Clinical recognition of varicella zoster virus vasculopathy

Chang GY.

Eur Neurol. 2012;67(5):297-9

Department of Neurology, Barrow Neurological Institute, Phoenix, Ariz., USA.

INTRODUCTION: It is important to recognize acutely evolving ischemic stroke attributable to reactivation of varicella zoster virus vasculopathy since antiviral agents are effective.

METHODS: Three cases seen by the author over a 2-year period are highlighted.

RESULTS: All patients presented with an evolving arterial or venous ischemia in the background of postherpetic neuralgia proceeding for weeks to months.

CONCLUSION: Chronic neuralgic pain in a dermatomal distribution of an evolving central nervous system vasculopathy is an important clue to its recognition.

Role of herpes simplex virus-1, cytomegalovirus and Epstein-Barr virus in atherosclerosis

Al-Ghamdi A.

Pak J Pharm Sci. 2012 Jan;25(1):89-97.

Department of Medical Microbiology, King Abdul-Aziz University, Jeddah, Saudi Arabia. ghonm5000 @ yahoo.com

Infectious agents such as herpes viruses may be implicated in the inflammatory atherosclerotic process. The aim of this study was to assess the levels of IgG antibody specific for Herpes simplex virus-1 (HSV-1), Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) among patients with atherosclerotic vascular diseases and to examine the relation between the levels of these antibodies and lipid profile, high-sensitive C-reactive protein (hsCRP) in these patients. Seventy five patients [20 with acute coronary artery disease (ACAD), 20 with chronic coronary artery disease (CCAD), 20 with cerebral stroke and 15 with peripheral arterial disease (PAD)] along with 15 healthy individuals as a control group. The studied individuals were subjected to complete history taking, thorough physical examination, and assessment of the blood glucose level, lipid profile, creatine kinase (CK), hsCRP by nephlemetry and virus-specific IgG antibodies by enzyme immunoassay (EIA). Results showed that the levels of cholesterol, triglycerides, LDL-c and hsCRP were significantly higher, while HDL-c was significantly lower among patients compared to that of the controls. A significantly (p<0.05) higher percentage of patients had CMV-specific IgG as compared to the controls. Higher percentage of patients had HSV- and EBV-specific IgG antibodies, however, there was no significant difference between the 2 groups. Individuals who had CMV-specific IgG were more liable to have vascular disease compared to those without (OR=4.10, CI= 1.07-15.75). The levels of CMV- and EBV-specific IgG antibodies were significantly (P<0.01 and < 0.05 respectively) elevated among patients with atherosclerotic vascular diseases when compared to those of the controls. There was no significant correlation between the levels of virus-specific IgG and lipid profile or hsCRP. In conclusion, the level of CMV-and EBV- specific antibodies are elevated among vascular disease patients and the presence of CMV-specific IgG is associated with development of the disease. Serum lipids and hsCRP were increased among the studied patients; however, no significant correlation was detected between antiviral IgG levels and lipid profile or hsCRP.

Recent developments regarding human immunodeficiency virus infection and stroke

Sen S, Rabinstein AA, Elkind MS, Powers WJ.

Cerebrovasc Dis. 2012;33(3):209-18.

University of South Carolina, Columbia, S.C., USA. souvik.sen @ uscmed.sc.edu

Human immunodeficiency virus (HIV) infection is strongly associated with ischemic stroke in the young. Data obtained from the Nationwide Inpatient Sample in the United States show an increase in the number of stroke hospitalizations in the HIV-infected population despite an overall decrease in the number of stroke hospitalizations. Few data exist, however, that address the mechanism of HIV-associated stroke. Recent studies have demonstrated that HIV may infect the endothelium and alter cerebrovascular functions. Whether the proposed mechanism alters the stroke risk is undetermined. Epidemiological studies suggest that HIV-related stroke is associated with a risk factor profile that differs from the HIV-negative youngstroke population in that HIV-associated strokes are less likely to have hypertension, diabetes, hyperlipidemia and smoking as risk factors. A large population-based study, moreover, suggests an association between antiretroviral therapy and increased cardio- and cerebrovascular risks. Specific antiretroviral agents such as protease inhibitors and non-nucleoside reverse transcriptase inhibitors have been implicated in the metabolic syndrome, accelerated atherosclerosis and an increased risk for ischemic stroke. In addition to discussing these developments, this paper also discusses the implications of recent data for stroke prevention in HIV-infected patients.

Varicella and stroke in children: good outcome without steroids

Bartolini L, Gentilomo C, Sartori S, Calderone M, Simioni P, Laverda AM.

Clin Appl Thromb Hemost. 2011 Nov-Dec;17(6):E127-30

Department of Pediatrics, University Hospital of Padua, Italy. dr.luca.bartolini @ gmail.com

Varicella zoster virus (VZV) is the only human virus known to replicate in arteries. After the acute infection, the virus persists in a noninfectious latent form in ganglia along the neuraxis, with intermittent periods of reactivation. Both primary and secondary reactivation are associated with stroke in children. These patients, regardless of the chosen treatment, have a high risk of recurrence, particularly those with worsening arterial stenosis. There are no specific therapy protocols for varicella-associated stroke in children, and the use of steroids or antiviral drugs is still controversial. We present a series of 4 children with stroke following varicella infection, with no recurrence and stable vascular stenosis at a mean follow-up of 18 months without steroid treatment. We also analyze possible correlations between anti-protein C, protein S and protein Z autoantibodies, and post-varicella arteriopathy.

Acute ischemic stroke and infections

Ionita CC, Siddiqui AH, Levy EI, Hopkins LN, Snyder KV, Gibbons KJ.

J Stroke Cerebrovasc Dis. 2011 Jan-Feb;20(1):

Department of Neurosurgery, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA. ccionita @ buffalo.edu

We present an overview of multiple infections in relation to acute ischemic stroke and the therapeutic options available. Conditions that are a direct cause of stroke (infectious endocarditis, meningoencephalitides, and human immunodeficiency virus infection), the pathophysiologic mechanism responsible for stroke, and treatment dilemmas are presented. Independently or in conjunction with conventional risk factors, chronic and acute infections can trigger an acute ischemic stroke through an accelerated process of atherosclerosis and immunohematologic alterations. Acute ischemic stroke has a negative impact on the antibacterial immune response, leading to stroke-induced immunodepression and infections, the most common poststroke medical complications. Poststroke infections are independent predictors of poor outcome. Antibiotic trials for poststroke infection prevention are reviewed. Although antibiotic prophylaxis is not the standard of care in acute stroke, current guidelines support prompt treatment of stroke-related infections.

Cerebrovascular disease in central nervous system infections

Chow FC, Marra CM, Cho TA.

Semin Neurol. 2011 Jul;31(3):286-306.

Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

Cerebrovascular disease is a complication of a variety of infections affecting the central nervous system (CNS). Infection may cause vasculitis affecting primarily the vessels at the base of the brain in the setting of meningitis; an immune-mediated parainfectious process leading to vasospasm or thrombosis; or a hypercoagulable state in combination with endothelial dysfunction resulting from activation of inflammatory and procoagulant cascades. Although systemic signs and symptoms may be present to aid in the diagnosis, cerebral infarction secondary to infection may be indistinguishable from more typical causes of stroke. Confirmation of an infectious vasculitis may also be challenging, as brain biopsy, the gold standard for diagnosis, is rarely pursued. In many CNS infections, vascular complications portend a poor prognosis as they are often associated with devastating neurologic outcomes, including death, underscoring the importance of early recognition and appropriate therapy. In this review, we address bacterial, viral, fungal, and parasitic causes of cerebrovascular disease.

Hepatitis C virus infection and increased risk of cerebrovascular disease

Lee MH, Yang HI, Wang CH, Jen CL, Yeh SH, Liu CJ, You SL, Chen WJ, Chen CJ.

Stroke. 2010 Dec;41(12):2894-900.

Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan.

Comment in: Stroke. 2011 Jun;42(6):e389; author reply e390-1.

BACKGROUND AND PURPOSE: The association between hepatitis C virus (HCV) infection and cerebrovascular disease remains controversial. This study aimed to assess the risk of lethal cerebrovascular diseases associated with chronic HCV infection.

METHODS: In this community-based prospective cohort study, 23 665 residents (aged 30 to 65 years) were enrolled in 1991 to 1992. They were personally interviewed using structured questionnaires and provided blood samples for various serological and biochemical tests at study entry. Serum HCV RNA level and HCV genotype were tested for participants seropositive for antibodies against HCV (anti-HCV). Deaths from cerebrovascular disease during follow-up were ascertained by computerized linkage with National Death Certification profiles from 1991 to 2008 (International Classification of Diseases, 9th Revision 430 to 438). Multivariate-adjusted hazard ratio with 95% CI was estimated for each risk predictor.

RESULTS: There were 255 cerebrovascular deaths during 382 011 person-years of follow-up. The cumulative risk of cerebrovascular deaths was 1.0% and 2.7% for seronegatives and seropositives of anti-HCV, respectively (P<0.001). The hazard ratio (95% CI) of cerebrovascular death was 2.18 (1.50 to 3.16) for anti-HCV seropositives after adjustment for several conventional risk factors of cerebrovascular disease. Compared with participants seronegative for anti-HCV as the referent, the multivariate-adjusted hazard ratio (95% CI) was 1.40 (0.62 to 3.16), 2.36 (1.42 to 3.93), and 2.82 (1.25 to 6.37), respectively, for anti-HCV-seropositive participants with undetectable, low, and high serum levels of HCV RNA (P<0.001 for trend). However, no significant association was observed between HCV genotype and cerebrovascular death.

CONCLUSIONS: Chronic HCV infection is an independent risk predictor of cerebrovascular deaths showing a biological gradient of cerebrovascular mortality with increasing serum HCV RNA level.

Infectious burden and carotid plaque thickness: the northern Manhattan study

Elkind MS, Luna JM, Moon YP, Boden-Albala B, Liu KM, Spitalnik S, Rundek T, Sacco RL, Paik MC.

Stroke. 2010 Mar;41(3):e117-22

Neurological Institute, 710 West 168th Street, Box 182, New York, NY 10032, USA. mse13 @ columbia.edu

BACKGROUND AND PURPOSE: The overall burden of prior infections may contribute to atherosclerosis and stroke risk. We hypothesized that serological evidence of common infections would be associated with carotid plaque thickness in a multiethnic cohort.

METHODS: Antibody titers to 5 common infectious microorganisms (ie, Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, and herpesvirus 1 and 2) were measured among stroke-free community participants and a weighted index of infectious burden was calculated based on Cox models previously derived for the association of each infection with stroke risk. High-resolution carotid duplex Doppler studies were used to assess maximum carotid plaque thickness. Weighted least squares regression was used to measure the association between infectious burden and maximum carotid plaque thickness after adjusting for other risk factors.

RESULTS: Serological results for all 5 infectious organisms were available in 861 participants with maximum carotid plaque thickness measurements available (mean age, 67.2+/-9.6 years). Each individual infection was associated with stroke risk after adjusting for other risk factors. The infectious burden index (n=861) had a mean of 1.00+/-0.35 SD and a median of 1.08. Plaque was present in 52% of participants (mean, 0.90+/-1.04 mm). Infectious burden was associated with maximum carotid plaque thickness (adjusted increase in maximum carotid plaque thickness 0.09 mm; 95% CI, 0.03 to 0.15 mm per SD increase of infectious burden).

CONCLUSIONS: A quantitative weighted index of infectious burden, derived from the magnitude of association of individual infections with stroke, was associated with carotid plaque thickness in this multiethnic cohort. These results lend support to the notion that past or chronic exposure to common infections, perhaps by exacerbating inflammation, contributes to atherosclerosis. Future studies are needed to confirm this hypothesis and to define optimal measures of infectious burden as a vascular risk factor.

Virus vasculopathy and stroke: an under-recognized cause and treatment target

Nagel MA, Mahalingam R, Cohrs RJ, Gilden D.

Infect Disord Drug Targets. 2010 Apr;10(2):105-11.

Department of Neurology, University of Colorado Denver School of Medicine, Denver, CO 80045, USA.

While arteriosclerotic disease and hypertension, with or without diabetes, are the most common causes of stroke, viruses may also produce transient ischemic attacks and stroke. The three most-well studied viruses in this respect are varicella zoster virus (VZV), cytomegalovirus (CMV) and human immunodeficiency virus (HIV), all of which are potentially treatable with antiviral agents. Productive VZV infection in cerebral arteries after reactivation (zoster) or primary infection (varicella) has been documented as a cause of ischemic and hemorrhagic stroke, aneurysms with subarachnoid and intracerebral hemorrhage, arterial ectasia and as a co-factor in cerebral arterial dissection. CMV has been suggested to play a role in the pathogenesis of arteriosclerotic plaques in cerebral arteries. HIV patients have a small but definite increased incidence of stroke which may be due to either HIV infection or opportunistic VZV infection in these immunocompromised individuals. Importantly, many described cases of vasculopathy in HIV-infected patients were not studied for the presence of anti-VZV IgG antibody in CSF, a sensitive indicator of VZV vasculopathy. Unlike the well-documented role of VZV in vasculopathy, evidence for a causal link between HIV or CMV and stroke remains indirect and awaits further studies demonstrating productive HIV and CMV infection of cerebral arteries in stroke patients. Nonetheless, all three viruses have been implicated in stroke and should be considered in clinical diagnoses.

Neurologic manifestations of varicella zoster virus infections

Amlie-Lefond C, Jubelt B.

Curr Neurol Neurosci Rep. 2009 Nov;9(6):430-4.

Department of Neurology, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI 53226, USA. Klefond @ mcw.edu

Varicella zoster virus (VZV) causes acute viral exanthema in childhood, becomes latent, and can reactivate years later to produce neurologic disease. Primary VZV infection is associated with acute cerebellitis and stroke, particularly in childhood. VZV reactivation may result in neuropathy, myelitis, stroke, and encephalitis, the latter two syndromes the result of small and large vessel vasculopathy. Prompt diagnosis and treatment are critical to minimize morbidity in herpes zoster as well as morbidity and death in VZV vasculitis and encephalitis. Detection of anti-VZV antibodies in cerebrospinal fluid is the most sensitive method of diagnosing varicella infection of the nervous system. Despite the advent of the VZV vaccine, varicella remains a significant cause of neurologic morbidity.

The role of latent virus infection of the central nervous system in acute hemorrhagic stroke

[Article in Russian]

Kul'chikov AE, Kositsyn NS, Makarenko AN, Vasil'eva IG.

Vopr Virusol. 2009 Jul-Aug;54(4):23-7.

The purpose of the investigation was to study whether latent virus infection may activate in the murine brain using a model of hemorrhagic stroke. Acute intracerebral hemorrhagic stroke was induced in the internal capsule in accordance with the original technology. For experimental reproduction of virus meningoencephalitis, albino mice were infected with a sublethal dose of herpes simplex virus. The investigation ascertained persistent virus activation, as shown by the polymerase chain reaction technique that detected herpes simplex virus type 1 in the blood and brain of the animals, as well as the development of a cerebral inflammatory lesion associated with acute hemorrhagic stroke. The findings suggest that encephalitis may develop in acute stroke due to herpes simplex virus reactivation from the latent state, which will improve monitoring and treatment quality in acute stroke.

Chronic infections and genetic factors in the development of ischemic stroke

Kis Z, Sas K, Gyulai Z, Treso B, Petrovay F, Kapusinszky B, Csire M, Endresz V, Burian K, Mandi Y, Vecsei L, Gonczol E.

New Microbiol. 2007 Jul;30(3):213-20.

Department of Virology, National Center for Epidemiology, H-1097 Budapest, Gyali ut 2-6, Hungary.

The aim of this study was to examine whether chronic infections and genetic factors of the host play roles in the pathophysiology of acute noncardioembolic ischemic stroke. Blood samples from 59 subjects with ischemic stroke and 52 control patients were investigated by nested PCR for the presence of C. pneumoniae DNA, HCMV DNA and enterovirus RNA, by ELISA for the levels of antibodies to C. pneumoniae, HCMV, HSV, HHV-6, EBV and the inflammatory chemokine IL-8, and by PCR for promoter polymorphism of the IL-8 and CD14 host genes. Associations of stroke with the HCMV IgG and HSV-1 IgA antibody levels were observed. No association of stroke was detected with the presence of C. pneumoniae, HCMV or enterovirus nucleic acids in the peripheral blood, C. pneumoniae IgM, IgG and IgA, the HSV IgG, the EBV IgG, or HHV-6 IgG antibody levels, the pathogen burden, the IL-8 or CD14 promoter polymorphisms, or with the serum levels of IL-8 in the overall study population. These results are consistent with the hypothesis that certain pathogens are involved in the development of ischemic stroke.

Serological markers of chronic Chlamydia pneumoniae and cytomegalovirus (CMV) infection in patients with peripheral occlusive artery disease--an initial report

[Article in Polish]

Rabczynski M, Jakobsche U, Adamiec R.

Przegl Lek. 2007;64(6):416-8.

Katedra i Klinika Angiologii, Nadcisnienia Tetniczego i Diabetologii Akademii Medyczne, Wroclaw. maciejrabczynski @ poczta.onet.pl

Involvement of infection agents in pathogenesis of atherosclerosis was described in several studies, particularly in patients with acute coronary syndrome or ischemic stroke. However, in very few studies an association of serological markers of chronic infection with peripheral occlusive artery disease was analysed. The prevalence and concentration of immunoglobulin G and A to Chlamydia pneumoniae and immunoglobulin G to CMV were measured in sera of 31 participants suffering from peripheral occlusive artery disease. Significant difference in the prevalance of immunoglobulin G to C. pneumoniae and CMV between study and control groups was documented. There was no such association in reference to immunoglobulin A to C. pneumoniae index. Serum concentration of all measured antibodies were significantly higher in the study group than in control.

High prevalence of anticardiolipin antibodies in patients with asymptomatic hepatitis C virus infection associated acute ischemic stroke

Cojocaru IM, Cojocaru M, Iacob SA.

Rom J Intern Med. 2005;43(1-2):89-95.

Carol Davila University of Medicine and Pharmacy, Clinic of Neurology, Colentina Hospital, Bucharest, Romania.

Anticardiolipin antibody (aCL) is considered to be one of the contributory factors in the development of acute ischemic stroke. Chronic hepatitis C virus infection (HCV) and the antiphospholipid syndrome are two conditions that have increased the risk of stroke. The purpose of this study was to investigate the prevalence of anticardiolipin antibodies in patients with asymptomatic chronic hepatitis C virus infection-related acute ischemic stroke. Fifty eight patients (39 women, 19 men), mean age 62 years (range 46-77 years) with acute ischemic stroke and asymptomatic chronic hepatitis C virus infection were studied; all were positive for anti-HCV antibodies. A control group of 36 patients (20 women, 16 men), mean age 58 years (range 44-75 years) with ischemic stroke without HCV were also tested. Both anti-HCV antibodies and IgG aCL antibodies were measured by enzyme-linked immunosorbent assay (ELISA). The significantly higher levels of IgG aCL antibodies were detected in serum samples of 27/58 (46%) patients with acute ischemic stroke and asymptomatic chronic hepatitis C virus infection. The control group had much lower levels of IgG aCL antibodies in 2/36 (5%) patients. This study clearly shows a high prevalence of IgG aCL antibodies in the serum of patients with acute ischemic stroke and HCV. Mean levels of serum IgG aCL antibodies were significantly higher among the HCV patients with acute ischemic stroke than the patients with acute ischemic stroke without HCV (94.8+/-7.6 GPL U/mL as compared to 27.2+/-3.2 GPL U/mL), p<0.001. We showed that a number of chronic hepatitis C virus infection-related ischemic strokes is associated with the presence of anticardiolipin antibodies, a condition predisposing to coagulopathy. These results suggest that anticardiolipin antibodies associated with HCV may be an important marker for acute ischemic stroke. The higher prevalence and titre of IgG aCL antibodies in patients with HCV suggests that these humoral factors might be involved in the pathogenesis of ischemic stroke.

Does chronic periodontitis play a role in the pathogenesis of cardiovascular and cerebrovascular diseases?

[Article in German]

Muller HP.

Gesundheitswesen. 2002 Feb;64(2):89-98.

Mund-, Zahn-, Kieferklinik der Ruprecht-Karls-Universitat Heidelberg, Germany. hp.muller @ hsc.kuniv.edu.kw

The role of chronic infections in the initiation of atherosclerotic lesions has been vividly discussed in recent years. A possible causal relationship between cardiovascular diseases and infections with, e. g., Chlamydia pneumoniae, Helicobacter pylori, or herpes viruses had also been established for chronic periodontitis, in particular after discovery of DNA of typical periodontal pathogens in atheromatous plaques. Especially in longitudinal epidemiologic studies, a low or moderate association between existing periodontitis and the development of, e.g., coronary heart disease or non-haemorrhagic stroke had been observed. In this article the respective literature is critically reviewed. In particular, the influence of incomplete or inappropriate adjustment for common risk factors for both diseases, i. e., cardiovascular disease and periodontitis should be analysed. In metaanalyses of prospective studies, in which the respective endpoint occurred after the investigation had commenced, relative risks of periodontitis of 1.12 (95 % confidence interval 0.95-1.33) for coronary heart disease and 1.73 (0.89-3.34) for ischaemic stroke were calculated. Whether chronic periodontitis actually represents an important risk for the development of cardiovascular diseases remains questionable. Already planned intervention studies appear to be premature and ethically highly problematic.

Identification of periodontal pathogens in atheromatous plaques

Haraszthy VI, Zambon JJ, Trevisan M, Zeid M, Genco RJ.

J Periodontol. 2000 Oct;71(10):1554-60.

Department of Oral Biology, School of Dental Medicine, State University of New York at Buffalo, USA.

BACKGROUND: Recent studies suggest that chronic infections including those associated with periodontitis increase the risk for coronary vascular disease (CVD) and stroke. We hypothesize that oral microorganisms including periodontal bacterial pathogens enter the blood stream during transient bacteremias where they may play a role in the development and progression of atherosclerosis leading to CVD.

METHODS: To test this hypothesis, 50 human specimens obtained during carotid endarterectomy were examined for the presence of Chlamydia pneumoniae, human cytomegalovirus, and bacterial 16S ribosomal RNA using specific oligonucleotide primers in polymerase chain reaction (PCR) assays. Approximately 100 ng of chromosomal DNA was extracted from each specimen and then amplified using standard conditions (30 cycles of 30 seconds at 95 degrees C, 30 seconds at 55 degrees C, and 30 seconds at 72 degrees C). Bacterial 16S rDNA was amplified using 2 synthetic oligonucleotide primers specific for eubacteria. The PCR product generated with the eubacterial primers was transferred to a charged nylon membrane and probed with digoxigenin-labeled synthetic oligonucleotides specific for Actinobacillus actinomycetemcomitans, Bacteroides forsythus, Porphyromonas gingivalis, and Prevotella intermedia.

RESULTS: Eighty percent of the 50 endarterectomy specimens were positive in 1 or more of the PCR assays. Thirty-eight percent were positive for HCMV and 18% percent were positive for C. pneumoniae. PCR assays for bacterial 16S rDNA also indicated the presence of bacteria in 72% of the surgical specimens. Subsequent hybridization of the bacterial 16S rDNA positive specimens with species-specific oligonucleotide probes revealed that 44% of the 50 atheromas were positive for at least one of the target periodontal pathogens. Thirty percent of the surgical specimens were positive for B. forsythus, 26% were positive for P. gingivalis, 18% were positive for A. actinomycetemcomitans, and 14% were positive for P. intermedia. In the surgical specimens positive for periodontal pathogens, more than 1 species was most often detected. Thirteen (59%) of the 22 periodontal pathogen-positive surgical specimens were positive for 2 or more of the targetspecies.

CONCLUSIONS: Periodontal pathogens are present in atherosclerotic plaques where, like other infectious microorganisms such as C. pneumoniae, they may play a role in the development and progression of atherosclerosis leading to coronary vascular disease and other clinical sequelae.