The 20th Congress of RSCANP,

Băile Felix, 18-21.09.2019

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The 42st National Conference of Child and Adolescent Neurology and Psychiatry and Allied Professions with international participation

New viral infections with influences on the nervous system

Autor: Eva-Maria Elkan Diana Ciortea Angel Liviu Trifan Ana-Maria Papuc Monica Laura Zlati Miruna Dragostin Beatris-Cela Stan Violeta Șapira
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The neurologic involvement in the viral infections is by far a public heatlth problem because they have a impact on the nervous system for short, medium
and long term. The infections with special patogenic agents is a challenge for the public health systems in the world and the reactions of public health care
specialists tends to be unitary for to meeting of the concepts and the gained knowledge until the present. The study of the betacoronaviruses and other
viral species have a great importance for the molecular study and the impact of the cytokines over the mechanism of generation of the viral invasion effects
as also from the point of view of the clinico-imagistic. We want to offer a overlook over the mechanism which can produce the impact on the central
nervous system on short, medium and long term. Apart on anecdotic findings and incidental findings the approach to the rare casuistry and with few frequencies permits a cautious questioning of some problems and the warning of the specialists on the subtle pathologies that can be combated through the prism of generally valid physiopathologic mechanismsin infections and inflammations of any type în infecții și inflamații de orice tip. The correlation
of the infections with corona virus with the acute respiratory dystress syndrome and the new therapeutic perspectives which merit to be discussed the
study of the surfactant and the immunoglobulines and the interferon merit the attention of the researchrs
Key words: special patogenes, coronavriride, surfactant, acute respiratory distress syndrome syndrome, neurologic involvement

INTRODUCTION Viruses which exert a very great affinity at the level of the breathing apparatus are the influenza type viruses, known is also the sincitial respiratory virus as also viruses form the category metapneumovirus [1]. The researches on the coronaviruses which are impacting the human body growed after the 1960 years and the dynamic of the researches has evolved and until 2003 there were known 24 types of coronaviruses on human or animals [2]. The virus CoVid 19 determines a pneumonia with severe symptoms which have some common characteristics with the infections determined by the infections of SARS-CoV and MERS-CoV. MERS-CoV means the infection which generates the Middle East respiratory syndrome [3]. Mers CoV have around 300.000 of nucleotides in his structure.The rate of fatal cases is much more, more precisely 43% than those of virus SARS CiV1 which gives a mortality of 15% [4]. Viruses which can persist in the nervous system and incorporate viruses which have in their structure DNA., the herpes simplex virus and the virus JC(John Cunningham) which is also a virus with DNA. On the other hand there can exist virusuri with RNA that can infect the brain like the measles virus., HIV and HTLV-1 [5]. From the group of the ARN patogens of the ARN from the coronaviridae group appears in children more frequent under the type of the viruses OC43 and NL 63 [6]. The human nervous system has a special particularity from the immunologic point of view and the cells with immunologic features in the nervous are the microglia and the astrocyte which
can realise some defense functions like the exposure to the antigen, fagocitosis and the production of cytokines. For example multiple sclerosis has the model of the reactivity of the autoreactive CD4 T cells. [7] PHYSIOPATHOLOGY The Coronaviruses together with the Arteriviridae and Roniviridae are included in a larger group named Nidoviruses classification which was made in 1996.The RNA of coronaviruses resemble 20-32 kilobases or 31.000 nucleotides with dimensions around 80-220 nm and the ARteriviridae have just 15 kilobases of 13.000 nucleotides and have the dimensions around 50-70 nm. The genetic material of the cronaviridae is a RNA with a single chain with positive sense. The coronaviruses have more proteins with important role in the physiopathology of the evolution of the events that they generate and this proteins are: the trimer of the Protein S which plays a role in the affinity of the virus for some tissues as also for the viral replication, the glycoprotein M and the Proteins N and the molecule of the sialic acid from the composition of the protein S helps to the growing of the attachment of the virus  [7,2]. SARS-CoV-2 has aslo the capacity to generate a protein which genetic code is owned by a gene orf8 and the resulting protein is called orf3b. This protein has influence on the activity of interferon β [8]. The viruses SARS CoV determine a diffuse involvement of the alveoles called diffuse alveolar damage (DAD) and the physiopatologic implications is the predominance of the impact over the pneumocytes type 1 in the beginning stages of the infections with exudate of liquid which contains proteins [9]. The virus SARS COV 2 is structured like a unui betacoronavirus. SARS CoV have the mechanism of cell attack through the angiotensin 2 converting enzyme which plays the role of a receptor, and MERS-CoV penetrates in the target cells predominantly thorugh the dipeptidilpeptidazei 4 – DDP4. In normal conditions ACE2, as also DDP4 are found in little amounts on the surface of the neuronal and glial cells so that are implicated other mechanisms of neuroinvasivity [3]. HEV 67 N is a coronatype virus that gained the interest of researchers because of the possibility to penetrate in the central nervous system and that was demonstrated in the case of the pigs. This type of virus can be situated in the solitary tract from the brainstem. In the case of the SARS CoV- there was demonstrate in animal models and in necroptic human pieces s-a that the virus was present in the brainstem and those facts conducted to the hypothesisi that the virus migrate through synapses to the cardio-repsiratory centers of the brainstem. These facts can explain partial the aparition of the manifestations of respiratory insufficiency associated to COVID-19 [3]. The mechanism of cerebral invasion is known through other viral infections of the nervous system caused by the varicelo-zoster virus and the types of infections given by the Japanese encephalitis. Also there is known the model of the infections with the measles virus and the influence of the infections with the HIV virus to the nervous system. The endothelium from the hematoencephalic barrier is exceeded through a mechanism known as transcitosis so they are passing through the cells. The lower velocity of the blood through the cerebral microcirculation favors the binding of the virus SARS CoV2 on the receptors ACE2 expressed on the surface of the endothelial cells, followed secondary by the overcoming of the hematoencephalic barrier and the local endothelial distruction causing possible cerebral haemorrhage [10]. A mechanism generating intense debates is that of the penetrating of the virus thorugh the olfactive nerves. A model of the penetration of the nervous system through the olfactive nerves is researched on the mouses infected with the virus HCoV-OC43. The interleukine -6 can raise in this cases in the CSF [1]. On animal
models was demonstrated also that some types of viruses like JHMV activates the cytokine system together with the chemokine system and especially the system of metalloproteinases of the infected cells. There exists also a reactivity which involves the growing of IFN alfa and IFN-β, as also IFN delta determinating finally the cytolysis of the astroglia and also the cytolysis of the microglia through the hiperactivation of the TCD8 Lymphocites. An important role is exerted by the chemokines which are exerting their actions through the membrane receptors coupled with the G proteins. This substances are linked with the immune system cells like the T lymphocites are and the macrophages and with the nervous system cells [11]. In the case of the virus JHMC the moment in which the virus appears to be in the nervous system is around the days 14-16 on the intranasal route. It was found that it produced vacuolar modifications in the brainstem and the spinal cord at 4 weeks after the viral infection [12]. Another type of virus is the hemaglutinating virus of porcine encephalomyelitis discovered in 1962 PHEV is also part of the betacoronavirus family [13]. Other corona type viruses which determine mild or moderate were identified like the HCoV-229E and also the CoVNL63 and HCoV-HKU1 viruses are. Since the 1960 from their discovery their study was enlarged. A breakthrough with a virus type of SARS Cov was in Nov 2002-until April 2004 but with few cases, around 8.000. In the case of HCov HKU1 it can not be excluded the coinfection with other viruses in the same pacient and those viruses can be the Sinicitial Respiratory Virus and the Influenza Virus [14]. The mechanism through which the SARS CoV would produce neurologic involvement like the hypoxia induced by the respiratory changes followed by the respiratory changes followed by a encephalopathy due to hypoxia the metabolic modifications and infectious as also cerebral edem and then followed by coma and death together with the other complications of the syndromes [15]. Another model of reactivity of the nervous system to the viruses type corona could be that in 1982 the researchers discovered that in patients with multiple sclerosis are existing antibodies in the cerebrospinal fluid straighten against the virus corona OC43 in 41% from the patients and in the case of the virus 226E and 21% from the patients [16]. The binding to the ACE2 receptor is influenced by the type of the mutations suffered by the virus and the mutation of N501 T of the 209 nCoV is studied because this would make it easier the for the virus to bind to this receptor located in the pneumocytes [17]. In the case of the patients with Parkinson it was found that viruses like von Economo encephalitis and the viruses Western Equine and the Japanese virus B. In 1985 Fishman demonstrated that a corona type virus MHV-A59 was more easier fixed on the basal ganglia a phenomen observed in mouses in some further epidemiologic studies showed the possibility to develop the Parkinson disease is more probable if the patient is a farmer. There was advanced the hypothesis that the viruses of type MHC as also the virus of type HCV-OC43 could affect the dopaminergic neurons from the substantia nigra in the case of a chronic affectation, because this patients have antibodies in the CSF against this viruses [18]. MiR155 is found at the T cells, as also in the NK cells and also in the dendrits. This marker is sensible to the virus of the Viral Choriomeningitis (LCMV), influenza virus but also herpes simplex virus (HSV). MiR155 has the role in the functioning of the T CD4 cells influencing the neuroinflamation [19]. Essential in the role of the SARS CoV is the fact that it can produce the apoptosis of the T cells and so inhibits the production of the antibodies mediated by the TCD4 cells which are inducing the B lymphocytes as also on the TCD8 cells which has the capacity to annihilate the cells which are infected by the virus. Very frequently vehiculated is the theory of the cytokine storm which can produce a severe multiorgan involvement and the known implicated cytokines are the TNFα, IL-1β, IL-2, IL-6, IFNα, IFNβ, IFNγ, and MCP-1 but sure there also other cytokines and chemokines are implicated as also the subtle bonds [20]. SYMPTOMS In the case of the patients with the infections with COVID-19 can appear also neurologic phenomens manifested with headache, but also with nausea and vomisments [3]. The coronaviruses can give rare necrotising enterocolitis in children and the stool samples reveal more the type HKU1virus [21]. Coronavirusurile can give symptoms of anorexia and can give symptoms of permanent fatigue [2]. Usually
the septic shock is accompanied by the involvement of the coagulation and metabolic acidosis which occurs after 7 days from the onset of the clinical picture [20]. Furthermore in this patient can be met the alteration of the smell progressing even to hipoosmia signs which are imposing supplementary for the neurologic involvement [10]. In the viral infections the neurological symptoms vary on a wide spectrum from the febrile convulsions to inaugural febrile status epilepticus which can appear and in children followed by encephalitis, encephalomyelitis, meningitis, meningoencephalitis [1]. In adults it was noted a 32 years old women in the day 22 of the disease with febrile generalised tonico-clonic convulsions of which mechanism was not ellucidated [22]. Also in adults were noted convulsions accompanied by the stiffness of the neck and this patient infected with SARS CoV2 in which were found viral RNA just in CSF and not in plasma [23]. In children the infections with SARS CoV occupies a little place <5% in the previous known epidemias as that known in Nov 2002. HCoV-OC43 and HCoV-NL63, can give extrarespiratory signs and abdominal pain and diarrhea in children. But the non SARS viruses HCoV can become dangerous for the newborn which have a fragile ground [14]. SARS CoV2 virus can give the involvement of the central nervous system in present being ongoing research but the patients can experiment headache, paresthesia but in some situations there can exist the lost of taste and smell [15]. After any critical involvement can appear polyneuropathy because of the perturbated metabolism and the prolonged inactivity, hypoxia the lack of movement as long the patient stays in the intensive care unit and which is called critical illness polyneuropathy (CIP). But in the infection with SARS it was found a polyneuropathy bound to this type of infections [23]. In the case of the viral encephalitis in children it can not be established the viral agent and they are included as idiopathic encephalopaties in 40% of the cases. Nillson has reported a case of a newborn aged 9 months old which associated encephalitis with HCoV OC43 with acute limfoblastic leucemia and the patient received Lopinavir 0,2 ml/kg/twice a day [24]. The viral S protein is implicated in the capacity to provoke viral infections of the nervous system for the virus OC43 [25]. In the table I are analysed the recent studies on the special viruses:

FURTHER RESEARCH FOR TREATMENT Besides the existing protocols we can anticipate some particular situations which can be taken in account so: – The monitoring of some interleukines in the pathologies generated by the special but also in other inflammatory pathologies can anticipate the reaction of the clinician and to modulate the treatment after the amplitude of this response and his variations in the evolution of the disease. The measurment of the Cd4/Cd8 ,the monitoring of the Feritine the IL-1, IL-3, IL-8, IL-13, IL-6, TNF alfa, IFN alfa, IFN beta, the N/L raport merit to be monitored in the severe cases.
Following this parameters and addressing the pshyiopathologic mechanisms which circumscribe the activity of the pathogen agent in the organism the researchers have oritented in the following ways. – The evaluation of the patients with MRI in the case of the neurologic involvement permits the evaluation of the patient in dinamic is a method which must be reserved carefully selected cases. – Long term EEG can evaluate the impact of the appearance of the encephalopathy and to detect nonconvulsivant status epilepticus which can give raise to exhaustion of the respiratory muscles influencing also the oxygenation of the tissues and the brain. The eventuality of the use of NICU EEG can reveal subtle neurologic pathologies which can be combatted with modern which are not sedating the patient and have minimal adverse effects. The Interferon 1 alfa will raise the neopterine which reflects the macrofage activity. Experimental it was demonstrated that the interferon 1 alfa which preceded the infection with a virus SARS reduced significant the instalation of DAD as also the viral load [9]. Some authors recommend nebulisations with Interferon. A interesant perspective is the study of ARDS and all his implications. It is known that ARDS has a high mortality of 40% in present with all the known therapeutic approaches. In those patients the tidal volume is put to 6-7 liters/min and to not expose the patient to to many repeated thoracic CT it is tested and the nitric oxygen as traces is used in concentrations under 5% to asses after volumes measurment the pulmonary which is present volume for the respiratory function.This approach is called Inspired sinewave techinque (IST) and is tested on pigs [26]. The surfactant influences the alveolar tension and has role to maintain the alveoles opened to have a good gas exchange for the alveoles [27]. When we confront with ARDS the ellection method is the mechanical ventilation which has also more types of used strategies. The surfactant is a substance which results from the mixture of phospholipids with proteins which are present in the penumocyte type II cells. In a metaanalysis presented by Meng et al it is shown that the surfactant as a treatment in adults in ARDS become in the attention of the specialists since 1994. And Weg et al presented the patients treated with surfactant after the installation of sepsis with the different types of surfactant administred as aerosols or intratracheal. This study made a review in which it was concluded that the administration of surfactant did not influence the mortality very much statistically. In children the surfactant is given 100-200 mg/kg. [28]. Ambroxol has a positive role in the secretion of surfactant. It can be given in some situations 50 mg/day for to favour the modelation of the action of the surfactant [29]. For to understand the impact on the hole body it is necessary to understand the mechanisms of ARDS which are different in neonate. The researchers concentrated on the administration of surfactant in some clinical trials
in this syndrome. There were made reserches in the ameliorating of pulmonary fonction in adult rabbits at the administration of surfactant poractant alfa or rSP-C33 [30]. In the case of the infection with MERS Cov it was tried a association between the interferon alfa and 2 b, and Ribavirin. In one of the cases the antibiotic adjuvant treatment was with Ceftriaxon and Azythromycine but also Methylprednisolon 500 mg for 3 days [31]. Helicases are some proteins implicated in the dissolution of the chains of the viral molecule of MERS and the nonstructural protein NSP13 makes part from this category being important for the power for replication of the virus. There are more molecules of Triazol in the study which have the helicases as a target which forbid the virus to replicate [4]. A new research idea is represented by the immunoglobulines prepared from the serum of the convalescent patients which could be administred to the patients infected with Covid 19. The disfunction of the cytokine system stays on the basis of the initiation of the therapy with immunoglobulines. In one of the analysed patients for this therapy the patient received also Oseltamevir and Azithromycin and there were also tried association with Moxifloxacin. This patient weighted 66 kg and received 25g/days of imunoglobuline for 5 days after he developed a very severe clinical picture [33]. DISCUSSIONS AND CONCLUSIONS The therapeutic strategy in the infections with special patogene viruses must be adapted to the national existing protocolls and coroborated with specific parameters for each patient and with the associated conditions and the existing therapeutic interactions. In the intensive care services the anaesthiosologist after the evaluation of the patient in collaboration with other medical and surgical specialities will evaluate the risks and opportunities of each treatment but in special situations it merits some methods which are part of the heroic medicine, but with all the precautions and respecting the deontologic codes and the codes of medical ethics. So we wanted to offer a review of some mechanisms and therapies which even they are not in the wide practice they can open the ways of new researches and opportunities of intervention in the complications which can happen in viral infections with special patogens.

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