Expert Review of Anti-infective Therapy

ISSN: 1478-7210 (Print) 1744-8336 (Online) Journal homepage: http://www.tandfonline.com/loi/ierz20

Focal herpes zoster encephalitis without a rash: diagnostic confusion between astrogliosis and lowgrade glioma Geoffrey C. Halling & Charles Grose To cite this article: Geoffrey C. Halling & Charles Grose (2016): Focal herpes zoster encephalitis without a rash: diagnostic confusion between astrogliosis and low-grade glioma, Expert Review of Anti-infective Therapy, DOI: 10.1080/14787210.2016.1248944 To link to this article: http://dx.doi.org/10.1080/14787210.2016.1248944

Accepted author version posted online: 17 Oct 2016. Published online: 27 Oct 2016. Submit your article to this journal

Article views: 34

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierz20 Download by: [95.181.217.17]

Date: 03 November 2016, At: 07:07

EXPERT REVIEW OF ANTI-INFECTIVE THERAPY, 2016 http://dx.doi.org/10.1080/14787210.2016.1248944

EDITORIAL

Focal herpes zoster encephalitis without a rash: diagnostic confusion between astrogliosis and low-grade glioma Geoffrey C. Hallinga and Charles Groseb a

Medical School, Wayne State University, Detroit, Ml, USA; bVirology Laboratory, Children’s Hospital, University of Iowa, Iowa City, IA, USA

ARTICLE HISTORY Received 1 August 2016; Accepted 12 October 2016 KEYWORDS Varicella virus; herpes zoster; encephalitis; astrocyte; acyclovir; glioma

Herpes zoster encephalitis can be a difficult diagnosis in the absence of a rash. The point of this editorial is to describe clinical cases in which magnetic resonance imaging (MRI) of brain led to the initial diagnosis of low-grade glioma rather than encephalitis. Herpes zoster has been considered to be the reactivation of the same varicella-zoster virus (VZV) strain that first infects an individual during the childhood disease varicella (chickenpox) [1]. Recent genomic analyzes also suggest that some adults have been infected with different VZV strains that can lead to recombination [2]. However, recombination between the live attenuated vaccine strain and a wildtype strain has not been detected during human disease. After the illness varicella, VZV enters the sensory nerves, travels to the dorsal root ganglia and the trigeminal ganglia, where the virus establishes latency [1]. Since the characteristic exanthem of varicella begins on the upper face, almost 30% of adults have latent VZV in their trigeminal ganglion. Consequently, the single most common ganglion from which VZV reactivates is the trigeminal ganglion (cranial nerve V) [3]. Recent surveys of encephalitis following varicella and herpes zoster have been published but the authors did not mention any instances of misdiagnosis by MRI [4]. Herpes zoster encephalitis occurs when VZV reactivates, for example, in the trigeminal ganglion, and subsequently enters the brain via neuronal conduits [5,6]. When the symptoms of central nervous system (CNS) infection are accompanied by an obvious case of herpes zoster, the diagnosis of herpes zoster encephalitis is easily made clinically and MRI is only used for localization [7–9]. This editorial describes the exception: three recently published cases of focal herpes zoster encephalitis without a concomitant zoster rash over the face. Furthermore, in two of the three cases, the viral diagnosis was delayed because a low-grade glioma was the initial diagnosis, based on an initial interpretation of a brain MRI.

1. Case reports The first case presented in an immunocompetent 22-year-old male, following a first time seizure episode [10]. The patient had experienced headaches in the left temporal area the week preceding the seizure but had no zosteriform rash. An MRI demonstrated a 15 x 14 × 9 mm lesion along the left inferior CONTACT Charles Grose,

[email protected]

© 2016 Informa UK Limited, trading as Taylor & Francis Group

temporal sulcus that was favored to be a low-grade glioma (Figure 1). Examination of the resected lesion revealed absence of neoplastic cells but presence of inflammatory cells, indicating a possible viral etiology. Further fluorescence-based testing included positive assays for varicella antigens. Subsequent PCR assay validated wild-type VZV DNA in the lesion. After confirmation of the VZV diagnosis, the patient was treated with valacyclovir (1 g tablet TID) for 12 months. The patient continued to be free of recurrence when interviewed three years after initial diagnosis. The second case involved an immunocompetent 66-yearold male presenting with fever and severe amnesia but no zosteriform rash [11]. MRI revealed symmetrical bilateral lesions in his medial temporal lobes. HSV encephalitis was suspected based on symptoms and the patient was started on intravenous acyclovir. However, after 11 days of treatment the patient had not recovered. Upon re-evaluation at another medical center, the patient’s fever had subsided but amnesia persisted. A detailed CSF analysis was positive for VZV DNA and negative for HSV DNA. The patient was treated with intravenous acyclovir (1500 mg/day) for another 19 days, as well as methylprednisolone therapy. Follow up assessment by MRI showed lessened signal intensity with atrophy of the affected brain; another CSF test was negative for VZV DNA but there was only slight improvement in his amnesia. The patient continued to have amnesia when examined three years after initial diagnosis. The third case evolved over a 5-year period [12]. In 2010, an immunocompetent 63-year-old male presented with herpes zoster of right S1–S2 dermatomal distribution, which was successfully treated with oral valacyclovir (1 g TID for 1 week). Six months later, he noticed transient global amnesia. MRI revealed a focal lesion in the white matter near the left ventricle. Glioma was considered as the most likely diagnosis; however, extensive investigation of a needle biopsy showed only a hypercellular astrocytic response with absence of neoplasia, vasculitis, or necrosis. His cognitive impairment gradually worsened over 2014–2015. Because of the publication of case 1 above, the original needle biopsy was re-examined by two different virology laboratories; both detected VZV antigens in the brain tissue by immunohistochemistry and immunofluorescence. The patient was treated in late 2015 with

University of Iowa Children’s Hospital, 200 Hawkins Drive, Iowa City, IA 52242, USA

2

EDITORIAL

Figure 1. Astrogliosis following focal herpes zoster encephalitis. (a) MRI of brain of case 1. The site of focal herpes zoster encephalitis in the temporal lobe is marked with an arrow. G = gray matter; W = white matter. (b) Activated astrocyte in the brain biopsy. The uninfected astrocyte is immunolabeled with antibody to GFAP. (c) Focus of VZV infection in temporal lobe. A 3-dimensional rendering of a focus of VZV-infection was made from numerous confocal images by the Imaris software program. Green = astrocytes infected with VZV and immunolabeled with antibody to the viral gH protein; red = uninfected astrocytes labeled with antibody to GFAP; blue = nuclei. Also see reference 17.

intravenous acyclovir (30 mg/kg/day) for 2 weeks followed by valacyclovir (1 g TID) for 3 months with marked improvement in cognitive testing.

2. Increasing incidence of herpes zoster in the twenty-first century A recent paper is relevant because the authors document an unexplained and unexpected increase in the rate of herpes zoster in the United States in the twenty-first century [13]. These authors examined the long-term trend of herpes zoster in the city of Rochester, Minnesota. The Mayo Clinic maintains the Rochester Epidemiology Project; the database includes over 8000 herpes zoster cases. The age- and sex-adjusted incidence rate of herpes zoster increased from 0.76 per 1000 person-years in 1945–1949 to 3.15 per 1000 person years in 2000–2007.

3. Persistence of zoster vaccine efficacy for 8 years The live attenuated herpes zoster vaccine contains the same live attenuated virus as the varicella vaccine, but the potency is at least 14× greater. The vaccine was approved for adults over 60 years of age in the United States in 2006. The LongTerm Persistence Substudy (LTPS), was undertaken to further assess vaccine efficacy in 6867 herpes zoster vaccine recipients, who were followed for 11 years post-vaccination [14]. Most importantly, when the data were analyzed year-by-year, the results showed that herpes zoster vaccination reduced the incidence of herpes zoster only through year 8 after vaccination.

4. Low-grade gliomas Low-grade gliomas are tumors that arise from supporting cells of the brain, and include astrocytomas, oligodendrogliomas, or mixed gliomas [15]. About 20% of all gliomas are diagnosed as low-grade gliomas. They occur most commonly in adults between the ages of 30–45 years. Epileptic seizures are a frequent symptom and may increase with progression of the glioma. Cognitive functioning is often impaired by a low-grade

glioma. Patients may have problems with memory and concentration as well as unusual difficulty with carrying our some tasks that were once familiar to them. In one small survey of 20 low-grade gliomas, the neurosurgeons found one misdiagnosed case that was actually focal acute encephalitis [16].

5. Astrogliosis after VZV infection in the brain Our first case of focal herpes zoster encephalitis is important because the entire lesion in the temporal lobe was removed neurosurgically. VZV proteins were easily detected in the brain tissue, using monoclonal antibodies with fluorescent tags (Figure 1). A subsequent unexpected finding was the presence of astrocytes and astrogliosis surrounding sites of VZV infection [17]. Astrocytes were visualized by immunostaining with antibody against glial fibrillary acidic protein (anti-GFAP). The proliferation of these astrocytes in response to a stressor such as virus infection is termed astrogliosis. Astrogliosis was not previously known to produce an MRI lesion closely resembling a low-grade glioma. As with case 1, the MRI from case 3 was interpreted to represent a low-grade glioma. Although the brain lesions in case 2 were not interpreted as a glioma, they were similar in appearance to the lesions seen in cases 1 and 3.

6. Comments about diagnosis and treatment Through the year 2012 [4], relatively few verified cases of VZV encephalitis without rash or primary vasculopathy were reported. In our three cases, one had a positive PCR test for VZV DNA in the cerebral spinal fluid, one had a positive VZV antigen test on brain biopsy and one had a positive brain biopsy by both VZV PCR and antigen testing. All three cases required MRI for diagnosis. A comparison of cases 1 and 3 is of interest in that both brain lesions seen on MRI were read initially as a low-grade glioma. We now know through a detailed microscopic analysis of case 1 that the lesion secondary to VZV-induced astrogliosis can resemble an astrocytoma by MRI (Figure 1). Furthermore, all three cases have been followed for at least 3 years and none developed an astrocytoma.

EXPERT REVIEW OF ANTI-INFECTIVE THERAPY

Since the incidence of herpes zoster is increasing and the duration of protection after herpes zoster vaccination declines by year 8, there will be an increasing percent of an older population susceptible to herpes zoster encephalitis. Case 3 may also reveal the time required for astrogliosis to become detectable by MRI. If the brain infection began at the same time as the episode of zoster on the leg, 6 months was the interval required for development of the astrogliosis lesion. With regard to duration of treatment, we point out that case 1 was treated for one year with oral valacyclovir. At a 3-year follow-up evaluation, he had no recurrence of CNS symptoms. Case 2 was treated with 4 weeks of intravenous acyclovir; his minimal recovery of CNS function may be related to his bilateral focal encephalitis. Once the diagnosis of focal herpes zoster encephalitis was made in case 3, he was treated with 2 weeks of intravenous acyclovir followed by 3 months of oral valacyclovir, with considerable recovery of CNS function. Pending the publication of further cases and their outcomes, we recommend prolonged therapy, especially with oral valacyclovir since the drug is well tolerated with few side effects; dosage adjustment may be required in patients with decreased renal function. Thus, this editorial lengthens earlier recommendations for treatment of viral encephalitis [18]

Funding This paper was supported by a grant from the National Institutes of Health (grant number: AI89716).

Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties

References Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

3

1. Weller TH. Varicella and herpes zoster. Changing concepts of the natural history, control, and importance of a not-so-benign virus. N Engl J Med. 1983;309:1434–1440. •• Review of VZV infection by Nobel Laureate. 2. Norberg P, Depledge DP, Kundu S, et al. Recombination of globally circulating varicella-zoster virus. J Virol. 2015;89:7133–7146. 3. Hope-Simpson RE. The nature of herpes zoster: a long-term study and a new hypothesis. Proc R Soc Med. 1965;58:9–20. 4. De Broucker T, Mailles A, Chabrier S, et al. Acute varicella zoster encephalitis without evidence of primary vasculopathy in a caseseries of 20 patients. Clin Microbiol Infect. 2012;18:808–819. 5. Esiri MM, Tomlinson AH. Herpes Zoster. Demonstration of virus in trigeminal nerve and ganglion by immunofluorescence and electron microscopy. J Neurol Sci. 1972;15:35–48. 6. Kleinschmidt-DeMasters BK, Gilden DH. Varicella-Zoster virus infections of the nervous system: clinical and pathologic correlates. Arch Pathol Lab Med. 2001;125:770–780. 7. Jemsek J, Greenberg SB, Taber L, et al. Herpes zoster-associated encephalitis: clinicopathologic report of 12 cases and review of the literature. Medicine (Baltimore). 1983;62:81–97. 8. Horien C, Grose C. Neurovirulence of varicella and the live attenuated varicella vaccine virus. Semin Pediatr Neurol. 2012;19:124–129. • Excellent overview of neurological infections. 9. Gilden D. Neuroinfections. Oxford: Oxford Press; 2013. 10. Halling G, Giannini C, Britton JW, et al. Focal encephalitis following varicella-zoster virus reactivation without rash in a healthy immunized young adult. J Infect Dis. 2014;210:713–716. 11. Yajima R, Utsumi K, Ishihara T, et al. Varicella-zoster virus encephalitis localized to the bilateral medial temporal lobes. Neurol Neuroimmunol Neuroinflamm. 2015;2:e108. 12. Gilden D, Grose C, White T, et al. Successful antiviral treatment after 6 years of chronic progressive neurological disease attributed to VZV brain infection. J Neurol Sci. 2016;368:240–242. 13. Kawai K, Yawn BP, Wollan P, et al. Increasing incidence of herpes zoster over a 60-year period from a population-based study. Clin Infect Dis. 2016;63:221–226. 14. Morrison VA, Johnson GR, Schmader KE, et al. Long-term persistence of zoster vaccine efficacy. Clin Infect Dis. 2015;60:900–909. 15. Bourne TD, Schiff D. Update on molecular findings, management and outcome in low-grade gliomas. Nat Rev Neurol. 2010;6:695–701. 16. Kondziolka D, Lunsford LD, Martinez AJ. Unreliability of contemporary neurodiagnostic imaging in evaluating suspected adult supratentorial (low-grade) astrocytoma. J Neurosurg. 1993;79:533–536. • First investigation of herpes zoster-induced astrogliosis. 17. Carpenter JE, Clayton AC, Halling KC, et al. Defensive perimeter in the central nervous system: predominance of astrocytes and astrogliosis during recovery from Varicella-Zoster virus encephalitis. J Virol. 2016;90:379–391. 18. Steiner I, Budka H, Chaudhuri A, et al. Viral encephalitis: a review of diagnostic methods and guidelines for management. Eur J Neurol. 2005;12:331–343.

Focal herpes zoster encephalitis without a rash: diagnostic confusion between astrogliosis and low-grade glioma.

Focal herpes zoster encephalitis without a rash: diagnostic confusion between astrogliosis and low-grade glioma. - PDF Download Free
640KB Sizes 0 Downloads 6 Views