Comparative Medicine Copyright 2015 by the American Association for Laboratory Animal Science
Vol 65, No 3 June 2015 Pages 266–5
Case Report
Self-Injurious Behavior Secondary to Cytomegalovirus-Induced Neuropathy in an SIVInfected Rhesus Macaque (Macaca mulatta) Elizabeth A Clemmons,1 Sanjeev Gumber,2,3 Elizabeth Strobert,1 Mollie A Bloomsmith,1 and Sherrie M Jean1,* A 3.5-y-old, female rhesus macaque (Macaca mulatta) inoculated with SIVmac239 presented 8 mo later for inappetence and facial bruising. Physical examination revealed a superficial skin abrasion below the left eye, bruising below the left brow, and epistaxis of the left nostril. There were no significant findings on CBC, serum chemistry, urinalysis, or radiographs. Differential diagnoses included infectious etiologies, self-injurious behavior, immune-mediated dermatitis, and neoplasia. Lack of response to antibiotic and analgesic therapy and observations of the macaque made it apparent that the skin lesions were self-inflicted. The excoriations rapidly progressed to extend over the nose, and the left palpebrae became edematous. Euthanasia was elected because the macaque appeared to be experiencing continued discomfort despite analgesic therapy. Histopathologic examination revealed systemic cytomegalovirus (CMV) infection involving the facial nerves, periocular nerves, meninges, and perimesenteric lymph nodes. CMV is a common infection in macaques, with adult seroprevalence close to 100% in most colonies. Infection in immunocompetent animals is usually asymptomatic but can cause significant clinical disease in immunodeficient hosts. CMV is associated with a painful peripheral neuropathy in human AIDS patients, and analgesic treatment is often unsatisfactory. Peripheral neuropathy secondary to CMV should be considered as an underlying cause of self-injurious behavior in SIV-infected macaques. Macaques affected by other diseases and disorders may also be at risk for development of painful peripheral neuropathies. Abbreviations: CMV, cytomegalovirus; HCMV, human CMV; RhCMV, rhesus CMV; SIB, self-injurious behavior.
Rhesus macaques (Macaca mulatta) are one of the most commonly used NHP species in biomedical research.9,25 They generally adapt well to captivity, but some develop abnormal behaviors such as stereotypies and self-injurious behavior (SIB).32 Examples of SIB include excessive hair-plucking, head banging, and self-biting that causes wounds in some cases.32 Self-inflicted wounding has been reported in 11% to 14% of individually housed rhesus macaques and can be difficult to manage.26,32,39 The most commonly discussed risk factors for the development of SIB are related to housing and management, and little is known about potential physiologic causes, such as neuropathic pain.18,26,32 Compulsive SIB directed toward a specific body part due to neuropathic pain or pruritus occurs in humans.12,28 Rhesus cytomegalovirus (RhCMV) is enzootic in rhesus macaques with close to 100% seroprevalence by 1 y of age in both wild and captive populations.22,42 As with human cytomegalovirus (HCMV), RhCMV infection is generally subclinical in immunocompetent animals but can cause serious disease in immunodeficient macaques.8 RhCMV can be highly pathogenic in SIV-infected animals, and HCMV is the most common viral Received: 18 Oct 2014. Revision requested: 12 Dec 2014. Accepted: 12 Jan 2015. Divisions of Animal Resources1 and Pathology,2 Yerkes National Primate Research Center, Emory University, Atlanta, Georgia; and 3Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia. *Corresponding author. Email: [email protected]
opportunistic infection in humans with AIDS.8,37 HCMV infection has been associated with painful peripheral neuropathies in AIDS patients.17,36,37 We here report a case of SIB associated with RhCMV-induced peripheral neuropathy in an immunocompromised macaque.
Case Report
The Yerkes National Primate Research Center of Emory University is a fully AAALAC-accredited facility. All NHPs in the colony are managed under IACUC-approved protocols in accordance with the applicable federal animal welfare regulations and the Guide for the Care and Use of Laboratory Animals.1,21 The Center has dedicated and specifically trained behavior management staff. Animals are observed regularly for abnormal behaviors, and those exhibiting such behaviors receive increased observations and interventions.31 Routine enrichment provided to all NHPs includes produce, foraging devices, and other manipulanda. A 3.5-y-old, indoor pair-housed, female rhesus macaque with no history of major medical problems was infected experimentally with SIVmac239. In accordance with the experimental design, the SIV-inoculated macaque was IACUC-approved to be maintained in single housing. In November 2013, 8 mo after SIV inoculation, the macaque presented for inappetence and facial bruising. Physical examination revealed a superficial skin abrasion below the left eye, mild bruising below the left brow, epistaxis of the
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left nostril, a loose deciduous left maxillary canine tooth, and splenomegaly. No abnormalities were seen on skull radiographs. CBC values were within normal limits. Serum chemistry results revealed mild hypoproteinemia (6.5 g/dL) and FACS analysis revealed an absolute CD4+ T cell count of 1452 cells/mm3. Initial differential diagnoses included dermatitis secondary to infectious etiology, tooth root abscess, SIB, immune-mediated dermatitis, and neoplasia. Analgesic and antibiotic therapy were initiated with flunixin meglumine (1 mg/kg SC every 6 h; Bimeda–MTC Animal Health, Cambridge, Ontario, Canada) and ceftriaxone (25 mg/kg SC daily; Hospira, Chennai, India) respectively. One day after presentation, the macaque was started on buprenorphine (0.02 mg/kg SC every 6 h; Reckitt Benckiser Pharmaceuticals, Richmond, VA) to provide additional pain relief. On repeat examination 4 d after initial presentation, the skin lesion under the left eye was larger and extended over the nose. The left palpebrae were edematous and erythematous. During oral exam, the loose deciduous tooth was removed, and there was no evidence of tooth root abscess. There were no changes on repeat radiographs, CBC evaluation, or serum chemistry analysis. Urinalysis values were within normal limits. Blood and urine cultures were negative for growth, and nasal flush culture revealed no significant pathogenic bacteria. Because our differential diagnoses at this time included allergic dermatitis, treatment with the antihistamine cetirizine (5 mg/kg PO daily; Perrigo, Allegan, MI), was initiated. Antibiotic therapy with enrofloxacin (7 mg/ kg SC daily; Bayer, Shawnee Mission, KS) was added for broader spectrum of activity against a potential infection. As part of routine management, trained behavioral observers collected data on this macaque 2 to 4 times weekly for a minimum of 5 min during each observation session, from mid-October 2012 to mid-November 2013. This effort generated about 15 h of data over the 58-wk period. A 1–0 sampling technique was applied by using an ethogram of abnormal behavior to record the occurrence of SIB, behaviors known to be precursors to SIB (for example, floating limb, eye poking), stereotyped behavior, oral-related abnormal behaviors, hair plucking, and fear-related behavior. During this entire behavioral assessment, no abnormal behaviors of any type were recorded for this animal. Coinciding with the acute presentation of the facial lesions, veterinary staff members observed this animal on multiple occasions actively scratching the affected area of the face, and the appearance of the wound was consistent with the trauma one expected to be induced by fingernails. In light of these observations, we concluded that the facial excoriations were self-inflicted. Due to the rapid progression of the lesions and the significant discomfort they appeared to cause despite pharmacologic intervention, euthanasia was elected. Postmortem examination revealed multiple linear abrasions on the facial skin and marked edema of the ventral half of the left cornea (Figure 1). The spleen was slightly enlarged. No other major gross findings were noticed. For histopathologic examination, various tissue samples were fixed in 10% neutral buffered formalin, routinely processed, paraffin-embedded, sectioned at 5 µm, and stained with hematoxylin and eosin. Microscopically, there were multifocal facial ulcerations, and subcutaneous nerves had moderate perineural and intraneural neutrophilic and histiocytic inflammation, with the presence of few cytomegalic cells (Figure 2). The trigeminal nerve fibers, meninges, and adjacent neuropil were infiltrated by numerous neutrophils intermixed with small numbers of macrophages,
Figure 1. There are multiple facial abrasions and marked left corneal edema.
Figure 2. The epidermis is multifocally ulcerated, with neutrophilic and histiocytic perineural and intraneural inflammation (inset, arrowhead). Hematoxylin and eosin stain.
cytomegalic cells, extravasated erythrocytes, small amounts of fibrinous exudate, and necrotic cellular debris (Figure 3). The blood vessels adjacent to trigeminal nerve fibers and in the meninges were disrupted multifocally and obscured by eosinophilic hyaline to fibrinoid material intermixed with cellular and karyorrhectic debris (fibrinoid necrosis). There were multifocal cytomegalic cells that occasionally contained large, eosinophilic, intranuclear, round to ovoid, 10- to 15-µm–diameter inclusion bodies (Figure 4). The periocular nerves exhibited similar changes, such as neutrophilic to histiocytic inflammation with cytomegalic cells (Figure 5). There was moderate necrosuppurative perimesenteric lymphadenitis with intranuclear viral inclusions. Immunohistochemical staining for CMV was performed by using an alkaline phosphatase–streptavidin–biotin procedure. The formalin-fixed, paraffin-embedded periocular nerve tissue sections were labeled with biotinylated rabbit antiRhCMV IE1 polyclonal antibody (gift from Peter A Barry, UC–Davis). The positive control tissues were sections of testicles from a CMV-infected rhesus macaque previously assayed for reaction with the primary antibody. The negative control was prepared by substituting the specific primary antibody with antibody diluent. A few cytomegalic cells labeled positively for RhCMV (Figure 5, inset).
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Figure 3. The trigeminal nerve fibers (arrowhead), meninges, and adjacent neuropil are expanded by numerous neutrophils, small numbers of macrophages, and small amounts of fibrinous exudate. Hematoxylin and eosin stain.
Figure 4. The blood vessels adjacent to trigeminal nerve fibers (NF) and in the meninges exhibit fibrinoid necrosis (arrow), and a few cytomegalic cells contain intranuclear inclusion bodies (arrowhead). Hematoxylin and eosin stain.
Discussion
The self-inflicted facial lesions in this case were most likely due to discomfort associated with RhCMV-induced peripheral neuropathy involving the trigeminal and facial nerves. Behavioral assessment of this macaque, including the period of single housing, indicated no history of expression of abnormal behavior. This finding supports our hypothesis that the SIB was not related to indoor housing in caging, single housing, or other common risk factors for SIB.18 There have been reports of SIB targeted toward a specific body part in humans with neuropathic pain.3,12,28 Specifically, SIB associated with facial lesions has been seen in humans with neuropathies affecting the trigeminal nerve.3,28 Self-inflicted facial excoriations are not a commonly reported form of SIB in rhesus macaques, but peripheral neuropathies often affect the distal extremities, which often are involved in SIB.32 HCMV is a common infection worldwide, with adult seroprevalence ranging from 50% to 90%.8 After primary infection, HCMV causes a latent infection that can reactivate periodically.8 Both
Figure 5. The periocular nerves (PN) contain severe neutrophilic inflammation and few cytomegalic cells. ON, optic nerve; S, sclera. Hematoxylin and eosin stain. Inset, Immunohistochemical staining for antiRhCMV IE1 shows a positively labeled cytomegalic cell.
primary infection and reactivation are typically asymptomatic, but immunocompromised hosts and neonates are at high risk for serious disease caused by HCMV.8 HCMV is a common opportunistic infection and frequent cause of peripheral neuropathy in AIDS patients.17,24,37 Like humans, macaques infected with RhCMV are usually asymptomatic, but immunodeficient animals may develop significant disease.8 One study reported a 8.7% prevalence of RhCMV-associated facial neuritis in 115 rhesus macaques coinfected with SIV and RhCMV.4 One animal in the study presented with a large labial ulcer, possibly associated with facial pain or desensitization and secondary self-trauma.4 CMV infection is common after immunosuppression in organ-transplant patients.11,20 Despite the frequency of HCMV infection in transplant recipients, peripheral neuropathies rarely are reported in this population.11,15 Neurologic disorders, such as HIV-associated dementia and peripheral neuropathy, are a frequent complication of HIV and have remained a challenge despite the introduction of combination antiretroviral therapy.41 HIV-associated peripheral neuropathy is often a painful and debilitating syndrome.13 Causes of HIV-associated peripheral neuropathy include direct and indirect effects of the virus itself, opportunistic infections such as HCMV, and antiretroviral drug toxicity.24 HIV can be directly neurotoxic through infection of neurons or cause indirect neurotoxicity through viral products and activation of the inflammatory cascade.38 SIV-induced peripheral neuropathy affecting the trigeminal and lumbar dorsal root ganglia of macaques has been reported to cause lesions similar to those seen in HIV-infected humans.30 In AIDS patients, combination antiretroviral therapy including nucleoside analog reverse-transcriptase inhibitors has been associated with a neuropathy that is clinically indistinguishable from HIV-induced peripheral neuropathy.38 In light of these findings, macaques in SIV studies may be at high risk for developing peripheral neuropathy due to SIV, RhCMV, or antiretroviral therapy. In addition, macaques experiencing naturally or experimentally induced diabetes, nerve trauma, Lyme disease, nutritional (vitamin B12) deficiency, leprosy, immunosuppression for organ transplantation, chemotherapy, or levodopa administration for Parkinson disease may have an increased risk of developing peripheral neuropathy.2,10,14,20,29,33,40,43
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Diagnosis of peripheral neuropathy in humans begins with carefully interviewing the patient and conducting a thorough physical and neurologic exam.5 Neuropathic pain often has a shooting or burning quality, with tingling or electric sensations and areas of hypersensitivity.7 Although the clinical signs commonly associated with peripheral neuropathy in macaques are currently unknown and given that we may never know exactly what they are feeling, we hypothesize that affected animals will present with signs similar to those in humans and consistent with established general signs of pain and discomfort. Our macaque demonstrated restlessness or anxiety and excessive scratching leading to self-inflicted wounds. We suspect that other behaviors observed in humans that potentially could also be associated with peripheral neuropathy in macaques include reluctance to use an affected limb, hair-plucking, pressure sores, and other trauma. After confirming the presence of peripheral neuropathy in humans, initial blood tests to identify the underlying cause often include CBC analysis, metabolic profiles, and fasting blood glucose, vitamin B12, and thyroid-stimulating hormone levels.5 In addition, secondary testing may include CSF analysis, urinalysis, and evaluation for infectious diseases such as HIV.5 If the diagnosis is still unclear, nerve conduction studies, electromyography and nerve biopsy may be considered.5 Therapy in humans with peripheral neuropathy focuses on treating the underlying disease and relieving symptoms.5 If the clinical presentation or elevated CMV antibody levels suggest active CMV infection in humans or macaques, treatment with the antiviral ganciclovir often is initiated.19,23,37 In patients with unacceptable side effects or ganciclovir-resistant infection, cidofovir or foscarnet may be used.6 A regimen of weekly CMV surveillance, prophylaxis, and treatment of reactivation has been described in macaques immunosuppressed for transplant- tolerance research.23 In humans with peripheral neuropathy, standard analgesic medications are often unsatisfactory for pain relief.30 The most clinically effective drugs include tricyclic and serotonin–noradrenaline reuptake-inhibiting antidepressants, opioids, and anticonvulsants such as pregabalin and gabapentin.7,16 Other drugs that have been investigated with varying success include topical lidocaine, cannabinoids, topical capsaicin, and injectable botulinum toxin.16 A combination of at least 2 drugs often is needed for adequate pain relief.7 However, many patients remain unable to obtain sufficient relief, and research is needed to identify new treatment options.16 For the macaque we present, opioid therapy was initiated immediately, and antidepressant therapy was considered later. The opioid therapy may have provided some pain relief, but it was insufficient to resolve the SIB. The rapid progression of the lesions in this case precluded the time needed for an antidepressant to take full effect. In both humans and animals, maximal improvement with antidepressant therapy often takes a week to several weeks to achieve.27,34,35 The macaque we present in this case report likely developed SIB secondary to RhCMV-induced neuropathy. Many concurrent diseases and disorders, especially those causing immunodeficiency (like SIV), may put macaques at risk for the development of painful peripheral neuropathies. Peripheral neuropathy should be considered as a potential underlying cause of SIB, particularly in the high-risk groups we just described. When the underlying disease causing peripheral neuropathy in a macaque is experimentally induced, therapy likely will focus on relief of secondary
pain and discomfort. Macaques have been considered as a potential model of HIV-associated peripheral neuropathy and may be helpful for identifying new treatments for this and other debilitating neuropathies.30
Acknowledgments
This work was supported by a NIH–NCRR base grant (P51OD11132) to YNPRC. We thank Cindy Courtney, the YNPRC necropsy staff, animal care staff, behavior management unit, and veterinary department for their assistance with this work. Immunohistochemistry was performed by the Yerkes Molecular Pathology Core. Presented at the National Meeting of the American Association for Laboratory Animal Science (San Antonio, 2014)
References
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17. Fuller GN. 1992. Cytomegalovirus and the peripheral nervous system in AIDS. J Acquir Immune Defic Syndr 5 Suppl 1:S33–S36. 18. Gottlieb DH, Capitanio JP, McCowan B. 2013. Risk factors for stereotypic behavior and self-biting in rhesus macaques (Macaca mulatta): animal’s history, current environment, and personality. Am J Primatol 75:995–1008. 19. Gracia-Ahufinger I, Gutierrez-Aroca J, Cordero E, Vidal E, Cantisan S, del Castillo D, Martin-Gandul C, Rivero A, Torre-Cisneros J. 2013. Use of high-dose ganciclovir for the treatment of cytomegalovirus replication in solid organ transplant patients with ganciclovir resistance-inducing mutations. Transplantation 95:1015–1020. 20. Haustein SV, Kolterman AJ, Sundblad JJ, Fechner JH, Knechtle SJ. 2008. Nonhuman primate infections after organ transplantation. ILAR J 49:209–219. 21. Institute for Laboratory Animal Research. 2011. Guide for the care and use of laboratory animals, 8th ed. Washington (DC): National Academies Press. 22. Jones-Engel L, Engel GA, Heidrich J, Chalise M, Poudel N, Viscidi R, Barry PA, Allan JS, Grant R, Kyes R. 2006. Temple monkeys and health implications of commensalism, Kathmandu, Nepal. Emerg Infect Dis 12:900–906. 23. Kean LS, Adams AB, Strobert E, Hendrix R, Gangappa S, Jones TR, Shirasugi N, Rigby MR, Hamby K, Jiang J, Bello H, Anderson D, Cardona K, Durham MM, Pearson TC, Larsen CP. 2007. Induction of chimerism in rhesus macaques through stem cell transplant and costimulation blockade-based immunosuppression. Am J Transpl 7:320–335. 24. Kolson DL, Gonzalez-Scarano F. 2001. HIV-associated neuropathies: role of HIV1, CMV, and other viruses. J Peripher Nerv Syst 6:2–7. 25. Lankau EW, Turner PV, Mullan RJ, Galland GG. 2014. Use of nonhuman primates in research in North America. J Am Assoc Lab Anim Sci 53:278–282. 26. Lutz C, Well A, Novak M. 2003. Stereotypic and self-injurious behavior in rhesus macaques: a survey and retrospective analysis of environment and early experience. Am J Primatol 60:1–15. 27. Magni G. 1991. The use of antidepressants in the treatment of chronic pain. A review of the current evidence. Drugs 42:730–748. 28. Mailis A. 1996. Compulsive targeted self-injurious behaviour in humans with neuropathic pain: a counterpart of animal autotomy? Four case reports and literature review. Pain 64:569–578. 29. Mancini F, Comi C, Oggioni GD, Pacchetti C, Calandrella D, Coletti Moja M, Riboldazzi G, Tunesi S, Dal Fante M, Manfredi L, Lacerenza M, Cantello R, Antonini A. 2014. Prevalence and features of peripheral neuropathy in Parkinson’s disease patients under different therapeutic regimens. Parkinsonism Relat Disord 20:27–31. 30. Mangus LM, Dorsey JL, Laast VA, Ringkamp M, Ebenezer GJ, Hauer P, Mankowski JL. 2014. Unraveling the pathogenesis of HIV
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Case Report
Self-Injurious Behavior Secondary to Cytomegalovirus-Induced Neuropathy in an SIVInfected Rhesus Macaque (Macaca mulatta) Elizabeth A Clemmons,1 Sanjeev Gumber,2,3 Elizabeth Strobert,1 Mollie A Bloomsmith,1 and Sherrie M Jean1,* A 3.5-y-old, female rhesus macaque (Macaca mulatta) inoculated with SIVmac239 presented 8 mo later for inappetence and facial bruising. Physical examination revealed a superficial skin abrasion below the left eye, bruising below the left brow, and epistaxis of the left nostril. There were no significant findings on CBC, serum chemistry, urinalysis, or radiographs. Differential diagnoses included infectious etiologies, self-injurious behavior, immune-mediated dermatitis, and neoplasia. Lack of response to antibiotic and analgesic therapy and observations of the macaque made it apparent that the skin lesions were self-inflicted. The excoriations rapidly progressed to extend over the nose, and the left palpebrae became edematous. Euthanasia was elected because the macaque appeared to be experiencing continued discomfort despite analgesic therapy. Histopathologic examination revealed systemic cytomegalovirus (CMV) infection involving the facial nerves, periocular nerves, meninges, and perimesenteric lymph nodes. CMV is a common infection in macaques, with adult seroprevalence close to 100% in most colonies. Infection in immunocompetent animals is usually asymptomatic but can cause significant clinical disease in immunodeficient hosts. CMV is associated with a painful peripheral neuropathy in human AIDS patients, and analgesic treatment is often unsatisfactory. Peripheral neuropathy secondary to CMV should be considered as an underlying cause of self-injurious behavior in SIV-infected macaques. Macaques affected by other diseases and disorders may also be at risk for development of painful peripheral neuropathies. Abbreviations: CMV, cytomegalovirus; HCMV, human CMV; RhCMV, rhesus CMV; SIB, self-injurious behavior.
Rhesus macaques (Macaca mulatta) are one of the most commonly used NHP species in biomedical research.9,25 They generally adapt well to captivity, but some develop abnormal behaviors such as stereotypies and self-injurious behavior (SIB).32 Examples of SIB include excessive hair-plucking, head banging, and self-biting that causes wounds in some cases.32 Self-inflicted wounding has been reported in 11% to 14% of individually housed rhesus macaques and can be difficult to manage.26,32,39 The most commonly discussed risk factors for the development of SIB are related to housing and management, and little is known about potential physiologic causes, such as neuropathic pain.18,26,32 Compulsive SIB directed toward a specific body part due to neuropathic pain or pruritus occurs in humans.12,28 Rhesus cytomegalovirus (RhCMV) is enzootic in rhesus macaques with close to 100% seroprevalence by 1 y of age in both wild and captive populations.22,42 As with human cytomegalovirus (HCMV), RhCMV infection is generally subclinical in immunocompetent animals but can cause serious disease in immunodeficient macaques.8 RhCMV can be highly pathogenic in SIV-infected animals, and HCMV is the most common viral Received: 18 Oct 2014. Revision requested: 12 Dec 2014. Accepted: 12 Jan 2015. Divisions of Animal Resources1 and Pathology,2 Yerkes National Primate Research Center, Emory University, Atlanta, Georgia; and 3Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia. *Corresponding author. Email: [email protected]
opportunistic infection in humans with AIDS.8,37 HCMV infection has been associated with painful peripheral neuropathies in AIDS patients.17,36,37 We here report a case of SIB associated with RhCMV-induced peripheral neuropathy in an immunocompromised macaque.
Case Report
The Yerkes National Primate Research Center of Emory University is a fully AAALAC-accredited facility. All NHPs in the colony are managed under IACUC-approved protocols in accordance with the applicable federal animal welfare regulations and the Guide for the Care and Use of Laboratory Animals.1,21 The Center has dedicated and specifically trained behavior management staff. Animals are observed regularly for abnormal behaviors, and those exhibiting such behaviors receive increased observations and interventions.31 Routine enrichment provided to all NHPs includes produce, foraging devices, and other manipulanda. A 3.5-y-old, indoor pair-housed, female rhesus macaque with no history of major medical problems was infected experimentally with SIVmac239. In accordance with the experimental design, the SIV-inoculated macaque was IACUC-approved to be maintained in single housing. In November 2013, 8 mo after SIV inoculation, the macaque presented for inappetence and facial bruising. Physical examination revealed a superficial skin abrasion below the left eye, mild bruising below the left brow, epistaxis of the
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SIB due to CMV-induced neuropathy in a rhesus macaque
left nostril, a loose deciduous left maxillary canine tooth, and splenomegaly. No abnormalities were seen on skull radiographs. CBC values were within normal limits. Serum chemistry results revealed mild hypoproteinemia (6.5 g/dL) and FACS analysis revealed an absolute CD4+ T cell count of 1452 cells/mm3. Initial differential diagnoses included dermatitis secondary to infectious etiology, tooth root abscess, SIB, immune-mediated dermatitis, and neoplasia. Analgesic and antibiotic therapy were initiated with flunixin meglumine (1 mg/kg SC every 6 h; Bimeda–MTC Animal Health, Cambridge, Ontario, Canada) and ceftriaxone (25 mg/kg SC daily; Hospira, Chennai, India) respectively. One day after presentation, the macaque was started on buprenorphine (0.02 mg/kg SC every 6 h; Reckitt Benckiser Pharmaceuticals, Richmond, VA) to provide additional pain relief. On repeat examination 4 d after initial presentation, the skin lesion under the left eye was larger and extended over the nose. The left palpebrae were edematous and erythematous. During oral exam, the loose deciduous tooth was removed, and there was no evidence of tooth root abscess. There were no changes on repeat radiographs, CBC evaluation, or serum chemistry analysis. Urinalysis values were within normal limits. Blood and urine cultures were negative for growth, and nasal flush culture revealed no significant pathogenic bacteria. Because our differential diagnoses at this time included allergic dermatitis, treatment with the antihistamine cetirizine (5 mg/kg PO daily; Perrigo, Allegan, MI), was initiated. Antibiotic therapy with enrofloxacin (7 mg/ kg SC daily; Bayer, Shawnee Mission, KS) was added for broader spectrum of activity against a potential infection. As part of routine management, trained behavioral observers collected data on this macaque 2 to 4 times weekly for a minimum of 5 min during each observation session, from mid-October 2012 to mid-November 2013. This effort generated about 15 h of data over the 58-wk period. A 1–0 sampling technique was applied by using an ethogram of abnormal behavior to record the occurrence of SIB, behaviors known to be precursors to SIB (for example, floating limb, eye poking), stereotyped behavior, oral-related abnormal behaviors, hair plucking, and fear-related behavior. During this entire behavioral assessment, no abnormal behaviors of any type were recorded for this animal. Coinciding with the acute presentation of the facial lesions, veterinary staff members observed this animal on multiple occasions actively scratching the affected area of the face, and the appearance of the wound was consistent with the trauma one expected to be induced by fingernails. In light of these observations, we concluded that the facial excoriations were self-inflicted. Due to the rapid progression of the lesions and the significant discomfort they appeared to cause despite pharmacologic intervention, euthanasia was elected. Postmortem examination revealed multiple linear abrasions on the facial skin and marked edema of the ventral half of the left cornea (Figure 1). The spleen was slightly enlarged. No other major gross findings were noticed. For histopathologic examination, various tissue samples were fixed in 10% neutral buffered formalin, routinely processed, paraffin-embedded, sectioned at 5 µm, and stained with hematoxylin and eosin. Microscopically, there were multifocal facial ulcerations, and subcutaneous nerves had moderate perineural and intraneural neutrophilic and histiocytic inflammation, with the presence of few cytomegalic cells (Figure 2). The trigeminal nerve fibers, meninges, and adjacent neuropil were infiltrated by numerous neutrophils intermixed with small numbers of macrophages,
Figure 1. There are multiple facial abrasions and marked left corneal edema.
Figure 2. The epidermis is multifocally ulcerated, with neutrophilic and histiocytic perineural and intraneural inflammation (inset, arrowhead). Hematoxylin and eosin stain.
cytomegalic cells, extravasated erythrocytes, small amounts of fibrinous exudate, and necrotic cellular debris (Figure 3). The blood vessels adjacent to trigeminal nerve fibers and in the meninges were disrupted multifocally and obscured by eosinophilic hyaline to fibrinoid material intermixed with cellular and karyorrhectic debris (fibrinoid necrosis). There were multifocal cytomegalic cells that occasionally contained large, eosinophilic, intranuclear, round to ovoid, 10- to 15-µm–diameter inclusion bodies (Figure 4). The periocular nerves exhibited similar changes, such as neutrophilic to histiocytic inflammation with cytomegalic cells (Figure 5). There was moderate necrosuppurative perimesenteric lymphadenitis with intranuclear viral inclusions. Immunohistochemical staining for CMV was performed by using an alkaline phosphatase–streptavidin–biotin procedure. The formalin-fixed, paraffin-embedded periocular nerve tissue sections were labeled with biotinylated rabbit antiRhCMV IE1 polyclonal antibody (gift from Peter A Barry, UC–Davis). The positive control tissues were sections of testicles from a CMV-infected rhesus macaque previously assayed for reaction with the primary antibody. The negative control was prepared by substituting the specific primary antibody with antibody diluent. A few cytomegalic cells labeled positively for RhCMV (Figure 5, inset).
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Figure 3. The trigeminal nerve fibers (arrowhead), meninges, and adjacent neuropil are expanded by numerous neutrophils, small numbers of macrophages, and small amounts of fibrinous exudate. Hematoxylin and eosin stain.
Figure 4. The blood vessels adjacent to trigeminal nerve fibers (NF) and in the meninges exhibit fibrinoid necrosis (arrow), and a few cytomegalic cells contain intranuclear inclusion bodies (arrowhead). Hematoxylin and eosin stain.
Discussion
The self-inflicted facial lesions in this case were most likely due to discomfort associated with RhCMV-induced peripheral neuropathy involving the trigeminal and facial nerves. Behavioral assessment of this macaque, including the period of single housing, indicated no history of expression of abnormal behavior. This finding supports our hypothesis that the SIB was not related to indoor housing in caging, single housing, or other common risk factors for SIB.18 There have been reports of SIB targeted toward a specific body part in humans with neuropathic pain.3,12,28 Specifically, SIB associated with facial lesions has been seen in humans with neuropathies affecting the trigeminal nerve.3,28 Self-inflicted facial excoriations are not a commonly reported form of SIB in rhesus macaques, but peripheral neuropathies often affect the distal extremities, which often are involved in SIB.32 HCMV is a common infection worldwide, with adult seroprevalence ranging from 50% to 90%.8 After primary infection, HCMV causes a latent infection that can reactivate periodically.8 Both
Figure 5. The periocular nerves (PN) contain severe neutrophilic inflammation and few cytomegalic cells. ON, optic nerve; S, sclera. Hematoxylin and eosin stain. Inset, Immunohistochemical staining for antiRhCMV IE1 shows a positively labeled cytomegalic cell.
primary infection and reactivation are typically asymptomatic, but immunocompromised hosts and neonates are at high risk for serious disease caused by HCMV.8 HCMV is a common opportunistic infection and frequent cause of peripheral neuropathy in AIDS patients.17,24,37 Like humans, macaques infected with RhCMV are usually asymptomatic, but immunodeficient animals may develop significant disease.8 One study reported a 8.7% prevalence of RhCMV-associated facial neuritis in 115 rhesus macaques coinfected with SIV and RhCMV.4 One animal in the study presented with a large labial ulcer, possibly associated with facial pain or desensitization and secondary self-trauma.4 CMV infection is common after immunosuppression in organ-transplant patients.11,20 Despite the frequency of HCMV infection in transplant recipients, peripheral neuropathies rarely are reported in this population.11,15 Neurologic disorders, such as HIV-associated dementia and peripheral neuropathy, are a frequent complication of HIV and have remained a challenge despite the introduction of combination antiretroviral therapy.41 HIV-associated peripheral neuropathy is often a painful and debilitating syndrome.13 Causes of HIV-associated peripheral neuropathy include direct and indirect effects of the virus itself, opportunistic infections such as HCMV, and antiretroviral drug toxicity.24 HIV can be directly neurotoxic through infection of neurons or cause indirect neurotoxicity through viral products and activation of the inflammatory cascade.38 SIV-induced peripheral neuropathy affecting the trigeminal and lumbar dorsal root ganglia of macaques has been reported to cause lesions similar to those seen in HIV-infected humans.30 In AIDS patients, combination antiretroviral therapy including nucleoside analog reverse-transcriptase inhibitors has been associated with a neuropathy that is clinically indistinguishable from HIV-induced peripheral neuropathy.38 In light of these findings, macaques in SIV studies may be at high risk for developing peripheral neuropathy due to SIV, RhCMV, or antiretroviral therapy. In addition, macaques experiencing naturally or experimentally induced diabetes, nerve trauma, Lyme disease, nutritional (vitamin B12) deficiency, leprosy, immunosuppression for organ transplantation, chemotherapy, or levodopa administration for Parkinson disease may have an increased risk of developing peripheral neuropathy.2,10,14,20,29,33,40,43
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SIB due to CMV-induced neuropathy in a rhesus macaque
Diagnosis of peripheral neuropathy in humans begins with carefully interviewing the patient and conducting a thorough physical and neurologic exam.5 Neuropathic pain often has a shooting or burning quality, with tingling or electric sensations and areas of hypersensitivity.7 Although the clinical signs commonly associated with peripheral neuropathy in macaques are currently unknown and given that we may never know exactly what they are feeling, we hypothesize that affected animals will present with signs similar to those in humans and consistent with established general signs of pain and discomfort. Our macaque demonstrated restlessness or anxiety and excessive scratching leading to self-inflicted wounds. We suspect that other behaviors observed in humans that potentially could also be associated with peripheral neuropathy in macaques include reluctance to use an affected limb, hair-plucking, pressure sores, and other trauma. After confirming the presence of peripheral neuropathy in humans, initial blood tests to identify the underlying cause often include CBC analysis, metabolic profiles, and fasting blood glucose, vitamin B12, and thyroid-stimulating hormone levels.5 In addition, secondary testing may include CSF analysis, urinalysis, and evaluation for infectious diseases such as HIV.5 If the diagnosis is still unclear, nerve conduction studies, electromyography and nerve biopsy may be considered.5 Therapy in humans with peripheral neuropathy focuses on treating the underlying disease and relieving symptoms.5 If the clinical presentation or elevated CMV antibody levels suggest active CMV infection in humans or macaques, treatment with the antiviral ganciclovir often is initiated.19,23,37 In patients with unacceptable side effects or ganciclovir-resistant infection, cidofovir or foscarnet may be used.6 A regimen of weekly CMV surveillance, prophylaxis, and treatment of reactivation has been described in macaques immunosuppressed for transplant- tolerance research.23 In humans with peripheral neuropathy, standard analgesic medications are often unsatisfactory for pain relief.30 The most clinically effective drugs include tricyclic and serotonin–noradrenaline reuptake-inhibiting antidepressants, opioids, and anticonvulsants such as pregabalin and gabapentin.7,16 Other drugs that have been investigated with varying success include topical lidocaine, cannabinoids, topical capsaicin, and injectable botulinum toxin.16 A combination of at least 2 drugs often is needed for adequate pain relief.7 However, many patients remain unable to obtain sufficient relief, and research is needed to identify new treatment options.16 For the macaque we present, opioid therapy was initiated immediately, and antidepressant therapy was considered later. The opioid therapy may have provided some pain relief, but it was insufficient to resolve the SIB. The rapid progression of the lesions in this case precluded the time needed for an antidepressant to take full effect. In both humans and animals, maximal improvement with antidepressant therapy often takes a week to several weeks to achieve.27,34,35 The macaque we present in this case report likely developed SIB secondary to RhCMV-induced neuropathy. Many concurrent diseases and disorders, especially those causing immunodeficiency (like SIV), may put macaques at risk for the development of painful peripheral neuropathies. Peripheral neuropathy should be considered as a potential underlying cause of SIB, particularly in the high-risk groups we just described. When the underlying disease causing peripheral neuropathy in a macaque is experimentally induced, therapy likely will focus on relief of secondary
pain and discomfort. Macaques have been considered as a potential model of HIV-associated peripheral neuropathy and may be helpful for identifying new treatments for this and other debilitating neuropathies.30
Acknowledgments
This work was supported by a NIH–NCRR base grant (P51OD11132) to YNPRC. We thank Cindy Courtney, the YNPRC necropsy staff, animal care staff, behavior management unit, and veterinary department for their assistance with this work. Immunohistochemistry was performed by the Yerkes Molecular Pathology Core. Presented at the National Meeting of the American Association for Laboratory Animal Science (San Antonio, 2014)
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