Abstract One of the most dreadful complications that can occur during the course of COVID-19 is the cytokine storm—also known as cytokine release syndrome—a form of systemic inflammatory response syndrome triggered by SARS-CoV-2 infection. The cytokine storm is an activation cascade of auto-amplifying cytokines, which leads to excessive activation of immune cells and generation of pro-inflammatory cytokines. It occurs when large numbers of white blood cells are activated and release inflammatory cytokines, in turn activating even more white blood cells, finally resulting in an exaggerated pro-inflammatory–mediated response and ineffective anti-inflammatory control, leading to tissue damage, multiorgan failure, acute respiratory distress syndrome and death. Although cytokine storm pathogenesis is multifactorial, we hypothesize there is a close association between hypoxemia and cytokine storms in COVID-19, although it is difficult to establish the direction of this relationship. Most probably they coexist and, given enough time, one triggers the other in a chain reaction. Careful analysis of the day-to-day clinical evolution of COVID-19 indicates that there are short and slight periods of hypoxemia (confirmed by pulse oximetry and arterial gasometry), even on the day of the onset of persistent cough and/or shortness of breath. We propose the use of continuous positive airway pressure in early stages of COVID-19, at the onset of respiratory symptoms. This non-invasive ventilation method may be useful in individualized treatments to prevent early hypoxemia in COVID-19 patients and thus avoid triggering a cytokine storm. We believe such an approach is relevant everywhere, and in Cuba in particular, since the country has initiated national production of mechanical ventilation systems, including non-invasive ventilators. Moreover, as Cuba’s COVID-19 protocols ensure early patient admission to isolation centers or hospitals, clinicians can prescribe the early use of continuous positive airway pressure as soon as respiratory symptoms begin, averting early hypoxemia and its triggering effect on cytokine storm development, and consequently, avoiding acute respiratory distress syndrome, multi-organ failure, and death.

ABSTRACT The actual Coronavirus Disease 2019 (COVID-19) infection is an ongoing pandemic, characterized by high morbidity and mortality produced by SARS-CoV-2 virus. Studies reported a stroke frequency around 5-20% in infected patients; however, SNC invasion and pathophysiological mechanisms related to stroke in COVID-19 patients are still unknown. Several studies have demonstrated that SARS-CoV-2 infection is linked to a prothrombotic state causing venous and arterial thromboembolism. Also, an overstated inflammatory response with recruitment of blood cells and disproportioned secretion of proinflammatory cytokines has been reported. Finally, cardioembolism and hypoxia have been proposed as surrogate mechanisms. It is essential to define the pathophysiological mechanisms of stroke during the infection in order to apply more specific treatments to avoid further stroke complications.

RESUMEN La actual pandemia de COVID-19 causada por el virus SARS-CoV-2, se caracteriza por una alta morbilidad y mortalidad. Algunos estudios han reportado que la frecuencia de ictus en pacientes infectados con el virus oscila entre un 5-20 %. A pesar de estas cifras alarmantes, las vías por las cuales el virus llega al sistema nervioso central y los mecanismos fisiopatológicos por los que puede ocurrir un ictus en estos pacientes no han sido totalmente esclarecidos. Numerosos estudios han demostrado que la infección por SARS-CoV-2 está asociada a un estado protrombótico, capaz de causar un tromboembolismo arterial y venoso. Además, se ha reportado una respuesta inflamatoria exacerbada, con reclutamiento de células sanguíneas y una secreción desproporcionada de citoquinas proinflamatorias. También la hipoxia y fenómenos cardioembólicos han sido propuestos como posibles mecanismos. Es esencial definir con exactitud los mecanismos fisiopatológicos que vincula la infección por SARS-CoV-2 con la ocurrencia del ictus, con la finalidad de aplicar tratamientos más específicos y evitar futuras complicaciones.

ABSTRACT Introduction: Several studies investigating blood biomarkers such as C-reactive protein (CRP) in the prognosis and mortality of stroke have not been conclusive. This may be related to the fact that age has not been taken into account for these analyses. Objective: In the present study, we evaluated the possible relationship of blood markers with the age and clinical characteristics of ischemic stroke patients. Methods: Two groups of acute ischemic stroke patients (≤ 55 years and > 55 years of age) who were paired with a control group were included. CRP, alpha 1 antitrypsin (AAT), complements C3 and C4, microalbuminura, ceruloplasmin, glucose, cholesterol, triglycerides, glutamic-piruvic transaminase (GPT), glutamic-oxalacetic transaminase (GOT), gamma glutamiltranspeptidase (GGT), creatinine, and uric acid were determined. Other clinical information, including NIH stroke scale was collected. Results: AAT, ceruloplasmin, microalbuminuria, GPT, GOT and GGT were significantly increased with respect to control subjects in both age groups. Nevertheless, CRP was increased only in patients older than 55 years. CRP and age were directly correlated in stroke patients, but not in the control group joint analysis of age and NIHSS revealed a tendency towards even higher CRP values in older patients with more severe neurological impairment. Levels of CRP increased significantly with age according to NIH score. Conclusions: Age should be considered when evaluating the usefulness of CRP and other blood biomarkers as clinical tools for predicting long or short-term neurological outcome or stroke recurrence events in ischemic stroke patients.

RESUMEN Introducción: Los estudios sobre marcadores sanguíneos incluido la proteína C reactiva (PCR) en el pronóstico y mortalidad del ictus no han sido concluyentes, quizás porque en sus análisis no se ha tenido en cuenta la edad los pacientes. Objetivo: Evaluar la relación de los marcadores sanguíneos con la edad y características clínicas de pacientes con ictus isquémico. Métodos: Se incluyeron en el estudio 2 grupos de pacientes con ictus isquémico (( y > 55 años) quienes fueron pareados con grupos controles. Fueron determinados: PCR, alfa 1 antitripsina (AAT), complementos C3 y C4, microalbuminuria, ceruloplasmina, glucosa, colesterol, triglicéridos, transaminasa glutámico-pirúvico (TGP), transaminasa glutámico-oxalacético (TGO), gamma glutamiltranspeptidasa (GGT), creatinina, y ácido úrico. También, se recogió información clínica (escala neurológica, etiología y localización del ictus). Resultados: La AAT, ceruloplasmina, microalbuminuria, TGP, TGO y GGT aumentaron significativamente respecto al grupo control de ambos grupos de estudio. Sin embargo, la PCR se incrementó solamente en pacientes mayores de 55 años. La PCR se correlacionó directamente con la edad de los pacientes, pero no en el grupo control. A su vez, se observó una tendencia hacia el aumento de la PCR en pacientes mayores de 55 años con mayor la severidad neurológica. Los valores de PCR se incrementaron estadísticamente con la edad de acuerdo al déficit neurológico. Conclusiones: La edad debiera ser considerada en la evaluación de la utilidad de la PCR y de otros marcadores como herramientas clínicas para predecir un desenlace neurológico fatal o recurrencia de nuevos eventos en pacientes con ictus isquémico.

ABSTRACT From 1991 to 1993, an epidemic of optic and peripheral neuropathy— the largest of the century—broke out in Cuba, affecting more than 50,000 people. Initially the main clinical features were decreased visual acuity, central and cecocentral scotomas, impaired color vision and absence of the papillomacular bundle. Later, peripheral and mixed optic–peripheral forms began to appear. Due to the magnitude of the epidemic, the Cuban government requested help from the international community at the 46th World Health Assembly in 1993. PAHO and WHO immediately responded by sending a mission of international experts. Several hypotheses regarding the pathogenesis of Cuban epidemic neuropathy were put forward including: toxic, nutritional, genetic and infectious. The authors refer to extensive studies by researchers sponsored by the Cuban government and PAHO/WHO, joined by scientists from several other countries, including the USA. This paper describes their multidisciplinary work, particularly devoted to investigating the hypothesis of a primary toxic–nutritional cause of the epidemic. Clinical aspects, such as case definition and clinical description, were vital issues from the start. Cuban physicians who first examined patients received a clear impression of its toxic–nutritional origin, later confirmed by international experts. Research then focused on the mechanisms contributing to damage under the toxic–nutritional hypothesis. These included injuries to the mitochondrial oxidative phosphorylation pathway, nutritional deficiencies, excitotoxicity, formate toxicity and dysfunction of the blood–brain barrier. It was expected that the results of such international collaboration into this major health problem would also shed more light on mechanisms underlying other nutritional or tropical myeloneuropathies.

ABSTRACT Arterial hypertension is the most prevalent non-communicable disease worldwide, and has long been recognized as a major risk factor for cardiovascular and cerebrovascular diseases. High blood pressure has deleterious consequences on the main target organs (heart, kidney, brain), and several studies have shown that brain damage is more frequent than heart and kidney involvement. Silent lesions can subsequently lead to cognitive decline, dementia or stroke. Nevertheless, screening for subclinical brain deterioration is rarely performed because it requires imaging techniques whose scarcity and high cost rule out routine use by primary care physicians. The challenge is thus early detection of asymptomatic brain lesions with cost-effective techniques to test thousands of patients in the community. In this review we present an update on the status of biomarkers explored as alternatives for early detection of brain damage in arterial hypertension, potentially useful to identify patients needing referrals for brain MRI: ambulatory blood pressure monitoring, quantitative retinal microvascular assessment, quantitative electroencephalography, carotid ultrasonography, neurocognitive studies and blood-based biomarkers. We place special emphasis on blood-based biomarkers, for which our group reported the first preliminary evidence of an association between serum neuron-specific enolase and severity of white matter lesions in patients with essential hypertension. This review consequently explores the potential for blood-based biomarkers to provide a faster, cheaper and more accessible early-detection solution, particularly beneficial in resource-limited settings such as Cuba’s.

A case-control prospective study was conducted in patients and controls to define the main lipid disorders in patients with cerebral infarction and to compare their relation with vascular risk factors. Significantly more elevated values of triglycerides, low density lipoproteins and atherogenic index were observed in patients compared with controls. There were no differences between the two groups as regards total cholesterol and low density lipoproteins. Arterial hypertension as a risk factor was associated with lower values of high density lipoproteins and with more elevated values of low density lipoproteins, triglycerides, very low density lipoproteins and atherogenic index. No relation was found between arterial hypertension and total cholesterol. It was concluded that it was necessary to control lipids in cerebral infarction.

Se realizó un estudio prospectivo tipo caso-control en pacientes y controles, para definir los principales desórdenes lipídicos en pacientes con infarto cerebral y comparar la relación de estos con factores de riesgo vascular. Se observaron valores significativamente más elevados de triglicéridos, lipoproteínas de baja densidad e índice aterogénico, en los pacientes respecto de los controles. No hubo diferencias para el colesterol total ni las lipoproteínas de muy baja densidad entre los 2 grupos. La hipertensión arterial como factor de riesgo se asoció con valores más bajos de lipoproteínas de alta densidad, y más elevados de lipoproteínas de baja densidad, triglicéridos, lipoproteínas de muy baja densidad e índice aterogénico. No se encontró relación entre la hipertensión arterial y el colesterol total. Se concluyó que era necesario controlar los lípidos en el infarto cerebral.

Among the metabolism inborn errors, there are the lysosomal storage diseases or lysosomal enzymopathies that are characterized by an specific enzymatic deficiency, excretion of metabollites in urine and accumulation of non-degraded compounds in various organs and tissues causing their dysfunction. These diseases have a recessive autosomal heredity, except for Fabry´s disease and Hunter’s disease in which the pattern of heredity is chromosome X-linked. These diseases have a low incidence in general although there are populations where they show a high incidence. Their importance lies in what they represent as a health problem because of the poor quality of life of these patients and their early death, therefore, it is necessary to prevent the birth of new infants affected with these diseases.

Dentro de los errores innatos del metabolismo se encuentran las enfermedades de almacenamiento lisosomal o enzimopatías lisosomales, las cuáles se caracterizan por un déficit enzimático específico, la excreción de metabolitos por la orina y la acumulación de los compuestos no degradados en diferentes órganos y tejidos que ocasionan la disfución de éstos. Tienen un patrón de herencia autosómico recesivo, excepto para la enfermedad de Fabry y la enfermedad de Hunter en las que el patrón de herencia está ligado al cromosoma X. Estas enfermedades tienen una baja incidencia en general, aunque hay poblaciones donde algunas de ellas tienen una alta incidencia. Su importancia radica en la magnitud que representan como problema de salud, por la pobre calidad de vida de esos pacientes, así como su fallecimiento prematuro, motivo por el cual hay que evitar los nacimientos de nuevos niños afectados.

We studied 62 patients aged 48 years as an average and diagnosed with bilateral optical neuropathy during an epidemics in Pinar del Río province. Of these patients, 42 showed the optical form whereas 20 had the mixed form of optical neuropathy. We researched into the levels of formate and folate in serum and cerebrospinal fluid samples and we found a marked deficiency of folates in more than 50 % of samples and high formate concentration levels in almost 25 % of samples. We concluded that nutritional shortages that lead to a reduction of folates, and the intake of small amounts of methanol in alcoholic drinks could lead to lacking energetic states which would facilitate that the optical nerve be affected and the epidemic optical neuropathy appear.

Se estudiaron 62 pacientes con neuropatía óptica bilateral, diagnosticados durante una epidemia en la provincia Pinar del Río, con una edad media de 48 años. De ellos, 42 tenían la forma óptica y 20 la forma mixta. Se investigaron los niveles de formato y folatos en muestras de suero y líquido cefalorraquídeo. Se encontró una marcada deficiencia de folatos en más de 50 % de las muestras y los niveles de formato con una elevación de su concentración en casi 25 % de las muestras. Se concluyó que deficiencias nutricionales que ocasionan la disminución de folatos y la ingestión de pequeñas cantidades de metanol en las bebidas alcohólicas, podían contribuir a la producción de estados energéticos deficitarios que facilitarían la afectación del nervio óptico y la aparición de la neuropatía óptica epidémica.

It was studied the aminoacids pattern in serum and cerebrospinal fluid of 12 and 8 patients, respectively, suffering from optic epidemic neuropathy diagnosed between 1995 and 1997 (endemic period). The cerebrospinal fluid of 16 patients diagnosed during the epidemic (1992) was also studied. The analysis of aminoacids in serum and cerebrospinal fluid was made by high resolution liquid chromatography with fluorescent detection, previous derivation with orthofthallic aldehyde. As in the previous study, no important deficiencies of the essential aminoacids were observed in the serum of the studied patients. Lower concentrations of threonine, aspartic acid and taurine were found in the serum of patients with epidemic optic neuropathy diagnosed in the endemic period. Taurine plays an important role in the structure and function of photoreceptors of the retina. It is synthesized in the necessary amounts in man, so it must be supplied in the diet. As it is only present in food of animal origin, it is considered that the deficiency of taurine may contribute to the development of optic epidemic neuritis in our patients. Samples of cerebrospinal fluid were analyzed during the epidemic and endemic periods and it was observed an increase of the glutamic and aspartic acid in the epidemic period and of glutamic acid during the endemia. The excess of excitotoxic aminoacids in the cerebrospinal fluid supports the previous neurocognitive studies that suggested the affection of the central nervous system in these patients.

Se estudió el patrón de aminoácidos en suero y líquido cefalorraquídeo (LCR) de 12 y 8 pacientes respectivamente, con neuropatía óptica epidémica diagnosticada entre 1995-1997 (período endémico). Además se estudió el LCR de 16 pacientes diagnosticados durante la epidemia (1992). El análisis de aminoácidos en suero y LCR se llevó a cabo por cromatografía líquida de alta resolución con detección fluorescente, previa derivatización con aldehído ortoftálico. Al igual que en el estudio anterior, no se observaron deficiencias importantes de los aminoácidos esenciales en el suero de los pacientes estudiados, aunque se encontraron concentraciones menores de treonina, ácido aspártico y taurina en el suero de los pacientes con neuropatía óptica epidémica diagnosticada en el período endémico. La taurina desempeña una función importante en la estructura y función de los fotorreceptores de la retina. En el hombre no es sintetizada en las cantidades necesarias, por lo que debe ser suplida en la dieta. Por encontrarse solamente en alimentos de origen animal, consideramos que la deficiencia de taurina podría ser un factor contribuyente al desarrollo de la neuritis óptica epidémica en nuestros pacientes. Se analizaron además muestras de LCR en los períodos epidémico y endémico, se observó aumento de ácido glutámico y aspártico en el período epidémico y de ácido glutámico durante la endemia. La presencia de un exceso de aminoácidos excitotóxicos en el LCR apoya los estudios neurocognitivos previos que sugerían afección del sistema nervioso central en estos pacientes.