Clinical-Pathological Case Study Section Editors: Neil R. Miller, MD Janet Rucker, MD
Bilateral Optic Neuropathy After Erythematous Rash Sarkis M. Nazarian, MD, Kelli Y. Shaon, OD, John D. Schwankhaus, MD, Joseph G. Chacko, MD, Patricia A. Hudgins, MD, Daniel J. Brat, MD, PhD Dr. Nazarian:
A
58-year-old farmer with a history of hypertension and hyperlipidemia was evaluated for a 2-day history of sudden painless binocular vision loss. He described “hazy darkness” in both eyes, “like sunglasses,” that had started peripherally and spread centrally. Visual acuity was 20/50 in the right eye and 20/40 in the left eye. There was bilateral optic disc swelling. A few weeks before his vision declined, the patient developed an erythematous rash that had started on his back and spread centrifugally onto his extremities, sparing his palms and soles (Fig. 1). He had experienced a headache, fever, and generalized malaise at the time the rash, which had been diagnosed as a heat rash while working on his farm. He had been treated with a cortisone injection, and the rash began to clear a few days later. The patient was admitted to a local hospital. A lumbar puncture revealed a normal opening pressure, elevated protein of 100 mg/dL (normal: 15–45 mg/dL), 50 red blood cells (RBC)/high power field (HPF), and 13 white blood cells/HPF (90% lymphocytes). His visual acuity declined to 20/100 in the right eye and 20/100 in the left eye. He was treated with intravenous methylprednisolone for presumed bilateral anterior optic neuritis and, with no improvement in his vision, he was referred to our neuroophthalmology clinic for assessment. On examination, the patient’s visual acuity was 20/150 in the right eye and 20/200 in the left eye, and color vision was reduced bilaterally. Pupils reacted sluggishly to light without a relative afferent pupillary defect. Extraocular
Departments of Neurology (SMN, JDS) and Ophthalmology, Jones Eye Institute (SMN, JGC), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Central Arkansas Veterans Healthcare System (SMN, JDS, JGC), Little Rock, Arkansas; Veterans Healthcare System of the Ozarks (KYS), Fayetteville, Arkansas; Departments of Radiology and Imaging Sciences (PAH) and Pathology (DJB), Emory University School of Medicine, Atlanta, Georgia. Supported in part by clinical programs at Central Arkansas Veterans Healthcare System (S.M.N., J.D.S., J.G.C.), Little Rock, AR, and Veterans Health Care System of the Ozarks (K.Y.S.), Fayetteville, AR. Presented in part at the North American Neuro-Ophthalmology Society, 39th Annual Meeting, Frank Walsh Session, February 10, 2013, Snowbird, UT. The authors report no conflicts of interest. Address correspondence to Sarkis M. Nazarian, MD, Department of Neurology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 500, Little Rock, AR 72205; E-mail: snazarian@ uams.edu Nazarian et al: J Neuro-Ophthalmol 2015; 35: 201-204
FIG. 1. Appearance of skin rash 2 weeks before onset of visual loss. Note that it is raised and erythematous. It also was pruritic.
movements were full, and anterior segment examination, including intraocular pressures, was normal. Both optic discs were swollen and the retinal veins somewhat dilated (Fig. 2). Kinetic perimetry showed multiple small pericentral islands of residual vision in both eyes (Fig. 3). Magnetic resonance imaging of the brain was obtained.
Dr. Hudgins: The entire study was unremarkable. This included the use of intravenous contrast and sequences included T1, T2, fluid-attenuated inversion recovery image, gradient echo, and the use of fat suppression. Projections were obtained in the axial, coronal, and sagittal planes. 201
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Clinical-Pathological Case Study
FIG. 2. Bilateral optic disc edema is present with mild dilation of the retinal veins.
Dr. Nazarian:
Dr. Nazarian:
The patient underwent a variety of serological studies, including tests for syphilis, sarcoidosis, brucellosis, toxoplasmosis, systemic lupus erythematosus, and neuromyelitis optica. All gave negative or normal results. Additional history revealed that the patient had suffered a tick bite about 2 weeks before the onset of his skin rash. Based on this information, Rocky Mountain Spotted Fever (RMSF), antigen titers were ordered. RMSF immunogloblin G (IgG) was positive by solid-phase enzyme immunoassay, and this result was confirmed using an indirect immunofluorescence assay (IFA) at 1:64 dilution.
Conditions causing a skin rash and unilateral or bilateral optic neuropathies include infections caused by spirochetes (e.g., syphilis, Lyme disease), viruses (e.g., West Nile, Epstein–Barr, Herpes Zoster, human immunodeficiency), bacteria (e.g., meningococcus, Bartonella sp), and rickettsia (e.g., R. rickettsii); inflammatory disorders (e.g., systemic lupus erythematosus, sarcoidosis, Kawasaki disease); nutritional deficiencies (e.g., beriberi); and less common entities such as porphyria and psoriasis. In our patient, the cause was RMSF. RMSF is caused by Rickettsia rickettsii, a small, pleomorphic, obligate intracellular coccobacillus spread by several tick vectors (1). It was first reported in the Snake River Valley of Idaho and the Bitterroot Valley of Montana in 1896. Nowadays, it is most common in the South Atlantic and South Central United States. The Centers for Disease Control typically receives somewhere between 300 and 1,200 case reports of RMSF each year although the number has been increasing in recent years (CDC Web site). As with many tick-borne infections, there is a seasonal peak in the late spring and summer months, with May, June, and July accounting for the most cases. More than 90% of cases are reported from April through September. The disease strikes children disproportionately; peak incidence is in the 5–9 age group, and more than half of reported individuals involve children younger than 15 years. African American men are at particular risk for serious complications of RMSF, as they are genetically more likely to be deficient in glucose-6-phosphate dehydrogenase (G6PD), an enzyme associated with the maintenance of membrane integrity in RBC. Rickettsiae enter the bloodstream after a vector bite (or through feces contaminating a bite wound) and are phagocytosed by, and thereby colonize, endothelial and smooth muscle cells of the vascular system (2). They cause vasculitis by destroying colonized cells, recruiting mononuclear leukocytes, promoting focal thrombosis and infarction, and causing edema due to increased vascular permeability. The enhanced vascular permeability results in hypovolemia, hypotension, hypoalbuminemia, and hyponatremia due to
Dr. Brat: Indirect IFAs for both IgM and IgG antibodies are most commonly used to diagnose rickettsial infections, but enzyme-linked immunosorbent assays and dot immunoassays also are available. Complement fixation is less sensitive and less frequently used. Immunostaining of biopsied skin rashes also can be performed with the results being available within a few hours; however, the test is only 70% sensitive. Thus, a negative result does not exclude the diagnosis of RMSF. Polymerase chain reaction assays for Rickettsia rickettsii DNA are considered perhaps the most specific test for RMSF overall but are not widely available.
Final Diagnosis: Bilateral anterior optic neuropathy due to RMSF.
Dr. Nazarian: The patient was treated with doxycycline 100 mg orally every 12 hours for 60 days. He had slow incomplete recovery of vision over the next several months with resolution of optic disc swelling and development of optic disc pallor. After 6 months, his visual acuity had improved to 20/60 in the right eye and 20/100 in the left eye with improvement in his visual fields (Fig. 3B). 202
Nazarian et al: J Neuro-Ophthalmol 2015; 35: 201-204
Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
Clinical-Pathological Case Study
FIG. 3. Kinetic perimentry. A. At onset, there are multiple, small pericentral islands of visual field. B. Six months after antibiotic treatment, visual fields are improved. (Stimulus used: IV4e).
secretion of antidiuretic hormone in response to the hypovolemia. RMSF manifests after a mean incubation period of 7 days with a triad of high fever, myalgias, and headache (2). A centripetal rash starts in the wrists and ankles by days 3–7 and characteristically spreads centrifugally to the palms and soles. It is eventually seen in about half of all patients with RMSF. Close to 5% of patients develop gangrene or skin necrosis, sometimes requiring amputation of the affected extremities. About 10%–15% of patients with RMSF never develop a rash. Central nervous system manifestations include lethargy and confusion (in about 25% of cases), ataxia (18%), coma (9%–10%), and seizures (8%) (2). Other neurologic manifestations include meningitis, cranial neuropathies, Nazarian et al: J Neuro-Ophthalmol 2015; 35: 201-204
deafness, paralysis, spasticity, vertigo, aphasia, and photophobia. In addition, RMSF may affect the respiratory, gastrointestinal, and renal systems. Ophthalmic manifestations of RMSF include conjunctivitis, anterior uveitis, retinal vasculitis, hemorrhages, and arterial occlusions. About 1.5% of reported patients develop optic disc swelling (3), including 1 patient with neuroretinitis (4). With optic nerve involvement, patients are usually left with permanent visual impairment. RMSF responds to tetracycline, doxycycline, and chloramphenicol. The usual doxycycline dosage is 200 mg/d in 2 divided doses. Treatment generally is continued until patients have been afebrile for at least 3 days; the usual treatment course is 7–10 days (1). 203
Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
Clinical-Pathological Case Study Severe cases may require intravenous administration or longer treatment duration. Pregnant mothers usually are treated with chloramphenicol, 50–75 mg/kg daily. Before the antibiotic era, RMSF had a mortality rate of up to 30%; however, this has dropped to about 3%–5% (1). Nevertheless, it remains the most common fatal tick-borne disease in the United States, with most of the fatalities occurring in the very young and very old, often due to delayed diagnosis and treatment.
204
REFERENCES 1. Dantas-Torres F. Rocky Mountain spotted fever. Lancet Infect Dis. 2007;7:724–732. 2. Helmick CG, Bernard KW, D’Angelo LJ. Rocky Mountain spotted fever: clinical, laboratory, and epidemiologic features in 262 cases. J Infect Dis. 1984;150:480–485. 3. Kim JH, Durack DT. Rickettsiae and the central nervous system. In: Schild WM, Whitley RJ, Durack DT, eds. Infections of the Central Nervous System. New York, NY: Raven Press, 1991:411–424. 4. Vaphiades MS. Rocky Mountain Spotted Fever as a cause of macular star figure. J Neuroophthalmol. 2003;23:276–278.
Nazarian et al: J Neuro-Ophthalmol 2015; 35: 201-204
Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
Bilateral Optic Neuropathy After Erythematous Rash Sarkis M. Nazarian, MD, Kelli Y. Shaon, OD, John D. Schwankhaus, MD, Joseph G. Chacko, MD, Patricia A. Hudgins, MD, Daniel J. Brat, MD, PhD Dr. Nazarian:
A
58-year-old farmer with a history of hypertension and hyperlipidemia was evaluated for a 2-day history of sudden painless binocular vision loss. He described “hazy darkness” in both eyes, “like sunglasses,” that had started peripherally and spread centrally. Visual acuity was 20/50 in the right eye and 20/40 in the left eye. There was bilateral optic disc swelling. A few weeks before his vision declined, the patient developed an erythematous rash that had started on his back and spread centrifugally onto his extremities, sparing his palms and soles (Fig. 1). He had experienced a headache, fever, and generalized malaise at the time the rash, which had been diagnosed as a heat rash while working on his farm. He had been treated with a cortisone injection, and the rash began to clear a few days later. The patient was admitted to a local hospital. A lumbar puncture revealed a normal opening pressure, elevated protein of 100 mg/dL (normal: 15–45 mg/dL), 50 red blood cells (RBC)/high power field (HPF), and 13 white blood cells/HPF (90% lymphocytes). His visual acuity declined to 20/100 in the right eye and 20/100 in the left eye. He was treated with intravenous methylprednisolone for presumed bilateral anterior optic neuritis and, with no improvement in his vision, he was referred to our neuroophthalmology clinic for assessment. On examination, the patient’s visual acuity was 20/150 in the right eye and 20/200 in the left eye, and color vision was reduced bilaterally. Pupils reacted sluggishly to light without a relative afferent pupillary defect. Extraocular
Departments of Neurology (SMN, JDS) and Ophthalmology, Jones Eye Institute (SMN, JGC), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Central Arkansas Veterans Healthcare System (SMN, JDS, JGC), Little Rock, Arkansas; Veterans Healthcare System of the Ozarks (KYS), Fayetteville, Arkansas; Departments of Radiology and Imaging Sciences (PAH) and Pathology (DJB), Emory University School of Medicine, Atlanta, Georgia. Supported in part by clinical programs at Central Arkansas Veterans Healthcare System (S.M.N., J.D.S., J.G.C.), Little Rock, AR, and Veterans Health Care System of the Ozarks (K.Y.S.), Fayetteville, AR. Presented in part at the North American Neuro-Ophthalmology Society, 39th Annual Meeting, Frank Walsh Session, February 10, 2013, Snowbird, UT. The authors report no conflicts of interest. Address correspondence to Sarkis M. Nazarian, MD, Department of Neurology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 500, Little Rock, AR 72205; E-mail: snazarian@ uams.edu Nazarian et al: J Neuro-Ophthalmol 2015; 35: 201-204
FIG. 1. Appearance of skin rash 2 weeks before onset of visual loss. Note that it is raised and erythematous. It also was pruritic.
movements were full, and anterior segment examination, including intraocular pressures, was normal. Both optic discs were swollen and the retinal veins somewhat dilated (Fig. 2). Kinetic perimetry showed multiple small pericentral islands of residual vision in both eyes (Fig. 3). Magnetic resonance imaging of the brain was obtained.
Dr. Hudgins: The entire study was unremarkable. This included the use of intravenous contrast and sequences included T1, T2, fluid-attenuated inversion recovery image, gradient echo, and the use of fat suppression. Projections were obtained in the axial, coronal, and sagittal planes. 201
Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
Clinical-Pathological Case Study
FIG. 2. Bilateral optic disc edema is present with mild dilation of the retinal veins.
Dr. Nazarian:
Dr. Nazarian:
The patient underwent a variety of serological studies, including tests for syphilis, sarcoidosis, brucellosis, toxoplasmosis, systemic lupus erythematosus, and neuromyelitis optica. All gave negative or normal results. Additional history revealed that the patient had suffered a tick bite about 2 weeks before the onset of his skin rash. Based on this information, Rocky Mountain Spotted Fever (RMSF), antigen titers were ordered. RMSF immunogloblin G (IgG) was positive by solid-phase enzyme immunoassay, and this result was confirmed using an indirect immunofluorescence assay (IFA) at 1:64 dilution.
Conditions causing a skin rash and unilateral or bilateral optic neuropathies include infections caused by spirochetes (e.g., syphilis, Lyme disease), viruses (e.g., West Nile, Epstein–Barr, Herpes Zoster, human immunodeficiency), bacteria (e.g., meningococcus, Bartonella sp), and rickettsia (e.g., R. rickettsii); inflammatory disorders (e.g., systemic lupus erythematosus, sarcoidosis, Kawasaki disease); nutritional deficiencies (e.g., beriberi); and less common entities such as porphyria and psoriasis. In our patient, the cause was RMSF. RMSF is caused by Rickettsia rickettsii, a small, pleomorphic, obligate intracellular coccobacillus spread by several tick vectors (1). It was first reported in the Snake River Valley of Idaho and the Bitterroot Valley of Montana in 1896. Nowadays, it is most common in the South Atlantic and South Central United States. The Centers for Disease Control typically receives somewhere between 300 and 1,200 case reports of RMSF each year although the number has been increasing in recent years (CDC Web site). As with many tick-borne infections, there is a seasonal peak in the late spring and summer months, with May, June, and July accounting for the most cases. More than 90% of cases are reported from April through September. The disease strikes children disproportionately; peak incidence is in the 5–9 age group, and more than half of reported individuals involve children younger than 15 years. African American men are at particular risk for serious complications of RMSF, as they are genetically more likely to be deficient in glucose-6-phosphate dehydrogenase (G6PD), an enzyme associated with the maintenance of membrane integrity in RBC. Rickettsiae enter the bloodstream after a vector bite (or through feces contaminating a bite wound) and are phagocytosed by, and thereby colonize, endothelial and smooth muscle cells of the vascular system (2). They cause vasculitis by destroying colonized cells, recruiting mononuclear leukocytes, promoting focal thrombosis and infarction, and causing edema due to increased vascular permeability. The enhanced vascular permeability results in hypovolemia, hypotension, hypoalbuminemia, and hyponatremia due to
Dr. Brat: Indirect IFAs for both IgM and IgG antibodies are most commonly used to diagnose rickettsial infections, but enzyme-linked immunosorbent assays and dot immunoassays also are available. Complement fixation is less sensitive and less frequently used. Immunostaining of biopsied skin rashes also can be performed with the results being available within a few hours; however, the test is only 70% sensitive. Thus, a negative result does not exclude the diagnosis of RMSF. Polymerase chain reaction assays for Rickettsia rickettsii DNA are considered perhaps the most specific test for RMSF overall but are not widely available.
Final Diagnosis: Bilateral anterior optic neuropathy due to RMSF.
Dr. Nazarian: The patient was treated with doxycycline 100 mg orally every 12 hours for 60 days. He had slow incomplete recovery of vision over the next several months with resolution of optic disc swelling and development of optic disc pallor. After 6 months, his visual acuity had improved to 20/60 in the right eye and 20/100 in the left eye with improvement in his visual fields (Fig. 3B). 202
Nazarian et al: J Neuro-Ophthalmol 2015; 35: 201-204
Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
Clinical-Pathological Case Study
FIG. 3. Kinetic perimentry. A. At onset, there are multiple, small pericentral islands of visual field. B. Six months after antibiotic treatment, visual fields are improved. (Stimulus used: IV4e).
secretion of antidiuretic hormone in response to the hypovolemia. RMSF manifests after a mean incubation period of 7 days with a triad of high fever, myalgias, and headache (2). A centripetal rash starts in the wrists and ankles by days 3–7 and characteristically spreads centrifugally to the palms and soles. It is eventually seen in about half of all patients with RMSF. Close to 5% of patients develop gangrene or skin necrosis, sometimes requiring amputation of the affected extremities. About 10%–15% of patients with RMSF never develop a rash. Central nervous system manifestations include lethargy and confusion (in about 25% of cases), ataxia (18%), coma (9%–10%), and seizures (8%) (2). Other neurologic manifestations include meningitis, cranial neuropathies, Nazarian et al: J Neuro-Ophthalmol 2015; 35: 201-204
deafness, paralysis, spasticity, vertigo, aphasia, and photophobia. In addition, RMSF may affect the respiratory, gastrointestinal, and renal systems. Ophthalmic manifestations of RMSF include conjunctivitis, anterior uveitis, retinal vasculitis, hemorrhages, and arterial occlusions. About 1.5% of reported patients develop optic disc swelling (3), including 1 patient with neuroretinitis (4). With optic nerve involvement, patients are usually left with permanent visual impairment. RMSF responds to tetracycline, doxycycline, and chloramphenicol. The usual doxycycline dosage is 200 mg/d in 2 divided doses. Treatment generally is continued until patients have been afebrile for at least 3 days; the usual treatment course is 7–10 days (1). 203
Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
Clinical-Pathological Case Study Severe cases may require intravenous administration or longer treatment duration. Pregnant mothers usually are treated with chloramphenicol, 50–75 mg/kg daily. Before the antibiotic era, RMSF had a mortality rate of up to 30%; however, this has dropped to about 3%–5% (1). Nevertheless, it remains the most common fatal tick-borne disease in the United States, with most of the fatalities occurring in the very young and very old, often due to delayed diagnosis and treatment.
204
REFERENCES 1. Dantas-Torres F. Rocky Mountain spotted fever. Lancet Infect Dis. 2007;7:724–732. 2. Helmick CG, Bernard KW, D’Angelo LJ. Rocky Mountain spotted fever: clinical, laboratory, and epidemiologic features in 262 cases. J Infect Dis. 1984;150:480–485. 3. Kim JH, Durack DT. Rickettsiae and the central nervous system. In: Schild WM, Whitley RJ, Durack DT, eds. Infections of the Central Nervous System. New York, NY: Raven Press, 1991:411–424. 4. Vaphiades MS. Rocky Mountain Spotted Fever as a cause of macular star figure. J Neuroophthalmol. 2003;23:276–278.
Nazarian et al: J Neuro-Ophthalmol 2015; 35: 201-204
Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
