PRES and RCVS: Two Distinct Entities or a Spectrum of the Same Disease?

OBJECTIVES: To report a case of a patient with overlapping posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS), and review the existing literature emphasizing the pathophysiological overlap of these two entities. MATERIALS AND METHODS: We conducted a literature search in electronic database PubMed identifying studies reporting the overlap of PRES and RCVS. RESULTS: PRES and RCVS are two increasingly recognized entities that share similar clinical and imaging features. PRES is characterized by vasogenic edema predominantly in the parieto-occipital regions, associated with acute onset of neurological symptoms including encephalopathy, seizures, headaches, and visual disturbances. RCVS is characterized by reversible segmental and multifocal vasoconstriction of the cerebral arteries and classically presents with thunderclap headache, with or without associated focal neurological deficits and seizures. PRES is frequently associated with uncontrolled hypertension but can also be seen in the setting of renal failure, exposure to cytotoxic agents, or pre-eclampsia. RCVS is often triggered by exposure to vasoactive agents, postpartum state, or immunosuppression. We report a case of a patient presenting with vision changes and hemiparesis, and found to have extensive cytotoxic and vasogenic edema involving the cortex and subcortical white matter on brain imaging. These changes were primarily noted in the parieto-occipital and brainstem regions, along with features of reversible vasculopathy on vascular imaging suggestive of coexisting PRES and RCVS. CONCLUSIONS: PRES and RCVS share precipitating factors, clinical and radiological features, and frequently co-exist, suggesting a common pathophysiological mechanism related to reversible dysregulation of cerebral vasculature, endothelial dysfunction, and breakdown of the blood-brain barrier.

Epileptiform Abnormalities in Acute Ischemic Stroke: Impact on Clinical Management and Outcomes.

PURPOSE: Studies examining seizures (Szs) and epileptiform abnormalities (EAs) using continuous EEG in acute ischemic stroke (AIS) are limited. Therefore, we aimed to describe the prevalence of Sz and EA in AIS, its impact on anti-Sz drug management, and association with discharge outcomes. METHODS: The study included 132 patients with AIS who underwent continuous EEG monitoring >6 hours. Continuous EEG was reviewed for background, Sz and EA (lateralized periodic discharges [LPD], generalized periodic discharges, lateralized rhythmic delta activity, and sporadic epileptiform discharges). Relevant clinical, demographic, and imaging factors were abstracted to identify risk factors for Sz and EA. Outcomes included all-cause mortality, functional outcome at discharge (good outcome as modified Rankin scale of 0-2 and poor outcome as modified Rankin scale of 3-6) and changes to anti-Sz drugs (escalation or de-escalation). RESULTS: The frequency of Sz was 7.6%, and EA was 37.9%. Patients with Sz or EA were more likely to have cortical involvement (84.6% vs. 67.5% P = 0.028). Among the EAs, the presence of LPD was associated with an increased risk of Sz (25.9% in LPD vs. 2.9% without LPD, P = 0.001). Overall, 21.2% patients had anti-Sz drug changes because of continuous EEG findings, 16.7% escalation and 4.5% de-escalation. The presence of EA or Sz was not associated with in-hospital mortality or discharge functional outcomes. CONCLUSIONS: Despite the high incidence of EA, the rate of Sz in AIS is relatively lower and is associated with the presence of LPDs. These continuous EEG findings resulted in anti-Sz drug changes in one-fifth of the cohort. Epileptiform abnormality and Sz did not affect mortality or discharge functional outcomes.

Clinical Reasoning: A 55-Year-Old Woman With Recurrent Episodes of Aphasia and Vision Changes.

A 55-year-old woman presented with recurrent episodes of headache, vision changes, and language disturbances. Brain MRI showed multifocal white matter lesions, microhemorrhages, and enlarged perivascular spaces. After an extensive and unrevealing workup, she underwent a biopsy of brain and meninges that revealed thick and hyalinized leptomeningeal and cortical vessel walls that were strongly positive for ß-amyloid by immunohistochemical staining, suggestive of cerebral amyloid angiopathy (CAA). CAA can present as a spectrum of inflammatory responses to the deposition of amyloid-ß in the vessel walls. Her clinical presentation, radiologic, and histopathologic findings supported a diagnosis of probable CAA-related inflammation (CAA-ri). Although an uncommon entity, it is important to recognize it because most patients respond to immunosuppressive therapy.

Post-infectious rhombencephalitis after coronavirus-19 infection: A case report and literature review.

A wide number of neurological manifestations have been described in association with coronavirus disease 19 (COVID-19). We describe an unusual case of a young man who developed severe rhombencephalitis after COVID-19. He demonstrated clinical and radiological improvement with high dose corticosteroids, plasma exchange and intravenous immune globulin. Our findings, along with previously reported cases that we review here, support an autoimmune para- or post-infectious mechanism and highlight a possible role for immunotherapy in patients with rhombencephalitis after COVID-19.

Telepsiquiatría en niños y adolescentes: aplicación en contexto de pandemia / Telepsychiatry in children and adolescents: application in the context of a pandemic

Telemedicina, se refiere a las prestaciones de salud a distancia. Existen muchos modelos de telemedicina descritos e implementados en distintos lugares del mundo. La telepsiquiatría (y telemedicina) que se está implementando hoy en Chile y el mundo, ya sea desde un marco institucional o privado, es directa hacia el paciente, esto implica que no es una "inter -o tele -consulta" donde hay un profesional presencial que se hace responsable de la indicación, en este caso la atención completa y directa médico-paciente se lleva a cabo a distancia, quebrando, de alguna manera, la regla de oro de la atención clínica que es la consulta presencial entre el médico y el paciente. Se revisan algunas sugerencias descritas en la literatura y otras que ha dado la experiencia. La idea de este artículo es discutir los desafíos clínicos, éticos y legales, junto con los beneficios y oportunidades de la telepsiquiatría en el contexto actual.Palabras claves: Telemedicina, telepsiquiatría, teleconsulta, médico-paciente, covid-19.

Summary. Telemedicine refers to remote health care. There are many telemedicine models described and implemented in different parts of the world. The telepsychiatry (and telemedicine) that is being implemented today in Chile and the world, either from an institutional or private framework, is directed towards the patient, this implies that it is not an "tele-consultation" where there is a another face-to-face professional who is responsible for the prescription of treatment. In our case, the complete and direct doctor-patient care is carried out at a distance, breaking in some way the golden rule of clinical care that is face-to-face consultation between the doctor and the patient. Some suggestions described in the literature are reviewed and we make other suggestions based on our experience. The idea of this article is to discuss clinical, ethical and legal challenges, along with the benefits and opportunities of telepsychiatry in the current context.Key words: Telemecine, telepsychiatry, tele-consultation, physician-patient, covid-19.

Tissue-type plasminogen activator regulates p35-mediated Cdk5 activation in the postsynaptic terminal.

Neuronal depolarization induces the synaptic release of tissue-type plasminogen activator (tPA). Cyclin-dependent kinase-5 (Cdk5) is a member of the family of cyclin-dependent kinases that regulates cell migration and synaptic function in postmitotic neurons. Cdk5 is activated by its binding to p35 (also known as Cdk5r1), a membrane-anchored protein that is rapidly degraded by the proteasome. Here, we show that tPA prevents the degradation of p35 in the synapse by a plasminogen-dependent mechanism that requires open synaptic N-methyl-D-aspartate (NMDA) receptors. We show that tPA treatment increases the abundance of p35 and its binding to Cdk5 in the postsynaptic density (PSD). Furthermore, our data indicate that tPA-induced p35-mediated Cdk5 activation does not induce cell death, but instead prevents NMDA-induced ubiquitylation of postsynaptic density protein-95 (PSD-95; also known as Dlg4) and the removal of GluR1 (also known as Gria1)-containing α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptors from the PSD. These results show that the interaction between tPA and synaptic NMDA receptors regulates the expression of AMPA receptor subunits in the PSD via p35-mediated Cdk5 activation. This is a novel role for tPA as a regulator of Cdk5 activation in cerebral cortical neurons.

Tissue-type plasminogen activator protects the postsynaptic density in the ischemic brain.

Cerebral ischemia causes the presynaptic release of tissue-type plasminogen activator (tPA). The postsynaptic density (PSD) is a postsynaptic structure that provides a matrix where signaling transduction of excitatory synapses takes place. The postsynaptic density protein-95 (PSD-95) is the most abundant scaffolding protein in the postsynaptic density (PSD), where it modulates the postsynaptic response to the presynaptic release of glutamate by regulating the anchoring of glutamate receptors to the PSD. We found that tPA induces the local translation of PSD-95 mRNA and the subsequent recruitment of PSD-95 protein to the PSD, via plasminogen-independent activation of TrkB receptors. Our data show that PSD-95 is removed from the PSD during the early stages of cerebral ischemia, and that this effect is abrogated by either the release of neuronal tPA, or intravenous administration of recombinant tPA (rtPA). We report that the effect of tPA on PSD-95 is associated with inhibition of the phosphorylation and recruitment of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors to the PSD, known to amplify the effect of the excitotoxic injury, and that this is followed by TrkB-mediated protection of dendritic spines from the harmful effects of the hypoxic insult. These data reveal that tPA is a synaptic protector in the ischemic brain.

A Cross Talk between Neuronal Urokinase-type Plasminogen Activator (uPA) and Astrocytic uPA Receptor (uPAR) Promotes Astrocytic Activation and Synaptic Recovery in the Ischemic Brain.

Urokinase-type plasminogen activator (uPA) is a serine proteinase that, upon binding to its receptor (uPAR), catalyzes the conversion of plasminogen into plasmin on the cell surface. Our previous studies indicate that uPA and uPAR expression increase in the ischemic brain during the recovery phase from an acute ischemic injury and that uPA binding to uPAR promotes neurological recovery after an acute ischemic stroke. Here, we used male mice genetically deficient on either uPA (uPA-/-) or uPAR (uPAR-/-) or with a four-amino acid substitution into the growth factor domain of uPA that abrogates its binding to uPAR (PlatGFDhu/GFDhu) to investigate the mechanism whereby uPA promotes neurorepair in the ischemic brain. We found that neurons release uPA and astrocytes recruit uPAR to their plasma membrane during the recovery phase from a hypoxic injury and that binding of neuronal uPA to astrocytic uPAR induces astrocytic activation by a mechanism that does not require plasmin generation, but instead is mediated by extracellular signal-regulated kinase 1/2 (ERK1/2)-regulated phosphorylation of the signal transducer and activator of transcription 3 (STAT3). We report that uPA/uPAR binding is necessary and sufficient to induce astrocytic activation in the ischemic brain and that astrocytes activated by neuronal uPA promote synaptic recovery in neurons that have suffered an acute hypoxic injury via a mechanism mediated by astrocytic thrombospondin-1 (TSP1) and synaptic low-density lipoprotein receptor-related protein-1 (LRP1). In summary, we show that uPA/uPAR-induced astrocytic activation mediates a cross talk between astrocytes and injured neurons that promotes synaptic recovery in the ischemic brain.SIGNIFICANCE STATEMENT To date, there is no therapeutic strategy to promote synaptic recovery in the injured brain. Here, we show that neurons release urokinase-type plasminogen activator (uPA) and astrocytes recruit the uPA receptor (uPAR) to their plasma membrane during the recovery phase from a hypoxic injury. We found that binding of neuronal uPA to astrocytic uPAR promotes astrocytic activation and that astrocytes activated by uPA-uPAR binding promote synaptic recovery in neurons that have suffered a hypoxic injury by a mechanism that does not require plasmin generation, but instead is mediated by ERK1/2-regulated STAT3 phosphorylation, astrocytic thrombospondin-1 (TSP1) and synaptic low-density lipoprotein receptor-related protein-1 (LRP1). Our work unveils a new biological function for uPA-uPAR as mediator of a neuron-astrocyte cross talk that promotes synaptic recovery in the ischemic brain.

Tissue-type plasminogen activator is a homeostatic regulator of synaptic function in the central nervous system.

Membrane depolarization induces the release of the serine proteinase tissue-type plasminogen activator (tPA) from the presynaptic terminal of cerebral cortical neurons. Once in the synaptic cleft this tPA promotes the exocytosis and subsequent endocytic retrieval of glutamate-containing synaptic vesicles, and regulates the postsynaptic response to the presynaptic release of glutamate. Indeed, tPA has a bidirectional effect on the composition of the postsynaptic density (PSD) that does not require plasmin generation or the presynaptic release of glutamate, but varies according to the baseline level of neuronal activity. Hence, in inactive neurons tPA induces phosphorylation and accumulation in the PSD of the Ca2+/calmodulin-dependent protein kinase IIα (pCaMKIIα), followed by pCaMKIIα-induced phosphorylation and synaptic recruitment of GluR1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. In contrast, in active neurons with increased levels of pCaMKIIα in the PSD tPA induces pCaMKIIα and pGluR1 dephosphorylation and their subsequent removal from the PSD. These effects require active synaptic N-methyl-D-aspartate (NMDA) receptors and cyclin-dependent kinase 5 (Cdk5)-induced phosphorylation of the protein phosphatase 1 (PP1) at T320. These data indicate that tPA is a homeostatic regulator of the postsynaptic response of cerebral cortical neurons to the presynaptic release of glutamate via bidirectional regulation of the pCaMKIIα /PP1 switch in the PSD.

Urokinase-type Plasminogen Activator (uPA) Binding to the uPA Receptor (uPAR) Promotes Axonal Regeneration in the Central Nervous System.

Axonal injury is a common cause of neurological dysfunction. Unfortunately, in contrast to axons from the peripheral nervous system, the limited capacity of regeneration of central nervous system (CNS) axons is a major obstacle for functional recovery in patients suffering neurological diseases that involve the subcortical white matter. Urokinase-type plasminogen activator (uPA) is a serine proteinase that upon binding to the urokinase-type plasminogen activator receptor (uPAR) catalyzes the conversion of plasminogen into plasmin on the cell surface. uPAR expression increases after an injury, and signaling through uPAR promotes tissue remodeling. However, it is yet unknown whether uPA binding to uPAR has an effect on axonal recovery in the CNS. Here, we used in vitro and in vivo models of CNS axonal injury to test the hypothesis that uPA binding to uPAR promotes axonal regeneration in the CNS. We found that newly formed growth cones from axons re-emerging from an axonal injury express uPAR and that binding of uPA to this uPAR promotes axonal recovery by a mechanism that does not require the generation of plasmin. Our data indicate that the binding of recombinant uPA or endogenous uPA to uPAR induces membrane recruitment and activation of ß1 integrin via the low density lipoprotein receptor-related protein-1 (LRP1), which leads to activation of the Rho family small GTPase Rac1 and Rac1-induced axonal regeneration. Our results show that the uPA/uPAR/LRP1 system is a potential target for the development of therapeutic strategies to promote axonal recovery following a CNS injury.

Tissue-type Plasminogen Activator (tPA) Modulates the Postsynaptic Response of Cerebral Cortical Neurons to the Presynaptic Release of Glutamate.

Tissue-type plasminogen activator (tPA) is a serine proteinase released by the presynaptic terminal of cerebral cortical neurons following membrane depolarization (Echeverry et al., 2010). Recent studies indicate that the release of tPA triggers the synaptic vesicle cycle and promotes the exocytosis (Wu et al., 2015) and endocytic retrieval (Yepes et al., 2016) of glutamate-containing synaptic vesicles. Here we used electron microscopy, proteomics, quantitative phosphoproteomics, biochemical analyses with extracts of the postsynaptic density (PSD), and an animal model of cerebral ischemia with mice overexpressing neuronal tPA to study whether the presynaptic release of tPA also has an effect on the postsynaptic terminal. We found that tPA has a bidirectional effect on the composition of the PSD of cerebral cortical neurons that is independent of the generation of plasmin and the presynaptic release of glutamate, but depends on the baseline level of neuronal activity and the extracellular concentrations of calcium (Ca2+). Accordingly, in neurons that are either inactive or incubated with low Ca2+ concentrations tPA induces phosphorylation and accumulation in the PSD of the Ca2+/calmodulin-dependent protein kinase IIα (pCaMKIIα), followed by pCaMKIIα-mediated phosphorylation and synaptic recruitment of GluR1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. In contrast, in neurons with previously increased baseline levels of pCaMKIIα in the PSD due to neuronal depolarization in vivo or incubation with high concentrations of either Ca2+ or glutamate in vitro, tPA induces pCaMKIIα and pGluR1 dephosphorylation and their subsequent removal from the PSD. We found that these effects of tPA are mediated by synaptic N-methyl-D-aspartate (NMDA) receptors and cyclin-dependent kinase 5 (Cdk5)-induced phosphorylation of the protein phosphatase 1 (PP1) at T320. Our data indicate that by regulating the pCaMKIIα/PP1 balance in the PSD tPA acts as a homeostatic regulator of the postsynaptic response of cerebral cortical neurons to the presynaptic release of glutamate.

The Plasminogen Activation System Promotes Dendritic Spine Recovery and Improvement in Neurological Function After an Ischemic Stroke.

Advances in neurocritical care and interventional neuroradiology have led to a significant decrease in acute ischemic stroke (AIS) mortality. In contrast, due to the lack of an effective therapeutic strategy to promote neuronal recovery among AIS survivors, cerebral ischemia is still a leading cause of disability in the world. Ischemic stroke has a harmful impact on synaptic structure and function, and plasticity-mediated synaptic recovery is associated with neurological improvement following an AIS. Dendritic spines (DSs) are specialized dendritic protrusions that receive most of the excitatory input in the brain. The deleterious effect of cerebral ischemia on DSs morphology and function has been associated with impaired synaptic transmission and neurological deterioration. However, these changes are reversible if cerebral blood flow is restored on time, and this recovery has been associated with neurological improvement following an AIS. Tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) are two serine proteases that, besides catalyzing the conversion of plasminogen into plasmin in the intravascular and pericellular environment, respectively, are also efficient inductors of synaptic plasticity. Accordingly, recent evidence indicates that both, tPA and uPA, protect DSs from the metabolic stress associated with the ischemic injury, and promote their morphological and functional recovery during the recovery phase from an AIS. Here, we will review data indicating that plasticity-induced changes in DSs and the associated post-synaptic density play a pivotal role in the recovery process from AIS, making special emphasis on the role of tPA and uPA in this process.

Deterioro óseo en la cirrosis: fisiopatología de la osteodistrofia hepática / Bone loss in hepatic cirrhosis: phisiopathology of hepatic osteodystrophy

La cirrosis es un estado avanzado de fibrosis, consecuencia de la progresión de la enfermedad hepática crónica, que se caracteriza por destrucción de la arquitectura hepática y predispone al desarrollo de carcinoma hepatocelular. La cirrosis produce cambios metabólicos complejos que conducen al desarrollo de alteraciones en el metabolismo óseo, conocidas como osteodistrofia hepática. En general, el deterioro de la masa y de la calidad ósea obedecen a factores múltiples, como son: las deficiencias nutricionales, el hipogonadismo, el uso de medicamentos, la deficiencia de vitamina D, la inflamación crónica y la gravedad de la enfermedad. La incidencia de osteoporosis es dos veces más alta en los pacientes con enfermedad hepática crónica, comparada con la de la población general. La tasa de fracturas vertebrales y no vertebrales se encuentra incrementada en la enfermedad hepática crónica, especialmente en mujeres posmenopáusicas. La disponibilidad de la densitometría ósea por absorciometría de rayos X de energía dual ha llevado a un aumento en el diagnóstico de osteoporosis y baja masa ósea en pacientes con enfermedad hepática. Por otra parte, la morfometría vertebral tiene un gran rendimiento para el diagnóstico de fracturas vertebrales asintomáticas. Se hace una actualización de la literatura científica de la enfermedad ósea en casos de hepatopatía crónica y de las recomendaciones para el manejo de pacientes con cirrosis, enfocado en la salud ósea.

Cirrhosis is an advanced stage of fibrosis; it is a consequence of the progression of chronic liver disease, characterized by destruction of architecture and predisposes to the development of hepatocellular carcinoma. Cirrhosis cause complex metabolic changes that led to the development of alterations in bone metabolism known as hepatic osteodystrophy (HO). In general deterioration of bone mass and quality are due to multiple factors such as nutritional deficiencies, hypogonadism, use of medications, vitamin D deficiency, chronic inflammation and severity of the disease. The incidence of osteoporosis is twice as high in patients with chronic liver disease compared with the general population. The rates of vertebral and nonvertebral fractures are increased in chronic liver disease, especially in postmenopausal women. The availability of DXA bone densitometry (BMD-DXA) has led to an increase in the diagnosis of osteoporosis and low bone mass (LBM)in patients with liver disease. Moreover, vertebral morphometry (VMP) has a high diagnostic yield of asymptomatic vertebral fractures. This an update of the literature on bone disease in patient with chronic liver disease and recommendations for the management of patients with cirrhosis, focusing on bone health.

[Sun exposure behaviors and knowledge among Chileans]. / Conocimientos y hábitos de exposición solar de la población Chilena.

BACKGROUND: Ultraviolet light exposure has a pathogenic effect on the development of skin cancer, whose prevalence increases worldwide. In Chile and the rest of the world, preventive educational campaigns are carried out to change high risk sun exposure behaviors. AIM: To study the behavior of the Chilean population towards skin cancer prevention and to identify erroneous preventive practices and concepts. MATERIAL AND METHODS: A survey containing 17 questions about sun exposure behaviors, photoprotective measures and knowledge about ultraviolet radiation and skin cancer was used. It was applied during January and February 2004, to 1,143 subjects (mean age 30 years, 409 males), taking vacations in beach resorts in Chile. RESULTS: The hours of higher sun exposure ranged from 12 AM to 4 PM. Thirty seven percent of subjects were exposed more than 2 hours during this high risk lapse. Women and subjects aged less than 25 years were those with the riskiest behaviors. Fifty four percent used some type of photoprotection and 50% used ocular protection. Seventy percent used creams with sun screen and 74% used a sun protection factor higher than 15. Seventy percent applied the sun screen as recommended. Thirty eight percent had at least one sun burn in the last two years. More than 90% of subjects were aware of the relationship between sun exposure and skin cancer but 60% did not know the hours of higher ultraviolet radiation. The information about sun exposure was obtained from television in 57% of surveyed individuals. CONCLUSIONS: More educational campaigns about the risk of sun exposure are needed to reduce risky behaviors in the Chilean population.

Local induction of angiotensin-converting enzyme in the kidney as a mechanism of progressive renal diseases.

Angiotensin Converting Enzyme (ACE) or Kininase II has a pivotal role determining the local activity of the renin angiotensin and kallikrein kinin systems. Angiotensin II (Ang II), a main hormone of the renin system, has a well established participation as a renal injury agent in models of renal disease with tubulointerstitial fibrosis. Although, since its discovery, ACE has been known to convert Ang I to Ang II, and to inactivate bradykinin (BK), only recently has been emerged evidence for a role of BK with renal protective and antifibrotic effects opposing Ang II. Pertinent to the tubulointerstitial injury, where infiltration and proliferation of macrophages and fibroblast occur, ACE also regulates the levels of the natural hemoregulatory peptide, N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). Owing the importance of tissue ACE, its distribution was studied in several models of renal injury. The results showed increased ACE in proximal tubules and ACE induction in the cell infiltrated tubulointerstitium (macrophages and myofibroblasts) of injured kidneys from hypokalemic, Goldblatt hypertensive, Ang II and phenylefrine infused rats, and in both human diabetic and membranous nephropathies. ACE, in addition to Ang II generation, may play a pathogenic role through the hydrolysis of BK and Ac-SDKP. Thus, local increase in ACE can be a novel mechanism involved in tubulointerstitial renal injury, providing, from an anatomical ground, a pathological basis for the putative deleterious effect of ACE in the diseased kidneys, and the beneficial effect of ACE inhibition.