Pneumococcal Meningitis Induces Hearing Loss and Cochlear Ossification Modulated by Chemokine Receptors CX3CR1 and CCR2.

PURPOSE: Pneumococcal meningitis is a major cause of hearing loss and permanent neurological impairment despite widely available antimicrobial therapies to control infection. Methods to improve hearing outcomes for those who survive bacterial meningitis remains elusive. We used a mouse model of pneumococcal meningitis to evaluate the impact of mononuclear phagocytes on hearing outcomes and cochlear ossification by altering the expression of CX3CR1 and CCR2 in these infected mice. METHODS: We induced pneumococcal meningitis in approximately 500 C57Bl6 adult mice using live Streptococcus pneumoniae (serotype 3, 1 × 105 colony forming units (cfu) in 10 µl) injected directly into the cisterna magna of anesthetized mice and treated these mice with ceftriaxone daily until recovered. We evaluated hearing thresholds over time, characterized the cochlear inflammatory response, and quantified the amount of new bone formation during meningitis recovery. We used microcomputed tomography (microCT) scans to quantify cochlear volume loss caused by neo-ossification. We also performed perilymph sampling in live mice to assess the integrity of the blood-perilymph barrier during various time intervals after meningitis. We then evaluated the effect of CX3CR1 or CCR2 deletion in meningitis symptoms, hearing loss, macrophage/monocyte recruitment, neo-ossification, and blood labyrinth barrier function. RESULTS: Sixty percent of mice with pneumococcal meningitis developed hearing loss. Cochlear fibrosis could be detected within 4 days of infection, and neo-ossification by 14 days. Loss of spiral ganglion neurons was common, and inner ear anatomy was distorted by scarring caused by new soft tissue and bone deposited within the scalae. The blood-perilymph barrier was disrupted at 3 days post infection (DPI) and was restored by seven DPI. Both CCR2 and CX3CR1 monocytes and macrophages were present in the cochlea in large numbers after infection. Neither chemokine receptor was necessary for the induction of hearing loss, cochlear fibrosis, ossification, or disruption of the blood-perilymph barrier. CCR2 knockout (KO) mice suffered the most severe hearing loss. CX3CR1 KO mice demonstrated an intermediate phenotype with greater susceptibility to hearing loss compared to control mice. Elimination of CX3CR1 mononuclear phagocytes during the first 2 weeks after meningitis in CX3CR1-DTR transgenic mice did not protect mice from any of the systemic or hearing sequelae of pneumococcal meningitis. CONCLUSIONS: Pneumococcal meningitis can have devastating effects on cochlear structure and function, although not all mice experienced hearing loss or cochlear damage. Meningitis can result in rapid progression of hearing loss with fibrosis starting at four DPI and ossification within 2 weeks of infection detectable by light microscopy. The inflammatory response to bacterial meningitis is robust and can affect all three scalae. Our results suggest that CCR2 may assist in controlling infection and maintaining cochlear patency, as CCR2 knockout mice experienced more severe disease, more rapid hearing loss, and more advanced cochlear ossification after pneumococcal meningitis. CX3CR1 also may play an important role in the maintenance of cochlear patency.

Endophthalmitis with bilateral deafness from disseminated Streptococcus suis infection.

Streptococcus suis is a Gram-positive cocci bacterium that are found mainly in pigs and can be transmitted to human through pigs or pork exposure. The disease is mainly found among occupations involving swine contact in western countries whereas in Asia the disease is usually contracted through raw pork consumption. In this case report, we present a case of a middle-aged Thai man who acquired the infection from raw pork consumption. He presented with endogenous endophthalmitis with infective spondylodiscitis, sepsis and meningitis and later developed blindness of the right eye and permanent bilateral hearing loss disseminated from S. suis infection. Our report suggests that S. suis infection be considered as a causative factor in patient presenting with established clinical symptoms and predisposing factors. Cultural habit of eating raw pork should be taken into account especially in Asian countries.

Dysfunction of GRAP, encoding the GRB2-related adaptor protein, is linked to sensorineural hearing loss.

We have identified a GRAP variant (c.311A>T; p.Gln104Leu) cosegregating with autosomal recessive nonsyndromic deafness in two unrelated families. GRAP encodes a member of the highly conserved growth factor receptor-bound protein 2 (GRB2)/Sem-5/drk family of proteins, which are involved in Ras signaling; however, the function of the growth factor receptor-bound protein 2 (GRB2)-related adaptor protein (GRAP) in the auditory system is not known. Here, we show that, in mouse, Grap is expressed in the inner ear and the protein localizes to the neuronal fibers innervating cochlear and utricular auditory hair cells. Downstream of receptor kinase (drk), the Drosophila homolog of human GRAP, is expressed in Johnston's organ (JO), the fly hearing organ, and the loss of drk in JO causes scolopidium abnormalities. drk mutant flies present deficits in negative geotaxis behavior, which can be suppressed by human wild-type but not mutant GRAP. Furthermore, drk specifically colocalizes with synapsin at synapses, suggesting a potential role of such adaptor proteins in regulating actin cytoskeleton dynamics in the nervous system. Our findings establish a causative link between GRAP mutation and nonsyndromic deafness and suggest a function of GRAP/drk in hearing.

Cochlear implant performance in children deafened by congenital cytomegalovirus-A systematic review.

BACKGROUND: Congenital cytomegalovirus (cCMV) infection is a major cause of sensorineural hearing loss in children. OBJECTIVE OF REVIEW: The objective of this systematic review was to compare performance in paediatric cochlear implant users with SNHL caused by cCMV compared to non-cCMV implantees. TYPE OF REVIEW: Systematic review SEARCH STRATEGY: PubMed, EMBASE and the Cochrane databases were searched from inception up to 15 May 2017 for children, cochlear implant, performance and their synonyms. EVALUATION METHODS: Titles, abstracts and full texts were screened for eligibility. Directness of evidence and risk of bias were assessed. From the included studies, study characteristics and outcome data (speech perception, speech production, receptive language and auditory performance of cCMV groups and non-cCMV groups) were extracted. RESULTS: A total of 5280 unique articles were screened of which 28 were eligible for critical appraisal. After critical appraisal, 12 studies remained for data extraction. Seven of 12 studies showed worse performance after cochlear implantation in cCMV children compared to non-cCMV children. Worse performance in cCMV children was attributed to cCMV-related comorbidities in six of these studies. Available data on asymptomatic cCMV children compared to non-cCMV children did not reveal an unfavourable effect on cochlear implant performance. CONCLUSIONS: The available evidence reveals that cCMV children often have worse cochlear implant performance compared to non-cCMV children, which can be attributed to cCMV related comorbidities. We urge physicians to take into account the cCMV related comorbidities in the counselling of paediatric CI users deafened by cCMV.

Bilateral sudden sensorineural hearing loss in Staphylococcus aureus endocarditis.

This case highlights the diagnostic challenges in patients presenting with bilateral sudden sensorinueral hearing loss (SNHL). The aetiology of bilateral sudden SNHL may span several medical disciplines. Therefore, clinicians should be mindful of such presentations, and consider aetiologies beyond otological and neurological causes. We present a case of a previously healthy 51-year-old woman who presented with coryzal symptoms and sudden audiovestibular failure. Examination revealed fever, tachycardia, bilateral profound hearing loss and nystagmus. Following investigations, an initial working diagnosis of vasculitis was made. Later, blood cultures revealed methicillin-sensitive Staphylococcus aureus (MSSA) and a transoesophageal echocardiogram confirmed endocarditis. The patient made a good recovery, but the hearing loss was permanent and managed with a cochlear implant.

Hearing impairment after childhood bacterial meningitis dependent on etiology in Luanda, Angola.

OBJECTIVE: Childhood bacterial meningitis (BM) damages hearing, but the potential of different agents to cause impairment in developing countries is poorly understood. We compared the extent of hearing impairment in BM caused by Haemophilus influenzae type b (Hib), Streptococcus pneumoniae or Neisseria meningitidis among children aged 2 months to 13 years in Luanda, Angola. METHODS: Hearing of 685 ears of 351 (78%) survivors among 723 enrolled patients was tested by brainstem-evoked response audiometry on day 7 of hospitalization. The causative agent was sought by cerebrospinal fluid culture, PCR or the latex-agglutination test. RESULTS: Altogether, 45 (12%) of the survivors were deaf (threshold >80 dB), and 20 (6%) had a threshold of 80 dB. The incidence of any kind of hearing loss, with ≥60 dB, was 34% with Hib, 30% with S. pneumoniae, 19% with N. meningitidis and 33% with other bacteria. Examining all ears combined and using the ≥60 dB threshold, the agents showed dissimilar harm (P=0.005), Hib being the most frequent and N. meningitidis the most infrequent cause. Compared to other agents, S. pneumoniae more often caused deafness (P=0.025) and hearing impairment at ≥60 dB (P=0.017) in infants, whereas this level of hearing loss in older survivors was most commonly caused by Hib (P=0.031). CONCLUSIONS: BM among children in Angola is often followed by hearing impairment, but the risk depends on the agent. S. pneumoniae is a major problem among infants, whereas Hib is mainly a risk beyond 12 months. N. meningitidis impairs hearing less frequently.

Cochlear implantation in children with bacterial meningitic deafness: The influence of the degree of ossification and obliteration on impedance and charge of the implant.

OBJECTIVES: To determine impedance values and charge consumption following cochlear implantation post-meningitic deaf children depending on the grade of cochlear ossification and obliteration. METHODS: Post-meningitic deaf (n=49) and control (n=43) children treated with cochlear implants were included in the study. Impedance and charge values were calculated for each group. The degree of ossification of the cochlea was evaluated from a high-resolution computed tomography (HRCT) scan whereas the degree of obliteration was determined intraoperatively by the surgeon. RESULTS: Pneumococci were the principal pathogen responsible for bacterial meningitis, followed by meningococci. In HRCT scans, the degree of ossification was 1 and 2 in 29% of patients. The results of the intraoperative assessment of the cochlea showed obliteration grade 1 in 38% and grade 2 in 23% of cases. Children in the meningitis group showed significant higher impedances comparing to the control group. A significantly increased charge consumption was observed in patients with a grade 2 ossification when compared to those without ossification (P=0.02). Discussion Cochlea implanted children with meningitis-related deafness exhibit higher impedances, especially in the region of the basal and middle turn, however, not depending on the degree of cochlear ossification. High impedances and charge in the meningitis group may be explained by alterations in the central auditory pathway or on the electrode surface. CONCLUSION: To optimize the outcome in post-meningitic deaf children, surgery is advisable at an early stage prior to the onset of cochlear ossification.

Rapidly progressive bilateral postmeningitic deafness in children: Diagnosis and management.

OBJECTIVES: To determine the diagnostic approach to severe or profound bilateral postmeningitic deafness and to propose management guidelines. MATERIAL AND METHODS: A retrospective review of five patients (two adolescents and three infants) with rapidly progressive severe bilateral deafness following an episode of meningitis managed between 2004 and 2010. RESULTS: The two adolescents presented Neisseria meningitidis meningitis and the three infants presented Streptococcus pneumoniae meningitis. Acquired bilateral deafness was diagnosed by audiometry an average of 68.8 days (range: 9-210) after the episode of meningitis. Behavioural audiological testing, adapted to age and state of health, was performed in all patients. Deafness was confirmed by Auditory Brainstem Response tests. All five patients were assessed by computed tomography (CT) and magnetic resonance imaging (MRI) within ten days. T2-weighted MRI sequences showed endolymph changes in four patients. CT scan demonstrated ossification in only one patient. Bilateral cochlear implant was performed in all patients, with complete electrode array insertion for eight implants and partial insertion for two implants (20 and 21 out of 22 electrodes inserted). Good results were obtained with cochlear implants in four cases. CONCLUSIONS: Bilateral deafness can occur immediately or several months after bacterial meningitis, regardless of the micro-organism responsible, justifying screening by behavioural audiological testing adapted to age for two years following bacterial meningitis. Auditory Brainstem Response testing can confirm audiometric findings. When severe or profound bilateral deafness is observed, MRI must be performed urgently to detect endolymph inflammation or ossification. Early bilateral cochlear implantation is recommended in the presence of ossification.

[A case report of syphilitic uveitis and deafness]. / Uvéite syphilitique et surdité : à propos d'un cas.

We report the case of a 43-year-old male patient presenting for neuro-ophthalmologic and uveitis consultation at Clermont-Ferrand University Medical Center for a reduction in visual acuity in his right eye. Two months previously, the patient had complained of decreased hearing on the left, which remained undiagnosed. Fundus examination and fluorescein angiogram showed the appearance of vasculitis with papillitis and a choroidal plaque. TPHA-VDRL serology was positive in blood and cerebrospinal fluid. Internal medicine work-up revealed many associated abnormalities: hyperhomocysteinemia, positive anticardiolipin antibody, positive anti-ß2GP1 antibodies, increased partial thromboplastin time not corrected by the addition of control plasma, presence of an anti-prothrombinase antibody, positive activated protein C resistance. ENT examination showed a left harmonic vestibular syndrome; audiography showed a sensorineural hearing loss of -40 dB. The patient received treatment for neurosyphilis, which led to the disappearance of the vasculitis, the choroidal plaque and the papillitis. From an ENT standpoint, the vestibular syndrome and the left vestibular areflexia resolved. The audiogram improved, with persistence of left hearing loss (about -20 dB) with useful speech intelligibility. Immunologic abnormalities had also disappeared. Our case illustrates the protean presentations of syphilis and its possible association with sensorineural deafness and immunological abnormalities.

The group B streptococcal serine-rich repeat 1 glycoprotein mediates penetration of the blood-brain barrier.

BACKGROUND: Group B Streptococcus (GBS) is the leading cause of bacterial meningitis in newborn infants. Because GBS is able to invade, survive, and cross the blood-brain barrier, we sought to identify surface-expressed virulence factors that contribute to blood-brain barrier penetration and the pathogenesis of meningitis. METHODS: Targeted deletion and insertional mutants were generated in different GBS clinical isolates. Wild-type and mutant bacteria were analyzed for their capacity to adhere to and invade human brain microvascular endothelial cells (hBMECs) and to penetrate the blood-brain barrier using our model of hematogenous meningitis. RESULTS: Analysis of a GBS (serotype V) clinical isolate revealed the presence of a surface-anchored serine-rich protein, previously designated serine-rich repeat 1 (Srr-1). GBS Srr-1 is a glycosylated protein with high molecular weight. Deletion of srr1 in NCTC 10/84 resulted in a significant decrease in adherence to and invasion of hBMECs. Additional mutants in other GBS serotypes commonly associated with meningitis showed a similar decrease in hBMEC invasion, compared with parental strains. Finally, in mice, wild-type GBS penetrated the blood-brain barrier and established meningitis more frequently than did the Deltasrr1 mutant strain. CONCLUSIONS: Our data suggest that GBS Srr glycoproteins play an important role in crossing the blood-brain barrier and in the development of streptococcal meningitis.

[The rhinogenic deafness and SPA therapy: clinical-experimental study]. / Sordità rinogena e terapia termale: studio clinico-sperimentale.

OBJECTIVES: The sulphur SPA inhalation therapy is useful in respiratory and otolaryngologic chronic inflammatory diseases in adult subjects and children. The therapeutic action relies on anti-inflammatory, mucolytic and trophic effects. Particularly in children, the sulphur SPA inhalation therapy, using endotympanic ventilation or Politzer method, would be suitable in the treatment of the rhinogenic deafness. Several reports have demonstrated the effectiveness of endotympanic ventilation while the results on the Politzer method are inconclusive. On the basis of these considerations, aim of our study was to analyze the effectiveness and the safety of the aerosol+Politzer with a sulphur mineral water in children affected by rhinogenic deafness or chronic inflammatory processes responsible for the onset or persistence of rhinogenic deafness. PATIENTS AND METHODS: The study has been performed on 23 subjects in pediatric age (61% women and 39% males; mean age: 6+/-2.4 years; age range: 3-14 years) affected by chronic catarrhalis otitis, chronic rhino-pharyngitis inflammations, chronic or recurrent adenoiditis with dysfunction of the Eustachian Tube. The investigated subjects underwent 12 consecutive days sulphur SPA inhalation therapy (aerosol+Politzer) at the Terme of Stabia in Castellammare (Naples, Italy). At the beginning and at the end of the SPA cycle the functionality of the middle ear and the tolerability were evaluated. RESULTS: The results have shown an increase of the impedance curves that correspond to the normal ventilation of the tympanic box (type A (13% before therapy and of 57% post-therapy) and a decrease of the pathological curves of type B and type C (87% pre-therapy and of 43% post-therapy); a significant increase of compliance (p 0.05) in pathological curves of type B and C. No adverse reaction to the SPA inhalation therapy has been reported during the study. CONCLUSIONS: In concordance with the literature our data demonstrated that the sulphur SPA inhalation treatment induce a improvement of middle ear function of the subjects examined with good local and systemic tolerability.

Nasopharyngeal aerobic bacterial flora and Staphylococcus aureus nasal carriage in deaf children.

OBJECTIVE: To determine the nasopharyngeal aerobic bacterial flora and Staphylococcus aureus nasal carriage in deaf children and the role of flora in deafness. STUDY DESIGN: A prospective, controlled study. METHODS: Nasopharyngeal and nasal swabs were collected from 87 deaf children with acquired etiology at Zonguldak primary school for the deaf and 56 healthy children. The children with genetic base (syndromic or nonsyndromic, familial or sporadic, AD, AR or X-linked recessive), and also with the history of drug exposure, head trauma, birth trauma, prematurity, hyperbilirubinemia and the viral diseases with high fever (like mumps and measles) were excluded from the study. Swabs were inoculated on to a variety of bacteriological culture media, which were then incubated in an appropriate atmosphere. Colonisation of Group A beta hemolytic streptococcus, Streptococcus pneumoniae, Haemophilus influenzae, Neisseria menengitidis, Moraxella catarrhalis and S. aureus in upper respiratory tract were investigated. Antimicrobial susceptibility testing of the isolates were determined according to National committee for clinical laboratory standards (NCCLS) guidelines. RESULTS: Although, the rates of colonization of the nasopharyngeal aerobic bacteria and nasal S. aureus did not differ significantly between deaf children and normal healthy subjects, less colonization rates were found in deaf children than normal healthy subjects. S. aureus was isolated from 18 (20.7%) deaf children. All S. aureus isolates from deaf children were susceptible to oxacillin. Penicillin susceptibility rate was 22.2%. CONCLUSION: It is considered that nasopharyngeal and nasal colonizations of deaf children with potentially pathogenic aerobic bacterial flora is not a significant risk factor for acquired infections when compared with healthy children.

Auditory consequences of recurrent acute purulent otitis media.

To investigate whether recurrent purulent otitis media results in permanent hearing loss, we studied 2 subgroups of children from a cohort, earlier prospectively followed from birth to the age of 3 years. One subgroup had recurrent acute otitis media (n = 12), and the other had no acute otitis media at all ("healthy" children; n = 21). At follow-up of these subgroups at the age of 10, no child had acute otitis media or secretory otitis media. There was no difference between the groups in hearing level thresholds at the frequencies 125 Hz to 8 kHz. However, in the children with recurrent acute otitis media, as compared with the controls, the hearing levels at high frequencies (8 to 16 kHz) and the acoustic middle ear reflex thresholds were elevated, the middle ear compliance was higher, and click-evoked otoacoustic emission response levels and middle ear pressures were lower. The results suggest that the middle ear mechanics of children with recurrent acute otitis media are affected, and also that their cochlear function might be disturbed.