Herpes zoster in neuro-ophthalmology: a practical approach

Abstract

Herpes Zoster (HZ) or shingles is the reactivation of the Varicella Zoster Virus (VZV), usually along a single sensory nerve, but can affect both sensory and motor cranial nerves. Major risk factors for HZ include immunosuppressed status and age older than 60 years. In the United States, the lifetime risk of HZ is approximately 30%. Worldwide, the median incidence of HZ is 4–4.5 per 1000 person-years across the Americas, Eurasia, and Australia. HZ ophthalmicus, occurring in 10–20% of patients, is an ophthalmic emergency characterized by VZV reactivation along the V₁ branch of the trigeminal nerve. Approximately half of this patient subgroup will go on to develop ocular manifestations, requiring prompt diagnosis and management. While anterior segment complications are more common, neuro-ophthalmic manifestations are rarer and can also occur outside the context of overt HZ ophthalmicus. Neuro-ophthalmic manifestations include optic neuropathy, acute retinal necrosis or progressive outer retinal necrosis, cranial neuropathy (isolated or multiple), orbitopathy, and CNS manifestations. Although typically a clinical diagnosis, diagnosis may be aided by neuroimaging and laboratory (e.g., PCR and serology) studies. Early antiviral therapy is indicated as soon as a presumptive diagnosis of VZV is made and the role of corticosteroids remains debated. Generally, there is wide variation of prognosis with neuro-ophthalmic involvement. Vaccine-mediated prevention is recommended. In this review, we summarize neuro-ophthalmic manifestations of VZV.

Introduction

Herpes zoster (HZ), commonly referred to as shingles, is the reactivation of latent varicella zoster virus (VZV) infection generally in the context of declining cell-mediated immunity [1]. A ubiquitous entity, the clinical course of VZV involves initial development of varicella (chickenpox) before latent re-manifestation as HZ in later life [1]. In the United States alone, approximately one million cases of HZ arise per year, and worldwide, a conservative estimate of 14.9 million cases occurred in 2020 [2, 3]. Among the greatest risk factors for HZ include advancing age, especially among adults older than 60 years, and immunosuppression [4]. In ophthalmology, relevant complications of HZ include postherpetic ophthalmic neuralgia, herpes zoster ophthalmicus (HZO), anterior segment involvement, and neuro-ophthalmological sequelae [5]. HZO is a commoner outcome of HZ and can result in ocular inflammation including conjunctivitis, uveitis, and keratitis [5]. However, in the context of this review, we provide a brief overview of epidemiology, pathophysiology, diagnosis, and management of HZO and focus on the rarer neuro-ophthalmic manifestations of HZ, which may or may not coincide with symptoms and signs of HZO. Herein, we first overview the epidemiology, pathophysiology, diagnosis, and management of HZ, before describing neuro-ophthalmic manifestations in further detail.

Disease entity and general pathophysiology

Human herpesvirus 3, known as varicella-zoster virus (VZV), is transmitted by expulsion of airborne virulent particulates (coughing and sneezing) or contact with viral shedding (from blisters, saliva, and mucus) [6]. In primary infection, known as chickenpox, the exposure precedes skin lesion eruption by 1–2 days, after which the lesions typically crust over 7–10 days thereafter [6].

Although primary infection (chickenpox) usually self-resolves, the VZV virus is not completely eliminated by the immune response and instead resides in latent refuge within dorsal sensory, autonomic or cranial nerve ganglion cells of the central nervous system [7–9]. Often decades after index infection, reactivation and viral replication occurs with antegrade transport of virions along the affected neuronal distribution [10]. This results in dermatomal vesicular rash, severe pain, and nearby tissue inflammation. While the mechanism behind VZV reactivation in HZ is not completely understood, it is generally thought that reactivation coincides with declining T-cell-mediated immunity, often seen with older age and immunocompromised [11].

HZO refers to VZV reactivation along the ophthalmic (V₁) division of the trigeminal nerve, manifesting as a unilateral vesicular rash along its distribution, with or without involvement of the eye and ocular adnexa. In cases of acute viral toxicity of ocular structures, anterior segment structures are usually afflicted first, although in rarer cases, inflammation may extend to posterior structures to involve the retina, choroid, ocular vasculature, optic nerve, and central nervous system [12].

Epidemiology

According to one review of 130 studies across 26 countries, the incidence of HZ is approximately 3–5/1000 person-years in populations in North America, Europe, and Asia-Pacific [5]. The lifetime risk is thought to range between 10 and 30%, although this estimate markedly rises to 50% among those older than 85 years [13]. Of more recent concern, occurrences of HZ appear to be increasing over time with the incidence rate in 1993 increasing from 2.5 cases per 1000 persons to 7.2 per 1000 persons by 2016 [3]. After the first episode of HZ, between 1 and 6% of patients experience recurrent outbreaks [5]. HZ-related hospitalization rates are estimated to range between 2 and 25/100,000 person-years with elderly populations comprising the highest at-risk group [5]. Among elderly patients, the mortality rate may range between 0.0022 and 82.21 per 100,000 [14].

Strong risk factors for HZ include immunosuppression, family history, advancing age, and physical trauma [15]. Other clinically relevant risk factors include female sex, non-African race, psychological stress, and various systemic diseases (e.g., diabetes, cardiovascular and renal morbidity, rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease) [15, 16]. Of note, HZ does not appear to follow a seasonal pattern for reactivation [12].

Few studies evaluate the risk of HZO among cohorts with VZV, though independent estimates generally ranged between 10.1 and 14.9%, or approximately 30.9 per 100,000 person-years [17–21]. Of note, the risk of HZO is relatively unchanged across the lifetime [17, 22]. Identified risk factors of HZO include female sex, Caucasian race, and immunosuppression [23, 24]. Neuro-ophthalmic manifestations of VZV are being increasingly reported; in one recent study of patients with VZV and CNS involvement, 81% of participants had neuro-ophthalmic complications [25].

Presentation and diagnosis of ocular herpes zoster

Presentation

Most cases of HZO are preceded by a prodromal phase of fever, malaise, headache, and eye pain [12, 26]. Subsequently, HZO manifests as a painful vesicular rash along a unilateral V₁ distribution of trigeminal nerve, most often involving the frontal division, but may also involve the nasociliary and lacrimal branches [12]. The nasociliary branch innervates cutaneous surfaces of the eyelids and nose in addition to the ocular surface, iris, and choroid; involvement of this branch is well-known to manifest as Hutchinson’s sign, referring to a vesicular lesion along the nose, which strongly predicts intraocular involvement and therefore raises suspicion of neuro-ophthalmic disease [12, 27, 28]. Figure 1 depicts a patient with Hutchinson’s sign [29]. Excluding nasociliary involvement, roughly one-third of cases have ocular involvement of any sort. Altogether, approximately 50% of HZO cases involve the ocular adnexa, more often affecting the anterior segment, but in rare neuro-ophthalmic cases, can affect the posterior segment and/or retroorbital structures [30]. The vesicular rash typically crusts over and resolves within 4 weeks [30]. In rare cases, Zoster Sine Herpete is characterized by ocular involvement without cutaneous lesions [31]. In immunocompromised patients, disseminated disease is more likely with potential bilateral involvement and affliction over several dermatomes [30].

Fig. 1. HZO with Hutchinson Sign, a highly suggestive sign of ocular adnexal disease, raising suspicion for neuro-ophthalmic manifestations.

However, the absence of this sign does not exclude the possibility of adnexal involvement. This figure had been taken from ‘VZV and the CNS’ by Joseph R. Berger, from the 2018 North American Neuro-Ophthalmology Society Annual Meeting and published by the Neuro-Ophthalmology Virtual Education Library – Spencer S. Eccles Health Sciences Library, University of Utah.

Common ophthalmic examination findings of the ocular exterior and anterior segment are detailed elsewhere [12, 30]. Less commonly, manifestations may occur within posterior segment and/or retroorbital structures. Examples of such involvement includes vitritis, optic neuropathy, retinal disease (acute retinal necrosis and progressive outer retinal necrosis), cranial neuropathies or lesions (whether lone or multiple nerve palsies, including cavernous sinus, orbital apex, and superior orbital fissure syndromes) [12, 32, 33]. We provide detailed descriptions of typical neuro-ophthalmic manifestation in subsequent sections.

Diagnostic approach

HZO is predominately a clinical diagnosis [33]. However, for clinically ambiguous cases such as zoster sine herpete or multi-systemic involvement, molecular testing is indicated to secure a diagnosis of HZO [33]. Most commonly, polymerase chain reaction (PCR; particularly multiplex real-time assays) can be used to non-invasively amplify and detect VZV DNA from infected (e.g., aqueous humor) or salivary samples, often with reliable sensitivity and specificity, both ranging between 98 and 100% [34]. Serological antibody testing (optimally, fluorescent antibody to membrane antigen testing) is more costly and less accessible than PCR and should be considered as a second-line study [33, 35]. Other diagnostic modalities include VZV-antigen testing and viral culture [30, 33, 36]. The possibility of false test positivity should be considered; for instance, 1.9–5.1% of patients in one study exhibited detectable salivary levels of VZV DNA in the absence of clinical signs and symptoms of active infection [37]. For suspected disseminated HZ and/or HZO, HIV testing should be considered [30]. Ultimately, one should defer to their regional diagnostic guidelines; for example, the European consensus-based guidelines recommend a tandem of real-time PCR and serology on paired serum and another specimen (e.g., cerebrospinal fluid, ocular fluid) obtained 2–3 weeks after neurological/neuro-ophthalmological symptom onset [38].

A common point of diagnostic confusion arises from differentiating between a diagnosis of herpes simplex virus (HSV; especially zosteriform) and VZV. In summary, features suggestive of VZV include more complete dermatomal involvement, severe vesicular pain and skin scarring with PHN, smaller corneal dendrite morphology (pseudodendrites), rarer recurrence of epithelial keratitis, and sectoral iris atrophy [39].

Neuro-ophthalmic manifestations of herpes zoster

Below, we detail several reported neuro-ophthalmic manifestations of herpes zoster.

Optic neuropathy

VZV has long been a well-known cause of optic neuropathy, albeit rare (<0.5% of HZO cases) [40]. While the pathophysiology of VZV-induced optic neuropathy is not completely understood, proposed mechanisms include direct optic nerve infection via the cavernous sinus or hematogenous routes and indirect causes (e.g., inflammatory demyelination; optic perineuritis; vascular inflammation causing ocular ischemia; extra-orbital infection leading to a reactive immune response with subsequent edema of the optic disc) [32, 33, 41].

Optic neuropathy from VZV may occur before (in some cases, preceding the rash), during, or most often as a post-acute complication reported up to 10 weeks post-onset of HZO [42, 43]. Given this, aggressive treatment during index viral reactivation may reduce the incidence of subsequent optic neuropathy [43]. Patients with VZV optic neuropathy may complain of acute vision loss with or without painful eye movements (may be unilateral or bilateral), typically within three months of an episode of VZV reactivation [43]. Although ophthalmic examination may reveal signs of anterior optic nerve involvement, the absence of fundoscopic findings should not exclude the possibility of an optic neuropathy. Other potential clinical findings include RAPD, which must be present in unilateral cases, visual field defects, and dyschromatopsia. Contralateral disc swelling to the side of HZO involvement, and even bilateral involvement, has also been reported [44, 45]. Most patients with optic neuropathy will have had a preceding uveitis.

In the past decade, evidence has implicated VZV with neuroinflammatory disorders, some of which are also known to cause optic neuritis. For instance, preliminary neurological reports have hypothesized a triggering role of VZV in the multifactorial development of subsequent neuromyelitis optic spectrum disorder, multiple sclerosis, and myelin oligodendrocyte glycoprotein disease [46–48]. One mechanism may be that VZV may contribute to breakdown of the blood-brain barrier (as demonstrated by elevated CSF serum-albumin ratio in HZ), thereby exposing CNS antigens to autoimmune response [46].

Evidence also implicates VZV with non-infectious causes of optic neuropathy. Of note, recent evidence implicates extracranial VZV vasculopathy as a potential trigger of giant cell arteritis (GCA) [49]. As well, reports have described cases of unilateral vision loss in the setting of GCA and VZV, although one report describes a severe case of bilateral vision loss [50]. Another report describes a case of GCA following VZV vaccination [50]. In the context of non-arteritic ischemic optic neuropathy, a preliminary report of seven cases with GCA-negative temporal artery biopsies (which were also subject to VZV analysis) suggests that atypical non-arteritic ischemic optic neuropathy (e.g., retinal pathology and subretinal hemorrhage, elevated cup/disc ratio and vascular gliosis at the disc, slow progression, and pain) may be related to VZV, thereby suggesting a potential role of antiviral therapy, which deserves further investigation [51]. The authors describe a wide spectrum of ischemia secondary to VZV vasculopathy, therefore potentially also predisposing to central retinal artery occlusions, retinal necrosis, and anterior/posterior ischemic optic neuropathies [51].

Even with high suspicion of VZV-related optic neuropathy, the differential diagnosis most crucially includes GCA and should therefore indicate autoinflammatory laboratory screening. The differentiation of VZV optic neuropathy with GCA is significant; while corticosteroids are indicated for the latter, they are controversial for application in the former [49]. Testing for other causes of optic neuritis (e.g., MOG-IgG or AQP4-IgG-related) is recommended as well. HZ-mediated optic neuropathy is usually a clinical diagnosis based on history and examination. There are no confirmatory laboratory or imaging tests for HZ-mediated optic neuropathy, although MRI is indicated to demonstrate signs of optic nerve inflammation (e.g., optic nerve enhancement), signs suggestive of HZ (e.g., hyperintensity of the trigeminal nucleus), and most crucially, indicate the extent of extra-orbital involvement [43]. Figure 2 depicts MRI findings of VZV optic neuropathy. Other imaging (e.g., fluorescein angiography and optical coherence tomography) may be considered to increase diagnostic confidence by elucidating other findings suggestive of optic nerve involvement by VZV (e.g., thickened peripapillary RNFL layer with hyper-reflective lesions and fluorescein leakage in acute HZO, or peripapillary axonal loss in chronic HZO), or co-involvement of surrounding structures (e.g., retina and vasculature). For optic neuropathy, CSF PCR can be considered to confirm active VZV reactivation. Of note, in cases where CSF is obtained early in the disease course, PCR studies may return falsely negative [52]. In such cases, repeat testing often returns a true positive result despite empiric acyclovir treatment [52]. When associated with encephalitis and meningitis, CSF studies most often show pleocytosis (>5 × 10⁹ white blood cells/L), typically predominated by lymphocytes, though neutrophilia may be appreciated in early illness [52]. CSF glucose is classically normal while protein may be normal or moderately elevated [52]. These findings should suggest viral involvement and therefore raise suspicion about falsehood of a negative PCR result. Aqueous sampling could also be considered in cases where there is at least a trace amount of associated uveitis.

Fig. 2. MRI imaging of a patient with right VZV optic neuropathy.

There is a short segment enhancement of the right optic nerve (red arrow).

Management

In terms of treatment, antiviral medication should be given. There is still controversy as to whether the oral or intravenous route is favored. The intravenous route should be given to those that are immunocompromised or have additional neurological involvement or MRI evidence of CNS involvement (e.g., systemic acyclovir 10–15 mg/kg three times daily for 2–3 weeks) [43]. Oral valacyclovir has high bioavailability than oral acyclovir and a dose of 2 g PO QID is comparable to IV acyclovir 10 mg/kg q8H in terms of area under the curve, but lower in terms of peak concentration [53, 54]. Some have argued that the lower peak concentration allows for a better safety profile [53, 54]. An oral medication may be considered for isolated HZ optic neuropathy, and we suggest using valacyclovir 2 g PO TID to QID [55]. As noted previously, the role of corticosteroids (oral, intravenous, or topical) is unclear on whether the benefit of inflammatory control outweighs the risk of subsequent retinal VZV involvement [43]. Our preference is to generally avoid oral or intravenous steroids in these cases while treating uveitis with topical steroids as indicated. With treatment, the prognosis of HZ optic neuropathy is variable with full recovery and incomplete recovery reported in the literature [55]. Poorer vision prognosis tends to be observed in patients with more severe visual loss at presentation and optic nerve restricted diffusion on MRI [43].

Retinal involvement

Retinal involvement of VZV typically, although not exclusively, manifests as acute retinal necrosis (ARN; associated with panuveitis and retinal arteriolitis; classically presenting with acute vision loss and high risk for retinal detachment) in immunocompetent patients, or pauci-inflammatory progressive outer retinal necrosis (PORN; associated with limited intraocular inflammation, predominant outer retinal and posterior pole involvement; classically presenting with non-specific complaints) in immunocompromised patients [56, 57]. Table 1 compares practical diagnostic features and management considerations for ARN, PORN, and cytomegalovirus retinitis (a common competing diagnosis) [57–63]. Both conditions carry a poor visual prognosis. Focused reviews on the surgical management of ARN and PORN are detailed elsewhere [64, 65].

Table 1.

Comparison of acute retinal necrosis (ARN), progressive outer retinal necrosis (PORN), and cytomegalovirus retinitis (CMV).

Non-visual cranial neuropathy and orbitopathy

VZV is well-known to afflict the non-visual cranial nerves. In most cases, a single nerve is affected (classically, V₁ in the context of HZO), but in rare cases, multiple cranial nerves can be impaired. In this review, we focus on relevant cranial neuropathies in a neuro-ophthalmology context. Table 2 provides an overview of manifestation of cranial nerve palsies associated with VZV. [30, 33, 66–69] Development of a cranial neuropathy may be secondary to direct viral invasion, immunologic demyelination, or VZV-associated vasculopathy [70, 71]. Further, clinical findings of CNS and/or cranial nerve involvement, whether single or multiple, should warrant neuroimaging and CSF studies.

Table 2.

Overview of documented cranial neuropathies in the context of herpes zoster.

Typical cranial nerve (CN) reactivation site	Example clinical manifestation(s)	Associated syndrome(s)
CN II, III, IV, V1, VI	V1 vesicular rash, more often isolated ophthalmoplegia (internal and external), raised intraocular pressure, optic neuritis, retinal necrosis, uveitis, ocular surface disease (conjunctivitis, episcleritis, keratitis).	Herpes Zoster Ophthalmicus
CN VII	Unilateral facial paralysis without vesicular lesions	Bell’s Palsy
CN VII, VIII	May include: Vesicular rash of the ear or oral mucosa, facial nerve palsy, otologic signs (hearing loss and vertigo). In rarer cases, may include signs of impairment to other cranial nerves.	Herpes Zoster Oticus/Geniculate Herpes/Ramsay Hunt Syndrome
Combination of CNS III, IV, VI, and V1/V2. sparing CN II.	Ophthalmoplegia, painful eye movement, ptosis, facial sensation loss. *Note: HZO may cause vision loss (e.g., corneal involvement). Thus, the presence of vision loss itself should not rule out involvement of the cavernous sinus.	Cavernous Sinus Syndrome
Combination of CN II, III, IV, VI ± V1.	Vision loss, ophthalmoplegia, painful eye movement, ptosis, facial sensation loss	Orbital Apex Syndrome
Combination of III, IV, VI, and V1. sparing CN II.	Ophthalmoplegia, painful eye movement, ptosis	Superior Orbital Fissure Syndrome
Any sensory ganglia	Severe chronic pain along distribution of resolved vesicular rash	Postherpetic neuralgia
CNS involvement	Possible symptoms of associated syndromes: Headache, meningismus, altered mental status, signs and symptoms of raised intracranial pressure, weakness below the head and neck, sensory loss or changes, autonomic dysregulation, paraparesis	Meningitis Encephalitis Transverse Myelitis Motor Neuropathy

The literature depicts numerous cases of external ophthalmoplegia due to VZV reactivation in the context of HZO. Such reports include isolated cranial nerves palsies of III, IV, and VI (7–31% of HZO cases) [33, 71]. Third nerve palsies are most frequent, followed by sixth nerve palsies, and rarely, fourth nerve palsies [32]. In these cases, patients typically complain of binocular diplopia, blurry vision, and partial limitations to ocular motility. Figure 3 depicts a patient with VZV-induced third nerve palsy, which is the most common cranial neuropathy affecting ocular motility [72]. In much rarer cases, multiple cranial nerves palsies can co-occur, thereby implying variable regional involvement including the cavernous sinus, orbit (e.g., orbital apex and superior orbital fissure syndromes), and diffuse brainstem involvement [66, 71, 73, 74]. In cases of complete ophthalmoplegia due to orbital involvement, proptosis may occur [75]. Figure 4 exhibits a case with complete left ophthalmoplegia due VZV involvement of the left cavernous sinus and orbit, with associated neuroimaging. Comparatively, Fig. 5 depicts a case with involvement of the orbital apex and cavernous sinus, evidenced by neuroimaging [60]. Diffuse brainstem involvement may be exemplified by exceptionally rare cases of multiple unilateral cranial neuropathies or bilateral internuclear ophthalmoplegia; for the former, the neuronal insult may occur diffusely along unilateral cranial nerve nuclei within the brainstem, and for the latter, this process may involve bilateral portions of the dorsal pons [70].

Fig. 3. Ocular motility in a patient with VZV-induced third nerve palsy.

This the most common cranial neuropathy affecting ocular motility. This figure had been taken from ‘Herpes Zoster Ophthalmicus with Third Nerve Palsy’ by Kathleen B. Digre, from the Neuro-Ophthalmology Virtual Education Library, and published by the North American Neuro-Ophthalmology Society – Spencer S. Eccles Health Sciences Library, University of Utah.

Fig. 4. Ocular motility in a patient with VZV affecting the left cavernous sinus and orbit.

The patient had a complete left ophthalmoplegia; a rarer form of cranial neuropathy affecting ocular motility. T1-post gadolinium MRI of this patient showed enlargement of the left cavernous sinus (red arrow) and left optic nerve sheath enhancement.

Fig. 5. Case of a patient with fixed third nerve palsy, mild sixth nerve palsy, and V₁ anesthesia.

MRI depicts enhancement of the orbital apex and cavernous sinus, with an area of diffusion restriction at the right centrum semi-ovale. This figure had been taken from ‘What to Do When VZV Affects the Retina, Optic Nerve, and Makes the Patient See Double?’ by Sachin Kedar, from the 2018 North American Neuro-Ophthalmology Society Annual Meeting and published by the Neuro-Ophthalmology Virtual Education Library – Spencer S. Eccles Health Sciences Library, University of Utah.

Management of external ophthalmoplegia

Evidence of any degree of ophthalmoplegia should warrant contrast-enhanced MR brain and orbits to confirm localization of the lesion and rule out competing causes [33]. If imaging depicts signs of intracranial involvement (e.g., VZV vasculopathy, parenchymal ischemia, or meningeal involvement), lumbar puncture with CSF analysis (including PCR and serology studies) is usually indicated. Management of external ophthalmoplegia is implicit with routine antiviral therapy. Lone cranial neuropathy may be treated via outpatient oral antiviral therapy [33]. However, for disseminated involvement of multiple cranial nerve, intravenous acyclovir (10–15 mg/kg, three times daily for 2-3 weeks) is often recommended [33]. There remains controversy surrounding the adjunctive role of corticosteroids. In one meta-analysis of 50 cases with HZ-ophthalmoplegia, the authors report a significant albeit minor association between duration of steroid treatment and status of complete symptomatic recovery (hazard ratio 1.1) [76]. In their analysis, neither patient age, gender, nor initial steroid dose were found to significantly impact recovery status [76]. Nonetheless, another systematic review found that the rate of complete recovery in patients with ophthalmoplegia was similar in those with antivirals compared to those treated with antivirals and steroids [77]. At six-month follow-up, 75% of patients treated with combination therapy and 86% of those treated with antivirals alone had complete recovery [77]. Age was the only significant predictor of complete recovery found in this study [77]. Further investigation is needed; thus, clinical judgment is recommending when deciding for or against the use of steroids. If steroids are given, a five-day course of Prednisone 1 mg/kg PO can be given. Our preference is to give a five-day course of oral prednisone 1 m/kg if there is minimal improvement with only antiviral treatment after the first 1–2 weeks. Generally, the prognosis of external ophthalmoplegia is favorable; in one report, 94% of patients achieved at least partial recovery albeit full remission of primary gaze diplopia by eight months [33, 71, 75, 78]. Prism glasses and even strabismus surgery should be considered for refractory cases by one-year follow-up [33].

Internal ophthalmoplegia

The literature includes case reports of rarer neuro-ophthalmic VZV presentations, such as cases of atypically reduced pupillary reactivity. While reports of pupillary involvement with HZO are longstanding, reports of isolated non-reactive pupils have been rare in the past 70 years [79]. Such cases often present unilaterally with anterior uveal involvement in 50% of cases [79]. The pathophysiology of atypical pupillary involvement is not well understood but may involve demyelinating, compressive, vasculitic-occlusive, direct neuropathic, and/or viral cytotoxic processes [80]. The localization of the lesion is not likely consistent across these rare cases, given varying levels of pupillary response to administration of pilocarpine or physostigmine. [79, 81–83] In one report, Blanco-Palmero and colleagues present two cases non-reactive mydriatic pupils; prior, only three cases have been reported since 1950 [79]. Other reported pupil abnormalities include several cases presenting with light-near dissociation [79, 80, 82]. One case describes antidromic migration of VZV, presenting with unreactive pupils before cutaneous rash, which was thought to be localized to the Gasser and Ciliary ganglia [83]. Horner Syndrome has also been reported as a rare pupillary manifestation of VZV [84]. There remains scarce evidence to guide management of pupillary involvement, although some reports indicate residual or resistant pupillary involvement after antiviral treatment with or without steroids. [79, 80, 82–85] In other cases, pupillary involvement may resolve with treatment, suggesting that other patient-related factors likely have a considerable role in treatment response [77].

CNS manifestations and other phenomena

VZV reactivation is well-known to involve deeper CNS structures, such as taking on forms of meningitis, encephalitis, and CNS vasculopathy [32, 33]. Figure 6 depicts an example of neuroimaging findings of VZV large- and small-vessel vasculopathy [29]. Phenomena of deeper CNS involvement, with delayed response after acute viral reactivation, have been reported in both immunocompromised and immunocompetent patients [86]. In some cases, there is no herpetic rash; therefore, VZV-mediated CNS involvement should be considered even in less suspicious cases. Focused discussions of neurological VZV manifestations are detailed elsewhere [32, 33].

Fig. 6. Left panel: angiography of large-vessel VZV vasculopathy, chiefly occurring in elderly immunocompetent patients.

Right panel: neuroimaging of small-vessel VZV vasculopathy, most typically in immunocompromised patients. This figure had been taken from ‘VZV and the CNS’ by Joseph R. Berger, from the 2018 North American Neuro-Ophthalmology Society Annual Meeting and published by the Neuro-Ophthalmology Virtual Education Library – Spencer S. Eccles Health Sciences Library, University of Utah.

Following acute HZO reactivation and symptomatic remission, the literature recently reports on cases of a post-VZV immune-mediated ophthalmic syndrome [32]. In one case, a patient developed birdshot chorioretinopathy over two years after resolution of contralateral VZV-induced ARN [87]. The authors hypothesize the role of ARN in exposing immune-privileged antigens of the outer retinal layers, thereby potentiating a phenomenon of a delayed autoimmune response after resolution of HZO [87]. Another report describes a patient with vision loss, ptosis, reduced pupil reactivity, and anterior segment inflammation, four weeks after resolution of the initial viral reactivation [88]. In both cases, subsequent treatment with acyclovir and systemic steroids yielded moderate-at-best symptomatic improvement [87, 88]. Further investigation is needed on this delayed response to HZO.

Postherpetic neuralgia (PHN)

PHN, the most common complication of VZV reactivation, is characterized by chronic, often refractory, neuropathic pain persisting over three months after HZ outbreak [69]. Common complaints of PHN include allodynia, paroxysmal lancinating pain, hyperalgesia, and a deep, burning or aching pain character along the prior distribution of infection [69].

PHN is often a longstanding complication requiring long-term analgesia; while evidence suggests that valacyclovir and famciclovir may reduce the severity of PHN, no antiviral therapy can prevent this complication [89]. Detailed management of PHN is explained elsewhere and should employ an interdisciplinary biopsychosocial approach to pain control [69]. In summary, although the optimal pain control regimen will likely vary between patients, PHN may be pharmacologically managed through a combination of alpha-2 delta ligands (e.g., pregabalin or gabapentin; effective for allodynia), anticonvulsants (e.g., carbamazepine), tricyclic antidepressants (e.g., amitriptyline, nortriptyline, and doxepin; effective for background or paroxysmal pain), topical analgesics (lidocaine or capsaicin applications; effective for allodynia or lancinating pain), and in refractory cases, opioids (e.g., sustained-release tramadol or controlled-release oxycodone) although controversial [69].

Prevention

Vaccination is the mainstay modality for prevention of HZ outbreak. For healthy adults 50 years of age or older, two approved vaccines are available in 62 countries, including a live-attenuated vaccine (Zostavax, Merck Corporation, single dosed) and an recombinant adjuvanted VZV glycoprotein E subunit vaccine (Shingrix, GlaxoSmithKline, double dosed) [90]. Evidence suggests better duration of protection (at least 10 years vs up to 8 years) and prophylactic efficacy against HZ (97.2% vs 51.3%) and PHN (91.2% vs 66.5%) of the recombinant compared to the live-attenuated vaccine [90]. Further, for immunocompromised individuals, the recombinant vaccine is favored for its use of nonreplicating material [90]. Any vaccine should not be delivered during acute shingles reactivation [90]. One should defer to their local guidelines on immunization schedules for these vaccines, albeit not all jurisdictions include recommendations for HZ vaccination, such as in the case of nine of 28 European Union countries [90]. Although not a standard practice, recent evidence indicates benefit of long-term primary prophylactic antiviral therapy, predominantly in the immunocompromised and transplant populations [91, 92]. Among ongoing trials on antiviral therapy for HZ, the Zoster Eye Disease Study is a significant, ongoing trial investigating whether suppressive oral valacyclovir (1000 mg) reduces complications of HZO over one-year [93].

Summary of management principles

Order of operations: diagnosis and treatment

As HZO is considered an ophthalmic emergency, there may be competing interests between securing a diagnosis and initiating prompt management. Indeed, premature treatment may distract from competing differential diagnoses, interfere with investigation results, or may innately cause harm. Since most routine cases of HZO proceed sufficiently with clinical diagnosis with subsequent management, this issue arises more often in rarer cases involving neuro-ophthalmic manifestations, intracranial involvement, disseminated disease, and/or atypical presentations (e.g., Zoster sine herpete) for which ancillary investigations are indicated. Some investigations (e.g., PCR and serologies) may take several days to yield critical results. Therefore, an order of operations with respect to investigations and treatment is warranted.

The literature is lacking with respect to investigations on the effect of early antiviral therapy on rates of false negative VZV results after PCR and/or serologies of CSF or aqueous samples. However, in a related context, one review suggests that patients with herpes simplex encephalitis are likely to remain PCR-positive from CSF for several days after initiating empiric acyclovir [52]. While both PCR and serology demonstrate excellent sensitivity, there remains possibility of false negative results, leading to catastrophic outcomes. From our experience, given that such tests may take several days for results, we recommend conservative initiation of antiviral therapy on the same day of first presentation for high clinical suspicion of HZO. Within hours of presentation, however, necessary investigations including lumbar puncture and aqueous/salivary sampling may be conducted prior to same day initiation of antiviral therapy. However, antiviral therapy should not be delayed if such investigations are not immediately available. As a result, patients benefit most from early antiviral therapy in presumptive HZO, and this regimen may be continued given positive or suspected false negative test results, or discontinued if the patient were later found to have a competing, non-emergent diagnosis. Our opinion is that this approach reduces the risk of false negative studies while recognizing that the benefit of imminent HZO treatment outweighs the rare risk of antiviral neurotoxicity [94]. Of note, use of real-time PCR to provide same day diagnostic confirmation may alleviate this issue altogether.

Another practical consideration is whether neuroimaging should always precede lumbar puncture. Generally, evidence suggests that delay of lumbar puncture due to neuroimaging can result in treatment delay and poorer outcomes [52]. Indeed, one study reports that time to lumbar puncture were 18.5 and 6 h for patients with and without prior CT, respectively [95]. Thus, when considering whether to proceed with neuroimaging, we defer to several guideline-recommended indications including focal neurological signs (often the case with neuro-ophthalmic manifestations), signs suggestive of papilledema, seizure history, or a Glasgow Coma Scale $\le$ 12 [96–98]. We recommend prioritizing neuroimaging prior to LP since an alternative diagnosis may be found. Regardless, as recommended by one guideline, delay of lumbar puncture over 6 h should warrant consideration of empiric antiviral therapy [97].

Antiviral therapy

Antiviral therapy is the mainstay treatment for ongoing HZ affliction [33]. Treatment should be initiated as soon as a presumptive diagnosis of HZ is made to control rash and pain severity, viral shedding, and adnexal involvement [30, 89]. Several classes of antiviral agents are available and are summarized in Supplementary Table 1. Acyclic purine nucleoside analogs (acyclovir, famciclovir, and valacyclovir) are typically first-line agents due to excellent effectiveness and safety characteristics even during pregnancy [33]. Supplementary Table 1 also summarizes the practical considerations for identifying an antiviral agent-of-choice (e.g., based on location and extent of manifestations, minimizing renal toxicity, and acyclovir resistance), albeit its recommendations are not dogmatic and there may be between-clinician variation in management [33, 99].

Adjunct corticosteroids

Corticosteroids use is controversial and has shown variable clinical trial results with potential for adverse events [30]. Posterior segment manifestations warranting consideration of systemic corticosteroids (in an immunocompetent patient) include HZ-induced optic neuritis, HZ-related ophthalmoplegia, retinitis, progressive outer retinal necrosis, and choroiditis [30, 43, 63, 76, 77, 100, 101]. Overall, until more definitive evidence is available, the risks and benefits of corticosteroid therapy should be carefully weighed. Due to lack of consistent and clinically important evidence for benefit with respect to isolated optic neuropathy and the risk of retinitis, we generally recommend forgoing initial oral or systemic steroids. A short 5-day course of oral Prednisone 1 mg/kg can be considered for cases of ophthalmoplegia if there is no significant improvement with antivirals alone within the first 1–2 weeks.

Follow-up in the acute HZO

In the acute phase, follow-up should proceed urgently within one week of the previous visit. With remission or chronic stable HZ, follow-up monitoring would proceed at a reduced frequency and it is recommended that the patient has routine follow-up on an annual or semi-annual basis for delayed sequelae (e.g., recurrence, ocular hypertension, cataract, corneal scarring,) [101]. Neurological and other medical consultation may also be considered. Indeed, HZ may carry a 1.3–4-fold elevated one-year risk of cerebrovascular events, especially among younger patients (<40 years of age), and may predispose to acute cardiac events [102].

Conclusion

Epidemiological evidence indicates rising reports of HZ and HZ-associated eye disease, inclusive of rarer neuro-ophthalmic manifestations. Growing evidence implicates a diverse collection of potential neuro-ophthalmic manifestations; therefore, VZV reactivation should be remain a potential differential diagnosis across the broad spectra of general ophthalmology presentations. Ongoing and future trials should better elucidate the role of corticosteroids and optimize management protocols for the rarer neuro-ophthalmic phenomena of HZ.

Author contributions

Conception/Design/Acquisition/Analysis/Interpretation (BT, JM), Acquisition (BT, JM), Drafting/Revision (all authors), Final Approval (all authors), Agreement of Accountability (all authors). Authorship: All authors attest that they meet the current ICMJE criteria for authorship.

Funding

This work received no direct financial support. BT is supported by the Eye Foundation of Canada.

Competing interests

The authors declare no competing interests.

Ethics approval

Exempt from institutional review board approval (under article 2.4 of the Tri-Council Policy Statement) since data was entirely extracted from publicly available sources. No identifiable information is revealed in this work.

Supplementary information

The online version contains supplementary material available at 10.1038/s41433-024-03030-3.