Rabies encephalitis following fox bite--histological and immunohistochemical evaluation of lesions caused by virus

Rabies caused by fox bite is uncommon, most cases being caused by bite of rabid dogs (95%). We report a 45-year-old lady with rabies encephalomyelitis caused by bite of a rabid wild fox (Vulpes vulpes), a species prevalent in the Deccan plateaus of Central India. Though foxes are known to be susceptible to rabies, literature on the pathological changes caused by fox bite rabies in humans is scarce. Unlike the mild histological alterations described in canine rabies, a florid encephalitic process evolved in fox bite rabies, in our case, with intense microglial reaction, neuronophagia and perivascular inflammatory infiltrates despite clinical manifestation as a paralytic rabies. Immunostaining using polyclonal antibodies to the rabies viral nucleocapsid antigen and to the whole virion demonstrated high viral load within neurons with extensive spread along dendritic arborization and axonal tracts. Genomic sequence analysis demonstrated close homology with canine virus strain with only minor variations.     

Rabies encephalitis in a patient with AIDS: a clinicopathological study

A 46-year-old man was bitten by a dog in Mali; anti-rabies vaccination was incomplete. Three months later he was admitted to hospital with fever and diarrhea. Human immunodeficiency virus (HIV) serology was positive and CD4 count was 70/mm³. His status worsened rapidly with confusion hydrophobia and hypersialorrhea. Despite anti-rabies serotherapy and vaccination, he died suddenly 12 days after admission. Immunofluorescence on cerebral tissue samples established rabies encephalitis. Neuropathology showed mild encephalitis with occasional Babès nodules and rare perivascular mononuclear cuffs. Intraneuronal Negri inclusion bodies were remarkably diffuse and abundant. They were clearly demonstrated by immunocytochemistry and electron microscopy. Apoptotic neurons were identified in the brain stem and hippocampus in the vicinity of inflammatory foci. In contrast, apoptosis could not be demonstrated in non-inflammatory areas, even where Negri bodies were numerous. There was no associated HIV encephalitis or opportunistic infection. The occurrence of rabies encephalitis in AIDS represents a random association, but is probably not exceptional as rabies is endemic in many countries and the AIDS epidemic is spreading worldwide. In this case, although the incubation duration and clinical presentation were comparable to those in classical rabies, the T-cell-mediated immunosuppression may account for the weak inflammatory reaction and unusually abundant viral multiplication. This observation confirms that all those at risk for rabies, particularly immunocompromised patients, should receive complete anti-rabies treatment including vaccines and specific immunoglobulins, as soon as possible after infection. Received: 1 February 1996 / Revised, accepted: 24 April 1996     

Chronic encephalitis associated with epilepsy: immunohistochemical and ultrastructural studies

Chronic encephalitis has been recognized as a cause of epilepsy since the work of Rasmussen et al. in the late 1950s. Despite this, few immunohistochemical studies of the affected brain tissue have been attempted. We have studied specimens of brain tissue from seven patients with this condition who underwent therapeutic multilobar cortical resection or hemispherectomy. Immunohistochemical studies were carried out using antibodies to glial fibrillary acidic protein (GFAP), proliferating cell nuclear antigen (PCNA, PC10), T lymphocytes (UCHL-1), B lymphocytes (L26), macrophages and microglia (HAM-56), and major histocompatibility complex molecules (LN3 and ₂microglobulin). Additionally, the results of preliminary immunohistochemical and ultrastructural investigation of possible immune complex deposition in blood vessel walls of affected brain tissue are presented. The pattern of GFAP immunoreactivity suggested a patchy and/or laminar disease process in most patients. GFAP immunoreactive cells were especially prominent around microvessels in some cases, suggesting an abnormality of the blood-brain barrier. Both microglial nodules and perivascular collections of inflammatory cells, seen to a variable extent in all cases, contained abundant cells immunolabelled with UCHL-1, LN3 and ₂microglobulin. L26-labelled B lymphocytes were extremely sparse. Anti-PCNA frequently labelled microvascular endothelial cells, rare pericytes and occasional cells with microglial/macrophage morphology. The data suggest that chronic encephalitis found in patients with epilepsy results from patchy but widespread parenchymal brain injury, in the course of which cells of both microglial and lymphocyte series accumulate or proliferate within brain. Despite the lack of clear evidence of a causal viral pathogen from other studies, the predominant T cell lymphocytic infiltrate is consistent with a viral cause for this disorder. However, autoimmune factors (possibly triggered by viral infection) may contribute to the extensive neuropathological abnormalities. Very preliminary results using anti-IgG immunocytochemistry showed that in Rasmussen's encephalitis brain there was scattered labelling of neuronal cell bodies and some microvessels. Ultrastructural examination of brain tissue from one patient also showed unusual electron-dense material in microvascular endothelial basement membranes.This work was presented in part at the 69th Annual Meeting of the American Association of Neuropathologists, Salt Lake City, Utah, June 1993 [Farrell et al. (1993) J Neuropathol Exp Neurol 52:270]     

Rabies viral encephalitis with proable 25 year incubation period!

We report a case of rabies viral encephalitis in a 48-year-old male with an unusually long incubation period, historically suspected to be more than 20 years. The case was referred for histological diagnosis following alleged medical negligence to the forensic department. The histology and immunocytochemical demonstration of rabies viral antigen established the diagnosis unequivocally. The case manifested initially with hydrophobia and aggressive behavior, although he suddenly went to the bathroom and drank a small amount of water. History of dog bite 25 years back was elicited retrospectively following clinical suspicion. There was no subsequent history to suggest nonbite exposure to a rabid dog to consider recent event causing the disease, although this cannot be totally excluded.     

Disseminated herpetic encephalitis: report of an autopsy case with immunohistochemical study

An autopsied case of disseminated herpetic encephalitis in a previously healthy one-year-and-three-month-old child is reported. He had fever, repeated convulsive crises and alterations of consciousness which progressed into a coma, leading to death in eight days. The neuropathological picture was characterized by necrosis and inflammation in multiple foci disseminated in the cerebral hemispheres, brainstem and cerebellum. The Avidin-Biotin-Peroxidase Complex technique showed, in neurons of the thalamus, intra-cytoplasmatic immunoreactivity, and, very rarely, intranuclear for the Herpes simplex virus type 1 antigens. This case differs from the other herpetic encephalitis ones described in the literature in two aspects: (1) by the dissemination of the lesions, in contrast with the forms topographically limited to the limbic system and, less commonly, to the brainstem; (2) by the presence of necrosis, inflammation and focal hemorrhage, which are alterations that practically do not exist in cases of disseminated encephalitis typically described in immuno-depressed individuals.     

The inflammatory reaction of paraneoplastic ganglionitis and encephalitis: an immunohistochemical study

To elucidate the cellular mechanisms of tissue injury in paraneoplastic states, tissues from two patients with small cell carcinoma of the lung and paraneoplastic neurological syndromes were studied. One patient had encephalitis with ganglionitis, and the other ganglionitis. Immunocytochemistry on brain and ganglia was per formed using monoclonal and polyclonal antibodies. The majority of the inflammatory cells in brain and ganglia were T-cells, of both helper and cytotoxic sub types. There were more macrophages in the inflammatory infiltrate of ganglia than in the brain of encephalitis. Major histocompatibility complex class I and II antigen expression was greater in the mononuclear cells in brain than in ganglia. There was no evidence of complement deposition and little evidence for antibody synthesizing cells. Our findings suggest a T-cell-mediated immune attack in paraneoplastic ganglionitis and encephalitis, with a greater role for macrophages in ganglionitis.     

Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis

Since its discovery in 2007, the encephalitis associated with antibodies against the N-methyl-D-aspartate receptor (NMDAR) has entered the mainstream of neurology and other disciplines. Most patients with anti-NMDAR encephalitis develop a multistage illness that progresses from psychosis, memory deficits, seizures, and language disintegration into a state of unresponsiveness with catatonic features often associated with abnormal movements, and autonomic and breathing instability. The disorder predominantly affects children and young adults, occurs with or without tumour association, and responds to treatment but can relapse. The presence of a tumour (usually an ovarian teratoma) is dependent on age, sex, and ethnicity, being more frequent in women older than 18 years, and slightly more predominant in black women than it is in white women. Patients treated with tumour resection and immunotherapy (corticosteroids, intravenous immunoglobulin, or plasma exchange) respond faster to treatment and less frequently need second-line immunotherapy (cyclophosphamide or rituximab, or both) than do patients without a tumour who receive similar initial immunotherapy. More than 75% of all patients have substantial recovery that occurs in inverse order of symptom development and is associated with a decline of antibody titres. Patients' antibodies cause a titre-dependent, reversible decrease of synaptic NMDAR by a mechanism of crosslinking and internalisation. On the basis of models of pharmacological or genetic disruption of NMDAR, these antibody effects reveal a probable pathogenic relation between the depletion of receptors and the clinical features of anti-NMDAR encephalitis.     

Herpetic brain stem encephalitis: report of an autopsied case with immunohistochemical and electron microscopy studies

A post-mortem examined case of herpetic brainstem encephalitis is presented. Clinically, the patient had cephalalgia followed by ataxia, drowsiness and multiple palsies of some cranial nerves, developing into death in eight days. The pathologic examination of the brain showed necrotizing encephalitis in multiple foci limited to the brainstem, more distinctly in the pons and medulla oblongata. The technique of immunoperoxidase revealed rare glial cells with intranuclear immunoreactivity for herpes antigen. Rare viral particles with the morphological characteristics of the herpesvirus were identified in the nuclei of neurons in 10% formol fixed material. This is the second reported case of herpetic brainstem encephalitis confirmed by post-mortem examination. The pathway used by the virus to reach the central nervous system and its posterior dissemination to the oral cavity, the orbitofrontal region and the temporal lobes as well as to the brainstem, after a period of latency and reactivation, are discussed.     

Rabies

Rabies is an important disease in wildlife in the United States and Canada, and dog rabies is still a major public health problem in many developing countries of the world. Rabies virus is transmitted in saliva by animal bites. Bats transmitted most recent cases of human rabies in the United States, often without known exposures. There have been recent developments in our understanding of rabies pathogenesis. Characteristic clinical features should raise the possibility of a diagnosis of rabies and initiation of appropriate diagnostic tests. Therapy of human rabies has been futile except in four patients who were immunized with rabies vaccine prior to the onset of their disease. Rabies can be prevented after an exposure in unimmunized patients with local wound cleansing and administration of rabies vaccine and human rabies immune globulin.     

Rabies

Rabies remains an important public health problem in developing countries, and the indigenous threat of rabies continues in developed countries because of wildlife reservoirs. A diagnosis of rabies is often not considered by physicians until late in the clinical course or after death in North America and Europe, even with typical clinical presentations. Transmission of rabies virus has occurred in association with transplantation of tissues and also recently with organs. In 2004 a young patient survived rabies in Wisconsin, but the reasons for this favorable outcome remain elusive. This article reviews current information and developments on a variety of neurologic aspects of rabies.     

Rabies

Despite increases in our understanding of rabies pathogenesis, it remains an inevitably fatal disease. Lack of awareness, low level of political commitment to rabies control, and failure to recognize and correlate clinical, laboratory, and neuroimaging features contribute to continuing deaths. Clinical symptomatology, once believed to be unique, may be variable, even in patients associated with lyssaviruses of the same genotype. This article discusses virus transport, the role of virus and host response mechanisms in relation to protean clinical manifestations, and mechanisms responsible for relative intactness of consciousness in human rabies. Differential involvement of the anterior horn cell in furious rabies and the peripheral nerve in paralytic rabies is summarized. Escape mechanisms from host defenses explain why a fatal outcome is unavoidable regardless of therapy. Neuroprotective treatment, using a coma-induction regimen, proves not to be beneficial. Survival of patients with excellent recovery relies on early innate and adaptive immunity plus adequate intensive care support.     

Rabies virus infection: An update

There are still many unanswered questions in the pathogenesis of rabies, but recent progress has been made. During most of the long incubation period of rabies, the virus likely remains close the site of viral entry. Centripetal spread to the central nervous system and spread within the central nervous system occur by fast axonal transport. Neuronal dysfunction, rather than neuronal death, is responsible for the clinical features and fatal outcome in natural rabies. Recent work has changed our perspective on the ecology of rabies virus under particular circumstances in certain species. Hopefully, advances in our understanding of rabies pathogenesis will lead to advances in the treatment of this dreaded disease.     

Rabies: Spongiform lesions in the brain

Summary Striped skunks (Mephitis mephitis) experimentally infected with street rabies virus developed spongiform lesions that light- and electron-microscopically were indistinguishable from those found in the transmissible spongiform encephalopathies of man and animals. These previously unreported lesions were also detected in naturally occurring cases of rabies. The spongiform lesions consisted of round or oval vacuoles in the neuropil, rarely in neuronal perikarya. The most severely affected areas were the thalamus and cerebral cortex. The implications of this finding include similarities in the pathogenetic mechanisms of rabies and the traditional spongiform encephalopathies and the possibility of lesion variation due to differences in rabies viral strains. The spongiform lesions of rabies will require consideration in differential diagnosis.     

Permanent or transient chronic ischemic stroke in the non-human primate: behavioral, neuroimaging, histological, and immunohistochemical investigations

Using multimodal magnetic resonance imaging (MRI), behavioral, and immunohistochemical analyses, we examined pathological changes at the acute, sub-acute, and chronic stages, induced by permanent or temporary ischemia in the common marmoset. Animals underwent either permanent (pMCAO) or 3-h transient (tMCAO) occlusion of the middle cerebral artery (MCAO) by the intraluminal thread approach. MRI scans were performed at 1 h, 8, and 45 days after MCAO. Sensorimotor deficits were assessed weekly up to 45 days after MCAO. Immunohistological studies were performed to examine neuronal loss, astrogliosis, and neurogenesis. Remote lesions were analyzed using retrograde neuronal tracers. At day 8 (D8), the lesion defined on diffusion tensor imaging (DTI)–MRI and T2-MRI was significantly larger in pMCAO as compared with that in the tMCAO group. At D45, the former still displayed abnormal signals in T2-MRI. Post-mortem analyses revealed widespread neuronal loss and associated astrogliosis to a greater extent in the pMCAO group. Neurogenesis was increased in both groups in the vicinity of the lesion. Disconnections between the caudate and the temporal cortex, and between the parietal cortex and the thalamus, were observed. Sensorimotor impairments were more severe and long-lasting in pMCAO relative to tMCAO. The profile of brain damage and functional deficits seen in the marmoset suggests that this model could be suitable to test therapies against stroke.     

Toxoplasma encephalitis of immunocompetent and nude mice: immunohistochemical characterisation of Toxoplasma antigen, infiltrates and major histocompatibility complex gene products

The experimental infection of immunocompetent and immunodeficient athymic mice with an avirulent encephalitogenic Toxoplasma strain (DX strain) was employed to study the ensuing encephalitic process by use of histological and immunocytochemical methods. In the acute phase of the infection Toxoplasma cysts and tachyzoites were accompanied by an infiltrate composed of macrophages, CD4+ and CD8+ T cells. In the chronic stage a granulomatous encephalitis developed. In contrast to immunocompetent NMRI mice, athymic nude NMRI mice died 3 weeks post-infection because of a generalized toxoplasmosis with predominant involvement of the brain. A salient feature of murine Toxoplasma encephalitis was up-regulation of class I and II major histocompatibility complex (MHC) gene products. Class I antigen was widely expressed on microglial cells and astrocytes. Class II antigen was only expressed on microglial cells despite a considerable astrogliosis. Our results indicate a differential expression of MHC-determined antigens on brain cells in acute and chronic murine Toxoplasma encephalitis.     

Rasmussen encephalitis: Epilepsia partialis continua secondary to chronic encephalitis

Rasmussen encephalitis is a disease consisting of chronic encephalitis with progressive neurologic deficits and focal intractable seizure activity. The etiology is unknown, but pathologic specimens revealed changes consistent with viral encephalitis. Even though neuroimaging techniques, such as positron emission tomography and magnetic resonance imaging, offer the prospect of specific, presurgical diagnostic criteria, the initial diagnosis usually is made on a clinical basis. Treatment modalities, including a wide variety of antiepileptic drug therapies and surgical interventions, may result in significant physical and mental impairments. We summarize the clinical presentation, diagnostic considerations, and different treatment protocols in a patient with this rare and debilitating disorder.     

Rabies virus receptors

There is convincing in vitro evidence that the muscular form of the nicotinic acetylcholine receptor (nAChR), the neuronal cell adhesion molecule (NCAM), and the p75 neurotrophin receptor (p75NTR) bind rabies virus and/or facilitate rabies virus entry into cells. Other components of the cell membrane, such as gangliosides, may also participate in the entry of rabies virus. However, little is known of the role of these molecules in vivo. This review proposes a speculative model that accounts for the role of these different molecules in entry and trafficking of rabies virus into the nervous system.     

Coxsackie B antigen in the central nervous system of a patient with fatal acute encephalitis: immunohistochemical studies of formalin-fixed paraffin-embedded tissue

Summary A case of fatal acute encephalitis due to Coxsackie B₁ virus is described. Confirmation of Coxsackie B virus as the etiological agent of encephalitis was based on identification of the virus antigen in formalin-fixed paraffin-embedded tissue sections. In the past, the diagnosis was obtained by serological studies of peripheral blood and viral isolation. This is the first report in which indirect immunofluorescent and immunoper-oxidase methods using rabbit antiserum raised against Coxsackie B types 1–6 was utilized in determining the etiology of encephalitis. It must be emphasized that these methods can be used both on biopsy or autopsy specimens, even retrospectively.Presented in part at the sixty-third Annual Meeting of the American Association of Neuropathologists, Seattle, Washington, June 11–14, 1987