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High-resolution MRI vessel wall imaging in varicella zoster virus vasculopathy

Introduction The vascular complications of herpes zoster are well recognised, however, there are few reports of central retinal artery occlusion. These clinical features have been well characterized by various imaging modalities, but not using fundus autofluorescence (FAF), a noninvasive method of evaluating the neurosensory retina and retinal pigment epithelium (RPE) based on the detection of endogenous fluorophores. Intravenous acyclovir and oral prednisolone were given simultaneously. We present here the first reported case of herpes zoster ophthalmicus complicated by orbital apex syndrome in a patient from Taiwan. From there it may travel along neurons to the sensory axons of the skin to form vesicular lesions. A and B, Nonenhanced and enhanced T2-weighted FLAIR images at the level of the pons show minimal abnormal high signal intensity in A and avid enhancement in B in the left ambient cistern, supracerebellar cistern, cerebellar vermis and adjacent subarachnoid space along the tentorium (arrowheads). The rest of the Topic content has been deleted including this subtopic.

Gender and disease laterality were not statistically different between the 2 groups. In the largest series of VZV vasculopathy, neurovascular imaging (conventional angiography or magnetic resonance angiography) demonstrated intracranial vessel involvement in up to 70% of the cases [2]. The ophthalmoplegia and optic neuritis, but not the anisocoria, gradually resolved during tapering of oral therapy. In the case of HSK, there is an 11 per cent risk of vision less than 20/200 in an affected eye at 20 years following the first occurrence. While treatment reduces further stroke [4], the course of resolution of vessel inflammation and stenosis is unknown. Recent studies using contrast-enhanced vessel wall imaging high-resolution MRI (HRMR) showed that vessel wall thickening and enhancement correlate with vessel wall inflammation in central nervous system vasculitis [5], including VZV vasculopathy [6,7], however, data on follow up imaging after treatment has not been previously published. Knowledge of the extent and evolution of vessel wall enhancement, which likely reflects inflammation, may help to guide treatment.

Zamora et al reported the case of a 69 year old female who presented with multiple bilateral branch retinal artery occlusions following a bilateral vitritis [4]. A previous study showed that the green-light FAF images (514 nm) are superior for the accurate analysis of small, central, pathologic changes, and for the determination of the central geographical atrophy lesion size. The patients were included only if they had initial and subsequent follow up HRMR as part of the evaluation. Neurological complications are less frequent than ocular complications, and may include ophthalmoplegia, optic neuritis, ptosis, and (rarely) orbital apex syndrome (OAS) [3]. Decreased sensation is very suspicious for herpes simplex virus (HSV). Imaging was performed on 3T whole-body scanners (Skyra; Siemens, Erlangen, Germany). Three complete topics are available for viewing using links at the top of this page or please register for a free trial for complete access to all Topics.

High-resolution imaging ensued using four T1-weighted spin-echo sequences in the coronal, axial and sagittal planes. The first scan was without contrast, and the following 3 were with contrast (Gadobutrol, Gadovist; Bayer Schering Pharma, Berlin, Germany): (1) a non-contrast T1 coronal 2-mm section with no gap (TR/TE = 11/544 ms), matrix = 256 × 256, and FOV=130×130 mm; (2) a post-gadolinium T1 coronal 2-mm section with no gap and fat suppression and a saturation band (TR/TE = 11/544 ms), matrix = 256×256, and FOV = 130× 130 mm; (3) a post-gadolinium T1 axial 2-mm section with no gap and fat suppression and a saturation band (TR/TE=11/750 ms), matrix=256×256, and FOV= 130×130 mm; and (4) a post-gadolinium sagittal 2-mm section with a 0.4-mm gap and no fat suppression and a saturation band (TR/TE=10/600 ms), matrix= 256×256, and FOV=130× 130 mm. MRI and computed tomographic images of the head showed no signs of meningitis or edematous changes in the cerebral parenchyma. There is some evidence that increasing the duration of treatment from 12 months to 18 months will reduce the recurrence rate further. Imaging outcome on HRMR was classified as stable, improved or worsened, based on changes in vascular stenoses and pattern of enhancement. Clinical characteristics, imaging and treatment are summarized in . Six patients with a diagnosis of VZV vasculopathy underwent initial and follow up HRMR between April 2011 and May 2014.

Dual therapy was commenced with ocular massage and intravenous acetazolamide and high dose intravenous (IV) methylprednisolone (1 gram daily) and oral famciclovir (500 mg TDS) for a possible underlying vasculitic cause or optic neuritis. (A-C) Color fundus photograph and fluorescein angiography demonstrating presentation of an ARN lesion and vasculitis. Of the patients with recurrent ischemic events, 3 of them also had non-specific symptoms that were not initially attributed to the ischemic events, including headache, dizziness, fatigue and memory changes. Physical examination showed markedly crusted skin lesions in the distribution of V1 on the left side, with a positive Hutchinson’s sign and complete levator paralysis. For episodes of scleritis, retinitis, choroiditis, and optic neuritis, systemic steroids by mouth or intravenous administration should be strongly considered. One patient had a liver transplant and was taking tacrolimus 5 months before cerebrovascular symptoms. The rest of the Topic content has been deleted including this subtopic.

After the onset of symptoms, the diagnosis of VZV vasculopathy was delayed by 1 month to 2 years, and was subsequently made based on CSF studies in association with intracranial vascular involvement. Five patients had a cerebral angiogram, one demonstrating a focal stenosis with post-stenotic dilatation, and the other four with diffuse irregularities and stenoses. Photographs of eye positions in all directions, and the pupils and face of our patient before treatment. All patients underwent HRMR on initial visit with a timing that varied from 1 month to 2 years from the onset of initial symptoms. Five of 6 patients (patients 1, 2, 4–6) had vascular stenoses and vessel wall enhancement on HRMR. In patient 3, motion-degradation precluded adequate assessment of thickening and enhancement, although stenosis was evident in the A1–A2 junction of the ACA bilaterally. Two patients had 1 follow-up HRMR, 3 patients had 2 follow-up HRMRs and 1 patient had 4 follow-up HRMRs.

JB, KK and AH contributed significantly to drafting the manuscript and reviewing for content. FAF changes have been reported in a case of PCR-proven varicella zoster-associated progressive outer retinal necrosis (PORN) and herpes simplex virus retinitis [13,14]. In patient 1, who was treated with intravenous acyclovir for 8 weeks followed by oral valacyclovir for 12 months, and in patient 2, who was treated with intravenous acyclovir for 3.5 weeks followed by oral valacyclovir for 3 months, follow-up HRMR showed complete resolution of both stenoses and enhancement at 21 months () and 3 months (), respectively. The patient was discharged after completion of the acyclovir therapy. ↑ Chapman RS, Cross KW, Fleming DM. None of these 4 patients had stroke recurrences. Three complete topics are available for viewing using links at the top of this page or please register for a free trial for complete access to all Topics.

Patient 6 had persistent enhancement with progression of stenoses at 5 months (); despite antiviral treatment, cerebral ischemia recurred and he died 8 months after onset of disease. Contrast-enhanced high-resolution MRI (HRMR) over time in Patient 1. Levels of cells and proteins in the cerebrospinal fluid were also decreased. Contrast-enhanced high-resolution MRI (HRMR) over time in Patient 2. At presentation, coronal (a) and axial (b) HRMR reveal vessel wall thickening and enhancement of both terminal ICA segments; 3 months later, coronal (c) and axial (d) HRMR demonstrate … Contrast-enhanced high-resolution MRI (HRMR) over time in Patient 4. At presentation, coronal (a), axial (b) and oblique magnified views (c) demonstrate stenosis, with post-stenotic dilatation of the M1 segment of the left MCA and vessel wall enhancement …

Contrast-enhanced high-resolution MRI (HRMR) over time in Patient 5. The areas of retinal atrophy seen on color fundus photography that previously demonstrated active retinitis on FA showed persistent hypoautofluorescence. Contrast-enhanced high-resolution MRI (HRMR) over time in Patient 6. Although we did not perform laboratory investigations to detect VZV, we consider that our patient was more likely to have VZV lesions than zosteriform herpes simplex virus lesions because of the lack of recurrence during 6 months of follow-up and the varying sizes of vesicles in the clusters. J Infect Dis 1992;166:1153-1156. Disease was not confirmed virologically until weeks to months after recurrent ischemia or progressive neurologic symptoms. The rest of the Topic content has been deleted including this subtopic.

In this series, all patients underwent additional modalities of vascular imaging, including MRA and/or cerebral angiography, which demonstrated focal and diffuse areas of stenosis. Contrast uptake in the vessel wall at the site of stenosis observed on initial HRMR likely reflected continued virus infection and vessel wall inflammation [5,9]. They used systemic prednisolone 30 mg followed by tapering. Although VZV vasculopathy can affect large and small intracranial vessels [2], small distal vessels are not well imaged with HRMR. This is certainly a limitation for this imaging technique since it does not provide accurate information on distal intracranial vessels that may be infected with VZV. The degree of vessel involvement as monitored by HRMR differed among the patients, and evolution of disease varied even during therapy, with resolution of both vessel wall enhancement and stenosis as early as 3 months and as late as 21 months after initial imaging. Resolution of vessel wall enhancement without change in the underlying stenosis, as well as persistent stenosis and enhancement with clinical worsening, were also observed.

Such variability might result from different duration of antiviral therapy, or might reflect different stages of arterial involvement by virus, especially since diagnosis was made at intervals ranging from 1 month to 2 years after the onset of symptoms and the timing of initial and follow-up imaging from onset of symptoms was not uniform. Only one patient was on immunosuppressive therapy (tacrolimus) at baseline, and steroids were used in only 3 patients during the treatment. It is possible that the variability in imaging and clinical response may have been influenced by the individual immune response of each patient, however, this cannot be determined in this small group of patients; thus, correlation between clinico-radiologic evolution and immunosuppressive treatment cannot be evaluated in this small cohort. Although the optimal therapy for OAS due to HZO remains unclear, the current mainstay of treatment is combined administration of systemic acyclovir and steroids [11-15]. Trans Am Ophthalmol Soc 1942;40:390-439. Treatment duration decisions are based on the disappearance of clinical symptoms, which does not necessarily indicate eradication of virus infection in the affected arteries. It manifests with bruising and bleeding into the rash.

Thus, HRMR is a powerful tool to help guide duration of therapy and may also be helpful in the presence of persistent vessel wall enhancement indicating continued inflammation. This study has several limitations. Dhingra et al9 reported a case of orbital apex syndrome associated with herpes zoster ophthalmicus and multiple myeloma. There was significant variability in the clinical presentation, the interval from disease onset to diagnosis, timing of initial and follow up imaging, as well as variable treatment modalities and duration. HRMR is a technique that is time consuming, not widely available, and that requires cooperative patients; additionally, it provides information centered in the proximal circle of Willis with poor visualization of small distal vessels. While our patients had VZV vasculopathy, they were not exempt from atherosclerotic risk factors, which can also lead to intracranial vessel involvement and it has been reported that contrast enhancement can be seen with atherosclerosis disease [5]. A relationship between VZV and atherosclerotic risk factors has not been established, and an interaction between these conditions cannot be ruled out.

The results of our study are hypothesis generating and should be interpreted cautiously. A larger prospective controlled trial is required to confirm our findings, and further investigate the evolution of VZV vasculopathy and response to therapy. In 4 of 6 patients treated with antiviral agents for VZV vasculopathy, clinical stability or improvement correlated with improvement in arterial stenosis, vessel wall enhancement or both. Orbital MRI should be performed to exclude more common causes of OAS. This work was supported in part by Public Health Service grants AG032958 and AG006127 from the National Institutes of Health. The authors thank Marina Hoffman for editorial assistance and Cathy Allen for the word processing and formatting of the manuscript. These lesions appeared on the face and trunk on day 3 of admission.

As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. The pathological mechanism for ophthalmoplegia in cases of herpes zoster ophthalmicus has not been determined. 9. Cerejo R, John S, Hammad T, et al. Vessel wall characteristics using high resolution magnetic resonance imaging in reversible cerebral vasoconstriction syndrome and central nervous system vasculitis. Stroke; International Stroke Conference; Honolulu.

February 6, 2013; 2013. AWMP55.