Acute retinal necrosis by herpes simplex virus type 1: an unusual presentation of a primary infection

Abstract

Herpes simplex virus (HSV) can affect the central nervous system causing meningitis, encephalitis and, rarely, acute retinal necrosis. We present a case of a 46-year-old man, previously healthy complaining of a 5-day persistent headache and sudden loss of vision of his left eye that progressed to the right. We started ceftriaxone, methylprednisolone and acyclovir for suspected encephalitis with vasculitis. HSV-1 was identified in vitreous and aqueous humour. Therapy with acyclovir was maintained and two intravitreous boluses of foscarnet were administered, without improvement. Usually being a benign infection, HSV can, in rare cases like this, have catastrophic effects in the optic tract.

Background

According to the WHO about 3.7 billion people, under the age of 50 years, are infected by herpes simplex virus (HSV). Usually associated with oral transmission, most individuals are asymptomatic carriers and some present occasionally symptomatic reactivation of the infection. Rarely, HSV can affect the central nervous system causing meningitis or encephalitis.¹

It can also cause acute retinal necrosis (ARN) that presents with uveitis, occlusive vasculitis and necrosis of the retina, ultimately leading to retinal detachment, optic nerve atrophy and severe vision loss.² Previous studies report an incidence of 1 case per 1.6–2.0 million people, usually associated with viral encephalitis.³ There is an equal gender distribution of the disease and most cases occur between the fifth and seventh decades of life.⁴

Several cases of ARN related to herpes simplex viral encephalitis have been well described; however, bilateral ARN is a very rare complication, especially without previous encephalitis.⁵ In none of the case reports, a bilateral ARN was observed as first presentation of herpes simplex infection, representing an even rarer case than the ones already described in most of the literature.

Case presentation

We present a case of an otherwise healthy 46-year-old man, admitted to the emergency department complaining of a 5-day persistent headache and sudden loss of vision of his left eye. In the following 48 hours, his status worsened with further loss of visual acuity of the left eye (OS) and right eye (OD) involvement. At presentation, best-corrected visual acuity (BCVA) was counting fingers (CF) bilaterally (OU). Physical and neurological exams were unremarkable. No meningeal signs were observed. The ophthalmological examination revealed bilateral optic nerve oedema, moderate vitritis, multiple retinal haemorrhages, peripheral areas of retinal oedema with severe vasculitis and macular involvement (figures 1 and 2). He was admitted in the infectious diseases department for treatment and further investigation. The patient started intravenous ceftriaxone, methylprednisolone and acyclovir for a possible encephalitis with associated vasculitis. However, there were no signs of improvement.

Figure 1.

Right eye fundus photograph on admission.

Figure 2.

Left eye fundus photograph on admission.

Investigations

The cerebral spinal fluid (CSF) analysis revealed 155 leucocytes with a predominance of lymphocytes with normal protein and glucose level. The blood serology for HSV-1 was negative, with no indication of previous infection by this virus. Blood, urine and CSF cultures and PCR were negative. All the autoimmune testing came back negative at this point. Brain MRI showed flair and T2-weighted hypersignal of both optic pathways with associated oedema of the optic nerve after contrast administration (figure 3). It was decided to perform an anterior chamber paracentesis for PCR analysis in order to search for an infectious agent. DNA of HSV-1 virus was identified. It was then diagnosed a bilateral ARN caused by HSV type 1.

Figure 3.

Hypersignal of the optic pathways in MRI with T2 ponderation.

Treatment

Therapy with intravenous acyclovir was maintained for 1 month and two intravitreous injections of foscarnet (2.4 mg/0.1 mL) were administered in both eyes. The patient was submitted to prophylactic panphotocoagulation in both eyes but unfortunately developed bilateral retinal detachment. During retinal detachment repair surgery, vitreous humour was obtained and sent for PCR analysis, which also confirmed the presence of HSV-1 DNA. Both eyes underwent vitrectomy, endolaser and silicone oil tamponade.

Outcome and follow-up

The patient was discharged 1 month after admission and maintained treatment with valacyclovir for 6 months. By the second month of follow-up, positive serology for HSV-1 was detected. An attempt was tried to remove silicone oil several months after the first surgery in the right eye, unfortunately, shortly after the procedure a retinal redetachment was detected, and the patient underwent new vitrectomy with silicone oil tamponade. The patient remains with silicone oil OU due to the high risk of retinal detachment and final BCVA is CF OU. The patient maintained regular follow-up in both infectious diseases and ophthalmology consultations.

Discussion

Although being a benign infection, HSV-1 can, in rare cases like this one, have catastrophic effects. In several case reports, it has been showed that ARN can present after a herpes simplex encephalitis or meningitis. In our case, the patient presented only with headache and loss of visual acuity. Normally, HVS encephalitis is characterised by altered mental status, confusion, somnolence or confusion, as well as, abnormal signals in the MRI of the temporal lobes, none of which were observed in this patient and make the diagnosis highly unlikely. However, even though the patient did not have fever, nausea, vomiting, lethargy or neck hypertonicity/stiffness, the increased cellularity with the predominance of lymphocytes in the CSF, makes it difficult to rule out a possible HVS-1 concomitant meningitis although the lack of identification of the virus in the CSF PCR.

According to the WHO, the number of people infected by HSV-1 is very high, being ~3.7 billion.¹ However, our patient presented a negative initial serology for HSV-1 (both IgM and IgG), that only became positive 2 months after this episode. The patient also referred that he never had symptoms compatible with HSV-1 infection before, which led us to believe that the ARN was the presentation of a primoinfection. As far as we know, there is no reported case in the literature of ARN with or without meningitis/encephalitis as a first presentation of an HSV-1 infection. A recent case report has been published describing a rare presentation in a patient who first was diagnosed with ARN and posteriorly with encephalitis, but the authors do not specify if it represents a primoinfection.⁶

Some cases have already been described, in which the interval between meningitis and ARN varied from 14 days to about 5 weeks.⁴ However, our patient was previously healthy, apart from a respiratory tract infection 2 weeks before. Even though this event might not have a direct correlation to the ARN, it can be the predisposing factor due to an alteration in the immune status of the patient. A recent retrospective study suggests that brief periods of immune compromise can lead to the development of ARN, especially in situations like pregnancy, surgery, vaccination and administration of immunosuppressive drugs.⁷ Unilateral disease is more commonly reported in cases of ARN, nevertheless, bilateral involvement can occur in 1/3 of patients, 1–6 weeks after the first eye. Bilateral presentation of ARN is more predominant in neonates and immunosuppressed individuals than in immunocompetent patients.⁸ However, in our patient, none of the studies performed revealed any primary or acquired immunosuppressive disease that could justify such an aggressive evolution.

This case represented a diagnostic and therapeutic challenge, due to its uncommon presentation, evolution and paucity of results. The spinal tap fluid only revealed an increased lymphocyte count, with all PCR analysis negative for viral encephalitis. Brain MRI, as in several of the reports, revealed a hypersignal of the optic pathway in the T2 and Flair-weighted images.⁸ The diagnosis was confirmed by PCR analysis for HSV-1 of the vitreous and aqueous humour, both sterile ocular fluids. A recent study correlated the clinical outcome with the quantitative DNA PCR, in which they found that a number of copies superior to 5.0×10⁶/mL was associated with a more extensive retinal disease, worse visual acuity and a higher probability of retinal detachment.⁹ In our case, the quantitative DNA of HSV-1 was not performed so there was no way of predicting the outcome of the patient. However, the macular and optic nerve involvement as well as retinal detachments in both eyes predicted a poor visual prognosis with very little chance for improvement.

We started treatment with intravenous acyclovir on admission and it was continued until discharge. However, with the progressive worsening of the visual acuity, it was our option to administer foscarnet in the left eye. There are no evidence-based guidelines for the treatment of ARN, but many centres with extensive experience recommend the treatment with both intravitreal and intravenous approach.⁷ Still, the doubt remained as to whether antiviral therapy should be maintained orally after discharge, changed or discontinued. The decision, after extensive literature research, was to continue valacyclovir for at least 6 months, even though there was no certainty of improvement of the visual acuity. The use of corticosteroids is also controversial. In the one hand, they are very helpful in decreasing the inflammation of the ARN and associated vasculitis, but on the other hand there are some reports of corticosteroid therapy worsening the necrotising retinopathy.^{8 10}

There is still much to learn about pathophysiology of the HSV-1 infection and several pathways for the migration of the virus in ARN have been hypothesised. When it comes to HSV encephalitis one of those pathways is the migration from the suprachiasmatic nucleus along the optic nerve to the retina, via retrograde axonal transport; other might be that the active virus present in the medial temporal lobes can be transported axonally to the retina through the optic nerve pathway.⁴

Furthermore, there is still no consensus in the literature on how to manage these patients, how to treat them or how to perform follow-up. Consequently, we conclude that it should be an individualised decision based on the extent of disease, severity of symptoms and disease progression. The volatile nature of this virus can sometimes cause severe complications that are difficult to diagnose and treat. Therefore, it is very important for clinicians to always consider herpes virus infection when a patient presents with extensive ARN, even with negative serologies.

Learning points.

• Bilateral acute retinal necrosis (ARN) is an uncommon presentation of a herpes simplex virus 1 infection. Differential diagnosis of progressive worsening of visual acuity should include ARN caused by herpes virus simplex infection.

• A multidisciplinary approach, with the collaboration of the infectious diseases and ophthalmology departments, was essential in the management of the treatment and complications arising from this infection.

• There are no guidelines or consensus on how to treat these patients because of the severity and rarity of the presentation of the disease. Patient should be referenced to infectious diseases or ophthalmology specialists and should be managed on a case-by-case basis.