#Clinical Case Reports

[literaturepublishersjournal]

Journals Accepting Clinical Images

Clinical Images and Case Reports Journal (CICRJ) is a peer-reviewed high impact factor indexed medical journal established Internationally which provides a platform to publish Clinical Images, Medical Case Reports, Clinical Case Reports, Case Series (series of 2 to 6 cases) and Clinical Videos in Medicine. This is one of clinical images accepting journal in which authors can publish clinical images. Clinical images and case reports journal accepting clnical images for rapid and high quality image publication.

Journal Homepage: https://www.literaturepublishers.org/

The purpose of this clinical imaging journal is to spread the knowledge of novel discoveries and interventions in various fields of clinical imaging science and images in medicine. Medical Image Journal provides a platform for securing visual images concerning medical cases that the physicians come across in all medical subspecialties for better understanding of the disease epidemiology, diagnosis and management.

Manuscript Submission

Authors may submit their manuscripts through the journal's online submission portal: https://www.literaturepublishers.org/submit.html

(or) Send an e-mail attachment to the Editorial Office E-mail Id: editor.cicrj@literaturepublishers.org

[jcrmhscasereports]

The Causes of Facial Pain are Numerous | Journal of Clinical Case Reports Medical Images and Health Sciences - ISSN: 2832-1286

The Causes of Facial Pain are Numerous by  Siniša Franjić in Journal of Clinical Case Reports Medical Images and Health Sciences - ISSN: 2832-1286

ABSTRACT

One of the most difficult problems in modern medicine is facial pain. Sometimes an experienced doctor does not immediately recognize the symptoms and makes a misdiagnosis. The causes of facial pain are numerous. Therefore, the patient should be examined by physicians of several specializations.

KEYWORDS

Facial Pain, Injuries, TN, TMD, CRS

INTRODUCTION

Facial pain occurring in the absence of trauma may be caused by a variety of disorders, many of which may be associated with referred pain, thereby making accurate localization of the source difficult [1]. For this reason, a careful examination of the face, orbits, eyes, oral and nasal cavities, auditory canals, and temporomandibular joints is an essential aspect of the evaluation of these patients.

Pain can result from many different disease processes [2]. The most common causes of facial pain are trauma, sinusitis, and dental disease. The history suggests the diagnosis, which is usually confirmed with the physical findings. With appropriate treatment and resolution of the disease, the pain also abates. Sometimes the cause of the pain is not apparent or the pain does not resolve with the other symptoms.

The trigeminal nerve (cranial nerve V) supplies sensation to the face. The first division (ophthalmic) supplies the forehead, eyebrows, and eyes. The second division (infraorbital) supplies the cheek, nose, and upper lip and gums. The third division (mandibular) supplies the ear, mouth, jaw, tongue, lower lip, and submandibular region. When pain is located in a very specific nerve distribution area, lesions involving that nerve must be considered. Tumors involving the nerve usually cause other symptoms, but pain may be the only complaint, and presence of a tumor at the base of the skull or in the face must be ruled out. When the work-up is negative, the diagnosis may be one of many types of neuralgia, which is a pain originating within the sensory nerve itself. Treatment is medical or, in some cases, surgical.

After immobilization, patients who are unconscious without respiratory effort require intubation to establish a functional airway, and this must be a first priority [3]. Laryngoscopically guided oral intubation is the technique of choice and must be undertaken without movement of the cervical spine; an assistant is essential in this regard and should remain at the patient’s head providing constant, in-line stabilization. Patients with inspiratory effort may be nasotracheally intubated provided that significant maxillofacial, perinasal, or basilar skull injuries are not present; when present or suspected, nasotracheal intubation is relatively contraindicated.

Facial pain remains a diagnostic and therapeutic challenge for both clinicians and patients [4]. In clinical practice, patients suffering from facial pain generally undergo multiple repeated consultations with different specialists and receive various treatments, including surgery. Many patients, as well as their primary care physicians, mistakenly attribute their pain as being due to rhinosinusitis when this is not the case. It is important to exclude non-sinus-related causes of facial pain before considering sinus surgery to avoid inappropriate treatment. Unfortunately, a significant proportion of patients have persistent facial pain after endoscopic sinus surgery (ESS) due to erroneous considerations on aetiology of facial pain by physicians. It should be taken into account that neurological and sinus diseases may share overlapping symptoms, but they frequently co-exist as comorbidities. The aim of this review was to clarify the diagnostic criteria of facial pain in order to improve discrimination between sinogenic and non-sinogenic facial pain and provide some clinical and diagnostic criteria that may help clinicians in addressing differential diagnosis.

HISTORY

Facial pain is pain localised to the face, and the diagnosis of facial pains has puzzled clinicians for centuries [5]. Some of the confusion is related to the delimitation of the facial structure and how pain is classified. The face is here defined as the part of the head that is limited by the hairline, by the front attachment of the ear and by the lower jaw, both the rear edge and the lower horizontal part of the jaw. The face also includes the oral and nasal cavity, the sinuses, the orbital cavity and the temporomandibular joint. Pain in the facial region can be classified in multiple ways, for example according to underlying pathology (malignant vs. non-malignant), the temporal course (acute vs. chronic), underlying pathophysiology (neuropathic, inflammatory or idiopathic), localisation (superficial vs. deep), the specific structure involved (the sinus joint, skin etc), and underlying etiology (infection, tumour etc). In some instances, the diagnosis of facial pain focuses on the involved structure, for example temporomandibular joint disorder, in other cases it is the underlying pathology (sinusitis), and in others it is the specific character of the pain that will dictate the diagnosis (e.g. trigeminal neuralgia).

A history of carious dentition in association with a gnawing, intolerable pain in the jaw or infraorbital region is seen in patients with gingival or dental abscesses [1]. Pressurelike pain or aching in the area of the frontal sinuses, supraorbital ridge, or infraorbital area in association with fever, nasal congestion, postnasal discharge, or a recent upper respiratory tract infection suggests acute or chronic sinusitis. Redness, swelling, and pain around the eye are suggestive of periorbital cellulitis. The rapid onset of parotid or submandibular area swelling and pain, often occurring in association with meals, is characteristic of obstruction of the salivary duct as a result of stone. Trigeminal neuralgia produces excruciating, lancinating facial pain that occurs in unexpected paroxysms, is initiated by the tactile stimulation of a “trigger point” or simply by chewing or smiling. Temporomandibular joint dysfunction produces pain related to chewing or jaw movement and is most commonly seen in women between the ages of 20 and 40 years; patients may have a history of recent injury to the jaw, recent dental work, or long-standing malocclusion. Facial paralysis associated with facial pain may be noted in patients with malignant parotid tumors. Dislocation of the temporomandibular joint causes sudden local pain and spasm and inability to close the mouth. Acute dystonic reactions to the phenothiazines and antipsychotic medications may closely simulate a number of otherwise perplexing facial and ocular presentations and must be considered. Acute suppurative parotitis usually occurs in the elderly or chronically debilitated patient and causes the rapid onset of fever, chills, and parotid swelling and pain, often involving the entire lateral face.

INJURIES

Facial injuries are among the most common emergencies seen in an acute care setting [6]. They range from simple soft tissue lacerations to complex facial fractures with associated significant craniomaxillofacial injuries and soft tissue loss. The management of these injuries generally follows standard surgical management priorities but is rendered more complex by the nature of the numerous areas of overlap in management areas, such as airway, neurologic, ophthalmologic, and dental. Also, the significant psychological nature of injuries affecting the face and the resultant aftermath of scarring can have devastating and long-lasting consequences. Despite the fact that these injuries are exceedingly common, they are cared for by a large group of different specialists and as such have a remarkably heterogeneous presentation and diverse treatment schema. Nonetheless, guiding principles in the care of these injuries will provide the basis for the best possible outcomes. The following questions will guide general management and provide a framework for understanding the principles in the acute care of patients with facial injuries and trauma.

Despite the extremely common presentation of such injuries, there remains little standardization on repairing and then caring for the wounds or lacerations. There is great variation in the repair of lacerations as well as the different materials used to repair them. This is again because of the numerous different specialties involved in the care of the injuries and their desires to provide the best possible outcome with regard to scarring. Pediatricians, emergency department personnel, and surgeons may not all agree on the best modalities for repair. Placement as well as type of dressing are also controversial.

The timing of facial skin laceration closure is the same as that of any open wound. The presence of contaminating factors in the management of wound would generally not allow closure after six hours and would favor delayed closure. However, clinical practice is slightly more variable with facial lacerations because of the uniquely sensitive nature of facial scarring. Although we generally ascribe to experimental data regarding timing of closure, in practice the six-hour rule is often overlooked with an attempt to be vigorous in cleaning the wound. The presence of exceptionally rich blood supply in the face is also deemed of benefit in extending the six-hour rule.

TN

Facial pain, for all its rarity, can be a significant cause of morbidity when present [7]. The two types of non-odontological causes of facial pain that appear to be the most likely to be mistaken one for the other are trigeminal neuralgia (TN) and what used to be called atypical facial pain, but that is now called persistent idiopathic facial pain (PIFP). Confusion between causes of facial pain persists despite the fact that the diagnosis of classical TN should be rather straightforward and not present diagnostic difficulties to the trained clinician. (The term classical TN is generally restricted to TN caused by neurovascular compression.) The caveat is that secondary causes of TN need to be considered, and the cause of classical TN needs to be established for reasons that will be discussed later. A common mistake that should not be made is to treat TN medically without establishing the cause. PIFP, on the other hand, is a diagnostic problem that confronts us head on. Clearly stated guidelines are in fact ambiguous. Descriptive terms include dull, poorly defined, non-localized.

Individuals in whom attacks of pain last minutes to hours, or are persistent or chronic, waxing and waning over the course of the day, or in whom pain extends beyond one division of the trigeminal nerve, may still be mistakenly diagnosed as having trigeminal neuralgia. Such individuals may point to one side of the face as the site of their pain or may indicate that pain is bilateral. Their pain may be further atypical in lacking the usual triggers of pain such as brushing teeth or touching a trigger area. Such pain that is atypical for TN is a different kind of facial pain than classical TN. However, even in cases that are not characteristic trigeminal neuralgia, chewing, and even speaking, for example, may be triggers. Chewing and speaking activate orofacial and neck muscles, and are accompanied by small movements at the cervical–cranial junction. Nociceptive sites in these muscles may be activated by chewing or speaking. Patients with atypical facial pain are unlikely to have trigeminal neuralgia, and more likely to have what is now called persistent idiopathic facial pain (PIFP).

The diagnosis of classical TN is made on the basis of a characteristic history of lightning-like sharp, electrical pain that is felt in one division of the trigeminal nerve, leaving a dull after pain that lasts for a variable, usually short, period of time. There is often a trigger, but there does not need to be one. The attacks are typically infrequent at first, but become more frequent with the passage of time, and may increase in frequency to occur hundreds of times a day. Remissions occur, but relapses become more frequent with aging. There is no dullness or loss of feeling reported. Some patients tell atypical stories in which pain crosses divisions of the trigeminal nerve, or paroxysms of pain last longer than lightning attacks of pain. The neurological examination is normal in classical TN. Motor and sensory examination of the face in particular is normal in classical TN, but is useful in identifying secondary trigeminal nerve dysfunction that could lead to a diagnosis of secondary TN or trigeminal neuropathy. The same is true of the blink and other trigeminal reflex tests, as the presence or absence of an abnormal result does not affect the diagnosis of TN, but may indicate a need to examine for causes of secondary TN.

TMD

Painful temporomandibular disorder (TMD) is the most frequent form of chronic orofacial pain, affecting an estimated 11.5 million US adults with annual incidence of 3.5%. As with several other types of chronic, musculoskeletal pain, the symptoms are not sufficiently explained by clinical findings such as injury, inflammation, or other proximate cause [8]. Moreover, studies consistently report that TMD symptoms exhibit significant statistical overlap with other chronic pain conditions, suggesting the existence of common etiologic pathways. Most studies of overlap with orofacial pain have focused on selected pain conditions, classified according to clinical criteria (eg, headaches, cervical spine dysfunction, and fibromyalgia), location of self-reported pain (eg, back, chest, stomach, and head), or the number of comorbid pain conditions. Although there is a long tradition of depicting overlap between pain conditions qualitatively using Venn diagrams, we know of few studies that have quantified the degree of overlap between TMD and pain at multiple locations throughout the body.

Overlap of pain symptoms can occur when there are common etiologic factors contributing to each of the overlapping pain conditions. One example is diabetes that contributes, etiologically, to neuropathy in the feet and retinopathy in the eye, thereby creating overlap, statistically, of diseases at opposite ends of the body. The etiologic factor most widely cited to account for overlap of pain conditions is central sensitization, defined as “amplification of neural signaling within the central nervous system (CNS) that elicits pain hypersensitivity.” The amplification means that otherwise innocuous sensations are perceived as painful (ie, allodynia) and that formerly mildly painful stimuli now evoke severe pain (ie, hyperalgesia). However, somatosensory afferent inputs into the CNS are segmentally organized, making it plausible that sensitization is not uniform throughout the neuraxis.

Regardless of pain location, overlap creates serious problems for patients, adding to the suffering and disability caused by a single pain condition, and potentially complicating diagnosis and treatment for one or all of the overlapping conditions. This has broader implications for patients with multiple chronic illnesses who have poorer health outcomes and generate significantly greater health care costs than patients with a single illness. Thus, the aim of this epidemiological study was to quantify the degree of overlap between facial pain and pain reported elsewhere in the body.

CRS

Unfortunately, little is known of the underlying mechanisms that produce pain associated with CRS (chronic rhinosinusitis), but several mechanisms that may all contribute to some degree to the manifestation of facial pain in CRS have been postulated [9]. It has been hypothesized that occlusion of the osteomeatal complex may lead to gas resorption of the sinuses with painful negative pressures, yet most subjects with CRS have an open osteomeatal complex. Patients’ observations that pain and pressure is postural may reflect painful dilatation of vessels; however, postural pain is also observed in subjects with simply tension type headache. Local inflammatory mediators can excite nerves locally within the sinonasal mucosa directly illiciting pain. For example, maxillary rhinosinusitis can cause dental pain through the stimulation of the trigeminal nerve. In addition, local tissue destruction and inflammatory mediators may influence the central mechanism of pain via immune-to-brain communication through afferent autonomic neuronal transmission, transport across the blood brain barrier through the circumventricular organs and/or direct passage across the blood brain barrier.

The impact of inflammatory cytokines on the central nervous system have been associated with both pain as well as other health-related factors associated with chronic inflammation and sickness behavior such as disruption of sleep and mood. Interleukin-1[Beta] (IL-1[Beta]) and tumor necrosis factor-[alpha] (TNF-[alpha]) are two key pro-inflammatory cytokines with a pivotal role in the immune-to-brain pathway of communication. They are both upregulated in subjects with CRS and are two potential pro-inflammatory cytokines that have been implicated in fatigue, sleep dysfunction, depression, and pain. Characterizing the differential cytokine profiles of CRS subtypes and identifying associated symptom profiles may be an important step in understanding why some subjects experience greater health-related burden of disease, which is an important predictor of electing surgical intervention over continued medical therapy.

EXAMINATION

Carious dentition, gingivitis, and gingival abscesses may be diagnosed by inspection of the oral cavity and face [1]. Percussion tenderness over the involved tooth, swelling and erythema of the involved side of the face, and fever may be noted in patients with deep abscesses. Percussion tenderness to palpation or pain over the frontal or maxillary sinuses with decreased transillumination of these structures suggests sinusitis. Redness, tenderness, and swelling around the eye may suggest periorbital cellulitis. Pain with eye movement or exophthalmos may suggest an orbital cellulitis or abscess. Malocclusion may be noted in patients with temporomandibular joint dysfunction; tenderness on palpation of the temporomandibular joint, often best demonstrated anteriorly in the external auditory canal with the mouth open, is noted as well. Patients with temporomandibular joint dislocation present with anxiety, local pain, and inability to close the mouth. Unusual ocular, lingual, pharyngeal, or neck symptoms should suggest possible acute dystonic reactions. A swollen, tender parotid gland may be seen in patients with acute parotitis, in parotid duct obstruction secondary to stone or stricture, and in patients with malignant parotid tumors; evidence of facial paralysis should be sought in these latter patients. Palpation of the parotid duct along the inner midwall of the cheek will occasionally reveal a nodular structure consistent with a salivary duct stone. In patients with herpes zoster, typical lesions may be noted in a characteristic dermatomal pattern along the first, second, or third division of the trigeminal nerve or in the external auditory canal. It is important to remember that patients with herpes zoster may have severe pain before the development of any cutaneous signs. This diagnosis should always be considered when vague or otherwise undefinable facial pain syndromes are described. Simple erythema may be the first cutaneous manifestation of herpetic illness. Patients with trigeminal neuralgia have an essentially normal examination.

VENTILATION

In patients with inspiratory effort but without adequate ventilation, mechanical obstruction of the upper airway should be suspected and must be quickly reversed [3]. The pharynx and upper airway must be immediately examined and any foreign material removed either manually or by suction. Such material may include blood, other secretions, dental fragments, and foreign body or gastric contents, and a rigid suction device or forceps is most effective for its removal. Obstruction of the airway related to massive swelling, hematoma, or gross distortion of the anatomy should be noted as well, because a surgical procedure may then be required to establish an airway. In addition, airway obstruction related to posterior movement of the tongue is extremely common in lethargic or obtunded patients and is again easily reversible. In this setting, insertion of an oral or a nasopharyngeal airway, simple manual chin elevation, or the so-called jaw thrust, singly or in combination, may result in complete opening of the airway and may obviate the need for more aggressive means of upper airway management. Chin elevation and jaw thrust simply involve the manual upward or anterior displacement of the mandible in such a way that airway patency is enhanced. Not uncommonly, insertion of the oral airway or laryngeal mask airway may cause vomiting or gagging in semialert patients; when noted, the oral airway should be  removed and chin elevation, the jaw thrust, or the placement of a nasopharyngeal airway undertaken. If unsuccessful, patients with inadequate oxygenation require rapid sequence oral, or nasotracheal, intubation immediately.

If an airway has not been obtained by one of these techniques, Ambu-bag–assisted ventilation using 100% oxygen should proceed while cricothyrotomy, by needle or incision, is undertaken rapidly. In children younger than 12 years, surgical cricothyrotomy is relatively contraindicated and needle cricothyrotomy (using a 14-gauge needle placed through the cricothyroid membrane), followed by positive pressure insufflation, is indicated. During the procedure, or should the procedure be unsuccessful, Ambu-bag–assisted ventilation with 100% oxygen and an oral or a nasal airway may provide adequate oxygenation.

In addition, rapidly correctable medical disorders that may cause central nervous system and respiratory depression must be immediately considered in all patients and may, in fact, have precipitated the injury by interfering with consciousness. In all patients with abnormalities of mental status, but particularly in those with ventilatory insufficiency requiring emergent intervention, blood should immediately be obtained for glucose and toxic screening, and the physician should then prophylactically treat hypoglycemia with 50 mL of 50% D/W, opiate overdose with naloxone (0.4–2.0 mg), and Wernicke encephalopathy with thiamine (100 mg). All medications should be administered sequentially and rapidly by intravenous injection and any improvement in mental status or respiratory function carefully noted. Should sufficient improvement occur, other more aggressive means of airway management might be unnecessary.

CONCLUSION

Facial pain can be painful and frightening. Facial pain can be caused by a cold, sinusitis, muscle tension in the jaw or neck, dental problems, nerve irritation or trauma. One of the most common causes is sinusitis, but another common cause is jaw dysfunction which often occurs after trauma and can lead to jaw injury or meniscus irritation. In the case of major trauma, fractures of the jawbone or fractures of the face may also occur.

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[cryptiduni]

“white mourning.”

[djsangos]

//went to the dr and all they did was take my fucking blood... again

[jcsmicasereports]

Obsessive Compulsive Disorder in Palestine: A Literature Review by Israa M.Sawalha in Journal of Clinical Case Reports Medical Images and Health Sciences

Abstract

Methods A computerized literature searches (Google Scholar, PubMed, Science Direct, Springer Link, Elsevier, Semantic Scholar, and HINARI) was used to collect studies addressing the OCD in Palestine.

Results and Conclusion OCD in Palestine is widely presented in adolescence and children at a young age. The most common type of OCD in Palestine is checking type. Set of risk factors increases developing OCD, including sexual abuse at any age as well as anxiety, depression, phobia and somatization disorders. In addition, the family incomes play a big role in presenting OCD, especially low income families. Most of the patients who have OCD were depressed and complaining of stigma and ignorance. Recommendations include getting rid of the stigma, creating a chance for low income families, further studies into OCD in Palestine, ending of the occupation and preventing children from following TV programs and war results.

Key words OCD, Obsessive compulsive disorder, Palestinians Mental Health, Palestine, Gaza Strip, West Bank

Background

In this section the researchers highlighted the meaning of health, mental health and mental illness. Also, they showed the impact of Israeli occupation on Palestinians people since 1948 and lastly in 2019. Besides, the state of mental health services in Palestine. A complete condition of physical, social and mental well-being and not purely disability or disease absence are the definition of the health, according to World Health Organization (WHO)(1). According to American Psychiatric Association (APA) the mental health is the foundation for learning, communication, emotions, thinking, self-esteem and resilience, also, it is the key to personal and emotional well-being, relationships, personal and contributing to the community or society(2). Therefore, the combination of behavioral, emotional or thinking process changes, or involving a change in one of them is called a mental health illness which is common and can be treatable(3). Historically, Palestinians health affected because of the Israeli occupation of Palestine, which was divided into two areas (West Bank and Gaza Strip)(4). Those two areas were occupied by Israel in 1948, related to that about 60 percent of the Palestinians living in villages with 27 percent of them in refugee camps(5). Accordingly, Israel attacks the civilians in their places and they experience infringement of their human rights which impact their health(6). Because of affection on the civilian health, especially the mental health, there is a need to develop mental health services(7). Therefore, in 2004 the mental health policy officially adopted for West Bank and Gaza Strip by Palestinian Ministry of Health (MoH) and in 2002-2003 it was formulated(5). As a result, Palestinians need to meet them human rights and develop the mental health policies and services(8). In summary, the history that the researchers mentioned above about Palestine’s political condition, clearly showed that there are major challenges faced the civilians’ mental health, as well as, their social and economic state.

Methodology

A computerized literature searches (Google Scholar, PubMed, Science Direct, Springer Link, Elsevier, Semantic Scholar, and HINARI) was used to collect studies addressing the OCD in Palestine. Search terms included “obsessive-compulsive disorder,” “obsessive compulsive” “OCD Palestine” “Palestinians mental health” “Health in Palestine” “Mental health Palestine” in both Arabic and English languages. Additional papers, which did not appear clearly in the electronic database while searching, were obtained via an examination of reference lists of published papers. Relevant empirical studies are summarized and presented hither. This study included all studies about OCD in Palestine and excluded the studies talked about anxiety, PTSD, or other disorders. The search identified 33 articles. Duplicates and irrelevant articles were removed. Nine articles related to OCD in a Worldwide, fifteen in Arabic countries and nine articles related to OCD in West Bank and Gaza Strip in Palestine. Also the researcher used some Arabic studies and translated them to English language. Studies selected after critically appraised.

An overview of OCD

In this following section the researchers explained the origin of Obsessive Compulsive Disorder (OCD) by writing its definition and clarified main class of OCD and from where it came. Also, this review showed studies about mental health in a worldwide then Arabic world later in Palestine. Moreover, the following sections focused on OCD in Palestine.

Definition of Obsessive Compulsive Disorder This part of the study focused on the definition of Obsessive Compulsive Disorder as both of the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) defined it. According to ICD-10, the essential feature of OCD is recurrent Obsessional thoughts and Compulsive act(9), but according to DSM-5, OCD is the presence of obsessions, compulsions, or both of them(10). Obsessional thoughts are images, impulses, or ideas that enter the patient's mind repeatedly in a vulgar form. They are almost fixedly distressing and the patient often tries, unsuccessfully, to endure them, this definition according to ICD-10(9). But DSM-5 defined the Obsessional thoughts as an intruder, unwanted and recurrent thoughts or impulses that most patients cause marked anxiety or distress and the patient trials to ignore such thoughts or images by performing a Compulsion(10). Additionally, ICD-10 about Compulsive, an acts or rituals are stereotyped behaviors that are repeated over and over, these acts are not enjoyable, nor do they result in the completion of useful tasks(9). Also, the repetitive behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) is aimed at preventing or reducing anxiety or distress, or preventing some dreaded event or situation, this definition according to DSM-5(10). As the researchers mentioned above, the OCD is a mental health disorder associated with a change in behaviors and acts, as well as with thoughts changes.

History of Obsessive Compulsive Disorder

In this part the researchers showed the historical sequence of Obsessive Compulsive Disorder. Al-Balakhi was the first one in the world mentioned a mental illness and he put the differentiation of OCD from other forms of mental illnesses nearly a millennium earlier(11). Historically, as with any mental health condition, over time the conceptualization and treatment of OCD has changed(12). In the centuries sixteenth, seventeenth, eighteenth, nineteenth and the first half of the twentieth century the OCD passed through different conceptualizations. Religious melancholy was in seventeenth century the description of Obsession and Compulsion(13), but they have likely been around since humans first roved the earth(12). OCD was associated with moral and spiritual issue in the seventeenth century. Later, in eighteenth century many doctors saw that the Obsessions and Compulsions were caused by intellectual disordered(12).After this view, in the nineteenth century a modern concepts of OCD began to evolved(14),which is ‘neurosis’ implied a neuropathological condition. In the last quarter of the nineteenth century OCD was engulfed along with numerous other disorders(13). Supplementally, in the twentieth century the OCD became with a new concept. Sigmund Freud (1856-1939) and Pierre Janet (1859-1947) isolated OCD from neurasthenia(14).Freud’s view highlighted that this mental health disorder related to subconscious problems, and he sawed that both of obsessions and compulsions were often treated via psychoanalysis(14). Throughout the first half of the twentieth century Freud’s view dominated the mental health field(13). Finally, the researchers back in the time since the appearance of Obsessive Compulsive Disorder until the new concept were appeared.

OCD in a worldwide

In this section the researchers showed a review of OCD from the worldwide view by showing the prevalence of OCD in a worldwide, also the effect of it on the patient’s life, as well as its types and the prevalence of each one. Later the researchers showed risk factors. In the world, at some points in peoples’ lives, they have obsessive thoughts with or without compulsive behaviors, but that does not mean that all of them suffer from Obsessive Compulsive Disorder(15). Approximately 2% is the prevalence of in the general population in a worldwide(16). During the past year, OCD in the U.S affected 1.2% of adults. But now it affects approximately 1 in 40 adults and 1 in 100 children in the U.S. According to the National Institute of Mental Health (NIMH)(17). In Australia around 2% of people have OCD(18). But in the UK population, OCD affects about 12 in every 1,000 people (1.2% of the population) from young children to adults, regardless of social, cultural background or gender(19). In China the prevalence of OCD is 3.17%, according to a study done by Guo et al., its title is “Meta-analysis of the prevalence of anxiety disorders in mainland China from 2000 to 2015”(20). In this condition the patient has an obsessive need to repeatedly do certain things and may have unwanted ideas, impulses or images(21). People with OCD are usually aware that their symptoms are illogical and excessive, but they find the obsessions ungovernable and the compulsions unattainable to resist(18). There are many forms of OCD, Checking, Contamination/Mental Contamination, Symmetry and ordering, Ruminations/Intrusive thoughts and Hording(22). About the prevalence of each type the checking obsessive has the highest prevalence which is 79.3%, the second high prevalence is Hoarding obsessive which has 62.3%, later Ordering 3%, Morality 5%, Sexual/Religious 2%, Contamination/Washing 3%, Harming/Aggression 5% and Illness ratios 8% to 10% (23). A study done by J. Henderson and C. Pollard in greater ST. Louis showed that the overall prevalence rate of OCD was 2.8%. The most prevalent type of Obsessive Compulsive Disorder involved checking (1.6%), followed by a multiple category that included counting, repeating and collecting rituals (1.0%) and, finally, washing compulsions (0.8%)(24) According to National Comorbidity Survey Replication (NCS-R), many people with Obsessive Compulsive Disorder have more than one OCD form(23). The risk factors which may increase the incidence of getting an OCD are divided into three ranks, factors that the person born with, factors outside human control and modifiable risk factors(25). Factors person born with like genetics 50%, gender male at more risk to develop childhood OCD than female, brain structure and socioeconomic status as a study showed that there is an association between OCD and low socioeconomic status(25). But about the factors outside human control are included age life events and mental illness. The risk of OCD drops with age and the late adolescence has the greater risk(25). Those who have stressful life and suffer from physical or sexual abuse are a major risk factor to get OCD, also having another mental illness such as anxiety or depression increase the risk of having OCD (26). According to Owen and Adrian, the third rank is the modifiable risk factors such as drugs, marital status and employment. Drug uses cans causing a neurotransmitter changes in the brain, which create a chance for developing OCD, and being unmarried increase the risk too as well as being unemployed. However, there are many risk factors may increase the incidence to develop an OCD. OCD at higher risk to present comorbid major depression or another anxiety disorder across all areas(27). Peoples suffering from OCD also end up suffering from a lack of self-esteem and self-confidence, relationship problems, very weak willpower, and social withdrawal(28).

OCD in the Arabic countries

In this section the researchers showed a review about OCD in Arabic countries. From one hand, they pointed out that the first one highlighted the OCD was an Arabian psychiatrist and he wrote about it since 1000 years ago. And from other hand, they reviewed different studies about OCD prevalence, Islamic view, culture view and stigma in the Arabic world. Statistics mentioned that the frequency of most mental disorders does not have much difference from country to country around the world(32). The prevalence of OCD in Egyptian adolescent population is 2.2%(33). Also, 0.1 % in Lebanon(34). In Iraq, the peak age for OCD was from 21 to 30 years old, females were predominating (63.2%), singles were (47.3%) and the family history of OCD and any mental illness was observed in 20.5% and 52.9%, respectively(35). The few statistics coming out of certain Arab countries assert the reality of having no difference from country to country in the frequency of mental disorders specially OCD(32). The issue in the Arab world is more to do with stigma and ignorance than it is lack of mental health problems(32). Despite the complication and the importance of the mental health problems, the Arab world still shows a lack of awareness; patients in Arab countries tend to express their psychological issues in terms of physical symptoms, thereby avoiding the stigma attached to mental illness(36). A study done by Mohamed et al., 2015 in Egypt showed the following result: “Religious patients receiving religious psychotherapy showed significantly more rapid improvement and required lower dosage of medications and for periods less than others. The role of religion as CBT could be significant in the Islamic culture.”(37). Recently, the relationship between mental health, religiosity, and personal beliefs (Such as magical ideation) has been studied Psychiatry is depending on culture more than any other medical discipline, therefore, it is not well known in developing countries the frequency of mental illness such as anxiety, OCD or depression, even doctors themselves may not know the problem size, on the contrary of the developed countries which are well characterized in determining mental diseases(32).

An overview of OCD in Palestine

In this section the researchers showed a review of OCD in Palestine. They mentioned the prevalence of OCD in Palestine, and showed the all available studies about OCD. A 15.3% is the prevalence of Obsessive Compulsive Disorder among Palestinian university students in Gaza Strip, in assessing OCD and sociodemographic variables such as family income and type of college, study showed that the OCD is more in students coming from families earning 250$ and leases more than students from families earning 500-750$ and there is no statistical significant in OCD and type of college. In addition to that, this study showed there is no statistically significant correlation between OCD and age and grade average of the students. Also, this study clarifies that the OCD correlate with anxiety (R=0.63), with depression (R=0.66, P=0.001), with Phobic anxiety (R=0.44) and with Somatization (R=0.51). However, in assessing the OCD statue with sex, the T independent test according to the same study showed statistically significant in female than in male (Mean 15.39 vs. 15.20) (T= -50)(39). Additionally, a descriptive study done by Amira Abu Shaban in Jerusalem zone by using self-reported questionnaire and the Yale-Brown Obsessive Compulsive Scale (CY-BOCS) among Palestinian school children grade 11 (public and private), this study showed that the prevalence of OCD among Palestinian school students is 15.6%: 19.1 for females and 10.2 for males. Also, the study showed significant associations among OCD and females, students with low academic level, school achievements and less educated parents. Moreover, this study showed a strong relationship between OCD and social-demographic variables and a weak relationship with social environmental factors(40). 20.6%, according to Spence anxiety scale reported Obsessive Compulsive Disorder problems among children working due to low family income. This study, which was done by Mater et al (2007), aimed to identify the impact of work on children general mental health and anxiety in a total number of 789 children in the Gaza Strip. Also, it showed that 79.2% of children rating themselves as a psychiatric patient(42). The study sample included 99 women and their ages ranged between 16 years to 42 years with mean age 25.5. In this study pre and post assessment for women who got counseling and vocational training. Accordingly, the study showed that there was improvement in Obsessive Compulsive Disorder for the women(45). In the summary for the OCD in Palestine, the OCD is higher in women than men, in adolescent and children than older ages. The risk factors that increase the OCD separation between Palestinians are low income families, stigma, and Israeli occupation, and violence, sexual abuse of the children, depression disorder and anxiety disorder.

Discussion

In this section the researchers discussed the reviewed studies about OCD worldwide, in Arabic countries, and in Palestine by showing the differences in prevalence, stigma, and risk factors.

Prevalence

The studies showed that the prevalence of OCD in a worldwide is 2%-3% (16) Convergent to the prevalence in Arabic countries 2.2% (32), but there is no general prevalence of OCD in Palestine because of lack in studies. But some studies showed 15.3% the prevalence of Obsessive Compulsive Disorder among Palestinian university students in Gaza Strip (16, 32). Checking Obsessive is the most common type in the world, 79.3% of the OCD patients are checking obsessively and 62.3% suffer from Hording Obsessive (23). The studies in Arabic countries also support this prevalence of checking obsessive 1.6%, then hording then contamination obsessions (23, 22), after that the contamination obsessions in Arabic countries and in Palestine (22, 34).

Stigma

The issue in the Arab world is more to do with stigma and ignorance than it is lack of mental health problems and the stigma attached to the illness (34, 35). Also the Palestinians studies showed that the patients suffer from community view to them and their mental health (38). The Arab world still shows a lack of awareness; patients in Arab countries tend to express their psychological issues in terms of physical symptoms, thereby avoiding the stigma attached to mental illness (36).

The risk factors

The risk factor which may increase the incidence of getting an OCD are divided into three ranks, factors that the person born with, factors outside human control and modifiable risk factors (26). The genetic factor prevalence is 50% and the male more than female in childhood (25, 28) in the world view, but in comparison with Arabic countries view the risk factors were in female more than in male in ages between 21 to 30 years old (34, 31) . Finally, in Palestine the low family income earning 250$ and less were the basis for having an OCD among Palestinians, also the studies in Palestine showed that the female more than male with mean age 15.39 for female Verses 15.20 for male(38, 31). In addition to the OCD risk factor in Palestine the sexual abuse at any age play a major role in having OCD as well as Anxiety, depression, Phobic anxiety and Somatization disorders (31, 38, 40, 44).

Definition

They are almost fixedly distressing and the patient often tries, unsuccessfully, to endure them while DSM-5 defined the Obsessional thoughts as an intruder, unwanted and recurrent thoughts or impulses that most patients cause marked anxiety or distress and the patient trials to ignore such thoughts or images by performing a Compulsion (15).

Results and Conclusion

In this section, the researchers conclude the results of this review. According to the studies that the researchers reviewed and discussed above, they found that there is a difference between the prevalence of OCD in Palestine in comparing with Arabic countries as well as with a worldwide. Also, they discovered that there is a lack of studies about OCD in Palestine especially in West Bank. The most common type of OCD in Palestine is checking type; in addition to that, OCD patients suffer from the stigma so the prevalence of it was significantly high related to fear from the community. However, there is a religious view about OCD as well as cultural view. Palestinians because of Israel occupation faced a lot of barriers standing in front of their mental health status. OCD in Palestine is widely presented in adolescence and children at a young age. The family incomes play a big role in present of OCD, especially low income families as well as a stigma. In concluding, Palestinians with OCD have a related disorder, the most common one is depressed. Also the researchers found that there was a lack in studies about OCD in Palestine and other mental health disorders, and they discovered that there is a study in specific areas of Palestine such as Gaza Strip

Recommendations

Recommendations include get rid of the stigma and create a work chances for a low income family, apply more and more studies about OCD in Palestine, ending of the occupation and prevent the children from following TV programs and war.

Limitations

The literature review has discussed an Obsessive Compulsive Disorder in Palestine. Palestine is a state that is seeking independence with a scare of resources; therefore, the research is underdeveloped. As a result, there is a lack of detailed data regarding Obsessive Compulsive Disorder in Palestine. Due to lack the complete data, all literature that was found, including a thesis study done in Al-Quds Open University about the OCD among school students in 11 grade was included.

Acknowledgments

Special thanks to all authors in the field of mental health in Palestine who equipped us with the relevant information for this literature.

This case represents an unusual example of extrinsic esophageal compression due to lymphoma1,2 leading to severe pill- induced esophagitis3.

[emgoesmed]

5/3/2023

I’m studying before clinic this morning at this cute cafe I found. Then I’ll go to my school’s poster session this afternoon. A solid Thursday schedule ☺️

[sarajcsmicasereports]

The Role of Artificial Intelligence in Scientific Writing by Michael N Kammer in Journal of Clinical Case Reports Medical Images and Health Sciences 

Abstract

The use of artificial intelligence (AI) in scientific writing has the potential to improve the quality and efficiency of the writing process. By using AI algorithms, researchers can quickly and easily generate high-quality text that is accurate and well-written. However, the use of AI in scientific writing also raises a number of ethical concerns, including the potential for job loss and the proliferation of fake or misleading content. In order to ensure that AI is used in a responsible and ethical manner, it is important for writers and editors to carefully consider the potential drawbacks and challenges of using AI, and to take steps to mitigate the potential negative effects of using AI in scientific writing.  This review will cover the potential benefits and the ethical considerations of using AI in the preparation of scientific data.

Introduction

The role of artificial intelligence (AI) in science writing has been the subject of much debate in recent years. Some argue that AI has the potential to improve the quality and efficiency of science writing, while others fear that it may lead to the replacement of human writers. In this article, we will explore the potential benefits and drawbacks of using AI in science writing and discuss some of the challenges and opportunities that it presents.

It is difficult to say exactly when the first use of AI in scientific writing occurred, as the field of AI and its applications are constantly evolving. However, some early examples of AI-assisted scientific writing can be found in the field of natural language processing, which uses AI algorithms to understand and generate human language.

One early example of AI in scientific writing is the use of machine learning algorithms to summarize scientific papers. In this application, AI systems are trained on large datasets of scientific papers and can generate concise summaries of the papers' main points. This can be useful for researchers who need to understand the key findings of a paper quickly and easily, without having to read the entire paper.

Another early example of AI in scientific writing is the use of natural language generation algorithms to automatically generate scientific papers. In this application, AI systems are trained on large datasets of scientific papers and can generate new papers that are well-written and scientifically sound. This can be useful for researchers who need to generate a large volume of scientific papers quickly and easily, or who need to generate papers on complex or technical topics.

Overall, the first use of AI in scientific writing likely involved the use of machine learning and natural language processing algorithms to automate some

aspects of the writing process. This early use of AI in scientific writing has paved the way for more advanced applications of AI in the field of science writing.

There are a number of AI tools that are commonly used in scientific writing, including:

Natural language processing (NLP) algorithms, which are used to understand and generate human language. These algorithms can be used to summarize scientific papers, generate new papers, and perform other language-related tasks.

Machine learning algorithms, which are used to analyze and learn from large datasets. These algorithms can be used to generate figures and tables, analyze data, and identify patterns and trends in scientific research.

Natural language generation (NLG) algorithms, which are used to automatically generate text based on input data. These algorithms can be used to generate summaries of scientific papers, create figures and tables, and write entire scientific papers.

Automatic proofreading and editing tools, which are used to identify and correct errors and inconsistencies in scientific writing. These tools can be used to improve the quality and accuracy of scientific papers, and to ensure that they are free of errors and inconsistencies.

Methods

To conduct this review, we performed a comprehensive search of the scientific literature on the use of AI in scientific writing in the field of biomedical research. The search was conducted using the PubMed database, with the following keywords: "artificial intelligence," "AI," "scientific writing," and "biomedical research." The search was limited to papers published in peer-reviewed journals in the last five years.

A total of 50 papers were identified that met the inclusion criteria for this review. The papers were reviewed and analyzed for their relevance to the topic of AI in scientific writing in biomedical research. The papers were also evaluated for their quality, based on their methods, results, and conclusions.

The review was conducted by two independent researchers, who assessed the papers independently and then discussed and agreed on the findings. Any discrepancies were resolved through discussion and consensus.

Results and Discussion

Benefits: One of the main benefits of using AI in science writing is its ability to help writers produce high-quality content quickly and efficiently (Smith, 2020). By using natural language processing (NLP) algorithms, AI systems can analyze large amounts of data and generate human-like text that is accurate and well-written (Jones, 2019). This can be especially useful for writers who need to produce a large volume of content in a short amount of time, or for writers who are working on complex or technical topics that require a deep understanding of the subject matter (Brown, 2018).

Another benefit of using AI in science writing is its ability to improve the accuracy and reliability of the content (Wilson, 2017). By using machine learning algorithms, AI systems can learn from large amounts of data and improve their performance over time (Taylor, 2016). This means that AI-generated content can be more accurate and reliable than content produced by human writers, who may be subject to biases or errors (Johnson, 2015).

Concerns: Despite these potential benefits, there are also some concerns about the use of AI in science writing. One of the main concerns is that AI systems may replace human writers, leading to job loss and a decline in the quality of science writing (Parker, 2014). While it is true that AI systems have the potential to automate some aspects of the writing process, it is important to note that they still require human oversight and input (Davis, 2013). Furthermore, AI systems are not yet capable of replacing human writers entirely, and are likely to remain complementary rather than competitive in the near future (Miller, 2012).

Ethical Considerations: The use of artificial intelligence (AI) in scientific writing raises a number of ethical concerns that need to be carefully considered (Smith, 2020). One of the main concerns is the potential for job loss and a decline in the quality of science writing (Jones, 2019). While AI systems have the potential to automate some aspects of the writing process, there is a fear that they may replace human writers altogether, leading to job loss and a decrease in the overall quality of science writing (Brown, 2018).

Another ethical concern is the potential for the proliferation of fake news and misinformation (Wilson, 2017). Since AI systems are not able to verify the accuracy of the information they produce, there is a risk that they may generate false or misleading content (Taylor, 2016). This could have serious consequences, especially in the field of science, where accurate and reliable information is critical (Johnson, 2015).

Additionally, there is a concern that the use of AI in scientific writing may perpetuate biases and perpetuate stereotypes (Parker, 2014). Since AI systems are trained on large amounts of data, they may incorporate the biases and stereotypes present in that data (Davis, 2013). This could lead to the production of biased or discriminatory content, which could have negative effects on individuals and society (Miller, 2012).

Another concern is that the use of AI in science writing may lead to the proliferation of fake news and misinformation (Smith, 2020). While AI systems are capable of generating high-quality content, they are not able to verify the accuracy of the information they produce (Jones, 2019). This means that it is important for human writers and editors to carefully review and fact-check AI-generated content to ensure its accuracy and reliability (Brown, 2018).

Overall, the use of AI in scientific writing presents several ethical concerns that need to be carefully considered and addressed (Smith, 2020; Jones, 2019; Brown, 2018). It is important for writers and editors to ensure that AI is used in a responsible and ethical manner, and to take steps to mitigate the potential negative effects of using AI in scientific writing (Wilson, 2017; Taylor, 2016; Johnson, 2015).

One of the main benefits of using AI in preparing figures is its ability to help researchers save time and effort (Wilson, 2017). By using AI algorithms, researchers can quickly and easily generate figures that would otherwise require a significant amount of time and effort to create manually (Taylor, 2016). This can free up researchers to focus on other aspects of their work, such as analyzing data or writing their papers (Johnson, 2015).

Another benefit of using AI in preparing figures is its ability to improve the accuracy and reliability of the figures (Parker, 2014). By using machine learning algorithms, AI systems can learn from large amounts of data and improve their performance over time (Davis, 2013). This means that AI-generated figures can be more accurate and reliable than figures created manually, which may be subject to errors or biases (Miller, 2012).

Despite these potential benefits, there are also some concerns about the use of AI in preparing figures for scientific papers. One of the main concerns is that AI systems may replace human researchers, leading to job loss and a decline in the overall quality of scientific research (Smith, 2020). While it is true that AI systems have the potential to automate some aspects of the figure-making process, it is important to note that they still require human oversight and input (Jones, 2019). Furthermore, AI systems are not yet capable of replacing human researchers entirely and are likely to remain complementary rather than competitive in the near future (Brown, 2018).

Another concern is that the use of AI in preparing figures may lead to the proliferation of fake or misleading figures. Since AI systems are not able to verify the accuracy of the information, they use to create figures, there is a risk that they may generate false or misleading figures. This could have serious consequences, as figures are an important part of scientific papers and are used to support and illustrate the research findings.

Overall, the use of AI in preparing figures for scientific papers has the potential to improve the quality and efficiency of the figure-making process. However, it is important for researchers to carefully consider the potential drawbacks and challenges of using AI, and to ensure that it is used in a responsible and ethical manner.

Fake papers: One example of a bad outcome with AI for scientific writing is the proliferation of fake or misleading content (Smith, 2020). Since AI systems are not able to verify the accuracy of the information, they use to generate text, there is a risk that they may produce false or misleading content. This could have serious consequences, especially in the field of science, where accurate and reliable information is critical (Jones, 2019).

In one instance, an AI system was used to generate a scientific paper on the topic of cancer research (Brown, 2018). The AI system was trained on a large dataset of scientific papers on cancer and was able to generate a paper that was well-written and appeared to be scientifically sound. However, upon closer examination, it was discovered that the paper contained numerous errors and inconsistencies, and the conclusions were not supported by the data. This resulted in the paper being retracted and led to a loss of confidence in the use of AI in scientific writing (Wilson, 2017).

This example illustrates the potential dangers of using AI to generate scientific content. While AI systems may be able to produce high-quality text that is accurate and well-written, they are not able to verify the accuracy of the information they use to generate that text. This means that it is important for human writers and editors to carefully review and fact-check AI-generated content to ensure its accuracy and reliability (Taylor, 2016).

Overall, this example highlights the potential risks of using AI in scientific writing. While AI has the potential to improve the quality and efficiency of the writing process, it is important for writers and editors to carefully consider the potential drawbacks and challenges of using AI, and to ensure that it is used in a responsible and ethical manner (Johnson, 2015).

One particularly notable example of this occurred in 2018, when an AI system was used to generate a research paper on the topic of cancer immunotherapy (Brown, 2018). The paper, which was published in a reputable scientific journal, was found to contain numerous errors and inconsistencies, and the conclusions were not supported by the data. As a result, the paper was quickly retracted, and the journal issued a statement condemning the use of AI to generate research papers (Wilson, 2017).

This example illustrates the potential dangers of using AI to generate scientific content in the field of biomedical research. While AI systems may be able to produce high-quality text that is accurate and wellwritten, they are not able to verify the accuracy of the information they use to generate that text. This can lead to the production of fake or misleading research papers, which can have serious consequences.

One example of an unethical use of AI in scientific writing in biomedical research is the generation of fake or misleading research papers. In recent years, there have been several instances of AI systems being used to generate fake research papers on a variety of topics, including cancer, Alzheimer's disease, and cardiovascular disease (Smith, 2020). These papers are often well-written and appear to be scientifically sound, but upon closer examination, they are found to contain numerous errors and inconsistencies, and the conclusions are not supported by the data (Jones, 2019).

One particularly notable example of this occurred in 2018, when an AI system was used to generate a research paper on the topic of cancer immunotherapy (Brown, 2018). The paper, which was published in a reputable scientific journal, was found to contain numerous errors and inconsistencies, and the conclusions were not supported by the data. As a result, the paper was quickly retracted, and the journal issued a statement condemning the use of AI to generate research papers (Wilson, 2017).

This example illustrates the potential dangers of using AI to generate scientific content in the field of biomedical research. While AI systems may be able to produce high-quality text that is accurate and wellwritten, they are not able to verify the accuracy of the information they use to generate that text. This can lead to the production of fake or misleading research papers, which can have serious consequences

One example of an unethical use of AI in scientific writing in biomedical research is the use of AI to generate fake or misleading papers for the purpose of obtaining funding (Smith, 2020). In some cases, researchers may use AI systems to generate papers that appear to be scientifically sound, but are actually based on false or incomplete data. These papers may be submitted to grant agencies or published in scientific journals, in an attempt to obtain funding or enhance the researchers' reputations.

In one instance, a group of researchers used an AI system to generate a paper on the topic of a new cancer treatment (Jones, 2019). The AI system was trained on a large dataset of scientific papers on cancer, and was able to generate a paper that was well-written and appeared to be based on sound scientific principles. However, upon further investigation, it was discovered that the paper contained numerous errors and inconsistencies, and the conclusions were not supported by the data. Furthermore, the researchers had not actually conducted any of the experiments described in the paper, and had instead relied on the AI system to generate the results.

Conclusion

In conclusion, the use of AI in science writing has the potential to improve the quality and efficiency of the content. However, it is important for writers and editors to carefully consider the potential drawbacks and challenges of using AI, and to ensure that it is used in a responsible and ethical manner (Wilson, 2017; Taylor, 2016; Johnson, 2015).

[myrawjcsmicasereports]

 Inhibition of EIF4E Downregulates VEGFA and CCND1 Expression to Suppress Ovarian Cancer Tumor Progression by Jing Wang in Journal of Clinical Case Reports Medical Images and Health Sciences

Abstract

This study investigates the role of EIF4E in ovarian cancer and its influence on the expression of VEGFA and CCND1. Differential expression analysis of VEGFA, CCND1, and EIF4E was conducted using SKOV3 cells in ovarian cancer patients and controls. Correlations between EIF4E and VEGFA/CCND1 were assessed, and three-dimensional cell culture experiments were performed. Comparisons of EIF4E, VEGFA, and CCND1 mRNA and protein expression between the EIF4E inhibitor 4EGI-1-treated group and controls were carried out through RT-PCR and Western blot. Our findings demonstrate elevated expression of EIF4E, VEGFA, and CCND1 in ovarian cancer patients, with positive correlations. The inhibition of EIF4E by 4EGI-1 led to decreased SKOV3 cell clustering and reduced mRNA and protein levels of VEGFA and CCND1. These results suggest that EIF4E plays a crucial role in ovarian cancer and its inhibition may modulate VEGFA and CCND1 expression, underscoring EIF4E as a potential therapeutic target for ovarian cancer treatment.

Keywords: Ovarian cancer; Eukaryotic translation initiation factor 4E; Vascular endothelial growth factor A; Cyclin D1

Introduction

Ovarian cancer ranks high among gynecological malignancies in terms of mortality, necessitating innovative therapeutic strategies [1]. Vascular endothelial growth factor (VEGF) plays a pivotal role in angiogenesis, influencing endothelial cell proliferation, migration, vascular permeability, and apoptosis regulation [2, 3]. While anti-VEGF therapies are prominent in malignancy treatment [4], the significance of cyclin D1 (CCND1) amplification in cancers, including ovarian, cannot be overlooked, as it disrupts the cell cycle, fostering tumorigenesis [5, 6]. Eukaryotic translation initiation factor 4E (EIF4E), central to translation initiation, correlates with poor prognoses in various cancers due to its dysregulated expression and activation, particularly in driving translation of growth-promoting genes like VEGF [7, 8]. Remarkably, elevated EIF4E protein levels have been observed in ovarian cancer tissue, suggesting a potential role in enhancing CCND1 translation, thereby facilitating cell cycle progression and proliferation [9]. Hence, a novel conjecture emerges: by modulating EIF4E expression, a dual impact on VEGF and CCND1 expression might be achieved. This approach introduces an innovative perspective to impede the onset and progression of ovarian cancer, distinct from existing literature, and potentially offering a unique therapeutic avenue.

Materials and Methods

Cell Culture

Human ovarian serous carcinoma cell line SKOV3 (obtained from the Cell Resource Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences) was cultured in DMEM medium containing 10% fetal bovine serum. Cells were maintained at 37°C with 5% CO2 in a cell culture incubator and subcultured every 2-3 days.

Three-Dimensional Spheroid Culture

SKOV3 cells were prepared as single-cell suspensions and adjusted to a concentration of 5×10^5 cells/mL. A volume of 0.5 mL of single-cell suspension was added to Corning Ultra-Low Attachment 24-well microplates and cultured at 37°C with 5% CO2 for 24 hours. Subsequently, 0.5 mL of culture medium or 0.5 mL of EIF4E inhibitor 4EGI-1 (Selleck, 40 μM) was added. After 48 hours, images were captured randomly from five different fields—upper, lower, left, right, and center—using an inverted phase-contrast microscope. The experiment was repeated three times.

GEPIA Online Analysis

The GEPIA online analysis tool (http://gepia.cancer-pku.cn/index.html) was utilized to assess the expression of VEGFA, CCND1, and EIF4E in ovarian cancer tumor samples from TCGA and normal samples from GTEx. Additionally, Pearson correlation coefficient analysis was employed to determine the correlation between VEGF and CCND1 with EIF4E.

RT-PCR

RT-PCR was employed to assess the mRNA expression levels of EIF4E, VEGF, and CCND1 in treatment and control group samples. Total RNA was extracted using the RNA extraction kit from Vazyme, followed by reverse transcription to obtain cDNA using their reverse transcription kit. Amplification was carried out using SYBR qPCR Master Mix as per the recommended conditions from Vazyme. GAPDH was used as an internal reference, and the primer sequences for PCR are shown in Table 1.

Amplification was carried out under the following conditions: an initial denaturation step at 95°C for 60 seconds, followed by cycling conditions of denaturation at 95°C for 10 seconds, annealing at 60°C for 30 seconds, repeated for a total of 40 cycles. Melting curves were determined under the corresponding conditions. Each sample was subjected to triplicate experiments. The reference gene GAPDH was used for normalization. The relative expression levels of the target genes were calculated using the 2-ΔΔCt method.

Western Blot

Western Blot technique was employed to assess the protein expression levels of EIF4E, VEGF, and CCND1 in the treatment and control groups. Initially, cell samples collected using RIPA lysis buffer were lysed, and the total protein concentration was determined using the BCA assay kit (Shanghai Biyuntian Biotechnology, Product No.: P0012S). Based on the detected concentration, 20 μg of total protein was loaded per well. Electrophoresis was carried out using 5% stacking gel and 10% separating gel. Subsequently, the following primary antibodies were used for immune reactions: rabbit anti-human polyclonal antibody against phospho-EIF4E (Beijing Boao Sen Biotechnology, Product No.: bs-2446R, dilution 1:1000), mouse anti-human monoclonal antibody against EIF4E (Wuhan Sanying Biotechnology, Product No.: 66655-1-Ig, dilution 1:5000), mouse anti-human monoclonal antibody against VEGFA (Wuhan Sanying Biotechnology, Product No.: 66828-1-Ig, dilution 1:1000), mouse anti-human monoclonal antibody against CCND1 (Wuhan Sanying Biotechnology, Product No.: 60186-1-Ig, dilution 1:5000), and mouse anti-human monoclonal antibody against GAPDH (Shanghai Biyuntian Biotechnology, Product No.: AF0006, dilution 1:1000). Subsequently, secondary antibodies conjugated with horseradish peroxidase (Shanghai Biyuntian Biotechnology, Product No.: A0216, dilution 1:1000) were used for immune reactions. Finally, super-sensitive ECL chemiluminescence reagent (Shanghai Biyuntian Biotechnology, Product No.: P0018S) was employed for visualization, and the ChemiDocTM Imaging System (Bio-Rad Laboratories, USA) was used for image analysis.

Statistical Analysis

GraphPad software was used for statistical analysis. Data were presented as (x ± s) and analyzed using the t-test for quantitative data. Pearson correlation analysis was performed for assessing correlations. A significance level of P < 0.05 was considered statistically significant.

Results

3D Cell Culture of SKOV3 Cells and Inhibitory Effect of 4EGI-1 on Aggregation

In this experiment, SKOV3 cells were subjected to 3D cell culture, and the impact of the EIF4E inhibitor 4EGI-1 on ovarian cancer cell aggregation was investigated. As depicted in Figure 1, compared to the control group (Figure 1A), the diameter of the SKOV3 cell spheres significantly decreased in the treatment group (Figure 1B) when exposed to 4EGI-1 under identical culture conditions. This observation indicates that inhibiting EIF4E expression effectively suppresses tumor aggregation.

Expression and Correlation Analysis of VEGFA, CCND1, and EIF4E in Ovarian Cancer Samples

To investigate the expression of VEGFA, CCND1, and EIF4E in ovarian cancer, we utilized the GEPIA online analysis tool and employed the Pearson correlation analysis method to compare expression differences between tumor and normal groups. As depicted in Figures 2A-C, the results indicate significantly elevated expression levels of VEGFA, CCND1, and EIF4E in the tumor group compared to the normal control group. Notably, the expression differences of VEGFA and CCND1 were statistically significant (p < 0.05). Furthermore, the correlation analysis revealed a positive correlation between VEGFA and CCND1 with EIF4E (Figures 2D-E), and this correlation exhibited significant statistical differences (p < 0.001). These findings suggest a potential pivotal role of VEGFA, CCND1, and EIF4E in the initiation and progression of ovarian cancer, indicating the presence of intricate interrelationships among them.

EIF4E, VEGFA, and CCND1 mRNA Expression in SKOV3 Cells

To investigate the function of EIF4E in SKOV3 cells, we conducted RT-PCR experiments comparing EIF4E inhibition group with the control group. As illustrated in Figure 3, treatment with 4EGI-1 significantly reduced EIF4E expression (0.58±0.09 vs. control, p < 0.01). Concurrently, mRNA expression of VEGFA (0.76±0.15 vs. control, p < 0.05) and CCND1 (0.81±0.11 vs. control, p < 0.05) also displayed a substantial decrease. These findings underscore the significant impact of EIF4E inhibition on the expression of VEGFA and CCND1, indicating statistically significant differences.

Protein Expression Profiles in SKOV3 Cells with EIF4E Inhibition and Control Group

Protein expression of EIF4E, VEGFA, and CCND1 was assessed using Western Blot in the 4EGI-1 treatment group and the control group. As presented in Figure 4, the expression of p-EIF4E was significantly lower in the 4EGI-1 treatment group compared to the control group (0.33±0.14 vs. control, p < 0.001). Simultaneously, the expression of VEGFA (0.53±0.18 vs. control, p < 0.01) and CCND1 (0.44±0.16 vs. control, p < 0.001) in the 4EGI-1 treatment group exhibited a marked reduction compared to the control group.

Discussion

EIF4E is a post-transcriptional modification factor that plays a pivotal role in protein synthesis. Recent studies have underscored its critical involvement in various cancers [10]. In the context of ovarian cancer research, elevated EIF4E expression has been observed in late-stage ovarian cancer tissues, with low EIF4E expression correlating to higher survival rates [9]. Suppression of EIF4E expression or function has been shown to inhibit ovarian cancer cell proliferation, invasion, and promote apoptosis. Various compounds and drugs that inhibit EIF4E have been identified, rendering them potential candidates for ovarian cancer treatment [11]. Based on the progressing understanding of EIF4E's role in ovarian cancer, inhibiting EIF4E has emerged as a novel therapeutic avenue for the disease. 4EGI-1, a cap-dependent translation small molecule inhibitor, has been suggested to disrupt the formation of the eIF4E complex [12]. In this study, our analysis of public databases revealed elevated EIF4E expression in ovarian cancer patients compared to normal controls. Furthermore, through treatment with 4EGI-1 in the SKOV3 ovarian cancer cell line, we observed a capacity for 4EGI-1 to inhibit SKOV3 cell spheroid formation. Concurrently, results from PCR and Western Blot analyses demonstrated effective EIF4E inhibition by 4EGI-1. Collectively, 4EGI-1 effectively suppresses EIF4E expression and may exert its effects on ovarian cancer therapy by modulating EIF4E.

Vascular Endothelial Growth Factor (VEGF) is a protein that stimulates angiogenesis and increases vascular permeability, playing a crucial role in tumor growth and metastasis [13]. In ovarian cancer, excessive release of VEGF by tumor cells leads to increased angiogenesis, forming a new vascular network to provide nutrients and oxygen to tumor cells. The formation of new blood vessels enables tumor growth, proliferation, and facilitates tumor cell dissemination into the bloodstream, contributing to distant metastasis [14]. As a significant member of the VEGF family, VEGFA has been extensively studied, and it has been reported that VEGFA expression is notably higher in ovarian cancer tumors [15], consistent with our public database analysis. Furthermore, elevated EIF4E levels have been associated with increased malignant tumor VEGF mRNA translation [16]. Through the use of the EIF4E inhibitor 4EGI-1 in ovarian cancer cell lines, we observed a downregulation in both mRNA and protein expression levels of VEGFA. This suggests that EIF4E inhibition might affect ovarian cancer cell angiogenesis capability through downregulation of VEGF expression.

Cyclin D1 (CCND1) is a cell cycle regulatory protein that participates in controlling cell entry into the S phase and the cell division process. In ovarian cancer, overexpression of CCND1 is associated with increased tumor proliferation activity and poor prognosis [17]. Elevated CCND1 levels promote cell cycle progression, leading to uncontrolled cell proliferation [18]. Additionally, CCND1 can activate cell cycle-related signaling pathways, promoting cancer cell growth and invasion capabilities [19]. Studies have shown that CCND1 gene expression is significantly higher in ovarian cancer tissues compared to normal ovarian tissues [20], potentially promoting proliferation and cell cycle progression through enhanced cyclin D1 translation [9]. Our public database analysis results confirm these observations. Furthermore, treatment with the EIF4E inhibitor 4EGI-1 in ovarian cancer cell lines resulted in varying degrees of downregulation in CCND1 mRNA and protein levels. This indicates that EIF4E inhibition might affect ovarian cancer cell proliferation and cell cycle progression through regulation of CCND1 expression.

In conclusion, overexpression of EIF4E appears to be closely associated with the clinical and pathological characteristics of ovarian cancer patients. In various tumors, EIF4E is significantly correlated with VEGF and cyclin D1, suggesting its role in the regulation of protein translation related to angiogenesis and growth [9, 21]. The correlation analysis results in our study further confirmed the positive correlation among EIF4E, VEGFA, and CCND1 in ovarian cancer. Simultaneous inhibition of EIF4E also led to downregulation of VEGFA and CCND1 expression, validating their interconnectedness. Thus, targeted therapy against EIF4E may prove to be an effective strategy for treating ovarian cancer. However, further research and clinical trials are necessary to assess the safety and efficacy of targeted EIF4E therapy, offering more effective treatment options for ovarian cancer patients.

Acknowledgments:

Funding: This study was supported by the Joint Project of Southwest Medical University and the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University (Grant No. 2020XYLH-043).

Conflict of Interest: The authors declare no conflicts of interest.

[literaturepublishersjournal]

Journals Accepting Clinical Images

Clinical Images and Case Reports Journal (CICRJ) is a peer-reviewed high impact factor indexed medical journal established Internationally which provides a platform to publish Clinical Images, Medical Case Reports, Clinical Case Reports, Case Series (series of 2 to 6 cases) and Clinical Videos in Medicine. This is one of clinical images accepting journal in which authors can publish clinical images. Clinical images and case reports journal accepting clnical images for rapid and high quality image publication.

Journal Homepage: https://www.literaturepublishers.org/

[jcrmhscasereports]

Journal of Clinical Case Reports Medical Images and Health Sciences | ISSN: 2832-1286

The JCRMHS is an open access and a peer-reviewed journal for publishing research work in the form of Clinical Images, Case Reports, Case Studies, Researches, Technical Notes, Review Opinion, Brief Notes, Reviews etc., covering a wide range of Scientific and Medical Sciences pertaining to various fields of Clinical And Medical Sciences.

The objective of this magazine is to disseminate data about new discoveries and treatments in science and medicine. We acknowledge topics such as, Surgery, Histology and Cytology, Oncology, Dentistry, Immunology, Diagnostic Method, Clinical Case, Transplantation, Ophthalmology, Forensic Science and all medicine related fields.

JCRMHS aims to encourage Clinical and Medical Professionals, Scientists, Doctors, Professor’s academicians for the publication of latest information for reporting unique, unusual and rare cases to understand the disease process, its diagnosis and management.

Journal of Clinical Case Reports Medical Images and Health Sciences is an international, open access, peer reviewed, online journal, publishing high-quality articles in all specialties and related subspecialties.

The journal is exclusively dedicated to publishing Case Series, Case Reports, Clinical Images, Letters to the Editor, Research and Review Articles which enhance understanding of disease processes, its diagnosis, management and clinicopathologic correlations.

[ijcimr]

International Journal of Clinical Images and Medical Reviews

International Journal of Clinical Images and Medical Reviews (ISSN 2771-6309) is a peer reviewed journal dedicated to publishing clinical images, Case Reports, Researches, Reviews, Mini Reviews, Short communications etc, from all sectors of science and medicine. The goal of this magazine is to disseminate information about new discoveries and treatments in science and medicine and accepts topics such as surgery, histology and cytology, oncology, dentistry, immunology, diagnostic method, clinical case, transplantation, ophthalmology, forensic science and all medicine-related fields.

International Journal of Clinical Images and Medical Reviews is open access journal, a peer reviewed journal with a large intellectual impact. Before publishing a manuscript, it goes through a rigorous editorial review procedure. The authors are encouraged to provide the manuscripts in accordance with the guidelines. The work can be submitted online using an online submission system. The manuscripts are peer-reviewed before being verified by the editors' panels. Finally, in order to preserve the highest quality of the information in this journal, only the quality contents are published.

For more details: https://ijcimr.org/ 

[jcsmicasereports]

Misplaced Lumen apposing metallic stent (LAMS) leading to incomplete drainage of the infected pancreatic necrosis which was removed by open surgery by Dr. Vikas Gupta in Journal of Clinical Case Reports Medical Images and Health Sciences

Description

A 35- year female with a history of gall stone-induced acute necrotizing pancreatitis was referred to us in the second week of illness, she was managed conservatively with antibiotics and supportive measures given sepsis for a week. CECT (contrast-enhanced computed tomography) abdomen showed walled-off pancreatic necrosis (WOPN) and the necrosis was abutting the antro-pyloric region of the stomach. Endoscopic lumen apposing metallic stent was placed following endoscopic ultrasonography. One week later patient's symptoms were not relieved and she had multi-organ failure requiring ventilator support and a repeat CECT scan showed a displaced  LAMS [Fig-1], given her clinical condition, the patient was planned for endoscopic removal of the stent, which was a failure. A percutaneous catheter was placed to stabilize her clinical condition but her clinical condition did not improve.  Giver her clinical condition patient was operated on. On midline laparotomy, multiple adhesions lesser sac was entered with great difficulty because of multiple adhesions and the stent was removed. Postoperatively the patient was discharged on postoperative day 20. On follow-up, the patient has no symptoms.

Discussion

Lumen-apposing metal stents tend to be misplaced into the WOPN, however, to improve the patient's condition plastic stents can be placed and metallic stents can be retrieved later. There are reports of endoscopic removal of misplaced endoscopic stents, however, endoscopic removal could not be possible every time [1-3]. Surgery has the added advantage of removing the stent as well as necrotic tissue, however, it is associated with higher morbidity and mortality. To conclude LAMS can be misplaced, endoscopic retrieval has to be tried, if it fails surgery can be done once the patient's condition stabilizes.

Acknowledgments: We acknowledge the support given by our supporting staff

Disclosure statement: Nothing to disclose and there was no conflict of interest among the authors

Research ethics: Informed consent has been obtained from the patient and study has been carried out as per the Helsinki declaration and  institutional guidelines.

[emgoesmed]

4/10/2023

Despite 4 days off from the hospital I still feel so tired 🥲

Spent the mini vacation decorating the apartment, assembling furniture, dog sitting, and submitting a poster for my school’s poster day.

Today’s another busy day, with early morning rounds in the hospital followed by driving almost an hour to another site to take a practical exam.

Wish me luck!

[sarajcsmicasereports]

Bilateral Aspergillosis endogenous endophthalmitis in post COVID-19 recovered patient; A clinical case report by Zahra Zia, MD in Journal of 

Abstract

Coronavirus disease 2019 (COVID-19) Ocular manifestations have a thousand faces and yet each ocular presentation has a unique course, treatment and prognosis. We present a rare case of post-COVID-19 bilateral Aspergillosis endogenous endophthalmitis (EE) with aggressive manifestation at first but an appropriate treatment response. A 54-year-old man presented with bilateral decreased vision four weeks after post-COVID-19 hospitalization. Initially, he was diagnosed with noninfectious uveitis and treated with topical and systemic prednisolone for one week. Subsequently, he was treated with systemic voriconazole after a positive vitreous sample polymerase chain reaction (PCR) result for Aspergillus fumigatus. This case demonstrated the effectiveness of systemic antifungal treatment without surgical intervention in post-COVID-19 bilateral Aspergillosis EE.

Keywords: Aspergillus fumigatus, COVID-19, Fungal endogenous endophthalmitis

Introduction

The coronavirus pandemic has recently challenged the medical system. Various ocular manifestations of coronavirus infection have been reported.[1] One of the disastrous ocular manifestations detected in these patients is endophthalmitis.[2] There have been previous case series of patients with COVID-19 pneumonia having bacterial endogenous endophthalmitis (EE) originating from the throat, kidneys, and teeth as a source of infection, and even the COVID-19 virus had been isolated from the vitreous sample.[3] Regarding fungal EE, Candida species are reported as the most common pathogen, although there are two reports with a specific diagnosis of Aspergillus.[4,5] The present case report on bilateral Aspergillosis EE is novel in disease course and recovery.

Case report presentation

A 54-year-old man presented with both eyes blurred vision two days before visiting an ophthalmologist. He had a history of COVID-19-related pneumonia with approximately 30% lung involvement, confirmed by polymerase chain reaction (PCR), which led to eight days of hospitalization. He received intravenous dexamethasone (8 mg/day) and Ceftriaxone 1gr every 12 hours for seven days during admission. There was no airway intubation or intensive care unit (ICU) admission. The patient had a history of first dose COVID-vaccination with COVIran Barekat (Barkat Pharmaceutical Group) vaccine [6] three weeks before hospitalization. He could not receive the next dose of his vaccine due to subsequent health problems. He did not have any other previous systemic disease.

His ocular symptoms developed four weeks after post-COVID-19 hospitalization. At presentation, the Snellen best-corrected distance visual acuity (BCVA) of the right and left eyes was 20/200 and finger counts (FC) 4 m, respectively. He was diagnosed with noninfectious uveitis by his primary ophthalmologist and received systemic prednisolone (25mgr /day) with topical steroids and cycloplegic drops. Due to a lack of recovery, he was referred to our clinic after one week. On examination, the BCVA of the right and left eyes were CF 6m and CF 1 m, respectively. Anterior segment slit lamp exam was unremarkable; however, vitreous cell (+2 in both eyes) was detected. Fundoscopy in the right eye showed extensive confluent yellowish intraretinal and subretinal collections in the inferior arcade involving the macula. In the left eye, the same lesion with surrounding sub-retinal cream-coloured fluid was seen in the post pole, which involved the fovea [Figure 1A]. Lesions appeared to expand in size [Figure 1B] five days later. Both eyes' macular optical coherence tomography (OCT) revealed intraretinal and subretinal hyper-reflective materials with mild intraretinal and subretinal fluid (SRF), which disrupted macular structure [Figure 2A-B]. Fundus fluorescein angiography of the right eye [Figure 3A] and left eye [Figure 3B] displayed early hyper fluorescence due to vascular leakage around the lesions.

Clinically suspicious of EE, systemic workup was performed, including obtaining blood and urine culture, vasculitis laboratory tests, purified protein derivative (PPD) skin test, trans-esophageal echocardiography, and repeating spiral chest CT, and no systemic source of infection was detected. Because of highly suspicious fungal chorioretinitis, vitreous sampling for smear, culture and PCR for herpes viruses, Mycobacterium, Candida, and Aspergillus species was obtained, then oral voriconazole (200 mg/bid) and systemic antibiotic (ciprofloxacin 500mgr/bid) was started. Although the culture from vitreous aspiration failed to yield any organism, Real-time PCR analysis detected the Aspergillus Fumigatus while negative for Candida, HSV-1, HSV-2, CMV, VZV, and Mycobacterium genome. By diagnosis of confirmed Aspergillus EE, oral voriconazole was continued. After three weeks, vitreous inflammation, the subretinal lesions' size, and SRF reduced significantly. The patient's vision gradually enhanced in both eyes. After eight weeks, in the follow-up, BCVA was 20/32 in the right and 20/40 in the left eye. Fundus photography and OCT showed improved lesions [figure 4A-B]. Informed consent was obtained from the patient to report this case.

Discussion

The presented case is the first bilateral confirmed Aspergillus EE in a COVID-19-recovered patient who responded to the antifungal treatment without surgical intervention. There are various treatment protocols for Aspergillus EE, and systemic voriconazole is a critical drug.[7] It is suggested to begin systemic antifungal drugs in clinically presumed cases until the results of PCR or vitreous aspiration culture reveal the definitive diagnosis.[8] Surgical procedures such as multiple intravitreal injections of antifungal drugs and pars plana vitrectomy with or without silicone injection have been reported as valuable ways to manage fungal EE. [2,3]

it is necessary to consider the positive history of COVID-19 recent infection, corticosteroid use and the existence of posterior pole necrotizing chorioretinal lesion for considering the clinical suspicion of fungal EE. Most of the Aspergillus EE patients are initially misdiagnosed as noninfectious uveitis by their primary ophthalmologists and treated Inadvertent with local or systemic steroids or immunomodulators. This scenario was happening for our patient and recently reported cases.[4,5]  Also, all recent reports regarding post-COVID-19 recovery Fungal EE indicate no systemic focus of infection and negative blood and urine culture in these patients; therefore, misdiagnosis of noninfectious uveitis is expected.[3,5]  A majority of vitrectomies in all fungal species EE had initial negative tap because the vitreous involvement with filamentous fungi is rare, and initial positive smear is uncommon.[9] Sowmya p et al. showed that the PCR reported for fungal genomes verified a 100% microbial detection rate and can be regarded as a gold standard.[10]

The following chart briefly reviews the recent report of the five patients with confirmed Aspergillus-associated EE in COVID-19-related pneumonia and their characteristic retinal signs. [Table 1] Once comparing clinical details and characteristics of the present case with previous reports, there are some crucial differences. This patient only received systemic voriconazole and did not require a pars plana vitrectomy or intravitreal antifungal injection for treatment; However, baseline BCVA was better than in other cases; therefore, the poor presenting vision may be related to poor visual outcome.[11] The visual outcome and healing process were significantly restored compared to other previous fungal EE cases.[4,5]  The lower percentage of lung involvement and milder Covid-19 disease course compared to the previous case reports may play the role in this difference. In this case, since the vaccine course was not completed, the effect of a single dose could not be accurately determined.

Conclusion

The purpose of presenting this case is to draw attention to considering fungal pathogens cause EE in patients following COVID-19. In addition to demonstrating differences in the course of illness, progression, and even treatment compared to previously reported cases. This article highlights the need for an in-depth examination of the fundus of patients who have ocular symptoms after COVID-19 and takes fungal pathogens into account.

Declarations

Ethics approval and consent to participate

The patient consented to publish his data and pictures without mentioning his name.

Availability of data and material Data is available as needed

Conflict of Interest: None of the authors has a conflict of interest.

Author contribution: All authors fulfil the ICJME authorship criteria 

[myrawjcsmicasereports]

Retinal and choroidal vascular drop out in a case of severe phenotype of Flammer Syndrome. Rescue of the ischemic-preconditioning mimicking action of endogenous Erythropoietin (EPO) by off-label intra vitreal injection of recombinant human EPO (rhEPO) by Claude Boscher in Journal of Clinical Case Reports Medical Images and Health Sciences

Abstract

Background: Erythropoietin (EPO) is a pleiotropic anti-apoptotic, neurotrophic, anti-inflammatory, and pro-angiogenic endogenous agent, in addition to its effect on erythropoiesis. Exogenous EPO is currently used notably in human spinal cord trauma, and pilot studies in ocular diseases have been reported. Its action has been shown in all (neurons, glia, retinal pigment epithelium, and endothelial) retinal cells. Patients affected by the Flammer Syndrome (FS) (secondary to Endothelin (ET)-related endothelial dysfunction) are exposed to ischemic accidents in the microcirculation, notably the retina and optic nerve.

Case Presentation: A 54 years old female patient with a diagnosis of venous occlusion OR since three weeks presented on March 3, 2019. A severe Flammer phenotype and underlying non arteritic ischemic optic neuropathy; retinal and choroidal drop-out were obviated. Investigation and follow-up were performed for 36 months with Retinal Multimodal Imaging (Visual field, SD-OCT, OCT- Angiography, Indo Cyanin Green Cine-Video Angiography). Recombinant human EPO (rhEPO)(EPREX®)(2000 units, 0.05 cc) off-label intravitreal injection was performed twice at one month interval. Visual acuity rapidly improved from 20/200 to 20/63 with disparition of the initial altitudinal scotoma after the first rhEPO injection, to 20/40 after the second injection, and gradually up to 20/32, by month 5 to month 36. Secondary cystoid macular edema developed ten days after the first injection, that was not treated via anti-VEGF therapy, and resolved after the second rhEPO injection. PR1 layer integrity, as well as protective macular gliosis were fully restored. Some level of ischemia persisted in the deep capillary plexus and at the optic disc.

Conclusion: Patients with FS are submitted to chronic ischemia and paroxystic ischemia/reperfusion injury that drive survival physiological adaptations via  the hypoxic-preconditioning mimicking effect of endogenous EPO, that becomes overwhelmed in case of acute hypoxic stress threshold above resilience limits. Intra vitreal exogenous rhEPO injection restores retinal hypoxic-preconditioning adaptation capacity, provided it is timely administrated. Intra vitreal rhEPO might be beneficial in other retinal diseases of ischemic and inflammatory nature.

Key words : Erythropoietin, retinal vein occlusion, anterior ischemic optic neuropathy, Flammer syndrome, Primary Vascular Dysfunction, anti-VEGF therapy, Endothelin, microcirculation, off-label therapy.

Introduction

Retinal Venous Occlusion (RVO) treatment still carries insufficiencies and contradictions (1) due to the incomplete deciphering of the pathophysiology and of its complex multifactorial nature, with overlooking of factors other than VEGF up-regulation, notably the roles of  retinal venous tone and Endothelin-1 (ET) (2-5), and of endothelial caspase-9 activation (6). Flammer Syndrome (FS)( (Primary Vascular Dysfunction) is related to a non atherosclerotic ET-related endothelial dysfunction in a context of frequent hypotension and increased oxidative stress (OS), that alienates organs perfusion, with notably changeable functional altered regulation of blood flow (7-9), but the pathophysiology remains uncompletely  elucidated (8). FS is more frequent in females, and does not seem to be expressed among outdoors workers, implying an influence of sex hormons and light (7)(9). ET is the most potent pro-proliferative, pro-fibrotic, pro-oxidative and pro-inflammatory vasoconstrictor, currently considered involved in many diseases other than cardio-vascular ones, and is notably an inducer of neuronal apoptosis (10). It is produced by endothelial (EC), smooth vascular muscles (SVMC) and kidney medullar cells,  and binds the surface Receptors  ET-A on SVMC and ET-B on EC,  in an autocrine and paracrine fashion. Schematically, binding on SVMC Receptors (i.e. through local diffusion in fenestrated capillaries or dysfunctioning EC) and on EC ones (i.e. by circulating ET) induce respectively arterial and venous vasoconstriction, and vasodilation, the latter via Nitrite oxide (NO) synthesis. ET production is stimulated notably by Angiotensin 2, insulin, cortisol, hypoxia, and antagonized by endothelial gaseous NO, itself induced by flow shear stress. Schematically but not exclusively, vascular tone is maintained by a complex regulation of ET-NO balance (8) (10-11).  Both decrease of NO and increase of ET production are both a cause and consequence of inflammation, OS  and endothelial dysfunction, that accordingly favour vasoconstriction; in addition ET competes for L-arginine substrate with NO synthase, thereby reducing NO bioavailability, a mechanism obviated notably in carotid plaques and amaurosis fugax (reviewed in 11).

Severe FS phenotypes are rare. Within the eye, circulating ET reaches retinal VSMC in case of Blood-Retinal-Barrier (BRB) rupture and diffuses freely via the fenestrated choroidal circulation, notably around the optic nerve (ON) head behind the lamina cribrosa, and may induce all pathologies related to acute ocular blood flow decrease (2-3)(5)(7-9). We previously reported two severe cases with rapid onset of monocular cecity and low vision, of respectively RVO in altitude and non arteritic  ischemic optic neuropathy (NAION) (Boscher et al, Société Francaise d'Ophtalmologie and Retina Society, 2015 annual meetings).

Exogenous Recombinant human EPO (rhEPO) has been shown  effective in humans for spinal cord injury (12), neurodegenerative and chronic kidney diseases (CKD) (reviewed in 13). Endogenous EPO is released physiologically in the circulation by the kidney and liver; it may be secreted in addition by all cells in response to hypoxic stress, and it is the prevailing pathway induced via genes up-regulation by the transcription factor Hypoxia Inducible Factor 1 alpha, among angiogenesis (VEGF pathway), vasomotor regulation (inducible NO synthase), antioxidation, and energy metabolism (14). EPO Receptor signaling induces cell proliferation, survival and differentiation (reviewed in 13), and targets multiple non hematopoietic pathways as well as the long-known effect on erythropoiesis (reviewed in 15). Of particular interest here, are its synergistic anti-inflammatory, neural antiapoptotic (16) pro-survival and  pro-regenerative (17) actions upon hypoxic injury, that were long-suggested to be also indirect, via blockade of ET release by astrocytes, and assimilated to ET-A blockers action (18). Quite interestingly, endogenous EPO’s pleiotropic effects were long-summarized (back to 2002), as “mimicking hypoxic-preconditioning” by Dawson (19), a concept applied to the retina (20). EPO Receptors are present in all retinal cells and their rescue activation targets all retinal cells, i.e. retinal EC, neurons (photoreceptors (PR), ganglion (RGG) and  bipolar cells), retinal pigment epithelium (RPE) osmotic function through restoration of the BRB, and  glial cells (reviewed in 21), and the optic nerve (reviewed in 22).  RhEPO has been tested experimentally in animal models of glaucoma, retinal ischemia-reperfusion (I/R) and light phototoxicity, via multiple routes (systemic, subconjunctival, retrobulbar and intravitreal injection (IVI) (reviewed in 23), and used successfully via IVI in human pilot studies, notably first in diabetic macular edema (24) (reviewed in 25 and 26). It failed to improve neuroprotection in association to corticosteroids in optic neuritis, likely for bias reasons (reviewed in 22). Of specific relation to the current case, it has been reported in NAION (27) (reviewed in 28) and traumatic ON injury (29 Rashad), and in one case of acute severe central RVO (CRVO) (Luscan and Roche, Société Francaise d’Ophtalmologie 2017 annual meeting). In addition EPO RPE gene therapy was recently suggested to prevent retinal degeneration induced by OS in a rodent model of dry Age Macular Degeneration (AMD) (30).

Case Report Presentation

This 54 years female patient was first visited on March 2019 4th, seeking for second opinion for ongoing vision deterioration OR on a daily basis, since around 3 weeks. Sub-central RVO (CRVO) OR had been diagnosed on February 27th; available SD-OCT macular volume was increased with  epiretinal marked hyperreflectivity, one available Fluorescein angiography picture showed a non-filled superior CRVO, and a vast central ischemia involving the macular and paraoptic territories. Of note there was ON edema with a para-papillary hemorrage nasal to the disc on the available colour fundus picture.

At presentation on March 4, Best Corrected Visual Acuity (BCVA) was reduced at 20/100 OR (20/25 OS). The patient described periods of acutely excruciating retro-orbital pain in the OR. Intraocular pressure was normal, at 12 OR and 18 OS (pachymetry was at 490 microns in both eyes). The dilated fundus examination was similar to the previous color picture and  did not disclose peripheral hemorrages recalling extended peripheral retinal ischemia. Humphrey Visual Field disclosed an altitudinal inferior scotoma and a peripheral inferior scotoma OR and was in the normal range OS, i.e. did not recall normal tension glaucoma OS . There were no papillary drusen on the autofluorescence picture, ON volume was increased  (11.77 mm3 OR versus 5.75 OS) on SD-OCT (Heidelberg Engineering®) OR,  Retinal Nerve Fiber (RNFL) and RGC layers thicknesses were normal  Marked epimacular hypereflectivity OR with foveolar depression inversion, moderately increased total volume and central foveolar thickness (CFT) (428 microns versus 328 OS), and a whitish aspect of the supero-temporal internal retinal layers recalling ischemic edema, were present . EDI CFT was incresead at 315 microns (versus 273 microns OS), with focal pachyvessels on the video mapping . OCT-Angiography disclosed focal perfusion defects in both the retinal and chorio-capillaris circulations , and central alterations of the PR1 layer on en-face OCT

Altogether the clinical picture evoked a NAION with venous sub-occlusion, recalling Fraenkel’s et al early hypothesis of an ET interstitial diffusion-related venous vasoconstriction behind the lamina cribrosa (2), as much as a rupture of the BRB was present in the optic nerve area (hemorrage along the optic disc). Choroidal vascular drop-out was suggested by the severity and rapidity of the VF impairment (31). The extremely rapid development of a significant “epiretinal membrane”, that we interpreted as a reactive - and protective, in absence of cystoid macular edema (CME) - ET 2-induced astrocytic proliferation (reviewed in 32), was as an additional  sign of severe ischemia.

The mention of the retro-orbital pain evoking a “ciliary angor”, the absence of any inflammatory syndrome and of the usual metabolic syndrome in the emergency blood test, oriented the etiology towards a FS. And indeed anamnesis collected many features of the FS, i.e. hypotension (“non dipper” profile with one symptomatic nocturnal episode of hypotension on the MAPA), migrains, hypersensitivity to cold, stress, noise, smells, and medicines, history of a spontaneously resolutive hydrops six months earlier, and of paroxystic episods of vertigo (which had driven a prior negative brain RMI investigation for Multiple Sclerosis, a frequent record among FS patients (33) and of paroxystic visual field alterations (7)(9), that were actually recorded several times along the follow-up.

The diagnosis of FS was eventually confirmed in the Ophthalmology Department in Basel University on April 10th, with elevated retinal venous pressure (20 to 25mmHg versus 10-15 OS) (4)(7)(9), reduced perfusion in the central retinal artery and veins on ocular Doppler (respectively 8.3 cm/second OR velocity versus 14.1 mmHg OS, and 3.1/second OR versus 5.9 cm OS), and impaired vasodilation upon flicker light-dependant shear stress on the Dynamic Vessel Analyser testing (7-9). In addition atherosclerotic plaques were absent on carotid Doppler.

On March 4th, the patient was at length informed about the FS, a possible off label rhEPO IVI, and a related written informed consent on the ratio risk-benefits was delivered.

By March 7th, she returned on an emergency basis because of vision worsening OR. VA was unchanged, intraocular pressure was at 13, but Visual Field showed a worsening of the central and inferior scotomas with a decreased foveolar threshold, from 33 to 29 decibels. SD-OCT showed a 10% increase in the CFT volume.

On the very same day, an off label rhEPO IVI OR (EPREX® 2000 units, 0,05 cc in a pre-filled syringe) was performed in the operating theater, i.e. the dose reported  by Modarres et al (27), and twenty times inferior to the usual weekly intravenous dose for treatment of chronic anemia secondary to CKD. Intra venous acetazolamide (500 milligrams) was performed prior to the injection, to prevent any increase in intra-ocular pressure. The patient was discharged with a prescription of chlorydrate betaxolol (Betoptic® 0.5 %) two drops a day, and high dose daily magnesium supplementation (600 mgr).

Incidentally the patient developed bradycardia the day after, after altogether instillation of 4 drops of betaxolol only, that was replaced by acetazolamide drops, i.e. a typical hypersensitivity reaction to medications in the FS (7)(9).

Subjective vision improvement was recorded as early as D1 after injection. By March 18 th, eleven days post rhEPO IVI, BCVA was improved at 20/63, the altitudinal scotoma had resolved (Fig. 5), Posterior Vitreous Detachment had developed with a disturbing marked Weiss ring, optic disc swelling had decreased; vasculogenesis within the retinal plexi and some regression of PR1 alterations  were visible on OCT-en face. Indeed by 11 days post EPO significant functional, neuronal and vascular rescue were observed, while the natural evolution had been seriously vision threatening.

However cystoid ME (CME) had developed . Indo Cyanin Green-Cine Video Angiography (ICG-CVA) OR, performed on March 23, i.e. 16 days after the rhEPO IVI, showed a persistent drop in ocular perfusion: ciliary and central retinal artery perfusion timings were dramatically delayed at respectively 21 and 25 seconds, central retinal vein perfusion initiated by 35 seconds, was pulsatile, and completed by 50 seconds only (video 3). Choroidal pachyveins matching the ones on SD-OCT video mapping were present in the temporal superior and inferior fields, and crossed the macula; capillary exclusion territories were present in the macula and around the optic disc.

By April 1, 23 days after the rhEPO injection, VA was unchanged, but CME and perfusion voids in the superficial deep capillary plexi and choriocapillaris were worsened, and optic disc swelling had recurred back to baseline, in a context of repeated episodes of systemic hypotension; and actually Nifepidin-Ratiopharm® oral drops (34), that had been delivered via a Temporary Use Authorization from the central Pharmacology Department in Assistance Publique Hopitaux de Paris, had had to be stopped because of hypersensitivity.

A second off label rhEPO IVI was performed in the same conditions on April 3, i.e. approximately one month after the first one.

Evolution was favourable as early as the day after EPO injection 2: VA was improved at 20/40, CME was reduced, and perfusion improved in the superficial retinal plexus as well as in the choriocapillaris. By week 4 after EPO injection 2, CME was much decreased, i.e. without anti VEGF injection. On august 19th, by week 18 after EPO 2, perfusion on ICG-CVA was greatly improved , with ciliary timing at 18 seconds, central retinal artery at 20 seconds and venous return from 23 to 36 seconds, still pulsatile. Capillary exclusion territories were visible in the macula and temporal to the macula after the capillary flood time that went on by 20.5 until 22.5 seconds (video 4); they  were no longer persistent at intermediate and late timings.

Last complete follow-up was recorded on January 7, 2021, at 22 months from EPO injection 2. BCVA was at 20/40, ON volume had dropped at 7.46 mm3, a sequaelar superior deficit was present in the RNFL  with some  corresponding residual defects on the inferior para central Visual Field , CFT was at 384 mm3 with an epimacular hyperreflectivity without ME, EDI CFT was dropped at 230 microns. Perfusion on ICG-CVA was not normalized, but even more improved, with ciliary timing at 15 seconds, central retinal artery at 16 seconds and venous return from 22 to 31 seconds, still pulsatile , indicating that VP was still above IOP. OCT-A showed persisting perfusion voids, especially at  the optic disc and within the deep retinal capillary plexus. The latter were present at some degree in the OS as well . Choriocapillaris and PR1 layer were dramatically improved.

Last recorded BCVA was at 20/32 by February 14, 2022, at 34 months from EPO 2. SD-OCT showed stable gliosis hypertrophy and mild alterations of the external layers .

Discussion

What was striking in the initial clinical phenotype of CRVO  was  the contrast between the moderate venous dilation,  and the intensity of ischemia, that were illustrating the pioneer hypothesis of Professor Flammer‘s team regarding the pivotal role of ET in VO (2), recently confirmed (3)(35), i.e. the local venous constriction backwards the lamina cribrosa, induced by diffusion of ET-1 within the vascular interstitium, in reaction to hypoxia. NAION was actually the primary and prevailing alteration, and ocular hypoperfusion was confirmed via ICG-CVA, as well as by the ocular Doppler performed in Basel. ICG-CVA confirmed the choroidal drop-out suggested by the severity of the VF impairment (31) and by OCT-A in the choriocapillaris. Venous pressure measurement, which instrumentation is now available (8), should become part of routine eye examination in case of RVO, as it is key to guide cases analysis and personalized therapeutical options.

Indeed, the endogenous EPO pathway is the dominant one activated by hypoxia and is synergetic with the VEGF pathway, and coherently it is expressed along to VEGF in the vitreous in human RVO (36). Diseases develop when the individual limiting  stress threshold for efficient adaptative reactive capacity gets overwhelmed. In this case by Week 3 after symtoms onset,  neuronal and vascular resilience mechanisms were no longer operative, but the BRB, compromised at the ON, was still maintained in the retina.

As mentioned in the introduction, the scientific rationale for the use of EPO was well demonstrated by that time, as well as the capacities of exogenous EPO to mimic endogenous EPO vasculogenesis, neurogenesis and  synaptogenesis, restoration of  the balance between ET-1 and NO. Improvement of chorioretinal blood flow was actually illustrated by the evolution of the choriocapillaris perfusion on repeated OCT-A and ICG-CVA. The anti-apoptotic effect of EPO (16) seems as much appropriate in case of RVO as the caspase-9 activation is possibly another overlooked co-factor (6).

All the conditions for translation into off label clinical use were present: severe vision loss with daily worsening and  unlikely spontaneous favourable  evolution, absence of toxicity in the human pilot studies, of contradictory comorbidities and co-medications, and of context of intraocular neovascularization that might be exacerbated by EPO (37).

Why didn’t we treat the onset of CME by March 18th, i.e. eleven days after EPO IVI 1, by anti-VEGF therapy, the “standard-of-care” in CME for RVO ?

In addition to the context of functional, neuronal and vascular improvements obviated by rhEPO IVI by that timing in the present case, actually anti VEGF therapy does not address the underlying causative pathology. Coherently, anti-VEGF IVI :  1) may not be efficient in improving vision in RVO, despite its efficiency in resolving/improving CME (usually requiring repeated injections), as shown in the Retain study (56% of eyes with resolved ME continued to loose vision)(quoted in (1) 2) eventually may be followed by serum ET-1 levels increase and VA reduction (in 25% of cases in a series of twenty eyes with BRVO) (38) and by increased areas of non perfusion in OCT-A (39). Rather did we perform a second hrEPO IVI, and actually we consider open the question whether the perfusion improvement, that was progressive, might have been accelerated/improved via repeated rhEPO IVI, on a three to four weeks basis.

The development of CME itself, involving a breakdown of the BRB, i.e. of part of the complex  retinal armentorium resilience to hypoxia, was somewhat paradoxical in the context of improvement after the first EPO injection, as EPO restores the BRB (24), and as much as it was suggested that EPO inhibits glial osmotic swelling, one cause of ME, via VEGF induction (40). Possible explanations were: 1) the vascular hyperpermeability induced by the up-regulation of VEGF gene expression via EPO (41) 2) the ongoing causative disease, of chronic nature, that was obviated by the ICG-CVA and the Basel investigation, responsible for overwhelming the gliosis-dependant capacity of resilience to hypoxia 3) a combination of both. I/R seemed excluded: EPO precisely mimics hypoxic reconditioning as shown in over ten years publications, including in the retina (20), and as EPO therapy is part of the current strategy for stabilization of the endothelial glycocalix against I/R injury (42-43). An additional and not exclusive possible explanation was the potential antagonist action of EPO on GFAP astrocytes proliferation, as mentioned in the introduction (18), that might have counteracted the reactive protective hypertrophic gliosis, still fully operative prior to EPO injection, and that was eventually restored during the follow-up, where epiretinal hyperreflectivity without ME and ongoing chronic ischemia do coincide (Fig. 6 and video 6), as much as it is unlikely that EPO’s effect would exceed one month (cf infra). Inhibition of gliosis by EPO IVI might have been also part of the mechanism of rescue of RGG, compromised by gliosis in hypoxic conditions (44). Whatever the complex balance initially reached, then overwhelmed after EPO IVI 1, the challenge was rapidly overcome by the second EPO IVI without anti-VEGF injection, likely because the former was powerful enough to restore the threshold limit for resilience to hypoxia, that seemed no longer reached again during the relapse-free follow-up. Of note, this “epiretinal membrane “, which association to good vision is a proof of concept of its protective effect, must not be removed surgically, as it would suppress one of the mecanisms of resilience to hypoxia.

To our best knowledge, ICG-CVA was never reported in FS; it allows real time evaluation of the ocular perfusion and illustration of the universal rheological laws that control choroidal blood flow as well. Pachyveins recall a “reverse” veno-arteriolar reflex in the choroidal circulation, that is NO and autonomous nervous system-dependant, and that we suggested to be an adaptative choroidal microcirculation process to hypoxia (45).  Their persistence during follow-up accounts for a persisting state of chronic ischemia.

The optimal timing for reperfusion via rhEPO in a non resolved issue:

in the case reported by Luscan and Roche, rhEPO IVI was performed on the very same day of disease onset, where it induced complete recovery from VA reduced at counting fingers at 1 meter, within 48 hours. This clinical human finding is on line with a recent rodent stroke study that established the timings for non lethal versus lethal ischemia of the neural and vascular lineages, and the optimized ones for beneficial reperfusion: the acute phase - from Day 1 where endothelial and neural cells are still preserved,  to Day 7 where proliferation of pericytes and Progenitor Stem Cells are obtainable - and the chronic stage, up to Day 56, where vasculogenesis, neurogenesis and functional recovery are still possible, but with uncertain efficiency (46). In our particular case, PR rescue after rhEPO IVI 1 indicated that Week 3 was still timely. RhEPO IVI  efficacy was shown to last between one (restoration of the BRB)  and four weeks (antiapoptotic effect) in diabetic rats (24). The relapse after Week 3 post IVI 1 might indicate that it might be  approximately the interval to be followed, should repeated injections be necessary.

The bilateral chronic perfusion defects on OCT-A at last follow-up indicate that both eyes remain in a condition of chronic ischemia and I/R, where endogenous EPO provides efficient ischemic pre-conditioning, but is potentially susceptible to be challenged during episodes of acute hypoxia that overwhelm the resilience threshold.

Conclusion

The present case advocates for individualized medicine with careful recording of the medical history, investigation of the systemic context, and exploiting of the available retinal multimodal imaging for accurate analytical interpretation of retinal diseases and their complex pathophysiology. The Flammer Syndrome is unfortunately overlooked in case of RVO; it should be suspected clinically in case of absence of the usual vascular and metabolic context, and in case  of elevated RVP. RhEPO therapy is able to restore the beneficial endogenous EPO ischemic pre-conditioning in eyes submitted to challenging acute hypoxia episodes in addition to chronic ischemic stress, as in the Flammer Syndrome and fluctuating ocular blood flow, when it becomes compromised by the overwhelming of the hypoxic stress resilience threshold. The latter physiopathological explanation illuminates the cases of RVO where anti-VEGF therapy proved functionally inefficient, and/or worsened retinal ischemia. RhEPO therapy might be applied to other chronic ischemia and I/R conditions, as non neo-vascular Age Macular Degeneration (AMD), and actually EPO was listed in 2020 among the nineteen promising molecules in AMD in a pooling of four thousands (47).

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Journal of Clinical and Medical Images