Each year, an estimated 1 million new episodes of herpes zoster (HZ) occur in the United States, with a lifetime risk of 30%. The median global incidence of HZ of 4–4.5 per 1,000 person-years seems to be increasing due to an aging population, creating an important public health problem (1). HZ results from reactivation of the varicella zoster virus (VZV) because of waning T-cell–mediated immunity in advancing age or immunocompromised conditions. About 10%–20% of all HZ involves the ophthalmic division of the trigeminal nerve resulting in herpes zoster ophthalmicus (HZO). About 50% of all HZO will have ocular involvement, most commonly of the anterior segment, while posterior segment involvement (vitritis, retinitis, and optic neuritis) is relatively uncommon. Postherpetic neuralgia (PHN), a debilitating chronic pain syndrome, is the commonest complication of HZ. Other significant neurological complications include meningoencephalitis, myelitis, vasculitis, and cranial neuritis. Zoster-related complications result in poor quality of life, increased mortality, and increased health care cost burden (2–5). In this review, we will discuss the recent advances and consensus guidelines for diagnostic and therapeutic interventions as applicable to the neuro-ophthalmology community.
VZV is one of the 8 members of the herpes virus family. It is an exclusive human neurotropic alpha herpes virus with an icosahedral nucleocapsid core that contains a double-stranded DNA genome. The core is surrounded by an amorphous protein material (tegument) and a lipid-rich envelope embedded with glycoproteins (6). Viral cycle involves injection of viral DNA into the host nucleus where it replicates and forms nucleocapsids, which then bud across the nuclear membrane acquiring the envelope (7).
VZV infects more than 95% of the human population before adolescence, producing the childhood exanthematous illness chicken pox, followed by a lifelong period of latency within neurons of the cranial, dorsal root, autonomic, and enteric ganglia as well as the adrenal glands (8). During latency, the virus exists in the host tissues in a nonintegrated circular concatemeric form with limited gene expression (9,10). Expression of gene 63 forms the hallmark of VZV latency (11).
VZV reactivates when host T-cell–mediated immunity diminishes. The virus replicates in the sensory ganglia and spreads transaxonally to the corresponding mucocutaneous surfaces. This results in an intense inflammatory reaction that produces the characteristic painful vesicular dermatomal zoster (shingles) rash (12). VZV reactivation can affect neuraxis at all levels. The most frequent dermatomes involved are thoracic (∼40%) followed by cranial (∼30%) and cervical (∼12%) segments (13). VZV reactivation along the ophthalmic (V1) division of trigeminal nerve produces HZO.
The pathogenesis of HZ-related complications likely involves infectious and inflammatory processes. The histopathologic features of HZ are intense inflammation with hemorrhagic tissue necrosis and neuritis resulting in the characteristic skin rash and acute pain (14). The pathogenesis of PHN remains unclear. Proposed mechanisms include altered neuronal excitability and chronic low-grade VZV infection of the sensory ganglionic neurons (15). The neuro-ophthalmic complications result from involvement of the optic and ocular motor nerves, through mechanisms that are not clear. These include direct viral invasion of the nerve through trans-synaptic or hematogenous routes, extension of inflammation from the meningeal/cerebral tissues, VZV-induced perineuritis, and ischemia secondary to VZV vasculitis (16,17).
The characteristic vesicular rash on an erythematous background grouped in a unilateral, single dermatomal distribution establishes a clinical diagnosis of HZ. Molecular diagnostic testing methods are needed if presentation is ambiguous (zoster sine herpete) or with systemic/organ system involvement (18,19).
Polymerase Chain Reaction
Detection of amplifiable VZV DNA using polymerase chain reaction (PCR) in biological specimens (skin vesicle fluid, cerebrospinal fluid (CSF), blood samples, tissue biopsy, and intraocular fluid) is the diagnostic modality of choice. Technological advances such as multiplex PCR assay allow for rapid detection and differentiation of HSV1, HSV2, and VZV, with excellent (>98%) sensitivity and specificity (20–22). Real-time PCR to detect amplifiable VZV DNA in the salivary specimens of HZ with a high degree of sensitivity and specificity, including patients with VZV encephalitis, has been suggested as a possible noninvasive marker for HZ (23–25). However, VZV DNA has been detected by PCR in the saliva of 5.1% of immunosuppressed (HIV-seropositive individuals) without clinically evident VZV infection and 1.9% of normal controls (26). Therefore, the presence of VZV in saliva must be interpreted cautiously, and larger studies are needed to establish the sensitivity and specificity of detecting VZV DNA in salivary specimens of patients with neurological or ophthalmological VZV infections (27).
Antibody testing is performed using enzyme-linked immunosorbent assay, enzyme immunoassay, fluorescent antibody to membrane antigen (FAMA), immune adherence hemagglutination, neutralization, and complement fixation to detect VZV-specific IgM, IgG, and IgA responses. Of these, FAMA is considered the gold standard and correlates best with immune status against varicella (20,28,29). Limitations of FAMA include labor-intensive protocol, expertise in test interpretation, and expense. Inability to detect IgM antibody response in about 50% cases and a delay of the response by days to weeks after onset of reactivation limits use of serological methods in diagnosing active HZ (30). These methods are mostly used to assess immune status in the context of varicella immunization to identify susceptible individuals and to assess response to immunization (29). Antibody testing is an important accompaniment of PCR because it may confirm the diagnosis of a VZV neurological disorder when CSF PCR for VZV is negative (31).
Antigen testing is performed using monoclonal antibodies to detect VZV-specific surface glycoproteins in tissue samples with direct fluorescent antibody or immunohistochemistry (IHC). IHC using monoclonal antibodies to the immediate early protein (IE63) and glycoprotein E was shown to have >90% diagnostic accuracy and 100% specificity (32). Limitations of the technique include the need for trained personnel and false positivity because of shared epitopes between VZV proteins and native tissue (33,34).
In general, most laboratories have a turnaround time of 24–48 hours for both PCR and serology. Although the actual testing time is short, reporting times vary between laboratories depending on specimen batching intervals (daily vs weekly). Additional delays occur if samples have to be shipped for testing (“send-out laboratory tests”).
The European consensus–based guidelines for management of HZ recommends real-time PCR combined with serology on paired serum and tissue fluids/specimens such as CSF and intraocular fluid obtained 2–3 weeks after onset as the diagnostic method of choice for HZ with neurological or ocular complications (35).
The purine nucleoside analogs (acyclovir, valacyclovir, and penciclovir) are the most commonly used agents in the management of HZ and HZO, due to excellent efficacy and safety profile including use during pregnancy (36). Table 1 lists the standard and alternative antivirals used in herpes zoster disease.
Acyclovir is a synthetic second-generation antiviral medication. It is converted to acyclovir triphosphate by virus-coded thymidine kinase and enters the viral DNA chain as a purine analog resulting in termination of DNA synthesis and viral protein synthesis. It has an excellent safety profile because the viral DNA polymerase has a 10- to 30-fold greater affinity for acyclovir triphosphate compared with cellular DNA polymerase (37). Compared with herpes simplex virus, inhibitory concentrations of acyclovir for VZV are approximately 4-fold higher. Thus, an oral dose of 800 mg 5 times a day is needed to achieve sufficient peak and trough levels to inhibit most strains of VZV (38). Acyclovir resistance is uncommon but may be seen in immunodeficient patients. Systemic vidarabine or foscarnet are the preferred treatments in these patients (39).
Valacyclovir is a third-generation, synthetic prodrug of acyclovir, which is hydrolyzed to acyclovir after gastrointestinal absorption. Valacyclovir has a 3- to 5-fold higher bioavailability compared with acyclovir after oral ingestion (40). Oral valacyclovir (1 g 4 times daily) results in plasma acyclovir levels comparable with levels after intravenous acyclovir (5 mg/kg body weight every 8 hours) resulting in comparable clinical efficacy (41). In a study of 1,141 immunocompetent patients with HZ (including 35 with HZO), the efficacy of valacyclovir (1 g oral 3 times a day for 7 or 14 days) was equivalent to acyclovir (800 mg oral 5 times daily for 7 days) in accelerating dermal healing and reduced viral shedding. Valacyclovir was significantly better than acyclovir in reduction of durations of acute zoster pain and PHN (42). Valacyclovir has an excellent safety profile in immunocompetent patients. It is contraindicated in immunosuppressed patients because of the risk of thrombocytopenic purpura/hemolytic uremic syndrome (43).
Famciclovir is a third-generation synthetic diacetyl ester prodrug of the antiviral penciclovir. It has excellent GI absorption and bioavailability after oral administration. In clinical trials, famciclovir treatment (500 mg 3 times daily for 7 days) was comparable with valciclovir (1 g 3 times a day for 7 days) for dermal healing, zoster pain, and postherpetic neuralgia with similar safety profiles (44).
HERPES ZOSTER OPHTHALMICUS
VZV reactivation along the ophthalmic (V1) division of trigeminal nerve produces HZO (Fig. 1). It is a chronic, recurrent disease with a 5-year recurrence rate of 25% (45). Although frontal branch of the ophthalmic nerve is most commonly affected (46), involvement of the nasociliary branch produces skin lesions along the side of the nose (Hutchinson sign) and increases the risk for corneal denervation and ocular inflammatory disease by 4.02 and 3.35 times, respectively (47). Ocular complications occur in about half of all patients with HZO, although rarely, it may occur in the absence of skin lesions (zoster sine herpete) (48). Common anterior segment manifestations of HZO include conjunctivitis, keratitis, neurotrophic and exposure keratopathy, uveitis, keratouveitis, episcleritis, scleritis, and ocular surface abnormalities (49,50). Posterior segment complications such as vitritis, retinitis, and optic neuritis are uncommon.
Although a clinical diagnosis can be established in cases with classic presentation, diagnostic testing using PCR and serology on paired serum/ocular fluid samples are needed in case of diagnostic uncertainty. Systemic antiviral treatment improves dermatologic healing, decreases pain, and reduces rates of severe ocular complications (51). Valacyclovir (1 g 3 times daily for 7–10 days) is preferred in uncomplicated HZO because of simplified dosing, better pharmacokinetics, and better efficacy in decreasing the duration of acute zoster pain and PHN (40,52). A short course of corticosteroids (60 mg/day tapered over 2 weeks) may be used as an adjunct to reduce acute zoster pain. The use of steroids, however, does not decrease frequency of PHN (53,54).
VARICELLA ZOSTER RETINAL DISEASE
VZV produces retinal perivasculitis and various forms of necrotizing retinopathy such as acute retinal necrosis (ARN) and progressive outer retinal necrosis (PORN). Although ARN is more common in immunocompetent individuals, PORN occurs in immunosuppressed patients. ARN is diagnosed clinically using the criteria established by the Executive Committee of the American Uveitis Society. These include the following: 1) presence of one or more clearly defined foci of retinal necrosis located in the retinal periphery (Fig. 2); 2) rapid disease progression in the absence of antiviral treatment with circumferential spread; 3) occlusive vasculitis with arteritis; and 4) significant anterior and posterior segment inflammation (55). Varicella retinitis is a devastating disease with poor visual outcomes; visual acuity is worse than 20/200 in about half of the affected eyes due to secondary complications such as retinal detachment, chronic vitritis, epiretinal membrane, and maculopathy (56).
Systemic antiviral treatment should be initiated immediately in a patient suspected of having varicella retinitis without waiting for diagnostic confirmation. Intravenous acyclovir (10 mg/kg 3 times daily for 14 days) followed by several months of oral antiviral therapy is the treatment of choice for improving visual outcomes by promoting regression of retinitis and reducing rates of retinal detachment and fellow eye involvement (57,58). Without antiviral treatment, about 60%–70% of affected patients will develop bilateral disease (57). Diagnostic viral confirmation should be obtained through PCR and serology performed on paired samples of serum and intraocular fluid (aqueous or vitreous). Appropriately dosed oral valacyclovir achieves equivalent plasma acyclovir levels and has been shown to have equivalent therapeutic efficacy compared with traditional doses of intravenous acyclovir (59–61). The American Academy of Ophthalmology guidelines on management of ARN recommend a 7- to 10-day induction course of oral valacyclovir (6,000–8,000 mg daily) followed by longer term maintenance therapy with valacyclovir 1,000 daily for 6 months or more as an alternative treatment option in patients with ARN without neurological involvement (62). Intravitreal foscarnet is recommended as an adjunct to systemic antiviral therapy in ARN. Compared with monotherapy with systemic antiviral, combined treatment using systemic antiviral and intravitreal foscarnet has been shown to provide better visual outcomes and reduced incidence of retinal detachment (63,64).
Optic neuropathy is an uncommon sequela of herpes zoster seen in less than 0.5% patients with HZO (65). Herpes zoster optic neuropathy (HZON) may develop in the acute or late stages of HZO. It may accompany anterior and/or posterior forms of HZO and may present with papillitis, posterior optic neuropathy, or optic atrophy (66). A clinical diagnosis of HZON is established on the basis of close temporal association of ON with HZO and exclusion of other etiology. Isolated cases of HZON developing before skin rash and in disparate dermatomes as the preceding skin rash (nontrigeminal or contralateral trigeminal) and bilateral HZON also have been reported (67–69). A review of 6 patients with HZON seen within 1 month of zoster rash offers insight into the difficulties experienced in the diagnosis and management of HZON (16). The pathophysiology of HZON is unclear, and multiple mechanisms have been proposed. These include optic nerve invasion of the VZV through continuous and hematogenous routes and ocular ischemia secondary to vascular inflammation (70–72).
Diagnostic testing using contrast-enhanced MRI and CSF studies were found to be of limited utility in most studies. The use of systemic antiviral treatment may result in modest improvement in visual function in about 50% patients. Adjunctive treatment with systemic corticosteroids does not show any clear benefit and may increase risk for VZV disease extension to the retina (73).
All patients with acute optic neuropathy in the setting of HZO should undergo MRI of the brain and orbit with fat-suppressed sequences to evaluate optic nerve changes. Confirmatory testing (PCR and serology) should be obtained on paired samples of serum and CSF (in isolated HZON) or intraocular fluid (in patients with uveitis). Patients with evidence of neurological involvement require prompt treatment with intravenous antiviral medications (acyclovir 10–15 mg/kg every 8 hours for 2–3 weeks). Those with isolated optic neuropathy may be managed with oral antiviral medications. We do not recommend adjunct steroid treatment because of unclear benefits and risk of VZV retinitis.
VARICELLA ORBITOPATHY AND CRANIAL NEUROPATHY
VZV can present with ophthalmoplegia from neurological or orbital lesions resulting in internuclear ophthalmoplegia, skew deviation, isolated or combined ocular motor cranial nerve (third, fourth, and sixth) palsy, and orbital myositis (74–77). Ocular motor cranial neuropathy has been reported to occur in 7%–31% HZO, whereas complete unilateral ophthalmoplegia is a rare manifestation of HZ. Higher rates of CSF pleocytosis and radiological features of orbital inflammation such as enlarged extraocular muscle and soft-tissue enhancement were reported in a review of 20 cases with complete ophthalmoplegia (78). HZO can rarely cause orbital signs such as proptosis, ptosis, chemosis, and ophthalmoplegia. Orbital MRI sequences in these patients may demonstrate enlargement of the extraocular muscle and enhancement of the extraocular muscle, orbital soft tissue, larcimal gland, and optic nerve sheath (79). The prognosis for recovery of ophthalmoplegia is excellent; greater than 90% patients achieve relief from diplopia in primary gaze by 6–12 months (17,77–79).
All patients with partial or complete ophthalmoplegia in the setting of HZ should have contrast-enhanced MRI of the brain and orbits. Lumbar puncture should be performed in patients with intracranial lesions on MRI imaging, such as meningeal enhancement, ischemic stroke, or vasculopathy (Fig. 1). Patients with imaging and/or CSF evidence of VZV (VZV DNA or intrathecal antibody production) should be treated with intravenous antiviral medications (acyclovir 10–15 mg/kg every 8 hours for 2–3 weeks). Patients with isolated cranial neuropathy can be managed with oral antiviral medications on an outpatient basis. Adjunctive treatment with a short course (5 days) of corticosteroids may be prescribed. Patients with persistent diplopia and ocular misalignment at 12 months may need optical (prism) or surgical correction.
PHN, the most common sequela of HZ, is defined as dermatomal pain, which persists at least 3 months after the initial episode of zoster. Pain symptomatology includes intermittent or constant burning, aching, or lancinating pain accompanied by allodynia and itch in the same dermatomal area as the skin rash. The prevalence of PHN varies from 5% to 30% depending on the study design and specific population studied (80). Age is an important risk factor with a 3-fold increase in PHN from 50 to 80 years of age (81). Other risk factors include female sex, increased severity of prodromal or acute zoster pain, premorbid functional status, immunocompromised condition, and involvement of the head and neck regions (82–84). PHN results in poor quality of life, psychosocial dysfunction, and loss of independence in the elderly (85). The pathophysiology of PHN is not well-understood and likely multifactorial. The presence of VZV-specific protein and DNA in mononuclear cells in patients with chronic recurrent ganglionitis suggests persistent VZV infection after HZ (86,87). Peripheral neuronal damage then sets into motion a sequence of events resulting in central neuronal changes, which makes pain management difficult (88). Postmortem studies have shown neuronal damage in the peripheral nerves and sensory ganglia, degenerative changes in the spinal cord, and brainstem including the mesencephalic trigeminal pain nucleus (89,90).
Management of PHN is difficult and requires a multidisciplinary approach with a clear plan for escalation depending on response. Table 2 lists the treatment modalities for PHN. Although a detailed discussion of individual treatments is beyond the scope of this review, familiarity with these modalities is helpful in management of the patient with HZO and intractable pain.
NEUROLOGICAL MANIFESTATIONS OF VARICELLA ZOSTER VIRUS
Table 3 summarizes the common neurological manifestations from VZV infection. Given its importance and relevance to neuro-ophthalmologists, we discuss VZV-related central nervous system (CNS) vasculopathy and its complications below.
VARICELLA ZOSTER VIRUS–RELATED CENTRAL NERVOUS SYSTEM VASCULOPATHY
VZV vasculopathy results from the transaxonal spread of VZV to the adventitia of cranial arteries. Transmural viral spread is followed by inflammation and intravascular thrombosis. A granulomatous arteritis with transmural inflammation, arterial media necrosis, and giant cell formation is noted on histopathologic examination (91). Large-vessel VZV vasculopathy is seen as focal and segmental arterial narrowing on angiography. It usually occurs in immunocompetent, older adults who present with stroke-like symptoms within a few weeks of HZ. Small-vessel vasculitis, on the other hand, typically occurs in immunocompromised individuals. Presentation is myriad with transient ischemic attack (TIA), ischemic or hemorrhagic stroke, seizures, headache, or altered mental status. Multifocal white matter lesions are seen on brain MRI. A meta-analysis of 11 observational study with more than 4 million subjects showed that there was a 30% increased risk for ischemic stroke/TIA after HZ and 90% increased risk after HZO. This risk was highest within 1 month of HZ (RR 1.92), for younger (less than 40 years) individuals (RR 2.03) and untreated HZ (RR 1.38) (92).
Vision loss from anterior ischemic optic neuropathy secondary to VZV vasculopathy also has been reported (71,72,93). A clinical diagnosis of CNS VZV vasculopathy may be evident when neurological signs and symptoms occur in the setting of a classical HZ skin rash. However, 30%–40% patients may have an absence of typical skin rash, a delay between skin rash and neurological symptoms, and normal CSF examination, which makes diagnosis difficult (94).
Diagnostic confirmation should be obtained in all patients with a neurological presentation. This includes an MRI and MR angiography of the brain and CSF examination. Less than a third of patients with VZV vasculopathy have detectable VZV DNA in the CSF. Serologic confirmation is more reliable. Greater than 90% patients have anti-VZV IgG antibody in CSF with a reduced serum/CSF ratio of anti-VZV IgG indicative of intrathecal synthesis of anti-VZV IgG (94,95). We recommend real-time PCR combined with serology on paired serum and CSF specimen to maximize diagnostic yield in these patients.
Patients who develop stroke-like symptoms should be evaluated and managed using standard guidelines for acute stroke management. On confirmation of VZV vasculopathy, patients should be treated aggressively with intravenous antivirals (10–15 mg/kg every 8 hours for 2–3 weeks). Patients with recurrent disease or immunocompromised patients require prolonged oral antivirals for 3–6 months after the induction treatment. We recommend a 5-day course of oral prednisone at treatment initiation (1 mg/kg/day) (96).
GIANT CELL ARTERITIS AND VARICELLA ZOSTER VIRUS
Similarities in the clinical presentation and pathology of giant cell arteritis (GCA) and varicella vasculopathy suggest a potential role for VZV in GCA. Using IHC, a group of investigators found VZV antigen in the walls of the temporal artery in 70% biopsy-positive GCA, 58% biopsy-negative GCA and 18% normal (autopsy) controls. The likelihood of finding VZV antigen was 3.89 times greater in the vessel wall of biopsy-positive GCA and 3.22 times in biopsy-negative GCA compared with controls. VZV antigen was also detected in the perineural cells expressing claudin-1 around nerve bundles adjacent to areas of adventitial inflammation in GCA-positive biopsy specimens. This led the investigators to hypothesize that GCA results from transaxonal transport of reactivated VZV from autonomic ganglia to the wall of the temporal artery, activating the dendritic cells, which results in arteritis (93,97–99). The evidence presented, however, is insufficient to prove causality by Hill's criteria (100). Lack of reproducibility (101–105) and lack of supportive clinical and epidemiologic evidence are major drawbacks. Despite increasing incidence of HZ, the incidence of GCA remains unchanged (1,106). Moreover, VZV vaccination has failed to decrease the incidence of GCA, despite a 50%–90% efficacy in reducing HZ in the vaccinated individuals (107). Finally, only 4% of GCA cases are preceded by HZ suggesting lack of temporal association between HZ and GCA (108). The role of VZV in the pathogenesis of GCA (if any) remains unclear, but it is quite possible that, in a subset of patients with GCA, VZV is the underlying etiology or a precipitating factor. There is insufficient information at present to recommend the routine use of antiviral therapies, except in patients with clear evidence of active HZ infection. In those individuals in whom immunosuppressive medications fail to control the disorder, antiviral therapy may be considered.
Prevention is better than cure! Two FDA-approved VZV vaccines are currently available for clinical use in adults. Zostavax, a live attenuated VZV vaccine, was approved in 2006. Shingrix, a recombinant subunit (glycoprotein E) vaccine, was approved in 2017 for use in immunocompetent adults over 50 years. Both vaccines have excellent efficacy in decreasing the incidence of HZ and PHN (109–111). Although the live attenuated vaccine reduces HZ rate by 51% at 3-year follow-up (107), the efficacy of the recombinant subunit vaccine was 91.3% for preventing HZ and 88.8% for preventing PHN in adults over 70 years (112). The vaccinations are anticipated to decrease the neurological and ophthalmological complications by reducing the incidence of HZ. The CDC recently issued guidelines for vaccination of individuals at risk for HZ (111). Shingrix is the preferred vaccine in healthy adults due to better efficacy. Immunocompetent adults aged 50 years and older should receive 2 doses of Shingrix separated by 2–6 months irrespective of previous history of HZ or Zostavax vaccination. Shingrix may be prescribed for patients with chronic medical conditions, unless there is a contraindication to its use such as a history of severe allergic reaction. For patients with acute HZ, it is advisable to wait for resolution of symptoms before administering Shingrix.
HZ can produce significant neurological and ophthalmological complications with postherpetic neuralgia occurring in a third of affected individuals. Involvement of the retina, optic nerve, orbit, and cranial nerves is relatively uncommon compared with dermatologic and ocular anterior segment manifestations. VZV DNA detection using PCR is the diagnostic modality of choice with 95%–100% sensitivity and specificity. Real-time PCR in combination with serology on paired serum and CSF or intraocular fluid in patients sampled 2–3 weeks after disease onset maximizes the diagnostic yield. Treatment with oral antiviral medications should be started within 48–72 hours of onset of the zoster rash. Intravenous acyclovir should be started immediately in patients with neurological and retinal manifestations. All adults above 50 years should be encouraged to receive VZV vaccination, which has excellent efficacy in decreasing HZ.
We reviewed medical literature published in the English language, through a search on PubMed and Google Scholar using combination of search terms Varicella Zoster, herpes zoster, zoster ophthalmicus, acute retinal necrosis, optic neuropathy, optic neuritis, third nerve palsy, fourth nerve palsy, sixth nerve palsy, postherpetic neuralgia, and antiviral treatment. Additional articles were identified through reference linkage from the original list of references from the search. We prioritized references that were recent and relevant to the topics being covered. The list of reference is not exhaustive.
STATEMENT OF AUTHORSHIP
Category 1: a. conception and design: S. Kedar; b. acquisition of data: S. Kedar and L. N. Jayagopal; c. analysis and interpretation of data: S. Kedar, L. N. Jayagopal, and J. R. Berger. Category 2: a. drafting the manuscript: S. Kedar and L. N. Jayagopal; b. revising it for intellectual content: S. Kedar, L. N. Jayagopal, and J. R. Berger. Category 3: a. final approval of the completed manuscript: S. Kedar, L. N. Jayagopal, and J. R. Berger.
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