Lupine Publishers| Schizophrenia, Carbonyl Stress and Carnosine

 Lupine Publishers| Journal of Neurology and Brain Disorders

Abstract

Recent research suggests that schizophrenia is associated with the development of an advanced aging phenotype (carbonyl stress) and erythrocytes from schizophrenics also exhibit symptoms of cellular aging (increased levels of glycated proteins and ubiquitinated proteins), possibly due to excessive glycolysis-induced methylglyoxal (MG) generation. The endogenous dipeptide carnosine (beta-alanyl-L-histidine), which can delay cellular aging, suppress glycolysis and inhibit MG-induced protein glycation, also exerts some beneficial effects towards schizophrenia. Carnosine is present in human erythrocytes and the olfactory bulb (olfactory dysfunction is associated with schizophrenia). It is suggested that enhanced erythrocyte and olfactory carnosine levels may be more therapeutic towards schizophrenia, if carnosine was also administered intra-nasally to avoid serum carnosinase activity.

 

Keywords:Carnosine; glycation; methylglyoxal; erythrocyte; aging; nasal administration

Introduction

 

Schizophrenia and carbonyl stress

Many studies have indicated a relationship between schizophrenia and dysfunctional energy metabolism [1-3] whilst others indicate that carbonyl stress and generation of advanced glycation end-products (AGEs) accompany schizophrenia [4,5]. Furthermore, a recent study suggests that changes in glycolysis and accelerated cellular aging in glial cells contribute to the condition [6]. The glycolytic intermediates glyceraldehyde-3-phosphate and dihydroxyacetone-phosphate are the most likely sources of AGE formation due to their ability to spontaneously decompose into methylglyoxal (MG). MG is well recognized as a major glycating agent and is thought to be responsible for much macromolecular modifications associated with type-2 diabetes and age-related neurodegenerative conditions [7,8]. However, there is no clear evidence whether suppression of MG generation, via decreased glycolytic activity, has any effect on schizophrenia. The suggestion that schizophrenia seems to be associated with accelerated cellular aging [6] is supported by another recent observation reporting that erythrocytes obtained from schizophrenics contain elevated mounts of ubiquitinated proteins [9]. This might arise from either increased generation of targets for ubiquitination (e.g. aberrant polypeptides or denatured misfolded proteins), or decreased de-ubiquitinating activity, or decreased proteasomal proteolytic activity which would normally complete polypeptide destruction. Interestingly, MG and other agents responsible for carbonyl stress, also induce protein cross-linking which not only renders the target protein less susceptible to proteolytic attack but can also result in inhibition of proteasome activity generally [10]. Thus, it is conceivable that excessive glycolysis can provoke an aging phenotype (AGE accumulation and proteostatic dysfunction) via increased MG generation; such a relationship has been demonstrated in mice fed a high glycemic- index diet [11]. Never-the-less it is necessary to show whether glycation compromises proteostatic in erythrocytes from schizophrenics.

 

Erythrocytes and schizophrenia

A number of recent papers have revealed that erythrocytes obtained from patients with neurological problems, such as Alzheimer’s Disease (AD) and Parkinson’s Disease (PD), exhibit symptoms typical of aging cells in general. For example, compromised proteolytic activity and MG detoxification were detected in AD erythrocytes [12] and accumulation of aggregated protein occurs in red cells from PD patients [13]. Furthermore, dysfunctional energy metabolism, especially in relation to glycolysis culminating in carbonyl stress, are now regarded as characteristics of both AD and PD [14,15]. Therefore, it is not surprising that evidence of carbonyl stress is also accompanied by enhanced protein glycation [16] and accumulation of ubiquitinated proteins [9] in erythrocytes (and possibly other cells) obtained from schizophrenic individuals [17]. Moreover, one of the glycated proteins from “schizophrenic” red cells has been identified as a selenium-binding protein (SBP1) [18]; dysfunctional selenium metabolism has long been regarded as an important contributor to schizophrenia [19,20]. Selenium plays an important role in Sulphur metabolism required for synthesis of antioxidant enzymes such as glutathione peroxidase [21]. Thus, one is beginning to understand the relationship between AGE generation, carbonyl and oxidative stress and the apparently disparate biochemical attributes to schizophrenia.

 

Carnosine, carbonyl stress and schizophrenia

That erythrocytes can contain elevated amounts of MG and glycated proteins suggests the possibility that such red cells could become systemic sources of MG and AGEs to the brain and other tissues, following MG-induced eryptosis [22]. Consequently, it is important to consider whether suppression of carbonyl stress, not only in erythrocytes but in astrocytes and glia, could possibly be a therapeutic strategy. The naturally occurring dipeptide carnosine (beta-alanyl-L-histidine) has been shown to suppress glycolysis in cultured cells [23,24], delay replicative senescence [25], stimulate proteolysis of long-lived proteins in late passage cells [26] and inhibit AGE formation [27]. Furthermore, there is one study showing that schizophrenics subjected to dietary supplementation with carnosine exhibited some beneficial effects [28], possibly due to the dipeptide’s pluripotent properties [29]. It is also interesting to note that

a) Olfactory dysfunction is also associated with schizophrenia [30,31] and

b) Carnosine is enriched in the olfactory bulb [32].

Thus, one has to consider whether raising olfactory carnosine levels could also be useful. However, all studies employing dietary carnosine supplementation are subject to the problem of the presence of serum carnosinase activity which would destroy the dipeptide [33]. There is an alternative route however, which is to use an intra-nasal approach. This could involve a nasal spray of a carnosine solution; another approach could involve use of carnosine powder. Indeed “snorting” carnosine could be far more useful than most white powders some people use, be it illegal drugs or “medicinal snuff “of old. In fact, intra-nasal delivery of potential therapeutic agents is currently being explored [34] with respect to neurodegenerative conditions, as proposed many years ago [35].

Carnosine has been detected in human erythrocytes [36] but in lower amounts when obtained from elderly individuals [36]. It is presumed that red cell carnosine is synthesized (from betaalanine and histidine) during erythropoiesis. Consequently, it would be useful to determine whether dietary supplementation with carnosine or beta-alanine raises erythrocyte carnosine levels and whether there are any beneficial effects with respect to the recognized changes in “schizophrenic” erythrocytes. Additionally, it is suggested that any carnosine (dietary or nasally administered) supplementation period should last for at least 120 days to ensure maximal numbers of carnosine-enriched erythrocytes. It has been proposed that excessive and continuous glycolysis in erythrocytes enhances red cell MG levels, and thus also facilitate delivery of erythrocyte MG to the tissues including the brain [22]. Consequently, it will be also important to determine whether such supplementation protocols decrease carbonyl stress and MG levels not only in red cells but the tissues generally including glia [6].

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Lupine Publishers| The Arapetic of the use of the Gum of Mascar in your Different Presentations to Minimize the Dream Inerance and Deprivation

 Lupine Publishers| Journal of Neurology and Brain Disorders

 

 

Abstract

Introduction: Sleep is defined as the natural, periodic and reversible decrease in perception of the external environment, with the preservation of a certain degree of reactivity to the environment and autonomous functions. Sleep consists of 2 phases, REM phase and NREM phase, these phases alternate at night in the form of five to six cycles; of which the NREM phase is 75% presented and the REM by 25%.

Thertita mark: Caffeine is a readily available short-acting stimulant that has been shown to reduce some of the deficits associated with sleep loss. With the rubber mark the absorption is carried out on the oral mucosa, which generates a greater bioavailability of the active substance and an immediate mechanism of action. The effective response dose can range from 100 mg to 200 mg and the effect arises from 6 min of administered the active substance. It is important to note that the dose of caffeine in chewing gum is directly proportional to the effects on sleep inertia, as well as the duration and maintenance of them.

Discussion: Being able to analyze the mechanisms of action of caffeine on sleep inertia, helps us to make a comparison of chewing gum with caffeine vs placebo (simple gum). Chewing generates for a short period of time the maintenance of performance on simple and complex tasks and improves alertness, with caffeine these same effects look prolonged for longer.

Conclusion: Caffeinated gum is an effective therapeutic presentation on sleep inertia. The dosage for a positive response ranges from 75 to 200 mg depending on the circumstances of sleep restriction. That is, thanks to the effects generated by chewing on the state of alertness and cognition and the potentialization and duration of them by caffeine.

 

Introduction

Sleep disorders cause alterations in the quality of life of each and every patient. At least two-thirds of those with chronic degenerative diseases are affected by sleep disorders, the most common being the female sex.

Many individuals are subjected to night jobs where a constant state of alertness is required and scientifically proven how this affects the quality of life of each of the employees; for sleep is one of the most indispensable pillars of daily life, as it maintains critical aspects of cognition for optimal mental performance, as well as in mood, alertness and performance during working days and activities of the and everyday life. Awakening abruptly involves something known as “sleep inertia,” which is characterized by impaired performance and subjective lack of alertness for a transitional period, which hardly progresses to a good cognition. It is well known that chewing facilitates concentration, maintains alertness and improves performance in cognitive tasks, but the question is how effective is by itself the effect of chewing a simple chewing gum vs to one that contains Caffeine? Therefore, one of the objectives of this research work, is to analyze the effects of chewing from a simple chewing gum to one that contains caffeine, verify the effectiveness by reversing the sleep inertia of each of them and know the mechanism of action , the pharmacokinetics, bioavailability and absorption of a caffeinated gum during sleep deprivation.

Theoretical mark

Normal sleep progresses in various stages: NREM (nonrapid eye movement) phase and REM (rapid eye movement) phase. These cycles alternate at night in the form of 5 to 6 cycles. In 75% of normal nighttime sleep is NREM and 25% REM.

Phase brake

It happens every 90 minutes or so. It is characterized by zero muscle tone, presence of active sleep, as the electrical activity of the brain is maximum while the body is at full rest, rapid eye movements, heart rate as well as respiratory evidence of increased basal metabolism and the amount of gastric juice.

Step nrem

Also known as “deep sleep,” it facilitates body rest and consists of 3 phases.
a) Phase N1 (Surface Sleep): very light sleep stage, lasting several minutes. It is characterized by a slight decrease in heart rate, breathing, muscle tone, general state of deep rest, relaxed and drowsy, maintaining active the ability to perceive external stimuli.
b) Phase N2 (Surface Sleep): characterized in EEG by sleep spindles and k complexes. Its duration is 10 to 15 minutes. At this stage the muscle tone relaxes further, slightly decreases body temperature and respiratory and cardiac rate, disappearing eye movements.
c) Phase N3 (Deep Sleep): Characterized by a global slowdown of the electrical path and the appearance of slow waves and high voltage (deltas) whose total duration must be greater than 20% and less than 50% of the plot. Sensory perception decreases markedly, as does heart and respiratory rates. Relaxation of the muscles is intensified. It is more difficult to wake up the subject, and if he does, he finds himself disoriented and confused. It is the fundamental stage for the subject to rest subjectively and objectively.

This research work was done based on various medical studies, where it is addressed from the rate of absorption, the bioavailability, the pharmacokinetics of caffeine in chewing gum, the effects of chewing, how is caffeine it reverses sleep inertia, assessing cognitive performance, mood and alertness after caffeinated gum is administered to the composition, formulation and design of said chewing gum. It will also include in a systematized way each and every one of the articles selected to carry out a bibliographic review and thus carry out a complete study of the effects and effectiveness of chewing gum with caffeine to minimize the inertia of sleep , based on scientific evidence from some experimental studies in which there is certainty of efficacy of it, since caffeine is involved in the autonomic nervous system and exerts its effects by acting as an adenosine receptor antagonist. The approach is an essential part of the daily life of the human being, since it is the pillar to be able to perform any cognitive activity, maintain an effective and consistent performance in order to successfully complete actions of daily life and working days. Fatigue can cause various complications and over time can affect the health of the individual, as well as leading to a reduction in efficiency during the day and the increase in the incidence of any type of accidents [1,2]. Caffeine is a white odorless powder that can have different molecular presentations, can range from an anhydride substance to contain a water molecule. Caffeine is a methylxanthine that inhibits the enzyme phosphodiesterase, generating an antagonistic effect on the central receptors of adenosine, this adenosine occurs during daily activities and binds to its receptors, generating a feeling of fatigue and consequently an induction into sleep. Due to the similarity of adenosine to caffeine, the latter takes place in adenosine receptors and thereby prevents the transmission of the fatigue signal generating that the person can continue performing his daily and work activities for a longer period, since contrary to the feeling of insomnia. Caffeine is a Central Nervous System (CNS) stimulant that can promote wakefulness and increase mental activity. In addition, it can stimulate the respiratory center, increase the frequency and depth of breathing and increase total muscle work. Caffeine is usually consumed and/or commonly administered in the form of a liquid substance, although there are other types of presentations such as tablets or capsules. A new way to consume caffeine is through chewing gum which in turn can provide additional advantages, some of them are:

a) Absorption is done through the oral mucosa, resulting in a greater bioavailability of the active substance at the systemic level.
b) Effective and immediate mechanism of action (oral mucosa).
c) It is easy to use and is suitable even for pediatric patients or patients with difficulty swallowing tablets or tablets.
d) It generates fewer side effects as the active substance is released in proportion to chewing.
e) The primary liver metabolism of the active substance is avoided, as they are absorbed directly by the oral mucosa.
f) Lower risk of overdose by chewing effect.

Chewing is a physiological motor activity involving many neural pathways, this action is associated with increased blood flow at the cerebral and orofacial level which in turn implies effectiveness in increasing alertness, physical well-being and improving memory performance. The active substance (caffeine) of chewing gum is released in proportion to chewing, this in turn is absorbed through the oral mucosa and another percentage of it is swallowed as a bolus with saliva, reaches the gastrointestinal tract and thanks to the caffeine is s the absorption rate is faster compared to that of the tablet. In addition, it is important to mention that the control of the release of caffeine in chewing gum is for a long time and improves the variability of the release and retention times of the drug, being these other advantages of this new form administration of the Caffeine.

It is important to note that the effectiveness of this chewing gum with the active substance which is caffeine, has to be argued based on studies that corroborate that effectiveness, such is the case of the P300 signal that is obtained thanks to an electroencephalogram, this signal is a neural record that is projected as a positive deflection and in turn measures the potential of the presence, magnitude, topography and duration of signaling of cognitive function. The signal is acquired more strongly around the parietal electrodes, although it has been suggested that there are also interactions between the frontal and temporal regions. Recent studies say that this P300 wave is composed of 2 secondary waves known as “P3A and P3B signals”, these components respond individually to different stimuli and it has been suggested that the P3A wave originates in the frontal care mechanisms driven by stimuli during task processing, while P3B originates from parieto-temporal activity associated with attention and memory processing.

The potential related to the P300 signal had shortened latency after chewing gum, and the frontal and temporal beta power was increased by chewing the gum after performing a sustained attention task. The quantitative effects on the EEG of chewing gum without cognitive performance seem to be moderated by the taste, suggesting that chewing gum may alter alertness in the absence of cognitive performance. Working under pressure, i.e. in a setback, was associated with increased activity in the anterior cingulate cortex and left frontal convolution, where the motor neural regions of alertness and executive tasks are located [3]. This same effect was found when chewing gum without taste or smell, suggesting that the motor activity of chewing may be a key factor in explaining these results, however it is unclear whether a higher level of motor activity in chewing will increase associated effects, as there is evidence that a more vigorous chewing or a greater resistance to chewing does not moderate the effects on memory, the fact that chewing gum can increase arousal, it therefore reaches a peak and descends and it’s while decreasing cognitive function in performing tasks that require attention (increasing heart rate and beta power during surveillance), this suggests that it is more plausible that more vigorous chewing can have a greater effect on attention to a short-term that in memory.

That is, chewing alone generates a potentization of the performance of a simple task as a result of a reflective motor activity that is generated in the body in the face of sleep deprivation, but this does not mean that this performance is maintained. One study shows that administering only 200 mg of caffeine in conjunction with chewing gum, improves nothing more the performance of simple and complex activities and/or tasks, but also improves alertness compared to chewing without the active substance. In turn the period of pre-eyetion and cardiac autonomous activity remain unchanged during chewing with or without caffeine, generating a response reflected in the increase of parasympathetic activity with changes in rr intervals in the EEG, the latter mentioned above are predictors of the speed and accuracy in the most complex cognitive tasks during sleep deprivation, alertness and performance maintenance during the realization of them.

Some other studies show evidence that the use of caffeine in chewing gum is also equally effective in dispensing sleep in the face of a post siesta; in a double-blind study with 15 adults as participants they were given this chewing gum containing 100 mg of caffeine at the hour and 6 hours after waking up vs. placebo, they were subsequently assigned psychomotor tasks before a watch dog at 0 , 6, 12 and 18 minutes. The rating of the tests was carried out based on the response rate and the number of hits during the tests. Among the results it was observed that 100 mg of caffeine did not fully restore performance, but showed an improvement in response rate by 85% compared to placebo 73%; since the effect of caffeine was evident at 6 min after waking up, which continued to improve performance until 18 minutes, i.e. the results indicate that 100 mg of caffeine substantially attenuates sleep inertia in the face of a sudden awakening by a time-values period, but higher doses (200 mg) are expected to more easily antagonize sleep inertia as a whole for a longer prolonging period.

 

Discussion
The purpose of this article is to evaluate based on a collection of articles the efficacy of caffeine as an active substance in a new therapeutic presentation vs placebo, studying the pharmacokinetics, bioavailability and half-life of caffeine. Among the bibliographic reviews that were addressed for the realization of this article, it is evidence that caffeine in chewing gum is a novel and new presentation that is effective in counteracting sleep inertia, improving alertness, cognition and maintaining performance during the simple and complex activities of daily life. It is important to note that the effects of caffeine are directly proportional to the dose administered in patients as well as on the route of administration. Chewing a gum without the active substance (placebo) generates a later maintenance of performance as well as alertness with the difference that these effects occur over a very short period of time.

 

Conclusion

Caffeine is an odorless powder that inhibits the enzyme phosphodiesterase, which generates an antagonistic effect on the central receptors of adenosine resulting in antagonism of the transmission of the fatigue signal, promoting wakefulness and increasing mental activity. The effect of chewing is associated with increased orofacial blood flow that increases alertness, physical well-being and memory performance. A combination of chewing gum with caffeine enhances and synergizes the effects that chewing alone generates, resulting in a new, novel and effective therapeutic presentation on sleep inertia, since it is easy to use and its absorption is done through the oral mucosa, which generates a greater bioavailability of the active substance and an immediate mechanism of action, in turn those effects are present for a prolonged period since the caffeine inside the gum is released in a way proportional to chewing. Caffeine can provide better alertness and performance at doses of 75 to 150 mg after acute sleep restriction and at doses of 200 to 600 mg after one night or more sleep loss. Caffeine is unlikely to have negative effects on sleep that follows 8 hours or more after administration. However, frequent use of caffeine can lead toilet and withdrawal syndrome.

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Lupine Publishers | Continuous or Intermittent? Which Regimen of Enteral Nutrition is Better for Acute Stroke Patients? a Systematic Review and Meta-Analysis

 Lupine Publishers| Journal of Neurology and Brain Disorders

 

Abstract

Background and purpose: Enteral nutrition via nasogastric tube in acute stroke patients with dysphagia is an important determinant of patient outcomes. It is unclear whether intermittent or continuous feeding is more efficacious. The aim of this review is to examine the current evidence comparing the effectiveness of intermittent versus continuous feeding in stroke patients in terms of nutritional status, gastrointestinal intolerance and other complications.

Methods: A systematic review of randomized controlled studies comparing intermittent with continuous nasogastric feeding in acute stroke patients was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Metaanalyses) guidance using predefined search terms. The search was conducted in MEDLINE and EMBASE up to 1st March 2019. Two independent reviewers assessed study quality using the Joanna Briggs Institute Critical Appraisal Tool. Meta-analyses were conducted, where appropriate, using a random-effects model to pool risk ratio with corresponding 95% CI.

Results: Three studies including a total of 184 patients were identified. All three were medium to low quality. The definition of intermittent enteral nutrition within each study varied considerably in terms of volume, rate and mode of delivery. Achievement of nutritional targets was the same for both feeding patterns in the one study it was reported. Only aspiration pneumonia and diarrhea were measured by all three studies. There was no significant difference in the incidence of aspiration pneumonia (RR 0.91, 95% CI 0.53-1.57, p=0.74, I2=50%) and diarrhea (RR 1.74, 95% CI 0.70-4.30, p=0.23, I2=42%) between the two patterns of feeding. Other outcomes including, vomiting, gastric retention, mortality, pre-albumin and nasogastric tube complications showed no significant differences.

Conclusion: There is very little and low-quality evidence to inform patterns of enteral feeding after stroke. The available evidence shows no significant difference in nutritional achievement and complications between intermittent and continuous nasogastric tube feeding in acute stroke patients.

Keywords: Stroke; Enteral; Nutrition; Nasogastric; Dysphagia

Background

Dysphagia occurs in up to 50% of patients following a stroke [1- 4] and increases the risk of pneumonia almost ten-fold [5]. Strokerelated pneumonia is associated with longer length of hospital stay, worse levels of disability and increased mortality [6-9]. In most dysphagic patients, adaptation of the consistency of diet and fluids is sufficient to ensure that the swallow is safe. However, in a small proportion insertion of a Nasogastric Tube (NGT) is required to ensure safe and adequate nutrition. Despite this, more than twothirds of NGT-fed stroke patients still develop pneumonia [10] Gastric dysmotility is a well-documented phenomenon that occurs in critically ill patients, including acute stroke patients, whereby incomplete gastric emptying results in stasis, heightening the risk of reflux and aspiration of gastric contents [10-13]. NGT bolus feeding was first described by Morrison et al. [14] in 1895 for children with Diphtheria, who received 6-ounce bolus feeds 3 times a day via NGT. However, it wasn’t until 1910s when Morgan et al. [15] and Jones et al. [16] began administering their enteral feeds “drop by drop” rather than as a bolus. Contemporaneously, the regimen most frequently used in most patients requiring enteral feeding is continuous (i.e. low volume pumped feed lasting 16-24 hours without interruption). However, recent attention has been afforded to examining whether a discontinuous feeding strategy - often described as either intermittent or bolus (i.e. high volume of feed administered over a short period multiple times a day) - could reduce patients’ risk of pneumonia and achieve better nutrition and digestive tolerance.

Intermittent feeding reflects normal human feeding patterns more closely than continuous feeding. A period of fasting interrupted by the ingestion of a discrete meal causes gastric distension and subsequent stimulation of gut motility, secretion of digestive enzymes and metabolic responses to nutrient loading [17- 18]. This physiological gastrointestinal response to intermittent feeding has been demonstrated in healthy adults, neonates and intensive care populations [17-20]. While there are good theoretical reasons to assume that intermittent feeding is more physiological, most stroke patients in the UK receive nasogastric feeding continuously, as there are concerns that intermittent feeding may be less well tolerated. Guidance and practice relating to enteral feeding after stroke differs between countries; with the American Heart Association [21] and the Royal College of Physicians [22] not addressing the issue, Australian Guidelines allowing for both options [23] and intermittent feeding described as “traditional” in China [24]. The aim of this systematic review is to determine whether there are differences in the achievement of adequate nutrition, gastrointestinal tolerance, and metabolic stability between intermittent and continuous nasogastric feeding.

Methods

This systematic review and meta-analysis were prepared according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [25].

Criteria for Considering Studies for this Review

The inclusion criteria for this review were:
a. Population: Acute stroke patients aged 18 or more with a nasogastric tube receiving enteral nutrition
b. Intervention: Intermittent enteral nutrition: by bolus, gravity systems or infusion pump several times a day with a rest between feeds
c. Control: Continuous enteral nutrition: with gravity systems or infusion pumps, without interruption for a minimum period of 12 hours/day
d. Outcomes: Nutritional status, aspiration pneumonia, diarrhea, vomiting, gastric distension, gastric retention, hyperglycemia, pre-albumin, mortality, length of stay, and NGT complications
e. Study Design: Randomized controlled trials or pseudo-randomised controlled trials (a study without true randomisation) that compared continuous and intermittent enteral feeding methods.

Search Strategy

A literature search was performed using MEDLINE (1966 – 1^st March 2019) and EMBASE (1974– 1st March 2019). Studies were searched for using the terms enteral, nutrition, nasogastric, gastrointestinal, feeding as Medical Subject Heading (MeSH) and free text terms. These were combined with the set operator “AND” with following terms: intermittent, continuous as both MeSH and free text terms. Publications were restricted to those studying adult populations, defined as greater than 18 years old, with a documented diagnosis of stroke according to accepted international criteria [26]. This search strategy is described in Appendix 1. The reference lists of all eligible studies that were identified were also comprehensively searched for studies not identified using the initial search strategy. This search was performed independently by two reviewers.

Selection of studies

Two reviewers (GDP and ET) assessed the studies independently for inclusion using the title and abstract. In cases where relevance could not be determined solely from the abstract, the full text was consulted. Any disagreements were resolved by consensus with a third reviewer (CR).

Data extraction and management

Data extraction was done manually by two reviewers (GDP and ET). Differences were discussed and adjudicated in faceto- face meetings. Foreign language papers were translated, and descriptions of each study were derived. This included authors, year of publication, type of participant, location, study design, sample size, age and gender of participants, exclusion criteria, when feeding was started, monitoring period, nasogastric tube size, type of feed and definitions of each intervention. In addition, data was extracted for definition and results of each outcome from all studies.

Assessment of risk of bias in included studies

Methodological quality of the studies was assessed using the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (MAStARI) Critical Appraisal tool for experimental studies [27].

Data synthesis

The studies presented in this review all fitted the conceptual definitions of intermittent and continuous enteral nutrition, as outlined in the inclusion criteria. However, there were differences in the volume, rate and temperature of nutrient delivered. In addition, two of the studies did not use true randomisation. Taking into consideration these limitations, a meta-analysis has been carried out with the outcome’s diarrhea and aspiration pneumonia, as these were the outcomes assessed by all studies. Narrative synthesis was used where outcomes did not allow meta-analysis. The meta-analysis was performed using Review Manager (RevMan) Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014. Data was extracted from all three studies for the outcome’s diarrhea and aspiration pneumonia. We calculated risk ratios (RR) and 95% CIs using the Mantel–Haenszel model. Statistical heterogeneity among trials was assessed by the I2 test, with I2 >50 representing possible substantial heterogeneity. The meta-analysis was performed with a random‐effects model irrespective of the level of heterogeneity as the included trials varied considerably in a number of methodological features.

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Lupine Publishers| Concomitant Cervical Spine Infection with Mycobacterium Tuberculosis and Pyogenic Bacteria Causing Spinal Cord Compression

 Lupine Publishers| Journal of Neurology and Brain Disorders

Case Report

A 57-year-old man presented to the emergency room with neck back pain for about 2 months, unresponsive to nonsteroidal antiinflammatory drugs and progressive course of upper and lower extremity weakness with no sphincter dysfunction. The patient had no predisposing risk factors such as recent spinal surgery, trauma, instrumentation, distal site of infection, immunosuppression, diabetes. He was apyrexial. Physical examination showed marked mid neck tenderness, no palpable masses were felt, no lymph nodes were felt. Neurological examination of his extremities, spasticity was positive, and power was decreased 3/5 in both lower extremities, 2/5 in both upper extremities. Bilateral Babinski signs were present and deep tendon reflexes were increased.

Full blood count and biochemistry showed white blood cell count (WBC) 10,269/L (neutrophils 71.3%; lymphocytes 21.8%; monocytes 2.2%; WBC 4.4 to 11.3/L); C-reactive protein 13.86 mg/dL (0.1 to 6 mg/dL). Magnetic Resonance imaging of the cervical spine showed the collapsed body of C4 with epidural abscess formation, complicating with spinal cord compression. He underwent urgent anterior cervical decompression and evacuation of anterior epidural abscess with fusion. The material underwent histologic examination and aerobic, anaerobic, fungal, mycobacterial cultures. A tuberculous granuloma was detected on histology. Ziehl-Neelsen stain confirmed the diagnosis. Cultures also detected Staphylococcus aureus. Treatment was started with rifampin (600 mg), Isoniazid (300 mg), ethambutol (25 mg/kg), pyrazinamide (25 mg/kg), and levofloxacin 750 mg for two months. This was followed by seven months of isoniazid and rifampin. The patient was referred to rehabilitation. One year later, the patient is able to walk independently, and the back pain is gone.

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Lupine Publishers| Neurological, Neuropsychiatric and Psychiatric Symptoms During COVID- 19 Infection and After Recovery: A Systematic Review of Observational Studies

 Lupine Publishers| Journal of Neurology and Brain Disorders

 

 

 

    

Abstract

Background: The SARS-CoV-2 virus causes a wide spectrum of disease severity. Initial manifestations include fever, dry cough, and constitutional symptoms, which may progress to respiratory disease. There may also be neurological and psychiatric manifestations, involving both the central and peripheral nervous system.

Methods: We performed a literature search of the databases PubMed, EMBASE, The Cochrane Library and Web of Science for observational studies reporting neurological, psychiatric, and neuropsychiatric effects of COVID-19. This was followed by a narrative synthesis to summarise the data and discuss neuropsychiatric associations, symptom severity, management, and recovery.

Findings: The most frequently reported neurological symptoms were ageusia, hyposmia/anosmia, dizziness, headache, and loss of consciousness. Statistically significant relationships were noted between Asian ethnicity and peripheral neuropathy (p=0·0001) and neuro-syndromic symptoms (p=0·001). ITU admission was found to have a statistically significant relationship with male sex (p=0·024). Depression and anxiety were also identified both during and after infection. The most frequent treatments used were intravenous immunoglobulins, followed by antibiotics, antivirals, and hydroxychloroquine; with mean treatment duration of 6 days.

Interpretation: Various neuropsychiatric symptoms have been associated with COVID-19 infection. More studies are required to further our knowledge in the management of neurological and psychiatric symptoms during and after COVID-19 infection

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) is a novel virus, initially discovered in the city of Wuhan, China [1]. SARS-CoV-2 causes coronavirus disease (COVID-19), which has led to an ongoing global pandemic. Despite belonging to the coronavirus family, which usually cause self- limiting upper respiratory tract infections, SARS-CoV-2 is often more virulent than most coronaviruses and may lead to severe respiratory disease [2].

The mechanism of action for SARS-CoV-2 may relate to a specific tropism for respiratory tract mucosal cells through the attachment of viral surface proteins to angiotensin-converting enzyme (ACE) 2 receptors [3]. After infection, the virus causes a wide spectrum of disease severity, with most patients suffering a mild self-limiting disease. Initial manifestations include fever, dry cough and constitutional symptoms (headache, fatigue, myalgia, arthralgia), progressing to respiratory disease of mild to moderate severity [2,4]. Other disease manifestations include gastrointestinal symptoms (nausea, vomiting, diarrhoea), sore throat, skin rashes, anosmia, ageusia, and chest pain [5]. In patients with underlying comorbidities or advanced age, the infection may be complicated with acute respiratory distress syndrome (ARDS), acute renal failure, sepsis, multi-organ failure and death [6,7]. As the pandemic of COVID-19 persists, the knowledge of the clinical disease spectrum is still unfolding. Medical literature of COVID-19 infected patients reveals a variety of extra-pulmonary organ involvement [8]. Among these, COVID-19 has been associated with several neurological and psychiatric effects, involving both the central and peripheral nervous system [9].

Methods

This systematic review follows the Preferred Reporting Items for Systematic reviews and MetaAnalyses (PRISMA) statement [10] and was registered in the PROSPERO International Prospective Register of Systematic Reviews (number CRD42020203770 at www.crd.york.ac.uk/PROSPERO).

Search Strategy

The literature search was performed in August 2020 using the databases PubMed, EMBASE, The Cochrane Library and Web of Science, from their respective inception dates. The following search terms were used:

(Neuro* OR Nervous OR Psychiatry* OR Mental) AND (COVID OR Corona*)

The search strategies incorporated both medical subject headings (MeSH) and free-text terms, which were adapted according to the database searched. Grey literature was also searched. Reference lists of the identified papers and reviews were hand-searched. Publication languages included English and Greek. There were no publication period restrictions.

Inclusion and Exclusion Criteria

Included studies were observational studies reporting neurological, psychiatric, and neuropsychiatric effects of COVID-19. The included participants were COVID-19 patients of any ethnic origin, sex/gender, age, country, and were either actively infected from COVID-19 at the time of the study or had recovered. We did not include studies examining psychiatric effects on the general population as an indirect result of the pandemic.

Main Outcomes

The main outcomes included neurological, psychiatric, and neuropsychiatric effects of COVID-19, either based on clinical diagnosis or relevant diagnostic questionnaires. Information about recovery and treatment was reported when available.

Screening

Titles were screened for inclusion, followed by screening of abstracts, and then content. One author (SS) screened the papers, and any disagreements were resolved by discussion with the review’s primary author (MS) and the other authors.

Data Extraction

The Cochrane good practice data extraction form was used for data extraction. Data extraction from reviews involved the NICE extraction form, and the data were extracted in an electronic format.

Risk of Bias/Quality Assessment

The quality and risk of bias were assessed by the Mixed Methods tool for Appraisal (MMAT). The guidance from the Centre for Reviews and Dissemination was used for the appraisal of review papers. Discrepancies were resolved by discussion within the authors’ team.

Strategy for Data Synthesis

We performed a narrative synthesis review of original studies and reviews reporting neurological, psychiatric, and neuropsychiatric effects in COVID-19 patients.

We summarised the data and discussed:

a) Neuropsychiatric associations

b) Symptom severity

c) Management and

d) Recovery

Information from the various identified studies was analysed, summarised, and compared.

Results

Following our literature search, we identified a total of 7,460 papers. After removing the duplicated and irrelevant papers, 328 full text articles remained to be assessed for eligibility using the inclusion and exclusion criteria. Of these, 313 studies were included in the final narrative synthesis: specifically, 307 studies for neurological symptoms and 7 studies for psychiatric symptoms, as shown in Figure 1. A total of 15 full text papers were excluded as they were either not relevant (n=4) or unrelated to COVID-19 infection (n=11).

Figure 1: PRISMA flowchart of selected studies.

Neurological Symptoms

A total of 307 studies for neurological symptoms were included in the narrative synthesis, as mentioned above, of which 202 were case reports, 53 case series, 2 retrospective studies, 21 cohort studies, 15 systematic reviews, 8 cross-sectional studies, 3 casecontrol studies, and 3 retrospective case series. A summary of the studies included in the systematic review is shown in Table 1, and a complete list of the studies is provided in Supplementary Material 1. The mean age of the patients included was 55·11 (±17.91) years. Most of the patients in our cohort were males (61%) and the majority of the participants were Asians (57%).

Table 1: Summary of studies included in the systematic review for neurological symptoms.

Clinical Presentation

A total of 107 studies (42·7%), involving 26,758 patients, included a full account of neurological symptoms experienced by the participants following COVID-19 infection. Table 2 presents the frequency of symptoms and their resolution. The most reported symptoms were ageusia (n=390), hyposmia/anosmia (n=480), dizziness (n=230), headache (n=860), and loss of consciousness (n=310).

Table 2: Frequency and recovery rates of different COVID-19 neurological presentations.

Moreover, a significant number of patients experienced severe neurological manifestations, such as seizures (n=260), acute cerebrovascular events (n=500), cerebellar syndromes (n=70), peripheral neuropathies (n=90), meningitis/encephalitis (n=380), encephalopathies (n=380), neurological syndromes such as Guillain-Barre syndrome (n=320), and spinal cord syndromes (n=30).

A statistically significant relationship was noted between ethnicity and peripheral neuropathy (p=0·0001) as well as between ethnicity and neuro-syndromic symptoms (p=0·001), with Asian patients being more likely to experience these symptoms. Both sexes were statistically as likely to present with symptoms of ageusia (p=0·0001), dizziness (p=0·033), gastrointestinal symptoms (p=0·0001), and anorexia (p=0·0001). However, flu-like symptoms were statistically more prevalent in females (p=0·008), whereas hyposmia (p=0·037) and haemoptysis (p=0·0001) was more frequent in males.

Following recovery from COVID-19 infection, a large proportion of patients demonstrated a complete resolution of their symptoms. Specifically, patients presenting with loss of consciousness and ageusia reported the highest resolution rates (93% and 92% respectively), while the patients that experienced spinal cord syndromes had the lowest resolution rates of their symptoms (33%).

Treatments

The most frequent treatments used in the studies analysed were intravenous immunoglobulins (IVIG) (20·17%), followed by antibiotics such as azithromycin (19·29%), antivirals (14·91%), and hydroxychloroquine (10·52%). However, a combination of therapies was required for treatment in some patients. Figure 2 illustrates the different types of drugs that the COVID-19 patients received during their admission and how the drug therapy is markedly heterogeneous among this group of patients.

Figure 2: Drug type administered to COVID-19 patients.

The most common route of drug administration was intravenous (65%), although oral drug administration and intramuscular injections were also utilised. Patients received treatment for a mean duration of 6 (±4) days.

Prognosis

Patients admitted to an Intensive Therapy Unit (ITU) were reported in 126 studies. Figure 3 shows the different types of management that patients received when admitted to ITU and illustrates that the most common cause of ITU admission was the need for respiratory support with intubation and mechanical ventilation (84% of the cases).

Figure 3: Types of ITU management received by patients.

ITU admission was found to have a statistically significant relationship with males (p=0·024), but not age. Interestingly, there was a statistically significant relationship with ITU admission and symptoms of hyposmia/anosmia (p=0·0001), headache (p=0·035), acute CVA (p=0·0001), seizure (p=0·001), meningitis (p=0·034), and encephalopathies (p=0·0001).

Psychiatric Symptoms

We identified seven studies reporting psychiatric effects, of which five were cross-sectional studies, one was a retrospective cohort study, and one was a case report. Details of the six studies are reported in Table 3. The studies involved 299,000 patients in total, of which 44% were male and 56% were female. Half of the studies were reported in China. Three studies involved 171 patients in hospital settings while having active COVID-19 infection, three studies involved 498 patients at home after recovery, and one study involved 62,354 patients covering both inpatients during infection and those at home after recovery. All studies identified depression and anxiety as being relevant to COVID-19 infection, both during and after infection. Additionally, one study reported suicidality during infection, two studies reported post-traumatic stress disorder after infection, one study suggested obsessivecompulsive disorder after infection, one study suggested insomnia after infection, one study suggested a higher incidence of psychosis, and two studies suggested a higher incidence of dementia diagnosis as being relevant to having been diagnosed with COVID-19.

Table 3: Studies reporting psychiatric effects related to COVID-19 infection.

Discussion

The literature published on the neurological symptoms observed in patients with COVID-19 is vast. Through our review, we aimed to summarise all available literature, as well as include more recent studies that older reviews may not have included. Our review specifically served to identify and examine the frequency and severity of these symptoms through combining this existing literature. In total, 307 neurological studies covering 60,097 patients, were included in this systematic review, which has shown that COVID-19 is associated with a large variety of neurological symptoms. The most frequently reported symptoms included ageusia, hyposmia/anosmia, dizziness, headache, and loss of consciousness. These symptoms are not specific to SARSCoV- 2 infection and are of low severity, however they may suggest neurotropism. They also associate with high resolution rates (all >80%). The most common severe neurological complication of COVID-19 was acute cerebrovascular events. This result is in keeping with other systematic reviews [18,19].

Direct neurological damage including ischemic strokes, meningitis/encephalitis, or Guillain-Barre syndrome are relatively common extra-pulmonary neurological presentations according to our review. These results should be the springboard for further research efforts aiming to distinguish whether these neurological entities are a consequence of direct brain injury/infection or an interaction with other vascular comorbidities of patients suffering severe/critical COVID-19 disease.

A significant proportion of COVID-19 patients were asymptomatic due to the course of SARS-CoV-2 infection. In addition, patients may not present with respiratory symptoms or fever but still have initial neurological manifestations. Thus, when patients present with neurological symptoms, despite the absence of respiratory symptoms, clinicians should maintain a high level of clinical suspicion for the possibility of underlying COVID-19 asymptomatic infection.

The resolution rates of neurological symptoms also varied. Patients presenting with loss of consciousness and ageusia reported the highest resolution rates (93% and 92% respectively), with ageusia resolution rates being 100% in one study [20]. On the other hand, patients who experienced spinal cord syndromes, such as acute myelitis, had the lowest resolution rates of their symptoms (33%). This finding is supported by the established poor overall outcomes associated with acute myelitis, with only approximately one-third of patients experiencing a favourable outcome [21].

A statistically significant relationship was noted between Asian ethnicity and peripheral neuropathy. The relationship between ethnicity and peripheral neuropathy in the context of COVID-19 has yet to be explored. However, peripheral neuropathy as a complication of diabetes has been found to be more prevalent among Caucasian patients [22] and less common in those with Indo- Asian and African- Caribbean origins [23]. Moreover, a statistically significant relationship was noted between Asian ethnicity and neuro-syndromic symptoms. Nonetheless, it is important to note that both of these relationships may have been influenced by the fact that the majority of the participants in the studies included were Asian and that a number of papers did not disclose the ethnicity of their participants.

Additionally, flu-like symptoms were statistically more prevalent in females, possibly because males have been found to have a higher risk of severe illness with COVID-19 [24]. Hyposmia and haemoptysis were statistically more prevalent in males. This is in contrast to several previous studies that found hyposmia to be more common in females with COVID-19 infection [25-28]. However, our patient cohort was predominantly male (62%), which may have contributed to the differing results. Regarding haemoptysis, it is a very uncommon presentation that was only present in 10 patients.

ITU admission was found to have a statistically significant relationship with male sex, but not with age. A meta-analysis of patients with COVID-19 also demonstrated a relationship between sex and ITU admission, with male patients having almost three times the probability of requiring ITU admission compared to females [29]. Surprisingly, our study did not determine any relationship between age and ITU admission. In contrast, another meta-analysis found that patients greater than 70 years old have a higher risk of needing intensive care [30]. Furthermore, there was a statistically significant relationship between ITU admission and the symptoms of hyposmia/anosmia, headache, acute CVA, seizure, meningitis, and encephalopathies.

Treatment varied, with several different therapies and drug routes being used depending on the neurological manifestation and severity of the presentation. The most frequent treatments used were intravenous immunoglobulins (IVIG), followed by antibiotics such as azithromycin, antivirals, and hydroxychloroquine, with patients receiving treatment for a mean duration of 6 days. A systematic review assessing treatment strategies for COVID-19 similarly found antivirals, antimalarials, and antibiotics to be the mainstay of treatment [31]. The frequency of IVIG can be attributed to its use in treating many different neurological conditions, most notably Guillain-Barre Syndrome, which was the fourth most common neurological complication reported in this review. Finally, it is important to consider that the COVID-19 pandemic is rapidly evolving and that treatment options are continually being trialled and developed.

Even though we established an abundance of studies for neurological symptoms, there appears to be a lack of studies regarding the psychiatric effects during and after COVID-19 infection. Nonetheless, all the studies we were able to identify reporting psychiatric effects have found depression and anxiety to be relevant, both during and after infection with COVID-19. In severe cases, there may even be a risk of patients attempting suicide. Compared to people who had flu or other respiratory tract infections, COVID-19 survivors were more likely to receive a diagnosis of anxiety of depression over the same period [17]. It was found that involving psychiatric care for these patients was effective in reducing their symptoms of anxiety and depression. Without proper psychiatric intervention, there is a risk that these psychiatric symptoms could increase the risk of suicidal ideation. Overall, it is recommended that psychiatric and/or psychological support should be available in hospitals to patients admitted to medical wards due to COVID-19, as well as in the community following recovery. This process may involve both the use of pharmacological and/or psychological interventions. Given the fact that COVID-19 survivors were at higher risk of receiving a diagnosis of dementia at 6-months follow-up, access to memory clinics should also be available to this group of patients. More studies examining the short-term and long-term psychiatric effects during and after COVID-19 infection are required in the future to obtain a better understanding of the symptoms, as well as to develop effective management strategies.

 

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