Diagnostic accuracy of new and old cognitive screening tools for HIV-associated neurocognitive disorders.

OBJECTIVES: Considering the similarities between HIV-associated neurocognitive disorders (HAND) and neurodegenerative dementias and the frequency of executive dysfunctions among HIV-positive patients, we evaluated the accuracy of the Frontal Assessment Battery and Clock-Drawing Test together with the Three Questions Test and International HIV Dementia Scale to screen for HAND. METHODS: A cross-sectional monocentric study was conducted from 2010 to 2017. The index tests were represented by the four screening tools; the reference standard was represented by a comprehensive neurocognitive battery used to investigate 10 cognitive domains. Patients were screened by a trained infectious diseases physician and those showing International HIV Dementia Scale scores ≤ 10 and/or complaining of neurocognitive symptoms were then evaluated by a trained neuropsychologist. RESULTS: A total of 650 patients were screened and 281 received the full neurocognitive evaluation. HAND was diagnosed in 140 individuals. The sensitivity, specificity, correct classification rate and area under the receiver operating characteristic curve (AUROC) were, respectively, as follows: Frontal Assessment Battery, 40.7%, 95.1%, 68.3% and 0.81; International HIV Dementia Scale, 74.4%, 56.8%, 65.4% and 0.73; Clock-Drawing Test, 30.9%, 73.4%, 53.8% and 0.56; and Three Questions Test, 37.3%, 54.1% and 45.7%. Raising the Frontal Assessment Battery's cut-off to ≤ 16 improved its sensitivity, specificity and correct classification rate to 78.0%, 63.9% and 70.8%, respectively. CONCLUSIONS: We observed poor screening performances of the Three Questions and Clock-Drawing Tests. While the International HIV Dementia Scale showed a poor specificity, the Frontal Assessment Battery showed the highest correct classification rate and a promising performance at different exploratory cut-offs.

Detectable cerebrospinal fluid JCV DNA in late-presenting HIV-positive patients: beyond progressive multifocal leukoencephalopathy?

In the absence of effective prophylaxis and treatment, therapeutic options in HIV-positive patients with progressive multifocal leukoencephalopathy (PML) are limited to antiretroviral therapy: nevertheless, outcome is poor. We conducted a retrospective study (2009-2015) describing the outcome of 25 HIV-positive patients with detectable cerebrospinal fluid JC virus DNA: 14 had a probable PML while the others had evidence of other inflammatory central nervous system (CNS) affecting disorders. In the former group, 6-month mortality was 45.5% vs 21.4 in the latter one: survival was higher than previously described but no predictor of poor outcome was identified. Two patients treated with 5HT2-inhibitors survived. The contributing role of JCV replication in other CNS-affecting disorders needs to be assessed as well as the benefits of 5HT2-inhibitors in HIV-positive patients with proven PML.

Blood Brain Barrier Impairment in HIV-Positive Naïve and Effectively Treated Patients: Immune Activation Versus Astrocytosis.

Blood brain barrier (BBB) damage is a common feature in central nervous system infections by HIV and it may persist despite effective antiretroviral therapy. Astrocyte involvement has not been studied in this setting. Patients were enrolled in an ongoing prospective study and subjects with central nervous system-affecting disorders were excluded. Patients were divided into two groups: treated subjects with cerebrospinal fluid (CSF) HIV RNA <50 copies/mL (CSF-controllers) and in late-presenters CD4+ T lymphocytes <100/uL. CSF biomarkers of neuronal or astrocyte damage were measured and compared to CSF serum-to-albumin ratio. 134 patients were included; 67 subjects in each group (50 %) with similar demographic characteristics (with the exception of older age in CSF controllers). CD4 (cells/uL), plasma and CSF HIV RNA (Log10 copies/mL) were 43 (20-96), 5.6 (5.2-6) and 3.9 (3.2-4.7) in LPs and 439 (245-615), <1.69 (9 patients <2.6) and <1.69 in CSFc. BBB impairment was observed in 17 late-presenters (25.4 %) and in 9 CSF-controllers (13.4 %). CSF biomarkers were similar but for higher CSF neopterin values in late-presenters (2.3 vs. 0.6 ng/mL, p < 0.001). CSARs were associated with CSF neopterin (rho = 0.31, p = 0.03) and HIV RNA (rho = 0.24, p = 0.05) in late-presenters and with CSF tau (rho = 0.51, p < 0.001), p-tau (rho = 0.47, p < 0.001) and S100beta (rho = 0.33, p = 0.009) in CSF-controllers. In HAART-treated subjects with suppressed CSF HIV RNA, BBB altered permeability was associated with markers of neuronal damage and astrocytosis. Additional treatment targeting astrocytosis and/or viral protein production might be needed in order to reduce HIV effects in the central nervous system.

Blood brain barrier impairment is associated with cerebrospinal fluid markers of neuronal damage in HIV-positive patients.

Blood brain barrier impairment occurs early in the course of infection by HIV and it may persist in a subset of patients despite effective antiretroviral treatment. We tested the hypothesis that HIV-positive patients with dysfunctional blood brain barrier may have altered biomarkers of neuronal damage. In adult HIV-positive highly active antiretroviral treatment (HAART)-treated patients (without central nervous system infections and undergoing lumbar punctures for clinical reasons) cerebrospinal fluid albumin to serum ratios (CSAR), total tau, phosphorylated tau, 1-42 beta amyloid, and neopterin were measured. In 101 adult patients, cerebrospinal fluid-to-serum albumin ratios were 4.8 (3.7-6.1) with 12 patients (11.9%) presenting age-defined impaired blood brain barrier. A significant correlation was observed between CSAR and total tau (p = 0.005), phosphorylated tau (p = 0.008), and 1-42 beta amyloid (p = 0.040). Patients with impaired blood brain barrier showed significantly higher total tau (201.6 vs. 87.3 pg/mL, p = 0.010), phosphorylated tau (35.3 vs. 32.1 ng/mL, p = 0.035), and 1-42 beta amyloid (1134 vs. 830 pg/mL, p = 0.045). Despite effective antiretroviral treatment, blood brain barrier impairment persists in some HIV-positive patients: it is associated with markers of neuronal damage and it was not associated with CSF neopterin concentrations.

Prevalence and predictors of blood-brain barrier damage in the HAART era.

Blood-brain barrier damage (BBBD) is prevalent in HIV-positive patients and may enhance cell trafficking to the central nervous system. A retrospective analysis in adult HIV-positive patients with no central nervous system disease was conducted in order to estimate the prevalence and risk factors of BBBD (according to cerebrospinal fluid to plasma albumin ratios). One hundred fifty-eight HIV-positive adult patients were included. BBBD impairment and intrathecal IgG synthesis were respectively observed in 45 (28.5 %) and 100 patients (63.3 %). Low CD4 nadir and high CSF HIV RNA were independently associated with both abnormalities. BBBD is common in HIV-positive patients, and its main determinants are advanced immune depression and compartmental viral replication.

Ischaemic stroke, factor V Leiden heterozygosity and left atrial thrombosis in sinus rhythm: a case report.

We describe a 63-year-old man in sinus rhythm (SR) with an ischaemic stroke involving basal ganglia region on the right side. The patient was known to be heterozygous for factor V Leiden (FVL) mutation. On diagnostic work-up, no arterial sources of embolism were found. Transoesophageal echocardiography evidenced a left atrial (LA) thrombosis without relevant cardiopathies. LA thrombosis is generally associated to atrial fibrillation, atrial enlargement, mitral valve stenosis and left ventricular dysfunction, whereas mitral regurgitation is considered protective. To our knowledge, this is the first report of cardioembolic stroke related to a LA thrombosis in a patient in SR without risk factors for thrombus formation except for FVL heterozygosity.

Recurrent cerebrovascular ischaemic events in patients with interatrial septal abnormalities: a follow-up study.

The aim of this study was to evaluate the risk of recurrent ischaemic cerebrovascular events (stroke or transient ischaemic attack (TIA)) in patients with patent foramen ovale (PFO) or atrial septal aneurysm (ASA) treated with different therapeutic regimens. We enrolled 86 patients aged 18-60 years with an unexplained ischaemic stroke or TIA referred to our inpatient department in the period May 1994-December 1999. Follow-up lasted until April 2003. Patients were excluded if the stroke or TIA was related to large-artery atherosclerosis, small artery occlusion, major cardiac sources of embolism or other uncommon causes. During a follow-up (mean+/-SD) of 64.1+/-28.8 months (range 8.1-105.6) a recurrent ischaemic cerebrovascular event occurred in 11/86 patients (12.8%) (5 TIA and 6 strokes). Eight events (4 TIA, 4 strokes) occurred in the 59 patients with PFO alone, three (1 TIA, 2 strokes) in the 21 with PFO plus ASA and none in the 6 patients with ASA alone. In the overall population the cumulative risk of recurrent stroke/TIA was 1.2% at 2 years, 5.5% at 4 years, 7.6% at 6 years and 23.6% at 8 years, and was similar in patients with PFO alone vs. patients with PFO plus ASA (9.0% vs. 6.1% at 6 years, 26.0% vs. 23.1% at 8 years; p>0.05). Nine cerebral ischaemic events (4 TIA, 5 strokes) occurred in the 48 patients treated with antiplatelet drugs (7 in patients with PFO, 2 in patients with PFO plus ASA), and two (1 TIA, 1 stroke) in the 17 patients treated with oral anticoagulants (1 with PFO, 1 with PFO plus ASA). No events occurred in patients submitted to transcatheteral closure.

Apolipoprotein E polymorphism and stroke subtypes in an Italian cohort.

BACKGROUND: Studies have indicated that apolipoprotein E (ApoE)-epsilon4 is a risk factor for ischemic cerebrovascular diseases (ICVD), but the existence of this association is still controversial. The aims of this study were: (1) to compare ApoE genotype and allele frequencies in Italian cases with ICVD and in healthy control subjects and (2) to compare ApoE allele frequencies among ischemic stroke subtypes. METHODS: A hospital-based cohort of 302 Italian subjects with ICVD and 228 healthy subjects have been recruited to investigate the role of ApoE polymorphisms as risk factors for ICVD. TOAST criteria were employed to stratify ICVD cases by subtypes. RESULTS: No significant differences in ApoE genotype and allele frequencies were found between cases and control subjects. The frequency of ApoE-epsilon4 was lower in cases than in control subjects (6% vs. 10.1%), although not significantly. No differences in ApoE genotype and allele frequencies were evident among ICVD subtypes. However, out of 36 ApoE-epsilon4 alleles 23 (3.7%) were found in subjects with ICVD related to primary degenerative arterial disease related to large vessel disease and small vessel disease, and 13 (2.1%) in remaining subjects. Using logistic regression analysis we assessed whether ApoE-epsilon4 allele was independently associated with risk of ICVD related to a primary degenerative arterial disease compared to other ICVD subtypes. While classical risk factors were significantly associated with higher risk for ICVD due to large vessel disease and small vessel disease than other ICVD subtypes, the role of ApoE-epsilon4 allele was not significant (OR 1.25, 95% CI 0.57-2.74). CONCLUSION: Our study shows similar ApoE-epsilon4 genotype and allele frequencies in patients with ICVD and in control subjects. No differences were found among different ICVD subtypes either.

Stroke in young patients: etiopathogenesis and risk factors in different age classes.

The aim of our study was to evaluate the etiopathogenesis and the vascular risk factors in a consecutive series of patients with juvenile ischemic stroke. We enrolled 273 patients (158 males and 115 females), aged between 16 and 49 years, with ischemic cerebrovascular events (ICVE), including transient ischemic attack (TIA) or stroke, referred to our neurology ward between January 1994 and December 2001. Our protocol included medical history, cardiac and neurological examinations, assessment of risk factors and laboratory tests. The instrumental assessment included transthoracic echocardiography (70%), transesophageal echocardiography (60%), conventional angiography (30%), MR angiography (30%), cranial computed tomography (100%) and brain MRI (48%). The ICVE was a stroke in 60% of the cases, a reversible ischemic neurologic deficit in 14% and a TIA in 26%. Thirty-three patients were aged less than 29, 59 were aged between 30 and 39 and 181 between 40 and 49. The percentage of females was higher in patients aged less than 29 while males were prevalent in the 4th and 5th decade. The patients were subtyped according to etiopathogenesis. A large-vessel disease (LVD) was diagnosed in 43 patients (16% of the cases), mostly in patients aged more than 40 years (36 cases). A small-vessel disease (SVD) was found in 48 patients (17% of cases), mostly in patients aged more than 40 years (41 cases). A cardioembolic stroke (CE) was diagnosed in 66 patients (24% of the cases). In the majority of the cases, the cardiopathies were at low-uncertain embolic risk: patent foramen ovale (PFO, 39 cases, in 8 patients associated with an atrial septal aneurism), atrial septal aneurism (12 cases) and myxomatous mitral valve prolapse (3 cases). Stroke due to other causes was found in 51 patients (19% of the cases). Arterial dissection, more frequently involving the carotid region, was diagnosed in 35 patients. Coagulopathies and vasculitis were found in 5 and 6 patients, respectively. Stroke of unknown etiology was found in 65 patients (24% of the cases) with a homogeneous distribution among decades. Our study highlights the role of minor cardiac sources of embolism and arterial dissection in the etiology of juvenile ischemic stroke, whereas coagulopathies and vasculitis are less relevant. LVD and SVD were relevant only in the 5th decade.

Natriuretic peptides as markers of preclinical cardiac disease in obesity.

BACKGROUND: Aim of the study was to evaluate the role of atrial (ANP) and brain natriuretic peptides (BNP) as markers of preclinical cardiac disease in obesity. METHODS: We selected 26 obese (BMI > 29 kg m(-2)) never-treated hypertensives (24-h BP > 140 and/or 90 mmHg), 26 obese normotensives (24-h BP < 130/80 mmHg) and 25 lean (BMI < or = 25 kg m(-2)) never-treated hypertensives. Each subject underwent measurements of ANP and BNP plasma levels, 24-h ambulatory blood pressure (BP) monitoring, digitized M-mode and Doppler echocardiography. RESULTS: Mean values of ANP and BNP were similar among the three groups. All the subjects had normal left ventricular (LV) systolic function. Within each group ANP levels were higher in patients with LV diastolic dysfunction than in patients with normal diastolic function, and BNP levels were higher in patients with LV hypertrophy and in patients with LV diastolic dysfunction. Within each group, ANP levels were inversely correlated with LV diastolic indices, whereas BNP levels were directly correlated with LV mass index and inversely correlated with LV diastolic indices. ANP and BNP levels were not correlated with other echocardiographic parameters, age, BMI or 24-h BP values. CONCLUSION: In normotensive and hypertensive obese subjects the relationships of ANP and BNP levels with LV morpho-functional characteristics follow the same trend as in lean hypertensives, with ANP mainly influenced by diastolic dysfunction and BNP influenced by both LV hypertrophy and LV diastolic dysfunction. Therefore ANP and BNP can be considered useful markers of preclinical cardiac disease in obesity.

Transoesophageal echocardiography in patients without arterial and major cardiac sources of embolism: difference between stroke subtypes.

We studied the records of 175 consecutive patients referred to our neurologic ward between January 1994 and February 2000 with a diagnosis of ischaemic cerebrovascular disease (ICVD) (stroke or transient ischaemic attack - TIA) who underwent transoesophageal echocardiography (TEE). We excluded patients with large vessel disease, high-risk embolic cardiopathies and other rare causes of stroke. According to clinical and neuroimaging findings, patients were divided into two groups. The lacunar (LAC) group (69/175 (39.4%)) and the nonlacunar (N-LAC) one (106/175 (60.6%)). The control population consisted of 78 consecutive patients, referred to the echocardiography laboratory for TEE without history of ICVD and known heart disorders. Patent foramen ovale (PFO) frequency was significantly higher in case patients than in control subjects (55/175 (31.4%) vs. 13/78 (16.6%); p = 0.02). Among case patients, PFO was more prevalent in the N-LAC group than in the LAC one (43/106 (40.6%) vs. 12/69 (17.4%); p = 0.0005). A large degree of shunt occurred in 53.5% of N-LAC patients and in 16.7% of LAC ones (p = 0.04). Atrial septal aneurysm (ASA) was detected in 12% of case patients and 1.3% of control subjects (p = 0.003) and was more frequent in the N-LAC group than in the LAC one (16 vs. 5.8%; p = 0.05). Mitral prolapse (MP) was present in 6/175 (3.4%) ICVD patients (vs. 1/78 among controls) in most cases associated with myxomatous valve redundancy. Aortic arch atheromas (AA) were detected in 12% of ICVD patients and in 10.2% of controls. The frequency was 9.4% in N-LAC and 15.9 in LAC. No complicated AA (plaque thickness >4 mm, ulcerated atheroma, superimposed thrombus) were detected. After multivariate analysis, PFO (OR = 3.8; 95% CI = 2.7-7.9) and ASA (OR = 8.01; 95% CI = 3.0-16.1) appeared to be independent predictors of ICVD. PFO (OR = 2.24; 95% CI = 1.24-4.92) was also independently associated with N-LAC stroke subtype and its importance was even higher in younger patients. Our study provides further evidence that TEE is a helpful diagnostic tool in stroke patients without arterial and major cardiac sources of embolism. However, its utility differs according to type and localization of the ischaemic lesion being more relevant in patient with N-LAC infarctions.

Higher lipoprotein (a) levels in atherothrombotic than lacunar ischemic cerebrovascular disease.

To investigate the role of plasma lipid abnormalities in ischemic cerebrovascular disease related to primary vessel disease, the authors assess lipid profiles in a hospital-based cohort of 202 consecutive patients with atherothrombotic or lacunar stroke subtypes. Lipoprotein (a) was the unique lipid parameter that differs between these two subtypes being its value twofold higher in patients with atherothrombotic than in lacunar stroke. This suggests that lipoprotein (a) promotes large vessel atheromatosis rather than small vessel arteriolosclerosis and favors thrombosis on atheromatous plaques by suppressing local fibrinolysis.

Left ventricular changes in isolated office hypertension: a blood pressure-matched comparison with normotension and sustained hypertension.

BACKGROUND: Isolated office (IO) hypertension is a benign condition according to some researchers, whereas others believe it is associated with cardiovascular abnormalities and increased cardiovascular risk. The aim of this study is to compare morphofunctional characteristics of the left ventricle (LV) in IO hypertensive subjects, normotensive subjects (hereafter, hypertensives and normotensives), and never-treated sustained hypertensives. The 3 groups were matched not only by age, sex, and body mass index but also by clinic blood pressure (BP) (IO hypertensives and sustained hypertensives) and daytime BP (IO hypertensives and normotensives). METHODS: We enrolled 42 IO hypertensives (clinic BP > 140 and/or 90 mm Hg and daytime BP < or = 130/80 mm Hg), 42 sustained hypertensives (clinic BP > 140 and/or 90 mm Hg and daytime BP > or = 140 and/or 90 mm Hg) and 42 normotensives (clinic BP < 135 and/or 85 mm Hg and daytime BP < or = 130/80 mm Hg). Left ventricular morphologic features and function were assessed using digitized M-mode echocardiography. RESULTS: Compared with normotensives, IO hypertensives had significantly thicker LV walls, increased LV mass, reduced diastolic function, increased prevalence of LV hypertrophy, and preclinical diastolic dysfunction. Sustained hypertensives, compared with IO hypertensives, had significantly thicker LV wall, higher LV mass, and lower diastolic function, whereas the prevalence of LV hypertrophy and preclinical diastolic dysfunction was greater than in IO hypertensives, but the difference did not reach statistical significance (P = .29). CONCLUSIONS: Comparing matched BP groups, IO hypertensives have LV morphofunctional characteristics considerably different from normotensives and qualitatively similar to sustained hypertensives. Therefore, our results support the hypothesis that IO hypertension should not be considered as simply a benign condition.

Microalbuminuria as a marker of preclinical diastolic dysfunction in never-treated essential hypertensives.

Using 24-h ambulatory blood pressure (BP) monitoring and digitized M-mode echocardiography, we evaluated whether microalbuminuria is related to preclinical left ventricular (LV) diastolic dysfunction in hypertensive patients. We selected 87 never-treated hypertensive patients (mean 24-h BP > 140 and/or > 90 mm Hg); albuminuria was evaluated as mean value of 24-h urinary albumin excretion (UAE) from two 24-h urine collections. Microalbuminuria was found in 28 patients, classified as MA+ (UAE 30 to 300 mg/24 h); 59 patients had normal UAE (< 30 mg/24 h) and were classified as MA-. The MA+ and MA- groups did not differ with regard to age, sex, body mass index, or 24-h heart rate, whereas 24-h, daytime, and nighttime systolic and diastolic BP were significantly higher in MA+ than in MA-. The LV mass index was greater in MA+, as was the prevalence of LV hypertrophy; peak shortening rate of LV diameter, index of systolic function, was normal in all, but was lower in MA+. Peak lengthening rate of LV diameter and peak thinning rate of posterior wall, indices of diastolic function, were lower in MA+ and the prevalence of diastolic dysfunction was higher in MA+. UAE was inversely correlated with both indices of LV diastolic function, also after correction for age, 24-h heart rate, 24-h BP, and LV mass. In conclusion, in never-treated hypertensive patients, microalbuminuria is not only associated with greater myocardial mass, but is also related with preclinical impairment of LV diastolic function. This relation, independent from increased BP or LV mass, strengthens the role of microalbuminuria as an early and reliable marker of preclinical cardiac involvement.

Clinical features, EEG findings and diagnostic pitfalls in juvenile myoclonic epilepsy: a series of 63 patients.

Juvenile myoclonic epilepsy (JME) is a common idiopathic generalized epileptic syndrome distinctively characterized by myoclonic jerks often associated to generalized tonic-clonic seizures (GTCS) and typical absence seizures. In spite of typical clinical and EEG profiles, JME is widely underdiagnosed. In the present study we retrospectively revised clinical and EEG data of JME patients referring to our Epilepsy Service. A diagnosis of JME could be made in 63 patients, that is 5.7% of all the epileptic patients referring to our Service and 25.9% of those suffering from an idiopathic generalized epilepsy. General features as well as modality of onset and course of the syndrome of our JME subjects were in accordance with literature. Regarding EEG findings, asymmetries were detected in 38.1% of cases. At referral to our Service only 31.7% of JME patients were correctly diagnosed. Main factors responsible for misdiagnosis were failure in eliciting a history of myoclonic jerks and misinterpretation of myoclonic jerks as simple partial seizures. EEG asymmetries were misleading in 13 patients. In conclusion, a correct JME diagnosis is strictly dependent on the knowledge of the syndrome leading the interviewer to look for and correctly interpret myoclonic jerks whereas EEG is just an ancillary diagnostic tool.

Atrial fibrillation and antithrombotic treatment in Italian hospitalized patients: a prospective, observational study.

BACKGROUND: We studied the prevalence of atrial fibrillation within a large Italian inpatient population, and evaluated the use of antithrombotic therapy among these individuals. METHODS: A prospective cross sectional study (Phase 1) with a 1-year follow-up period (Phase 2) was conducted at a single Italian centre. During Phase 1, we conducted a chart review of all inpatients on 5 separate days, each 1 month apart, between January and May 1999. During Phase 2, at 1-year of follow-up, patients or their families were contacted to document the occurrence of new clinical events, as well as current antithrombotic therapy use. RESULTS: A total of 3121 patient charts were reviewed. The prevalence of atrial fibrillation was 7.2%. Of these 224 patients, 21.3% were on oral anticoagulants, 29.7% on antiplatelets, while 49% received neither. Patients on oral anticoagulants were significantly younger (mean age 72.3 years) than those on antiplatelets (mean age 80.6 years; p<0.001) or neither therapy (mean age 80.7 years; p<0.001). At 1 year follow up, an acute ischaemic stroke occurred among 7.4% of the 121 contacted patients. Among patients with chronic atrial fibrillation [98], 25.5% were receiving an oral anticoagulant. CONCLUSIONS: Despite clear evidence from clinical trials, oral anticoagulants are significantly underused among patients with chronic atrial fibrillation. Methods should be developed to improve both physician and patient knowledge about the overall benefits of anti-thrombotic therapy among these individuals.