Intra-axonal virus in demyelinative lesions of experimental herpes simplex type 2 infection

Three-week-old mice which had been infected intracerebrally with herpes simplex virus type 2 (HSV-2) were examined electron-microscopically for the presence of intra-axonal virus in or near optic nerve and spinal cord demyelinative lesions. Acute lesions and their margins frequently contained a very small proportion of abnormal axons, and in a few of these mature virus particles, nucleocapsids, or other incomplete forms were found. A similar range of particle morphology was present in the cytoplasm of infected and degenerating glia. Axons containing similar particles were not identified in fibers in normal white matter surrounding demyelinative lesions. It is proposed that neuronal infection and axonal transport of virus may lead to foci of oligodendroglial infection, destruction and central nervous system (CNS) demyelination near to or remote from the cell bodies of infected neurons. In some instances, the topography of lesions could reflect a tract association. Anatomical features of nervous tissue could favor amplification of demyelination from a relatively minimal neuronal infection, with little evidence of tract degeneration. This hypothesis is consistent with the great predominance of demyelination relative to gray matter disease seen experimentally in non-fatal CNS infections with HSV-2. It would also explain the marked tendency for demyelinative lesions in at least certain CNS locations to be greatly elongated in the long axis of fiber tracts. This mechanism could be of importance in other animal models of virus-induced demyelination, and perhaps also in multiple sclerosis.     

Herpes simplex encephalitis: an autopsy case with isolation of type 1 herpes simplex virus

Summary An adult case of herpes simplex encephalitis was studied after autopsy. Postmortem examination revealed necrotizing encephalitis associated with Cowdry type A intranuclear inclusion bodies in glial cells. Herper simplex virus type 1 was isolated from the removed brain. Herpes simplex virus antigens were detected diffusely in wide areas of the brain by immunofluorescent test and viral particles characteristic to herpes simplex virus were demonstrated by electron microscopy. There was an apparent discrepancy between severity of histological changes and distribution of virus antigen.     

Seroprevalence of herpes simplex virus type 2 in multiple sclerosis

BACKGROUND: It has been proposed that multiple sclerosis (MS) might be a sexually transmitted disorder. There is evidence that seropositivity to herpes simplex virus type 2 (HSV-2) correlates well with the number of sexual partners. Accordingly, a raised overall HSV-2 seroprevalence in MS would lend support to this theory. MATERIALS AND METHODS: Serum from 497 UK subjects with clinically definite MS was tested for antibodies to HSV-2 and compared with matched historical controls from within and outside London, blood donors and genito-urinary medicine (GUM) clinics. RESULTS: The unadjusted MS seropositivity rate was 14%. HSV-2 seroprevalence in MS patients aged 35-64 years was significantly higher overall compared with a non-London general population in an unadjusted comparison. HSV-2 seroprevalence in London MS patients compared with London blood donors was significantly greater irrespective of age, but the MS seropositive rate was lower than GUM clinic attenders. In a logistic regression analysis, increased age, female sex and MS diagnosis all independently increased the odds of seropositivity after adjustment for each other. CONCLUSION: It is concluded that there is increased likelihood of HSV-2 exposure in patients with MS and this may indicate a higher than average number of partners.     

Two cases of necrotizing myelopathy associated with malignancy caused by herpes simplex virus type 2

Summary Two cases of necrotizing myelopathy were autopsied; one was complicated with lung carcinoma and the other with chronic type adult T cell leukemia (ATL leukemia). To our knowledge, they were the first cases of their type in Japan. In both cases, necrosis of the spinal cord was observed in the gray and white matter along most of its extent. Marked changes were found in the lumbar segment. The patients were not treated with intravenous cancer chemotherapy or irradiation. Immunohistochemical and electron microscopic examination revealed an extremely strong infection of herpes simplex virus (HSV) type 2. However, HSV type 1 and cytomegalovirus antigens were not detected.     

Virus spread and initial pathological changes in the nervous system in genital herpes simplex virus type 2 infection in mice

Summary Mice were infected by the vaginal route with the MS strain of herpes simplex virus type 2 (HSV-2). Serial vaginal cultures were used to confirm infection and to select mice for this study. Two mice were killed by perfusion on days 2–6 post infection (p.i.) and lumbar and sacral cord with cauda were fixed and embedded for electron microscopy. Semithin Epon-sections were stained for viral antigen using a rabbit anti-HSV-2 antiserum and the Avidin-Biotin (ABC) method. Thin sections from antigen-positive blocks were examined by electron microscopy, and the number and types of infected cells detected by these two methods were compared. A good correlation was found between detection of infected cells by these methods. Infected cells included neurons of dorsal root ganglia and spinal cord, satellite cells of dorsal root ganglia, non-myelinating Schwann cells, astrocytes, oligodendrocytes and arachnoidal cells. Infected cells were first detected in the cauda on day 3 p.i. and in the spinal cord on day 5 p.i. The temporal and spatial distribution of infected cells was consistent with neural spread to and within the CNS. The pathological lesions showed a good correlation with the distribution and number of infected cells and are probably due to a direct virus effect. The similar sensitivity of the Epon-ABC method to electron microscopy in detecting infected cells indicates that this method may have useful applications in both experimental and diagnostic work.     

Herpes simplex virus type 2 meningitis without genital lesions: An immunoblot study

Summary Two sexually active female patients presented with acute meningitis. The CSF abnormalities were severe and persistent. In spite of the absence of genital lesions, serological studies revealed a primary infection by herpes simplex virus type 2. An immunoblot study revealed intrathecal synthesis of anti-herpes antibodies early in the course of the disease.     

Herpes simplex virus type 2 DNA detected in cerebrospinal fluid of 9 patients with Mollaret's meningitis

We present clinical and virological data on 9 patients, 7 women and 2 men aged 31–56 years, with recurrent aseptic meningitis (Mollaret's meningitis). Polymerase chain reaction detected Herpes simplex virus type 2 DNA in cerebrospinal fluid samples from all patients collected during their latest attacks of meningitis. Six patients had no history of genital herpes. Only 1 patient was offered prophylactic antiviral treatment during the study period (45 months).     

Myelin lesions in the rabbit eye model as a bystander effect of herpes simplex and visna virus sensitization

Summary Rabbits were immunized with herpes simplex and visna virus in complete Freund's adjuvant. Uv-inactivated herpes virus and the purified visna virus protein p 25 injected intraocularly into these rabbits elicited a moderate inflammatory cell infiltration in the epiretinal myelinated nerve fiber bundles accompanied by signs of demyelination. It is therefore apparent that also viral antigen can induce myelin lesions as a socalled bystander effect of a cell-mediated immune response (bystander demyelination).     

Discrimination of herpes simplex virus types 1 and 2 cerebral infections in a rat model

Summary A rat model was used to evaluate intertypic differences after intracranial (i.c.) inoculation of herpes simplex virus (HSV) types 1 and 2 strains with regard to neurovirulence and neuropathology, and influence of age on susceptibility. In adult rats, HSV-1 strains were more virulent than HSV-2 strains. HSV-1 replicated to higher titers in the central nervous system (CNS) of rats, as compared with HSV-2. In rats of less than 2–3 weeks of age, HSV-1 and HSV-2 were equally virulent, but morphological examination of rat brains showed typespecific differences in pathology and viral distribution already at the early postnatal stage. After HSV-1 infection, neuronal infection of the hippocampus, followed by cortical infection and edematous destruction dominated, while a preponderance of meningitis and invasive encephalitis was seen after HSV-2 infection. We suggest that the rat might be a useful model for human HSV infection in the CNS with discrimination between HSV-1 and HSV-2 infections, also at the early postnatal stage.Supported by the Swedish Medical Research Council (proj. no. 4514 and 07121), the Göteborg Medical Society, and the Swedish Medical Society     

Targets of herpes simplex virus type 1 infection in a mouse corneal model

Summary In animal models, spread of herpes simplex virus type 1 (HSV-1) from epithelial replication sites to the peripheral and central nervous system is known from analysis of individually dissected tissues. To examine virus spread in undissociated tissues, corneas of adult mice were inoculated with HSV-1. After 1 to 13 days groups of mice were perfused with formalin, and decalcified blocks of head and neck were embedded in paraffin. At intervals, serial sections were screened for HSV antigen. On days 1 and 2, viral antigen was restricted to cornea and conjunctiva but by days 3 and 4 was also seen in autonomic ganglia and the trigeminal system. On day 6, HSV antigen reached its maximum extent; infected sites included the trigeminal complex (ganglion, root, peripheral ophthalmic and maxillary branches and spinal nucleus and tract), ehtmoid sinus and olfactory buld, visual system, and autonomic ganglia (ciliary, pterygopalatine and superior cervical). Antigen progressively diminished on days 8 and 10, and was not detected on day 13. This method demonstrates a broader range of infected tissues and suggests a more complex pattern of HSV spread than has been previously recognized. Virus appears to reach the intracranial compartment by four different neural routes. When effects of higher and lower corneal inoculation doses were compared, a lower dose resulted in lower peak HSV titers in trigeminal ganglion and brain stem and later virus appearance in these tissues. Thus, dose may influence the kinetics of HSV spread from the peripheral inoculation site to the CNS.Supported in part by U.S.U.H.S. grant, R07396. the opinions or assertions contained herein are the private views of the authors and should not be construed as official or necessarily reflecting the views of the Uniformed Services University of the Health Sciences or Department of Defense. There is no objection to its presentation and/or publication     

Valacyclovir treatment ameliorates the persistently increased pentylenetetrazol-induced seizure susceptibility in mice with herpes simplex virus type 1 infection

Herpes simplex virus type 1 (HSV-1) is an important pathogen related to epilepsy. We have shown previously that corneal inoculation of mice with HSV-1 causes acute spontaneous behavioral and electrophysiological seizures and increases hippocampal excitability and kainite-induced seizure susceptibility. In this study, we aimed to determine whether early-life HSV-1 infection in mice might cause short- and long-term enhanced susceptibility to pentylenetetrazol (PTZ)-induced seizures and to evaluate whether early antiviral drug therapy was effectively ameliorating this deficit. Seizure threshold was calculated by the latency of onset of the myoclonic jerk, generalized clonus, and maximal tonic-clonic convulsion. We demonstrate that the localization of viral antigens was predominantly within the bilateral temporal areas (amygdala, piriform, and entorhinal cortex) of HSV-1-infected mice. We also present evidence that mice of all HSV-1-infected groups had a shorter latency and higher severity to PTZ-induced seizures than in age-matched, mock-infected controls. Treatment of HSV-1-infected mice with valacyclovir, a potent inhibitor of HSV-1 replication, produced a dose-dependent decrease in the signs of neurological deficits, pathological damages, and PTZ-induced seizure severity. Our results are consistent with the hypothesis that early-life HSV-1 infection leads to persistent enhancement of neuronal excitability in limbic circuits, which could result in an overall increased propensity to induce seizures later in life. Additionally, prompt optimal antiviral therapy effectively decreases seizure susceptibility in HSV-1-infected mice by limiting the level of viral replication and inflammatory response induced by virus. The present study provides not only experimental evidence, but also a new therapeutic strategy in HSV-1-associated human epilepsy.     

Resistance of rat CNS to brain stem infection with herpes simplex virus type 1

Infection of the CNS by herpes simplex type 1 (HSV-1) via the trigeminal route to the brain stem was elucidated in a rat model. In contrast to the earlier described cortical and hippocampal infection after intracranial injection, the CNS showed a profound resistance to HSV-1 infection when the virus was administred by nose inoculation, as judged by histopathology and immunohistochemistry. In contrast, when the distribution of HSV-1 in the brain was investigated after nose inoculation by polymerase chain reaction, viral DNA was detected at all levels from the ganglia to the cortex. When replication of HSV-1 was assayed in primary cell cultures of rat astrocytes derived from brain stem, striatum, hippocampus and cerebral cortex, significantly lower virus yields were obtained in brain stem-derived astrocytes cultures as compared with in cortex-derived astrocytes. This finding was independent of whether HSV-1 strains used originated from brains of patients suffering from herpes simplex encephalitis or from patients with oral cutaneous lesions and lacking neurological symptoms. Also, by immunocytochemistry of cultures after HSV-1 infection, a lower number of plaques were seen in brain stem-derived astrocytes as compared with cortex-derived astrocytes. The observed relative resistance of brain stem-derived astrocytes to replicate HSV-1 might contribute to the ability of the brain stem to withstand infection during reactivation of this virus in the trigeminal neurons.Financial support was received from the Swedish Medical Research Council, the Medical Society of Göteborg, the Swedish Medical Society, and the Faculty of Medicine, University of Göteborg     

脊髓型多发性硬化的MRI表现

目的总结分析脊髓型多发性硬化的MRI表现。方法搜集经临床证实的脊髓型多发性硬化11例,均行MRI检查,对其临床及MRI资料进行回顾性分析。结果脊髓型多发性硬化的特征性MRI表现为,11例患者的病灶以颈髓多见,病变脊髓在T1WI像为低或等信号,T2WI像为高信号,病灶位于脊髓两侧和后部,病灶活动期呈斑片状或边缘强化,应用糖皮质激素试验性治疗对脊髓出现的可疑脱髓鞘病灶者有一定的帮助。结论脊髓型多发性硬化有其特征性MRI表现,MRI有助于脊髓型多发性硬化的诊断,是目前诊断脊髓型多发性硬化最敏感的影像学方法 。     

Incontinentia pigmenti mimicking a herpes simplex virus infection in the newborn

Introduction Incontinentia pigmenti is a rare, X-linked dominant multisystem genodermatosis that presents at or soon after birth with characteristic cutaneous signs. The main features occur in the skin where a blistering rash occurs in the newborn period, followed by the blisters becoming raised-like warts. After the skin, the central nervous system is the next most affected system. Case report We report a female infant who was born with vesicular eruptions who was initially thought to have congenital herpes simplex virus infection. Conclusion This case report emphasises that incontinentia pigmenti should be included in the differential diagnosis of cutaneous blistering lesions and central nervous system involvement in neonates. This case was presented in part at the 22nd International Symposium on Neonatal Intensive Care, Milan, Italy, October, 2006.     

Latent herpes simplex virus type 1 in human geniculate ganglia

Summary Viral infection, especially by reactivation of herpes simplex virus (HSV) has been considered to be a possible explanation for the pathogenesis of idiopathic peripheral facial nerve palsy (Bell's palsy). We investigated whether the geniculate ganglia of man contain latent HSV type 1 (HSV-1), and compared the frequency of HSV-infected ganglia and that of latently infected neurons in human geniculate ganglia and in trigeminal ganglia. From autopsy specimens of eight adults 15 geniculate ganglia and 16 trigeminal ganglia were examined by means of in situ hybridization and immunohistochemical staining. The HSV-1 genome was detected in 11 of the 15 (71%) geniculate ganglia and in 13 of the 16 (81%) trigeminal ganglia. No HSV antigen was noted in any of the ganglia. The incidence of latently infected neurons was 0.9% in the trigeminal ganglia and 5.3% in the geniculate ganglia. The difference in percentages between the two types of ganglia was significant. Our results suggest that reactivation of latent HSV in the geniculate ganglia is a probable cause of some cases of herpetic stomatitis and of idiopathic peripheral facial nerve palsy.Supported by Special Grant-in-Aid for Promotion of Education and Science in Hokkaido University (to K.N.) and Grant-in-Aid for Scientific Research (C) (03670803 to S.F.) provided by the Ministry of Education, Science and Culture     

儿童单纯疱疹病毒性脑炎11例临床分析

目的 分析单纯疱疹病毒性脑炎(HSE)的临床特征、诊断方法及治疗措施.方法 对11例HSE患者进行回顾性分析.结果 11例均为急性起病,均有发热、抽搐及意识障碍.其中嗜睡1例,昏迷10例,脑神经损害6例,精神症状3例.神经症状出现最早时间为24 h.血清及脑脊液检测HSV-IgM均为阳性,全部病例进行脑电图、头颅CT、...     

Central nervous system infection and immune response in mice inoculated into the lip with herpes simplex virus type 1

Virus may be recovered from various areas of the central nervous system (CNS) of mice for as long as 11 days after inoculation of herpes simplex virus type 1 (HSV-1) into the lip. The probability of isolation from any particular region of the CNS seems to be a function of the distance of that area from the root-entry zone of the trigeminal nerve. It is also mouse strain-dependent, with much more extensive evidence of brain infection being found in BALB/c and C3H rather than C57BL/6 mice, in which it is limited to the pons. The virus could not be isolated from the CNS of BALB/c mice after 10 days, though HSV-1 is readily recovered from the trigeminal ganglia at least through day 38. Significant concentrations of HSV-1-specific immunoglobulin (Ig) were demonstrated consistently in cerebrospinal fluid (CSF) from day 12 after exposure to virus. The persistence of relatively high concentrations of IgM in the CSF indicates that much of this antibody may be synthesized locally in the brain.     

Dopaminergic neurotransmission in chronic herpes simplex virus brain infection in rabbits

Summary In this study we have examined brain concentrations of monoamine neurotransmitters and striatal and mesencephalic D-2 receptors in a chronic model of herpes simplex virus (HSV) encephalitis. The HSV-inoculated rabbits were killed two months after inoculation. Dopamine (DA), noradrenaline, serotonin and their metabolites were determined in the substantia nigra, caudate nucleus, putamen, nucleus accumbens, and olfactory tubercles using HPLC with electrochemical detection. The B_max and K_d values of D-2 receptors were studied in the striatum and in the mesencephalon using³H-spiroperidol as ligand.The animals showed rotational behaviour, consisting of posture tilting to the inoculated side and circling in the same direction during the first week, then slowly subsiding. Compared with controls, the concentration of homovanillic acid (HVA) was reduced in the ascending DA system on both sides. Neither in the number nor affinity of D-2 receptors were there any differences between the HSV-inoculated and control rabbits.The decreased HVA concentrations suggest that dopaminergic hypofunction can develop as a consequence of previously experienced acute HSV brain infection.     

Differentiation of herpes simplex virus 1 and 2 in cerebrospinal fluid of patients with HSV encephalitis and meningitis by stringent hybridization of PCR-amplified DNAs

Differentiation of herpes simplex virus (HSV) types 1 and 2 in cerebrospinal fluid of 17 patients with serological1y diagnosed HSV encephalitis and meningitis or acute limbic encephalitis was determined by stringent hybridization of polymerase chain reaction — amplified DNAs. Ten of 17 patients were positive; six with HSV 1 isolates and four with HSV 2 isolates. We detected HSV type 1 in two cases of meningitis, although meningitis is generally thought to be caused by type 2. Additionally, HSV type 2 was found in one case of acute adult encephalitis, which is generally due to HSV type 1. HSV DNAs could be detected for over I month after onset, although our patients included several prolonged and recurrent cases. HSV DNA genomes were not detected in three cases of acute limbic encephalitis. Our study indicates that this method can be used for type differentiation in HSV CNS infections.