Neisseria Meningitidis Endophthalmitis: Use of Polymerase Chain Reaction to Support an Etiologic Diagnosis

We report a case of endogenous endophthalmitis in which the suspected etiology, Neisseria meningitidis, was supported by use of a specific polymerase chain reaction test on vitreous humor. This technology may be especially valuable in the future for those cases in which systemic and eye cultures are nonrevealing. Bacterial endophthalmitis is a rare, vision-threatening condition in children. Infection can be acquired by either the endogenous or the exogenous route. In a 10-year retrospective review in 1994, only 1 of 28 cases of endogenous endophthalmitis occurred in persons ≤18 years of age. 1 Several decades ago Neisseria meningitidis and Streptococcus pneumoniae predominated as the causes of endogenous endophthalmitis; more recently, however, Staphylococcus aureus, Bacillus cereus and streptococcal species other than S. pneumoniae have become more prevalent. 2 Virtually all cases of N. meningitidis- related endophthalmitis have occurred in patients with a systemic infection, especially meningitis. Recently one case of endogenous endophthalmitis caused by N. meningitidis was reported in an adolescent in the absence of an identifiable systemic infection. 3 In that case N. meningitidis was recovered only from cultures obtained from the anterior and posterior chambers of the eye. We report a case of endophthalmitis in which N. meningitidis was suspected as the etiology. The case involved an adolescent with N. meningitidis isolated from an atypical skin lesion but with sterile systemic and vitreous humor cultures. The N. meningitidis etiology was supported by specific PCR testing performed on fluid obtained from the anterior chamber. Case report. A 13-year-old, previously healthy young woman presented to the Medical College of Georgia with a 7-day history of bilateral progressive loss of vision associated with minimal pain. On the first day of symptoms she had conjunctival injection bilaterally with minimal discharge on awakening. The redness started in the left eye and progressed to the right eye. Initially there was no associated pain or photophobia. She also had bilateral leg pain and right elbow pain presumably related to skateboarding on that same day. On the following day she applied tobramycin ophthalmic drops. Her medication was left over from treatment for a case of conjunctivitis that her mother experienced 6 to 8 months before this child’s illness. On the fourth day of illness, she began complaining of blurred vision. At that time she also had increasing elbow pain with minimal swelling and decreased range of motion. She developed a rash on her lower extremities that the child’s mother described as blisters. On the sixth day of the illness, she complained of vision loss involving both eyes and of feeling warm. A local emergency department recorded her temperature as 100.4°F. She was treated for conjunctivitis with ofloxacin ophthalmic gel but received no systemic antibiotics. One day after this visit, an ophthalmologist admitted her to the hospital because of worsening vision loss. The patient reported no history of sexual activity or intravenous drug usage. She did not have any previous ophthalmologic problems and denied contact lens use. Two days before the patient’s symptoms began, a sister had conjunctivitis that resolved quickly with no further ocular complaints. There was no history of rhinorrhea or headache and no reported trauma to either eye. Physical examination revealed a well-developed, well nourished adolescent girl in no acute distress. Her vital signs were stable and normal for her age. A normal oral temperature was recorded. Skin examination revealed a small, nontender vesicle on both her left knee and right calf. No petechiae or purpura were observed. There were multiple hyperpigmented, discrete skin lesions with central clearing and serpiginous borders. These lesions were primarily on her lower extremities. There were no lesions on her mucous membranes. Her right elbow was painful on full extension and had a minimal amount of soft tissue swelling. There was no effusion present. All other joints were normal. With the exception of her eyes, the remainder of the physical examination, including the neurologic examination, was normal. On ophthalmologic examination her visual acuity was light perception only bilaterally. The pupils could not be assessed because they had been pharmacologically dilated. There was no eyelid edema. On slit lamp examination of the conjunctivae, 3+ chemosis was present bilaterally. There were fibrinous plaques on the central corneal endothelium bilaterally. In the anterior chamber a thick, fibrinous reaction was seen bilaterally. Full examination of the iris and lens could not be performed. An ultrasound revealed vitreous opacifications bilaterally; both retinas were attached. There was posterior choroidal thickening on the left. A pars plana vitrectomy was performed and intravitreal antibiotics were injected. However, the fibrinous material in the anterior chamber could not be removed without sacrificing the lens. Aspiration of the vitreous yielded almost 1 ml of turbid fluid. Bilateral anterior chamber and vitreous humor samples were taken for Gram stain, aerobic and anaerobic bacterial cultures, acid-fast bacillus stain, fungal stain and cultures as well as for cytology. After the sample collection intravitreal ceftazidime and vancomycin along with subconjunctival gentamicin and triamcinolone acetonide were administered. She was given vancomycin, ceftazidime and prednisone intravenously. Topical tobramycin ophthalmic drops and steroids were also administered every hour during the day. Laboratory studies included a white blood cell count of 10 700/mm3 with a differential of 76% neutrophils, 3% band forms, 14% lymphocytes and 7% monocytes, a hemoglobin of 10.8 g/dl and a platelet count of 337 000/mm3; the erythrocyte sedimentation rate was 113 mm/h, and a C-reactive protein was 6.2 mg/dl (normal, ≤1.0 mg/dl). A blood culture obtained on admission was sterile. A chest radiograph was normal. The patient was evaluated by pediatric cardiology for endocarditis as a primary source for the endophthalmitis. An echocardiogram was normal with no vegetative lesions seen. Fluid from the blister on her left knee was sent for a Gram stain and culture. The Gram-stained smear revealed rare Gram-negative cocci and many segmented neutrophils. Culture of this fluid subsequently grew one colony of N. meningitidis susceptible to penicillin, ceftriaxone and ciprofloxacin. The initial vitreous humor culture and all subsequent vitreous humor and blood cultures were sterile. A sample of vitreous humor obtained on Hospital Day 6 demonstrated Gram-negative cocci on a smear; however, culture of this sample revealed no growth. N. meningitidis- specific real time PCR was performed by Dr. Tanja Popovic’s laboratory at the Centers for Disease Control and Prevention on a sample of vitreous humor and was positive for N. meningitidis serogroup C. The N. meningitidis isolate from the initial skin lesion was also serogroup C. The patient received a total of 14 days of antibiotic treatment. The vancomycin and ceftazidime were changed to ceftriaxone when fluid from the skin lesion was identified as N. meningitidis. The patient, her immediate family and other known close contacts were given antibiotic prophylaxis with either rifampin or ciprofloxacin depending on their ages. The patient slowly improved throughout hospitalization. After 7 days of antibiotic treatment, the C-reactive protein had fallen to 0.8 mg/dl, the skin lesions had cleared and the joint symptoms had resolved. Because of persistent anterior chamber and vitreous opacification, the patient underwent removal of the anterior chamber membranes, cataract extraction and pars plana vitrectomy on each eye. A large choroidal hemorrhage occurred at the time of surgery on the left eye, requiring subretinal drainage and silicone/fluid exchange. Three months after initial presentation, visual acuity improved to 20/100 in the right eye with light perception only in the left eye. Discussion. Similar to the patient presented by Malhotra and Krilov 3 in September 1999, our patient also had N. meningitidis endophthalmitis without evidence of meningitis or significant systemic involvement. N. meningitidis has become a rare pathogen causing bacterial endophthalmitis during the past 50 years. A retrospective 10-year review by Okada et al. 1 in 1993 found that the most common organism causing endogenous bacterial endophthalmitis was Staphylococcus aureus. As reported by Wong and Balakrishnan, 2 only 22 cases of endogenous meningococcal endophthalmitis were documented in the literature between 1943 and 1999. An additional case that they presented along with the case of Malhotra and Krilov brings to 24 the total number of cases reported caused by N. meningitidis during this time. In the review of the previously reported 22 cases, Wong and Balakrishnan 2 found that 75% of the patients regained useful vision (20/200 or greater) and 71% achieved vision of 20/50 or better. Our patient presented a diagnostic challenge because all routine cultures from the anterior chambers of both eyes as well as the blood revealed no growth even before systemic antibiotics were begun. Although the infectious etiology was suspected to be N. meningitidis, based on the recovery of a single bacterial colony from an atypical skin lesion, this etiology was further supported through use of PCR. Acute bacterial endophthalmitis is a serious illness. A systemic infection, including meningitis, should be suspected in all such patients at presentation. All patients should have blood cultures. In the patient series compiled by Okada et al., 1 18 of 25 patients who had blood cultures obtained were positive for bacteria. Given the rarity of this disease in children, the vast number of bacterial agents that have been implicated and the likelihood of systemic involvement, consultation with both ophthalmology and infectious disease specialists should be strongly considered in all such cases. Several studies have shown PCR to be a reliable tool for the identification of the specific organism involved in cases of endophthalmitis. As many as 20 to 60% of cases of endophthalmitis are reportedly culture-negative. 4 Cultures can be negative for many reasons including the small volume of the sample size and the use of antibiotics before sampling. The devastating complications associated with endophthalmitis, as well as the need to distinguish between an infectious etiology and a purely inflammatory ocular process necessitate rapid diagnosis and identification of the organism responsible. In a study done in 2000, Okhravi et al. 4 examined ocular samples to determine the ability of a panbacterial PCR to detect microorganisms in patients presumed to have bacterial endophthalmitis. Of the 37 samples 20 were culture-positive, and all 20 of those were PCR-positive; 17 of the samples were culture-negative; but all of those samples were PCR-positive for bacteria. Therefore PCR detected bacteria in 100% of the samples from individuals with suspected bacterial endophthalmitis. This percentage was compared with only a 68% yield in routine cultures. 4 A study by Therese et al. 5 in 1998 examined 58 intraocular specimens from patients with endophthalmitis. The investigators found that intraocular specimens positive for a microorganism on PCR compared with routine culture increased from 46.5% to 75.8%. 5 Testing for N. meningitidis by PCR is not currently commercially available. 6 Although PCR methods combined with enzyme-linked immunosorbent assay have confirmed suspicious cases of meningococcal meningitis that are culture-negative, 7 the use of a specific PCR method as a standardized diagnostic test for N. meningitidis is still in development and should not be used as the sole criterion for diagnosis. Although PCR as a diagnostic tool is still evolving in pediatric infectious diseases, 6 the case scenario presented here, in which all blood and ocular cultures were sterile, illustrates a supportive role for the use of specific PCR testing in the evaluation of endophthalmitis on a case by case basis. Acknowledgment. We thank Dr. Colin Shepard of the Centers for Disease Control and Prevention for his assistance in this case.