Recurrent Fevers and Neuro-ophthalmic Disorders in a Mathematical Genius.

Horner's syndrome coexisting with an ipsilateral fourth cranial nerve palsy is a rare occurrence and likely localises to pathology in the cavernous sinus. One such case may have occurred in the 18th century affecting the renowned mathematician Leonhard Euler. A review of his biographies, eulogies, and three finely detailed facial portraits suggest that these two neuro-ophthalmic conditions, along with visual loss and a decades-long intermittent febrile illness, may have been the result of an orbital cellulitis and septic cavernous sinus thrombosis, from an underlying chronic brucellosis infection.

Microbiological Investigations of ReNu Plastic Bottles and the 2004 to 2006 ReNu With MoistureLoc-Related Worldwide Fusarium Keratitis Event.

PURPOSES: The purposes of this study were to determine whether the contact lens solution RevitaLens Ocutec (containing the antimicrobial agents alexidine and polyquaternium-1) would inhibit Fusarium organisms when heated in ReNu plastic bottles; whether alexidine would inhibit Fusarium organisms when heated in non-ReNu plastic bottles; and whether an alexidine-neutralizing compound leaches from heated ReNu bottles. METHODS: RevitaLens and an alexidine solution (0.00045%), previously stored in ReNu bottles at room temperature (RT) and 56°C, were incubated with 7 different Fusarium organisms. The alexidine solution was similarly stored in seven non-ReNu plastic bottles and incubated with these same organisms. To determine if an alexidine-neutralizing compound might be leaching from heated ReNu bottles, phosphate-buffered saline (PBS) was incubated at RT and 56°C in ReNu bottles, combined with alexidine, and then tested for anti-Fusarium capability. RESULTS: After being heated in ReNu bottles, RevitaLens retained its anti-Fusarium capability, whereas the alexidine solution did not. The alexidine solution heated in seven non-ReNu plastic bottles retained its anti-Fusarium capability. The alexidine solution retained its anti-Fusarium capability when incubated with a PBS solution that had been heated in ReNu bottles, indicating, microbiologically, that an alexidine-neutralizing compound did not leach from the heated ReNu bottle. CONCLUSIONS: Alexidine uniquely fails to inhibit Fusarium organisms when heated in a plastic ReNu bottle, but not in seven other plastic bottles, whereas the anti-Fusarium capability of RevitaLens (containing the antimicrobial agents alexidine and polyquaternium-1) is unaffected by heating in a ReNu bottle. There does not seem to be an alexidine-neutralizing compound leaching from heated ReNu bottles. An interaction between alexidine and its heated ReNu bottle may have been a critical factor in the worldwide ReNu with MoistureLoc-related Fusarium keratitis event of 2004 to 2006.

Pan-antimicrobial failure of alexidine as a contact lens disinfectant when heated in Bausch & Lomb plastic containers: implications for the worldwide Fusarium keratitis epidemic of 2004 to 2006.

OBJECTIVE: ReNu with MoistureLoc (ReNuML), containing the antimicrobial agent alexidine 0.00045%, was associated with the Fusarium keratitis epidemic of 2004 to 2006. Although a single-point source contamination was ruled out, only Fusarium organisms were reported during the outbreak. This study investigated whether the reported loss of antimicrobial effectiveness toward Fusarium of ReNuML after exposure to heat in high-density polyethylene (HDPE) plastic containers could also be demonstrated with other common fungal and bacterial agents of keratitis. METHODS: A buffered solution of alexidine 0.00045% was incubated in glass and ReNu HDPE plastic containers at room temperature (RT) and 56°C for 4 weeks, serially diluted, and tested for its ability to inhibit the growth of 20 bacterial isolates, 12 non-Fusarium fungal isolates, and 7 Fusarium isolates originally involved in the keratitis epidemic. RESULTS: A statistically significant loss of antimicrobial capability was seen with all fungi, all gram-positive bacteria, and all isolates of Klebsiella when alexidine 0.00045% was incubated at 56°C in ReNu HDPE containers compared with RT or glass incubation (P≤0.0001). CONCLUSIONS: Heating of an alexidine solution in ReNu HDPE plastic (but not glass) containers results in the same loss of anti-Fusarium activity as reported when testing the original ReNuML solution. This loss of inhibitory activity is not specific to Fusarium and occurs with other fungi and bacteria that cause keratitis. The reasons for the lack of reports of bacterial and/or non-Fusarium fungal keratitis during the original Fusarium keratitis epidemic remain unclear at this time.

Rhino-orbital-cerebral mucormycosis: a review.

Rhino-orbital-cerebral mucormycosis (ROCM) is an acute, often fatal, fungal infection caused by members of the class Zygomycetes and the order Mucorales. The genus Rhizopus accounts for most cases of ROCM. The disease is characterized by fungal hyphal invasion of blood vessels resulting in thrombosis and infarction of the nasal, paranasal sinus, orbital, and cerebral tissues. The most commonly associated condition is diabetes mellitus; other associated conditions include immunocompromised states, renal disease, deferoxamine use, and acidotic states. Common clinical findings include rhinitis, periorbital and facial swelling, facial and mucosal necrosis, ophthalmoplegia, multiple cranial nerve palsies, facial pain, and headache. Definitive diagnosis is made by demonstration of fungal hyphae in tissue specimens. The mainstay of treatment is aggressive surgical debridement of infected tissue and administration of amphotericin B. ROCM has a mortality rate of 40-50%; 70% of survivors are left with residual defects. Early diagnosis and treatment are imperative in the successful management of patients afflicted with this devastating sight- and life-threatening disease.

Radionuclide dacryocystography.

Radionuclide dacryocystography (RNDCG) is a safe, physiologic method of evaluating lacrimal drainage. The technique is performed by placing a radioactive "tear" in the eye(s) and following the passage of radioactivity through the lacrimal drainage apparatus with a scintillation (gamma) camera. RNDCG is indicated in any patient with tearing who has a lacrimal drainage system which is open to irrigation. It is also useful in children, when clinical signs are equivocal. Interpretation is made by comparing a patient's scan to "normal" scans, or in unilateral cases, by comparing the symptomatic side to the asymptomatic side. Many causes of functional or partial lacrimal drainage obstruction can be detected and differentiated from various tear hypersecretion abnormalities. RNDCG also has many research applications.

Henry B. Stallard, MD: The 1924 Paris Olympics, and Chariots of Fire.

Hyla Bristow Stallard was one of the greatest middle-distance runners in British athletic history. While an English medical student, he won the bronze medal in the 1500-meter run at the 1924 Paris Olympics, immortalized in the critically acclaimed 1981 epic British film, Chariots of Fire. He later became one of the most famous ophthalmologists in the world for his pioneering work in radiation therapy of malignant eye disease. He was an inspiring role model for both athletes and physicians. As a gifted individual who enjoyed two international careers, he is worthy of great admiration and emulation.

Effects of time, temperature, and storage container on the growth of Fusarium species: implications for the worldwide Fusarium keratitis epidemic of 2004-2006.

OBJECTIVE: To demonstrate the effects of time, temperature, and container properties on the ability of ReNu with MoistureLoc (ReNuML; contains the antimicrobial agent alexidine) to inhibit growth of Fusarium species. METHODS: ReNu with MoistureLoc was stored in its Bausch & Lomb (Rochester, New York) plastic or similarly sized glass containers for 1 and 4 weeks at room temperature, 42°C, and 56°C, and then tested for its ability to inhibit growth of 7 Fusarium isolates. RESULTS: ReNu with MoistureLoc stored in glass containers for 1 or 4 weeks at all 3 temperatures demonstrated no significant fungistatic deterioration. However, ReNuML stored at 56°C in its Bausch & Lomb plastic container demonstrated a statistically significant fungistatic deterioration compared with room temperature storage in its original plastic container or with glass container storage at any temperature. CONCLUSION: When exposed to elevated storage temperature, it appears that an interaction between ReNuML and its Bausch & Lomb plastic container adversely affects the fungistatic properties of ReNuML, which could have contributed to the Fusarium keratitis epidemic of 2004 through 2006.

A retrospective statistical analysis of the Fusarium keratitis epidemic of 2004-2006.

PURPOSE: A retrospective statistical analysis of the Fusarium keratitis epidemic of 2004-2006 was performed. METHODS: Poisson and binomial probability distributions were performed in conjunction with statistical data reported from Singapore's Fusarium keratitis outbreak in order to identify the earliest theoretical point in time that this outbreak and its cause could have been recognized. RESULTS: The outbreak in Singapore could, theoretically, have been recognized after only three months (three cases), P = 0.0067. The cause of the Singapore outbreak could, theoretically, have been determined after only four months (five cases), P = 0.0024. CONCLUSIONS: The worldwide Fusarium keratitis epidemic of 2004-2006 could, theoretically, have been recognized much earlier by the application of basic statistical methods to the outbreak in Singapore. The lessons learned from this analysis may help prevent future epidemics.

Root cause analysis of the fusarium keratitis epidemic of 2004-2006 and prescriptions for preventing future epidemics.

PURPOSE: A root cause analysis of the Fusarium keratitis epidemic of 2004-2006 was performed. METHODS: Three US Food and Drug Administration (FDA) documents were analyzed. Poisson and case-control studies were performed on outbreak data from Singapore. Irreversible thermochromic labels were applied to cartons of contact lens solution bottles, which were then subjected to elevated temperatures. RESULTS: The 1997 FDA guidance document concerning storage temperatures of contact lens care products predicted temperature-related solution instability. Bausch & Lomb (B&L) requested FDA approval for ReNu with MoistureLoc, claiming that it was substantially equivalent to other products. FDA Form 483 stated that cases of ReNu-related Fusarium keratitis from Asia had not been reported, the removal of the product from the Asian markets was unreported, and B&L had not performed biocidal testing on samples associated with Asian cases. The outbreak in Singapore could have been recognized after only 3 cases (Pr = .0067). The cause of the Singapore outbreak could have been determined after the recognition of only 3 (P = .0429), 5 (95% confidence interval [CI], 1.15-126.0), or 15 cases (95% CI, 1.60-14.1). Thermochromic labels can irreversibly change color when exposed to elevated temperatures, thus warning of potential antimicrobial failure. CONCLUSIONS: The worldwide Fusarium keratitis epidemic of 2004-2006 could, theoretically, have been prevented entirely, recognized much earlier, or mitigated by much more rigorous oversight by the FDA, by strict adherence by B&L to FDA guidelines and requirements, by the application of basic statistical methods, and/or by the use of temperature indication technology. The lessons learned from a root cause analysis of this pharmacologic catastrophy may help avert or mitigate future epidemics.

Use of the poisson probability mass function in a retrospective evaluation of the worldwide Fusarium keratitis epidemic of 2004-2006.

PURPOSE: The Poisson distribution can be used to model discrete events that occur infrequently in time, and it was applied, retrospectively, to recently reported clusters of Fusarium keratitis. METHODS: This distribution was utilized with data reported from 6 geographically diverse ophthalmic centers during the worldwide Fusarium keratitis epidemic of 2004-2006. The expected numbers of cases, determined from published historical data, were compared with the observed and probabilities were calculated. The Poisson probabilities were also used to determine the numbers of cases in each cluster required to reach statistical significance. RESULTS: The probabilities that the numbers of cases observed in the various clusters were a chance variation from the expected, and not due to an outbreak, were between 3.83 x 10(-5) and 4.72 x 10(-47). The recognition of the first 2 or 3 cases in each cluster was sufficient to establish that an outbreak was present. CONCLUSIONS: Because these probabilities are all much less than 0.05, multiple Fusarium keratitis outbreaks have thus been documented. Future use of the Poisson distribution may serve as an "early warning system" that a new, potentially modifiable, factor may be operating to increase the occurrence of a disease above its historic baseline endemic rate.

Temperature instability of ReNu with MoistureLoc: a new theory to explain the worldwide Fusarium keratitis epidemic of 2004-2006.

PURPOSE: A 2006 US Food and Drug Administration (FDA) inspection of Bausch & Lomb's (B&L's) Greenville, South Carolina, manufacturing site indicated that B&L failed to regulate storage and transport temperatures of their products. The present study investigated the effect of storage temperature on the ability of contact lens solutions to inhibit growth of Fusarium species. METHODS: SIX CONTACT LENS SOLUTIONS WERE STUDIED: ReNu with MoistureLoc (ReNu ML), ReNu MultiPlus, Complete Moistureplus, AQuify, Clear Care, and OPTI-FREE RepleniSH. Two bottles of each solution were separately stored at room temperature and 60 degrees C for 4 weeks, serially diluted, then tested for their ability to inhibit growth of 11 Fusarium isolates (7 of which were associated with the keratitis epidemic). RESULTS: ReNu ML demonstrated the greatest decline in efficacy after 60 degrees C storage. Clear Care and ReNu MultiPlus performed the best. Regarding the keratitis epidemic isolates only, the ReNu ML bottle stored at room temperature allowed growth in 27 of 84 combinations vs 67 of 84 combinations with the 60 degrees C stored bottle. CONCLUSIONS: When exposed to prolonged temperature elevation, ReNu ML loses its in vitro fungistatic activity to a much greater extent than other products. Improper temperature control of ReNu ML may have contributed to the Fusarium keratitis epidemic of 2004-2006.

Temperature instability of ReNu With MoistureLoc: a new theory to explain the worldwide Fusarium keratitis epidemic of 2004-2006.

OBJECTIVE: To investigate the effect of storage temperature on the ability of contact lens solutions to inhibit growth of Fusarium species. A 2006 Food and Drug Administration inspection of Bausch & Lomb's Greenville, South Carolina, manufacturing site indicated that Bausch & Lomb failed to regulate storage and transport temperatures of their products. METHODS: Six contact lens solutions were studied: ReNu with MoistureLoc, ReNu MultiPlus, COMPLETE Moistureplus, AQuify, Clear Care, and OPTI-FREE RepleniSH. Two bottles of each solution were separately stored at room temperature and 60 degrees C for 4 weeks, serially diluted, and then tested for their ability to inhibit growth of 11 Fusarium isolates (7 of which were associated with the keratitis epidemic). RESULTS: ReNu with MoistureLoc demonstrated the greatest decline in efficacy after 60 degrees C storage. Clear Care and ReNu MultiPlus performed the best. Regarding the keratitis epidemic isolates only, the ReNu with MoistureLoc bottle stored at room temperature allowed growth in 27 of 84 combinations vs 67 of 84 combinations with the 60 degrees C-stored bottle. CONCLUSIONS: When exposed to prolonged temperature elevation, ReNu with MoistureLoc loses its in vitro fungistatic activity to a much greater extent than other products. Improper temperature control of ReNu with MoistureLoc may have contributed to the Fusarium keratitis epidemic of 2004-2006.

Evaluation of intraocular and orbital pressure in the management of orbital hemorrhage: an experimental model.

OBJECTIVE: To evaluate orbital pressure (OP), intraocular pressure (IOP), and the effectiveness of canthotomy, cantholysis, and septolysis using an experimental orbital hemorrhage model. METHODS: Expired whole blood was injected into the retrobulbar space of 10 human cadaver orbits. At 1-mL increments, OP, IOP, and globe position were documented. The mean (SD) time interval between the injections was 84 (36) seconds. Following injection of 22 mL, lateral canthotomy, cantholysis, and septolysis were performed. An additional 10 mL of blood was then injected. RESULTS: After injecting 22 mL of whole blood, mean (SD) OP and IOP were 68.4 (32.2) and 71.5 (19.1) mm Hg, respectively. The OP and IOP correlated closely throughout the experiment, with a mean (SD) difference of 11.4 (4.9) mm Hg (Pearson coefficient, 0.97). Following canthotomy, cantholysis, and septolysis, there was a mean (SD) decrease of 48.0 (27.2) mm Hg (70%) and 50.0 (18.1) mm Hg (59%) in OP and IOP, respectively. With additional injection of 10 mL of blood, OP and IOP increased rapidly. CONCLUSIONS: The IOP and OP rose in direct proportion to the volume of whole blood injected; OP lagged behind IOP by 11 mm Hg, and surgical release of the orbit reduced OP by 70%. This effect was short-lived in the setting of continued simulated hemorrhage.