alexa
Reach Us +44-7482878454
HIV-Associated JC Virus-Granule-Cell Neuronopathy (JCV-GCN) with the Hot-Cross-Bun Sign | OMICS International
ISSN 2155-6113
Journal of AIDS & Clinical Research

Like us on:

Make the best use of Scientific Research and information from our 700+ peer reviewed, Open Access Journals that operates with the help of 50,000+ Editorial Board Members and esteemed reviewers and 1000+ Scientific associations in Medical, Clinical, Pharmaceutical, Engineering, Technology and Management Fields.
Meet Inspiring Speakers and Experts at our 3000+ Global Conferenceseries Events with over 600+ Conferences, 1200+ Symposiums and 1200+ Workshops on Medical, Pharma, Engineering, Science, Technology and Business

HIV-Associated JC Virus-Granule-Cell Neuronopathy (JCV-GCN) with the Hot-Cross-Bun Sign

Antoine Moulignier1*, Julie Bottero2, Julien Savatovsky3, Jennifer Aboab1 and Pierre-Marie Girard2

1Service de Neurologie, Fondation Adolphe de Rothschild, 75019 Paris, France

2Service des Maladies Infectieuses et Tropicales, APHP, Hôpital Saint-Antoine, 75012 Paris, France

3Service d’Imagerie Médicale, Fondation Adolphe de Rothschild, 75019 Paris, France

*Corresponding Author:
Antoine Moulignier
Service de Neurologi
Fondation Adolphe de Rothschild, 25
rue Manin, 75019 Paris, France
Tel: +33148036860
Fax: +33148036859
E-mail: [email protected]

Received date: June 22, 2014 Accepted date: September 07, 2015 Published date: September 14, 2015

Citation: Moulignier A, Bottero J, Savatovsky J, Aboab J, Girard PM (2015) HIVAssociated JC Virus–Granule-Cell Neuronopathy (JCV–GCN) with the Hot-Cross-Bun Sign. J AIDS Clin Res 6:500. doi:10.4172/2155-6113.1000500

Copyright: © 2015 Moulignier A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Visit for more related articles at Journal of AIDS & Clinical Research

Abstract

Progressive multifocal leukoencephalopathy has long been described as the sole feature of JC virus (JCV) infection of the central nervous system. Over the past decade, its spectrum has extended to new forms of encephalopathy, notably affecting neurons. We describe an HIV-infected patient with worsening cerebellar symptoms, progressive cerebellar atrophy and a hot-cross-bun sign attributed to JCV–granule-cell neuronopathy (GCN), and 20 years of follow-up.

Keywords

Progressive multifocal leukoencephalopathy; Granulecell neuronopathy; HIV; AIDS; Hot-cross-bun sign

Introduction

Progressive multifocal leukoencephalopathy (PML) remains an important complication of HIV-1/AIDS, despite widespread combined antiretroviral therapy (cART). As its name implies, it was long thought to be only a demyelinating disease restricted to brain white matter. However, JC virus (JCV), the causative agent of the classic PML form, infects glial cells and neurons, and is now known as the etiology of granule-cell neuronopathy (JCV–GCN), the productive JCV encephalopathy of cortical pyramidal neurons, and productive JCV meningitis of leptomeningeal and choroid plexus cells [1]. Histological studies demonstrated that neurons are infected more frequently than clinically recognized, especially the cerebellar granular layer [2]. Herein, we describe the particular MRI pattern of our JCV–GCN patient to alert physicians to recognize its origin and deal with it appropriately.

Case Report

In December 1994, cerebral frontal and retinal toxoplasmosis abscesses revealed HIV infection (15 CD4 cells/μl) in a 52-year-old man. Under anti-toxoplasma therapy, the brain abscess completely disappeared without any sequelae but low vision as a macular sequela persisted. In January 1995, he started retrovir and lamivudine bitherapy. One month later, cerebellar kinetic syndrome-associated gait disturbance and dysarthria appeared. Brain MRI showed marked cerebellar atrophy, with no gadolinium enhancement, no visible lesion and no hot-cross-bun (HCB) sign. Normal cerebrospinal fluid (CSF) analysis (cell count, glucose and protein levels) was negative for bacteria, fungi and viruses, except for JCV-positive PCR. Laboratory test results were: normal vitamins B1, B12 and E; negative for paraneoplastic neuronal antibodies and spinocerebellar ataxia mutations; and no alcoholism. PML was suspected [3]. Neurological findings remained stable throughout 1995 and only CSF PCR JCVpositivity persisted in April 1995. After thorough reexamination in 1999 following the publication of 10 cases of HIV-infection–associated isolated cerebellar atrophy [4], only the JCV etiology persisted; CSF JCV-PCR was negative. Between 2002 and 2005, his bilateral cerebellar syndrome progressed with more pronounced gait ataxia and cerebellar atrophy on brain MRI without HCB sign. Since 2005, cART has very well-controlled his HIV (550-750 CD4 cells/μl and plasma virus load (PLVL) <200 copies/ml).

In December 2014, on raltegravir (800 mg/d), darunavir (800 mg/d) and ritonavir (100 mg/d), he underwent a new thorough work-up because of worsening gait ataxia: CD4-cell count: 832/μl; CD4/CD8 ratio: 1.15; PLVL: <20 copies/ml; truncal ataxia; bilateral cerebellar kinetic syndrome; saccadic pursuit eye movements; motor and sensory examinations: normal deep-tendon reflexes, flexor plantar response and walking without assistance; neither autonomic dysfunction nor Parkinsonism; normal electrocardiogram; brain MRI: the known cerebellar atrophy, particularly in the vermis, no lesions suggestive of PML, and an HCB sign (Figure 1); laboratory findings: normal CSF, with all viral PCRs, including JCV, negative; and normal or inconclusive vitamin E, paraneoplastic neuronal and deamidated gliadin peptide antibodies, mutations for spinocerebellar ataxias and Fragile X syndrome, anti-JCV antibody-positivity (STRATIFY JCVDxSelect test, Focus Diagnostics). Neurological stablility was confirmed April 2015.

aids-clinical-research-abnormalities

Figure 1: Brain MRI. (A, B) 3D-Gradient–echo T1-weighted sequence with coronal and sagittal reformats showing cerebellar atrophy (arrowheads) and pons atrophy (arrows). (C) Axial T2-sequence with an HCB sign (arrows), similar to abnormalities seen in MSA. (D) Axial T2-FLAIR sequence shows cerebellar PML-related hyperintense abnormalities (arrowheads) and middle cerebral peduncles associated with pons hyperintense abnormalities. (E) Ponto-cerebellar transverse fibers fractional anisotropy is lower on diffusion tensor imaging.

Discussion

Differential diagnoses of HIV-infection–associated cerebellar involvement principally include opportunistic infections, non- Hodgkin lymphoma and metastases, paraneoplastic diseases and postinfectious immune-mediated processes [5]. The cause of the cerebellar disorder can usually be established based on clinical, radiological and CSF features with PCR. Hence, today, cerebellar biopsy is rarely needed to establish a specific diagnosis.

Since 1994 [3], intriguing progressive cerebellar syndromes with debilitating manifestations without direct evidence of HIV infection, opportunistic infection or malignancy, and MRI-visualized unexplained marked cerebellar atrophy have been described [4]. PCR-JCV detection in the cerebellar biopsy of one of 10 patients had evoked its potential role [4]. Indeed, 1993 autopsy-study results [6] demonstrating an elective JCV infection of the cerebellar GCN layer were confirmed in 2003 [7]. In 2005, Koralnik et al. coined the term JCV–GCN that defined new JCV-infection form [8].

JCV–GCN differs from classic PML and results from mutant JCV harboring a small VP1-capsid–protein deletion that shifts viral tropism from glial cells to cerebellar GCs [1,2], thereby explaining the dominant cerebellar dysfunction clinical picture. The exact mechanism(s) inducing mutations and modifying GC tropism are unknown. JCV– GCN diagnosis relies on brain MRI, visualizing marked cerebellar atrophy, and CSF analyses, showing normal cell count and protein level, but with JCV-positive PCR negative for all other infectious pathogens. JCV–GCN is sometimes associated with T2-weighted/fluid-attenuated inversion recovery (FLAIR) hyperintense white matter abnormalities typical of PML but is a distinct clinical entity [1]. Only 24 cases of HIVassociated JCV–GCN, including our patient, have been reported [9-16].

Satisfying JCV–GCN diagnosis criteria, our patient has survived 20 years [8]. In burnt-out PML, the classic histological features present in the acute-stage biopsy are absent at autopsy [17]. Virus and viral antigen are also absent in old burnt-out lesions devoid of affected oligodendrocytes [18] and 80% of long-term PML survivors having cleared JCV [19], thereby explaining our patient’s early PCR JCV-positivity and CSF JCV-PCR–negativity 20 years later. PMLprogression heterogeneity has been described since the first cases and long-term survival (10%) is known since 1988 [20]. Albeit remarkable, our patient’s prolonged survival is consistent with other JCV–GCN observations [8,9,16]. Whether JCV–GCN has a better prognosis than other PML forms is unclear. Our patient probably benefited from cART-restored immunity. Another striking point of our observation is the progression of the cerebellar syndrome despite cART. This has already been observed in another published case [9]. The JCV-GCN developed and gradually progressed in this HIV-infected patient despite good HIV-control indices (undetectable PLVL and 350 CD4 cells/μl) at presentation and during his follow-up. In our patient, JCV-GCN has probably reduced the cerebellar neuronal reserve since onset. Hence, concurrent normal age-related cerebellar cells neurodegeneration might also be an explanation to his gait worsening 20 years after the first symptoms [21].

The MRI HCB sign, characterized by cruciform T2- and FLAIRsignal hyperintensity within the pons (Figure 1), has been described in only 6 HIV-associated JCV–GCN patients [9,10,15,16]. It is said to be highly specific, but not pathognomonic, for multiple-system atrophy (MSA). Whether HCB occurs from onset or is a feature of later JCV– GCN stages is discussed. Our patient’s long radiological monitoring supports the latter hypothesis, as previously suggested [10]. GCs are a major class of cerebellar interneurons in synaptic contact with Purkinje cells. We think the HCB sign in JCV–GCN results from the progressive retrograde degeneration of the axons of various cerebellar connections, accompanying Wallerian degeneration of the pontocerebellar tracts with gliosis.

MSA was excluded because of the long follow-up without neurological deterioration and any dysautonomic sign, notably the absence of characteristic early and severe autonomic failure, i.e. no orthostatic blood pressure decrease or urinary incontinence [22]. Approximately half the patients require walking aids within 3 years after motor-symptom onset, 60% require a wheelchair after 5 years and the patient becomes bedridden within a median 6-8 years [22]. Brain MRI can also help distinguish these two entities: FLAIR cerebellar atrophy and hyperintensities are more asymmetric in JCV–GCN than in MSA, while putamen atrophy with the “putaminal rim sign” is present only in MSA [22].

Conclusion

Our case highlights JCV’s ability to infect neurons and not only glial cells, with the sole neurological feature being clinical cerebellar syndrome. As awareness of central JCV-infection types other than PML grows, this currently under-recognized JCV–GCN could become frequent in persons living with HIV (PLHs). Moreover, the HIV epidemic is entering a chronic phase in which most PLHs have life expectancies approaching general population norms [23]. Therefore, more >50-year-old PLHs represent the majority of all PLHs in Western countries. Perhaps because PLHs are prone to developing age-related diseases earlier or simply that they are reaching ages at which the incidences of these age-related neurodegenerative diseases are more frequent means clinicians will have to consider alternative diagnoses to HIV-related neurological consequences and aging, as recently illustrated with Parkinson’s disease [24]. Because MSA can start as a cerebellar syndrome, it will be important to distinguish JCV–GCN with HCB sign from early MSA because their treatments differ.

Acknowledgements

The authors thank Janet Jacobson for editorial assistance and Gilbert Lesage for bibliographic assistance.

References

  1. Tan CS, Koralnik IJ (2010) Beyond progressive multifocal leukoencephalopathy: expanded pathogenesis of JC virus infection in the central nervous system. Lancet Neurol 9: 425-437.
  2. Wüthrich C, Cheng YM, Joseph JT, Kesari S, Beckwith C, et al. (2009) Frequent infection of cerebellar granule cell neurons by polyomavirus JC in progressive multifocal leukoencephalopathy. J NeuropatholExpNeurol 68: 15-25.
  3. Sweeney BJ, Manji H, Miller RF, Harrison MLG, Gray F, et al. (1994) Cortical and subcortical JC virus infection: two unusual cases of AIDS associated progressive multifocal leukoencephalopathy. J NeurolNeurosurg Psychiatry 57: 994-997.
  4. Tagliati M, Simpson D, Morgello S, Clifford D, Schwartz RL, et al. (1998) Cerebellar degeneration associated with human immunodeficiency virus infection. Neurology 50: 244-251.
  5. Pruitt AA (2014) Infections of the cerebellum. NeurolClin 32: 1117-1131.
  6. Kuchelmeister K, Bergmann M, Gullotta F (1993) Cellular changes in the cerebellar granular layer in AIDS-associated PML. NeuropatholApplNeurobiol 19: 398-401.
  7. Du Pasquier RA, Corey S, Margolin DH, Williams K, Pfister LA, et al. (2003) Productive infection of cerebellar granule cell neurons by JC virus in an HIV+ individual. Neurology 61: 775-782.
  8. Koralnik IJ, Wüthrich C, Dang X, Rottnek M, Gurtman A, et al. (2005) JC virus granule cell neuronopathy: A novel clinical syndrome distinct from progressive multifocal leukoencephalopathy. Ann Neurol 57: 576-580.
  9. Wijburg MT, van Oosten BW, Murk JL, Karimi O, Killestein J, et al. (2015) Heterogeneous imaging characteristics of JC virus granule cell neuronopathy (GCN): a case series and review of the literature. J Neurol 262: 65-73.
  10. Jain RS, Nagpal K, Tejwani S (2014) 'Hot-cross bun' and 'inverse trident sign' in progressive multifocal leukoencephalopathy with HIV seropositivity. Neurol India 62: 341-342.
  11. Otis CN, Moral LA (2005) Images in pathology: granule cell loss in AIDS-associated progressive multifocal leukoencephalopathy. Int J SurgPathol 13: 360.
  12. Tan IL, Brew BJ (2009) Possible JCV granular cell neuronopathy in a patient with HIV infection. Neurology 73: 1598-1599.
  13. Shang T, Delgado A, Adams D (2011) JC virus granule cell neuronopathy and hyper-IgE in HIV disease. Neurology 76: 1941-1942.
  14. Roux D, Bouldouyre MA, Mercier-Delarue S, Seilhean D, Zagdanski AM, et al. (2011) JC virus variant associated with cerebellar atrophy in a patient with AIDS. J ClinMicrobiol 49: 2196-2199.
  15. Yadav R, Ramdas M, Karthik N, Kulkarni GB, Dawn R, et al. (2011) "Hot cross bun" sign in HIV-related progressive multifocal leukoencephalopathy. Neurol India 59: 293-294.
  16. Henry C, Jouan F2, De Broucker T2 (2015) JC virus granule cell neuronopathy: A cause of infectious cerebellar degeneration. J NeurolSci 354: 86-90.
  17. Price RW, Nielsen S, Horten B, Rubino M, Padgett B, et al. (1983) Progressive multifocal leukoencephalopathy: a burnt-out case. Ann Neurol 13: 485-490.
  18. Arai Y, Tsutsui Y, Nagashima K, Shinmura Y, Kosugi T, et al. (2002) Autopsy case of the cerebellar form of progressive multifocal leukoencephalopathy without immunodeficiency. Neuropathology 22: 48-56.
  19. Taoufik Y, Delfraissy JF, Gasnault J (2000) Highly active antiretroviral therapy does not improve survival of patients with high JC virus load in the cerebrospinal fluid at progressive multifocal leukoencephalopathy diagnosis. AIDS 14: 758-759.
  20. Berger JR, Mucke L (1988) Prolonged survival and partial recovery in AIDS-associated progressive multifocal leukoencephalopathy. Neurology 38: 1060-1065.
  21. Chen WT, Chou KH, Liu LK, Lee PL, Lee WJ, et al. (2015) Reduced cerebellar gray matter is a neural signature of physical frailty. Hum Brain Mapp 36: 3666-3676.
  22. Fanciulli A, Wenning GK (2015) Multiple-system atrophy. N Engl J Med 372: 249-263.
  23. Sabin CA (2013) Do people with HIV infection have a normal life expectancy in the era of combination antiretroviral therapy? BMC Med 11: 251.
  24. Moulignier A, Gueguen A, Lescure FX, Ziegler M, Girard PM, et al. (2015) Does HIV Infection Alter Parkinson Disease? J Acquir Immune DeficSyndr 70: 129-13 6.
Select your language of interest to view the total content in your interested language
Post your comment

Share This Article

Article Usage

  • Total views: 15317
  • [From(publication date):
    September-2015 - Dec 15, 2019]
  • Breakdown by view type
  • HTML page views : 11473
  • PDF downloads : 3844
Top