Anterior ischemic optic neuropathy following dengue fever.

Dengue fever is caused by a flavivirus. This infection is endemic in the tropics and warm temperate regions of the world. Ocular manifestations of dengue fever include subconjunctival, vitreous, and retinal haemorrhages; posterior uveitis; optic neuritis; and maculopathies, haemorrhage, and oedema. However anterior ischemic optic neuropathy is a rare presentation. Optic nerve ischemia most frequently occurs at the optic nerve head, where structural crowding of nerve fibers and reduction of the vascular supply may combine to impair perfusion to a critical degree and produce optic disc oedema. Here we present a case of anterior ischemic optic neurapathy associated with dengue fever.

Introduction

Dengue fever (DF) is caused by flavivirus which is borne by the Aedes mosquito. The infection is endemic in the tropics and warm temperate regions of the world. The highest incidence occurs in Southeast Asia, India, and the American tropics. Worldwide cases of illness exceed 100 million/year.[12] Ocular manifestations of DF include subconjunctival, vitreous, and retinal hemorrhages; posterior uveitis; optic neuritis; and maculopathies, hemorrhage, and edema. After reviewing the literature, this case, to the best of our knowledge, is a rare presentation of unilateral anterior ischemic optic neuropathy (AION) following DF, which has not been reported so far.

Case Report

A 62-year-old male presented to us with a complaint of painless diminution of vision in his left eye, which he noticed for 3 months. He gave a history of hospital admission nearly 3 months back for fever with chills which was intermittent in nature and associated with body ache and pain on the right side of the abdomen, following which the diminution of vision occurred. He was diagnosed to have DF. His medical records during the hospital admission revealed a total count of 2800, reduced platelet count of 36,000/cumm, low packed cell volume of 32%, and a positive NS1 titer for dengue, which were normalized after the treatment with intravenous fluids and administration of antipyretics. His records also showed episodes of hypotension during the hospital stay. Ultrasonography report of the abdomen revealed free fluid in perihepatic, right-sided Morrison's pouch and perisplenic areas.

On examination, his visual acuity in the right eye was 6/9 and in the left eye was 6/12 with the best-corrected visual acuity of 6/6 in the right eye and 6/9 in the left eye. Examination of pupillary reflexes showed left Marcus Gunn pupil. Rest of the anterior segment was normal. Color vision was normal in both the eyes. Intraocular pressure taken with Perkins tonometer was 12 mmHg in both the eyes. Dilated fundus examination showed normal fundus of the right eye. The left eye showed pallid disc edema with obliteration of the cup [Figures 1 and 2]. Blurring of the disc margins was present. Macula and periphery appeared normal. Static visual field testing (the Humphrey Field Analyzer central 30–2 threshold test; Carl Zeiss Meditec AG, Oberkochen, Germany) showed no abnormalities in the right eye; however, the left eye showed inferior altitudinal scotoma [Figure 3]. Optical coherence tomography (OCT) of the optic nerve head was performed using Cirrus HD-OCT Model 500 (Carl Zeiss Meditec AG). The right eye OCT was normal. Retinal nerve fiber layer was thickened in the left eye and obliteration of the optic disc cup was present [Figure 4]. Visual evoked potential (VEP) was carried out which showed a prolonged P100 latency of 136 ms and a decreased amplitude of 3.8 μV. Responses from the inferior field following the inferior field stimulation of the left eye were not recordable and correlated the results of the visual field testing. Blood investigations were repeated which showed C-reactive protein value of 2.8 mg/L, erythrocyte sedimentation rate of 32 mm/h, total count of 5600, and 1.29 lakhs/cumm platelets. A diagnosis of anterior ischemic optic neuropathy secondary to DF was established. A trial of oral prednisolone 1 mg/kg body weight was given for 2 weeks. His vision in the left eye recorded after 2 weeks was 6/18, however, slight disc edema persisted.

Figure 1

Fundus picture of the left eye

Figure 2

Fundus picture of the left eye using red-free filter

Figure 3

Static visual field testing (the Humphrey Field Analyzer central 30-2 threshold test; Carl Zeiss Meditec AG, Oberkochen, Germany) showing inferior altitudinal scotoma in the left eye

Figure 4

Optical coherence tomography of the optic nerve head using Cirrus HD-OCT Model 500 (Carl Zeiss Meditec AG) showed thickening of the retinal nerve fiber layer and narrowing of the optic disc cup in the left eye

Discussion

DF is caused by the dengue virus, a flavivirus, of which there are four serotypes (DEN 1, 2, 3, and 4), and is transmitted by the Aedes aegypti mosquito. It is considered to be one of the most important arthropod-borne diseases in the tropical and subtropical regions.[3] Clinical manifestations range from asymptomatic infection to DF, dengue shock syndrome, and dengue hemorrhagic fever. It presents with fever for 2–4 days, headaches, myalgia, and thrombocytopenia, resulting in bleeding manifestations such as a purpuric rash, positive tourniquet test, epistaxis, and hematemesis. Hypotension may also occur in the dengue shock syndrome which carries a high mortality rate.[3] DF is associated with thrombocytopenia (<100 × 109 cells/L) and hemoconcentration (hematocrit >20% above baseline).[4]

The pathogenesis for ophthalmic complications in DF is not much understood. Ophthalmic signs can occur secondary to a bleeding diathesis. Interstitial dendritic cells located in the epithelia are believed to constitute the first line of the defense against invading dengue virus after the initial bite by an infected mosquito. Dendritic cells, which are the antigen-presenting cells, carry the viral antigens and migrate to regional lymph nodes. Natural killer (NK) cells proliferation and activation are thus induced by the interferon (IFN) α/β present in the virus-infected cells and dendritic cells. Early activation of NK cell and IFN-dependent immunity may be important in limiting viral replication at the early time of dengue infection.[5] Infection of cells with dengue virus has been postulated to cause a shift in the balance of the cell-mediated immunity from TH1 and TH2, resulting in CD4/CD8 inversion and release of proinflammatory mediators including IFN and tumor necrosis factor-alpha that can directly affect vascular endothelial cell causing apoptosis and resultant increased vascular permeability. Autoantibodies against endothelial cells and platelets as a result of increased interleukin-6 production or molecular mimicry against dengue virus structural proteins have also been reported. Other postulates include viral mutations, viral virulence, and thost susceptibility.[67] Increased vascular permeability due to immune-mediated cytokine release can account for macular edema. During dengue viremia, the immune-mediated injury to the vessel wall, due to immune complex deposition, may lead to vasculitis. Dengue viremia may be the triggering factor for immune complex formation in patients who are predisposed to developing autoimmune disease.[8]

There are three stages of clinical presentation, namely, febrile, toxic, and convalescent.[4] The patients initially develop an abrupt onset of high fever (39–40°C) with malaise, headache, nausea, vomiting, myalgia, and sometimes, abdominal pain. During the acute febrile stage, which lasts 2–7 days, hemorrhagic manifestation is invariably present but usually mild. Petechial hemorrhage on the skin is commonly found. DF has also been found to affect the eyes, with resultant loss of vision. The most common ocular involvement reported in an East Indian population was a petechial type of subconjunctival hemorrhage (37%), which was associated with a platelet count of <50,000 μl.[9] The fundal manifestations typically occur 1 week after the onset of fever, just as the fever has settled, and the platelet count is recovering.[101112] It generally presents bilaterally. The main fundal findings[13] were retinal hemorrhage (45%), venular sheathing (45%), yellow subretinal dots (28%), retinal pigment epithelium mottling (17%), round foveal swelling (foveolitis) (16%), disc hyperemia (14%), disc edema (11%), and arteriolar sheathing (4%). The prevalence of dengue maculopathy among patients hospitalized for DF was 10%.[14]

The differential diagnoses that came to our mind, in this case, were optic neuritis and AION. However, our patient had presented with painless diminution of vision, unilateral pallid disc edema, and inferior altitudinal scotoma, which are more in favor of AION.

Further investigations of OCT and VEP also supported our diagnosis.

Optic nerve ischemia most frequently occurs at the optic nerve head, where structural crowding of nerve fibers and reduction of the vascular supply may combine to impair perfusion to a critical degree and produce optic disc edema. The most common such syndrome is termed “anterior ischemic optic neuropathy” (AION).[15] In general, AION is categorized as either arteritic (associated with temporal arteritis) or nonarteritic. Nonarteritic AION (NA-AION) is most often idiopathic, but specific etiologies such as systemic hypotension and radiation injury have been identified.

Arteritic anterior ischemic optic neuropathy (A-AION) results from the short posterior ciliary artery vasculitis and the resultant optic nerve head infarction. Segments of these vessels in some cases were occluded by inflammatory thickening and thrombus.[16] NA-AION has a rapid onset, stable course with generally poor recovery, association with vasculopathic risk factors, and similarity to A-AION has implied a vascular cause for NA-AION as well. The most commonly proposed pathogenic theory states that insufficiency of the optic disc circulation, exacerbated by structural crowding of nerve fibers and supporting structures at the nerve head, eventually reaches a point at which inadequate oxygenation produces ischemia and swelling of the disc. These features may be mild and subclinical (no visual loss), reversible to some degree, or irreversible (infarction). In some cases, a cycle of ischemia, axonal swelling, microvascular compression, and further ischemia may lead to progressive nerve damage.

Many systemic factors, including surgical procedures, may cause blood flow reduction in the posterior ciliary artery. The other risk factors of AION are high serum cholesterol, triglycerides, hyperlipidemia, hyperfibrinogenemia, prolonged smoking history, hypertension, and diabetes mellitus.[17] NA-AION is the most common type of ischemic optic neuropathy. It is of two types. In the first type, transient nonperfusion or hypoperfusion of the optic nerve head circulation occurs. This is by far the most common cause of NA-AION. Transient nonperfusion or hypoperfusion of the optic nerve head circulation can be caused by a variety of factors. Available evidence indicates that in the vast majority of cases, it is a transient fall of blood pressure, most commonly during sleep (nocturnal arterial hypotension) or a nap during the day, or shock. A transient fall of perfusion pressure (perfusion pressure = mean blood pressure minus intraocular pressure) in the optic nerve head capillaries below the critical autoregulatory range in susceptible persons results in ischemia of the optic nerve head and development of NA-AION. The second type occurs due to embolic lesions of the arteries/arterioles feeding the optic nerve head. This is a rare cause of NA-AION. Compared to the hypotensive type of NA-AION, the extent of optic nerve head damage in this type is usually massive, severe, and permanent, depending on the size of the artery involved and the area of the nerve supplied by the occluded artery.

Various drugs such as IFNs and sildenafil are known to cause AION by deposition of the immune complexes in the optic disc circulation[181920] or by decreasing the optic nerve head perfusion by interfering with the autoregulation of blood flow.[21] However, the drugs used in the treatment of DF have not been documented so far to cause any effect on the optic nerve or its perfusion.

Anterior ischemic optic neuropathy associated with DF is a rare manifestation. Usually, the initial presentation is often unilateral. Bilateral simultaneous AION is more commonly arteritic. The cause of AION in our patient has been unknown. It could be thought to occur due to the inflammatory changes in the vascular endothelium resulting in vascular leakage. The ischemia can be the result of hypovolemia or vasculitis caused by immune-mediated damage due to dengue viremia. However, there is also a possibility that the AION in our patient could be a coincidental finding. Treatment with steroids is justified as the dengue virus incites an immune-mediated damage to the vessels. However, the clinical systemic condition has to be considered as it is to be used with caution in acute viremia. Visual recovery, in the form of improvement of signs and symptoms, may take several weeks to reach a steady state.

Conclusion

Thus, we conclude based on the presented case and the published data that AION can occur in association with DF. DF can lead to visual impairment which can be detectable by ophthalmological examinations. However, the ocular complications of dengue are usually overlooked because of improper examinations. Hence, a thorough ophthalmological examination of a person having DF should be included in the clinical practice.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.