Neuro symptom virus

The inflammation accompanied by COVID disease has been observed to correlate with thrombophilic risk. In addition, the capability of SARS-CoV-2 to infect endothelial cells leads to endothelial dysfunction and complex interactions with the coagulatory system Boccia et al. The laboratory findings in COVID patients — low lymphocyte count, prolonged prothrombin time, and elevated lactate dehydrogenase levels, with increased D-dimer, creatinine and creatine kinase levels additionally put the patient at risk for vascular complications.

A state of hypoxia, inflammation, and hypercoagulability would contribute to the occurrence of stroke Fan et al. Indeed, a retrospective report found a cohort of COVID patients to be at higher risk of ischemic stroke compared to patients with influenza Merkler et al.

Different types of vasculopathic brain lesions were demonstrated. A case series of 10 patients also supports the pathogenesis described above, with a wide range of ischemic brain lesions observed Franceschi et al.

In addition, the risk of developing a cytokine storm on a systemic level is increased by the RAAS dysfunction, which will be discussed next.

An efficient innate immune response against the virus is critical in the process of developing life-saving immunity. Pattern recognition receptors PRRs play a crucial role in the innate immune response against pathogens. This detection of viral particles triggers an immune response and the production of cytokines and interferons by immune cells Thompson et al. This inadequate systemic hyperinflammatory state have adverse effects on brain homeostasis and neuronal cell function and can lead to cognitive and behavioural changes Sankowski et al.

Cytokines and chemokines released during infection gain access to the CNS through the circumventricular organs and by opening the blood-brain barrier due to the cerebral inflammatory state.

The implications of the cytokine storm in neurological complications of COVID have been demonstrated in a case series of two patients with encephalitis. Further, the immunological stress SARS-CoV-2 leads to needs to be considered for a wide array of immunological conditions.

Such as multiple sclerosis patients risking serious disease outcome as a consequence of immunomodulatory drug use Landtblom et al. The effects of the cytokine storm in the nervous system can further be interpreted in the context of the above-mentioned section on RAS dysfunction and endothelial disease. A massive replication of the virus when the defense of the immune system is inadequate leads to mass depletion of ACE2 receptors.

Consequently, hyperactive AT1 receptor signalling can subsequently promote multiple organ failure in parallel with the developing cytokine storm. Notably, ACE1 hyperactivity is present in many underlying conditions, making these patients a risk group, more susceptible to severe COVID disease, and warrant clinical attention Xiao et al. One of them describes a patient with myalgia as a consequence of acute necrotising encephalopathy.

Concentrations of viral particles may be too low to be detected in the CSF by conventional methods, with endo - and exonucleases present in the liquid acting as inhibitors.

The cell-cell dependent viral spread could also explain the relative absence of viral particles in CSF Paniz-Mondolfi et al.

Either way, most case reports early in the pandemic had not proceeded with CSF testing by other methods than the commercial PCR assay. More recently, there have been studies performed with larger cohorts of COVID patients with associated neurological complications.

The report suggests that neurological complications are a consequence of indirect mechanisms, rather than direct viral infection of the CNS. A case series wherein six patients with COVID associated neurological symptoms, encephalopathy in four of these cases, have undergone extensive CSF analysis was recently published. There are a few cases of neurological symptoms being observed in infants Dugue et al.

These are perhaps not numerous enough to spawn any meaningful discussion. In a recent review, it was suggested that similar case reports have been slowly accumulating, but neurological symptoms in neonates and children are rare and mostly not as severe as those in adults Paniz-Mondolfi et al.

While case reports of CSF positivity are increasing, no significant patterns seem to have emerged, contributing to the difficulty of understanding the pathophysiological mechanisms of SARS-CoV-2 in relation to the CSF. The syndrome typically occurs following a gastrointestinal or respiratory infection. Moreover, reports from northern Italy, a region that has been severely affected by the virus, revealed an increased incidence of GBS Filosto et al.

There, the mean age of the patients was 55 years, with a significant majority of men GBS developed from 2 to 33 days from symptom onset in 68 of these cases. Cranial nerve involvement was observed in A duality in the viral spike protein has been found, which potentially makes gangliosides a target for autoimmune reactions targeting PNS neurons Dalakas, The analysis was performed by comparing the SARS-CoV-2 amino acid sequence with 41 human proteins associated with known types of immune-mediated neuropathies.

There is a case where nerve ultrasonographic studies showed endoneurial or epineurial inflammatory edema in the ventral rami of the cervical nerves Berciano and Gallardo, Overall, GBS in COVID patients has shown a great variability in timing and has been shown to be the presenting feature of the disease in most patients, with some delayed post-infectious cases. The most common hypothesis regarding the development of GBS symptoms are autoimmune reactions targeting peripheral nerves Paliwal et al.

To provide an overview of the most relevant findings concerning the neurological effects of COVID, we generated a timeline of relevant publications Fig. This timeline consists of a number of articles that presented new aspects of the COVID pathophysiology, discussed in this review. From the early s several articles from predominantly mice models proved to be important for the discussion of potential neuroinvasive mechanisms.

Articles from early on the timeline show how more and more SARS-CoV-2 affected systems and organs were discovered during the pandemic Mao et al.

There is enough evidence to conclude that neurological symptoms and complications are an important feature of SARS-CoV-2 infection. COVID prompts a range of neurological complications, from common and somewhat mild symptoms, such as transient anosmia and ageusia; to more severe complications, albeit rarer, such as stroke, encephalitis or encephalopathy. More clinical and epidemiological studies are necessary to clarify these important issues. Moreover, while many articles discuss potential mechanisms and targets of SARS-CoV-2 infection, many of these mechanisms need further research and confirmation to fully, and convincingly, explain the observed neurological manifestations.

An article that contributes to this has been published online as an unedited accelerated article preview in Nature. By using single-nucleus gene expression profiles in brain tissue, the authors suggest the involvement of the choroid plexus in relaying the peripheral inflammation to the CNS during COVID disease. Microglia and astrocytes show pathological transcriptional profiles with shared features with those in neurodegenerative diseases Yang et al.

This molecular study, as well as future ones, are needed to further our understanding of the COVID associated neurological manifestations. Dissemination through peripheral nerves has been discussed as a potential neuroinvasive mechanism in a recently proposed hypothesis. Future research will be needed to either refute or support this model. The funders had no role in the design of the study or in the writing of the manuscript.

Illustrations were created using Biorender. National Center for Biotechnology Information , U. J Neuroimmunol. Published online Jul Anton Johansson , a Mohamed S. Mohamed , a Thiago C. Moulin , a and Helgi B. Mohamed S. Thiago C. Helgi B. Author information Article notes Copyright and License information Disclaimer.

Elsevier hereby grants permission to make all its COVIDrelated research that is available on the COVID resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. This article has been cited by other articles in PMC.

Open in a separate window. Conclusions and future perspectives There is enough evidence to conclude that neurological symptoms and complications are an important feature of SARS-CoV-2 infection. Funding T. Declaration of Competing Interest No competing interest to declare.

Acknowledgments Illustrations were created using Biorender. References Abdi S. The association of SARS-CoV-2 infection and acute disseminated encephalomyelitis without prominent clinical pulmonary symptoms. What did we learn from the previous coronavirus epidemics and what can we do better: a neuroinfectiological point of view. Journal for ImmunoTherapy of Cancer. Clinical Infectious Diseases. Muscle Nerve. Lack of dyspnea in patients with Covid another neurological conundrum?

COVID and coagulative axis: review of emerging aspects in a novel disease. Monaldi Arch. Chest Dis. Science Advances. Genomic characterization of the novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan.

Emerging Microbes and Infections. Anatomy and cellular constituents of the human olfactory mucosa: a review. Clinical and immunological features of severe and moderate coronavirus disease Clinical characteristics of deceased patients with coronavirus disease retrospective study. The BMJ. COVID and the chemical senses: supporting players take center stage. A mouse model for chikungunya: young age and inefficient type-I interferon signaling are risk factors for severe disease.

PLoS Pathog. Visit our coronavirus hub and follow our live updates page for the most recent information on the COVID pandemic. This week, they presented their findings at Neuroscience This event is the annual meeting of the Society for Neuroscience , which is the largest global society for scientists and clinicians focused on issues of brain and nervous system health.

They also provide insight into the effects it has once it has entered this part of the body. These symptoms and other, less common ones can range in severity from mild to life threatening. As well as these respiratory symptoms, clinicians and researchers have also observed various neurological symptoms associated with COVID Speaking with Medical News Today , Dr. For Dr. John H. Morrison , director of the California National Primate Research Center at the University of California, Davis, presented research on a study using rhesus monkeys.

We were particularly interested in whether or not aged type 2 diabetic T2D monkeys were more vulnerable to neuroinvasion by the virus than young monkeys, given that aging and T2D are key comorbidities in humans. The major findings are that:. For Prof. A quarter of the studies took place in China studies with at least 27, participants. This gives an overview of the countries in which neurological symptoms of COVID are under investigation, although it was not determined whether all participants were within the country stated.

There may also be publication bias as this review excluded reviews that were not in English. Throughout the studies, 18 neurological symptoms were described. These are summarised in Table 4. As can be seen, neurological manifestations of COVID include catastrophic symptoms such as cerebrovascular disease CVD , encephalitis and Guillain—Barre Syndrome GBS , which are understandably hugely concerning and have therefore generated intense discussion and research.

COVID has also been found to cause symptoms such as fatigue, dizziness, ataxia, dysphagia and headache, which, although more benign, can be disabling if they become chronic. Notably, the main symptoms of Long Covid are increasingly similar to symptoms of CFS fatigue, inability to concentrate, myalgia, headache.

Echoing concerns raised recently by the British Medical Association, 7 the findings of this review highlight the impact that short- and long-term neurological symptoms of COVID may have on current health services.

Symptoms seen in Long Covid such as facial pain, muscle issues, neuralgia, fatigue and insomnia, may become long term and disabling, requiring sustained support from healthcare services such as pain-, fatigue- and sleep-clinics, neurological services and primary care.

For example, COVID has affected delivery of health care services, through reduction in use of emergency services during the peak of the pandemic in the UK as patients were worried about contracting the virus from hospitals. On the other hand, most outpatient appointments and elective surgeries were postponed, leading in some cases to deaths as an indirect result of COVID Combined with the previously mentioned potential increase in demand for neurological services, there are likely to be wide reaching financial implications.

This research is therefore useful for aiding future patient management while helping to develop policies for response to COVID and its critical outcomes. Key sources differ in their description of FND symptoms, indicating that there is no comprehensive list of all FND symptoms. Conversely, COVID can be diagnosed quickly and easily with a test leaving aside the possibilities of false results.

The authors of this research are concerned that, within neurological services, priority may be given to patients who have had COVID, who may actually experience some level of prestige because they have survived a disease feared by all, and any neurological symptoms they experience might be automatically accepted, extensively researched and supported, to the detriment of other neurological conditions.

There is already evidence of this skewing of services, as large sums of money and research at pace are contributing to a greater understanding of long-term symptoms of COVID, 69 and the NHS has declared its intention to provide a COVID rehabilitation service. However, some patients with emerging Long Covid have similar experiences to those with less accepted conditions, particularly those who were unable to get a test early in the pandemic.

It is important to highlight the similarities between symptoms of Long Covid and other conditions, providing education for health professionals, informing future practice and illustrating the need for more funding for neurological services to meet increased demand. They may be taken more seriously, and more funding may be made available for appropriate neurological services unrelated to the cause of the symptoms.

Scientific reports centred on neurological effects of COVID are still scarce, and risk of publication bias is high. For example, within the reviews included in this research, a quarter of the studies were undertaken in China and a further quarter in Europe Only three studies were conducted in the African continent and nine were conducted in the South American continent.

Quality assessment has, however, been undertaken as described earlier and the reviews were deemed high quality. Retrospective and prospective studies of larger cohorts are necessary to correctly assess nervous system involvement, which has not been possible yet for COVID as it is a very new disease and it is unclear how much it mimics other coronavirus diseases.

There is an array of evidence to show that COVID causes neurological symptoms and, although it is difficult to ascertain how long term the symptoms may become, there is increasing evidence of the presence of Long Covid, symptoms persisting beyond 3 months. Although this paper is primarily UK-focussed, these concerns are likely to be similar in other countries.

Concerns about the potential impact of these findings on the delivery of neurological and wider healthcare services are considered alongside the potential effect COVID may have on perceptions of neurological symptoms, particularly those relating to FND and CFS. Further research is recommended to explore whether the neurological symptoms of COVID will improve acceptance and understanding of FND, or whether this will worsen the experience for those who suffer from FND.

Further thought for future planning of health care resources also needs to be taken into consideration in light of this pandemic. Conflict of interest statement: The authors declare that there is no conflict of interest. Supplemental material: Supplemental material for this article is available online.

National Center for Biotechnology Information , U. Ther Adv Chronic Dis. Published online Jan Tamar Wildwing and Nicole Holt. Author information Article notes Copyright and License information Disclaimer.

Email: ku. Received Sep 19; Accepted Nov 6. This article has been cited by other articles in PMC. Associated Data Supplementary Materials sj-pdftaj Abstract Aims: In response to the rapid spread of COVID, this paper provides health professionals with better accessibility to available evidence, summarising findings from a systematic overview of systematic reviews of the neurological symptoms seen in patients with COVID Results: The results indicated that COVID exhibits two types of neurological symptoms; life-threatening symptoms such as Guillain—Barre Syndrome GBS and encephalitis, and less devastating symptoms such as fatigue and myalgia.

Conclusion: Implications for neurological healthcare services in the United Kingdom UK may include longer waiting times and a need for more resources including more qualified health professionals. Methods A systematic overview of current systematic reviews was conducted to explore the potential impact of the longer-term neurological symptoms of COVID Open in a separate window.

Figure 1. Table 1. Q2 Did the authors look for the right type of papers? Q3 Do you think all the important, relevant studies were included? Q5 If the results of the review have been combined, was it reasonable to do so? Q6 What are the overall results of the review? Q7 How precise are the results? Q8 Can the results be applied to the local population? Q9 Were all important outcomes considered? Q10 Are the benefits worth the harms and costs?

CASP, critical appraisal skills programme; n, no; y, yes. Table 2. Characteristics of the reviews and number of studies in each country. First author No. Abdullahi 12 60 10, 11, To summarize the evidence on the neurological and musculoskeletal symptoms of the disease. This may help with early diagnosis, prevention of disease spread, and treatment planning. Abu-Rumeileh 13 52 58 73 To provide a comprehensive and updated overview of all case reports and series of COVIDrelated GBS to identify predominant clinical, laboratory, and neurophysiological patterns and to discuss the possible underlying pathophysiology.

Almqvist 15 41 11, 14, To systematically summarise neurological and neuroimaging manifestations of all known HCoVs in order to provide possibilities to predict short- and long-term neurological complications of COVID Collantes 20 47 49 To determine the neurological manifestations and complications, including laboratory findings, and outcomes among patients with COVID infection.

Correia 21 4 7 To describe the main neurological manifestations related to coronavirus infection in humans. Secondary objective was to compare the results between patients with severe and non-severe infection.

Dinakaran 23 31 12 To report the available evidence of neuropsychiatric morbidity during the current COVID crisis. The authors also discuss the postulated neuronal mechanisms of the corona virus infection sequelae. Fatima 24 6 39 To determine the aetiology, underlying risk factors and outcomes among patients with COVID presenting with stroke. Ghannam 25 43 42 82 To clarify the neurological complications of SARS-CoV-2 infection including the potential mechanisms and therapeutic options.

Katal 27 21 28 not stated To systematically review the available imaging findings of patients diagnosed with neurological symptoms associated with coronavirus infections. Katyal 28 11 16 To analyse the current literature on neuromuscular complications associated with SARS-COV-2 and highlighted possible mechanisms of neuromuscular invasion.

Montalvan 31 20 67 To review the neurological aspects of SARS-cov2 and other coronavirus, including transmission pathways, mechanisms of invasion into the nervous system, and mechanisms of neurological disease. Narula 32 11 13 To review current literature on seizures linked with SARS-COV 2 infection Nepal 33 37 To inform and improve decision-making among the physicians treating COVID by presenting a systematic analysis of the neurological manifestations experienced within these patients.

Pinzon 37 33 To conduct a systematic review and meta-analysis on the neurologic characteristics in patients with COVID Pousa 38 28 To summarize the most common extrapulmonary manifestations in paediatric patients with COVID, as well as to discuss clinical, epidemiological and pathophysiological aspects of these clinical presentations in children.

Sharifan 42 17, not stated To summarise available information regarding the potential effects of different types of CoV on the nervous system and describes the range of clinical neurological complications that have been reported thus far in COVID Taherifard 43 21 22 57 To systematically review the neurological complications in patients with SARS-CoV-2 infection and the methods used to diagnose both neurological complications and coronavirus infection.

Tsai 46 36 not stated To review and integrate the neurologic manifestations of the COVID pandemic, to aid medical practitioners who are combating the newly derived infectious disease. Uncini 48 33 21 42 To clarify the clinical and electrophysiological phenotype, to discuss, on the basis of the available data, whether the disease mechanism could be parainfective or post-infective and to speculate on the possible pathogenesis.

Wang 51 41 not stated To systematically collect and investigate the clinical manifestations and evidence of neurological involvement in COVID Werner 52 14 not stated not stated To conduct a review of the reported data for studies concerning COVID pathophysiology, neurological manifestations and neuroscience provider recommendations and guidelines. Wilson 54 10 not stated To evaluate and summarize the current status of the COVID literature at it applies to neurology and neurosurgery.

Neurological symptomatology, neurological risk factors for poor prognosis, pathophysiology for neuro-invasion, and actions taken by neurological or neurosurgical services to manage the current COVID crisis are reviewed.

Table 3. Number of studies and participants in each country. Table 4. Table 5. The impact of these findings on neurological healthcare services and primary care Echoing concerns raised recently by the British Medical Association, 7 the findings of this review highlight the impact that short- and long-term neurological symptoms of COVID may have on current health services. Limitations Scientific reports centred on neurological effects of COVID are still scarce, and risk of publication bias is high.

Conclusion and implications for future research There is an array of evidence to show that COVID causes neurological symptoms and, although it is difficult to ascertain how long term the symptoms may become, there is increasing evidence of the presence of Long Covid, symptoms persisting beyond 3 months. Supplemental Material sj-pdftaj References 1.

Stevens R. How does coronavirus affect the brain? Management of post-acute covid in primary care. BMJ ; : m Nabavi N. Long covid: how to define it and how to manage it. Garner P. Mahase E.

Rimmer A. Covid impact of long-term symptoms will be profound, warns BMA. Ann Intern Med ; : — Critical Appraisal Skills Programme. Abdelaziz O, Waffa Z.