This review article explores the telocytes’ roles in inflammatory bowel diseases (IBD), presenting the mechanisms and hypotheses related to epithelial regeneration, progressive fibrosis, and dysmotility as a consequence of TCs’ reduced or absent number. Based on the presented mechanisms and hypotheses, we aim to provide a functional model to illustrate TCs’ possible roles in the normal and pathological functioning of the digestive tract. TCs are influenced by the compression of nearby blood vessels and the degree of fibrosis of the surrounding tissues and mediate these processes in response. The changes in intestinal tube vascularization induced by the movement of the food bowl, and the consequent pH changes that show an anisotropy in the thickness of the intestinal tube wall, have led to the identification of a pattern of intestinal tube development based on telocytes’ ability to communicate and modulate surrounding cell functions. In the construction of the theoretical model, given the predictable occurrence of colic in the infant, the two-layer arrangement of the nerve plexuses associated with the intestinal tube was considered to be incompletely adapted to the motility required with a diversified diet. There is resulting evidence of possible therapeutic targets for diseases associated with changes in local nerve tissue development. Telocytes (TCs) are interstitial cells with distinct features ,2,3. TheThis article explores in a review the telocytes’ roles in inflammatory bowel diseases (IBD), presenting the mechanisms and hypotheses related to epithelial regeneration, progressive fibrosis, and dysmotility as a consequence of TCs’ reduced or absent number. Based on the presented mechanisms and hypotheses, we aim to provide a functional model to illustrate TCs’ possible roles in the normal and pathological functioning of the digestive tract. The digestive tract retains its basic structural layers along its path, despite the presence of significant functional changes from one area to another. In addition, the digestive tract presents important muscular and nervous components that sustain the movement of the fecal bowl. This, in correlation with the ability of TCs to react to mechanical stimuli through calcium as a second mediator, provides a perspective for understanding the maturation and functioning of digestive tract motility. This article first covers the implications of TCs’ functions in inflammatory bowel diseases, then details the model proposed for TC signaling and discusses the application of our model in intestinal colic, Crohn’s disease, ulcerative colitis, and irritable bowel syndrome in subsequent sections. Furthermore, possible novel treatment targets in these pathologies are discussed within each chapter.TCs represent a distinct category among stromal cells, which include pericytes, myofibroblasts, fibroblasts, vascular endothelial cells, macrophages, and dendritic cells. They have long protrusions (telopodes) consisting of alternating structures, namely podomers (thin segments) and podoms (dilated regions)—both of which contain endoplasmic reticulum, caveolae, and mitochondria . A distiTelocytes distinguish themselves among the aforementioned cell types in GI layers by participating with interstitial Cajal cells (ICC) in the formation of 2D networks between the mucosal, submucosal, and circular muscle layers or 3D networks in the other muscle layers and the myenteric plexus. To date, TC subtypes have been described according to their location in the GI’s layers and the GI organ ,13,14 asWithin the mucosal layer, TCs are involved in the transduction of sensory and immune signals, and in the maintenance of mucosal homeostasis ,10. ReceThe stem cell compartment is located at the base of the crypts along with the Paneth cells. Stem cell behavior can be modulated by several signal pathways . These pathways seem to be crucial in inflammatory bowel diseases (IBD). Stem cells can differentiate into Paneth cells mainly by the Wnt signaling pathway through the TCF4 transcription factor which triggers the expression of several genes including alpha-defensins . Paneth TCs are connected with immune cells and endothelial cells by gap junctions and communicate in a paracrine fashion (exo/ectosomes). Hence, TCs seem to be involved in immunomodulatory effects, angiogenesis, and tissue regeneration by inhibiting oxidative stress and, consequently, cellular aging ,10,15. ATCs along with fibroblasts organize and control the extracellular matrix (ECM) . They coA crucial role of TCs in the GI layers is related to facilitating neurotransmission and regulating gut motility by establishing a functional connection between: (i) the nerve endings in the submucosal plexus and myenteric plexus, (ii) the pacemakers of gut motility and neurotransmission (the ICC), and (iii) smooth muscles (SMC) ,10,15. C7–108 organisms/gram in the distal ileum up to 1011–1012 organisms/gram in the luminal content of the colon. As a result, epithelial injury and subsequent pathogen influx trigger an enhanced immune response [Crohn’s disease (CD) and ulcerative colitis (UC) represent the main inflammatory bowel diseases (IBD) with an increasing worldwide incidence. IBD’s clinical presentation is a consequence of the chronic inflammation of the whole intestine with recurrent episodes triggering abdominal pain, bloody stools, and GI dysmotility. In CD, the inflammation affects all the GI layers and involves the whole GI tract, but the terminal ileum and/or the colon are predominantly affected. In UC, the inflammation leads to ulcers affecting both the mucosa and submucosa in the colon and rectum. In IBD, chronic inflammation eventually leads to mucosal loss and severe fibrosis with debilitating dysmotility which is typically more severe in CD. Multiple factors have been incriminated in IBD’s chronic inflammation; however, several independent factors have been found to be associated with its etiology . Geneticresponse . AlthougMoreover, recent reports highlight the progressive loss of TCs leading to a reduced number or even absence of TCs in fibrotic areas in both CD and UC, correlating to the severity of the disease. Consequently, TCs and ICC reduction have been proposed as key events in the dysmotility observed in IBD ,10,15. IVariables such as time, delay, and phase-shift can be utilized to describe the behavior of three-dimensional structures when subjected to a non-uniform or non-isotropic stimulus. In the intestinal tube, signaling can occur by means of mechanical stimuli  which exhibit a directional preference across the gastrointestinal tract. Simultaneously, chemical stimuli which mediate the different signaling pathways have the potential to create differentiated delays in accordance with local vascularization and its modulation and compression, as well as local fibrosis which may hinder the diffusion of signaling factors within the surrounding 3D structures. The disposition in the concentric vascular muscular and nervous plexus layers within the digestive tract enhances the anisotropy of the described signaling mechanisms and can allow for the development of subtle morphogenetic pathways. Understanding these pathways may lead to new therapeutic strategies in intestinal tube motility disorders.Due to the lack of a full understanding of TC functionality, many authors have preferred to use the term ICC-like cells (ICC-LC). To highlight the role of TCs in cavity motility, it is necessary to study the extreme conditions achieved by the obstruction of the tubular organs in which they are found. There is a decrease in ICC-LC in obstructions , with a 2+ pathway. Identifying Wnt signaling pathways in TCs [The differentiated development of the myenteric and the submucosal plexus is suggestive of a mechanism regulating the function of the muscle mass situated in the immediate proximity of each plexus. The involvement of calcium channels with a degree of mechanosensitivity in signaling, which is induced by mechanical stimuli on telocytes  along wis in TCs  and TCs’s in TCs  paves thThe balance between the different signaling pathways could lead to an understanding of telocytes’ behavior depending on environmental stimuli . MaintaiFibrosis can modulate tissue permeability for signaling factors and can be the result of several pathways such as ones involving mast cells ,27, partThe involvement of the Wnt-β-catenin signaling pathway in stem cells’ behavior and the development of intestinal polyps  correlat2+ signaling pathway may have several functions depending on the local cellular environment. One of them is modulating vascular smooth cell function directly through gap junctions [The Caunctions . This hiunctions ,35. ThroTCs have been found in lamina propria, i.e., proximal to the lumen of the digestive tract . ImportaTCs have the ability to signal via TGF-β1  with morInterrelations between neurons, their supporting cells, and TCs suggest a distal-to-proximal organization of telomeres in the submucosal space, with a similar orientation of neurons through modulatory mechanisms of synaptogenesis. In the present model, the existence of the myenteric nervous plexus near the submucosal nervous plexus, with diffuse connections between them, creates an opportunity for organizing the myenteric plexus in the opposite direction due to the synaptic plasticity considerations . Our hypothesis explores the differences between the peak of the pH changes and the peak of the mechanical changes in pH anisotropy  as a repChanges induced by pH anisotropy are sufficiently sensitive to be modulated by bacterial flora in the intestinal lumen. This may explain the need to have a uniformly distributed flora along the digestive tract, although conditions vary slightly from one area to another. The decrease in colonic microbiotic dysplasia  presentsThe theoretical model proposed to explain intestinal colic allows us to understand the interaction between TCs, surrounding tissues, and microbes. In addition, it opens a window toward understanding the pathologies that affect the normal functionality of TCs and their modulating role in morphogenesis. Due to the limited spatial changes in the reduction in the number of bacterial clones in intestinal colic, we can extrapolate the information that TCs communicate via extracellular vectors, and consequently, they are modulated by the different locally available membrane lipids. The effect of intestinal bacteria is outlined not only as an intestinal bolus with a spatially-appropriate mechanical consistency varying with location along the intestinal tract, but also as a lipid source that can alter membrane fluidity and the processes that depend on this fluidity. For example, TCs could modify the response to channel-mediated mechanical stimulation , while aAn explanation of the pattern of intestinal colic is outlined as a punctual decrease in the rate of migration of TCs in the submucosa, which can lead to a consecutive decrease in the myenteric plexus. This theoretical model would explain a punctual decrease in the rate of fecal bolus movement, and consequently a slight distension and colic-specific pain. The occurence of punctual localizations would explain the relatively consistent association with the time of food intake and would provide insight into the disappearance of local dysmotility and associated symptoms by the action of the unaffected proximal muscles .This can explain the need for the adaptation of intestinal flora with the transition from an exclusive diet to a rich diet, which is also associated with changes in the maturation of intestinal structures according to new environmental conditions. To alleviate the stress factors affecting the child and the family, and to ease the transition of intestinal flora and intestinal tract adaptation to these changes, a potential treatment using a combination of different lactobacillus subclones with a high clonal diversity—highlighting missing subclones according to age and food supplementation—can be proposed. Due to the variation along the digestive tract in the optimum conditions for each cell subclone, extracellular lipid feeding can be supplemented as a feasible measure to oppose the low viability of cell clones induced by food intake .To validate the theoretical model of the involvement of TCs in the maturation and functioning of the intestinal nerve plexus, the choice of these three pathologies, which are relatively different from each other but have diarrhea as a common element, shows promise. CD accompanies a discontinuous network of TCs . This caThis concentration of the initial changes in the submucosal plexus, with the existence of ulcerative lesions, suggests the existence of impaired pH-dependent vasodilator reflexes, which lead to the acceleration of local TC migration, but also to the occurrence of ischemic ulcers. The local character of the lesions, with the presence of healthy areas between affected ones, suggests the involvement of a genetic mosaicism. Based on our theoretical model for the explanation of Crohn’s disease, potential therapeutic targets can be identified by attempting to manipulate TCs through clonal strains and extracellular lipids to decrease the rate of migration of TCs into the submucosal plexus. Additionally, vascular targeting by direct modulators of pH-mediated vasoconstrictive reflexes or indirectly by calcium channel modulators could result in effective ulcerative and diarrheal treatment via modulation of TCs by aligning the rate of migration of TCs to the submucosal layer .UC is defined by the contiguity of lesions without healthy areas between afflicted areas. According to the proposed theoretical model, lesions are not centered on the pathophysiological vascular component. It is possible to extrapolate a decrease in TCs by exhausting distal reserves (from the rectum) through the proximal migration process. Ulcerative lesions could be explained by a protective relationship between TCs and the vascular bed. This mechanism is incompletely understood. There is probably a TC-induced vasopressor tone, in the absence of which the distal vessels fail to maintain their integrity. This could be explained by the importance of calcium channel signaling  and the If the described hypothesis is confirmed, an auto synthesis of TCs would be required as a rectal cell reservoir for the initial treatment of lesions. While the suggested treatment may only be provisional, if confirmed to be effective, it could open up new therapeutic opportunities for the recirculation of TCs from the myenteric plexus to the submucosal plexus. If the aforementioned secondary mechanism is deficient, a stimulation of TC migration to the intestinal lumen could be achieved by increasing the response to mechanical stimuli  by modulThe irritable bowel can be interpreted in terms of the proposed theoretical model if we consider the apparent correlation between colic and migraines . Due to In all three of the proposed pathologies, possible non-correlations with the proposed theoretical model could be explained by a relatively small number of modifiable variables. This suggests a high probability of the validity of the proposed theoretical model.The theoretical model of migrating TCs into the submucosal layer in the anti-peristaltic direction and TCs in the peristaltic myenteric plexus layer with a possible reintroduction of TCs from the myenteric to the submucosal layer could explain a significant number of disorders which have thus far been incompletely understood. Developing from our model, a significant number of relatively easy-to-use therapeutic strategies allow for the validation or invalidation of its various components. Even a partial confirmation of the described theoretical model could explain the importance of TCs in interacting with the environment and the in-vitro characterization difficulties of their functions. The simplified model of the digestive tract, which shows relatively small changes in one area compared to another adjacent area, creates the opportunity to understand the complex mechanisms of interaction with the environment. In confirming their ability to modulate nerve plexus function at this level, a new stage opens in understanding the functioning of TCs’ interactions with neurons in areas with higher structural and functional complexities.


Rhino-orbital cerebral mucormycosis has been commonly seen during the coronavirus disease 2019 (COVID-19) pandemic. Several factors responsible for etiology and pathophysiology have been identified, among which corticosteroids and diabetes have contributed to the lion’s share of the outbreak of mucormycosis. In this report, we discuss a case of a 41-year-old non-diabetic male with a recent convalescence from COVID-19 infection presented with gradual vision loss and loss of sensations in his right eye. He was found to have periorbital swelling, restriction of extraocular movements in all gazes, chemosis, ptosis of the right eye, and right maxillary sinus tenderness. His serum investigations, radiologic findings, and blood culture were indicative of rhino-orbital cerebral mucormycosis. He was started on systemic liposomal amphotericin B immediately and underwent aggressive surgical debridement. A high index of clinical suspicion, aggressive multifaceted management, and follow-up are needed to have successful outcomes, thereby lowering the morbidity of coronavirus-associated mucormycosis. Coronavirus disease 2019 (COVID-19) has been associated with a wide range of bacterial and fungal co-infections and superinfections. COVID-19 symptoms vary widely, ranging from simple upper respiratory infections to fatal complications . We repoA 41-year-old male with a recent convalescence from COVID-19 infection presented with complaints of vision loss in the right eye associated with headache and nasal congestion for the last 15 days. Loss of vision in the right eye was gradual in onset and progressive in nature and was preceded by intermittent episodes of headache and nasal congestion over the last month. His history revealed a recent recovery from COVID-19 infection after a course of dexamethasone and hydrocortisone for 28 days, along with symptomatic management. He had no history of similar episodes in the past. His past medical history was non-significant, and he stopped smoking five years ago.On initial evaluation, he was alert and oriented to person, place, and time. He was vitally stable and had a mild fever 100°F). On physical examination, there was eyelid edema, mid-dilated and fixed pupil, proptosis, chemosis, and restriction of extraocular movements of the right eye in all directions (Figure 00°F. On His laboratory, radiographic, and microbiological evaluation resulted in the provisional diagnosis of pansinusitis with mucormycosis and right orbital cellulitis. He was started on systemic liposomal amphotericin B 10 mg/kg daily and was planned for aggressive surgical debridement with lid-sparing orbital exenteration of the right eye and endoscopic debridement of the right sinuses to prevent the spread of the infection to the cerebral veins.Histopathology of the lesion confirmed the presence of right-angled non-septate hyphae and was diagnosed with rhino-orbital cerebral mucormycosis. The swelling subsided, and symptoms gradually improved. Postoperative MRI of the brain and orbits showed residual sinus disease features, right orbital, and intracranial extension with a fungal abscess resolving in the right frontal region. He was continued on amphotericin B for the next four weeks, and the patient was monitored for drug compliance and possible side effects at regular visits. He was discharged after otolaryngology and neurology consultation.Rhizopus oryzae [Although mucormycosis exhibits a wide spectrum of clinical syndromes, one of the most devastating manifestations would be rhino-orbital cerebral mucormycosis . This ras oryzae . It is as oryzae . Other os oryzae ,7. Majors oryzae .R. oryzae [Mucormycosis is highly resistant to most antifungal drugs; however, amphotericin B, posaconazole, and isavuconazole have been significantly effective in managing mucormycosis ,10. Muco. oryzae .Important interventions for controlling mucormycosis are early diagnosis, reversing the predisposing factors, surgical debridement of the infected tissue, and relevant therapeutic antifungal therapy . COVID-1Early diagnosis and prevention of the spread of mucormycosis are crucial because of its high mortality and morbidity. COVID-19-associated mucormycosis is managed by a multidisciplinary team to improve the outcome of the disease. Using corticosteroids judiciously, having access to expert evaluation to diagnose the infection, and increasing awareness are important aspects of controlling the infection. In addition, antifungal treatment and timely surgery are keys to higher survival rates in patients diagnosed with mucormycosis.


In view of the complex mechanism of hearing, it is not difficult to understand that hearing impairment may result from a wide variety of genetically determined anomalies and various environmental factors. Specific mutations in the mitochondrial DNA 12S rRNA gene are responsible for maternally inherited non-syndromic hearing loss, and for increased susceptibility to the ototoxicity of aminoglycoside antibiotics.To asses the presence of C1494T mutation among individuals with normal hearing and hearing impairment who used aminoglycosides and those who had not had contact with the antibiotic.The study was composed of 20 patients with ***nonsyndromic sensorineural hearing loss without prior use of aminoglycosides and 40 premature and high-risk newborns who used ototoxic drugs, of whom 20 had good hearing and 20 had hearing loss. The samples were analyzed by PCR-RFLP with the restriction enzyme Hph I.Experimental.The mitochondrial 12S rRNA C1494T mutation was not detected in any of the samples analyzed.Our data suggest that the hearing loss of the individuals we analyzed was not related to the ototoxicity of mutation C1494T, showing that this mutation is not frequent in our population. In recent years, there has been a major progress in our understanding of hearing mechanisms; numerous genes involved in this process have been discovered and the ways by which they interact has been broadly investigated. The hearing deficiency etiology can involve mutations in one single gene or a combination of mutations in different genes, and also environmental factors, including perinatal infection, brain trauma involving the cochlea or ototoxic drugs -aminoglycosides, or even the interaction between environmental and genetic factorsMutations in mitochondrial DNA (mtDNA) are responsible for a variety of disorders which affect numerous organs and tissuesMost molecular alterations found in the mitochondrial DNA, which are associated with hearing impairment are present in genes 12S rRNA and tRNA. Especially, mutations affecting gene 12S rRNA are responsible for non-syndromic sensorineural hearing loss and a raise in susceptibility to the ototoxicity caused by aminoglycoside antibioticsThese antibiotic agents are clinically important drugs, used everywhere in the world, especially in developed countries, in order to control bacterial infections in hospitalized patients. Notwithstanding, in developing countries these drugs are still routinely used in lesser infectionsLiterature reports that aminoglycoside ototoxicity may be associated with a genetic predisposition with a dominant autosomal inheritance pattern, recessive, X-linked or mitochondrial. In family cases of ototoxic hearing impairment caused by aminoglycoside hypersensitivity is frequently transmitted by maternal inheritance, suggesting involvement of mitochondrial genomeStudies held with the mitochondrial genome with patients with aminoglycoside ototoxicity revealed the identification of mitochondrial DNA mutations in gene 12S rRNA. A1555G mutation was the first mitochondrial mutation describedThe A1555G mutation is structurally equivalent to mutation C1494T. They are both located in a highly preserved region of the 12S rRNA, associated with the binding of the aminoglycoside to the bacteriaMany biochemical studies report the pathogenic potential of mutation C1494T, indicating that aminoglycosides modulate the hearing impairment expression potential and penetrance when associated with such mutationThis study was characterized by a clinical and experimental research , of individuals with hearing impairment without exposure to aminoglycoside antibiotics and in normal-hearing and hearing impaired newborns, premature and of high risk who remained in the NICU  and had contact with the antibiotic.The series was made up of 60 individuals, 20 with hearing impairment and no history of sensitization regarding the use of aminoglycosides (Group B), 20 hearing individuals (Group C) and with audiologic diagnosis of non-syndromic sensorineural hearing loss  who used aminoglycosides.Sample analysis was carried out in DNA isolated by the phenol-chloroform methodThe individuals were previously analyzed as to the presence of mutations to genes GJB2 and GJB6, since mutations to these genes are responsible for a large proportion of cases of non-syndromic hearing loss with recessive autosomal inheritanceFrom the samples of DNA extracted from the peripheral blood, a 441pb fragment from the 12S rRNA gene sequence (GenBank: NC_001807), was amplified by PCR using primers C1494TF (5′-GTCGAAGGTGGATTTAGCAGT-3′) and C1494TR (5′-GCAGAAGGTATAGGGGTTAG-3′). The amplification reaction was carried out using 200 to 500ng of genomic DNA, 10mM of solution containing deoxynucleotides , 10pmol/ml of each primer; 2,0U of Taq DNA polymerase; PCR 10X buffer (Tris-HCl 10mM pH 8.8) and 3mM of MgCl2, in a final volume of 50ml, under the following conditions: a denaturation cycle at 95°C for 5 min; 30 denaturation cycles at 94°C for 30s; annealing at 54°C for 2 min, extension at 65°C for 1mim; 7 min of final extension at 65°C. Amplification products were submitted to electrophoresis in 1% agarose gel and subsequently dyed in ethide bromide.C1494T mutation identification on gene 12S rRNAMolecular investigation of mutation C1494T on the 12S rRNA gene was carried out by analysis of the polymorphism of the restriction fragments (PCR-RFLP) using enzyme Hph I, according to manufacturer's specifications and, analyzed in 1.5% agarose gel. Allele 1494T abolishes the Hph I site in the sequence creating a fragment of 441pb. Thus, individuals with the 1494C allele have fragments of 370pb and 71pb.In an attempt to clear up the molecular aspects of the aminoglycosides' ototoxic effects, we tracked down the C1494T mutation in 40 patients with non-syndromic sensorineural hearing loss. Of these, 20 patients had a history of using aminoglycosides. Other 20 normal hearing individuals exposed to aminoglycosides, were also studied. After amplifying a fragment of gene 12S rRNA (441pb)  and subsFunctional studies show that the C1494T mutation causes a mild mitochondrial dysfunction and sensitivity to aminoglycosides, therefore indicating that the C1494T mutation alone is not responsible for the hearing impairment phenotype. Nonetheless, the hearing loss can be increased by external modifying factors, such as aminoglycosides, and gene interactions. In cases when there is no exposure to aminoglycosides, the C àT transition in position 1494 of gene 12S rRNA has, in vivo, a weak pathogenic potentialAminoglycoside ototoxicity is due to their binding to the receptors of inner ear hair cells. The aminoglycoside-receptor complex formation causes changes to the cell membrane, to its permeability, affecting cilia function and, later causing the destruction of these cellsData reported from a Chinese family show that the interaction of mutation C1494T with other genes, in which those individuals with this mutation had hearing impairment regardless of exposure to aminoglycosides. On the other hand, it has also been disclosed that individuals with the C1494T mutation who were not exposed to the antibiotic did not have hearing lossIn the present study, we assessed the presence of C1494T mutation in hearing individuals and those with hearing impairment who used aminoglycosides and those who did not use the antibiotic. Nonetheless, we did not find positive cases for this mutation, reinforcing the results found in previous studies, who reported that the C1494T mutation is not very frequent in the world populationOur data suggests that the hearing impairment in the analyzed individuals is not related to the ototoxicity of mutation C1494T. Nonetheless, the lack of C1494T mutation in the mitochondrial genome of these individuals does not rule out the possibility of existing mutations in other genes not evaluated in this study. Thus being, later studies with other genes are necessary to clarify the hearing impairment etiology of these individuals.


To elucidate the long-term impacts of hearing loss, tinnitus and balance in people living with and beyond cancer (LWBC) treated with platinum-based chemotherapy (PBCT).A literature search was conducted between March and June 2022 using PubMed, Web of Science and Google Scholar. Full-text papers in English were included. Articles explored the impacts of hearing loss, tinnitus and balance and discussed them in the context of treatment. If PBCT was used in conjunction with other treatments, the article was included. There were no constraints on age, cancer type, publication date, location, study design or data type. Sixteen studies and two reviews were included.Hearing loss and tinnitus can cause communication difficulties and subsequent social withdrawal. There were deficits in cognition, child development and educational performance. Employment and the ease of everyday life were disrupted by hearing loss and tinnitus, whereas poor balance interfered with walking and increased the risk of falls. Depression and anxiety were related to ototoxicity. Most notable were the differing mindsets experienced by adults LWBC with ototoxicity. There was evidence of inadequate monitoring of ototoxicity by clinicians and a lack of communication between clinicians and patients about ototoxicity as a side effect.Ototoxicity has a negative long-term impact on multiple areas of life for adults and children LWBC. This can compromise their quality of life.Increased awareness, monitoring and education surrounding these issues may lead to earlier intervention and better management of ototoxicity, enhancing the quality of life of people LWBC.The online version contains supplementary material available at 10.1007/s11764-022-01314-9. To be diagnosed with cancer is a life-changing and life-threatening event, which can naturally evoke feelings of fear and uncertainty in patients. In 2020, there were approximately 20 million new cases of cancer and almost 10 million deaths worldwide . AlthougSolid tumours, such as ovarian, breast and testicular cancers, as well as head, neck and non-small cell lung cancers, are often treated with platinum-based chemotherapies (PBCT), namely cisplatin, carboplatin and oxaliplatin . AlthougWithin the general population, hearing loss has been related to social isolation, loneliness, mental health problems i.e., depression, as well as cognitive dysfunction such as dementia –17]. Si. Si17]. This literature review aims to serve as an update on the current literature and research on this topic. We aim to collect and summarise what is known on how hearing loss, tinnitus and poor balance affect the quality of life of people LWBC who have undergone PBCT. Although increasing, this is currently an understudied research area. For the purposes of conciseness, the focus will remain on PBCT only or PBCT in combination with other treatments i.e., radiotherapy. It will not discuss the extent of hearing loss, tinnitus etc. in those LWBC but rather the wider impacts of these on quality of life. Issues regarding the monitoring of ototoxicity and the lack of patient awareness of this as a treatment side effect will also be discussed.Literature searches were conducted between March and June 2022 using PubMed, Web of Science and Google Scholar. The keywords, ‘cancer’, ‘survivor’, ‘chemotherapy’, ‘platinum’, ‘cisplatin’, ‘carboplatin’, ‘oxaliplatin’, ‘ototoxicity’, ‘vestibulotoxicity’, ‘hearing loss’, ‘tinnitus’, ‘balance’, ‘long term’ and ‘quality of life’ were inputted in various combinations using Boolean operators (see Online Resource 1 for details on the search strategy).n = 41), 486 titles remained. This number was then reduced through title and abstract screening by the primary author, OP (n = 42). Full-text reading by the primary author reduced this further, according to the inclusion/exclusion criteria (n = 14). However, four additional articles found by manually searching reference lists (n = 3) and through the ‘similar articles’ feature on PubMed (n = 1) were also included. The total number of included titles was, therefore, 18. This process is summarised in Fig. To facilitate a complete and holistic understanding of the topic, few constraints were imposed and the search remained broad. There were no limitations on publication date, location, study design or data type . Reviews were included if they referred to the impacts of audio-vestibular dysfunction in relation to cancer treatment. We focused on published literature only; therefore, grey literature was excluded. No age constraints were applied, meaning articles concerned both adults and children treated for any type of cancer. Pre-clinical and in vitro studies were excluded. Only clinical data published as full-text papers in English were included. The articles must have explored the impacts of hearing loss, tinnitus and poor balance as a primary or secondary outcome and discussed them in the context of treatment. Articles that simply described the prevalence of ototoxicity after treatment were excluded. Given that our focus is on PBCT, articles concerning the use of other treatments alone  were also excluded. However, if chemotherapy was used in conjunction with other treatments, the article was included. The initial searches found 527 titles. After removing duplicates n = 4, 486 titOf the 18 titles accepted, 16 of them were individual studies and two of them reviews. In total, the number of participants included in the studies of this literature review sum to 12,210 . The included studies have been summarised in Tables n = 4531 . All studies included patients who had received PBCT, with cisplatin being the most common, however some patients also underwent alternative treatments either in conjunction with PBCT or instead of PBCT. These included surgery (n = 4/13), neck dissection (n = 1/13), radiotherapy (n = 9/13), taxane-based chemotherapy (n = 3/13), bone marrow transplantation (n = 2/13), and chemotherapy with stem cell support (n = 1/13). Twelve out of 13 studies measured hearing loss, however the measurement of tinnitus and balance was much less common . The type of follow-up varied, with ten studies reporting the time since diagnosis and three reporting the time since the last dose of treatment. Follow-up ranged from just 2 months to over 40 years. Measurements included a variety of subjective and objective methods. For example, hearing loss was measured using objective methods such as otoacoustic emissions (n = 2/13), bone conduction thresholds (n = 5/13), air conduction thresholds (n = 6/13), tympanometry (n = 5/13), otoscopy (n = 1/13), speech audiometry (n = 2/13) and auditory steady-state responses (n = 1/13). Hearing loss was also measured using subjective methods, such as SSQ12 (n = 1/13), MDASI-HN (n = 1/13) and questionnaires created by the research team (n = 2/13). Tinnitus was measured using the HMS questionnaire (n = 1/13), MDASI-HN survey (n = 1/13) and FACT/GOG-Ntx (n = 2/13), whereas measurements of balance included CIPNAT, TUG, FAB  and the WinFDM platform (n = 1/13). In six studies, participants were children. Three of these included parent-reported outcomes and two included child-self-reported outcomes. Nine studies had a control group which compared those LWBC with hearing loss to those without.Table n = 421 . Two studies used semi-structured interviews to collect primary data, whereas one analysed secondary data in the form of online healthcare forums. Within these forums, those LWBC suffering from the effects of treatment discuss how ototoxicity impacts their quality of life. All three studies used thematic analysis. Only one study explicitly stated the age of participants, another described them as ‘adults’ and it is assumed through their use of online healthcare forums that participants in the remaining study were also adults. Two studies provided data on cancer type. PBCT was used in all three studies, however treatments also included non-platinum agents and radiotherapy.Table n = 7258 . This excludes one outlier from Weschler and Wood (2021) [n = 13) and for missing data. The review by Wang et al. (2021) [Table . (2021)  only incThis literature review aimed to highlight the challenges faced by those LWBC after treatment. During the literature search, it became apparent that whilst hearing loss is relatively well researched in cancer populations, there are fewer publications on the effects of tinnitus and poor balance. Despite this, there were several clear themes concerning the long-term impacts of treatment-induced ototoxicity, supported by evidence in this review. These long-term impacts are of a social and cognitive nature. It can also have severe impacts on the development of children and their later academic performance. Employability prospects are affected as well as the ease of completing simple everyday tasks. Finally, ototoxicity can also result in mental health problems. These themes will be discussed in turn below.A commonly reported impact of hearing loss after PBCT is the inability to perceive and hear speech. This renders communication with others, therefore participation in social events or group conversations, extremely challenging. For example, a qualitative study of 24 adults of childhood/young adult cancer found that hearing loss discourages those LWBC from participating in group conversations, with some reporting that they nod along or pretend to know what has been said when actually, they have not heard . Other bf/, /s/, /v/), which make up 50% of English consonants, rely on the perception of high frequencies. However, these are the frequencies initially lost after ototoxic cancer treatments, which makes distinguishing between phonemes challenging, even with mild hearing loss [It is not only hearing within a group that is problematic. Hearing outdoors, whilst travelling, or even watching television can also be difficult , 28. Gening loss .As with hearing loss, tinnitus also impedes communication and causes frustration in those LWBC. For example, someone reported, ‘I’m knackered and it’s just hiss. People can stand in front of me and speak and I’m stressing because I just hear hiss’ . AnotherThe above barriers to communication can cause social anxiety and withdrawal from situations associated with this anxiety , 28, 33.Communicating with others is not the only measure of impaired social attainment after PBCT. This can extend to other facets of life too. For example, in a sample of 226 adults of non-CNS  cancers where it had been at least 10 years since diagnosis, Brinkman et al. (2015)  found thTogether, the above research suggests that ototoxicity after cancer treatment permeates many facets of social functioning in later life. It increases barriers to social support, decreases the size of social networks and restricts community integration. This is especially problematic for those LWBC, who may require greater support and reliance on others. In addition to other long-term and late effects and how these comorbidities impact an individual, the addition of ototoxicity can impact a person’s independence. Given that humans are a naturally social species, perceived social isolation has negative repercussions on several health outcomes, such as mental health, cognition, physical health and all-cause mortality , 36. ThiOtotoxicity has also been demonstrated to negatively affect the cognitive abilities of those LWBC. Cognition is a broad term encapsulating processes such as attention, memory, executive function, processing speed and language . Cross-sCognitive deficits have also been observed for tasks which are less dependent on language. Compared to patients with normal or mild hearing loss, those with severe hearing loss show deficits in attention, processing speed, executive function and cognitive flexibility. They also have slower visuomotor speed . This isThis decline in cognitive abilities in these quantitative studies are supported by qualitative data too. Using semi-structured interviews, adults LWBC complained of ‘chemo-brain’. Interviewees referred to losing things and feeling disorganised . Others s/, approximately the third most frequently occurring consonant, as well as for determining tense and sex [To experience post-chemotherapeutic ototoxicity has deleterious consequences for those LWBC, however these are especially wide-reaching and long-lasting for pediatric patients who are in a critical stage of their speech and language development. Given that mechanisms of word learning include repeated verbal cues  as well  and sex . The impThe impaired ability to perceive and discriminate speech can permeate the academic performance of children with hearing loss. For example, tests of broad reading abilities were administered to patients of medulloblastoma, aged five and older. Specific subsets that were assessed included passage comprehension, reading fluency and letter-word identification. Results demonstrated a steady decline in overall reading ability until five years post-diagnosis in those with severe hearing loss, however not in those without . The samand maths abilities. In a group of 137 childhood survivors of neuroblastoma (mean age of 12 years), those with hearing loss had twice the risk of parent-reported reading and maths difficulties than those without [A contrasting cross-sectional study, however, has demonstrated that patients with ototoxicity have impaired reading  without . Further without . Despite without .These deficits in reading and maths ability can affect academic achievements in adolescence. Cross-sectional research with adults treated for non-CNS tumours, aged nine at diagnosis but aged 31 at follow-up, showed that severe hearing loss was associated with an estimated twofold increased risk of failing to graduate high school (or be unemployed) . NeverthSocial and emotional difficulties can also arise due to ototoxicity. Compared to children whose hearing remained normal after treatment, those with hearing loss had poorer emotional well-being as reported by parents . ParentsThe academic, social and emotional challenges faced by children with hearing loss may lead to a failure to achieve their full potential, for example by having to re-sit school grades, having poorer self-esteem and less social support . As mentHearing loss after chemotherapy has been associated with an increased likelihood of unemployment , 44. It The everyday simple intricacies of life, which no doubt are often taken for granted by healthy individuals, are heavily impacted by the long-term effects of treatment. In general, adults LWBC with ototoxicity have reported a lower quality of life , 44. ThiGait, defined as an individual’s pattern of walking, can also be compromised after chemotherapy. Adults LWBC have demonstrated a slower gait speed and reduced stride length as chemotherapy continues . ImpaireHearing loss and tinnitus also interfere with the simple tasks encountered in everyday life. Compared to adults LWBC who have not developed ototoxicity, those with moderate to severe tinnitus and hearing loss report greater interference in general activity, walking and working. In fact, they also report greater interference in the enjoyment of life . As mentA diagnosis of cancer can place a mental burden on patients . Adding These impacts on mental health are already burdensome, however they can become more extreme. Qualitative research has shown that adults LWBC with ototoxicity can adopt a suicidal mindset, with one even alluding to overdosing themselves due to the addition of hearing loss to their original diagnosis and chemotherapy . AnotherHowever, not all adults LWBC possess this suicidal mindset. Some, in fact, adopted a survival mindset and expressed gratitude to be alive , preferrBased on the findings of this review, it is evident that further gaps and limitations exist in the literature. Firstly, greater standardisation in the reporting of patient characteristics is required. Most of the included quantitative studies failed to note the range of age at diagnosis. Furthermore, four of them did not report the average age at diagnosis. Given the importance of age to health risks we argue that such reporting needs to be mandatory, especially given that younger age at diagnosis is associated with more severe ototoxicity . There wnew normal, where they can function and achieve to the same extent as peers, should be provided by healthcare professionals.Despite inconsistencies in the literature, it is clear that coping with cancer, ototoxicity and other possible long-term effects of treatment is challenging, distressing and at times, disheartening. It is of an urgent matter to ensure support is offered from multiple disciplines to help people LWBC regain a sense of normality. This may not be the ‘normal’ that they are familiar with, but the tools and the opportunity to create a Throughout this review the importance of monitoring ototoxicity in those LWBC has been emphasised. Importantly, a baseline hearing assessment should be conducted . This prevents clinicians overestimating the prevalence of ototoxicity, since it may be pre-existing due to noise exposure or presbycusis (age-related hearing loss) . It willThis issue has also been explored from the perspective of professionals working within hearing services. One qualitative research study used an online questionnaire to assess the management of patients with ototoxicity in the UK . RespondFailure to monitor ototoxicity during and after treatment can result in a delay in help-seeking. Given the social, cognitive and educational impacts that may arise as a result of ototoxicity, as well as the impacts on child development, employment and mental health, early intervention is crucial. This could include the provision of hearing aids, cochlear implants, counselling or modifying the type/dosage of treatment . To ensuA further problem experienced by those LWBC is the lack of awareness of ototoxicity as a side effect. Qualitative research has found that patients did not know that tinnitus and hearing loss were side effects of cancer treatment until they experienced it themselves , 29, 32.The above research highlights the essential role of the clinician, whether that be an audiologist, oncologist or nurse. To enhance the understanding of ototoxicity as a side effect, information should be delivered to the patient in a patient-centred manner, i.e., at a time and in a format tailored to the individual. This could ameliorate the stress, anxiety and shock associated with ototoxicity and the speculation over its permanence. Families of the patients should also be informed to aid their own understanding. Greater information provision may speed up the help-seeking process and prevent negative feelings towards clinicians. It is important that this relationship remains intact, since there is evidence that patients whose oncologist was supportive were more forthcoming about their hearing loss/tinnitus than those whose oncologist was not .It must be noted that although the studies in this literature review all included PBCT, many also included other forms of treatment . Therefore, we cannot rule out the possibility that hearing loss, tinnitus and imbalance (and any subsequent negative consequences) were caused by these treatments instead. Furthermore, the studies in this literature review, and in the literature in general, are heterogenous in terms of methodology, participant demographics and measurements of ototoxicity. Therefore, caution must be exercised when making comparisons with regards to incidence and severity. Finally, in this review, screening of the literature was completed by the primary author only. This may reduce how reliable source selection was as there was no second screener to verify the included/excluded papers.Although the number of individuals surviving cancer is increasing, the long-term effects of treatment continue to burden several aspects of life for those LWBC. This comprises exclusion and anxiety associated with social scenarios, cognitive difficulties in linguistic and non-linguistic tasks, attention and processing speed. Ototoxicity can affect child development, especially in terms of language acquisition and academic performance. Issues related to impaired audio-vestibular functioning extend into adulthood, with individuals experiencing challenges surrounding the practicalities of everyday life and a greater likelihood of unemployment. Ototoxicity in those LWBC can also have a negative effect on mental health. The risks of depression and anxiety may increase as well as the development of suicidal thoughts. However, not everyone LWBC experiences this. Some have a positive coping mindset and are grateful to have survived even if they have acquired hearing loss or tinnitus. Future research should investigate why this discrepancy exists in order to identify and provide support to individuals with suicidal thoughts, as well as to promote more productive coping strategies.To reduce these impacts of hearing loss, tinnitus and imbalance early intervention is crucial. However, there is evidence that baseline measurements of ototoxicity and subsequent monitoring is inadequate. Furthermore, many patients felt as though healthcare professionals had not informed them of ototoxicity as a side effect, which caused feelings of anger and distrust. This could cause a breakdown in the patient-clinician relationship. Future research could investigate why these issues exist, which would be beneficial since resolving them could increase the speed at which interventions are sought and may prevent further decline in quality of life. In addition, there is relatively less research on imbalance relative to tinnitus and hearing loss, despite it interfering with daily life and increasing the risk of falls and injury. More research should be dedicated to this long-term debilitating effect of chemotherapy.Although the aim of cancer treatment is survival, ototoxicity encountered after PBCT, which is often permanent and not preventable, should not be neglected by clinicians and researchers. It is crucial that we direct more of our attention towards this topic to enhance the care of patients and help them adapt to life with ototoxicity. We ought to investigate which aspects of daily life are compromised so that tailored interventions can be applied to situations where help is needed the most. It is the joint responsibility of healthcare professionals and researchers to facilitate this.Supplementary file1 (PDF 68 KB)Below is the link to the electronic supplementary material.


Aunilateral hearing loss is characterized by reduced hearing in one ear. The problems caused by sensory deprivation can be minimized with the use of hearing aids (HA).To analyze the correlation between the prescribed grain and the insertion gain difference and with the results obtained regarding the benefit and satisfaction with the use of hearing aids in unilateral hearing impaired patients.Prospective study with 15 subjects, mean age of 41.6 years, of both genders, users of hearing aids effectively. We used the International Questionnaire Results for hearing aids , measured with a probe microphone.The mean values in the analyses of the IOI-HA per item were positive and higher than four points. In relation to the objective measures, the frequencies in which we obtained the gain values which were closer to the target were: 1K Hz, 2K Hz and 500 Hz, respectively.The satisfaction of individuals using hearing aid unilaterally is not completely correlated to the prescribed gain, because even if the target is not being reached in some frequencies, the individuals were pleased as to the use of their hearing aids. Hearing is one of the fundamental senses in life, playing a very important role in society, being considered the basis for human communication development. Individuals with hearing impairment may suffer handicaps in their social, psychological and professional livesAccording to the 2002 Census (IBGE)Many are the causes which contribute to the increase in the number of hearing impaired individuals: presbycusis, hereditary diseases, metabolic disorders, use of ototoxic drugs, acoustic trauma, excess noise, different types of neoplasia, infections and vascular damage. Among the resulting effects, we stress anxiety, frustration, feeling of insecurity, emotional instability, depression, social phobia, a feeling of frustration and incapacity to guide oneselfUnilateral hearing loss is characterized by hearing reduction in only one ear and it happens, predominantly among malesThe effects of unilateral hearing loss are lower than the ones caused by bilateral hearing loss, which can also cause problems. Under room noise, individuals with unilateral hearing loss find more difficulties than their normal hearing counterparts to understand speech, even when the best ear is positioned towards the source of speech. Moreover, the spatial location of the sound source is compromisedThe problems brought about by sensorial deprivation can be minimized with the use of an Individual Sound Amplification Device (ISAD) - hearing aid, which enables one to bring back the perception of speech sounds, besides environmental sounds, bringing about an improvement in communication skillsThere are many factors which contribute to the successful use of amplification. Age, type and degree of the hearing loss, physical factors , auditory processing skills, prior use of sound amplification device and hearing loss extension, which together, have a crucial role for accepting the amplification. Added to this, the perception of the auditory handicap, cost, personal expectations, satisfaction, performance and benefits may indicate whether or not we will have a happy and satisfied user of a sound amplification deviceAcceptance may be characterized in two ways: either the device is accepted or rejected; but it can also be characterized as a psychological process of dealing with the idea and the sensation of sound amplification, at the same time as it incorporates the device to your lifestyle. Satisfaction is built according to the subjective impressions of the individual. Thus, it becomes clear that, while there is no acceptance, there will never be satisfaction, just like not all acceptance and benefit associated with the device are enough parameters to guarantee satisfaction. While the benefits can be shown through objective tests, personal satisfaction is a very personal assessment of the value of the sound amplification device after a given time of useIt is possible to state that the checking procedures, as the functional gain and the insertion measures, are not enough to assess the individual's satisfaction with the device in daily communication tasks. There was a growing interest in the development of validation procedures which enabled to study the user's benefit outside the clinical settings, making up self-assessment questionnaireshandicap, it is possible to optimize the time it takes for the person to adapt him/ herself to the amplificationThe self-assessment is a simple, fast and efficient procedure which enables the assessment of the individual in his process of ISAD's adaptation. This procedure enables the comparison between different devices and/ or calibrations, as well as the assessment of the benefit achieved with the same ISAD along time, enabling the user to recognize the advantages provided by the ISAD in relation to the individual's auditory difficulties and psychosocial disadvantages. Thus, by means of questionnaires which enable the measuring and analysis of these auditory difficulties or that of the There are numerous assessment instruments which have scores used to assess the level of individual satisfaction, even because there are numerous factors which influence different dimensions associated with the use of a sound amplification deviceAbbreviated Profile of Hearing Aid Benefit), the IOI-HA , the HHIE (Hearing Inventory for the Elderly) and the HHIA (Hearing Handicap Inventory for the Adults) among them, were translated and adapted to our reality in Brazil, investigating the degree of user satisfaction, the benefits obtained from using ISADs and the reduction in auditory capacity with the use of amplification, and others with the goal of comparing the benefit of different Technologies and checking the ISAD fitting by means of objective and subjective measuresIn Brazil, some self-assessment questionnaires, the APHAB .-Age range: adult individuals (18 to 60 years);-Hearing loss: mixed unilateral or sensorineural of moderate, severe and profound levels;-Effective ISAD user for more than six (6) months.Participant inclusion criteria were:The HI degree was classified using the audiometric thresholds of the 500; 1,000; 2,000; 3,000 and 4,000 Hz frequencies: mild HI (mean between 26 and 40 dBHL), moderate HI (mean between 41 and 60 dBHL), severe HI (mean between 61 and 80 dBHL) and profound HI (mean higher than 81 dBHL), according with the WHOInternational Outcome Inventory for Hearing Aids - IOI-HA developed as the product of an international workshop on self-assessment measures in auditory rehabilitationWe used the The questionnaire was used as an individual interview in order to make sure all the questions would be answered and that the individual had fully understood the question.-software used for the probe microphone measures in a way as to generate the gain prescribed by the NAL-NL1 rule.we inserted the threshold tonal audiometry data, obtained through air conduction and bone conduction in the -with the aim of making the probe tube acoustically transparent we did the calibration, positioning the tube in the horizontal plane at 30cm away from the speaker and near the reference microphone.-º azimuth in relation to the speaker.the patient was seated at 50cm away from the sound speaker with the ears in a horizontal plane vis-à-vis the speaker and at 1.5m away from the walls of the room and at a 0-the insertion of the probe microphone in the external acoustic meatus placed at 27-30mm of depth in the external acoustic meatus, using the method in which the probe tube is placed at approximately 3mm from the tip of the ear mold.-Real Ear Unaided Response (REUR) followed by measuring the response with the ISAD in the external ear - Real Ear Aided Response (REAR) thus obtaining the Real Ear Insertion Gain (REIG) using the following calculation: REIG=REAR-REUR. At the end, we noticed that the REIG result reached the target rule, in other words, the calculated target considering the prescription rule formula: NAL-NL1 by previous selection of the equipment software.In order to obtain the REIG, the procedure was carried out in the following sequence: measuring response on the external ear without the ISAD During the checking process, we carried out measures with a probe microphone according to indications from international protocolsMeasurements were carried out with stimuli of 50, 65 and 80 dBSPL of the modulated speech typeWe used description by mean and absolute values for the statistical study.We scored the IOI-HA instrument of the 15 individuals who answered the questionnaire. On We created graphs so as to better see the results associated with the insertion gains in the frequencies of 500; 1,000; 2,000; 3,000 and 4000 Hz.International Society of AudiologyThere are numerous protocols available to use in the selection and fitting of a hearing aid, such as the one from Ordinance 587 from the Health DepartmentThe application of these procedures in the clinical routine requires knowledge of the ISAD technology, which is to be fit to a patient, and the tests chosen for applicationIn order to analyze the benefit and satisfaction, we used the IOI-HA questionnaire, and the use of validated questionnaires is a must in a gold standard protocolAs far as the use is concerned, 66.67% of the individuals reported using the ISAD for more than 8 hours per day, and 26.67% reported uses between 4 and 8 hours per day, and it was possible to notice that all the patients effectively used their hearing aids.As far as the benefit is concerned, 73.34% reported that the hearing aid helped them much in the situations in which before they had major hearing difficulties; 13.33% of the individuals reported that the ISAD helped them moderately in the situations in which they had hearing difficulties; and 13.33% reported that the hearing aid helped them very much in the situations in which before they had hearing difficulties.As to the residual limitation in activities, 40% of the individuals reported that they did not have any difficulties in daily hearing situations, 33.33% had little difficulties; and 20% reported still having moderate difficulties in these activities, even with the use of ISAD. These data tell us that the users of unilateral ISAD had improvements concerning the hearing difficulties they had had before the amplification.When asked about satisfaction concerning the use of the hearing aids, 60% of the individuals reported that it is really worth using the ISAD; and 40% reported that it is reasonably worth using them unilaterally.Concerning the restriction towards daily activities after fitting the individual sound amplification device, 80% of the individuals reported that with the unilateral fitting of the devices, their hearing difficulties no longer affected their daily activities.As to the impact the hearing loss causes on people, 60% of the individuals reported that their hearing difficulties did not affect or bother other people; 13.33% reported it affected moderately their relations with other people.And finally, when the individuals were asked about their quality of lives associated with the use of the sound amplification device, 53.33% reported that after fitting the hearing aid, they became happier with life; 13.33% reported no changes as improvements in quality of life; 13.33% reported a little more happiness in with life after fitting the ISAD; and 13.33% reported a lot more happiness with life after they started using their hearing aids. This data depicts the importance of using these devices in order to enable a better quality of life for those individuals with unilateral hearing loss.IOI-HA was used for being a brief, encompassing type of measurement, accessible to different cultural and social factors for use and different types of comparisonsStill concerning the IOI-HA, we may say that the mean values obtained in the analysis per item were positive and higher than 4 points, keeping in mind that the maximum score per question is five. Consequently, the analysis of the summation of all the questions was also positive, indicating a good subjective result in ISAD fitting.Cox and Alexandertarget in all the frequencies assessed, had a maximum score in the IOI-HA questionnaire.As far as the objective measures go, they noticed that the frequencies in which the gain obtained was closer to the target were: 1,000 HZ; 2,000 Hz and 500 HZ, respectively , 3 and 1We stress that those individuals who were pleased with the use of sound amplification, even not reaching the target, likely because one of the ears did not have normal hearing, since it is known that when the target is not reached, there is a loss for the hearing impaired concerning speech reception and understanding. This indicates that by not doing the checking with objective measures compromises the values programmed in the ISAD, since these can be different from the prescribed target value. In fact, the checking process is crucial, and it is possible to identify the performance of the amplification being provided - both an under-amplification, which may bring about losses in the amplification of speech sounds, as well as an over-amplification, which may cause discomfort and even worsening of the hearing lossSpeech and hearing therapy requires studies which may contribute to the fitting of a hearing aid in unilateral hearing loss cases, especially concerning the way with which the checking process is carried out and the use of objective measures in the centers certified by the National Policy for Hearing Health CareIn terms of the insertion gain, its results are extremely versatile, and when well utilized, the method enables the recording of the ISAD performance. This is a powerful tool in the process of selecting and fitting these devices, providing objective data and essential information to the process, enabling greater precision in the adjustments and in the evaluation of the amplification characteristics received by the hearing impaired individualBy means of the self-assessment questionnaire we report on the satisfaction of individuals with unilateral hearing aids, even when the gain necessary to overcome the difficulties brought about by hearing impairment is not reached.The satisfaction of those individuals users of unilateral hearing aids is not totally associated with the prescribed gain, even though this is an important characteristic for the effective fitting of a hearing aid.ATTACHMENT1Consider the time during which you used your hearing aid in the last two weeks. For how many hours did you use it during a normal day?Did not use itLess than 1 hour per dayBetween 1 and 4 hours per dayBetween 4 and 8 hours per dayMore than 8 hours per day2Think about in which situation you would like to be able to hear better before and after obtaining the hearing aid. In the last two weeks, how did the device (s) help you in this same situation?It did not help at allIt helped a littleIt helped moderatelyIt helped muchIt helped very much3Consider again the same situation in which you would like to be able to hear better before and after the ISAD. Which is the level of difficulty you still have in this same situation using the hearing aids?Very much difficultyMuch difficultyModerate difficultyLittle difficultyNo difficulty at all4Taking everything into account, do you think it is worth using hearing aids?It is not worth itIt is a little worth itIt is moderately worth itIt is much worth itIt is very much worth it5Think about your last week using the ISADs. How much did your hearing problem affected you in your activities?Very muchMuchModeratelyA littleNot at all6Consider the last two weeks using the ISADs. How much did your hearing problems affect or bothered other people?Very muchMuchModeratelyA littleNot at all7Taking everything into account, how do you think your ISADs change your joy in living or your enjoyment of life?To worse, or less joy in livingThere was no changeA little more joy in livingMuch joy in livingVery much joy in living


Aspergillus and Mucorales, fungi cause morbidity. We present a case of disseminated mucormycosis due to Cunninghamella bertholletiae after ABO-incompatible living donor liver transplantation (LDLT).Fungal infection may develop because of immunosuppression after organ transplantation, in which invasive types, such as C. bertholletiae was identified from a specimen using polymerase chain reaction, thus establishing a diagnosis of mucormycosis. Multiple infarctions in the brain, heart, and kidney developed within 2 weeks. Treatment with amphotericin B was ineffective. The patient developed circulatory collapse, and a temporary pacemaker and percutaneous coronary intervention were required for cardiac infarction. The recipient died of cardiac failure 27 days after the LDLT. Autopsy revealed disseminated mucormycosis involving the brain, thyroid, heart, lung, liver, gastrointestinal tract, and both kidneys. In addition, fungal endocarditis may have been responsible for septic emboli in multiple organs, resulting in multiple organ invasion. Hypothrombocytopenia was present since the pre-transplant period, and the recipient was diagnosed posthumously with myelodysplastic syndrome due to hereditary abnormalities. Multiple factors such as organ transplantation, bone marrow dysfunction, immunosuppression, and inadequate administration of antifungal reagents might have promoted mucormycosis development in our patient.A 47-year-old man with decompensated liver cirrhosis and hepatocellular carcinoma underwent an ABO-incompatible LDLT using a graft procured from his son, who had a different blood type. Rituximab and mycophenolate mofetil were administered 3 weeks before LDLT as immunosuppressive therapy. Although liver graft function improved, mass-like infiltrates appeared in the lungs following intubation for > 1 week due to impaired consciousness. The brain magnetic resonance imaging findings were normal. Decreased ejection fraction and ST elevation were detected on echocardiography and electrocardiography, respectively. There was no dominant stenosis on coronary arteriography. The recipient underwent segmentectomy of the right lung 20 days after LDLT. C. bertholletiae is a fatal complication; thus, early diagnosis and treatment are warranted before multiple organ invasion.Mucormycosis by  Aspergillus and Mucorales fungi, cause mortality in over 90% and 60% of liver transplant recipients, respectively [Cunninghamella bertholletiae have significantly higher mortality rates than those of other Mucorales [C. bertholletiae after ABO-incompatible living donor liver transplantation (LDLT).Fungal infections develop in 20–42% of liver transplant recipients due to immunosuppression after liver transplantation . Invasivectively . Mucormyd glucan were negative. The HCC lesion was 2 cm in diameter within the Milan criteria.A 47-year-old man with diabetes mellitus, decompensated liver cirrhosis due to non-alcoholic steatohepatitis, and hepatocellular carcinoma (HCC) underwent LDLT with splenectomy using a right hemiliver graft procured from his son. His pre-transplant model for end-stage liver disease score was 18 points, indicating that he was a suitable (not too severe) candidate for liver transplantation. Preoperative culture screening and β-2 3 weeks before the LDLT and oral mycophenolate mofetil (MMF) 2 g/day starting 2 weeks prior to the LDLT for induction immunosuppression. Post-transplant immunosuppression comprised tacrolimus, MMF, and steroids. The patient received oral fluconazole (100 mg/day) for 10 days to prevent fungal infections before switching to micafungin. The trough level of tacrolimus was adjusted by daily measurement, targeting a concentration of 10 ng/mL  on echocardiography and ST elevation on electrocardiography. There was no dominant stenosis on cardiac arteriography on POD 19.C. bertholletiae was identified by polymerase chain reaction (PCR) from operative specimens cultured using Sabouraud dextrose agar culture medium  , and amphotericin B (AmB) was started at 5 mg/kg IV on POD 22  had appeared. Pulmonary lesions are common in immunocompromised patients, including solid organ transplant recipients with mucormycosis , 10, 12.ividuals . Pulmonaividuals . Mucormynecrosis . Our casCardiac mucormycosis caused Takotsubo myocarditis and an ultimately fatal cardiac infarction. Multiple myocardial infarctions due to fungal emboli were pathologically proven in autopsy specimens. The myocardia were most commonly affected in patients with disseminated pulmonary mucormycosis following solid organ transplantation .C. bertholletiae infection after kidney transplantation [Autopsy also revealed fibrin-containing hyphae covering the endothelium in all heart chambers, suggesting fungal endocarditis. Multiple organ infarctions occurred in quick succession; dissemination to multiple organs may have occurred originating from fungal endocarditis. Zhang et al. reported a case of endocarditis caused by antation .Previous solid organ transplantation was associated with an increased risk of pulmonary, gastrointestinal, or disseminated infection in patients with mucormycosis . An undeAspergillus infection was suspected before diagnosing mucormycosis. Jeong et al. reported that prior antifungal prophylaxis, including voriconazole and fluconazole, was administered to 11% of patients with mucormycosis [Previous use of voriconazole is a significant risk factor for mucormycosis development , 17. We rmycosis . DissemiMucorales were grown on culture, and histopathological features contributed to a definitive diagnosis of mucormycosis [C. bertholletiae infection is difficult and may only be confirmed on autopsy [C. bertholletiae was ultimately identified by PCR, detecting specific fungal DNA sequences.The risk of mortality is approximately 11-fold higher in patients with disseminated mucormycosis than in those with localized disease . Mucoralrmycosis . The prermycosis . However autopsy . Modern  autopsy . We suspPatient mortality increases if AmB-based therapy is delayed . High-doC. bertholletiae after liver transplantation is a rare but fatal complication; the subsequent organ invasion can be fast and aggressive. Early diagnosis and appropriate treatment using antifungal agents and surgery are necessary to prevent dissemination to multiple organs.Mucormycosis caused by


Aim: To estimate the prevalence of hearing loss in patients with cancer using the American Speech-Language-Hearing Association (ASHA), the Pediatric Oncology Group Toxicity (POGT), and the Bilateral Hearing Loss (PAB) criteria. Study design: a prospective study. Material and Methods: 94 patients admitted between 2003 and 2004 were analyzed. Visual inspection of the external auditory meatus and an audiologic evaluation were done. Descriptive statistics was used to characterize the sample, and Kappa statistics was used to investigate concordance of hearing loss in the three types of classification. Results: The prevalence of hearing loss was 42.5% using ASHA, 40.4% using POGT, and 12.8% using PAB. The concordance of hearing loss was weak for POGT and PAB (k=0.36) and for PAB and ASHA (k=0.33). The concordance between ASHA and POGT was almost perfect (k=0.96). Conclusions: Hearing loss is an important side effect of the treatment of cancer in children. Periodic audiology monitoring is recommended to detect early hearing loss and to revise the treatment if necessary. Adoption of a classification system that detects mild hearing loss (ASHA) is recommended.The treatment of cancer in children has several side effects, including ototoxicity. Inner ear structures may be affected and hearing loss may ensue.  The increase in survival rates of children and adolescents with malignant tumors in the last two decades reflects more effective treatments - including combined chemotherapy, better diagnostics, better surgical techniques and radiotherapy, the combined use of different treatment modalities, better support and increase in survival and quality of lifeSide effects may manifest themselves earlier on, or in the long run, depending on treatment type and child’s age. Hearing loss is among these many side effectsOtotoxicity is defined as a toxic reaction that affects the inner ear, both the auditory and/or the vestibular system and may cause hearing lossOne commonly used classification to assess hearing losses in audiology clinics is the one from Davis and Silverman (1970), mentioned by Russo and Santos (1993)According to Haggard and Primus (1999)In assessing the child’s hearing loss, it is important to highlight that even mild loss, which would not impact adults, may interfere in children’s capacity to acquire and develop language skills. Hearing loss, even if transitional, between 25 and 35 dBHL, this reduction is not enough to prevent the child from hearing, however, it may impair the child’s ability to understand some phonemaIn 1991, the American Speech-Language-Hearing Association - ASHA In 1994, the American Speech-Language-Hearing Association - ASHA proposed another specific classification for patients treated with ototoxic drugs, the Ototoxicity Criteria According to Brock et al. (1991)In 1999, the Pediatric Oncology Group Toxicity - POGT Another classification was proposed by the National Cancer Institute (NCI), the Common Toxicity Criteria version 2.0 (CTC) (1999)Recently, another classification was proposed by the National Cancer Institute (NCI), the Common Terminology Criteria for Adverse Events version 3.0 (CTCAEv3) (2003)16. This classification breaks down hearing loss in levels from 1 to 4, by comparing the results of prior audiologic assessments: Level 1 , Level 2 , Level 3  and Level 4 (hearing loss requiring a hearing aid or even a cochlear implant).Although the classifications proposed by Brock et al. (1991)The present investigation was developed in an institute which is the national reference center for the treatment of pediatric cancer, and was approved by the Research Ethics Committee of the School of Public Health of the University of São Paulo, under protocol # 1186 and the Ethics Committee for the Analysis of Research Projects - CAPPesq of the University of São Paulo Hospital Executive Board, protocol # 104/06.After surveying patients’ charts, we noticed that 325 new cases were seen in 2003; and 342 in 2004; most of them, 469 children (= 70.3%), did not have the diagnosis of cancer confirmed and were referred to another unit for specific treatment.Therefore, we selected 87 new cases seen in 2003 and 111 new cases seen in 2004 for our investigation, making up a total of 198 patients. Of these, 44 (22.2%) died and 12 (6.1%) were transferred to other treatment centers located in other cities/capitals, leaving a total of 142 patients. Since pre-treatment audiologic evaluation is not carried out routinely in this institute, these patients were not included in this study.We first assessed the medical chart of these patients in order to fill out the form and, later we scheduled their audiologic exam.Among the 142 patients, we were able to do the audiologic exam in 94 patients.We first carried out an anamnesis in order to look for any symptom or hearing loss complaint. Later on, we visually inspected the external acoustic meatus with an otoscope, checking for wax or any other thing that could prevent these exams. If a wax ball was seen, the patient was then referred to the otorhinolaryngologist to remove it, and only afterwards the exam was carried out.Following that, auditory thresholds were evaluated, by means of conditioned response methods .In order to define the hearing loss, three classifications were used: American Speech-Language-Hearing Association (ASHA), Bilateral Hearing Loss (BHL) and the Pediatric Oncology Group Toxicity (POGT).The sample was characterized by means of descriptive statistics  and we analyzed the three classifications insofar as their agreement is concerned in terms of hearing loss by means of the Kappa statistics. In all statistical analysis we used the 5% level of statistical significance.We used the Epi Info v. 6.04 for DOS software for database double entry and data consistence; and the SPSS v. 12.0 for Windows for statistical analyses.The audiologic evaluation did not involve any invasive procedure and all parents and guardians signed the informed consent. At the end of the exam, we handed the results of this audiologic evaluation to the children’s parents or guardians.There were more males in the sample (52.1%) than females. Caucasians were also more common (83.0%), followed by browns (11.7%). Age at diagnosis varied between 0 and 18 years , and less than half of the patients were diagnosed before 5 years of age (45.7%). Current age varied between 1 and 18 years  and the most frequently found age range was between 5 and 9 years (38.3%), followed by that of 10 years and above (36.2%).The most frequent diagnosis was of lymphoid leukemia (30.8%), followed by the bone tumors group (8.5%) and Willms’s tumor (8.5%) . PatientOf the 94 patients, 38 (40.4%) had pain in their bodies at the time of diagnosis, followed by fever (34.0%) and increase in body mass volume (31.9%). The less frequent symptom was motor change (3.2%), mentioned only by three patients.Among the 94 patients, 67 (71.3%) were alive without chemical or radiotherapy treatment at the time of the last visit recorded in their medical charts; and 27 (28.7%) were alive and under treatment.2 (standard deviation = 32.69 mg/m2), maximum individual dose of 140 mg/m2, maximum cumulative dose of 1120 mg/m2 and average number of treatment cycles of 4.24 (standard deviation = 1.55 cycles).2 (standard deviation = 208.21 mg/m2), maximum individual dose of 775 mg/m2, maximum cumulative dose of 4500 mg/m2 and number of cycles mean value of 4.14 (standard deviation = 2.82 cycles).21 patients (22.3%) received carboplatin, cisplatinanalogue drug, however of lower ototoxic potential, at a mean individual dose of 330.75 mg/mMost commonly mentioned hearing complaint was otitis (22.3%), followed by otalgia (16.0%), dizziness (16.0%), hearing difficulties (14.9%) and upper airway infections (13.8%).The agreement in the hearing loss diagnosis according to classifications POGT and PAB was weak , and the only difference was that two patients were classified as Level 0 by POGT, but were considered as having mild loss in frequencies below 4000 Hz by the ASHA classification.The major agreement in the hearing loss diagnosis between ASHA’s and POGT’s classification happened thanks to the threshold used as cutting point to determine the hearing loss (15 dBHL for ASHA and 20 dBHL for POGT).When the POGT’s classification was used to classify hearing losses, 40.4% of the patients evaluated had hearing loss between levels 1 and 4. Among the studies that used this classification, the one from Marina et al. (2005)17 with 24 patients with germ cells tumors, treated with cisplatin, found 75% of patients with hearing loss between levels 2 and 4. In the study developed by Ruiz et al. (1989)18, the researchers used the threshold above or equal to 20 dBHL to classify the hearing loss, and 100% of their patients treated with cisplatin had hearing loss.In the BHL, only those thresholds above or equal to 40 dBHL are classified as hearing loss. Thus, the number of patients with hearing loss using this classification is much lower when compared to the other two. The agreement between the BHL and the ASHA classifications was weak (Kappa=0.33), and the same happened with the POGT classification (Kappa=0.36).When we used the BHL classification, 12.8% of the patients evaluated had hearing loss between levels 1 and 4. Since this classification only considers hearing loss above 40 dBHL, the mild or light hearing loss in the ASHA classification is classified as Level 0 in the BHL.In Skinner et al.’s study (1990)7 involving 22 children and adolescents diagnosed with solid tumors and treated with cisplatin, 73% had hearing loss. Brock et al. (1991)8 found hearing loss in 48% of the 29 children with different diagnoses, treated with cisplatin.Other studies adopted a threshold equal to or above 25 dBHL in any frequency, between 250 and 8000 Hz as a means of hearing loss classification. The percentage of loss varied between 43% and 81%Allen et al. (1998)20 carried out a retrospective study with 11 children below 18 years of age who received cisplatin during chemotherapy between 1985 and 1994. They found hearing loss between 25 and 90 dBHL in 81% of the children. We found similar figures in the present investigation (83%), when compared to the POGT classification (the closest one for the cutting point at 25 dBHL).Another means to analyze and classify hearing loss was by comparing the hearing thresholds of the audiologic evaluations before and after treatment. Studies which adopted an increase in the threshold in any frequency equal to or greater than 10 dBHL when compared to the previous audiologic evaluation, found between 77% and 88% of hearing loss in the patients evaluatedOther studies did not report on which was the classification used to classify hearing loss, and hearing loss rate varied between 7% and 42%Therefore, we see that comparing hearing loss in children and teenagers with cancer is very difficult - above all - by the use of more or less strict criteria to assess hearing.Smits et al. (2006)We must highlight that using more strict criteria, such as the one proposed by the American Speech-Language-Hearing Association - ASHA, for hearing loss in children is fundamental, because in order to communicate well, the child must be able to hear, identify and discriminate all speech-related sounds. A reduction in hearing, even if mild, compromises the development of such skills, impairing understanding and thus, oral communication, it may cause emotional, behavioral and educational problems.


CDKL5 gene. First seizures developed in the fifth week of life and have progressed steadily since then. The child’s psychomotor development was strongly delayed, and generalized hypotonia was noticed since birth. Brain MRI showed areas of incomplete myelination, posterior narrowing of the corpus callosum, a pineal cyst of up to 3 mm, and open islet lids. Intensive antiseizure medications (ASMs), a ketogenic diet, and steroid therapy were not successful. Short-term improvement was achieved with the implantation of a vagal nerve stimulator (VNS). Due to the progressive course of the disease, the boy requires frequent modification of ASMs.CDKL5 deficiency disorder (CDD) is a developmental encephalopathy caused by pathogenic variants in the X-linked cyclin-dependent kinase 5 (CDKL5) gene. This rare disorder occurs more frequently in females than in males. The incidence is estimated to be approximately 1: 40,000–60,000 live births. So far, 50 cases have been described in boys. The clinical course in males tends to be more severe and is often associated with death in the first or second decade of life. The authors present an unreported 2.5-year-old male patient with drug-resistant epilepsy who was diagnosed with a de novo mutation in the  CDKL5 deficiency disorder (CDD) is a rare and often profound neurodevelopmental encephalopathy caused by pathogenic alterations in the CDKL5 gene and a deficiency of functional cyclin-dependent kinase-like 5 (CDKL5) [CDKL5 plays an important role in the formation and maturation of neurons and also in the development and function of synapses [CDKL5 is estimated to be approximately 1 in 40,000–60,000 live births [CDKL5 disorders are not uniform and may be due to the type and location of the mutation and to the influence of epigenetic and environmental factors. CDKL5 pathogenic variants are diagnosed in 8–16% of girls with early-onset epilepsy [CDKL5 is located on the X chromosome (Xp22), and CDKL5 deficiency disorder (CDD) is four times more common in women than in men, suggesting that it is mainly a fatal mutation in male fetal life [CDKL5 is located on the X chromosome, men with CDD do not have functional CDKL5 in any of their cells, while women have a mosaic of cells: about 50% of cells will express wild-type CDKL5, and 50% of cells will not express functional CDKL5 (due to random X inactivation during development) [CDKL5 gene were first linked to the human disease in 2004 by observing cohorts of patients with Rett syndrome who had no changes in the MeCP2 (methyl CpG 2 binding protein) gene. However, CDD is not, nor is it even a variant of, Rett syndrome, but a unique, distinct, and complex disorder that is particularly rare in the male population [ CDKL5) . The trasynapses ,3. The m . The trepilepsy . CDKL5 imosome Xp2, and CDpulation .CDKL5 gene was confirmed, a de novo substitution of one nucleotide c.513C > G, resulting in a nonsense mutation with the formation of a premature STOP codon (p.Tyr171X) disrupting normal protein synthesis. The first EEG performed in the sixth month of life showed generalized paroxysmal discharges with a pattern resembling “burst-suppression” but without the typical episodes of bioelectrical silence, with normal sleep characteristics. A second EEG was performed in the boy’s second year of life. In the record of the brain’s bioelectric activity, there were continuous seizure changes described in the routine examination. During video EEG recording, limb tearing and incidents of eye rotation were observed. At that time, continuous paroxysmal discharges were present in the recording of bioelectrical activity of the brain. Brain MRI at age 2 showed areas of unfinished myelination in the lateral ventricular triangles and around the occipital horns , positive bilateral Babinski sign, and Chaddock’s and Oppenheim’s signs were slightly positive. He reacted poorly to environmental stimuli. He also clenched his fists and had a tendency to turn his head to the right. The patient has contractures in various joints, including the ankles, right knee, shoulder, left elbow, and to a slight degree in the hip joints. The child has been fed with blended, not solid meals. The first epileptic seizures were noticed at the age of 5 weeks as 30 s convulsions of the whole body accompanied by apnea. The seizures mainly occurred while falling asleep. After 2–3 months, the seizures began to occur with greater frequency and duration. With time, the boy experienced up to 30 seizures a day. They were dominated by epileptic spasms and myoclonus seizures, as well as focal motor seizures. The boy was repeatedly hospitalized for the intensification of his epileptic seizures. Brain CT at two months of age showed increased pericerebral spaces within the Sylvian fissure. In the fifth month of life, based on genetic work-up, a pathogenic variant of the al horns a–c and aExtensive pharmacotherapy, including antiepileptic treatment  and steroid therapy  were administered. However, due to the development of severe dyskinesias and dystonia, steroid therapy was discontinued. The patient repeatedly required modification of ASMs, as the drugs used did not bring significant clinical improvement. The patient is currently taking levetiracetam 2 mL-0-3.5 mL and lamotrigine, the dose of which, due to persistent seizures, has been increased from 0-0-1 mL to 1-0-1 mL. This modification initially yielded good results, but over time the symptoms began to worsen again.CDKL5 mutation, a vagal nerve stimulator (VNS) was implanted. The frequency of epileptic seizures was reduced by about half, but after about five months they became more frequent again, requiring modification of the neurostimulation parameters by the consulting neurosurgeon. Due to reluctance to drink and increased dystonic movements, the ketogenic diet was discontinued after 5 days. Since birth, the patient has been receiving rehabilitation; at present, he is without visual and verbal contact and not able to lift his head.Two months after the diagnosis of the CDKL5. It should be suspected in patients with early-onset epilepsy, severe developmental delay, and poor response to antiepileptic medicaments [CDKL5 pathogenic variants or multigene panel testing for early-onset epilepsy [CDKL5 variants are not pathogenic but benign, the variants must be considered pathogenic according to recognized pathogenicity assessment guidelines to confirm a diagnosis [CDKL5 disorder, originally classified as a variant of Rett syndrome, is now recognized as an independent disorder and classified as a developmental epileptic encephalopathy . The diaicaments . CDKL5 depilepsy ,11. Sinciagnosis ,9. MRI biagnosis ,9,12.CDKL5 deficiency disorder is a rare condition, more common in females than in males. To the best of our knowledge, 50 males with CDD have been described so far . AffecteCDKL5 pathogenic variant which has not yet been described in the literature. CDKL5 pathogenic variants and a new case. For comparison, we have chosen boys whose disease onset was around the first month of life. We are dealing with various pathogenic variants, most of which were created “de novo” (87.5%), as in the case presented by us; only two (12.5%) were created through a germinal mosaic  uses both pharmacological treatments and non-pharmacological treatments, such as vagal nerve stimulator implantation. The main aim of treatment is to relieve symptoms and improve the patient’s quality of life. Scientific data on the treatment of patients with CDD are relatively scarce and are mainly limited to the treatment of epilepsy. Most patients have a short-term response to treatment . The most commonly used medications include the broad-spectrum antiepileptic medicaments clobazam, valproate, topiramate, levetiracetam, and vigabatrin . The patThe information collected in The National Library of Medicine reports that only four boys have been registered with a very similar mutation to our boy. Only one case has been described, so we present another . Table 1n = 104) followed a ketogenic diet. The mean time on the diet was 17 months. Of the 69 caregivers who reported changes in seizure activity, 61 (88%) reported positive benefits from the treatment. However, only one-third of the patients ultimately did not quit the ketogenic diet treatment. Patients usually cited lack of efficacy as the reason for quitting [One of the treatment options available is the ketogenic diet. The International CDKL5 Disorders Database collected 204 patients, of whom more than half . Only 38 (17%) of 224 individuals in the CDKL5 International Disorders Database had a VNS implanted between the ages of 4 and 9 years . AustralCDD is a condition that causes significant delay in a child’s psychophysical development, so a multidisciplinary approach to care is essential. Unpublished data from the International CDKL5 Disorder Database suggest that caregivers believe that children benefit from physiotherapy and occupational therapies . PatientBrain, a team from Imperial developed and tested a therapy that aims to introduce functional CDKL5 into brain cells lacking a functioning copy of the gene, using a novel serotype of AAV (adeno-associated virus). The therapy has only been tested on mice and human cells, and beneficial results have been obtained. However, the study is still at an early stage, and further work is needed to refine the gene therapy before it can move beyond animal studies. However, the hope remains that it represents a potential pathway for future treatment of this rare disease [Current treatments for the neurological features of CDD are symptom-based and empirical, rather than CDD-specific, although clinical trials for CDD are emerging. Disease-specific and disease-modifying treatments are under development. One recent clinical trial involved ganaxolone, which was approved based on data from the Phase 3 Marigold trial NCT03572933), a double-blind, placebo-controlled study 33, a dou. Other t disease .CDKL5 deficiency is a disorder with a heterogeneous phenotype, with a poor prognosis and a more severe clinical course in males. It requires an individualized approach to treatment that often requires modification of antiepileptic therapy as the disease progresses. Failure to respond to antiepileptic medications often results in the need for other methods of treatment, such as the ketogenic diet, vagal nerve stimulation (VNS), or steroid therapy. Currently, no specific therapies are available for people with CDD , so medical management is symptomatic and supportive. A multidisciplinary team approach is most effective. Emphasis should be placed on early therapeutic interventions, such as physiotherapy, occupational therapy, and supportive speech and communication therapy. There are few reported cases of vagal nerve stimulation (VNS) treatment in young children, the reason being that the FDA approved this therapy relatively recently. An early-implanted vagal nerve stimulator (VNS) seems to be an opportunity for patients with drug-resistant epilepsy, at least in alleviating the symptoms of the disease and improving quality of life. However, more research is still needed on this subject, with studies including larger groups of described patients, especially patients with VNSs implanted before the age of 5. Considering that genotype–phenotype correlations are still limited for CDD, our data for the affected boy provide additional insights and a better understanding of the variability in the disorder and the possibilities of response to antiseizure medications, the ketogenic diet, steroid therapy, and the use of VNS.