慢性实验性变应性猴脑脊髓炎的超微结构改变

目的：探讨自身免疫性中枢神经系统脱髓鞘疾病慢性型的病理特点及其可能机制。方法：成功建立猴实验性态反应性脑脊髓炎模型数年后，根据MR摄片结果位病灶并作分类，然后进行病理取材和电镜观察超微结构。结果：（1）活动性病灶内成片的髓鞘松解、断裂或融合，轴突空泡样变性，皱缩或消失，少突胶质细胞变性，未见淋巴细胞浸润，仅见散在巨噬细胞，伴明显的间质水肿；（2）可疑活动性病灶内见部分髓鞘内板松解，其内轴突有较度空泡样变，亦见少突胶质细胞变性，散在巨噬细胞，未见淋巴瘤浸润，结论：慢性EAE的病理改变不仅有髓鞘的变性，同时轴突的病变也十分明显。     

Clinical study in 28 patients with infection-related acute onset encephalitis]

Of the 75 patients with infection-related acute encephalopathy or encephalitis treated by us in the last 10 years, 28 had acute onset encephalitis. The results of clinical studies on these 28 patients were as follows: (1) The number of cases who exhibited CNS manifestations during (A) and after pyrexia (B) were 15 and 13, and the ages of predilection were infancy and school age, respectively. (2) MRI studies in cases of A revealed multifocal CNS lesions in 1 case, localized lesions in 7 and normal findings in 7. In B, there were 3 cases with multifocal lesions, 8 of focal lesions and 2 of normal findings. (3) The 7 cases of localized lesions in A were divided into 5 of herpes encephalitis and 2 of suspected vasculitis. Vasculitis was suspected in 3 of 8 cases of localized lesions in B. Thus, vasculitis is considered to be an important cause of encephalitis. (4) Brain lesions in the 5 cases of herpes encephalitis were occipital dominant in 4. Only one case had a temporal lesion. (5) All cases with focal MRI lesions and CSF pleocytosis, having evidence of direct viral invasion, were herpes encephalitis. Direct viral invasion was not proven in any other cases. (6) Although the term encephalitis is often used in clinical practice, the process by which the CNS lesions occur in acute viral infection is still unknown. Therefore it is not easy to establish the diagnosis. The diagnostic criteria of encephalitis should be reconsidered. New specific methods to analyze the cause of CNS lesions are necessary.     

Chronic brainstem encephalitis with mental symptoms and ataxia: report of three cases with necropsy.

Three necropsied cases of chronic, sporadic brainstem encephalitis of unknown aetiology are presented. Since their outstanding symptoms were dementia and ataxia of a progressive nature, a noninflammatory disease of the central nervous system was suspected. Neuropathological studies showed chronic inflammatory changes mainly in the brainstem without the presence of inclusion bodies or viral particles. Compared to cases previously reported as brainstem encephalitis, the clinical and pathological findings observed in these cases have rather peculiar characteristics.     

Characterization of relapsing–remitting and chronic forms of experimental autoimmune encephalomyelitis in C57BL/6 mice

Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system (CNS). Like MS, the animal model experimental autoimmune encephalomyelitis (EAE) is characterized by CNS inflammation and demyelination and can follow a relapsing–remitting (RR) or chronic (CH) disease course. The molecular and pathological differences that underlie these different forms of EAE are not fully understood. We have compared the differences in RR‐ and CH‐EAE generated in the same mouse strain (C57BL/6) using the same antigen. At the peak of disease when mice in both groups have similar clinical scores, CH‐EAE is associated with increased lesion burden, myelin loss, axonal damage, and chemokine/cytokine expression when compared with RR‐EAE. We further showed that inflammation and myelin loss continue to worsen in later stages of CH‐EAE, whereas these features are largely resolved at the equivalent stage in RR‐EAE. Additionally, axonal loss at these later stages is more severe in CH‐EAE than in RR‐EAE. We also demonstrated that CH‐EAE is associated with a greater predominance of CD8⁺ T cells in the CNS that exhibit MOG_35–55 antigen specificity. These studies therefore showed that, as early as the peak stage of disease, RR‐ and CH‐EAE differ remarkably in their immune cell profile, chemokine/cytokine responses, and histopathological features. These data also indicated that this model of CH‐EAE exhibits pathological features of a chronic‐progressive disease profile and suggested that the sustained chronic phenotype is due to a combination of axonal loss, myelin loss, and continuing inflammation. © 2009 Wiley‐Liss, Inc.     

Diagnostic difficulties in herpes simplex encephalitis patients: report of three cases

Herpes simplex encephalitis (HSE) is a rare infection of the central nervous system. The prognosis is poor, even in those receiving anti-herpetic therapy (about 20% of patients die, and in 40% of cases neurological sequelae are severe). The diagnosis is based on clinical signs of encephalitis, typical pathological changes in MRI, and on the presence of anti-HSV antibody and/or HSV-DNA in the cerebrospinal fluid. Three cases of encephalitis are presented. The clinical course and pathological changes in the temporal lobes seen in MRI were characteristic of the HSV etiology. Early intrathecal synthesis of anty-HSV antibodies were not detected despite an increase in their serum level in the course of the disease. HSV-DNA detection with PCR was not performed. Nevertheless in all cases aciclovir therapy was introduced on the first day of hospitalization. Possibilities of diagnosing HSE on the basis of clinical signs and MRI scans during the first week of the disease are discussed, as well as the tissue whether the course of treatment would be changed accordingly to the PCR test results.     

Visualization of Central European tick-borne encephalitis infection in fatal human cases

Central European tick-borne encephalitis (TBE) is caused by a flavivirus vectored by the Ixodes ricinus tick. In severe infections, TBE presents as (myelo)meningoencephalitis with considerable mortality. Characteristic neuropathologic changes feature a multinodular to patchy polioencephalomyelitis accentuated in spinal cord, brainstem, and cerebellum. Visualization of viral infection by immunohistochemistry has not yet been achieved. We analyzed immunohistochemically the distribution of viral antigens and its correlation with neuropathologic changes, serological data, and disease duration in 28 brains of cases with a clinical diagnosis of TBE and neuropathologically confirmed (meningo)encephalomyelitis. In 20 brains (including 10 seropositives), viral antigens were detectable. These cases were characterized by relatively short clinical duration ranging from 4 to 35 days. Immunoreactivity was most prominent in perikarya and processes of Purkinje cells and large neurons of dentate nucleus, inferior olives, and anterior horns. In addition, immunoreactivity was detected in neurons of other brainstem nuclei, isocortex, and basal ganglia. There was an inverse topographical association of severe inflammatory changes with presence of viral antigens. Some cytotoxic T cells were in direct contact with tick-borne encephalitis virus (TBEV)-infected neurons. We conclude that 1) TBE viral antigens are immunohistochemically detectable in brains of fatal cases with relatively short natural clinical course; 2) TBE virus neurotropism preferentially targets large neurons of anterior horns, medulla oblongata, pons, dentate nucleus, Purkinje cells, and striatum; 3) topographical correlation between inflammatory changes and distribution of viral antigens is poor; and 4) immunologic mechanisms may contribute to nerve cell destruction in human TBE.     

多病程Wistar大鼠实验性变态反应性脑脊髓炎的病理研究

目的:在建立wistar大鼠多病程实验性变态反应性脑脊髓炎(EAE)的动物模型的基础上,进行病理学研究,探讨不同发病类型EAE的基本病理改变如炎细胞浸润、脱髓鞘和轴索损伤等方面的差别,为多发性硬化(MS)的研究提供实验依据。方法:以豚鼠全脊髓匀浆(GPSCH)为抗原免疫Wistar大鼠建立EAE的动物模型,进行常规HE染色、Weil髓鞘染色和改良的Bielschowsky,并行GFAP免疫组化染色,观察不同发病类型EAE的病理政变。结果:根据病理和临床表现可将Wistar大鼠EAE模型分为5种发病形式:急性型、缓解-复发型、持续进展型、良性型和隐匿型。光镜下可见不同发病时期的EAE的病理改变有所不同,急性型EAE炎症浸润明显,尤脱髓鞘改变,缓解-复发型和持续进展型EAE髓鞘脱失和轴索损伤更明显,且有陈旧病灶周围的星型胶质细胞增生,而新发病灶无此表现,良性型EAE则改变接近正常。结论:首次建立了Wistar大鼠多病程EAE,且病理证实不同类型EAE的炎细胞分布、髓鞘脱失及轴索损伤等基本病理改变是不同的,它具有人类MS的许多发病特点,其中多病程的发病形式和主要病理特点与MS极其相似,是理想的MS动物模型。     

Human Hendra virus infection causes acute and relapsing encephalitis

Aim : To study the pathology of two cases of human Hendra virus infection, one with no clinical encephalitis and one with relapsing encephalitis. Methods : Autopsy tissues were investigated by light microscopy, immunohistochemistry and in situ hybridization. Results : In the patient with acute pulmonary syndrome but not clinical acute encephalitis, vasculitis was found in the brain, lung, heart and kidney. Occasionally, viral antigens were demonstrated in vascular walls but multinucleated endothelial syncytia were absent. In the lung, there was severe inflammation, necrosis and viral antigens in type II pneumocytes and macrophages. The rare kidney glomerulus showed inflammation and viral antigens in capillary walls and podocytes. Discrete necrotic/vacuolar plaques in the brain parenchyma were associated with antigens and viral RNA. Brain inflammation was mild although CD68⁺ microglia/macrophages were significantly increased. Cytoplasmic viral inclusions and antigens and viral RNA in neurones and ependyma suggested viral replication. In the case of relapsing encephalitis, there was severe widespread meningoencephalitis characterized by neuronal loss, macrophages and other inflammatory cells, reactive blood vessels and perivascular cuffing. Antigens and viral RNA were mainly found in neurones. Vasculitis was absent in all the tissues examined. Conclusions : The case of acute Hendra virus infection demonstrated evidence of systemic infection and acute encephalitis. The case of relapsing Hendra virus encephalitis showed no signs of extraneural infection but in the brain, extensive inflammation and infected neurones were observed. Hendra virus can cause acute and relapsing encephalitis and the findings suggest that the pathology and pathogenesis are similar to Nipah virus infection.     

Emerging and re-emerging epidemic encephalitis: a tale of two viruses

Two major epidemics of viral encephalitis occurred in Asia in 1997 and 1998. The first was a re-emergence of neurovirulent strains of enterovirus 71, which caused severe encephalomyelitis in children in Malaysia, Taiwan and Japan, on a background of hand, foot and mouth disease. Necropsy studies of patients who died of enterovirus 71 infection showed severe perivascular cuffing, parenchymal inflammation and neuronophagia in the spinal cord, brainstem and diencephalon, and in focal areas in the cerebellum and cerebrum. Although no viral inclusions were detected, immunohistochemistry showed viral antigen in the neuronal cytoplasm. Inflammation was often more extensive than neuronal infection, suggesting that other factors, in addition to direct viral cytolysis, may be involved in tissue damage. The second epidemic of viral encephalitis was the result of a novel paramyxovirus called Nipah, which mainly involved pig handlers in Malaysia and Singapore. Pathological evidence suggested that the endothelium of small blood vessels in the central nervous system was particularly susceptible to infection. This led to disseminated endothelial damage and syncytium formation, vasculitis, thrombosis, ischaemia and microinfarction. However, there was also evidence of neuronal infection by the virus and this may also have contributed to the neurological dysfunction in Nipah encephalitis. Some patients who seemed to recover from the acute symptoms have been re-admitted with clinical findings suggestive of relapsing encephalitis. As these two epidemics indicate, the emergence and re-emergence of viral encephalitides continue to pose considerable challenges to the neuropathologist, in establishing the diagnosis and unravelling the pathogenesis of the neurological disease.     

Effects of regional spinal X-irradiation on demyelinating disease caused by Theiler's virus, mouse hepatitis virus or experimental allergic encephalomyelitis

The effects of X-irradiation on the course of chronic demyelinating disease were examined in mice with experimental allergic encephalitis (EAE), mouse hepatitis virus (MHV) or Theiler's virus (DAV) infection. One month after the induction of EAE or 2-16 months after inoculation of DAV, exposure of the cervical spinal cord to 20 Gy X-rays caused local exacerbation of disease activity but spinal irradiation did not affect MHV-induced demyelination. In EAE, there was a significant increase in the number of inflammatory cells in the irradiated part of the cord. Mice infected with DAV showed locally increased demyelination and axonal degeneration but no change in the titer of infectious virus within the cord. Thus in DAV infection, as in EAE, the exacerbation of disease seemed to be due to vascular or immunological factors rather than viral reactivation.     

疱疹病毒性脑炎并发视力下降二例

目的探讨疱疹病毒性脑炎和视力下降的关系。方法对2例疱疹病毒性脑炎患者腰椎穿刺,行脑脊液测压、常规、生化、细胞学及病原学检查及头颅磁共振(MRI)检查;例1患者行眼科超声检查。结果2例患者均在入院治疗过程中出现视力下降。例1为单纯疱疹病毒感染,例2为巨细胞病毒感染。2例患者头颅MRI扫描均有脑实质炎性改变,均涉及岛叶。例1眼科超声提示视网膜坏死及视网膜脱离。结论疱疹病毒感染与急性视网膜坏死综合征及视神经炎有关。对于病毒性脑炎患者应给与足够的抗病毒治疗,期间若出现视力下降,警惕合并急性视网膜坏死综合征及视神经炎。     

A fatal case of coxsackievirus B4 meningoencephalitis

BACKGROUND: Coxsackieviruses and echoviruses are common causes of aseptic meningitis, but they rarely cause life-threatening illness. We report a fatal case of coxsackievirus B4 meningoencephalitis in a woman who developed extrapyramidal symptoms suggestive of encephalitis lethargica. The exact causative agent of encephalitis lethargica has rarely been found, but most cases of the syndrome are assumed to be of viral origin. CASE DESCRIPTION: A 33-year-old woman previously treated with methylprednisolone and cyclophosphamide for Henoch-Sch?nlein purpura was transferred from a referring hospital because of sore throat, fever, and chills. Her neurologic findings progressed from headache with mild photophobia to lethargy, cogwheeling, increased tone in all 4 limbs, and brisk reflexes. The patient was diagnosed as having coxsackievirus B4 meningoencephalitis and, despite treatment with the experimental antiviral agent pleconaril, died of an overwhelming central nervous system infection and myocarditis. Magnetic resonance imaging showed focal hyperintense lesions in the substantia nigra that corresponded to the location of pathological changes seen at autopsy. CONCLUSIONS: This patient had a fulminant coxsackievirus B4 viral meningoencephalitis with a clinical pattern reminiscent of encephalitis lethargica and striking focal abnormalities in the substantia nigra identified on magnetic resonance imaging. The magnetic resonance imaging findings correlated with pathological changes identified at autopsy that were similar to the pathological findings observed in patients with encephalitis lethargica and postencephalitic parkinsonism. It is likely that the patient's immunocompromised state led to an overwhelming infection from an otherwise relatively innocuous viral infection.     

Emerging epidemic viral encephalitides with a special focus on henipaviruses

In the last few decades, there is an increasing emergence and re-emergence of viruses, such as West Nile virus, Enterovirus 71 and henipaviruses that cause epidemic viral encephalitis and other central nervous system (CNS) manifestations. The mortality and morbidity associated with these outbreaks are significant and frequently severe. While aspects of epidemiology, basic virology, etc., may be known, the pathology and pathogenesis are often less so, partly due to a lack of interest among pathologists or because many of these infections are considered “third world” diseases. In the study of epidemic viral encephalitis, the pathologist’s role in unravelling the pathology and pathogenesis is critical. The novel henipavirus infection is a good example. The newly created genus Henipavirus within the family Paramyxoviridae consists of two viruses, viz., Hendra virus and Nipah virus. These two viruses emerged in Australia and Asia, respectively, to cause severe encephalitides in humans and animals. Studies show that the pathological features of the acute encephalitis caused by henipaviruses are similar and a unique dual pathogenetic mechanism of vasculitis-induced microinfarction and parenchymal cell infection in the CNS (mainly neurons) and other organs causes severe tissue damage. Both viruses can cause relapsing encephalitis months and years after the acute infection due to a true recurrent infection as evidenced by the presence of virus in infected cells. Future emerging viral encephalitides will no doubt continue to pose considerable challenges to the neuropathologist, and as the West Nile virus outbreak demonstrates, even economically advanced nations are not spared.     

Extralimbic autoimmune encephalitis associated with glutamic acid decarboxylase antibodies: an underdiagnosed entity?

Nonparaneoplastic glutamic acid decarboxylase antibody (GADAb)-related autoimmune encephalitis is a syndrome characterized by refractory seizures, progressive cognitive deficits, and psychiatric manifestations. The limbic subtype is well described, has characteristic affective and memory disturbances, and typical mesial temporal MRI abnormalities. We found only one single case report of the extralimbic subtype. We report clinical, radiological, and pathological findings of two additional cases with contrast-enhancing lesions. One of our cases presented as vasculitis, and the other imitated a tumor. Pathological evidence of both vasculitis and encephalitis has never been previously reported in any inflammatory condition affecting the brain. Our cases confirm prior reports that immune therapy can better control seizures associated with GADAb autoimmune encephalitis, and support the rationale for assaying for GADAb titers in patients with etiologically unclear extralimbic lesions and refractory epilepsy, independent of seizure types.     

Computerized tomography as a diagnostic aid in acute hemorrhagic leukoencephalitis

Computerized tomography (CT) in a pathologically proven case of acute hemorrhagic leukoencephalitis (AHL) showed a mass effect and increased absorption coefficient in the right hemisphere within 18 hours of the onset of neurological symptoms. The changes corresponded to the site of white matter edema, necrosis, and petechial hemorrhages demonstrated postmortem. The early changes of CT reflect the hyperacute nature of AHL and differ from those of herpes simplex encephalitis.     

2014-2015年石家庄地区儿童病毒性脑炎临床流行病学及临床表现

目的研究石家庄地区儿童病毒性脑炎的临床特点、临床流行病学及病原学特征,为临床诊治提供依据。方法选取2014-2015年于河北省儿童医院住院治疗、出院诊断为病毒性脑炎的1091例石家庄地区患儿,随机抽取200例进行分析,入选病例急性期脑脊液(CSF)检测病毒Ig M抗体,标本选择检测的病毒抗体种类由临床医生根据临床症状及特点选择相应的病毒抗体检测。结果 200例患儿年龄为1.5岁~12岁,平均年龄4.91±0.06岁,以学龄前儿童多见(72.6%);散居儿童(64.5%)多于托幼儿童及学生(35.5%);男性116例,女性82例(男女比例为1.4:1);发病地区以正定(38.0%)、藁城(30.0%)为主,乡村111例,城市89例(比例为1.2:1);发病至入院平均时间3.21±0.89d;所有患儿均出现发热,症状依次为恶心、呕吐(84.5%);头痛、头晕(81.5%);腹痛(58.0%);嗜睡(51.5%);腹泻(12.0%);皮疹(1.6%),病理征阳性(1.4%)。病原学检查均为肠道病毒,分别为埃可病毒176例(88.0%)及柯萨奇病毒24例(12.0%),全年均有发病,流行高峰为夏秋季节。结论肠道病毒是2014-2015年石家庄地区病毒性脑炎流行的主要病原,且在时间和地区分布上有明显集中趋势,应加强对病毒性脑炎的预警和防范。     

EEG findings in tick-borne encephalitis.

EEG findings of epidemiologically and serologically confirmed tick-borne encephalitis patients were compared with findings of patients having acute encephalitis of viral or undetermined origins. Tick-borne encephalitis patients had more bilaterally synchronous bursts of slow waves and more focal abnormalities than did controls. Moreover, their EEGs remained mildly pathological, with increased slow and beta activity and intermittent focal abnormalities in some patients, whereas, EEGs in the controls became normal or borderline, usually within two months. EEG can thus reveal differences between individuals' responses to encephalitis and between different types of encephalitis, even though the clinical pictures are rather similar. Finally, the study shows that tick-borne encephalitis causes changes in the EEG that persist long after the clinical disease appears to have resolved.     

Steroid-responsive encephalopathy associated with autoimmune thyroiditis and primary CNS demyelination

Steroid responsive encephalopathy associated with autoimmune thyroiditis is a well-recognized complication of autoimmune thyroid disease. However, the characterization of the histopathological features of steroid responsive encephalopathy associated with autoimmune thyroiditis are limited to six cases. Reported pathological features include vasculitis involving venules and arterioles, lymphocytic perivascular cuffs and microglial activation. We report a case of SREAT with biopsy proven (on two occasions) primary CNS demyelination and radiological evidence of steroid responsiveness, identifying primary CNS demyelination as a complication of autoimmune thyroid disease.     

Primary angiitis of CNS : neuropathological study of three autopsied cases with brief review of literature

Primary angiitis of CNS(PACNS) or granulomatous angiitis of CNS is a rare inflammatory disease of small blood vessels mostly confined to the CNS. The clinical and pathological features of 3 autopsied cases are described. Clinically all the three PACNS patients were young males, age ranging from 19 to 31 years. All presented with varied neurological manifestations. There was no evidence of systemic disease in any of the cases. The ESR was normal and CSF analysis showed chronic meningitic pattern. The cerebral angiogram in one case was normal and the CT scan done in another case showed multiple intracerebral haematoma due to vasculitis. Brain biopsy was not done. Diagnosis was made at post-mortem examination. Histology showed characteristic but variable degree of granulomatous and non-granulomatous angiitis of small vessels. Venulitis with parenchymal haemorrhages was the predominant feature and in one case phlebitis with thrombosis was noted. Since the disease responds to steroids and immunosuppressive therapy, establishing antemortem diagnosis is important. In view of the association of angiitis of CNS with bacteria and viral infections, their role in the evolution of the disease needs to be investigated.