Journal of Neuro-Ophthalmology, June 1999, Volume 19, Issue 2

Disseminated Histoplasmosis Cuasing Reversible Gaze Palsy and Optic Neuropathy

Subacute disseminated histoplasmosis is an uncommon entity. Typical neuro-ophthalmologic manifestations are usually secondary to histoplasmomas or encephalitis. A 45-year-old man noted blurred vision while receiving empiric antituberculosis therapy for fever and diffuse granulomatous disease of unknown origin. Vertical-gaze palsy, right horizontal-gaze paresis, and mild right optic neuropathy were found on neuro-ophthalmologic examination. Further questioning revealed a history of frequent contact with fighting cocks from South America. Magnetic resonance images were consistent with multiple hemorrhagic infarcts, areas of inflammation, or both, and cerebral angiography showed changes consistent with vasculitis. A previously obtained biopsy specimen from the duodenum was restained and found to be positive for fungal elements. Serum antigen titers for Histoplasma capsulatum demonstrated evidence of active infection. This case is a rare example of a supranuclear ocular motility disturbance and optic neuropathy secondary to an occlusive vascular process in a patient with subacute disseminated histoplasmosis.

Journal ofNeuw- Ophthalmology 19( 2): 140- 143, 1999. © 1999 Lippincott Williams & Wilkins, Inc., Philadelphia Disseminated Histoplasmosis Causing Reversible Gaze Palsy and Optic Neuropathy Julian D. Perry, M. D., Christopher A. Girkin, M. D., Neil R. Miller, M. D., and Risa B. Mann, M. D. Subacute disseminated histoplasmosis is an uncommon entity. Typical neuro- ophthalmologic manifestations are usually sec­ondary to histoplasmomas or encephalitis. A 45- year- old man noted blurred vision while receiving empiric antituberculosis therapy for fever and diffuse granulomatous disease of un­known origin. Vertical- gaze palsy, right horizontal- gaze pare­sis, and mild right optic neuropathy were found on neuro-ophthalmologic examination. Further questioning revealed a history of frequent contact with fighting cocks from South America. Magnetic resonance images were consistent with multiple hemorrhagic infarcts, areas of inflammation, or both, and cerebral angiography showed changes consistent with vas­culitis. A previously obtained biopsy specimen from the duo­denum was restained and found to be positive for fungal ele­ments. Serum antigen titers for Histoplasma capsulatum dem­onstrated evidence of active infection. This case is a rare example of a supranuclear ocular motility disturbance and optic neuropathy secondary to an occlusive vascular process in a patient with subacute disseminated histoplasmosis. Key Words: Disseminated histoplasmosis- Gaze palsy- Histoplasma capsulatum- Optic neuropathy. Disseminated histoplasmosis frequently affects the central nervous system ( CNS) and appears in a variety of manifestations, including chronic basilar meningitis, fo­cal or diffuse encephalitis, and intracranial abscesses or pyogranulomas ( 1). Often, these conditions are thought to be caused by tuberculosis ( 2). We present a case of subacute disseminated histoplasmosis initially mistaken for tuberculosis. This disorder caused diffuse CNS vas­culitis associated with several neuro- ophthalmologic manifestations. FIG 1. A duodenal biopsy specimen shows large epithelioid granuloma ( arrowheads). Colonic and bone marrow specimens showed similar findings. Hematoxylin- eosin, magnification x400. Manuscript received March 10, 1998; accepted January 13, 1999. From the Departments of Ophthalmology ( J. D. P., C. A. G., N. R. M.) and Pathology ( R. B. M.), The Johns Hopkins Hospital, Baltimore, Maryland, U. S. A. Address correspondence and reprint requests to Neil R. Miller, M. D., Wilmer Eye Institute, 600 North Wolfe Street, Baltimore, MD 21287- 9240. FIG. 2. Enhanced T1- weighted coronal magnetic resonance im­age shows multiple densely enhancing lesions in the basal gan­glia and thalamus ( large arrowheads). The right brain stem showed a similar enhancing lesion. 140 DISSEMINATED HISTOPLASMOSIS IN REVERSIBLE GAZE PALSY 141 • J& FIG. 3. Results of angiography. A: Right internal carotid arteriogram, lateral view, shows mild narrowing of the supraclinoid portion of the right internal carotid artery ( arrowhead). B: Right internal carotid arteriogram, anteroposterior view, shows marked narrowing of the proximal portion of the right middle cerebral artery and the A1 segment of the right anterior cerebral artery ( arrowheads). The distal portion of the right middle cerebral artery also appears irregularly narrowed. C: Left internal carotid arteriogram, lateral view, shows tapering of supraclinoid segment of the right internal carotid artery ( arrowhead). D: Left vertebral arteriogram shows marked narrowing of the P2 segment of the left posterior cerebral artery ( arrowhead). These changes are consistent with vasculitis. CASE REPORT In June 1992, a 45- year- old right- handed man sought medical attention for abdominal pain, fever, and cachex­ia of 6 weeks' duration. Blood cultures were negative for all organisms. Analysis of specimens obtained in duode­nal, colonic, and bone marrow biopsies all revealed non-caseating granulomas ( Fig. 1). A chest radiograph was negative; an assay for angiotensin- converting enzyme was not obtained. Intradermal purified- protein derivative testing was negative, but injections of mumps and Can­dida were also negative, suggesting anergy. Serum test­ing for human immunodeficiency virus ( HIV) was nega­tive. Acid- fast bacilli stains of bone marrow, duodenal, and colon tissue were negative; however, the patient was thought to have tuberculosis and was treated with rifampin, isoniazid, and pyrazinamide. When his condi­tion did not respond to this therapy, the patient was given oral corticosteroids with an initial favorable response; however, his symptoms recurred when steroids were ta­pered. In September 1992, the patient was noted to have cognitive decline. He also had a severe headache, stag­gering gait, and occasional blurred vision. The patient was admitted to an outside hospital on October 4, 1992, where rifampin, isoniazid, pyrazina­mide, and dexamethasone were prescribed again. Over J Neuro- Ophthalmol, Vol. 19, No. 2, 1999 142 J. D. PERRY ETAL. FIG. 4. The previous duodenal biopsy specimen shows fungal organisms morphologically consistent with the budding yeast forms of Histoplasma capsulatum ( arrowhead). Gomori methe-namine silver stain; magnification, x630. the next 2 days the patient's condition deteriorated, and he was transferred to the Johns Hopkins Hospital on October 6, 1992. On admission, the patient was lethargic and disoriented, with a temperature of 103.2° F. Overall motor tone was decreased and deep- tendon reflexes were exaggerated, with extensor plantar reflexes. Magnetic resonance imaging after intravenous injection of gado-linium- DPTA showed multiple, small, densely enhanc­ing lesions in the basal ganglia, thalamus, and right brain stem ( Fig. 2). Lumbar puncture showed 80 white blood cells/ mm3 ( 61% lymphocytes, 36% polymorphonuclear leukocytes, 3% monocytes), 130 erythrocytes/ mm3, glu­cose 24 mg/ dl%, and protein 229 mg/ dl%. India ink preparation, cultures, and Gram stain were negative. Ce­rebral angiography showed narrowing of the supracli-noid portion of the right internal carotid artery, the Al segment of the right anterior cerebral artery, the left proximal middle cerebral artery, and the P2 segment of the left posterior cerebral artery, consistent with vascu­litis ( Fig. 3). The distal arterial branches appeared nor­mal. Antituberculosis therapy and dexamethasone were continued, but the patient's fevers persisted despite sta­bilization of cognitive status. Approximately 2 weeks after admission, the patient reported blurred vision, and he was therefore referred to the neuro- ophthalmology unit for consultation. Neuro- ophthalmologic examination on October 22, 1992, revealed visual acuity of 20/ 25 OD and 20/ 20 OS. Color vision using Hardy- Rand- Rittler color plates was 9/ 10 OD and 10/ 10 OS. Pupils were 6 mm on the right and 4 mm on the left. The right pupil was sluggishly reactive to light, and there was a trace right afferent pupillary defect. Visual fields were full to count fingers in both eyes. Motility examination revealed limitation of right horizontal gaze and a nearly complete absence of voluntary vertical gaze; however, oculocephalic testing showed a full range of movement in both eyes. Slit lamp and fundus examination results were normal in both eyes. Further questioning showed that the patient imported and raised South American chickens for cock fighting. Urine, serum, and cerebrospinal fluid studies for Histo­plasma capsulatum antigen were subsequently obtained, and all were positive. The serum titer was 1: 64, demon­strating active infection. The previous duodenal biopsy from June 1992 was then restained with Gomori methe-namine silver and found to be positive for organisms consistent with H. capsulatum ( Fig. 4). Intravenous am­photericin B 0.8 mg/ kg- day was instituted, and the pa­tient's condition gradually improved. When re- evaluated 6 months later, the patient had visual acuity of 20/ 20 OU, full visual fields in both eyes, and no relative afferent pupillary defect. He was able to make normal pursuit and saccadic eye movements in both the vertical and hori­zontal planes. DISCUSSION H. capsulatum is endemic in an area of the eastern central United States, but it is present in soil throughout the world ( 3). Cultures of soil specimens show an in­creased prevalence of the organism where heavy accu­mulations of avian excrement are present ( 4). Our patient had a history of frequent, close contact with chickens. The two most important factors that determine the course of infection are the size of the inoculum and the prein-fection immune status of the patient ( 5). Symptoms de­velop in only 1% to 10% of patients who have initial pulmonary infection ( 6), and most symptomatic cases are self- limited. Our patient had no history of an immune disorder and no evidence of HIV infection, so his un­common and severe infection may have been related to the size of the inoculum. Subacute disseminated histoplasmosis is an uncom­mon entity, but it frequently affects the gastrointestinal tract ( 7) and the CNS ( 1,2), as in our patient. The disor­der can cause a variety of conditions affecting the CNS, including chronic basilar meningitis, focal or diffuse en­cephalitis, and intracranial abscesses or pyogranulomas. Patients with these manifestations are often initially thought to have tuberculosis ( 2). Neuro- ophthalmologic manifestations are usually sec­ondary to focal or diffuse encephalitis or histoplasmomas ( 2). In addition to signs of meningitis and encephalitis, patients may experience focal signs, including vestibular nystagmus ( 8), visual field defects ( 9), and ocular motor nerve palsy ( 10). Our patient had supranuclear horizontal and vertical gaze palsies in addition to a mild right optic neuropathy, all of which improved after treatment. Im­aging studies in some patients have revealed changes consistent with brain stem encephalitis or granulomas. Although the lesions found on MR imaging in our patient may have been areas of inflammation, we think it more likely that they were multiple areas of hemorrhagic in­farction, because cerebral angiography showed signs of vasculitis. The neurologic deficits in our patient thus seem to have resulted from a vaso- occlusive process sec­ondary to vasculitis. In any event, this case represents an uncommon manifestation of subacute disseminated his- J Neuro- Ophthalmol, Vol. 19, No. 2, 1999 DISSEMINATED HISTOPLASMOSIS IN REVERSIBLE GAZE PALSY '. 43 toplasmosis and enlarges the spectrum of CNS disease caused by this organism. REFERENCES 1. Wheat LJ, Batteiger BE, Sathapatayavongs B. Histoplasma cap­sulation infections of the central nervous system: a clinical review. Medicine 1990; 69: 244- 60. 2. Shapiro JL, Lux JJ, Sprofkin BE. Histoplasmosis of the central nervous system. Am J Pathol 1955; 31: 319- 35. 3. Edwards LB, Acquaviva FA, Livesay VT, Cross FW, Palmer CE. An atlas of sensitivity to tuberculin, PPD- B, and histoplasmin in the United States. Am Rev Respir Dis 1969; 99: 1- 132. 4. Emmons CW, Klite PD, Baer GM, Hill WB. Isolation of Histo­plasma capsulatum from bats in the United States. Am J Epidemiol 1966; 84: 103- 9. 5. Goodwin RA, Lloyd JE, Des Prez RM. Histoplasmosis in normal hosts. Medicine 1981; 60: 231- 66. 6. Sathapatayavongs B, Batteiger BE, Wheat JL, Slama TG, Wass JL. Clinical and laboratory features of disseminated histoplasmosis during two large urban outbreaks. Medicine 1983; 62: 263- 70. 7. Brett MT, Kwan JT, Bending MR. Cecal perforation in a renal transplant patient with disseminated histoplasmosis. J Clin Pathol 1988; 41: 992- 5. 8. Couch JR, Abdou NI, Sagawa A. Histoplasma meningitis with hyperactive suppressor T cells in cerebrospinal fluid. Neurology 1978; 28: 119- 23. 9. White HH, Fritzlen TJ. Cerebral granuloma caused by Histoplasma capsulatum. J Neurosurg 1962; 19: 260- 3. 10. Rivera IV, Curless RG, Indacochea FJ, Scott GB. Chronic pro­gressive CNS histoplasmosis presenting in childhood: Response to fluconazole therapy. Pediatr Neurol 1992; 8: 151- 3. J Neuro- Ophthalmol, Vol. 19, No. 2. 1999