In November 2009, an 11-year-old boy had symptoms of upper respiratory tract infection, including cough, sore throat, and rhinorrhea. A rapid influenza diagnostic test showed a positive result for influenza A, suspicious of pandemic H1N1. Oral antiviral oseltamivir phosphate 75 mg (Tamiflu; Roche, Basel, Switzerland) was administered twice per day for 5 days with a smooth course of recovery. One month later, he developed ocular symptoms, including bilateral blurred vision, central scotoma, colorful spider-like illusion, ocular pain, photophobia, and red eyes. There were neither neurological or systemic symptoms nor a family history of neurological or ocular diseases.
On ocular examination, his best-corrected visual acuity was 20/20 in the right eye and 20/50 in the left eye. The intraocular pressure was 14 mm Hg bilaterally. His color vision was normal on Ishihara color test plates. Slit-lamp biomicroscopy showed 1+ cells in the anterior chamber and fine keratic precipitates in both eyes, and posterior synechia of the inferior iris in the right eye. There was no relative afferent pupillary defect. Funduscopy revealed bilateral disc edema, tortuosity and engorgement of retinal vessels, and macular star-shaped exudation in the left eye (Fig. 1A). Fluorescein angiography showed dye leakage at the optic discs (Fig. 1B). Optical coherence tomography showed bilateral disc edema and swelling of the peripapillary nerve fiber layers (Fig. 1C). Visual field testing revealed enlarged blind spots, central or paracentral scotomas, and arcuate defects in both eyes (Fig. 1D). The other physical and neurological examinations were unremarkable. Immunochemical studies showed elevated levels of serum complement component 3 (198 mg/dL; normal: 58 to 147 mg/dL), complement component 4 (35.9 mg/dL; normal: 11 to 35 mg/dL), erythrocyte sedimentation rate (20 mm/h; normal: 0 to 10 mm/h), and C-reactive protein (21.6 mg/dL; normal: 0 to 8 mg/dL). Hematological and biochemical examinations were normal. Magnetic resonance imaging of the head showed normal optic nerves.
Figure 1. (A) Fundus photographs at the initial ocular manifestation showing edema and hyperemia of bilateral optic discs, tortuosity and engorgement of retinal vessels, and macular star-shaped exudation in the left eye. (B) Fluorescein angiography showing dye leakage at bilateral optic discs. (C) Optical coherence tomography showing bilateral disc edema and swelling of peripapillary nerve fiber layers. (D) Visual field testing showing enlarged blind spots, central and paracentral scotomas, and superior and inferior arcuate defects. OD = right eye; OS = left eye.
Under the diagnosis of bilateral acute anterior uveitis, papillitis in the right eye, and neuroretinitis in the left eye, the patient was prescribed topical prednisolone acetate ophthalmic suspension eye drops (Pred Forte; Allergan, Irvine, CA) every 2 hours and intravenous methylprednisolone 5 mg/kg every 6 hours for 3 days, followed by a maintenance dose of oral prednisolone 0.4 mg/kg/day, with resolution of anterior chamber inflammation and retinal or disc findings within 1 week (Fig. 2A). At the 3-month follow-up, his corrected visual acuity improved to 20/20 in both eyes, with sequelae of residual visual field defects (Fig. 2B) and focal posterior synechia of the inferior iris in the right eye (Fig. 3).
Figure 2. (A) Fundus photographs 1 month after steroid pulse therapy showing resolution of optic disc edema and macular exudation. (B) Optical coherence tomography showing gradual improvement of optic disc edema. (C) Visual field testing 3 months later showing residual visual field defects. OD = right eye; OS = left eye.
Figure 3. Slit-lamp photograph of the right eye showing residual focal synechia between the iris and the anterior capsule of the lens at the inferior pupillary margin (arrow).
The current novel influenza A H1N1 virus has been pandemic since 2009; therefore, clinicians should be aware of its possible related complications. From a limited number of case reports, ocular complications following influenza include impaired ocular movement, paralysis of the parasympathetic ocular nerve, macular lesion, and frosted branch angiitis.3,4 Our patient was a boy diagnosed as having bilateral acute anterior uveitis, papillitis in one eye and neuroretinitis in the other eye. Papillitis constitutes 35% of cases with optic neuritis, and neuroretinitis is a more extensive form of papillitis. To the best of our knowledge, this case is the first report of acute anterior uveitis and optic neuritis after influenza A infection.
Uveitis is classified into anterior, intermediate, posterior, or pan-uveitis based on the anatomical involvement. Anterior uveitis is the most common form and acute anterior uveitis is the most common pattern. Acute anterior uveitis is well known to be induced by infection or autoimmune diseases.5 Influenza A virus has only once been reported as a pathogen directly causing panuveitis.6 However, because the onset of acute anterior uveitis in our patient was delayed, we suggest that it was caused by a postviral autoimmune response, which is different from those reported in the literature.5,6
On the other hand, optic neuritis is usually either idiopathic or associated with multiple sclerosis. Less commonly, it can accompany other systemic inflammatory disorders, such as systemic lupus erythematosus, polyarteritis nodosa, sarcoidosis, or Behçet disease.7 An unusual but underdiagnosed entity known as autoimmune optic neuritis (or autoimmune optic neuropathy) has serologic markers, such as antinuclear antibody and anticardiolipin antibody, but lacks clinical manifestations of a systemic collagen vascular disease.8 Rarely, optic neuritis has been reported as a neurological complication associated with viral or bacterial infection, such as hepatitis B, mumps, and Mycoplasma pneumoniae,9,10 or associated with vaccination for influenza, rabies, smallpox, diphtheria, and tetanus, as well as Bacillus Calmette–Guérin vaccines.11–14
Some other neurological complications of viral or bacterial infections include acute hemorrhagic leukoencephalitis, Guillain–Barré syndrome, transverse myelitis, brainstem encephalitis, acute disseminated encephalomyelitis, cerebellar ataxia, and central white matter disease.9,10,15 Most of these diseases related to infection or vaccination occurring predominantly in children.9–15 An autoimmune reaction has been proposed as the underlying pathogenic mechanism, which is supported by some reports that antibodies to myelin and neural tissue were detected in such diseases and neurological symptoms were ameliorated by plasmapheresis and removal of these antibodies.9 Although uveitis and optic neuritis have a variety of etiologies, the temporal association between the antecedent influenza A infection in our patient and his uveitis and optic neuritis raised the likelihood of ocular inflammation after infection related to influenza A. In addition, his abnormal immunochemical profiles (elevated levels of serum complement component 3, complement component 4, erythrocyte sedimentation rate, and C-reactive protein) support the mechanism of autoimmune-mediated pathogenesis.
Community studies indicate that school-aged children have the highest rates of influenza infection.2 Postviral optic neuritis also predominates in children and is typically bilateral and simultaneous in onset.16 However, the association between influenza infection and optic neuritis has not been well evaluated. According to previous reports, complications after influenza infection in children include acute otitis media, respiratory failure, febrile convulsions, sinusitis, myocarditis, and encephalopathy.2 We report this case to demonstrate that optic neuritis after infection, a rare ocular complication, can develop following influenza A infection. Children usually tend to neglect some symptoms, such as blurred vision, or unconsciously adapt to them, and are often unable to express their ocular discomfort exactly and early. This results in their problems being overlooked or misleads parents into believing that children have recovered from influenza infection. Therefore, the ophthalmologist should be aware of this and carefully examine the ocular conditions in pediatric patients.
Influenza A was confirmed in our patient by rapid influenza diagnostic test in November 2009 when H1N1 2009 was prominent and extremely prevalent world wide.1,2,17 According to the database of the Centers for Disease Control in Taiwan, 336 influenza A viruses collected from patients were examined at contracted laboratories for the subtypes and 302 (89.9%) of them were proved to be the pandemic H1N1 2009 virus.18 Therefore, although the subtype in our case was not identified, the pandemic H1N1 2009 subtype was highly suspected at this time. Even without viral culture or reverse transcription polymerase chain reaction, empiric antiviral therapy is recommended by the Centers for Disease Control and Prevention in the United States and in the literature,2 as seen in our patient. Our patient also responded well to pulsed-dose steroid therapy for 3 days, with smooth recovery from blurred vision and ocular inflammation beginning at 7 days of treatment. The marked response to steroids suggested an immune-mediated etiology as the underlying cause.
Although optic neuritis after infection or vaccination is often a monophasic illness with excellent prognosis after appropriate treatment,15 as in our case, some reports describe initial improvement followed by worsening after discontinuation of steroids, leading to a poor visual outcome.14 Thus, high-dose steroid therapy should be followed by a slow tapering off to avoid relapse or recurrence.
This 11-year-old boy developed acute anterior uveitis and optic neuritis 1 month after influenza A infection (probably the novel H1N1 strain), which alerts ophthalmologists to the unusual association between systemic infection and ocular inflammation. Although the pathogenic mechanisms remain to be elucidated, we suggest that influenza A infection be considered as a potential etiology for visual blurring and ocular inflammation within a few weeks after infection. In addition, high-dose steroid therapy is the treatment of choice and is often effective in these rare but potentially devastating ocular complications.