Neisseria meningitidis Endogenous Endophthalmitis with Meningitis in an Immunocompetent Child

Ocular Immunology & Inflammation, Early Online, 1–5, 2013 ! Informa Healthcare USA, Inc. ISSN: 0927-3948 print / 1744-5078 online DOI: 10.3109/09273948.2013.854392 LETTER TO THE EDITOR Neisseria meningitidis Endogenous Endophthalmitis with Meningitis in an Immunocompetent Child Imran H. Yusuf, MB ChB (Hons), MRes, MRCP (UK), Ocul Immunol Inflamm Downloaded from informahealthcare.com by University of Oxford on 12/04/13 For personal use only. and Larry Benjamin, Zuzana Sipkova, BM BS, Sejal Patel, MB ChB, FRCS(Ed), FRCOphth, DO Stoke Mandeville Hospital, Department of Ophthalmology, Mandeville Road, Aylesbury, UK ABSTRACT Neisseria meningitidis is a major cause of childhood morbidity and mortality worldwide. We describe an exceptional case of an immunocompetent 15-month-old child presenting with a unilateral anterior uveitis, hypopyon, and sepsis. Anterior chamber aspirate demonstrated gram-negative cocci before Neisseria meningitidis was identified in blood and cerebrospinal fluid. Meningococcal endophthalmitis presents variably with sepsis, meningitis, or isolated ocular symptoms. Diagnosis is a clinical challenge, requiring diagnostic sampling and treatment from both pediatricians and ophthalmologists. Delayed or incorrect treatment risks blindness, disability, or death. Simultaneous invasion of meningococcus across intact blood–brain and blood– ocular barriers in this child suggests antigenic correlates between meningeal and ocular endothelial interfaces. Meningococcus is an exclusively human pathogen; research is hampered by the lack of animal models. This clinical observation suggests the potential of a novel in vitro experimental approach of using ocular tissue from eye banks to further elucidate the meningococcal–endothelial interaction that underpins meningococcal disease. Keywords: Blood-brain barrier, blood-ocular barrier, endogenous endophthalmitis, endothelium, hypopyon, meningcoccal sepsis, meningitis, meningococcus CASE REPORT observations and cardiovascular, respiratory, and gastrointestinal examinations were within normal limits. There was no frank meningism on presentation but head movements were resisted and right-sided photophobia was evident. Blood tests revealed an acute-phase response with raised white cell count, neutrophilia, and elevated C-reactive protein (Table 1). He was started on empiric systemic antibiotics, ceftriaxone, and gentamicin. Ophthalmic examination demonstrated normal visual behavior but binocular acuity was not examined formally. Right-sided ciliary injection was evident with a hypopyon measuring approximately 2 mm. The right pupil was unreactive to light due to posterior synechiae. B-scan ultrasonography of the right eye suggested a clear vitreous and flat retina. Examination under anesthesia further revealed an intraocular pressure of 18 mmHg with healthy optic A previously healthy 15-month-old boy presented to the emergency department with a 3-day history of fever and vomiting. He had been incredibly fractious, drawing blood from his own thighs with his fingernails; a source of pain was not discernible. His parents reported increasing redness of the right eye over the preceding day with the development of a cloudy appearance over the pupil. There was no rash or history of rheumatic symptoms. There was no past medical history. He was delivered by normal vaginal delivery after an unremarkable pregnancy. His development was normal and immunizations up to date. He had received two meningitis C vaccinations at 3 and 12 months of age, according to the standard UK immunization schedule. On examination, the patient was alert but pale and irritable. His temperature was 38.5  C. General Received 8 July 2013; revised 28 August 2013; accepted 8 October 2013; published online 13 November 2013 Correspondence: Larry Benjamin, Stoke Mandeville Hospital, Department of Ophthalmology, Mandeville Road, Aylesbury, Buckinghamshire HP21 8AL, UK. E-mail: Larry.Benjamin@buckshealthcare.nhs.uk 1 2 I. H. Yusuf et al. TABLE 1. Summary of results of clinical investigations. Blood tests Hemoglobin White cell count Neutrophils Platelets C-reactive protein Result 9.5 g/L 17.7  109/L 14.1  109/L 183  109/L 166 mg/L Normal range 111–141 6–16 1–7 200–550 0–5 Ocul Immunol Inflamm Downloaded from informahealthcare.com by University of Oxford on 12/04/13 For personal use only. Microbiology Anterior chamber aspirate Gram stain: gram-negative cocci Culture: no growth after 5 days Blood cultures Neisseria meningitidis group B Type 4 subtype (p1.7/NT/NT) Cefuroxime, sensitive; penicillin, sensitive; ceftriaxone, sensitive; chlorapmhenicol, sensitive; rifampicin, sensitive Meningococcal DNA PCR (serum) Neisseria meningitidis group B Pneumococcal DNA PCR (serum) Negative Midsteam urine specimen 4105 Escherichia coli Cerebrospinal fluid Macroscopic appearance White cell count Red cell count Protein Glucose (paired serum glucose) Turbid fluid 2420 cells/mm3 (95% neutrophils) 25 cells/mm3 0.85 g/L 1.4 mmol/L Gram stain CSF culture Meningococcal PCR 5.0 mmol/L Gram-negative cocci No growth after 48 h Neisseria meningitidis group B Immunodeficiency screen C3 C4 IgA IgG IgM Pneumococcal polysaccharide Ab Haemophilus influenzae B Ab Serum electrophoresis Lymphocyte function studies Imaging CT head MRI head (at presentation) Abdominal ultrasound 238 mg/dL 49 mg/dL 0.90 g/L 8.32 g/L 1.68 g/L 67 u/ml 2.22 u/ml Normal electrophoresis panel Normal function of all lymphocyte subsets (CD4þ/CD8þ T lymphocytes, CD 19þ B lymphocytes, CD3/CD16þ/CD56þ NK cells) 0–5 cells/mm3 0 cells/mm3 0.15–0.45 2.2–3.3 or 60% of serum glucose 63–250 14–65 (0.1–0.8) (2.4–9) (0.2–1.4) (6.8–0) (0.15–0) No signs of raised intracranial pressure or subdural collections. Focal dilatation of the posterior horn of the left lateral ventricle, suggestive of ventriculitis. No focal intraparenchymal lesion or extra-axial collection. The spleen is normal in outline and echo pattern, of normal size. No other abnormalities are identified. disc and retina. Fundal view was limited centrally by an anterior capsular plaque. Examination of the left eye was normal. Anterior chamber fluid aspirate was sent for microbiological analysis. The provisional diagnosis was early endogenous endophthalmitis with isolated anterior chamber involvement; gentamicin 5 mg and cefuroxime 25 mg were injected subconjunctivally. Gram stain of anterior chamber fluid and cerebrospinal fluid (CSF) demonstrated gram-negative cocci, but sterile cultures. Polymerase chain reaction (PCR) of CSF and serum confirmed Neisseria meningitidis serogroup B; blood cultures identified a wide antibiotic sensitivity (Table 1). Endogenous meningococcal endophthalmitis was treated with topical cefuroxime 5% and dexamethasone 0.1% eyedrops 4 times daily. Anterior chamber inflammation resolved within 48 h. Topical treatment was continued a total of 20 days. Close contacts of the patient received antibiotic prophylaxis against carriage of N. meningitidis. The patient’s temperature continued to spike despite systemic antibiotics prompting further neuroimaging; MRI brain scan revealed dilatation of the Ocular Immunology & Inflammation Ocul Immunol Inflamm Downloaded from informahealthcare.com by University of Oxford on 12/04/13 For personal use only. Neisseria meningitidis Endogenous Endophthalmitis posterior horn of the left lateral ventricle, with a small abscess adjacent to the left lateral ventricle. He was treated with a 4-week course of iv ceftriaxone and oral rifampicin 100 mg twice daily. Serological analysis of complement and seroconversion to previously administered immunizations did not demonstrate evidence of impaired immunity. Abdominal ultrasound revealed a structurally normal spleen. Further investigations are summarized in Table 1. Ophthalmic examination 1 month after presentation revealed a binocular visual acuity of 6/12 (Cardiff cards) with stereoacuity of 340 seconds of arc (Frisby). Monocular acuity assessment was not possible. Ophthalmic examination revealed a quiet right eye with clear media and normal-appearing optic disc and macula. Repeat MRI had revealed resolution of ventriculitis and associated abscess. The child was kept under ophthalmic follow-up. DISCUSSION Endogenous meningococcal endophthalmitis is a rare ocular disorder associated with severe ocular morbidity and acutely life-threatening manifestations of systemic meningococcal disease—sepsis and/or meningitis. Clinical presentation of meningococcal endophthalmitis is highly variable; patients may present with a primary clinical picture of sepsis,1–3 meningitis,4,5 or isolated ocular signs without systemic illness,1,6,7 yet develop other expressions of meningococcal disease subsequently. Ocular manifestations are similarly inconsistent and may be unilateral1,4,6–8 or bilateral,2,3,5 with anterior6,7 or posterior segment signs,5,8 or panophthalmitis.1,2,4,8 Endogenous meningococcal endophthalmitis and may occur in infants,3 teenagers,5,6,8 or adults1,2,4— patients are almost universally immunocompetent.1–8 The variable clinical presentation of meningococcal endophthalmitis presents a diagnostic challenge to both pediatricians and ophthalmologists. Diagnosis requires the expertise of the two collaborating teams, both in the demonstration or exclusion of meningococcus in sterile body fluids and in the joint management of ocular and systemic disease. Delay in referral between the two specialties—and therefore diagnosis—risks severe ocular morbidity, disability, or death. This case is remarkable for the atypical presentation of each expression of meningococcal disease: (1) absence of a petechial rash or severe sepsis at any stage of illness despite confirmed meningococcemia on blood cultures and PCR; (2) subacute onset of confirmed meningococcal meningitis without a fulminant course typical of pyogenic meningitis; and (3) presentation of meningococcal endophthalmitis with a unilateral, isolated anterior uveitis. A hypopyon was the most instructive clinical sign in this systemically unwell child. The differential ! 2013 Informa Healthcare USA, Inc. 3 diagnosis included noninfectious uveitis (juvenile idiopathic arthritis), masquerade syndromes (retinoblastoma and acute lymphocytic leukemia), and endogenous endophthalmitis. Empirical treatment of uveitis with topical steroids without first excluding endogenous endophthalmitis—with early diagnostic aqueous or vitreous aspirate according to clinical findings—may lead to fatal delay in diagnosis and initiation of antibiotic therapy. Subconjunctival antibiotics were administered empirically in this child in response to presumed endophthalmitis predominantly affecting the anterior segment. It is not sufficient in isolation in the setting of meningococcal meningitis or sepsis. In this case, urgent anterior chamber aspirate identified Neisseria meningitidis, prompting lumbar puncture, CT head, and PCR studies of blood and CSF—unraveling the unifying diagnosis. The diagnosis of disseminated meningococcal disease from initial identification in ocular fluids has been reported previously.1,2,6 PCR of aqueous, blood, or CSF may provide a rapid and sensitive diagnostic test for Neisseria meningitidis, particularly in low-volume aqueous samples to reduce false-negative aspirates.9,10 A high index of suspicion for endogenous endophthalmitis and low threshold for early, invasive diagnostic sampling must be adopted in this patient group. A systematic review of endogenous endophthalmitis identified 15 cases attributable to Neisseria meningitidis worldwide between 1985 and 2001,10 with a further 12 reported since—equating to one report annually worldwide. Neisseria meningitidis serogroup B is the most common cause of meningococcal disease in developed countries.11 Relentless research efforts have recently yielded an effective vaccine against meningococcus serogroup B (response rates of 79–99%11); routine, widespread inoculation may further reduce the incidence of all expressions of meningococcal disease, including endogenous endophthalmitis. Children under 2 years of age have increased susceptibility to Neisseria meningitidis, despite normal immune status. Neisseria meningitidis is a gram-negative coccus with a highly charged polysaccharide capsule permitting evasion of complement and phagocytic cells of the innate immune system.12 Stimulating adaptive immunity through immunization is therefore critical to prevent encapsulated bacteria—Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae—from causing meningitis, particularly in infants where adaptive immunity is immature. Neisseria meningitidis is an exclusively human pathogen, present in the host flora of the nasopharynx in 5–15% of human adults.12 The molecular mechanism of bacterial invasion across both the nasociliary epithelium and luminal cerebral endothelium of the blood–brain barrier—intact 4 I. H. Yusuf et al. TABLE 2. Molecular characterization of neurotropic bacterial invasion: summary of neurotropic bacteria, human colonization, and mechanism of invasion. Bacteria Colonization Neisseria meningitidis Nasopharynx Streptococcus pneumoniae Haemophilus influenzae14 Nasopharynx Nasopharynx Route of access to CNS and eye Bacterial surface ligands Endothelial surface ligands Transcellular (induced transcytosis) Type IV pili (PilC, tip-located adhesion) OPA proteins PilQ, PorA (LamR binding adhesin) Transcellular (induced transcytosis) Transcellular (induced transcytosis) Choline-binding protein A12 (LamR binding adhesin) Outer membrane protein (OmpP2; LamR binding adhesin) ERM binding protein family (CD-44, CD-46,a ICAM-1) Ezrin, cortical actin, f-actin cytosolic complex ErbB212 Laminin receptors (LamR)14 Platelet activating factor Laminin receptors (LamR)14 Laminin receptor (LamR)14 Ocul Immunol Inflamm Downloaded from informahealthcare.com by University of Oxford on 12/04/13 For personal use only. Microbial cell surface antigens and corresponding endothelial candidate surface ligands are identified for each bacteria. a CD-46 has been considered a candidate endothelial cell receptor for type IV pili. monolayers with intercellular tight junctions—is of particular research interest. Few extracellular bacteria possess the structural capability to invade the meninges from a state of bacteremia. Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae possess cell surface ligands to permit adherence to the human host cell and trigger nonlethal transcytosis to cross the host nasociliary epithelium before exocytosis at the basolateral interface to access the systemic circulation (Table 2).12 These bacteria are principal causes of pyogenic meningitis, and all are recognized causes of endogenous endophthalmitis.10 The reported child suffered both meningitis and endogenous endophthalmitis with anterior segment involvement; Neisseria meningitidis further invaded the endothelial interface of the child’s blood–CSF barrier and blood– aqueous barrier (composed of iridovascular endothelia and ciliary epithelium).13 Critical to the development of targeted future therapies is the molecular characterization of meningococcal penetration into sterile tissues such as the CNS and the eye. Pathological studies reveal that Neisseria meningitidis invades the meninges across the transcellular pathway without disturbing the endothelial tight junctions protecting paracellular migration. Membrane expression of type IV pili is critical to meningococcal adherence to human cerebral endothelium and nasociliary cell surface receptors—potentially through interaction with CD46—exploiting host cell signaling pathways to promote bacterial internalization, with co-activation of tyrosine kinase receptor, ErbB2.12 Laminin receptors have been strongly suggested as the common endothelial binding sites enabling CNS penetration of multiple encapsulated bacteria (Table 2).14 Such adhesins are key determinants of bacterial virulence and tropism to the CNS and, potentially, the eye. Humans are the sole hosts of Neisseria meningitidis; animal models of meningococcal meningitis or endophthalmitis are not possible.12 Establishing in vitro blood–brain barrier models to further characterize the mechanism of endothelial invasion has been difficult. This report and others documenting co-invasion of the blood–brain and blood–ocular barriers by meningococcus suggests common antigenic expression in cerebral and ocular endothelial beds. Retinal endothelial cells share many functional characteristics to the blood–brain barrier, including exclusion of leucocytes, microorganisms, and molecular toxins.13 Taken together, these observations suggest the potential of using isolated anterior ciliary and ophthalmic arteries from eye bank tissue to elucidate bacterial virulence in meningitis and endophthalmitis. Ocular tissue may be more practically acquired than brain tissue and acquired from living donors with far greater potential for further investigation. Elucidating the molecular flora of the ocular endothelium may permit a more complete understanding of microbial invasion across blood–ocular barriers to cause endogenous endophthalmitis. This is an essential prerequisite for the development of future targeted therapies, such as the explicit inactivation of bacterial ligands to prevent ocular and CNS invasion in patients with isolated meningococcal sepsis. DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. REFERENCES 1. Agrawal P, Yellachich D, Kirkpatrick N. Retinal detachment following meningococcal endophthalmitis. Eye (Lond). 2007;21:450–451. 2. Chacko E, Filtcroft I, Condon PI. Meningococcal septicemia presenting as bilateral endophthalmitis. J Cataract Refract Surg. 2005;31:432–434. 3. Gartaganis SP, Eliopoulou MJ, Georgakopoulos CD, et al. 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