Epidemiology of Patent Foramen Ovale in General Population and in Stroke Patients: A Narrative Review.

Introduction: Percutaneous closure of patent foramen ovale (PFO) in selected patients with cryptogenic cerebrovascular ischemic events (CEs) decreases the risk of recurrent stroke; however, optimal patient selection criteria are still under investigation. Candidates for PFO closure are usually selected from the pool of CE patients with a high risk of Paradoxical Embolism (RoPE) score. The RoPE score calculates the probability that PFO is causally related to stroke, based on PFO prevalence in patients with CE compared with that in healthy subjects. The latter has been set at 25% based on the average of autopsy and transesophageal echocardiography (TEE) studies. Methods: We conducted a comprehensive review of studies investigating PFO prevalence in general population and in patients with CE and non-CE using autopsy, TEE, transcranial Doppler (TCD) or transthoracic echocardiography (TTE). Studies were excluded if they (1) reported data from referred subjects with underlying cerebrovascular disease or (2) did not specify etiologically the events. Results: In healthy/control subjects, PFO prevalence was 24.2% (1,872/7,747) in autopsy studies, 23.7% (325/1,369) in TEE, 31.3% (111/355) in TCD, and 14.7% (186/1,267) in TTE studies. All diagnostic modalities included PFO prevalence was higher in CE compared with healthy/control population [odds ratio (OR) = 3.1, 95% confidence interval (CI) = 2.5-3.8] and compared with non-CE (OR = 2.3, 95% CI = 2.0-2.6). In patients with CE, PFO prevalence in the young compared to the old was higher when the diagnostic modality was TEE (48.9 vs. 27.3%, p < 0.0001, OR = 2.6 with 95% CI = 2.0-3.3) or TCD (58.1 vs. 41%, OR = 1.9, 95% CI = 1.6-2.5), but not TTE (53.3 vs. 37.5%, p = 0.16). Regarding non-CE, PFO prevalence in the young compared to the old was higher when the diagnostic modality was TEE (20 vs. 12.9%, OR = 1.7, 95% CI = 1.0-2.8) but not TTE (10.4 vs. 7.8%, p = 0.75) or TCD (22.8 vs. 20.1%, p = 0.56). Conclusions: Given the limitations of autopsy and TEE studies, there is good reason not to take a fixed 25% PFO prevalence for granted. The estimation of degree of causality may be underestimated or overestimated in populations with PFO prevalence significantly lower or higher than the established. Given the high sensitivity, non-invasive nature, low cost, and repeatability of TCD, future large-scale TCD-based studies should investigate potential heterogeneity in PFO prevalence in different healthy racial/ethnic populations.

Prevalence of patent foramen ovale in the Greek population is high and impacts on the interpretation of the risk of paradoxical embolism (RoPE) score.

BACKGROUND: The risk of paradoxical embolism (RoPE) score calculates the probability that patent foramen ovale (PFO) is causally related to stroke (PFO attributable fraction, PFOAF), based on PFO prevalence in patients with cryptogenic stroke (CS) compared with that in the general population. The latter has been estimated at 25%; however, PFO prevalence in nonselected populations varies widely. METHODS: Since PFO prevalence in Greece remains unknown, we evaluated it and we calculated PFOAF stratified by RoPE score in a cohort of patients with CS ⩽55 years old. PFO was detected according to the international consensus transcranial Doppler (TCD) criteria in 124 healthy subjects (H), in 102 patients with CS, and in 56 patients with stroke of known cause (nonCS). Each subject underwent unilateral middle cerebral artery recording after infusion of agitated saline, at rest, and after a controlled Valsalva maneuver. We characterized PFO as large (>20 microbubbles or curtain), moderate (11-20), and small (⩽10). RESULTS: PFO was detected in 42.7% of H, 49% of CS, and 25% of nonCS (p = 0.013). Large PFOs were numerically higher in CS [28.4% (29/102)] compared with H [19.3% (24/124); p = 0.1] and to nonCS [7.1% (4/56), p = 0.04]. The median RoPE score in patients with CS and PFO was seven. Even patients with very high RoPE score (9-10) had moderate PFOAF (57%). For any individual stratum up to RopE score 8, PFOAF was <33%. CONCLUSIONS: PFO prevalence in the Greek population is much higher than the widely accepted 25%. PFO may be the cause of stroke in one out of nine Greek patients with CS. Among Greek CS patients who harbor a PFO, the latter is causal in one out of five. The established RoPE score cutoff of ⩾7 for having a probable PFO-associated stroke may overestimate the probability in patients deriving from populations with high PFO prevalence.

Connexin43 and connexin47 alterations after neural precursor cells transplantation in experimental autoimmune encephalomyelitis.

Exogenous transplanted neural precursor cells (NPCs) exhibit miscellaneous immune-modulatory effects in models of autoimmune demyelination. However, the regional interactions of NPCs with the host brain tissue in remissive inflammatory events have not been adequately studied. In this study we used the chronic MOG-induced Experimental Autoimmune Encephalomyelitis (EAE) model in C57BL/six mice. Based on previous data, we focused on neuropathology at Day 50 post-induction (D50) and studied the expression of connexin43 (Cx43) and Cx47, two of the main glial gap junction (GJ) proteins, in relation to the intraventricular transplantation of GFP(+) NPCs and their integration with the host tissue. By D50, NPCs had migrated intraparenchymally and were found in the corpus callosum at the level of the lateral ventricles and hippocampus. The majority of GFP(+) cells differentiated with simple or ramified processes expressing mainly markers of mature GLIA (GFAP and NogoA) and significantly less of precursor glial cells. GFP(+) NPCs expressed connexins and formed GJs around the hippocampus more than lateral ventricles. The presence of NPCs did not alter the increase in Cx43 GJ plaques at D50 EAE, but prevented the reduction of oligodendrocytic Cx47, increased the number of oligodendrocytes, local Cx47 levels and Cx47 GJ plaques per cell. These findings suggest that transplanted NPCs may have multiple effects in demyelinating pathology, including differentiation and direct integration into the panglial syncytium, as well as amelioration of oligodendrocyte GJ loss, increasing the supply of potent myelinating cells to the demyelinated tissue.

Early onset degenerative dementias: demographic characteristics and etiologic classification in a tertiary referral center.

Early onset dementia (EOD) is a major diagnostic challenge as it often presents with atypical features and may be attributed to treatable diseases. Primary degenerative dementias (Alzheimer's disease-AD, frontotemporal lobar degeneration-FTLD, Lewy body dementia-LBD), although traditionally considered to affect older people, are still a main cause of EOD. 491 demented patients were assessed from January 1, 2003 to December 31, 2010 in the Neurology Department of a tertiary referral center. Patients were classified as AD, behavioral variant frontotemporal dementia (bvFTD), non-fluent agrammatic variant primary progressive aphasia (naPPA), semantic variant PPA (svPPA), corticobasal degeneration (CBD), or progressive supranuclear palsy (PSP) who also met criteria for naPPA and LBD. Finally, their demographic characteristics were analysed, according to age at onset (EOD <65 years, late onset dementia-LOD ≥65 years). From the 491 patients, 137 (27.9 %) were EOD. In the EOD group, 52 (38 %) were diagnosed with bvFTD, 34 (24.8 %) with AD, 27 (19.7 %) with naPPA, 10 (7.2 %) with svPPA, 12 (8.8 %) with CBD or PSP, and 2 (1.5 %) with LBD. Demographic characteristics did not differ significantly among diagnostic categories in the EOD group, while in the LOD group FTLD patients were younger and more frequently men compared to both AD and LBD patients. EOD patients had more years of education than LOD patients. Degenerative disorders as causes of EOD are not rare. High clinical alertness is warranted to achieve correct and timely diagnosis.

Spinal cord involvement in chronic inflammatory demyelinating polyradiculoneuropathy: a clinical and MRI study.

Concomitant central nervous system (CNS) involvement in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is rare. Although the spinal nerve roots may present MRI abnormalities in CIDP, hitherto, the spinal cord has been investigated in a single study. We retrospectively investigated clinically and with MRI a cohort of patients with definite CIDP diagnosis (EFNS/PNS criteria) for evidence of brain and spinal cord involvement, who were initially admitted in our department during the last 4 years. Among 12 patients with CIDP (men: 8, mean age: 59.3 years, mean disease duration: 3.8 years), nine patients had their MRI scan during a clinical relapse and three during remission. Brain MRI did not document typical multiple sclerosis lesions in any patient. We did not identify any MRI abnormalities in ten patients without clinical evidence of spinal cord involvement. Conversely, MRI disclosed extensive lesions of the thoracic cord in two patients with an overt spinal cord syndrome, whom we describe. This represents the biggest MRI study of CIDP patients who have been investigated for spinal cord involvement. Our data support earlier observations that a minority of CIDP patients may additionally develop CNS involvement of variable degree.

Changes in thyroid hormone receptors after permanent cerebral ischemia in male rats.

Thyroid hormones (TH) and receptors (TRs) may play an important role in the pathophysiology of acute cerebral ischemia. In the present study, we sought to determine whether serum triodothyronine (T3)/thyroxine (T4) and brain TRs (TRα1, TRß1) might change after experimental stroke. Male adult Wistar rats were subjected to permanent middle cerebral artery occlusion (group P) and compared to sham-operated controls (group S). Animals were followed clinically for 14 days until brain collection for Western blot (WB) or neuropathological analysis of TRs in three different brain areas (infarcted tissue, E1; noninfarcted ipsilateral hemisphere, E2; and contralateral hemisphere, E3). Analysis of serum TH levels showed a reduction of T4 in group P (p = 0.002) at days 2 to 14, while half of the animals also displayed "low T3" values (p = 0.012) on day 14. This T4 reduction was inversely correlated to the clinical severity of stroke and the concomitant body weight loss (p < 0.005). WB analysis of TRα1 and TRß1 protein expression showed heterogenic responses at day 14: total and nuclear TRα1 were similar between the two groups, while total TRß1 decreased 7.5-fold within E1 (p ≤ 0.001) with a concomitant 1.8-fold increase of nuclear TRß1 in E2 area (p = 0.03); TRß1 expression did not differ in E3. Neuropathological analysis revealed that activated macrophages/microglia exclusively expressed nuclear TRα1 within the infarct core. Astrocytes mildly expressed nuclear TRα1 in and around the infarct, along with a prominent TRß nuclear signal restricted in the astrocytic scar. Neurons around the infarct expressed mainly TRα1 and, to a milder degree, TRß. Surprisingly enough, we detected for the first time a TRß expression in the paranodal region of Ranvier nodes, of unknown significance so far. Our data support that cerebral ischemia induces a low TH response, associated with significant and heterogenic changes in brain TR expression. These findings could imply an important role of TH signaling in cerebral ischemia.

Characterization of in vitro expanded bone marrow-derived mesenchymal stem cells isolated from experimental autoimmune encephalomyelitis mice.

Extensive experimental studies indicate that autologous bone marrow mesenchymal stem cells (BMSCs) are able to ameliorate experimental autoimmune encephalomyelitis (EAE) and potentially multiple sclerosis. However, the impact that the inflammatory environment present in EAE may have on the biological properties of BMSCs expanded in vitro for transplantation is yet to be clarified. It was investigated whether BMSCs isolated from EAE-induced C57bl6/J mice and expanded in vitro preserve the properties of BMSCs isolated from healthy donors (BMSCs-control). The mesenchymal origin, the differentiation potential, and the transcriptional expression profile of six histone-modifying genes were studied in both groups of BMSCs. BMSCs-EAE exhibited distinct morphology and larger size compared to BMSCs-control, higher degree of proliferation and apoptosis, differences in the adipogenesis and the osteogenesis induction, and differential expression of stromal markers and markers of progenitor and mature neuronal/glial cells. Moreover, BMSCs-EAE exhibited different expression patterns on a number of histone-modifying genes compared to controls. We recorded manifold differences, both phenotypical and functional, of in vitro expanded BMSCs-EAE in comparison to their healthy donor-derived counterparts that may be attributed to the inflammatory environment they originated from. Whether our findings may be of any clinical relevance needs to be clarified in future studies, in vivo.

The frontotemporal dementias in a tertiary referral center: classification and demographic characteristics in a series of 232 cases.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) comprises of behavioral variant frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA) with its 3 main variants, namely nonfluent/agrammatic (naPPA), semantic (svPPA) and logopenic (lvPPA). Recently a clinical syndrome with predominant right temporal atrophy was recognized (rvFTD). FTLD often overlaps with parkinsonism plus syndromes such as corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), as well as with motor neuron disease (FTD-MND). While FTLD syndromes were thought to be rare and difficult to diagnose ante mortem, revised diagnostic criteria as well as recent studies highlighted the plausibility of accurate clinical diagnosis. METHODS: 232 FTLD patients were assessed from January 1, 2003 to December 31, 2010 in the Neurology Department of a tertiary referral center. Patients were classified as bvFTD, naPPA, svPPA, lvPPA, CBD/PSP and rvFTD and their demographic characteristics were analyzed. RESULTS: From the 232 patients, 111 (47.8%) were diagnosed with bvFTD, 56 (24.1%) with naPPA, 21 (9.1%) with svPPA, 6 (2.6%) with lvPPA, 20 (8.6%) with CBD or PSP and 18 (7.8%) with rvFTD. 44% of the patients were under 65 years old at onset of symptoms, while only 4.3% reported family history of dementia. FTLD subgroups did not differ with respect to demographic characteristics, but early onset cases had higher educational level. DISCUSSION: FTLD represents a syndrome with different but clinically distinguishable phenotypes. Cultural, educational and socioeconomic status differences might regulate patients' access to medical care and therefore influence age of reported onset and prevalence of FTLD in clinical studies. High clinical alertness and sensitive neuropsychological tests could lead to timely clinical diagnosis in a common presenile type of dementia.

Rich collaterals in clinically unsuspected basilar artery occlusion-as good as it gets.

Basilar artery occlusion (BAO) is generally considered an emergency and is associated with high mortality and poor functional outcome. Although cases with more benign course without thrombolysis treatment have occasionally been reported, to our knowledge there is only one previous report in which angiography, almost accidentally revealed a clinically unsuspected BAO. A 45-year-old man with treated hypertension and lipidemia had three distinct isolated episodes of dizziness, 2-3 months before he was referred by an internist for an ultrasound neurovascular evaluation. Neurological examination and extensive laboratory work-up was normal; however, transcranial Doppler (TCD) unexpectedly provided findings that first raised the suspicion of BAO, alerting for further work-up. Cerebral angiography demonstrated BAO, just beyond the anterior inferior cerebellar artery origin, as well as extensive intracerebellar collateral circulation. On 6-year follow-up, he remains normal with no further episodes, although serial TCD shows persistent BAO.

Confusional state in the syndrome of HaNDL.

BACKGROUND: The association of headache with transient neurological deficits and cerebrospinal fluid lymphocytosis (HaNDL) is recognized as a distinct benign, self-limited headache syndrome. Aphasic, sensory and motor disturbances predominate the clinical picture and to our knowledge, only 2 detailed cases of confusion and agitation have been previously described. CASE: We present our recent experience with 2 cases of the HaNDL syndrome who, in addition to the focal neurological deficits, developed confusional state of variable degree, with no signs of aphasia that could jeopardize the clinical picture. An extensive laboratory and neuroimaging work-up excluded all other possible entities and both patients treated conservatively showed an excellent functional recovery. CONCLUSION: We suggest that, although the HaNDL syndrome has a focal plateau, explaining the focal deficits; diffuse manifestations in the form of confusion may well be part of the clinical spectrum of this disorder.