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Background The neurological manifestations in COVID-19 adversely impact acute illness and post-disease quality of life. Limited data exist regarding the association of neurological symptoms and comorbid individuals. Objective To assess neurological symptoms in hospitalized patients with acute COVID-19 and multicomorbidities. Methods Between June 2020 and July 2020, inpatients aged 18 or older, with laboratory-confirmed COVID-19, admitted to the Hospital São Paulo (Federal University of São Paulo), a tertiary referral center for high complexity cases, were questioned about neurological symptoms. The Composite Autonomic Symptom Score 31 (COMPASS-31) questionnaire was used. The data were analyzed as a whole and whether subjective olfactory dysfunction was present or not. Results The mean age of the sample was 55 ± 15.12 years, and 58 patients were male. The neurological symptoms were mostly xerostomia (71%), ageusia/hypogeusia (50%), orthostatic intolerance (49%), anosmia/hyposmia (44%), myalgia (31%), dizziness (24%), xerophthalmia (20%), impaired consciousness (18%), and headache (16%). Furthermore, 91% of the patients had a premorbidity. The 44 patients with subjective olfactory dysfunction were more likely to have hypertension, diabetes, weakness, shortness of breath, ageusia/hypogeusia, dizziness, orthostatic intolerance, and xerophthalmia. The COMPASS-31 score was higher than that of previously published controls (14.85 ± 12.06 vs. 8.9 ± 8.7). The frequency of orthostatic intolerance was 49% in sample and 63.6% in those with subjective olfactory dysfunction (2.9-fold higher risk compared to those without). Conclusion A total of 80% of inpatients with multimorbidity and acute COVID-19 had neurological symptoms. Chemical sense and autonomic symptoms stood out. Orthostatic intolerance occurred in around two-thirds of the patients with anosmia/hyposmia. Hypertension and diabetes were common, mainly in those with anosmia/hyposmia.

While there is sustained growth of the older population worldwide, ageing is a consistent risk factor for neurodegenerative diseases, such as Parkinson’s-disease (PD). Considered an emblematic movement disorder, PD comprises a miscellany of non-motor symptoms, for which effective management remains an unfulfilled need in clinical practice. Highlighted are the cardiovascular abnormalities, that cause significant burden in PD patients. Evidence suggests that key biological processes underlying PD pathophysiology can be modulated by diet-derived bioactive compounds, such as green propolis, a natural functional food with biological and pharmacological properties. The effects of propolis on cardiac affection associated to PD have received little coverage. In this study, a metabolomics approach and Positron Emission Tomography (PET) imaging were used to assess the metabolic response to diet supplementation with green propolis on heart outcomes of rats with Parkinsonism induced by 6-hydroxydopamine (6-OHDA rats). Untargeted metabolomics approach revealed four cardiac metabolites (2-hydroxybutyric acid, 3-hydroxybutyric acid, monoacylglycerol and alanine) that were significantly modified between animal groups (6-OHDA, 6-OHDA + Propolis and sham). Propolis-induced changes in the level of these cardiac metabolites suggest beneficial effects of diet intervention. From the metabolites affected, functional analysis identified changes in propanoate metabolism (a key carbohydrate metabolism related metabolic pathway), glucose-alanine cycle, protein and fatty acid biosynthesis, energy metabolism, glutathione metabolism and urea cycle. PET imaging detected higher glucose metabolism in the 17 areas of the left ventricle of all rats treated with propolis, substantially contrasting from those rats that did not consume propolis. Our results bring new insights into cardiac metabolic substrates and pathways involved in the mechanisms of the effects of propolis in experimental PD and provide potential novel targets for research in the quest for future therapeutic strategies.

Parkinson’s-disease (PD) is an incurable, age-related neurodegenerative disease, and its global prevalence of disability and death has increased exponentially. Although motor symptoms are the characteristic manifestations of PD, the clinical spectrum also contains a wide variety of non-motor symptoms, which are the main cause of disability and determinants of the decrease in a patient’s quality of life. Noteworthy in this regard is the stress on the cardiac system that is often observed in the course of PD; however, its effects have not yet been adequately researched. Here, an untargeted metabolomics approach was used to assess changes in cardiac metabolism in the 6-hydroxydopamine model of PD. Beta-sitosterol, campesterol, cholesterol, monoacylglycerol, α-tocopherol, stearic acid, beta-glycerophosphoric acid, o-phosphoethanolamine, myo-inositol-1-phosphate, alanine, valine and allothreonine are the metabolites that significantly discriminate parkinsonian rats from sham counterparts. Upon analysis of the metabolic pathways with the aim of uncovering the main biological pathways involved in concentration patterns of cardiac metabolites, the biosynthesis of both phosphatidylethanolamine and phosphatidylcholine, the glucose-alanine cycle, glutathione metabolism and plasmalogen synthesis most adequately differentiated sham and parkinsonian rats. Our results reveal that both lipid and energy metabolism are particularly involved in changes in cardiac metabolism in PD. These results provide insight into cardiac metabolic signatures in PD and indicate potential targets for further investigation.

Abstract There are no clinical interventions to prevent post-injury epilepsy, a common and devastating outcome after brain insults. Epileptogenic events that run from brain injury to epilepsy are poorly understood. Previous studies in our laboratory suggested Proechimys, an exotic Amazonian rodent, as resistant to acquired epilepsy development in post-status epilepticus models. The present comparative study was conducted to assess (1) stroke-related brain responses 24-h and 30 days after cortical photothrombosis and (2) post-stroke epilepsy between Proechimys rodents and Wistar rats, a traditional animal used for laboratory research. Proechimys group showed smaller volume of ischemic infarction and lesser glial activation than Wistar group. In contrast to Wistar rats, post-stroke decreased levels of pro-inflammatory cytokines and increased levels of anti-inflammatory mediators and growth factors were found in Proechimys. Electrophysiological signaling changes assessed by cortical spreading depression, in vitro and in vivo, showed that Wistar’s brain is most severely affected by stroke. Chronic electrocorticographic recordings showed that injury did not lead to epilepsy in Proechimys whereas 88% of the Wistar rats developed post-stroke epilepsy. Science gains insights from comparative studies on diverse species. Proechimys rodents proved to be a useful animal model to study antiepileptogenic mechanisms after brain insults and complement conventional animal models.

ABSTRACT Background: This mini-review aims to summarize and discuss previous and recent advances in the clinical presentation, pathophysiology, diagnosis, treatment, and outcome of SARS-CoV-2-associated peripheral neuropathies. Methods: Literature review. Results: Altogether, 105 articles about SARS-CoV-2-associated neuropathy describing 261 patients were retrieved. Peripheral neuropathy in patients with COVID-19 is frequent and predominantly due to immune mechanisms or neurotoxic side effects of drugs used to treat the symptoms of COVID-19 and, to a lesser extent, due to the compression of peripheral nerves resulting from prolonged bedding in the Intensive Care Unit (ICU) and pre-existing risk factors such as diabetes. SARS-CoV-2 does not cause viral neuropathy. Neurotoxic drugs such as daptomycin, linezolid, lopinavir, ritonavir, hydro-chloroquine, cisatracurium, clindamycin, and glucocorticoids should be administered with caution and patients should be appropriately bedded in the ICU to prevent SARS-CoV-2-associated neuropathy. Patients with Guillain-Barré syndrome (GBS) benefit from immunoglobulins, plasma exchange, and steroids. Conclusions: Neuropathies of peripheral nerves in patients with COVID-19 are frequent and mostly result from immune mechanisms or neurotoxic side effects of drugs used to treat the symptoms of COVID-19 and, to a lesser extent, from the compression of peripheral nerves due to prolonged bedding on the ICU. SARS-CoV-2 does not cause infectious neuropathy.

Abstract Mounting evidence implicates dysfunctional GABAAR-mediated neurotransmission as one of the underlying causes of learning and memory deficits observed in the Ts65Dn mouse model of Down syndrome (DS). The specific origin and nature of such dysfunction is still under investigation, which is an issue with practical consequences to preclinical and clinical research, as well as to the care of individuals with DS and anxiety disorder or those experiencing seizures in emergency room settings. Here, we investigated the effects of GABAAR positive allosteric modulation (PAM) by diazepam on brain activity, synaptic plasticity, and behavior in Ts65Dn mice. We found Ts65Dn mice to be less sensitive to diazepam, as assessed by electroencephalography, long-term potentiation, and elevated plus-maze. Still, diazepam pre-treatment displayed typical effectiveness in reducing susceptibility and severity to picrotoxin-induced seizures in Ts65Dn mice. These findings fill an important gap in the understanding of GABAergic function in a key model of DS.

ABSTRACT There is increasing evidence that COVID-19 can be associated with ischemic stroke (COVID-stroke). The frequency and pathogenesis of COVID-stroke, however, remains largely unknown. This narrative review aimed at summarizing and discussing current knowledge about frequency and pathogenesis of COVID-stroke in 455 patients collected from the literature. COVID-stroke occurs in all age groups and predominantly in males. The anterior circulation is more frequently affected than the posterior circulation. COVID-stroke is most frequently embolic. The severity of COVID-stroke ranges from NIHSS 3 to 32. Cardiovascular risk factors are highly prevalent in patients with COVID-stroke. COVID-stroke occurs simultaneously with the onset of pulmonary manifestations or up to 40 days later. Clinical manifestations of COVID-19 are most frequently mild or even absent. The majority of patients with COVID-stroke achieve complete or partial recovery, but in one-quarter of patients, the outcome is fatal. In conclusion, the frequency of ischemic stroke has not increased since the outbreak of the SARS-CoV-2 pandemic. COVID-stroke predominantly affects males and the anterior circulation. COVID-stroke is multifactorial but predominantly embolic and more frequently attributable to cardiovascular risk factors than to coagulopathy.

The types of epileptiform activity occurring in the sclerotic hippocampus with highest incidence are interictal-like events (II) and periodic ictal spiking (PIS). These activities are classified according to their event rates, but it is still unclear if these rate differences are consequences of underlying physiological mechanisms. Identifying new and more specific information related to these two activities may bring insights to a better understanding about the epileptogenic process and new diagnosis. We applied Poincaré map analysis and Recurrence Quantification Analysis (RQA) onto 35 in vitro electrophysiological signals recorded from slices of 12 hippocampal tissues surgically resected from patients with pharmacoresistant temporal lobe epilepsy. These analyzes showed that the II activity is related to chaotic dynamics, whereas the PIS activity is related to deterministic periodic dynamics. Additionally, it indicates that their different rates are consequence of different endogenous dynamics. Finally, by using two computational models we were able to simulate the transition between II and PIS activities. The RQA was applied to different periods of these simulations to compare the recurrences between artificial and real signals, showing that different ranges of regularity-chaoticity can be directly associated with the generation of PIS and II activities.

Evidence is accumulating that SARS-CoV-2 infections and SARS-CoV-2 vaccinations can induce Guillain-Barre syndrome (GBS). More than 400 GBS cases after SARS-CoV-2 infection respectively vaccination have been reported as per the end of 2021. GBS is usually diagnosed according to the Brighton criteria, but also the Besta criteria or Hadden criteria are applied. The diagnosis can be supported by MRI with contrast medium of the cranial or spinal nerves showing enhancing nerve roots. As GBS can be complicated by autonomic dysfunction such as pupillary abnormalities, salivatory dysfunction, reduced heart rate variability, bowel disturbance (constipation, diarrhea), urinary hesitancy, urinary retention, or impotence, it is crucial to investigate GBS patients for autonomic involvement. Before diagnosing GBS various differentials need to be excluded, including neuropathy as a side effect of the anti-SARS-CoV-2 medication, critical ill neuropathy in COVID-19 patients treated on the ICU, and compression neuropathy in COVID-19 patients requiring long-term ventilation.

A classic method to evaluate autonomic dysfunction is through the evaluation of heart rate variability (HRV). HRV provides a series of coefficients, such as Standard Deviation of n-n intervals (SDNN) and Root Mean Square of Successive Differences (RMSSD), which have well-established physiological associations. However, using only electrocardiogram (ECG) signals, it is difficult to identify proper autonomic activity, and the standard techniques are not sensitive and robust enough to distinguish pure autonomic modulation in heart dynamics from cardiac dysfunctions. In this proof-of-concept study we propose the use of Poincaré mapping and Recurrence Quantification Analysis (RQA) to identify and characterize stochasticity and chaoticity dynamics in ECG recordings. By applying these non-linear techniques in the ECG signals recorded from a set of Parkinson’s disease (PD) animal model 6-hydroxydopamine (6-OHDA), we showed that they present less variability in long time epochs and more stochasticity in short-time epochs, in their autonomic dynamics, when compared with those of the sham group. These results suggest that PD animal models present more “rigid heart rate” associated with “trembling ECG” and bradycardia, which are direct expressions of Parkinsonian symptoms. We also compared the RQA factors calculated from the ECG of animal models using four computational ECG signals under different noise and autonomic modulatory conditions, emulating the main ECG features of atrial fibrillation and QT-long syndrome.

Depression is the most frequent psychiatric comorbidity seen in mesial temporal lobe epilepsy (MTLE) patients with hippocampal sclerosis (HS). Moreover, the HS is the most frequent pathological hallmark in MTLE-HS. Although there is a well-documented hippocampal volumetric reduction in imaging studies of patients with major depressive disorder, in epilepsy with comorbid depression, the true role of the hippocampus is not entirely understood. This study aimed to verify if patients with unilateral MTLE-HS and the co-occurrence of depression have differences in neuronal density of the hippocampal sectors CA1–CA4. For this purpose, we used a histopathological approach. This was a pioneering study with patients having both clinical disorders. However, we found no difference in hippocampal neuronal density when depression co-occurs in patients with epilepsy. In this series, CA1 had the lowest counting in both groups, and HS ILAE Type 1 was the most prevalent. More studies using histological assessments are needed to clarify the physiopathology of depression in MTLE-HS.

SARS-CoV-2 vaccinations are not free from side effects. Usually, they are mild or moderate but occasionally severe. One of these severe side effects is Guillain-Barré syndrome (GBS). This review summarizes and discusses GBS as a side effect of SARS-CoV-2 vaccinations (SCoVaG) based on recent research reports. Altogether, nine articles reporting 18 patients with SCoVaG were identified and one more report on another patient is under review. The age for the studies ranged between 20-86y. Nine patients were male, and ten were female. In all 19 patients, SCoVaG developed after the first dose of the vaccine. The Astra Zeneca vaccine was used in fourteen patients, the Pfizer vaccine in four patients, and the Johnson & Johnson vaccine was applied in one patient. The latency between vaccination and onset of GBS ranged from 3h to 39d. The treatment of SCoVaG included IVIGs (n=13), steroids (n=3), or no therapy (n=3). Six patients required mechanical ventilation. Only a single patient recovered completely and partial recovery was achieved in nine patients. In conclusion, GBS may develop time-linked to the first dose of a SARS-CoV-2 vaccination. Though a causal relationship between SARS-CoV-2 vaccinations and SCoVaG remains speculative, more evidence is in favour than against it.

Abstract In this letter we raise several concerns regarding the interesting article by Walter and Krämer about rhomb-encephalitis as a complication two months after the vaccination with an mRNA-based SARS-CoV_2 vaccine. The causal link between the vaccination and encephalitis remained unproven, a SARS-CoV-2 infection, Bickerstaff encephalitis were not excluded, the MRI rather suggests brainstem-encephlaitis than pure rhomb-encephalitis, and the cerebro-spinal fluid was not investigated for cytokines or glial markers. Neurologists are called to make all available effort to convincingly evaluate the etiology and the pathophysiological background of an undetermined condition.

Coronavirus disease (COVID-19) usually starts with pulmonary signs and symptoms. However, in some cases, the initial clinical presentations are extrapulmonary. This literature review aimed at summarizing and discussing the extrapulmonary onset manifestations of COVID-19. The most frequent initial extrapulmonary manifestations include hypogeusia, hyposmia, non-specific abdominal symptoms, corneal congestion, and deep venous thrombosis. Several rarer extrapulmonary manifestations in locations such as the brain, peripheral nerves, muscles, eyes, ears, myocardium, intestines, skin, or vessels have been additionally reported as onset presentations of COVID-19. In conclusion, it is crucial for clinicians and health care providers to consider extrapulmonary presentations at the onset of COVID-19 to avoid overlooking the infection and contributing to the spread of the disease.

ABSTRACT Purpose To evaluate the preventive cardioprotective effects of resveratrol and grape products, such as grape juice and red wine, in animal model of cardiac ischemia and reperfusion. Methods Male Wistar rats orally pretreated for 21-days with resveratrol and grape products were anesthetized and placed on mechanical ventilation to surgically induce cardiac ischemia and reperfusion by obstruction (ischemia) followed by liberation (reperfusion) of blood circulation in left descending coronary artery. These rats were submitted to the electrocardiogram (ECG) analysis to evaluate the effects of pretreatment with resveratrol and grape products on the incidence of ventricular arrhythmias (VA), atrioventricular block (AVB) and lethality (LET) resulting from cardiac ischemia and reperfusion. Results It was observed that the incidence of AVB was significantly lower in rats pretreated with resveratrol (25%), grape juice (37.5%) or red wine (12.5%) than in rats treated with saline solution (80%) or ethanol (80%). Similarly, incidence of LET was also significantly lower in rats pretreated with resveratrol (25%), grape juice (25%) or red wine (0%) than in rats treated with saline solution (62.5%) or ethanol (75%). Conclusions These results indicate that the cardioprotective response stimulated by resveratrol and grape products prevents the lethal cardiac arrhythmias in animal model of ischemia and reperfusion, supporting the idea that this treatment can be beneficial for prevention of severe cardiac arrhythmias in patients with ischemic heart disease.

Abstract Purpose To evaluate whether the attenuation of mitochondrial Ca2+ overload produced by pharmacological blockade of mitochondrial Ca2+ uniporter (MCU) protects the myocardium against injuries caused by cardiac ischemia and reperfusion (CIR). Methods CIR was induced in adult male Wistar rats (300-350 g) by occlusion of the left anterior descendent coronary artery (10 min), followed by reperfusion (120 min). Rats were treated with different doses of MCU blocker ruthenium red (RuR), administered 5 min before ischemia or reperfusion. Results In untreated rats, the incidences of ventricular arrhythmias (VA), atrioventricular block (AVB) and the lethality (LET) induced by CIR were 85%, 79% and 70%, respectively. In rats treated with RuR before ischemia, the incidences of VA, AVB and LET were significantly reduced to 62%, 25% and 25%, respectively. In rats treated with RuR after ischemia, the incidences of VA, AVB and LET were significantly reduced to 50%, 25% and 25%, respectively. Conclusion The significant reduction of the incidence of CIR-induced VA, AVB and LET produced by the treatment with RuR indicates that the attenuation of mitochondrial Ca2+ overload produced by pharmacological blockade of MCU can protect the myocardium against injuries caused by CIR.

Males of Proechimys guyannensis, a rodent living in the Amazon rainforest are studied in biomedical research because of their antiepileptogenic mechanism. Females are usually taken from experimental designs, because of limited data of this sex. This study aimed to characterize the estrous cycle to include females together with males in research in a more balanced approach. The estrous cycle of P. guyannensis based through exfoliative cytology, determination of the vaginal occlusion membrane state, and hormonal analysis. In this study, cytological analyses of vaginal smears were performed for three months, three times a day. The observed length of the estrous cycle was 247 ± 81 h (mean ± SD) with a reproductive phase of 27.08 ± 17.39 h (estrus stage). We observed a frequent presence of both the open and closed states of the vaginal membrane in the estrus stage (fertile period) although only the open stage is a prerequisite for successful copulation. High levels of progesterone and estradiol were detected in proestrus. Levels of follicle-stimulating hormone peaked at the estrus stage. These data will establish the parameters and subsidies to set the grounds for future research either for investigating the biology of this species or to use P. guyannensis in research that previously excluded females. Information regarding female Proechimys is relevant to not only describe the species but also explain the interaction between sex hormones and physiological responses. Moreover, the present results will enhance rigor and reproducibility in preclinical studies. In conclusion, P. guyannensis reproductive cycles can occur spontaneously and cyclically independent of mating stimulation and the high levels of FSH in the estrus stage, suggest that ovulation occurs in the late phase of the estrus.

Abstract Human hippocampal slice preparations from patients with temporal lobe epilepsy (TLE) associated with hippocampal sclerosis (HS) are excellent material for the characterization of epileptiform-like activity. However, it is still unknown if hippocampal regions as cornu Ammonis (CA) 1, CA3 and CA4, generate population epileptiform-like activity. Here, we investigated epileptiform activities of the subiculum, CA1, CA2, CA3, CA4 (induced by elevation of extracellular potassium concentration) and the dentate gyrus (induced with hilar stimulation and elevation of potassium concentration) from sclerotic hippocampi of patients with drug-resistant TLE. Five types of epileptiform-like activity were observed: interictal-like events; periodic ictal spiking; seizure-like events; spreading depression-like events; tonic seizure-like events and no activity. Different susceptibilities to generate epileptiform activity among hippocampal regions were observed; the dentate gyrus was the most susceptible region followed by the subiculum, CA4, CA1, CA2 and CA3. The incidence of epileptiform activity pattern was associated with specific regions of the hippocampal formation. Moreover, it was observed that each region of the hippocampal formation exhibits frequency-specific ranges in each subfield of the sclerotic human tissue. In conclusion, this study demonstrates that epileptiform-like activity may be induced in different regions of the hippocampal formation, including regions that are severely affected by neuronal loss.

Abstract Purpose: To evaluate the cardioprotective response of the pharmacological modulation of β-adrenergic receptors (β-AR) in animal model of cardiac ischemia and reperfusion (CIR), in spontaneously hypertensive (SHR) and normotensive (NWR) rats. Methods: CIR was induced by the occlusion of left anterior descendent coronary artery (10 min) and reperfusion (75 min). The SHR was treated with β-AR antagonist atenolol (AT, 10 mg/kg, IV) 5 min before CIR, and NWR were treated with β-AR agonist isoproterenol (ISO, 0.5 mg/kg, IV) 5 min before CIR. Results: The treatment with AT increased the incidence of VA, AVB and LET in SHR, suggesting that spontaneous cardioprotection in hypertensive animals was abolished by blockade of β-AR. In contrast, the treatment with ISO significantly reduced the incidence of ventricular arrhythmia, atrioventricular blockade and lethality in NWR (30%, 20% and 20%, respectively), suggesting that the activation of β-AR stimulate cardioprotection in normotensive animals. Serum CK-MB were higher in SHR/CIR and NWR/CIR compared to respective SHAM group (not altered by treatment with AT or ISO). Conclusion: The pharmacological modulation of β-AR could be a new cardioprotective strategy for the therapy of myocardial dysfunctions induced by CIR related to cardiac surgery and cardiovascular diseases.