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The Interface of Infectious Disease and Neuro-ophthalmology

Berger, Joseph R. MD

doi: 10.1097/WNO.0b013e318263e275

Department of Neurology, University of Kentucky College of Medicine, Lexington, Kentucky.

Address correspondence to Joseph R. Berger, MD, Department of Neurology, University of Kentucky College of Medicine, Kentucky Clinic L-445, 740 S. Limestone Street, Lexington, KY 40536-0284; E-mail:

The author reports no conflicts of interest.

Five articles in this issue of the Journal of Neuro-Ophthalmology are interwoven by a common thread, namely, infectious disease as the underlying etiology of neuro-ophthalmic disorders. Affecting both the afferent and efferent visual systems, these reports encompass virtually every form of infectious agent ranging from viruses to parasites.

Sridhar et al (1) describe 3 patients seen in south Florida who developed neuro-ophthalmic complications of fungal disease. The entity they describe, allergic fungal sinusitis (AFS), is very different than the more familiar form of invasive fungal sinusitis. Invasive fungal sinusitis can be classified into 3 types (2). The acute (fulminant) type is characterized by headache, fever, nasal crusting, and epistaxis. One example is mucormycosis, characterized by hyphal invasion of blood vessels, vasculitis with thrombosis, and tissue infarction. Granulomatous invasive fungal sinusitis occurs with Aspergillus flavus infection and presents with proptosis in an immunocompetent host. Chronic invasive fungal sinusitis is distinguished by a prolonged course coupled with dense accumulation of hyphae and vascular invasion. It is associated with diabetes mellitus and corticosteroid treatment and may cause orbital apex syndrome. However, the patients described by Sridhar et al (1) had AFS. They developed painless visual loss, ophthalmoplegia, and ptosis due to allergic reaction to dematiaceous fungal sinus disease. This disorder is likely underrecognized and arises from several varieties of ubiquitous fungi. A number of features distinguish this disorder from the invasive fungal sinusitis. Patients with AFS are not immunocompromised, there appears to be a geographic distribution of AFS with most cases reported in hot humid environments, and it occurs as an allergic response to the fungus rather than as consequence of the organism's capacity to invade and destroy tissue. While not a novel suggestion, the authors propose that hurricanes, by increasing the exposure to dematiaceous fungi, may predispose individuals to AFS. Importantly, AFS is a treatable disorder in which recovery follows surgical evacuation of the fungal mass and corticosteroid administration. Since there have been no randomized controlled therapeutic trials for AFS, issues regarding duration of corticosteroid therapy and the role of antifungal agents remain unknown. These patients typically have an allergic diathesis, and immunotherapy directed against allergens to which they are sensitive may have a role in management (3).

Lyme disease would not be the first diagnosis to come to mind in a 90-year-old woman presenting with painless ptosis, but Xu et al (4) describe such a patient. They emphasize the importance of considering Lyme disease in the differential diagnosis of orbital cellulitis. This complication must be quite unusual as the authors were able to identify only 4 cases in their review of the literature. In the patient described by Xu et al (4), the serological studies for Lyme disease obtained proximate to the tick bite were negative. Six months later, at the time of presentation with orbital cellulitis, there was convincing evidence of serological conversion with Western blot (WB) for Borrelia burgdorferi immunoglobulin G (IgG). The sensitivity and standardization of immunoblots for Lyme have improved substantially with the use of recombinant antigens, and detection rates for serum antibodies varies between 20% and 50% in localized infection, 70%–90% in disseminated early disease, and approaches 100% in late disease (5). Several well-established antibiotic regimens, including oral antimicrobial therapy for European neuroborreliosis, have been demonstrated to be effective (6). Antimicrobial therapy for more than 4 weeks is unnecessary and is associated with significant morbidity.

A wide variety of ocular abnormalities have been described with cat scratch disease (7). Neuroretinitis is a frequent manifestation of cat scratch disease due to Bartonella henselae. Like Lyme disease, cat scratch disease also may be difficult to diagnose if one relies solely on serological studies. Neither patient reported by Gulati et al (8) in this issue of the Journal initially fulfilled serological criteria for B. henselae infection. Repeat testing supported the diagnosis in both cases and demonstrates the importance of having a high index of suspicion for this infection and pursuing the diagnosis with serial sampling. Several different serological tests are used for the diagnosis of cat scratch disease, including the immunofluorescence assay (IFA), the enzyme-linked immunosorbent assay, and WB analysis. The sensitivities of different IFAs range from 14% to 100%, depending on the antigen used, the cut-off chosen, and the test procedures (9). Alternatively, presumptive treatment based on reasonable clinical suspicion may be a necessary and appropriate course of action.

Elston et al (10) describe a 69-year-old Caucasian woman who presented with facial skin lesions and unilateral trigeminal and facial neuropathies coupled with a peripheral neuropathy and similar dermatological lesions over her extremities. Establishing the diagnosis of multibacillary leprosy required skin biopsy although her history of having lived in Indonesia for 8 years, an endemic area for leprosy, 3 years before returning to the United Kingdom and the nature of her clinical findings were highly suggestive of leprosy. Despite the appropriate antimicrobial therapy, complications attributable to Mycobacterium leprae seem to have progressed, but the patient succumbed to lung cancer within several months. When cranial nerve involvement occurs with leprosy, the trigeminal and facial nerves are most commonly involved (11). Eighteen percent of leprosy patients attending a neurology clinic in Vellore, India, had cranial nerve involvement (11). The patient described by Elston et al (10) illustrates the importance of obtaining a travel history. While leprosy is a treatable and a potentially curable disorder, persistent infection and relapse have been observed (12,13).

Every physician should recognize that nystagmus coupled with an altered level of consciousness might indicate an underlying seizure disorder. Lee et al (14) report a patient with herpes encephalitis who developed ictal nystagmus occurring with nonconvulsive status epilepticus. The diagnosis in their patient was not established with detection of herpes simplex virus (HSV) in the cerebrospinal fluid (CSF) by polymerase chain reaction (PCR), but rather by demonstrating IgG directed against HSV in the CSF. While CSF PCR for HSV is highly sensitive and specific, in the first 72 hours of illness, false-negative tests may occur (15). The electroencephalography findings reported by Lee et al (14) suggest that the ictal nystagmus was believed to have emanated from cortical saccade regions of the brain and resulted in nystagmus with the fast phase beating to the opposite side. While epileptic nystagmus complicating HSV encephalitis is unusual, physicians should be alert to the possibility of this CNS infection in any patient presenting with new onset seizure coupled with fever and headache.

These case reports and case series illustrate the importance of keeping infectious disease in the differential diagnosis of patients presenting with neuro-ophthalmic disorders. They illustrate the diversity of causative organisms, the variety of clinical manifestations confronting the neuro-ophthalmologist, and the difficulties encountered in establishing the diagnosis. Yet, it is essential that infectious conditions be recognized in a timely fashion as they are potentially entirely reversible if treated promptly and appropriately.

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