Vision-threatening complications in herpes zoster ophthalmicus: lessons from two unvaccinated patients with orbital apex syndrome

Herpes zoster ophthalmicus (HZO) is a vaccine-preventable neurocutaneous disease associated with vision- and life-threatening sequelae. Immunisation of eligible groups is critical, particularly among the elderly and immunocompromised in whom the risk of recurrent disease and complications is over twofold greater. Systemic antiviral treatment within 72 hours of rash is associated with significant reductions in the risk of postherpetic and ocular complications such as orbital apex syndrome (OAS), a vision-threatening complication characterised by ptosis, ophthalmoplegia and optic neuritis occurring secondary to varicella zoster virus (VZV) vasculopathy. We review presentations of HZO with secondary OAS in two elderly, immunocompromised and unvaccinated patients with devastating visual outcomes. We emphasise to physicians and ophthalmologists the importance of vaccination, the requirement for a multidisciplinary approach to antiviral and steroid therapy and the need for early recognition of significant neuro-ophthalmic sequelae.

Case 1

An 88-year-old male with a background of chronic lymphocytic leukaemia (CLL) in remission for 12 years presented to the emergency department with 7 days of left parietal headache and 4 days of vesicular rash in the distribution of the left ophthalmic nerve (V1). He was unvaccinated for shingles. Baseline visual acuity was 6/9 in the right eye and 6/12 in the left eye, with classic pseudodendrites on corneal fluorescein staining consistent with uncomplicated HZO. He was prescribed oral valaciclovir 1000mg three times daily and discharged for routine outpatient 5-day follow-up.

The patient re-presented the next day in new rapid atrial fibrillation and was transitioned to intravenous (IV) aciclovir 10mg/kg twice daily. At ophthalmic review on day 4 of admission, the left eye was found proptosed and anaesthetised with complete internal and external ophthalmoplegia, complete ipsilateral ptosis and total vision loss, consistent with dysfunction of cranial nerves II, III, IV, VI and the ophthalmic division of cranial nerve V. Secondary OAS was diagnosed (Figure 1, Figure 2).

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Computed tomography (CT) brain venogram was negative for cerebral venous sinus thrombosis (CVST), while magnetic resonance imaging (MRI) of the orbits with gadolinium contrast demonstrated classical findings of OAS (Figure 3). A multidisciplinary team of neurologists, ophthalmologists, infectious diseases physicians and general medical physicians commenced 3 days of IV methylprednisolone 1000mg with step-down to oral prednisolone 50mg in a 6-week taper, with 2-weeks of IV aciclovir followed by 1 week of oral valaciclovir 1000mg three times daily.

Twenty-one weeks after rash onset, the patient’s ophthalmoplegia partially resolved with a residual 25% deficit in left eye abduction and persisting partial ptosis. The left pupil remained fixed and dilated, and the eye was non–light perceiving.

Case 2

A 77-year-old male with a background of CLL under surveillance presented to the emergency department with a 3-day history of severe, left-sided, pulsatile headache refractory to opioid analgesia and triptans. He was unvaccinated for shingles. Initial CT and MRI of the brain were unremarkable. The patient was admitted for analgesic optimisation, with cluster headache, status migrainosus and trigeminal autonomic cephalalgia the differential diagnoses.

On day 9 of admission a new vesicular rash was noted in the distribution of the left ophthalmic nerve with significant pseudodendrites on corneal fluorescein staining, consistent with HZO. Baseline visual acuity was 6/9 in the right eye and 6/24 in the left. He was commenced on IV aciclovir 10mg/kg three times daily for 2 weeks in the context of immunosuppression. Vesicular lesion swab polymerase chain reaction testing was positive for VZV DNA.

On day 13 of admission, the patient noted subjective visual deterioration. The left eye demonstrated complete ptosis, and complete internal and external ophthalmoplegia, except in abduction with a 25% deficit (Figure 2). Visual acuity was count-fingers in the affected left eye. Secondary OAS was diagnosed, with the diagnosis subsequently confirmed by MRI of the brain (Figure 3). In consultation with a multidisciplinary team, the patient received pulse IV methylprednisolone 1000mg for 5 days with step-down to oral prednisolone 75mg in 6-week taper, with 2 weeks of IV aciclovir.

Six weeks after rash onset, best corrected left eye visual acuity had significantly improved to 6/24. Extraocular muscles demonstrated normal abduction, with a 50% residual deficit in elevation and depression and 100% deficit in adduction.

Discussion

Herpes zoster (shingles) is a vaccine-preventable neurocutaneous disease characterised by reactivation and retrograde migration of latent VZV within sensory ganglia. The lifetime risk of shingles is 20–30% among the general population,¹ while the incidence and recurrence rate is over twofold greater among the elderly and immunocompromised.^2,3 HZO is characterised by reactivation within the ophthalmic division of the trigeminal nerve and is the second most frequent distribution after thoracic disease, accounting for 10–20% of cases.¹ Ocular involvement occurs in 50% with HZO within 6 months of rash onset, with a reduction to 30% following appropriate antiviral use.⁴ Keratitis and anterior uveitis are common, while more significant complications include neurotrophic keratopathy and acute retinal necrosis.¹ Hutchison’s sign (cutaneous involvement of the lateral dorsum, tip or root of the nose) strongly suggests ocular involvement.⁵ Postherpetic neuralgia occurs in 47.5% of patients with shingles 70 years and older, and is thought to affect patients with HZO more frequently than other dermatomal distributions.^1,6

OAS is an exceedingly rare yet sight-threatening neuro-ophthalmic complication of HZO characterised by dysfunction of cranial nerves II, III, IV, VI and the ophthalmic division of cranial nerve V. Of uncertain incidence, the hallmarks of disease are complete unilateral ptosis, internal and external ophthalmoplegia and reduced visual acuity, typically occurring within 4 weeks of rash onset.⁷ While the true pathophysiology of OAS remains unclear, VZV vasculopathy is postulated to be the underlying mechanism, with ischaemic optic and cranial neuropathies developing secondary to an occlusive vasculitis.^7,8

No specific risk factors for secondary OAS have been identified, although affected patients tend to be older and present with delayed treatment initiation, as in our cases.⁸ High-resolution MRI with gadolinium contrast and fat-suppressed sequences is essential for both diagnostic clarification and to exclude more common aetiologies of OAS such as trauma, haemorrhage and CVST.⁷ Typical findings include enlargement of the extraocular muscles and diffuse post-contrast enhancement of the orbital apex involving the optic nerve (Figure 2).⁸ The visual prognosis is poor; while approximately 90% demonstrate improvements in extraocular motility, 50% retain irreversibly poor visual acuity,⁷ as in our cases.

Vaccination of eligible populations is critical. Recombinant VZV glycoprotein E vaccination (RZV, Shingrix, GlaxoSmithKline) is recommended for use in patients 50 years and older and immunocompromised patients 18 years and older. As of December 2022, Shingrix has replaced live-attenuated vaccination (Zostavax, Merck & Co.) on the National Immunisation Schedule Wātaka Tuku Awhikiri ā-Motu,⁹ surpassing it in both efficacy and duration of immunity.¹⁰ A recent retrospective cohort study of over 170,000 individuals in the United States of America who received 2 doses of RZV identified an overall adjusted effectiveness of 89.1% against HZO in clinical settings.¹¹ Contrastingly, caution is suggested when considering vaccination in patients with a history of HZO, in whom RZV is associated with a higher likelihood of HZO recurrence within 56 days of vaccination.¹²

Management of uncomplicated HZO in immunocompetent patients is 7 days of systemic antivirals, with ophthalmic referral being mandatory.⁷ Treatment within 72 hours of rash onset is strongly associated with a reduced incidence of postherpetic complications.⁷ For OAS, no unifying treatment regimen has been defined. Multidisciplinary care with systemic antivirals and steroids in an empirical tapering pattern over 2–6 months appears routinely within the literature.⁸ Although not statistically significant, treatment within 72 hours of rash onset appears correlated with improved visual recovery.⁷ This may explain the contrasting visual outcomes in our cases.

Conclusion

HZO is a common neurocutaneous disease associated with vision-threatening sequelae. Both clinicians and patients should remain vigilant for new-onset ptosis, ophthalmoplegia and reduced visual acuity within 4 weeks of rash onset, which should prompt urgent consideration of OAS, a rare and sight-threatening complication occurring secondary to VZV vasculopathy. Recombinant zoster vaccination is critical in eligible populations, especially the elderly and immunocompromised.