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",isbn:"978-1-83969-057-0",printIsbn:"978-1-83969-056-3",pdfIsbn:"978-1-83969-058-7",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"5f388543a066b617d2c52bd4c027c272",bookSignature:"Prof. Christophe Hano and Dr. Jen-Tsung Chen",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10539.jpg",keywords:"Plant Description, Botany, Phylogeny, Genome, Phytochemical Analysis, Extraction, Phytochemical Diversity, Phytochemical Analysis, Extraction, Phytochemical Diversity, Biotechnological Production, Traditional Medicinal Uses",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 8th 2020",dateEndSecondStepPublish:"November 23rd 2020",dateEndThirdStepPublish:"January 22nd 2021",dateEndFourthStepPublish:"April 12th 2021",dateEndFifthStepPublish:"June 11th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Assistant Professor at the University of Orleans at Research INRAE Lab LBLGC USC1328 and a member of the Cosm'ACTIFS Research Group (CNRS GDR3711). He authored and co-authored more than 100 scientific papers, reviews, and book chapters in internationally renowned journals.",coeditorOneBiosketch:"Dr. Jen-Tsung Chen is currently a professor at the National University of Kaohsiung in Taiwan. He teaches cell biology, genomics, proteomics, medicinal plant biotechnology, and plant tissue culture in college. Dr. Chen's research interests are bioactive compounds, chromatography techniques, in vitro culture, medicinal plants, phytochemicals, and plant biotechnology. He has published over 60 research papers, reviewed over 260 manuscripts, and edited at least 150 papers in international peer-review journals.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"313856",title:"Prof.",name:"Christophe",middleName:null,surname:"Hano",slug:"christophe-hano",fullName:"Christophe Hano",profilePictureURL:"https://mts.intechopen.com/storage/users/313856/images/system/313856.jpg",biography:"Dr. Christophe Hano (male, 1978), who completed his PhD in 2005 in Plant Physiology, Biochemistry and Molecular Biology, is now Assistant Professor at the University of Orleans at Research INRAE Lab LBLGC USC1328 and a member of the Cosm'ACTIFS Research Group (CNRS GDR3711). His research career has focused on applied plant metabolism and plant biotechnology. He has written more than 100 scientific papers, reviews and book chapters in internationally renowned journals and edited one book as well as a variety of journal topical issues on plant secondary metabolism, including polyphenols. He is Academic, Assistant Editor and/or Editorial Board Member of several renowned Q1 Journals in Plant Biochemistry and Biotechnology (including Plos ONE, Biomolecules, Plant Cell Tissue and Organ Culture, Frontiers in Plant Science, Cosmetics). He was reviewers for more than 500 papers for ca 35 International Journals, and recognized scientific expert for several national and international Institutions. Currently, he is developing research projects aimed at studying plant secondary metabolism to lead to the development of natural products with interests in pharmacology or cosmetics. His research focuses on the green extraction and analytical methods applied to plant polyphenols, elucidation of biosynthetic mechanisms of plant natural products and their exploitation by metabolic engineering approaches. He was a leader (project manager) in 6 scientific projects and major investigator in several more. In this context he conducts research projects in cooperation with industrial companies and he coordinates in the European Le Studium® Consortium Action on the bioproduction of bioactive extracts for cosmetic applications through plant cell in vitro cultures. In this context, he explores the potential of the Loire Valley Flora Area for cosmetic applications. (Cited over 1450 times; H=20; i10=44; orcid.org/0000-0001-9938-0151).",institutionString:"Laboratoire de Biologie des Ligneux et des Grandes Cultures INRA USC1328",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Orléans",institutionURL:null,country:{name:"France"}}}],coeditorOne:{id:"332229",title:"Dr.",name:"Jen-Tsung",middleName:null,surname:"Chen",slug:"jen-tsung-chen",fullName:"Jen-Tsung Chen",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000031RJmlQAG/Profile_Picture_1600760167494",biography:"Dr. Jen-Tsung Chen is currently a professor at the National University of Kaohsiung in Taiwan. He teaches cell biology, genomics, proteomics, medicinal plant biotechnology, and plant tissue culture in college. Dr. Chen's research interests are bioactive compounds, chromatography techniques, in vitro culture, medicinal plants, phytochemicals, and plant biotechnology. 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From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"67918",title:"Ion Beam Experiments to Emulate Nuclear Fusion Environment on Structural Materials at CMAM",doi:"10.5772/intechopen.87054",slug:"ion-beam-experiments-to-emulate-nuclear-fusion-environment-on-structural-materials-at-cmam",body:'Structural materials for nuclear fusion applications will have to withstand a very hard environment in the future reactor. Very energetic neutrons which will produce displacement cascades, transmutation into light atoms, nuclear activation and nuclear heating will be produced during operation. These neutron reactions, along with stresses produced by the reactor weight itself, and cyclic loads due to thermal and electromagnetic stresses draw a very harsh panorama for these materials [1, 2, 3, 4].
Neutrons from nuclear fusion reaction induce elastic and inelastic nuclear reactions. The very first atoms from the matrix displaced by the incident neutron are denominated Primary Knock-on Atoms (PKA) spectrum, and this PKA spectrum is generated by both elastic and inelastic reactions. Generally speaking, depending on the isotope considered, the larger contribution to the total displacement is due to the elastic reactions (90%). However, atoms initially displaced for their lattice site by neutrons (PKA spectrum) will induce elastic reactions, which produce additional displacement damage (displacement cascades) because they eventually will produce large collision cascades, since the secondary atom impacted by the PKA has enough energy to move a third one and so on.
Therefore, this PKA spectrum will be responsible to deposit the displacement damage in the material. On the other hand, if the neutron produced an inelastic reaction, an induced transmutation by neutron collision will be produced, generating light atoms as helium and hydrogen until hundreds of atomic parts per million (appm) in the whole life service of the reactor along with PKAs depending on the energy deposited [5].
Regarding helium atoms, one of the main issues in terms of structural material degradation is the nucleation and growth of He bubbles at grain boundaries which would produce a reduction of service lifetime. This degradation comes due to helium atoms produced by transmutation reaction of Fe; around 4 MeV of neutron energy may produce the following reaction generating alpha particles 56Fe (n.a) 53Cr [6]. It is well known that the combination between helium atoms and vacancies is very energetically favorable, so it will form eventually He bubbles. For that reason a deeper understanding of the effect of those bubbles in the evolution of microstructure and further degradation of mechanical properties are critical. However, several parameters have to be controlled and studied to determine properly the evolution of He bubbles during irradiation such as temperature, He production rate, displacement rate, and dose (accumulation of He).
Candidate materials for being used as structural materials are reduced activation ferritic martensitic (RAFM) steels, since they show a high resistance to irradiation damage, higher thermal conductivity, good corrosion resistance, and good liquid metal compatibility than austenitic steels. Several studies have shown that grain boundaries or phase boundaries may also act as sinks for radiation-induced point defects and the cluster formed during irradiation [7].
On the other hand, collision cascades known as accumulation of atoms displaced will form a complex form of Frenkel pair defects such as interstitial clusters which may turn into large dislocation loops or vacancy-type voids. Those irradiation-induced defects act as barriers to the dislocation movement, so they produce a significant hardening and hence a ductility reduction.
Neutron irradiation is not the most used technique to irradiate materials since the nuclear activation of the specimens makes necessary to have available hot cells to characterize the samples. On the other hand, nowadays there is no facility to emulate neutron fusion environment; for that reason ion beam irradiations are used to emulate neutron irradiation, of course, having into consideration the main differences such as shallow depth of irradiated material, elevated dose rate, and, clearly, not transmutation.
Current neutron sources with an energy spectrum typical of fusion reactions (14 MeV neutrons) are far from the fluence expected in a fusion reactor, and they are only useful for a few cases involving functional materials not exposed to high radiation doses [8, 9]. Therefore, a common approximation to test fusion materials consists of using ion irradiation to emulate the effects of neutron irradiation [10]. Ion irradiation can yield higher damage rates generating negligible activation levels in the irradiated samples at a reduced cost than other approximations to the problem like fission reactor irradiations. These elevated dose rates are very interesting to obtain samples submitted to an accelerated damage aging that would take several years to be achieved by fission irradiation. It is necessary to consider, however, that these accelerated tests may be driven by aging mechanisms very different from the real processes taking place under the low damage rate produced by real fusion conditions.
Another important difference that must be considered is the low ion penetration in the material (typically several microns for heavy ion energy in the range of 1–20 MeV) compared to the tenths of centimeters that a neutron can travel before interacting with a material nucleus. Since the particle accelerators have a fixed energy, a selective filter or energy degrader system is required to obtain an almost uniform spectrum of beam energies to allow a particle implantation in the most controlled possible way. The thickness of the filter determines the final energy of the beam, so to obtain a certain energy spectrum, it has been thought of a multifilter revolver-type system, consisting of a design in the form of a rotating daisy, with peripheral aluminum foils of different thicknesses in order to achieve different mitigations of the beam energy [11].
As stated before, to date, most of the studies on these structural materials have been focused on material behavior as a function of different parameters as irradiation dose, particle energy, and irradiation temperature, among others [12]. However, next-step fusion devices, such as the International Thermonuclear Experimental Reactor (ITER) [13] and demonstration power plant (DEMO) [2, 14, 15], are magnetically confined devices, and the performance of the materials under reactor conditions when high magnetic fields are present is still unexplored. Besides, theoretical predictions suggest that magnetism can be a non-negligible factor in defining the defect properties induced by He irradiation or in determining the atomic distribution in FeCr alloys [16, 17]. Material microstructural properties can be modified by defect propagation due to irradiation. It is considered that such propagation may be affected by external magnetic fields, as recently pointed in Ref. [18]. For this reason, more detailed experimental knowledge of structural materials is sought, in particular with regard to mobility and clustering, as well as helium and hydrogen accumulation in reactor conditions. Thus, expanded experimental knowledge of structural material response to irradiation under magnetic fields has become critical.
In this chapter, the development of a new sample holder located at a vacuum chamber of standard (STD) irradiation line at CMAM is presented. Preliminary results have been obtained in this system for a series of FeCr alloy (10–15% Cr), alloy specimens irradiated with 1 MeV Fe+ ions under the effect of the magnetic field produced by a permanent magnet (0.5 T) at STD irradiation line at CMAM.
As sometimes, experiments are costly even with ion beams and are not always available; modeling is one of the key tools to predict long-term defect evolution. However, irradiation damage predictive simulation is still under development and needs many experimental results as inputs to validate their simulations. So, sometimes, irradiation experiments are headed not only to study the degradation of complex microstructure materials such as RAFM candidates but to obtain results of irradiating very simple and pure such as very high pure iron, iron chromium model alloys in order to study the effect of certain alloying elements on irradiation defects evolution.
Electrostatic accelerators over the world present a variety of shapes and sizes and can be classified attending to different factors. The fundamental features that characterize a DC accelerator are mainly three: the type of particle that can accelerate, the beam current and the maximum kinetic energy achievable. These defining parameters determine the subsequent research field of application.
In this section, we describe the fundamentals of a 5 MV Tandetron delivered by high-voltage engineering (HVE) for ion beam analysis (IBA) and ion beam modification of materials (IBMM) at operation in CMAM in the Universidad Autónoma de Madrid (Spain) [19]. In Figure 1 it is possible to observe (a) plan view of the mentioned accelerator and (b) all the lines which are nowadays working. This kind of facility is also of great interest to investigate fusion-induced material damages by creating a controlled environment to simulate these effects.
The Tandetron ion accelerator is a tandem type that counts with a Cockroft-Walton high-voltage generator system that will be presented briefly in the following paragraphs, describing sources for ion beam generation, beam acceleration, and two of the beamlines available used for experiments for nuclear fusion.
The first step for IBA or IBMM experiments is to generate the beam, i.e., to produce ions from neutral matter, extract them, and focus the beam. Since the selected ion and the current are a function of the experimental needs, the source constraints are of critical importance. CMAM facility is provided with two sources: a plasma source for gaseous substances and a sputtering source to obtain practically any element of the periodic table from a solid target.
The range of current that can be obtained from the source varies from a few nA to tens of μA, depending on the source and the ion. As will be presented later, the tandem configuration requires the production of negative ions, which are more difficult to obtain than positive ones. It is much easier to rip off electrons from an atom than to add them on. It is not even possible to obtain negative ions from all elements, as is the case of nitrogen, so unstable that in practice cannot be produced [23].
This section addresses basic ideas of two specific kinds of ion sources, duoplasmatron and negative sputtering source.
In this configuration, negative ions are effectively produced from a solid target which contains the desired beam material inside a cylindrical refrigerated copper cathode, the sputter target holder. A cesium reservoir is heated providing vapor to the main cavity of the source. The neutral flux of Cs has two functions: on the one hand, the cesium condensates over the target surface, and, on the other hand, a fraction of the Cs atoms in the gas becomes positively ionized by contact with a heated ionizer surface. The ionizer is kept at positive voltage with respect to the cathode so that positive Cs ions bombard the target producing the ejection of sputtered atoms that pass through the optimally cesiated surface with a low work function [20, 21]. By this surface effect method that involves cesium as a great electron donor, sputtered atoms from the target become negative (secondary negative ions). Those ions are repelled from the cathode to the extraction section of the source and focus into a negative beam. Beam currents of 2–40 μA are achieved, depending on the species. Elements with negative electronic affinity, such as nitrogen, can be extracted from the source in the form of a molecular beam (e.g. NH-) and broken into its components at a later stage. Any element of the periodic table from hydrogen to uranium can be delivered, with the important exception of helium.
The duoplasmatron source permits two modes of operation, positive and negative ion beam extraction from a gas (typically H2 or He). Positive operation is required for helium atoms because being a noble gas is not possible to efficiently obtain negative helium ions directly from the source. After positive extraction, He+ ions pass through a charge-exchange cell filled with lithium vapor where the final negative beam emerges for further acceleration. Only about 1% of the He+ ions coming from the source turn negative, a fact that limits the maximum achievable current to a few μA versus tens of μA obtained when working in negative operation.
The working principle of ion generation consists of a two-stage discharge where the gas is leaked into the source and the molecules are ionized. The first discharge is produced by means of thermo-ionic emission from a hot filament, between the filament (cathode) and the intermediate electrode (IE). A strong confining magnetic field guides the electrons through an aperture to the second discharge region between the intermediate electrode and the anode [22]. The magnetic field and the geometry of the IE are specially configured to enhance plasma density and high ionization degree. Finally, regarding the extraction direction, just comment that the ions are axially extracted from the plasma.
The ions in the beam exiting the source are shaped, focused, and led to the entrance of the accelerator, passing through a 90° analyzing magnet that bends the beam and selects the proper mass of the single negative-charged ions. Mass separation is done by tuning the magnetic induction so that only a given q/√m ratio is transmitted through the entrance and exit collimators. This is necessary because the beam exiting the source contains several species along with the desired one due to imperfect vacuum or impurities in the target. The electromagnet is water-cooled and capable of inflecting all ions in the periodic table, selecting them by momentum per unit charge, i.e., by magnetic rigidity [Eq. (1)] [23]:
where B is the tunable magnetic induction, m the desired mass of the particle, E its energy, q its charge, and r the radius of curvature of its trajectory, which is determined by the entrance and exit of the magnet.
The guidance and focusing of the beam during its trajectory are achieved by electrostatic and magnetic devices called lenses for the analogy that can be drawn with the effect of thick optical lenses on light. Moreover, electrostatic or magnetic deflectors properly steer the beam into the optical axes of the lenses so that adjusting the lens will alter the focus but not the position of the beam.
(a) Plan view of the tank and the lines of CMAM accelerator and (b) detail of the accelerator lines (courtesy of Jorge Álvarez Echenique, CMAM).
Following the injector system, the beam containing negative ions at a certain kinetic energy defined by the extraction voltages of the sources (tens of kV) goes through the next stage, the accelerator.
A tandem-type accelerator system consists of a two-step acceleration process. The high-voltage terminal electrode is enclosed in the center of a pressure vessel midway between the entrance and the exit of the acceleration tube, both at ground potential. Once injected into the low-energy part of the tube, the ions get attracted toward the positive terminal, increasing their energy in nVT electronvolts, where VT is the terminal voltage and n is the charge state, equal to 1. At this point, the beam passes through a region where N2 gas circulates, getting stripped off from one or more electrons, thus inverting their polarity and getting accelerated again to ground along the high-energy tube. The beam is composed now of a distribution of positive charge states n that vary from 1 to Z, Z being the atomic number of the atom. This second step leads to an energy gain of nVT electronvolts that depends on the specific charge state of each ion [24].
The extra energy obtained by inverting the polarity is the primary benefit of tandem-type accelerators over single-ended ones and the reason why negative ion sources are required. Additionally, this system allows the sources to be outside the tank, a fact that implies easier maintenance and simpler operation of the sources. On the contrary, the charge-exchange process results in a reduction of beam intensity, especially for heavy ions, being the transmission up to 50%. However, for IBA analysis and many material experiments, these currents are adequate.
The total kinetic energy achieved at the end of the accelerator tube is given in electronvolts [Eq. (2)]:
where Eext is the extraction energy and VT is the positive terminal voltage, with a maximum nominal value of 5 MV.
Effective focusing of the beam waist at stripper canal is achieved by optically matching the injector part to the accelerator with a pre-acceleration electrode called Q-snout.
The engineering challenge of electrostatic accelerators relies on how to produce high voltages, which main limitation is the breakdown due to insulation problems.
As was previously described, the positive high-voltage terminal is located at the center of the tube. But in electrostatic accelerators, the high voltage is gradually distributed among multiple equipotential tubes with a slightly increased value, so that the ions feel a stepwise acceleration in the insulated gaps between each segment. That keeps a reduced value of the local electric field.
The accelerator at CMAM produces the terminal voltage by means of a Cockroft-Walton (C-W) generator system, a design based on a cascade-type voltage multiplier circuit that was implemented for the first time in a DC accelerator in 1932 by J. D. Cockcroft and E. T. Walton [23] at the Cavendish Laboratory in England. It consists of a circuit feed by radio-frequency (RF) voltage power that supplies a higher DC voltage level. It is constituted by an assembly of repeated units of capacitors and rectifier diodes that double the voltage amplitude with each additional block. A final voltage of 2 nV is obtained, where n is the number of repeated blocks, 50 in the case of CMAM Tandetron [24], and Vo is the amplitude of the AC voltage. A simplified scheme of the multiplier circuit invented by Greinacher [25, 26] in 1921 is shown in Figure 2.
Simplified scheme of the Cockroft-Walton generator. The voltage across each stage of the cascade is equal to twice the peak input voltage in a half-wave rectifier.
The hole voltage multiplier structure is placed around the evacuated acceleration tube in a coaxial configuration. High vacuum is required inside the tube to minimize unwanted secondary electron production by collisions of the ions with atoms of the residual gas. Furthermore, small magnets are placed to suppress these backstreaming electrons before they get accelerated generating hard X-rays. The electrodes are parallel fed with the increasing potential by resistive grading, and thus the voltage is smoothly distributed from terminal to ground. All the assembly is enclosed inside a pressurized tank filled with insulating sulfur hexafluoride gas (SF6) to prevent electrical breakdown, and every component is specifically designed to reduce local electric stress to avoid corona and sparking [22].
The advantage of C-W generator system relies on being entirely based on a solid-state circuit. The absence of moving parts, the high RF driving frequency (~38 kHz), a special RC filtering, and the feedback circuits that monitor the terminal voltage through a generating voltmeter (GMV) provide a remarkable terminal voltage stability and low terminal voltage ripple (less than 50 V at 5 MV). As a result, a superior beam energy resolution is achieved.
After acceleration, the beam is finally focused by an electrostatic quadrupole triplet lens. The first and third quadrupoles focus in the vertical direction (Y-axis) and defocus horizontally (X-axis), while the quadrupole in the middle makes the opposite.
A second magnet with seven exit ports at different angles steers the beam to direct it through an evacuated pipe to the selected experimental station. Since the beam is composed of a distribution of charge states n, the switching magnet has the additional important role of discriminating a certain charge state in order to establish well-defined beam energy.
CMAM counts with six operative beamlines devoted to different research fields: standard multipurpose beamline, internal μ-beam line, ERDA-ToF line, implantation beamline, external μ-beam line, and nuclear physics beamline.
The essential features of two of the routinely used beamlines for experiments for structural materials for nuclear fusion applications at CMAM accelerator are outlined below.
This line is attached to the 30° port of the switching magnet and is the one that was initially installed and tested by HVE. The experimental chamber is placed 3.5 meters away from the magnet, not needing additional focusing. A set of two slits separated 2 m from each other are used to control the size and divergence of the beam, and the current can be measured with a Faraday cup located immediately before reaching the chamber [27].
The standard line is mainly devoted to Rutherford backscattering spectrometry (RBS) and elastic recoil detection, but several ports are available to position additional setup. The entire structure is kept under high-vacuum conditions by means of a turbomolecular pump assisted by a rotary pump.
A fixed Si barrier particle detector is located at 170° with respect to the incident beam, while another movable detector can be positioned at any angle, counting with a carousel with different foils and slits that can be positioned in front of the movable detector. Also, an SDD detector for simultaneous particle-induced X-ray emission (PIXE) performance is implemented.
The sample holder is mounted on a three-axis goniometer and a vertical platform that permits to position the samples and to orient them with respect to the incident beam, so random and channeling experiments can be performed. The sample holder is electrically isolated; it can be biased at +180 V to suppress the effect of secondary electron emission, and the total dose or fluence can be monitored during irradiation by means of a current meter and integrator from HVE [28].
The implantation CMAM beamline is at −20° with respect to the accelerator axis, 6 meters after a second switching magnet located at 0° line.
Ion beam modification of materials (IBMM) is the main research field carried out in this line, given that high electronic stopping powers and penetrations of several microns are achievable. Irradiation with ions from H to Pb at maximum terminal voltage can be performed selecting their more prolific charge state, i.e., irradiating with the highest current beam attainable. That allows heavy ion irradiations within the range of 2–50 MeV and currents up to a few μA, depending on the ion. The experimentation chamber is electrically isolated and designed for ultrahigh vacuum (UHV). Samples’ temperature can be modified with a cryostat/furnace designed at CMAM within a range of −180–600°C and precisely controlled during irradiations with a system of thermocouples located at the sample holder and a thermographic camera.
An important feature of this beamline is the capability of performing irradiations over large areas, up to 10 × 10 cm2 on target. An electrostatic beam sweeper of HVE is installed, which deflects the beam a maximum of 9 mm both in vertical and horizontal directions. The beam sweeper permits to scan the irradiation area at 2 and 31 kHz rates in X and Y directions, controlling the beam offset position and scan amplitude. In that way, homogeneous quasi-static beam areas are delivered, as observed in several images below (Figures 8,9,11, and 13).
The irradiation fluence is calculated by measuring the beam current with a Faraday cup in the line and the irradiation area with the aid of a scintillator.
As it was described above, many applications of particle accelerators require varying the beam energy in an experimental beamline without changing accelerator settings. A multifoil (variable thickness) beam energy degrader provides a fast, reliable, and reproducible way of setting the beam energy, obtaining a uniform damage and implantation profile for both, heavy and light ions. The prototype installed at the implantation line of the CMAM has a disc with a diameter of 120 mm (Figure 3), which rotates at a thousand revolutions per minute to avoid foil melting under high-current beam irradiation [27]. On the outside the disc has nine aluminum foils of different thicknesses to achieve an energy sweep from maximum energy absorption (thicker foils) and minimum energy of ions to minimum energy absorption of the primary ion beam (thinner foils). The tenth window is free to let the ion beam pass without any energy mitigation. The aluminum foil thicknesses chosen for this prototype were 6–50 microns for H and He ions and 0.8–4 microns for heavier ions like Fe.
Umbrella shaped wheel of the beam energy degrader prototype.
A water-cooled motorized ferrofluid feedthrough has been chosen with its rotation controller for installation in the specific irradiation chamber of the beam degrader. The controller is able to maintain constant rotation at 1000 rpm and to stop the wheel in the open-blade position to avoid foil damage. The steel vacuum chamber has been designed and manufactured to house properly the degrader wheel, the sample holder itself, and its diagnostics (Figure 4a). The necessary set of vacuum pumps and gauges for the degrader chamber has been also installed in the line. Proper butterfly and venting valves were also installed in the vacuum chamber to avoid foil damage during the first stages of chamber air evacuation and venting. The vacuum chamber includes a sample holder with an oven specially designed to operate at controlled temperature in the range between room temperature (RT) and 600°C (Figure 4b) and also it is equipped with an XYZ motorized sample holder for multi-sample experiments (Figure 4c).
(a) Vacuum chamber, (b) sample holder oven operating in vacuum at 450°C and (c) vacuum chamber inner view with the degrader wheel and powered sample holder.
Several irradiation experiments have been performed using the beam energy degrader. Cu, Fe, and steel samples have been irradiated with H and He ions (current ~ 1 μA) with an energy of 2.25 and 9 MeV, respectively, obtaining implantation profiles with good uniformity from the surface up to 22 μm depth for both ions. This is especially interesting as it is therefore possible to implant both chemical species in the same sample volume. Figure 5a shows a SEM cross section of EUROFER97 steel sample implanted with 9 MeV He through a beam degrader with aluminum foils with a thickness from 6 to 50 μm. The implanted sample was etched with Marble’s reagent (CuSO4 hydrochloric acid and water) to exhibit the fringes of implanted He. The simulated profile calculated by stopping and range of ions in matter (SRIM) showed great similarities with the real one. Some other experiments have been developed with thinner aluminum foils (0.8–3 μm) and Fe ions with different energies on Fe samples. Figure 5b presents the SRIM calculation of the implantation profile of 6 MeV Fe ions on a Fe sample with an average current of 200 nA of Fe2+ ions using the degrader device.
(a) SEM cross section view of the 9 MeV He irradiation profile on EUROFER97 steel with SRIM simulation and (b) SRIM implantation profile of 6 MeV Fe ions on Fe sample using the thin foil (0.8–3 μm) energy degrader.
Consecutive triple irradiation (Fe, He, H) at temperatures of interest for fusion research (350–550°C) is also available with the experimental setup described in this section, which may be a way to get the nuclear fusion condition with only one accelerator instead of having three of them [29, 30]. To emulate the effects of neutron irradiation, it is therefore possible to irradiate an Fe or steel sample with 20 MeV Fe4+ ions with the degrader wheel stopped at the open window (no energy reduction) to obtain a region damaged by Fe ions from the surface up to 2 μm (most Fe ions will stop in the 2–3 μm range generating too many interstitials for a realistic analysis). After that an irradiation with H+ or He+ ions can take place with the degrader wheel spinning with the thinnest foils mounted (0.8–6 μm) and an energy of 1 MeV (H+) and 2 MeV (He+). This procedure would allow to obtain a damaged region uniformly implanted with H and/or He.
The new vacuum chamber and the beam energy degrader mounted on the implantation line of CMAM irradiation facility also allow the implementation of innovative techniques for material research. In this case we have installed a microtensile test module (Figure 6) inside the vacuum chamber in order to carry out mechanical strain/stress tests of materials under irradiation or irradiate structural materials (Fe, Cu, steel), while the sample is submitted to a constant stress. The chamber base shown above and holding the XYZ sample holder can be easily changed by a new one with the microtensile module installed and connected with the proper Fischer feedthrough. Especial connectors are also incorporated for temperature measurements (thermocouple and oven) during the tests.
Microtensile test module mounted in the vacuum chamber base (a) and detail of the test section with a probe (b).
In order to investigate the influence of an external magnetic field on ion-induced damage, a new experimental system has been developed at the STD line of CMAM. It consists on a dedicated custom sample holder with a permanent magnet embedded behind one of the samples (see Figure 7a). Here the samples are irradiated in pairs with and without external magnetic field (B = 0.4 T) with field lines oriented normal to the sample surface in order to avoid ion beam spreading. Commissioning of the system was performed by the irradiation of a luminescent material deposited on a metal support plate. In this way, it was observed that the ions impacting on the luminescent material showed good magnetic field uniformity. In addition, the complete system, i.e., the holder, the permanent magnet, and a UHP-Fe test sample, was also tested during 4 h of irradiation by a 2 MeV, 200 nA current H+ beam at a sample temperature of −100°C, with and without magnetic field, getting a good temperature control during irradiation and a same ion beam footprint in sample without B and with B. Although irradiations can generally be performed at low temperature, the analysis is always carried out at RT.
(a) New sample holder for the irradiation of samples in pairs. It has a permanent magnet behind the right sample. The setup is connected to a LN cooled finger (by a Cu mesh) to achieve low temperature if required. A thermocouple is touching one of the samples for temperature measurements; (b) ANSYS simulation of the magnetic field in the sample near the permanent magnet.
In parallel, prior to starting the experiments, ANSYS simulations were done for Fe90Cr10 slice (1 mm thick) embedded in the center of a long solenoid (giving 1 T in the central column) in order to emulate the effect of B on the surface of the sample. Figure 7b shows that although a high concentration of magnetic field lines is observed at the edge, there is good magnetic flux uniformity about the irradiated zone (sample central region), thus validating the experimental setup for use with these samples.
A series of experiments have carried out with this sample holder to study the damage in FeCr alloy (14% Cr content) when irradiated at low temperature by heavy (Fe+) and light (He+) ions, single and sequentially, and additionally, the influence of an external magnetic field (B = 0.4 T) was also analyzed [31]. In this context, the influence of B on defects shows small but significant differences in the magnitudes studied here by conversion electron Mössbauer spectroscopy (CEMS) and slow positron annihilation spectroscopy (SPAS). Mössbauer spectra point to less clustering for a sample damaged by He+ (being closer to the as-received sample) than irradiation without B. SPAS points to slightly lower values of vacancy-type defects over a large region when a sample is damaged by self-ions (Fe+, high dose) or by sequential irradiation: Fe+ and He+ (again compared to irradiation without B). SPAS results further support the conclusion that the size or concentration of the vacancy clusters created during the Fe + ion irradiation diminishes in the presence of B.
Also, FeCr alloy (10% Cr) damaged by Fe+ up to 15 dpa (displacement per atom) was analyzed by CEMS and found differences when the magnetic field is present during irradiation [18]. The results indicate that the Cr distribution in the neighborhood of the iron atoms could be changed by the application of an external field.
The detailed studies carried out up to date [18, 31] indicate that an external magnetic field may be an important parameter to take into account in predictive models for Cr behavior in FeCr alloys and especially in fusion conditions where intense magnetic fields are required for plasma confinement. Experiments with higher B and higher sample temperature are currently in progress in order to elucidate if external magnetic fields are a key parameter in the structural materials damage.
Acquiring knowledge concerning fusion transmutation product (He and H) effects on structural materials is difficult to study because of the lack of proper facilities. Using an ion beam accelerator, nuclear fusion-related amount of He was incorporated into the structural material, EUROFER97, using two different ways in terms of beam configuration—defocused beam and raster beam. This is a critical matter to consider because different defect evolution has been detected depending on which method has been taken into consideration to perform the irradiations [32, 33].
For this research, a defocused beam was used to implant He into the RAFM steel. This kind of beam configuration has a Gaussian-like profile in terms of ion current with its consequent reduction in density. To establish a valid methodology which allow repetitive and successful experiments, it is necessary to fix some experimental parameters such as ion current, the size of the beam and integration time of the camera that acquires the images from the sample camera because the higher the integration time is, the brighter the image is and the beam size measurements can be wrongly calculated and hence the implanted dose. In order to diminish the numbers of variables to study, irradiation temperature was fixed as room temperature. Hence, the relationship between ion energy, implanted dose, and steel microstructure was studied in terms of radiation defects observed afterward in transmission electron microscopy (TEM).
Regarding the sample holder, as observed in Figure 8a, STD line offers a very high flexibility in terms of geometry and size of the samples. Two different squared specimens of steel were attached to the holder along with a wire that was placed underneath to measure the ion current properly and with a current integrator, the implanted dose was calculated accurately. The characteristics of the He ion beam were evaluated by means of ionoluminescence on fused silica, which was used to set up the beam properly: size and stability of the beam prior to irradiation (Figure 8b).
(a) Irradiation sample holder for implantation beamline. (b) Helium beam irradiating quartz used to measure the quality and size of the beam.
Before irradiation, simulation code MARLOWE [34, 35] was used to determine the maximum irradiation depth (obtained with 15 MeV in this experiment) and the resultant concentration of He for each energy. It is well known that although the fluence is the same (1.65 × 1015 He ions/cm2) when increasing the ion energy, the peak experiences a broadening, therefore the concentration is the same (integrating the area under the peaks) but the maximum value decreased.
As ion implantation depth is quite shallow in comparison to nuclear irradiation, a stair-like profile of He concentration was used, starting for 15 He MeV and ending with 2 MeV, decreasing the energy in steps of 1 MeV. After implantation, samples were cut and polished through its cross section and were etched in diluted Marble as described before. The etching revealed some lines which represented each and one of the He implantation peaks. Afterwards, the microstructure was observed with a scanning electron microscope (SEM) in order to measure the depth and eventually compare with the simulated position of the stopping peaks for all the implanted energies. The result was that the simulation (Figure 9a) and the experiment (Figure 9b) matched completely [36]. In addition, it is possible to observe a clear difference with Figure 5, where the lines are more diffuse because of the use of a degrader; however, in this experiment, the irradiation peaks are very clear to identify.
(a) Depth and helium ion concentration profiles as obtained using MARLOWE code. b) SEM micrograph of EUROFER97 steel implanted with He ions from 15 to 2 MeV, showing the ion stopping region matches with simulation. Published in [36].
The other possibility to perform He irradiation by means of ion beams is using a raster beam. In this case, the beam swept a certain area with a very high frequency. Figure 10 showed a fused silica emitting light because of the He beam. On the image on the left, the beam swept only the x-axis, the image of the center swept only the y-axis, and on the image on the right, the beam scanned both axes covering the whole area.
Ionoluminescence produced by raster beam in different sweeping axes during beam setup. The following images were taken when beam was moving along a) x axis, b) y axis and c) x and y axes together.
Regarding beam heating, as the beam is more focused than the over-focused beam, it is possible that the material experiences a heating which is critical to be measured since the irradiation defects are very temperature sensitive.
A thermographic camera was used to control the aforementioned heating, using as reference a small sample of fused silica because its emissivity and its dependence with temperature are very well known. In Figure 11, images taken from the camera are shown after some minutes of irradiation. No important heating was measured, only 15–20°C maximum.
Thermographic camera images during x-axis (a), y-axis (b), and both axes simultaneously (c) sweeping.
The sample holder belonging to this line is very flexible, so several specimens can be mounted as observed in Figure 12a On the other hand, Figure 12b was taken during irradiation. For raster beams, there is no need to measure the beam size before irradiation, since it was determined with the sweeping parameters. However, a way to observe if the beam experienced any kind of sparkling (or any other phenomena which can indicate malfunction) a piece of fused silica was placed along with the specimens in order to observe the beam during irradiation (Figure 12b) by means of ionoluminescence as it was done with the defocused beam experiment.
(a) Sample holder in STD line for raster experiments. (b) Sample holder during irradiation with a circle-shape beam.
Once the experiment is ended, TEM studies were performed to characterize the defects produced on the steel because of He irradiation. In this case, some TEM discs were prepared by electropolishing, keeping the transparent area within the irradiated area. As mentioned in the introduction, He irradiation may produce bubbles, and it is well known that a typical way to detect them is through focus serial method, changing the objective length focus distance. When the specimen is found under-focused, the bubbles are observed with white contrast, and on the other hand, when it is over-focused, the bubbles are dark. However, if there are any other microstructural characteristic as secondary phases, grain boundaries, or similar, their contrast remained grayscale-like. In Figure 13, three micrographs are presented showing EUROFER97 microstructure with large bubbles within the microstructure (Figure 13 (a) over-focused, (b) in-focus, and (c) under-focused).
TEM micrographs showing He bubbles within steel matrix in (a) over-focused (bubbles in black), (b) in-focus (poor contrast), and (c) under-focused (white bubbles).
It has been demonstrated that both beam configurations are valid to carry out He implantations. However, more experiments have to be conducted to determine which one is closer to nuclear fusion environment.
Neutron irradiation produces atomic cascades, as described above, in which the atoms from the matrix moved from their equilibrium positions, generating certain atomic disorder. This disorder stays reflected in dislocation defects as an accumulation of Frenkel pairs. In addition, neutrons also produced transmutation reactions not only generating He and H but radioactive isotopes, thus it would be necessary to keep and test the samples in hot cells. For that reason, a safer and more afforadable way to emulate defects produced by neutrons is to irradiate iron-based alloys such as steels, with Fe ions. Those ions, although they alter a very shallow layer of materials, do not produce transmutation nor modify the chemical composition of the samples so they are called self-ions. There are some examples of irradiations with larger atoms as Xe [37, 38] or Kr [39], although the objective is not the emulation of nuclear fusion environment, since they produce a significant chemical change in the material composition.
Unlike He irradiation, the effect of self-ion irradiation in the microstructure is hard to characterize since the dislocation loops are a very complex features to observe properly and it needs long time and effort, along with a great knowledge of TEM (microscope operation, exquisite sample preparation, and insight of on the theory on irradiation defect generation [40, 41]). In addition, in this field there is a huge gap between simulation models and experiments headed to validate such simulations within the frame of nuclear fusion, so it is an opportunity of irradiating simple alloys which are the base of the complex alloys (i. e. EUROFER97, F82H, ODS steels…). Regarding He bubbles, there is relatively large literature about modeling bubbles in actual steels [42, 43, 44, 45, 46, 47, 48], and due to this, the irradiations headed to the understanding of He bubble nucleation and growth carried in this matter are subjected to steels instead of more simple alloys. As in the case of Fe implantation that pure iron is used.
For these experiments, the sample holder used was the motorized one which allows high temperature heating as shown in Figure 14, This study required a wide range of irradiation temperatures because dislocation loops are very temperature sensitive. The type of beam used was defocused, since the specimens were small (TEM discs), and it was not required to move the beam to cover all the area of interest.
(a) Motorized sample holder for Fe ion irradiations. (b) Light produced by ionoluminescence because of the irradiation of Fe ions onto MACOR piece.
The main goal of this research was to determine if there is a difference in the developing of microstructural irradiation defects because of the temperature and the specimen thickness. The energy used was 20 MeV, and the temperature was 300 and 450°C up to a dose of 5 dpa at the irradiation peak. Several irradiations took place, in order to study two thin foils and two discs (bulk samples) at the two aforementioned temperatures. In Figure 15, the damage profile obtained with SRIM is shown. The red curve represented the whole damage peak produced in the bulk samples whose thickness was around 100 μm. On the other hand, the damage generated in the thin foils with a thickness approximately of 100–150 nm fabricated by electropolishing, as the regular TEM disc preparation, is showed with the blue curve, because the ions pass through the thin films. For that reason in bulk specimens, the damage reached the maximum, 5 dpa. However, in thin films the damage is much lower (0.1 dpa), although the ion energy was the same.
SRIM profile of bulk irradiation (red curve) and thin-film irradiation (blue curve).
Once the irradiations were finished, the samples were studied by TEM. Dislocation loops were found in all the specimens (both bulk and thin foils), but size and distribution were completely different between bulk and thin-film experiments. In the first one, although the damage was much higher, the maximum loop observed was 22 nm, and the distribution was quite heterogeneous, being maximum at the damage peak depth (Figure 16a and b). Nevertheless, in thin films, in spite of the small amount of thickness and the small amount of damage deposited by self-ions, very large loops were detected, even larger than 500–600 nm distributed homogeneously within the material (Figure 16c and d). In addition, differences between Burger vectors and population density have been found. Deep characterization is being carried out, but those preliminary results proved that the configuration (accelerator device, irradiation parameters, and sample holder) used in CMAM facility provides the tools required to perform high quality experiments whose results will be of a great support for modeling scientists.
Dislocation loops found in pure Fe in different experiments in bulk experiments at 5 dpa and (a) 350°C and (b) 450°C and in thin foils at 0.1 dpa at (c) 350°C and (d) 450°C.
The importance of ion beam accelerators to perform experiments which gain insight with about the possible synergies between radiation damage, microstructure, strain, and magnetic fields regarding degradation of structural materials for nuclear fusion applications has been presented in this chapter. It is well known that there is a gap between neutron irradiation and ion irradiation, but it is still a very important source of knowledge until the scientific community has the possibility of using a facility which emulates the nuclear fusion environment as DONES [5].
CIEMAT has been carrying out for several years numerous experiments in this field generating vast knowledge about irradiation effects on structural materials, with the help of CMAM facility and its researchers and staff.
Therefore, it has been demonstrated that ion beam accelerators are a fundamental tool to the developing of the future nuclear fusion reactors.
This work has been supported by Ministerio de Ciencia, Innovación y Universidades Projects, ENE2015-70300-C3-1-RE, ENE2016-76755-R, NE2016-76755-R, and MAT2012-384407-C03-01, and TechnoFusion Project (S2013/MAE-2745) of the Comunidad Autónoma Madrid (CAM) and partially by the European Communities within the European Fusion Technology Programme 2014–2018 under agreement No 633053. “The views and opinions expressed herein do not necessarily reflect those of the European Commission.”
The authors wanted to thank the National Center for Electron Microscopy (CNME) staff and all the researchers and technician from CIEMAT, specially the researchers working on simulation: F. Mota, C. Ortiz, and F. Jiménez-Piñero. In addition, the authors wanted to extend their gratitude to all CMAM staff for their help, kindness, and contribution with this work. Finally, the authors do not want to miss the opportunity to express the appreciation to High Voltage Engineering Europa B.V. to allow and check this publication.
Zika virus (ZIKV) is a mosquito-borne viral disease caused by a flavivirus from the Flaviviridae family and transmitted by species belonging mainly to genus Aedes, discovered in 1947 in Uganda in infected rhesus monkeys [1, 2] with the first human cases reported in Africa and Asia [3]. Latin America and the Caribbean started to be affected with outbreaks, the first one reported in 2015 in Brazil [4]. Systemic symptoms include fever, maculo-papular rash, headache, arthralgia and conjunctivitis [2, 5].
Ocular involvement of ZIKV is not an uncommon manifestation in a patient with Zika virus infection. There are two main situations in which ocular pathology can occur: The first one is the manifestation of the virus in an adult patient, including the non-purulent conjunctivitis and more rarely ocular inflammation, especially in the anterior segment [6, 7]. Non-purulent conjunctivitis occurs between 55 and 63% of patients, as reported in outbreaks from Yap Islands and French Polineise, however according to other studies, conjunctivitis only occurs between 10 and 25% of patients infected with ZIKV [8, 9, 10].
The second way implies ocular abnormalities of congenital etiology, that belongs to the congenital Zika syndrome (CZS) [11]. The most prevalent congenital disorder is brain calcifications (42.6; 95%CI, 30.8–54.4), meanwhile the prevalence of ocular disorders was less frequent (4.2; 95% CI, 1.0–7.5) [10]. The overall presentation rate of ocular manifestations in infants with CZS is 21.4–55% [11, 12]. Infection due to ZIKV in the first trimester of pregnancy can trigger the presentation of CZS in 1–13% of the cases with ocular manifestations in patients present up to 70% of cases [13].
First report in literature about ocular manifestation in CZS was published in 2016 with three cases of children with mothers exposed to the virus during gestational age, leading to macular chorioretinal atrophy in all cases [14]. A second report of ocular anomalies related to CZS was done in a 10 case-series, informing horizontal nystagmus in 10% of cases, exophoria in 40% of cases, esophoria in 20% of cases, macular alterations like gross pigment mottling and/or chorioretinal atrophy and optic nerve anomalies like hypoplasia with double-ring sign, pallor, and/or increased cup-to-disk ratio in 75 and 45% of evaluated eyes respectively [15]. An interesting fact about these ocular anomalies is that it is not required the presence of microcephaly to get an ocular involvement, like was reported by Ventura et al. in an infant with cerebral calcifications and an unilateral chorioretinal scar in macular region [16] .
In the same year, it was reported a case series including 29 patients with microcephaly due to CZS, in which 36.5% had some degree of ocular involvement: Lens subluxation, bilateral iris coloboma, optic nerve abnormalities and chorioretinal atrophy in 5.9, 11.8, 47.1 and 64.7% of cases respectively [17]. Afterwards, in 2017, in a bigger sample (70 children with microcephaly),36% were positive to ophthalmological findings like macular and optic nerve anomalies (26% of ocular cases), strabismus/nystagmus (10% of ocular cases) and suboptimal visual acuity (100% of ocular cases) [18]. Zin et al. reported a cohort of 112 children with 21.4% of cases with positive ocular findings: 79.2% of cases with optic nerve abnormalities, 58.3% with retinal involvement, 25% with nystagmus, 4.2% with microphthalmia [19].
In Colombia and near countries like Venezuela, exists studies reporting ocular findings [20], like a study with 43 microcephalic children, of which 12% presented optic nerve hypoplasia, 63% macular pigment mottling, 7% lacunar maculopathy and 12% developed congenital glaucoma [21]. Alvarado-Socarras et al. reported a case series of children born from women infected with ZIKV, where two children had intraretinal hemorrhages, hyper/hypopigmented lesions. The increased risk for ocular ZIKV in these cases where derived from the presence of microcephaly and the infection during pregnancy [22].
In an attempt to assess the risk factors associated to ocular manifestations, Ventura et al. conducted a cross-sectional study including 40 microcephalic children, 60% of them with ZIKV positive infection. There was a statistically significant relationship of ocular manifestations to children with smaller cephalic diameter at birth (95%CI, −2.56 to −0.51; P = 0.004) and infants whose mothers reported symptoms during the first trimester (95%CI, 0.02–0.67; P = 0.04) [23]. It is relevant to mention that not only ocular structural changes are manifest in children with CZS, but also functional abnormalities like ocular motor disorders, visual fields defects (45.1% of cases), low contrast sensitivity (81.3% of cases), hypoaccomodation and refractive errors. Prevalence rate of severe visual impairment without structural changes is present in 84.6% of cases, related to cortical/cerebral involvement [24]. According to Baran et al., visual acuity losses occur in children with gestational infection, with a slowing of visual development even in the absence of microcephaly [25].
It is not necessary the presence of microcephaly in children or ZIKV systemic symptoms in pregnant women to manifest ocular abnormalities. Ocular involvement caused by Zika virus should be included in differential diagnosis, especially in endemic areas, of any patient presenting ocular manifestations and a history of fever. This chapter describes the most important aspects of the ocular compromise caused by ZIKV, items that the clinicians should consider when approaching a patient with a suspected ocular involvement by the mentioned virus.
ZIKV, similar to other flaviviruses, has an icosahedral envelope with positive single-stranded RNA as a genetic material that encodes a polyprotein processed by viral and cellular proteases into three structural proteins: capsid proteins, membrane and envelope that form the viral particle and mediate the binding of the virus, allowing entry and encapsidation. Seven non-structural proteins (NS) (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5), play a role for polyproteins processing and the induction of an innate antiviral response in the host. The main surface glycoprotein involved in the binding of the host cell and the fusion of the viral membrane is the envelope protein, which allows the fixation and fusion of the viral particle to the host cell and is a useful tool in the diagnosis [26]. Viral reproduction is achieved through non-structural proteins (NS1–NS5), which serve as self-dividing peptidases, together with viral RNA-dependent RNA polymerase [27].
Through the endocytosis process, the virion enters the cytoplasm of the cells [28]. Non-structural proteins bind to the endoplasmic reticulum, where viral replication of RNA is performed using cell structure and dynamics and released by cellular apoptosis. Subsequently, it takes the viral phase that occurs between 3 and 5 days after the first symptoms, then hematogenous spread to organs and tissues occurs. It is believed that the virus could have neuronal (pantropic) and other organ tropism, because viral RNA has been found in the brain, as well as in the liver, kidney, heart and spleen [29]. There are also other forms of transmission called non-vector, such as vertical transmission [30, 31], sexual transmission and blood transfusion [32, 33].
The pathophysiology of the ocular findings is not known in detail so far. It has been studied in animal models and deceased fetuses that have tried to demonstrate the great retinal compromise that includes macular abnormalities such as pigment spots and chorioretinal atrophy, loss of retinal pigment epithelium, perivascular choroidal inflammatory infiltrate and optic nerve abnormalities such as hypoplasia, paleness and increased cup-disc ratio. Other publications describe additional findings, such as iris coloboma, lens subluxation, cataracts, glaucoma, and microphthalmia [15, 34, 35]. At the ocular level, Zika virus infection can affect any part of the uveal tract (iris, ciliary body, retina and choroid), since most clinical cases have defects in the posterior segment [14, 15]. The hematoretinal barrier formed by vascular endothelial cells of the inner retina and external RPE (Retinal Pigment Epithelium) cells constitutes the first protective barrier that is responsible to control the entry of innate immune cells and pathogens into the posterior eye segment [36, 37]. The type I interferon (IFN) response is an important defense mechanism against most flaviviruses. A129 mice, which are deficient in IFN α and β receptors, have been commonly used as an animal model to study ZIKV infection [38, 39].
By detection of RNA nucleic acids in animal models, it has been suggested that the ocular infection can spread hematogenously to the brain and the eye simultaneously, although it is not possible to rule out the transfer through the optic nerve, in which there has been shown that houses the higher concentration of viral antigen. Therefore, the spread of the virus at the ocular level could be hematogenous or axonal, as studies show, however the viral peak during viremia suggests the hematogenous route through the choroid choroid as a more important initial mechanism. After day 3, the progressive increase in viral RNA levels in the eye is markedly different from that of peripheral blood [40]. In a hypothetical study using human target cells, it was shown that the pathophysiology of ocular ZIKV begins when it spreads throughout the retinal bed through the retinal arteries affecting the endothelial cells and the retinal pericytes of the internal hematoretinal barrier and then compromises the choroid to infect the external hematoretinal barrier by compromising the RPE cells and allowing the amplification and spread of the virus in the retinal bed. It was found that retinal endothelial cells are highly permissive for ZIKV and showed important cytopathic effects. It was shown that Müller cells are not permissive for ZIKV infection and photoreceptor cells appear to be even less so. The highest levels of ZIKV transcription were observed in retinal pericytes [41].
It has been documented that the entry and binding of several viruses at the cellular level is facilitated by the TAM (tyrosine kinase) receptors as well as the TLR [36] (toll like receptor) that play an important role in the organization of the innate responses of the retina in the microbial infection. Among them, AXL (TAM type receptor) was identified as the main receptor involved and together with the TLR3 (toll like receptor) that is involved in the viral infection, they allow the binding of the virus and its respective anchorage to the cellular guest machinery. These findings suggest that ZIKV can use AXL as an input receptor to gain access to hematoretinal barrier cells and therefore cause retinal pathology. Host cells employ intracellular pathogen recognition receptors, such as TLR and RIG-I-like receptors, for the recognition and initiation of innate immune responses, in particular with the generation of the interferon pathway (IFN type I). ISG15 induced by type I IFN is generally considered an antiviral gene that plays a protective role in the retina against ZIKV infection. Although, ISG15 has been shown to influence viral replication both positively and negatively. The expression of several IFN-induced antiviral genes has also been demonstrated, including OAS2 and MX1 [40, 41, 42].
In animal models it has been seen that by day 9 of the infection process, there is activation of local glial cells and the start of cell recruitment given a subtle increase in the gene expression of MHC, B2m and STAT1. In addition, there is an increase in TNFα, granzyme, perforin and IFNγ without evidence of CD3 or CD8 T markers, suggesting that possibly NK cells reach the eye in the early stages of the disease [40, 42]. A few days later (days 12–16), when mice develop clinical signs of encephalitis, chemokine expression in the eyes peaks. The analysis of the profile of cytokines and adhesion molecules reveals a marginal increase in the levels of β2-m, GMCSF and MCP1 and a moderate increase in the expression of ICAM-1, IL-6 and VCAM-1; and higher levels of RANTES expression (Regulators after activation, normal T cells expressed and presumably secreted) are evidenced in ZIKV infected cells. This elevation recruits inflammatory cells in the retinal microenvironment and produces chronicity [41]. Recent studies in mouse models suggest that ZIKV is located in the iridocorneal angle and in the trabecular meshwork where through the already mentioned mechanisms, they induce cell death at the level of the trabecular meshwork, leading to induction of inflammatory response that causes trabeculitis and could be one of the potential mechanisms for the IOP increase and glaucomatous pathology [43]. Furthermore, once the infection is located at the ocular level, panuveitis can be generated in the presence of ZIKV in the layers of the cornea, choroid, bipolar and ganglion cells of the retina and optic nerve and therefore the viral RNA can be secreted from tear glands or detached from the cornea to the tears [44].
Several studies have been conducted in animal models to try to address the pathophysiological mechanism involved in the development of eye disorders. Van den Pol et al. studied an animal model in infected newborn mice, which exhibit a brain development process similar to the human brain fetus in the second trimester. They mainly analyzed the brain and the visual pathway, identifying the damage caused by ZIKV in the entire visual system, including the retina, the optic chiasma, the suprachiasmatic nucleus, the lateral geniculate nucleus and/or the superior colliculus. The theory postulated that ZIKV can be transported axonally, which improves the spread of the virus within the brain, with a fundamental role of glial cells to understand the mechanism behind neurological and ocular findings [45].
Singh et al. also conducted an animal model study that only analyzed the pathophysiology of retinal findings demonstrating that retinal cells, including those of the RPE, are permissible for ZIKV replication and express receptors for them. In addition, they are susceptible to ZIKV-induced cell death, leading to retinal lesions because of the virus ability to break the integrity of the hematoretinal barrier. They suggested that ISG15 (Interferon-stimulated gene 15) and its antiviral activity, plays a role in the innate defense of the retina against ZIKV infection [46].
In a subsequent study with a murine model, Zhao et al. showed that ZIKV can infect the retina in immunodeficient and immunocompetent mice and affect multiple retinal layers. ZIKV preferentially infects RPE and Müller cells, which are key support cells for neuronal survival, function and repair of retinal lesions. Müller cell ablation causes neurological and vascular pathological effects that resemble the ocular characteristics of congenital eye disease due to ZIKV. Müller cells show a decreased neurotrophic function with a post-infection up-regulation of cytokines levels [47]. In a more recent study, Aleman et al. [48]. provided the first evidence in-vivo in humans that shows central retinal degeneration with severe loss of ganglion cells and a borderline thinning of nerve fibers, as well as a less prominent loss of photoreceptors. The findings provide the first evidence to date, in humans, that ganglion cells -and perhaps surrounding glia cells- are the primary cellular targets in the retina of patients with ZIKV infection, which is consistent with the murine disease model that suggest a depletion of this neuronal population in the uterus as a result of the infection [44]. Figure 1, resumes some of the pathogenic theories involving the ZIKV and its infection to some of the retinal cells.
Pathogenic infection process by ZIKV to the retinal pigment epithelium.
The most important findings of ophthalmologic abnormalities associated with Zika virus infection are reported in infants with microcephaly due to Zika congenital infection, leading to a broad spectrum of ophthalmological manifestations. It is proposed that the ocular findings could be a result of the direct effect of Zika virus itself and not only a consequence of microcephaly, because of the known deleterious effects of the virus on the central nervous system [14, 49, 50, 51]. The increased neurotropism of the virus explains why the retina and optic nerve are the main structures affected in infants with congenital Zika virus syndrome. It has been proposed that the typical optic nerve hypoplasia is more related to microcephaly, and the retinal anomalies specially found in the neurosensory retina are associated to an inflammatory reaction due to the virus toxin. The majority of findings are bilateral [23, 52]. There is no report of uveitis in congenital cases [53].
Zika exposure without infection during gestation does not seem to affect ocular status, visual acuity or visual development. When the Zika virus is vertically transmitted to the fetus and the subsequent infection is confirmed, the infant may show ophthalmologic and visual function damage. There has been described retinal abnormalities in children with microcephaly attributed to Zika virus infection during pregnancy, found in 60–85% of the affected patients with ocular findings, including optic nerve abnormalities and macular alterations [23, 51]. It is hypothesized that the most sever ophthalmic manifestations occur when the infection takes place in the first or second trimester of pregnancy, because of the Zika’s tropism related to the neural precursors, which are available in the early phases of cerebral differentiation [10, 23, 54, 55]. It has been found that retinal findings are more prevalent when the infection takes place in the first trimester and the related viral load may be relevant to the final process that results affecting the macula. In the other hand, the optic nerve could be affected in all trimesters [5].
Optic nerve hypoplasia is one of the most important findings in infants with congenital Zika virus infection [51]. This condition can be identified with the double ring sign as a manifestation of a small and undeveloped optic nerve [23, 52, 56, 57] (Figure 1). Other typical signs of insult to the optic nerve include pallor and increased cup-to-disk ratio [13, 15, 56, 57] (Figure 2). The most frequent macular findings associated with congenital Zika virus infection include gross pigment mottling, foveal reflex loss and chorioretinal atrophy, which differs from toxoplasmosis scars because of the absence of intraocular inflammatory signs and the presentation of a typical dark pigmentation rim around the atrophic area [15, 18, 58]. The circumscribed macular atrophy observed in the affected children seems to be pathognomonic to congenital Zika syndrome [5, 6, 50]. The macular atrophy caused by Zika virus infection is mostly associated with involvement of the outer retinal layers and choriocapillaris (Figure 3). Inner retinal vascular abnormalities could also be present and associated with post-viral neurological sequelae of Zika virus infection, in addition to the well-known outer retinal effects of the infectious disease [59].
Optic disc hypoplasia with double-ring sign associated with hyperpigmented mottling and one sharply demarcated chorioretinal atrophy on the macula. Image courtesy from Camila Ventura, MD, PhD. Altino Ventura foundation (FAV) - HOPE eye hospital. reproduced with permission.
Macular chorioretinal atrophy, hyperpigmented mottling, vascular attenuation and optic disc hypoplasia. Image courtesy of Camila Ventura, MD, PhD. Altino Ventura foundation (FAV)-HOPE eye hospital. reproduced with permission.
Anterior ocular findings related to Zika virus infection include iris coloboma, cataracts, lens subluxation, intraocular calcifications and microphthalmia even in the absence of microcephaly [34, 60]. However, it is known that the incidence of structural eye alterations, visual acuity loss and fundus abnormalities are significantly higher when the infected child exhibits concomitant microcephaly [14, 25].
Among infants with congenital Zika virus infection, the most commonly reported ocular motility disturbances include early-onset strabismus, nystagmus and ocular flutter [21, 25, 60]. The vascular findings are mainly subretinal hemorrhages and abnormalities in peripheral retinal vasculature, including abnormal termination of the retinal vessels, tortuosity and vascular attenuation [21].
This condition is rare (2.6%) but can occur in infants presenting with CZS and microcephaly. The related findings include and enlarged and cloudy cornea, buphthalmos, photophobia and excessive tearing [11, 57, 61].
The important increase in the prevalence of microcephaly in newborn infants in the Americas, in association with the previously described abnormal and vision-threatening ocular findings, should promptly lead to suspect the diagnosis of congenital infection due to Zika virus in these epidemic regions, which could be confirmed with real-time polymerase chain reaction in the first 5 days of acute phase of infection, after ruling out TORCH infections [62]. It is clear that infants with microcephaly should be screened for ocular lesions, but it is so important to consider that infants without microcephaly may have eye lesions. Then all children of the epidemic areas, such as South America, Central America and the Caribbean, with potential maternal Zika virus exposure at any time during pregnancy should be screened for ocular implication regardless of the presence of central nervous system alterations, because ocular findings could be underdiagnosed if microcephaly continues to be the main inclusion criterion in the screening of this group of children [16, 19, 63]. In addition, all newborns with mothers infected with Zika virus during pregnancy should have an early ophthalmological evaluation including the proper posterior pole examination through full dilation of the pupil [17, 64, 65].
The most important difference between infants and adults is that in adults there could be seen symptoms and signs of an active infectious process with the chance of detecting the Zika virus during a viremic period. In adults, only 20% of adults are symptomatic, and therefore the majority of adults with an acute Zika virus infection are asymptomatic [66]. Instead, in infants the related ocular findings are usually scars, as a manifestation of a post-infection process.
Symptomatic patients infected with Zika virus can exhibit a non-purulent conjunctivitis as a non-specific manifestation in the mild course of the disease [8, 67, 68]. Hypertensive iridocyclitis secondary to Zika virus infection has been reported during the acute phase of the disease, associated with ocular discomfort, redness and blurry vision, variable ciliary injection and anterior chamber reaction, miosis and elevation of the intraocular pressure. The findings usually ease after the viremia decreases and the use of topical treatment with steroids, cycloplegic and ocular hypotensive agents [69, 70, 71].
Other ocular findings in adults during acute infection include unilateral acute maculopathy, which exhibits a grayish annulus and pigment mottling as fundoscopic alterations, as well as disruption of the outer retinal and retinal pigment epithelium architecture in the central macula on optical coherence tomography and early hypofluorescence with irregular late central staining on angiogram, in addition to prompt resolution with visual function recovery [72, 73]. Neuroretinitis with a macular-star pattern has also been described in literature [74]. There could be found associated placoid or multifocal non-necrotizing chorioretinal lesions, especially in immunocompromised patients, that usually evolve with scaring and posterior improvement of visual acuity. Then, these chorioretinal lesions may be a manifestation of the active phase of infection in patients with viremia [24, 40, 75].
After clinical evaluation in individuals showing clinically compatible symptoms, the laboratory diagnosis of acute infection is based on the use of molecular tests for direct detection of viral nucleic acids (RNA) in blood and other biological samples and serological tests with tests of Enzymatic immunosorption (ELISA) or immunofluorescence assays (IFA) which allow the detection of IgM and IgG antibodies in serum. In a specialized manner, virus neutralization assays can also be performed to confirm the specificity of the ELISA or IFA tests, as well as cell cultures to isolate the virus [8, 76].
During the acute phase of the infection, the diagnosis is based on the detection of viral nucleic acid (RNA) by (RT-PCR) polymerase chain reaction of reverse transcription in blood, urine and saliva samples as well as in others biological samples such as CSF, amniotic fluid, semen [77], fetoplacental tissue and aqueous humor. Furtado et al. reported the case of a patient using aqueous humor to perform RT-PCR [70]. Two separate samples should be collected: the first during the acute phase and the second in the next 2–3 weeks [78]. If the result is negative, serological tests such as IGM should be supplemented, if they are positive, the plaque reduction neutralization test (PRNT) is performed as complement to determine whether or not there is a recent infection [76]. The conjunctival fluid contains virus for up to 7 days compared to urine and saliva samples of less than 20 days [79, 80].
The Center for Disease Control recommends that an initial clinical evaluation should be performed in all infants with evidence of exposure to ZIKV or with suggestive laboratories, regardless of whether they have abnormalities consistent with ZIKV infection. There should be also evaluated those infants with abnormal clinical or neuroimaging findings, such as intracranial calcifications that were detected prenatally or during childbirth, and whose mothers were potentially infected with ZIKV during pregnancy [81].
According to the ECDC, a case is defined as confirmed when at least one of the following laboratory criteria is present: nucleic acid detection (RNA), antigens in a clinical sample; virus isolation in a clinical sample; detection of specific antibodies (IGM) in serum samples and confirmation by neutralization test; seroconversion or quadruple increase in the titer of specific antibodies against ZIKV in paired serum samples. A case is defined as probable if specific IgM antibodies are detected in serum. Epidemiological criteria must be taken into account [82]. It is recommended to perform funduscopy under pharmacological dilation in those patients with risk factors at least once within the first month and repeat at 3 months as a follow-up for those patients with confirmed diagnosis.
ZIKV infection can occur with a wide spectrum of ocular findings, the most characteristic being the mottled pigment and chorioretinal atrophy that are commonly observed in the posterior pole especially in the macular area. There has been reported cases in the literature with manifestations that include conjunctivitis, uveitis [70], unilateral acute idiopathic maculopathy, chorioretinal lesions of acute onset, self-resolution, non-necrotizing multifocal placoids or manifestations such as manifestation of active chorioretinitis due to virus [75], optic neuropathy and congenital glaucoma [61], retinal vasculopathy [59], and hypertensive iridocyclitis [71].
The funduscopy is clinically important as a diagnostic tool and atrophic pigmented macular and peri-macular lesions, diffuse RPE damage and chorioretinal atrophy can be observed [14]. There are reports where funduscopy revealed pigmented external retinal lesions, retinal vascular abnormalities as tortuosity and dilation and atrophy of the optic nerve [11, 83]. In the peripheral retina a hypolucid spot can be observed as well as scattered subretinal hemorrhages external to the macula.
In fluorescein angiography early blockage and late staining in the retinal pigment epithelium is present. In autoflorescence, multimodal images showed a group of hyperautofluorescent lesions, it has also been described that there were focal areas of presumed choroiditis visualized as hypercynesic lesions in indocyanine green angiography [83].
Furtado et al. reported the case of a patient diagnosed with Zika by molecular and serological tests as well as positive ZIKV RNA in (RT-PCR) in aqueous humor obtained by anterior chamber paracentesis and described bilateral conjunctival hyperemia, bilateral non-granulomatous keratic precipitates and positive cellularity in the anterior chamber [70]. Parke et al. presented the case of a patient in whom alterations in the RPE with a gray ring around the fovea were observed and evidence by optical coherence tomography in the external retina and with macular area compromise. The above findings were in relation to a positive result for molecular testing with PRNT neutralization reduction technique of ZIKV [73].
For a better understanding of the ocular findings and as a follow-up to the characteristics probably related to ZIKV infection at the ocular level, some studies that analyzed the retinal tissue have been performed, Ventura et al. for example described the related findings by OCT in a series of consecutive cross-sectional cases that included 8 infants. The main OCT findings in the affected eyes included disruption of the ellipsoid zone and hyperreflectivity underlying the retinal pigment epithelium, thinning of the retina and choroid, and a colobomatous excavation [84].
Oliveira et al. described that the OCT results show a wide range of retinal damage caused by congenital ZIKV infection, and reinforced the findings compatible with chorioretinal atrophy [85]. Campos et al. described a case report with similar findings that correspond to retina thinning with atrophy of the external retina, including the outer nuclear layer and the ellipsoid zone, associated with hyperreflectivity of the RPE and increased OCT penetration into deeper layers of the choroid and sclera (Figure 4) [86] .
Spectral domain OCT of a macular lesion in an infant with presumed Zika virus-associated microcephaly, demonstrating retinal thinning with atrophy of the outer retina, including the outer nuclear layer and ellipsoid zone, associated with retinal pigment epithelium hyper-reflectivity and increased penetration of OCT into deeper layers of the choroid and sclera. Taken from Campos AG, Lira RP, Arantes TE. Optical coherence tomography of macular atrophy associated with microcephaly and presumed intrauterine Zika virus infection. Arq bras Oftalmol. 2016;79(6):400–1. Reproduced with the permission from the author according to creative commons attribution license.
Henry et al. used images of fluorescein-like fundus lesions and indocyanine green angiography, autofluorescence and optical coherence tomography associated with ZIKV and described acute and multifocal posterior non-necrotizing placoid epitheliopathy lesions that could be characteristic of active chorioretinitis due to ZIKV [75]. The findings described by OCT suggested that the neurotropism manifested by the ZIKV corresponds to significant necrosis areas of the retinal tissue.
There is no specific approved antiviral treatment nor vaccines for the ZIKV infection to date. Actual treatment due to this virus is focused in control of symptoms (rest, fluid ingestion, antipyretics as paracetamol) [2, 53]. There are several compounds been tested in-vitro, each one with different action mechanism between each other’s: Inhibition of the replication of the virus at early and late phases (For instance the Direct Acting Agents);inhibition of the molecular attachment, endocytosis and fusion mechanisms of the virus leading to block the viral entry, like duramycin, suramin and nanchangmycin [87, 88]. Some different molecules are being studied in animal models such as Z2 synthetic peptide inhibitor and the cholesterol-25-hydroxylase, which interfere vertical transmission in pregnant mice and cause cholesterol oxidation respectively [89, 90]. Novobioctin, lopinavir-ritonavir and bromocriptine cause an inhibition of the protease activity (NS2B-NS3 vial protease protein) [91, 92].
There is a growing interest in developing a vaccine against the ZIKV that could be used, especially in pregnant women. Animal models have been implemented, like knockout mice with shortcomings in IFN-I or IFN-II receptors, recreating many of the characteristics of the infection. The vaccine candidates that are been studied are in phase I or II, being the most promising a ZIKV-purified inactivate virus, or nucleic acid and adenovirus-based vaccines against the prM and E proteins providing long term protection in monkeys and mice [93, 94, 95, 96, 97].
There is no existence of guidelines or clinical trials about the treatment of ocular manifestation in ZIKV infection. The available data is extracted of case reports and case series. It is mandatory to focus the treatment according to the ophthalmic clinical context of each patient. In a patient with ophthalmologic manifestations that are presumed to be derived from ZIKV, it is necessary to exclude other causes before, then specific treatment is established.
In adults, ocular compromise in acute phases of the ZIKV infection could be treated with topical steroids, cycloplegic, and hypotensive topical medication according to ocular signs and symptoms present at that moment. Ocular compromise in children require a multidisciplinary approach and a focused treatment according to the present ocular conditions [53]. Cases with refractive errors, anisometropias, hypoaccomodation, amblyopia, and strabismus requires visual development therapies (eyeglasses, patching, ortoptics, and strabismus surgery) that are key in visual rehabilitation [12, 98].
Cases of anterior uveitis derived from ZIKV infection, usually are self-limiting course, which makes redundant the need of therapy [99]. However, there are cases of hypertensive acute anterior uveitis treated with β-Blockers and carbonic anhydrase inhibitor eyedrops accompanied or not with topical steroids and cycloplegics with normalization after treatment [70, 71, 100]. Kodati et al. reported an adult case of posterior uveitis and chorioretinal lesions in an inmunocompetent patient treated with loteprednol etabonate 0.5% three times daily, then reaching visual acuities of 20/20, with remaining photopsias [69].
Cases of bilateral optic neuritis in adults related to ZIKV were treated with intravenous methylprednisolone for 3 days followed by oral prednisolone for 11 additional days leading to a modest and partial recovery of visual acuity [61, 101]. Ocular flutter in a ZIKV post-infection state patient with neurological additional symptoms were described with improvement after intravenous immunoglobulin for 5 days [60].
Retinal disease associated to ZIKV, sometimes manifested as perifoveal microaneurysms with no involvement of visual function did not require any additional treatment beyond observation [59]. Acute maculopathy with bull’s-eye shape were reported in an adult case, with total improvement of visual acuity after 6 weeks without any treatment [73]. There is a study were the pharmacological inhibition of ABCG1, a membrane transporter of cholesterol, resulted in reduced ZIKV infectivity of RPE [42].
Glaucoma in Congenital Zika syndrome is a visual-threatening condition that need special attention and early treatment, were the use of hypotensive topical medications and surgery like trabeculotomy, trabeculectomy, trabeculotomy plus trabeculectomy or goniotomy are the most used strategies [13, 21, 57, 61].
The infants affected with congenital Zika virus syndrome may manifest many structural ocular findings in addition to the typical ones than involve the posterior pole, presenting low contrast sensitivity, visual field defects, hypoaccommodation, refractive errors and ocular motor disorders such as strabismus and nystagmus, commonly associated to neurological conditions, that finally interfere with the development of stereopsis and binocular vision. The sum of all of these findings results in severe visual impairment, regardless of the abnormalities of the retina and optic nerve [24].
There has been reported that even in the absence of apparent ocular abnormalities, there is a high prevalence of visual impairment between infants with microcephaly due to congenital Zika syndrome, suggesting that cerebral visual impairment, as a result of extensive damage to the central nervous system, could be the most frequent cause of blindness in affected infants [98, 102, 103]. This condition is known as cortical visual impairment, which is a reduction in visual response due to a neurologic issue. Then, the visual prognosis could be committed even in absence of ocular damage because of the severe cerebral malformation and abnormal brain development related to Zika infection. The affected infants usually have some vision and then they could exhibit improvement of their abilities over time. There could be seen the necessity of multidisciplinary teams for early cognitive and visual stimulation of newborns affected by congenital Zika virus syndrome, in order to decrease the impact of these infants and their families and achieve better quality of life. Further studies with long follow-up periods are needed to recognize the impact of the described ocular and neurological abnormalities, as well as for a better understanding and description of the natural history related to Zika infection and its ocular sequelae [13].
The early recognition, assessment and intervention of children with congenital Zika virus syndrome is crucial, especially in those ones that present hypoaccommodation and refractive errors, because they could show a significant improvement in visual acuity if they receive an early intervention with proper eyeglasses, as part of an integral visual stimulation therapy. For achieving significant changes in their refractive status it is necessary to guarantee periodical updates over time.
In general terms, there is a benign visual evolution in adults, because the symptoms and signs are associated with a self-limited viral process related to the acute phase of Zika virus infection that usually resolves once the virus is cleared. Then, the vision returns to normal in the majority of the cases.
Non-purulent conjunctivitis is the most common non-congenital and self-limited ocular manifestation of Zika virus infection [101]. The adults that course with chorioretinal lesions, like immunocompromised patients that are in higher risk for presenting these fundus alterations, usually evolve as acute-onset and self-resolving lesions, with scaring and posterior improvement of visual acuity. Then this finding of Zika virus chorioretinitis may be a clear representation of the active phase of infection in a significant context of viremia. In the case of diagnosis of unilateral acute maculopathy related to Zika virus infection, the patient can be carefully monitored because there is usually visual function recovery, with improvement in the pigment epithelial and outer retinal architecture on optical coherence tomography after the acute illness [52].
There has been described many non-congenital ocular complications related to arboviral infection, including epiescleritis, keratitis, uveitis, vitritis, macular atrophy, retinal vascular occlusion, optic neuritis and macular edema, with no specific or pathognomonic ocular lesion for Zika virus infection. Most patients recover completely, but there is always a small percentage of patients that evolve with permanent damage and subsequently can lead to long-life visual impairment [65]. Uveitis can be identified in adults during active Zika virus infection and has a benign prognosis. It is considered the principal difference between the ocular manifestations seen in acquired Zika infection and those observed in congenital Zika virus syndrome, because uveitis has been only reported in the acquired cases during viremia. Most cases evolve to complete regression and recovery of visual acuity after the viremia decreases and the use of topical treatment with steroids, cycloplegic and ocular hypertension drops [12].
Ocular involvement by ZIKV is related to the ability to break the blood-retinal barrier and axonal transportation, leading to manifestations in children and adults. Among the affected infants, the most common ophthalmologic manifestations include optic nerve hypoplasia, increased cup-to-disk ratio, macular scarring and focal pigmentary retinal mottling, as well as anterior ocular findings and ocular motility alterations. The most sever ophthalmic manifestations occur when the infection takes place in the first trimester of pregnancy, exposure to the virus during pregnancy can cause devastating effects on the developing fetus, specially affecting the central nervous system. The associated pattern of birth defects is known as congenital Zika virus syndrome among adults, the manifestations are usually self-limited and in some cases require some kind of treatment. It is needed to focus the treatment according to the ophthalmic clinical context of each patient. Cases with CZS should be enrolled in an integral and multidisciplinary team for providing early-intervention services including cognitive and visual rehabilitation. Further studies are necessary to recognize the impact of ocular damage and neurological abnormalities and its long-term consequences in the affected children.
The authors thank Camila Ventura, MD, PhD from Altino Ventura Foundation (FAV) and HOPE Eye Hospital, and Adriana Gondim de Moura Campos from Universida de Federal de Pernambuco for having provided images from their daily clinical practice and previous works, being a great complement to this chapter.
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