups, respectively). There was no correlation between plasma and cerebrospinal-fluid HIV-1-RNA concentrations (r = 0.18, p = 0.35). After 12 weeks of treatment none of the individuals had detectable HIV-1-RNA concentrations in the cerebrospinal fluid. The highest drug concentration in the cerebrospinal fluid was for lamivudine followed by stavudine and zidovudine. Concentrations were consistent over time, unlike plasma concentrations. Therefore, we found time-dependent cerebrospinal-fluid to plasma drug-penetration ratios, which were highest for zidovudine followed by stavudine and lamivudine., Interpretation: The two drug combinations were equally effective in the decrease of cerebrospinal fluid HIV-1-RNA concentrations. All drugs penetrated the cerebrospinal fluid. Antiretroviral drugs other than zidovudine might be useful in the prevention of AIDS dementia complex.

A 48-year-old man with systemic lupus erythematosus (SLE) was admitted with fever, headache and mental change. On admission he was treated with daily doses of cyclophosphamide 100 mg and prednisone 7.5 mg. Orientation and attention were diminished and visual examination revealed right-sided homonymous hemianopia. MRI of the brain showed a ring-enhanced, space occupying lesion in the left occipital lobe. An infectious disease cause was considered, because disease activity parameters of SLE were all negative (anti-dsDNA and the complement profile). The anti-Toxoplasma titre was elevated in cerebrospinal fluid (57 IU/ml) and in serum (1140 IU/ml), both IgG. A tentative diagnosis of Toxoplasma encephalitis was made and a trial anti-toxoplasmosis treatment with pyrimethamine and sulfadiazine was administered. Two weeks later the patient was normal at neurological examination and his brain MRI had greatly improved. The anti-Toxoplasma titre had dropped significantly.