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Optic neuritis after anthrax vaccination1
Optic Neuritis after Anthrax Vaccination John B. Kerrison, MD,1 David Lounsbury, MD,2 Charles E. Thirkill, PhD,3 R. Gary Lane, MD,1 Martha P. Schatz, MD,1 Renata M. Engler, MD4 Objective: To report the occurrence of optic neuritis after anthrax vaccination in two patients. Design: Observational case reports, review of literature. Methods: Description of clinical history, examination, neuroimaging, and further studies in two patients experiencing optic neuritis in temporal association with anthrax vaccination. Main Outcome Measures: Visual acuity, visual fields. Results: Two patients, 39 and 23 years of age, were seen with acute optic neuritis 1 month and 2 weeks, respectively, after anthrax booster vaccination and successfully treated with intravenous methylprednisolone. The first patient had a typical presentation and course of unilateral retrobulbar optic neuritis with excellent visual recovery. The second patient had a bilateral anterior optic neuritis and has required chronic immunosuppression to maintain his vision. Retinal and optic nerve autoantibodies were present in the second patient. No crossreactive epitopes between anthrax vaccine and retina/optic nerve were identified. Conclusion: Optic neuritis is a potential adverse reaction of anthrax vaccination. Ophthalmology 2002;109: 99 –104 © 2002 by the American Academy of Ophthalmology. Bacillus anthracis is a biologic weapon threat because of its stability in spore form, its ease of culture, the absence of natural immunity in industrialized nations, and the severity of infection in its gastrointestinal and pulmonary forms. If untreated, the case-fatality rate of inhaled anthrax approaches 80%. At least 17 nations are suspected of developing offensive biologic weapons programs,1 and one terrorist group has used anthrax.2 Iraq has acknowledged producing and weaponizing anthrax.3 As U.S. military servicemen may potentially be exposed to anthrax, the Department of Defense announced on December 15, 1997, a plan to vaccinate the entire force against anthrax by 2004. At present, those individuals being deployed to high-threat areas are being vaccinated. The anthrax vaccine adsorbed (Bioport Inc., Lansing, MI), licensed by the Food and Drug Administration in 1970, consists of a six-dose primary series with annual boosters.4 The safety and efficacy of the vaccination was affirmed by an Originally received: February 16, 2001. Accepted: April 29, 2001. Manuscript no. 210106. 1 Department of Ophthalmology, Wilford Hall Medical Center, Lackland AFB, Texas. 2 United States Navy Medical Clinic, London, England. 3 Department of Ophthalmology, University of California at Davis, Davis, California. 4 Walter Reed Army Medical Center, Washington, DC. Presented at the annual meeting of the North American Neuro-Ophthalmology Society, February 2001, Palm Springs, California. Supported in part by unrestricted funding from Research To Prevent Blindness, Inc., New York, NY, and NEI core grant 1 P30 EY12576-01 (CET). The features expressed in the article are those of the authors and do not reflect the official policy of the Department of Defense or other departments of the United States government. Reprint requests to John B. Kerrison, MD, Department of Ophthalmology, Wilford Hall Medical Center, 2200 Bergquist Drive, Suite 1, Lackland AFB, TX 78236. © 2002 by the American Academy of Ophthalmology Published by Elsevier Science Inc.
independent advisory panel in 1985. Nevertheless, several service members are reluctant to receive the vaccine because of concern about adverse events. Recent surveys of service members who have received anthrax vaccine absorbed have failed to identify unexpected local reactions or systemic adverse events.5 This report documents two cases of optic neuritis after anthrax vaccination.
Case 1 A 39-year-old African American man presented with loss of vision in his right eye associated with pain on eye movement the day after receiving an anthrax booster vaccination. He received his initial anthrax vaccination on January 5, 1999, after which he experienced arm soreness lasting approximately 24 hours. One month after his initial vaccine, he began to experience a “spot” in the vision of his right eye. On February 11, 1999, he received his second dose of anthrax vaccine. The following day, he had a headache associated with pain on eye movement and an increase in the “spot” in the vision of his right eye. He was seen by an eye care provider the following day. His medical history was unremarkable. He had no other neurologic complaints. On initial examination, he had a visual acuity of 20/25 in the right eye and 20/20 in the left eye. A trace relative afferent pupil defect and decreased color vision were present in the right eye. On automated, static perimetry (Humphrey 24 –2), he had a superior visual defect and inferior nasal loss in the right eye (mean deviation, ⫺19.31 decibels) (Fig 1). The visual field of the left eye was normal. He had normal-appearing optic nerves in both eyes without swelling, hemorrhages, or pallor. A computed tomography scan of the orbits was normal. A magnetic resonance imaging (MRI) scan of the brain without contrast demonstrated three T2weighted hyperintensities involving the right centrum semiovale (Fig 2), the deep white matter of the parietal lobe, and the right frontal horn. No treatment was recommended. He returned on February 24, 1999, with worsening vision in the right eye. His visual acuity in the right eye was 20/40. He had a 2⫹ right relative afferent pupillary defect. On visual field testing of the right eye, his mean deviation was ⫺28.14 decibels (Fig 1). He had no optic nerve swelling. Examination of the left eye was normal, ISSN 0161-6420/02/$–see front matter PII S0161-6420(01)00844-2
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Figure 1. Case 1. Visual fields (Humphrey 24 –2) performed 2 days after receiving anthrax booster vaccination demonstrate a superior visual defect and inferior nasal loss in the right eye and a normal examination of the left eye (top). Ten days later, the visual field in the right eye had worsened (middle). Approximately 3 weeks after initial presentation and after intravenous methylprednisolone, his visual field in the right eye was much improved (bottom).
although no visual field testing was performed. Laboratory evaluation included a complete blood count, thyroid-stimulating hormone, human immunodeficiency virus, rapid plasma reagin, antinuclear antibody, B12, and folate level, all of which were normal. His erythrocyte sedimentation rate was 2. Chest x-ray showed small scattered nodules without hilar adenopathy attributed to old granulomatous disease. Lumbar puncture revealed clear and colorless cerebrospinal fluid with normal glucose, protein, cell count, and differential. Cerebrospinal fluid Venereal Disease Research Laboratory test was negative, but oligoclonal bands were present. Routine aerobic and anaerobic bacterial cultures were negative. He was treated with intravenous methylprednisolone, 1000 mg a day for 5 days, followed by oral prednisone, 60 mg per day, for a total of 14 days. Over the next several days, he experienced improvement in his vision. On March 3, 1999, he had a visual acuity of 20/20 in the right eye, a trace right relative afferent pupillary defect, and a continued normal-appearing right optic nerve. His visual field in the right eye was markedly improved with a mean deviation of ⫺5.12 decibels (Fig 1). He has not received any further anthrax vaccinations. Over the 18 months after this episode, he had no further neurologic complaints. Follow-up MRI scans at 2 months and 9 months demonstrated no change.
Case 2 A 23-year-old African American man presented with bilateral loss of vision associated with orbital pain 2 weeks after anthrax booster vaccination.
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Figure 2. Case 1. A magnetic resonance imaging scan of the brain without contrast demonstrated a T2-weighted hyperintensity involving the right centrum semiovale (arrow). T2-weighted hyperintensities were also observed in the deep white matter of the parietal lobe and right frontal horn.
Within 2 weeks of his 6-month anthrax vaccination in April 2000, he had blurred vision develop in his left eye, worsening over 2 days and associated with pain on eye movement. Within the next few days, he had similar symptoms develop in his right eye. On May 5, 2000, ophthalmologic examination disclosed a visual acuity of counting fingers in the right eye and 20/30 in the left eye. He had a right relative afferent pupil defect and optic nerve swelling in both eyes. Vitreous cells were present inferiorly in the right eye, but no retinal perivascular inflammation was present. Antinuclear antibody, fluorescent treponemal antibody absorption test, rapid plasma reagin, rheumatoid factor, complete blood count, sedimentation rate, lysozyme, angiotensin-converting enzyme, and Lyme titers were either normal or unremarkable. Western blot of the patient’s serum with an extract of bovine retina and optic nerve revealed the presence of an antibody to a protein with a molecular weight of 200 Kd. Indirect immunohistochemistry on sectioned rhesus money eye with the patient’s serum showed immunologic reactivity extending from the nerve fiber layer into the optic nerve, as well as weak reactivity with components of the outer plexiform layer and the outer segments of photoreceptor cells. Western blot of a sample of anthrax vaccine with both rabbit antiretina serum and rabbit antioptic nerve serum failed to demonstrate cross-reactivity. Chest x-ray and gallium scan were normal. MRI scan of the brain with and without contrast was unremarkable. MRI scan of the spine showed no foci of demyelination. Lumbar puncture with
Kerrison et al 䡠 Optic Neuritis after Anthrax Vaccination
Figure 3. Case 2. Visual fields (Humphrey 24 –2) at the time of worsening during attempted slow steroid taper (top). After an intravenous methylprednisolone pulse, the reinstitution of oral steroids at a higher dose, and ultimately the addition of azathioprine as a steroid-sparing agent, he had improvement in his visual fields obtained 3 months later (bottom).
cerebrospinal fluid analysis demonstrated normal glucose, protein, cell count, and differential. No oligoclonal bands were present. He was treated with intravenous methylprednisolone, 250 mg four times a day for 3 days with no oral steroid taper, and his vision improved. On May 22, 2000, he had a visual acuity of 20/20 in each eye. Over the next week, he had worsening of the vision in his right eye associated with pain. By May 30, 2000, his visual acuity had deteriorated to no light perception in the right eye and 20/50 in the left eye. He was treated with 5 days of intravenous methylprednisolone, 1 g/day in divided doses, followed by 5 days of oral prednisone taper. By June 8, 2000, he had visual acuity of 20/100 in the right eye and 20/30 in the left eye. During gradual tapering of steroids on two further occasions, he had worsening vision (Fig 3), treated with pulse intravenous methylprednisolone followed by oral prednisone. He has begun azathioprine with a target dosage of 2 mg/kg/day and tapering of his steroids without relapse. He has not received any further anthrax vaccinations. Seven months after his initial episode, his visual acuity remains 20/40 in the right eye and 20/25 in the left eye with bilateral optic atrophy. He has had no further neurologic complaints.
Discussion Optic neuritis is a well-recognized complication of immunization, although it has not been reported after anthrax vaccination. Other ocular complications of vaccination include uveitis,6 –10 vaccinia keratouveitis after accidental ocular autoinoculation from a recent vaccination site,11 anterior ischemic optic neuropathy,12 and multiple evanescent
white dot syndrome.13 Neurologic complications of vaccination include seizures, Bell’s palsy, transverse myelitis, acute disseminated encephalomyelitis, and Guillian Barre´ syndrome.14,15 Optic neuritis may be a manifestation of acute disseminated encephalomyelitis,16 and isolated optic neuritis after immunization might be considered a forme fruste of acute disseminated encephalomyelitis. Optic neuritis has been most commonly reported after influenza vaccination6,17–20 but has also been reported with multiple other inoculations including smallpox vaccination combined with diphtheria-tetanus toxoid,21 rubella vaccination,22 combined rubella-measles vaccination,23 combined rubella-measles-mumps vaccination,24 hepatitis B vaccination,25 bacille Calmette-Gue´ rin vaccination,26 and simultaneous administration of hepatitis B and polio vaccines (Table 1).27 The ages of previously reported patients with optic neuritis after vaccination range from 6 to 61 at an interval after immunization of 5 to 21 days. Pain has been reported in 60%, bilaterality in 80%, and disc edema in 80% of previously reported cases of postvaccination optic neuritis. Although postvaccination optic neuritis is often a monophasic illness with excellent recovery, some cases have been associated with initial recovery followed by worsening after discontinuation of steroids22 or poor outcome.18,19,27 An MRI scan, performed in a limited number of previously reported cases,19,20,27 has been reported to be normal. The first case is similar to previous cases with regard to the presence of pain and its remitting, monophasic course. It differs from previously reported cases with regard to its unilateral nature and retrobulbar involvement. The patient initially noticed an abnormality in his vision approximately 1 month after vaccination but did not become fully symptomatic until after receiving booster immunization. Although the typical interval between vaccination and optic neuritis reported in the literature is approximately 1 to 3 weeks, acute disseminated encephalomyelitis may occur up to 1 month after vaccination.28 His presentation after a booster vaccination may represent an acute anamnestic response. The second case is consistent with prior reports of postvaccination optic neuritis with regard to the interval between vaccination and disease onset, the presence of pain, the anterior optic nerve involvement, bilaterality, and normal neuroimaging. It differs from previous cases in its chronicity, characterized by the need for long-term immunosuppressive therapy. Nevertheless, several reports of postvaccination optic neuritis have been associated with poor visual outcomes when not treated with long-term immunosuppression.18,19,27 Both patients underwent evaluation for causes associated with optic neuritis. Case 1 had a chest x-ray that was suggestive of prior granulomatous disease often attributed to Histoplasma exposure. In addition, the presence of T2weighted hyperintensities and oligoclonal bands would suggest an underlying diagnosis of multiple sclerosis, although these may be nonspecific features seen with an inflammatory, demyelinating process initiated by anthrax vaccination. Evaluation for other causes associated with optic neuritis in case 2 was unrevealing. Because optic neuritis occurs from other causes in the absence of immunization and the
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Ophthalmology Volume 109, Number 1, January 2002 Table 1. Clinical Characteristics of Previously Author
Vaccine
Kline LB et al22
Rubella
Kazarian EL and Gager WE24
Measles/mumps/rubella
25
Albitar S et al
Hepatitis B
Yen MY and Liu JH26 27
Bacille Calmette-Gue´ rin
Stewart O et al
Hepatitis B/polio
Perry HD et al17
Influenza
Ray CL and Dreizin IJ20
Influenza
Hull TP and Bates JH19
Influenza
23
Stevenson VL et al
Measles/rubella
McReynolds WU et al21
Smallpox/diptheria/tetanus
Cangemi FE and Bergen RL18
Swine flu
Bienfang DC et al6
Influenza
Presenting Visual Acuity
Age (yrs)
Onset After Vaccine
20/25 RE 20/200 LE 20/25 RE Count fingers LE 20/200 RE 20/200 LE Count fingers RE Count fingers LE 6/18 RE 6/12 LE
31
5 days
Pain
6
3 wks
Pain
28
1 wk
Pain
12
5 days
No pain
44
1 wk
Pain
58
6 days
Pain
61
3 wks
No pain
59
2 wks
No pain
13
3 wks
Pain
7
2 wks
No pain
38
3 wks
No pain
27
3 wks
Pain
No light perception RE; Light perception LE 20/200 RE 20/40 LE LP RE LP LE 1/60 RE 6/36 LE 6/100 RE No light perception LE Count fingers RE 20/30 LE 20/15 RE 20/30 LE
Pain/ No Pain
LE ⫽ left eye; RE ⫽ right eye.
frequency of optic neuritis in this selected population is not known, it is not possible to definitively demonstrate a causeand-effect relationship based on case reports. The Vaccine Adverse Events Reporting System (VAERS) is used to evaluate adverse events potentially related to vaccinations. The Defense Medical Surveillance System consolidates VAERS reports related to anthrax vaccination for the Anthrax Vaccine Immunization Program. Between March 1998 and December 2000, 1984,785 doses of vaccine have been administered to 495,013 personnel (personal communication, LTC John D. Grabenstein, RPh, PhD, Nov. 30, 2000). Review of the VAERS database has revealed one other prior self-reported case of optic neuritis. Unfortunately, no other details are available. Other neurologic adverse events associated with the anthrax vaccination reported in VAERS include two cases of transverse myelitis and three cases of Guillian Barre´ syndrome. Assuming all cases of optic neuritis have been reported, the estimated incidence of optic neuritis is approximately 0.6/100,000 individuals undergoing immunization. Because optic neuritis does not necessarily represent an immediate complication, it may go unrecognized and be underreported. The pathogenesis of optic neuritis in these patients is presumed to be an immune-mediated response to optic nerve antigens stimulated by vaccination. Nevertheless, direct cross-reactive antibodies between anthrax vaccine and the patient’s retina/optic nerve are unlikely, because neither
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antiretina antibodies nor antioptic nerve antibodies react with the anthrax vaccine. Thus, an epitope shared by both the anthrax vaccine and the retina/optic nerve was not detected. Although autoantibodies to retina and optic nerve were identified in case 2, they are of uncertain significance. Autoantibodies to retina and optic nerve have been reported in other optic neuropathies including glaucoma,29 Leber’s hereditary optic neuropathy,30 and paraneoplastic optic neuropathy.31 They may represent an epiphenomenon in response to nonspecific tissue damage.31 Both patients responded to immunosuppressive therapy with steroids, although case 2 required long-term therapy and was switched to azathioprine as a steroid-sparing measure. Another therapeutic option that may merit consideration in such patients is intravenous immunoglobulin32 or plasmapheresis. In summary, optic neuritis may occur after anthrax vaccination, although it seems to be a rare event. Although some patients may have a benign course with excellent visual recovery, others may require long-term immunosuppressive therapy to maintain vision. Retinal and optic nerve autoantibodies may be observed in postvaccination optic neuritis, although cross-reactive epitopes between the vaccine and retina/optic nerve were not identified. Acknowledgment. The authors thank LTC John D. Grabenstein, RPh, PhD, Deputy Director for Clinical Operations, Anthrax Vaccine Immunization Program Agency technical assistance.
Kerrison et al 䡠 Optic Neuritis after Anthrax Vaccination Reported Cases of Optic Neuritis after Vaccination Anterior/ Retrobulbar
Unilateral/ Bilateral
Treatment
Anterior
Bilateral
Prednisone, 40 mg/day
Anterior
Bilateral
Oral prednisone, 40 mg/day
Retrobulber
Bilateral
Prednisone, 1 mg/kg/day
Anterior
Bilateral
Anterior
Bilateral
Anterior
Bilateral
Anterior
Bilateral
Intravenous desamethasone, 5 mg every 6 hrs Intravenous methylprednisolone, 1 g/day, followed by oral prednisone, 1 mg/kg/day, with slow taper Bilateral retrobulbar methylprednisolone injection, 40 mg; oral prednisone, 40 mg twice a day Intravenous dexamethasone
Anterior
Bilateral
Intravenous corticosteroids
Anterior
Bilateral
Intravenous methylprednisolone
Anterior
Bilateral
Anterior
Unilateral
Corticotropin, 20 U every 8 hrs; mannitol hexanitrate, 15 mg every 8 hrs No treatment
Retrobulbar
Unilateral
Oral prednisone
Final Visual Acuity 20/20 RE 20/20 LE 20/20 RE 20/20 LE 20/25 RE 20/25 LE 20/15 RE 20/15 LE Count fingers RE Count fingers LE
Recurrence after initial treatment; encephalomyelitis developed
20/20 RE 20/20 LE
Worse during steroid taper, treated with oral steroids for a year
20/25 RE 20/30 LE 20/30 RE LP LE 6/5 RE 6/12 LE 6/6 RE 6/6 LE “Profound visual acuity loss persisted” “Normal visual acuity”
References 1. Cole LA. The specter of biological weapons. Sci Am 1996; 275:60 –5. 2. Inglesby TV, Henderson DA, Bartlett JG, et al. Anthrax as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA 1999;281: 1735– 45. 3. Zilinskas RA. Iraq’s biological weapons. The past as future? JAMA 1997;278:418 –24. 4. Friedlander AM, Pittman PR, Parker GW. Anthrax vaccine: evidence for safety and efficacy against inhalational anthrax. JAMA 1999;282:2104 – 6. 5. Surveillance for adverse events associated with anthrax vaccination—U.S. Department of Defense, 1998 –2000. MMWR Morb Mortal Wkly Rep 2000:49:341–5. 6. Bienfang DC, Kantrowitz FG, Noble JL, Raynor AM. Ocular abnormalities after influenza immunization [letter]. Arch Ophthalmol 1977;95:1649. 7. Blanche P, Decrette C, Sicard D. Development of uveitis following vaccination for influenza [letter]. Clin Infect Dis 1994;19:979. 8. Islam SMM, El Sheikh HF, Tabbara KF. Anterior uveitis following combined vaccination for measles, mumps and rubella (MMR): a report of two cases. Acta Ophthalmol Scand 2000; 78:590 –2. 9. Knopf HLS. Recurrent uveitis after influenza vaccination. Ann Ophthalmol 1991;23:213– 4. 10. Esmaeli-Gutstein B, Winkelman JZ. Uveitis associated
Comment
11.
12.
13.
14. 15.
16.
17.
18. 19. 20. 21.
with varicella virus vaccine. Am J Ophthalmol 1999;127: 733– 4. Lee SF, Buller R, Chansue E, et al. Vaccinia keratouveitis manifesting as a masquerade syndrome. Am J Ophthalmol 1994;117:480 –7. Kawasaki A, Purvin VA, Tang R. Bilateral anterior ischemic optic neuropathy following influenza vaccination. J Neuroophthalmol 1998;18:56 –9. Baglivo E, Safran AB, Borruat FX. Multiple evanescent white dot syndrome after hepatitis B vaccine. Am J Ophthalmol 1996;122:431–2. Fenichel GM. Neurological complications of immunization. Ann Neurol 1982;12:119 –28. Stu¨ ve O, Zamvil SS. Pathogenesis, diagnosis, and treatment of acute disseminated encephalomyelitis. Curr Opin Neurol 1999;12:395– 401. Hamed LM, Silbiger J, Guy J, et al. Parainfectious optic neuritis and encephalomyelitis. A report of two cases with thalamic involvement. J Clin Neuroophthalmol 1993;13:18 –23. Perry HD, Mallen FJ, Grodin RW, Cossari AJ. Reversible blindness in optic neuritis associated with influenza vaccination. Ann Ophthalmol 1979;11:545–50. Cangemi FE, Bergen RL. Optic atrophy following swine flu vaccination. Ann Ophthalmol 1980;12:857– 63. Hull TP, Bates JH. Optic neuritis after influenza vaccination. Am J Ophthalmol 1997;124:703– 4. Ray CL, Dreizin IJ. Bilateral optic neuropathy associated with influenza vaccination. J Neuroophthalmol 1996;16:182– 4. McReynolds WU, Havener WH, Petrohelos MA. Bilateral
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22. 23. 24. 25. 26. 27.
optic neuritis following smallpox vaccination and diphtheriatetanus toxoid. Am J Dis Child 1953;86:601–3. Kline LB, Margulies SL, Oh SJ. Optic neuritis and myelitis following rubella vaccination. Arch Neurol 1982;39: 443– 4. Stevenson VL, Acheson JF, Ball J, Plant GT. Optic neuritis following measles/rubella vaccination in two 13-year-old children [letter]. Br J Ophthalmol 1996;80:1110 –1. Kazarian EL, Gager WE. Optic neuritis complicating measles, mumps, and rubella vaccination. Am J Ophthalmol 1978;86: 544 –7. Albitar S, Bourgeon B, Genin R, et al. Bilateral retrobulbar optic neuritis with hepatitis B vaccination. Nephrol Dial Transplant 1997;12:2169 –70. Yen MY, Liu JH. Bilateral optic neuritis following bacille Calmette-Gue´ rin (BCG) vaccination. J Clin Neuroophthalmol 1991;11:246 –9. Stewart O, Chang B, Bradbury J. Simultaneous administration
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28. 29. 30. 31. 32.
of hepatitis B and polio vaccines associated with bilateral optic neuritis [letter]. Br J Ophthalmol 1999;83:1200 –1. Murphy J, Austin J. Spontaneous infection or vaccination as cause of acute disseminated encephalomyelitis. Neuroepidemiology 1985;4:138 – 45. Tezel G, Edward DP, Wax MB. Serum autoantibodies to optic nerve head glycosaminoglycans in patients with glaucoma. Arch Ophthalmol 1999;117:917–24. Smith PR, Cooper JM, Govan GG, et al. Antibodies to human optic nerve in Leber’s hereditary optic neuropathy. J Neurol Sci 1995;130:134 – 8. Luiz JE, Lee AG, Keltner JL, et al. Paraneoplastic optic neuropathy and autoantibody production in small-cell carcinoma of the lung. J Neuroophthalmol 1998;18:178 – 81. Guy J, Aptsiauri N. Treatment of paraneoplastic visual loss with intravenous immunoglobulin. Report of 3 cases. Arch Ophthalmol 1999;117:471–7.
independent advisory panel in 1985. Nevertheless, several service members are reluctant to receive the vaccine because of concern about adverse events. Recent surveys of service members who have received anthrax vaccine absorbed have failed to identify unexpected local reactions or systemic adverse events.5 This report documents two cases of optic neuritis after anthrax vaccination.
Case 1 A 39-year-old African American man presented with loss of vision in his right eye associated with pain on eye movement the day after receiving an anthrax booster vaccination. He received his initial anthrax vaccination on January 5, 1999, after which he experienced arm soreness lasting approximately 24 hours. One month after his initial vaccine, he began to experience a “spot” in the vision of his right eye. On February 11, 1999, he received his second dose of anthrax vaccine. The following day, he had a headache associated with pain on eye movement and an increase in the “spot” in the vision of his right eye. He was seen by an eye care provider the following day. His medical history was unremarkable. He had no other neurologic complaints. On initial examination, he had a visual acuity of 20/25 in the right eye and 20/20 in the left eye. A trace relative afferent pupil defect and decreased color vision were present in the right eye. On automated, static perimetry (Humphrey 24 –2), he had a superior visual defect and inferior nasal loss in the right eye (mean deviation, ⫺19.31 decibels) (Fig 1). The visual field of the left eye was normal. He had normal-appearing optic nerves in both eyes without swelling, hemorrhages, or pallor. A computed tomography scan of the orbits was normal. A magnetic resonance imaging (MRI) scan of the brain without contrast demonstrated three T2weighted hyperintensities involving the right centrum semiovale (Fig 2), the deep white matter of the parietal lobe, and the right frontal horn. No treatment was recommended. He returned on February 24, 1999, with worsening vision in the right eye. His visual acuity in the right eye was 20/40. He had a 2⫹ right relative afferent pupillary defect. On visual field testing of the right eye, his mean deviation was ⫺28.14 decibels (Fig 1). He had no optic nerve swelling. Examination of the left eye was normal, ISSN 0161-6420/02/$–see front matter PII S0161-6420(01)00844-2
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Ophthalmology Volume 109, Number 1, January 2002
Figure 1. Case 1. Visual fields (Humphrey 24 –2) performed 2 days after receiving anthrax booster vaccination demonstrate a superior visual defect and inferior nasal loss in the right eye and a normal examination of the left eye (top). Ten days later, the visual field in the right eye had worsened (middle). Approximately 3 weeks after initial presentation and after intravenous methylprednisolone, his visual field in the right eye was much improved (bottom).
although no visual field testing was performed. Laboratory evaluation included a complete blood count, thyroid-stimulating hormone, human immunodeficiency virus, rapid plasma reagin, antinuclear antibody, B12, and folate level, all of which were normal. His erythrocyte sedimentation rate was 2. Chest x-ray showed small scattered nodules without hilar adenopathy attributed to old granulomatous disease. Lumbar puncture revealed clear and colorless cerebrospinal fluid with normal glucose, protein, cell count, and differential. Cerebrospinal fluid Venereal Disease Research Laboratory test was negative, but oligoclonal bands were present. Routine aerobic and anaerobic bacterial cultures were negative. He was treated with intravenous methylprednisolone, 1000 mg a day for 5 days, followed by oral prednisone, 60 mg per day, for a total of 14 days. Over the next several days, he experienced improvement in his vision. On March 3, 1999, he had a visual acuity of 20/20 in the right eye, a trace right relative afferent pupillary defect, and a continued normal-appearing right optic nerve. His visual field in the right eye was markedly improved with a mean deviation of ⫺5.12 decibels (Fig 1). He has not received any further anthrax vaccinations. Over the 18 months after this episode, he had no further neurologic complaints. Follow-up MRI scans at 2 months and 9 months demonstrated no change.
Case 2 A 23-year-old African American man presented with bilateral loss of vision associated with orbital pain 2 weeks after anthrax booster vaccination.
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Figure 2. Case 1. A magnetic resonance imaging scan of the brain without contrast demonstrated a T2-weighted hyperintensity involving the right centrum semiovale (arrow). T2-weighted hyperintensities were also observed in the deep white matter of the parietal lobe and right frontal horn.
Within 2 weeks of his 6-month anthrax vaccination in April 2000, he had blurred vision develop in his left eye, worsening over 2 days and associated with pain on eye movement. Within the next few days, he had similar symptoms develop in his right eye. On May 5, 2000, ophthalmologic examination disclosed a visual acuity of counting fingers in the right eye and 20/30 in the left eye. He had a right relative afferent pupil defect and optic nerve swelling in both eyes. Vitreous cells were present inferiorly in the right eye, but no retinal perivascular inflammation was present. Antinuclear antibody, fluorescent treponemal antibody absorption test, rapid plasma reagin, rheumatoid factor, complete blood count, sedimentation rate, lysozyme, angiotensin-converting enzyme, and Lyme titers were either normal or unremarkable. Western blot of the patient’s serum with an extract of bovine retina and optic nerve revealed the presence of an antibody to a protein with a molecular weight of 200 Kd. Indirect immunohistochemistry on sectioned rhesus money eye with the patient’s serum showed immunologic reactivity extending from the nerve fiber layer into the optic nerve, as well as weak reactivity with components of the outer plexiform layer and the outer segments of photoreceptor cells. Western blot of a sample of anthrax vaccine with both rabbit antiretina serum and rabbit antioptic nerve serum failed to demonstrate cross-reactivity. Chest x-ray and gallium scan were normal. MRI scan of the brain with and without contrast was unremarkable. MRI scan of the spine showed no foci of demyelination. Lumbar puncture with
Kerrison et al 䡠 Optic Neuritis after Anthrax Vaccination
Figure 3. Case 2. Visual fields (Humphrey 24 –2) at the time of worsening during attempted slow steroid taper (top). After an intravenous methylprednisolone pulse, the reinstitution of oral steroids at a higher dose, and ultimately the addition of azathioprine as a steroid-sparing agent, he had improvement in his visual fields obtained 3 months later (bottom).
cerebrospinal fluid analysis demonstrated normal glucose, protein, cell count, and differential. No oligoclonal bands were present. He was treated with intravenous methylprednisolone, 250 mg four times a day for 3 days with no oral steroid taper, and his vision improved. On May 22, 2000, he had a visual acuity of 20/20 in each eye. Over the next week, he had worsening of the vision in his right eye associated with pain. By May 30, 2000, his visual acuity had deteriorated to no light perception in the right eye and 20/50 in the left eye. He was treated with 5 days of intravenous methylprednisolone, 1 g/day in divided doses, followed by 5 days of oral prednisone taper. By June 8, 2000, he had visual acuity of 20/100 in the right eye and 20/30 in the left eye. During gradual tapering of steroids on two further occasions, he had worsening vision (Fig 3), treated with pulse intravenous methylprednisolone followed by oral prednisone. He has begun azathioprine with a target dosage of 2 mg/kg/day and tapering of his steroids without relapse. He has not received any further anthrax vaccinations. Seven months after his initial episode, his visual acuity remains 20/40 in the right eye and 20/25 in the left eye with bilateral optic atrophy. He has had no further neurologic complaints.
Discussion Optic neuritis is a well-recognized complication of immunization, although it has not been reported after anthrax vaccination. Other ocular complications of vaccination include uveitis,6 –10 vaccinia keratouveitis after accidental ocular autoinoculation from a recent vaccination site,11 anterior ischemic optic neuropathy,12 and multiple evanescent
white dot syndrome.13 Neurologic complications of vaccination include seizures, Bell’s palsy, transverse myelitis, acute disseminated encephalomyelitis, and Guillian Barre´ syndrome.14,15 Optic neuritis may be a manifestation of acute disseminated encephalomyelitis,16 and isolated optic neuritis after immunization might be considered a forme fruste of acute disseminated encephalomyelitis. Optic neuritis has been most commonly reported after influenza vaccination6,17–20 but has also been reported with multiple other inoculations including smallpox vaccination combined with diphtheria-tetanus toxoid,21 rubella vaccination,22 combined rubella-measles vaccination,23 combined rubella-measles-mumps vaccination,24 hepatitis B vaccination,25 bacille Calmette-Gue´ rin vaccination,26 and simultaneous administration of hepatitis B and polio vaccines (Table 1).27 The ages of previously reported patients with optic neuritis after vaccination range from 6 to 61 at an interval after immunization of 5 to 21 days. Pain has been reported in 60%, bilaterality in 80%, and disc edema in 80% of previously reported cases of postvaccination optic neuritis. Although postvaccination optic neuritis is often a monophasic illness with excellent recovery, some cases have been associated with initial recovery followed by worsening after discontinuation of steroids22 or poor outcome.18,19,27 An MRI scan, performed in a limited number of previously reported cases,19,20,27 has been reported to be normal. The first case is similar to previous cases with regard to the presence of pain and its remitting, monophasic course. It differs from previously reported cases with regard to its unilateral nature and retrobulbar involvement. The patient initially noticed an abnormality in his vision approximately 1 month after vaccination but did not become fully symptomatic until after receiving booster immunization. Although the typical interval between vaccination and optic neuritis reported in the literature is approximately 1 to 3 weeks, acute disseminated encephalomyelitis may occur up to 1 month after vaccination.28 His presentation after a booster vaccination may represent an acute anamnestic response. The second case is consistent with prior reports of postvaccination optic neuritis with regard to the interval between vaccination and disease onset, the presence of pain, the anterior optic nerve involvement, bilaterality, and normal neuroimaging. It differs from previous cases in its chronicity, characterized by the need for long-term immunosuppressive therapy. Nevertheless, several reports of postvaccination optic neuritis have been associated with poor visual outcomes when not treated with long-term immunosuppression.18,19,27 Both patients underwent evaluation for causes associated with optic neuritis. Case 1 had a chest x-ray that was suggestive of prior granulomatous disease often attributed to Histoplasma exposure. In addition, the presence of T2weighted hyperintensities and oligoclonal bands would suggest an underlying diagnosis of multiple sclerosis, although these may be nonspecific features seen with an inflammatory, demyelinating process initiated by anthrax vaccination. Evaluation for other causes associated with optic neuritis in case 2 was unrevealing. Because optic neuritis occurs from other causes in the absence of immunization and the
101
Ophthalmology Volume 109, Number 1, January 2002 Table 1. Clinical Characteristics of Previously Author
Vaccine
Kline LB et al22
Rubella
Kazarian EL and Gager WE24
Measles/mumps/rubella
25
Albitar S et al
Hepatitis B
Yen MY and Liu JH26 27
Bacille Calmette-Gue´ rin
Stewart O et al
Hepatitis B/polio
Perry HD et al17
Influenza
Ray CL and Dreizin IJ20
Influenza
Hull TP and Bates JH19
Influenza
23
Stevenson VL et al
Measles/rubella
McReynolds WU et al21
Smallpox/diptheria/tetanus
Cangemi FE and Bergen RL18
Swine flu
Bienfang DC et al6
Influenza
Presenting Visual Acuity
Age (yrs)
Onset After Vaccine
20/25 RE 20/200 LE 20/25 RE Count fingers LE 20/200 RE 20/200 LE Count fingers RE Count fingers LE 6/18 RE 6/12 LE
31
5 days
Pain
6
3 wks
Pain
28
1 wk
Pain
12
5 days
No pain
44
1 wk
Pain
58
6 days
Pain
61
3 wks
No pain
59
2 wks
No pain
13
3 wks
Pain
7
2 wks
No pain
38
3 wks
No pain
27
3 wks
Pain
No light perception RE; Light perception LE 20/200 RE 20/40 LE LP RE LP LE 1/60 RE 6/36 LE 6/100 RE No light perception LE Count fingers RE 20/30 LE 20/15 RE 20/30 LE
Pain/ No Pain
LE ⫽ left eye; RE ⫽ right eye.
frequency of optic neuritis in this selected population is not known, it is not possible to definitively demonstrate a causeand-effect relationship based on case reports. The Vaccine Adverse Events Reporting System (VAERS) is used to evaluate adverse events potentially related to vaccinations. The Defense Medical Surveillance System consolidates VAERS reports related to anthrax vaccination for the Anthrax Vaccine Immunization Program. Between March 1998 and December 2000, 1984,785 doses of vaccine have been administered to 495,013 personnel (personal communication, LTC John D. Grabenstein, RPh, PhD, Nov. 30, 2000). Review of the VAERS database has revealed one other prior self-reported case of optic neuritis. Unfortunately, no other details are available. Other neurologic adverse events associated with the anthrax vaccination reported in VAERS include two cases of transverse myelitis and three cases of Guillian Barre´ syndrome. Assuming all cases of optic neuritis have been reported, the estimated incidence of optic neuritis is approximately 0.6/100,000 individuals undergoing immunization. Because optic neuritis does not necessarily represent an immediate complication, it may go unrecognized and be underreported. The pathogenesis of optic neuritis in these patients is presumed to be an immune-mediated response to optic nerve antigens stimulated by vaccination. Nevertheless, direct cross-reactive antibodies between anthrax vaccine and the patient’s retina/optic nerve are unlikely, because neither
102
antiretina antibodies nor antioptic nerve antibodies react with the anthrax vaccine. Thus, an epitope shared by both the anthrax vaccine and the retina/optic nerve was not detected. Although autoantibodies to retina and optic nerve were identified in case 2, they are of uncertain significance. Autoantibodies to retina and optic nerve have been reported in other optic neuropathies including glaucoma,29 Leber’s hereditary optic neuropathy,30 and paraneoplastic optic neuropathy.31 They may represent an epiphenomenon in response to nonspecific tissue damage.31 Both patients responded to immunosuppressive therapy with steroids, although case 2 required long-term therapy and was switched to azathioprine as a steroid-sparing measure. Another therapeutic option that may merit consideration in such patients is intravenous immunoglobulin32 or plasmapheresis. In summary, optic neuritis may occur after anthrax vaccination, although it seems to be a rare event. Although some patients may have a benign course with excellent visual recovery, others may require long-term immunosuppressive therapy to maintain vision. Retinal and optic nerve autoantibodies may be observed in postvaccination optic neuritis, although cross-reactive epitopes between the vaccine and retina/optic nerve were not identified. Acknowledgment. The authors thank LTC John D. Grabenstein, RPh, PhD, Deputy Director for Clinical Operations, Anthrax Vaccine Immunization Program Agency technical assistance.
Kerrison et al 䡠 Optic Neuritis after Anthrax Vaccination Reported Cases of Optic Neuritis after Vaccination Anterior/ Retrobulbar
Unilateral/ Bilateral
Treatment
Anterior
Bilateral
Prednisone, 40 mg/day
Anterior
Bilateral
Oral prednisone, 40 mg/day
Retrobulber
Bilateral
Prednisone, 1 mg/kg/day
Anterior
Bilateral
Anterior
Bilateral
Anterior
Bilateral
Anterior
Bilateral
Intravenous desamethasone, 5 mg every 6 hrs Intravenous methylprednisolone, 1 g/day, followed by oral prednisone, 1 mg/kg/day, with slow taper Bilateral retrobulbar methylprednisolone injection, 40 mg; oral prednisone, 40 mg twice a day Intravenous dexamethasone
Anterior
Bilateral
Intravenous corticosteroids
Anterior
Bilateral
Intravenous methylprednisolone
Anterior
Bilateral
Anterior
Unilateral
Corticotropin, 20 U every 8 hrs; mannitol hexanitrate, 15 mg every 8 hrs No treatment
Retrobulbar
Unilateral
Oral prednisone
Final Visual Acuity 20/20 RE 20/20 LE 20/20 RE 20/20 LE 20/25 RE 20/25 LE 20/15 RE 20/15 LE Count fingers RE Count fingers LE
Recurrence after initial treatment; encephalomyelitis developed
20/20 RE 20/20 LE
Worse during steroid taper, treated with oral steroids for a year
20/25 RE 20/30 LE 20/30 RE LP LE 6/5 RE 6/12 LE 6/6 RE 6/6 LE “Profound visual acuity loss persisted” “Normal visual acuity”
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