Neurological manifestations of patients with COVID-19:potential routes of SARS-CoV-2 neuroinvasion from the periphery to the brain

Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has caused a global pandemic in only 3 months.In addition to major respiratory distress,characteristic neurological manifestations are also described,indicating that SARS-CoV-2 may be an underestimated opportunistic pathogen of the brain.Based on previous studies of neuroinvasive human respiratory coronaviruses,it is proposed that after physical contact with the nasal mucosa,laryngopharynx,trachea,lower respiratory tract,alveoli epithelium,or gastrointestinal mucosa,SARS-CoV-2 can induce intrinsic and innate immune responses in the host involving increased cytokine release,tissue damage,and high neurosusceptibility to COVID-19,especially in the hypoxic conditions caused by lung injury.In some immunecompromised individuals,the virus may invade the brain through multiple routes,such as the vasculature and peripheral nerves.Therefore,in addition to drug treatments,such as pharmaceuticals and traditional Chinese medicine,non-pharmaceutical precautions,including facemasks and hand hygiene,are critically important.

Detailing the ultrastructure’s increase of prion protein in pancreatic adenocarcinoma

BACKGROUND Recent evidences have shown a relationship between prion protein(PrPc)expression and pancreatic ductal adenocarcinoma(PDAC).Indeed,PrPc could be one of the markers explaining the aggressiveness of this tumor.However,studies investigating the specific compartmentalization of increased PrPc expression within PDAC cells are lacking,as well as a correlation between ultrastructural evidence,ultrastructural morphometry of PrPc protein and clinical data.These data,as well as the quantitative stoichiometry of this protein detected by immuno-gold,provide a significant advancement in understanding the biology of disease and the outcome of surgical resection.AIM To analyze quantitative stoichiometry and compartmentalization of PrPc in PDAC cells and to correlate its presence with prognostic data METHODS Between June 2018 and December 2020,samples from pancreatic tissues of 45 patients treated with pancreatic resection for a preoperative suspicion of PDAC at our Institution were collected.When the frozen section excluded a PDAC diagnosis,or the nodules were too small for adequate sampling,patients were ruled out from the present study.Western blotting was used to detect,quantify and compare the expression of PrPc in PDAC and control tissues,such as those of non-affected neighboring pancreatic tissue of the same patient.To quantify the increase of PrPc and to detect the subcellular compartmentalization of PrPc within PDAC cells,immuno-gold stoichiometry within specific cell compartments was analyzed with electron microscopy.Finally,an analysis of quantitative PrPc expression according to prognostic data,such as cancer stage,recurrence of the disease at 12 mo after surgery and recurrence during adjuvant chemotherapy was made.RESULTS The amount of PrPc within specimen from 38 out of 45 patients was determined by semi-quantitative analysis by using Western blotting,which indicates that PrPc increases almost three-fold in tumor pancreatic tissue compared with healthy pancreatic regions[242.41±28.36 optical density(OD)vs 95±17.40 OD,P<0.0001].Quantitative morphometry carried out by using immuno-gold detection at transmission electron microscopy confirms an increased PrPc expression in PDAC ductal cells of all patients and allows to detect a specific compartmentalization of PrPc within tumor cells.In particular,the number of immuno-gold particles of PrPc was significantly higher in PDAC cells respect to controls,when considering the whole cell(19.8±0.79 particles vs 9.44±0.45,P<0.0001).Remarkably,considering PDAC cells,the increase of PrPc was higher in the nucleus than cytosol of tumor cells,which indicates a shift in PrPc compartmentalization within tumor cells.In fact,the increase of immuno-gold within nuclear compartment exceeds at large the augment of PrPc which was detected in the cytosol(nucleus:12.88±0.59 particles vs 5.12±0.32,P<0.0001;cytosol:7.74.±0.44 particles vs 4.3±0.24,P<0.0001).RESULTS In order to analyze the prognostic impact of PrPc,we found a correlation between PrPc expression and cancer stage according to pathology results,with a significantly higher expression of PrPc for advanced stages.Moreover,24 patients with a mean follow-up of 16.8 mo were considered.Immuno-blot analysis revealed a significantly higher expression of PrPc in patients with disease recurrence at 12 mo after radical surgery(360.71±69.01 OD vs 170.23±23.06 OD,P=0.023),also in the subgroup of patients treated with adjuvant CT(368.36±79.26 OD in the recurrence group vs 162.86±24.16 OD,P=0.028),which indicates a correlation with a higher chemo-resistance.CONCLUSION Expression of PrPc is significantly higher in PDAC cells compared with control,with the protein mainly placed in the nucleus.Preliminary clinical data confirm the correlation with a poorer prognosis.

Role of chemokines and cytokines in the neuropathogenesis of African trypanosomiasis

Trypanosoma brucei spp. cause human African trypanosomiasis(HAT) or sleeping sickness in humans and nagana in animals. The early stages of the disease have no specific symptoms; however, the late stage of the disease involves neurological signs of the disease, including disturbance of sleep patterns from which the disease derives the name sleeping sickness. During the late stage of African trypanosomiasis parasites, increased numbers of white blood cells and levels of cytokines and/or chemokines are found in the brain parenchyma and/or cerebrospinal fluid of animal models and HAT patients. In this mini review, contemporary findings on how chemokines and cytokines are thought to play an important role in the central nervous system invasion by the parasites, inflammation and the neuropathology of the disease are discussed. The levels of various cytokines and chemokines, such as interferongamma(IFN-γ), interleukin-1 beta(IL-1β), IL-6, IL-10, tumor necrosis factor-alpha(TNF-α), C-C motif chemokine 2(CCL2), CCL3, C-X-C motif chemokine 8(CXCL8, IL-8) and CXCL10, in the cerebrospinal fluid(CSF) of HAT patients correlate with the severity or stage of the disease. Thus, these molecules are possible candidates for differentiating between early and late stage HAT. The role of cytokines and chemokines in parasite invasion of the central nervous system is also being eluci-dated. IFN-γ, TNF-α and CXCL-10 are some of the cytokines and chemokines now known to facilitate parasite penetration of the brain parenchyma. Interestingly, they also constitute some of the candidate molecules with potential to differentiate between stage 1 and 2 of HAT. The increased levels of cytokines, such as IL-1β, IL-6, IFN-γ and TNF-α, as well as prostaglandins, during African trypanosomiasis might contribute to the neurological dysfunctions that occur during HAT.

Cauda equina arachnoiditis–a rare manifestation of West Nile virus neuroinvasive disease:A case report

BACKGROUND Data regarding the neuroradiology features of the West Nile virus neuroinvasive disease(WNV NID)is rather scarce.To contribute to the knowledge of the WNV NID,we present a patient with a combination of encephalitis and acute flaccid paresis,with cauda equina arachnoiditis as the main magnetic resonance(MR)finding.CASE SUMMARY A 72-year-old female patient was admitted due to fever,headache and gait instability.During the first several days she developed somnolence,aphasia,urinary incontinence,constipation,and asymmetric lower extremities weakness.Cerebrospinal fluid analysis indicated encephalitis.Native brain computed tomography and MR were unremarkable,while spinal MR demonstrated cauda equina enhancement without cord lesions.Virology testing revealed WNV IgM and IgG antibodies in serum and cerebrospinal fluid,which confirmed acute WNV NID.The treatment was supportive.After two months only a slight improvement was noticed but cognitive impairment,loss of sphincter control and asymmetric inferior extremities weakness remained.The patient died after a month on chronic rehabilitation.CONCLUSION Cauda equina arachnoiditis is a rare,but possible neuroradiological feature in acute flaccid paresis form of WNV NID.

Impacts of Increasing Temperature on the Future Incidence of West Nile Neuroinvasive Disease in the United States

Multiple studies have identified links between climate and West Nile virus disease since the virus arrived in North America. Here we sought to extend these results by developing a Health Impact Function (HIF) to generate county-level estimates of the expected annual number of West Nile neuroinvasive disease (WNND) cases based on the county’s historical WNND incidence, annual average temperature, and population size. To better understand the potential impact of projected temperature change on WNND risk, we used the HIF to project the change in expected annual number of WNND cases attributable to changing temperatures by 2050 and by 2090 using data from five global climate models under two representative concentration pathways (RCP4.5 and RCP8.5). To estimate the costs of anticipated changes, as well as to enable comparisons with other public health impacts, projected WNND cases were allocated to nonfatal and fatal outcomes, then monetized using a cost-of-illness estimate and the U.S. Environmental Protection Agency’s value of a statistical life, respectively. We found that projected future temperature and population changes could increase the expected annual number of WNND cases to ≈2000 - 2200 cases by 2050 and to ≈2700 - 4300 cases by 2090, from a baseline of 970 cases. Holding population constant at future levels while varying temperature from a 1995 baseline, we estimated projected temperature change alone is responsible for ≈590 and ≈960 incremental WNND cases in 2050 and 2090 (respectively) under the RCP4.5 scenario, and ≈820 and ≈2500 cases in 2050 and 2090 (respectively) for the RCP8.5 scenario, with substantial regional variation. The monetized impact of these temperature-attributable incremental cases is estimated at $0.5 billion in 2050 and $1.0 billion in 2090 under the RCP4.5 scenario, and $0.7 billion in 2050 and $2.6 billion in 2090 under the RCP8.5 scenario (undiscounted 2015 U.S. dollars).

Persistent delayed auditory memory and executive function deficits 5 years after West Nile Virus Encephalitis: A neuropsychological and neuroimaging single case study

There are presently no in-depth published neuropsychological studies of West Nile Virus (WNV) encephalitis patients that have been well-correlated with high resolution structural MRI. In this study a middleaged male who developed West Nile Virus encephalitis five years previously was examined three times over a two year period. We examined him with the Wechsler Adult Intelligence Scales—Fourth Edition and the Wechsler Memory Scale—Fourth Edition (WAIS-IV/WMS-IV) and Advanced Clinical Solutions battery supplemented by tests of attention, executive, motor and sensory functions. Neuroradiological imaging revealed hypodensities within the left hippocampus in the axial and coronal planes with T2-FLAIR MRI. The man was previously high functioning and although he had prior history of well-controlled epilepsy it seems unlikely that the epilepsy could fully account for the neuropathological changes. The patient had previously completed a demanding six year double science degree program before he became ill with WNV and he had been a successful manager and director of a research company. Delayed auditory memory scores were at least two standard deviation units below age expected levels and semantic fluency and Booklet Category Tests of executive function were also in the impaired range. Moreover the illness onset profile of muscle weakness, extreme fatigue, memory complaints as well as inability to carry out research projects involving planning on the job were highly consistent with WNV encephalitis. If the memory and executive function deficits had been premorbid manifestations of epilepsy it is unlikely he would have attained the levels he did educationally and occupationally. This left hippocampal lesion is characteristic of other encephalitic viral infections such as herpes simplex virus. To our knowledge this is the first lateralized WNV encephalitis medial temporal lobe patient in the published literature.

Neurological diseases caused by coronavirus infection of the respiratory airways

Infections of the central nervous system(CNS)infections are critical problems for public health.They are caused by several different organisms,including the respiratory coronaviruses(Co Vs).Co Vs usually infect the upper respiratory tract causing the common cold.However,in infants,and in elderly and immunocompromised persons,they can also affect the lower respiratory tract causing pneumonia and various syndromes of respiratory distress.Co Vs also have neuroinvasive capabilities because they can spread from the respiratory tract to the CNS.Once infection begins in the CNS cells,it can cause various CNS problems such as status epilepticus,encephalitis,and long-term neurological disease.This neuroinvasive properties of Co Vs may damage the CNS as a result of misdirected host immune response,which could be associated with autoimmunity in susceptible individuals(virus-induced neuro-immunopathology)or associated with viral replication directly causing damage to the CNS cells(virus-induced neuropathology).In December 2019,a new disease named COVID-19 emerged which is caused by Co Vs.The significant clinical symptoms of COVID-19 are related to the respiratory system,but they can also affect the CNS,causing acute cerebrovascular and intracranial infections.We describe the possible invasion routes of coronavirus in this review article,and look for the most recent findings associated with the neurological complications in the recently published literature.