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 encephalomyelitis: clinical, neuroradiological, and pathological findings in 4 transplant recipients

BACKGROUND: Three patients received solid organ transplants from a common donor and were subsequently discharged from the hospital following an uneventful hospital course. Within 30 days, all 3 organ recipients returned to the hospital with varying symptoms that progressed to rapid neurological deterioration, coma, and death. OBJECTIVE: To describe the clinical, neuroradiological, and pathological findings of rabies virus infection in organ transplant recipients infected from a common donor. DESIGN: Case series involving a common donor and 3 organ recipients ascertained through review of clinical course and autopsy findings. A fourth case was determined by review of pending autopsy cases in which death occurred within the same time interval. Portions of postmortem central nervous system and organ tissues were frozen and formalin-fixed. Fluids and tissues were also collected for cultures, serology, and molecular studies. Postmortem fluids and tissues and antemortem fluids and tissues from all 4 transplant recipients and serum and banked lymphocyte or spleen cells from the donors were sent to the Centers for Disease Control and Prevention for further evaluation. SETTING: Transplant unit of an urban teaching hospital. RESULTS: Antemortem cerebrospinal fluid analysis for 3 of the 4 recipients was consistent with a viral etiology. Neuroimaging and electroencephalogram studies were suggestive of an infectious encephalitis or a toxic encephalopathy. Initial laboratory testing did not demonstrate an infectious etiology. Postmortem histologic analysis, immunohistochemistry, electron microscopy, and direct fluorescence antibody testing revealed rabies virus infection. Serological testing done postmortem confirmed rabies virus infection in the common donor. CONCLUSIONS: These cases demonstrate a risk for transmitting rabies virus infection through solid organ and tissue transplantation, and this diagnosis should be considered in any rapidly progressing neurological disease.     

Tollwut und Bornavirus-Enzephalitis

A severe, often fatal encephalitis needs to be extensively and carefully clarified, especially when it occurs in a patient weeks or months after an organ transplantation. If the donor was viremic at the time of the organ removal or living viruses were present in the organ tissue, many viruses can be transferred to the organ recipient. This has been repeatedly reported in recent years and decades. In this overview rabies is discussed as a particularly important form of viral encephalitis, which is transferred via organs and always has a fatal outcome, because patients carry a high risk of infection for all caregivers. Bornavirus has been known in veterinary medicine for many decades and in human medicine has been discussed as possibly being associated with psychiatric diseases. Very recently Bornavirus has been identified as the causative pathogen of fatal encephalitis in organ recipients. The aim of this article is to raise awareness for rabies and Bornavirus disease in intensive care medicine and neurology for organ donors and those taking care of organ recipients. Prevention by knowledge can be lifesaving.     

West Nile encephalitis and myelitis

PURPOSE OF REVIEW: This article will review the recent experience with West Nile virus encephalitis and myelitis. RECENT FINDINGS: In the summer of 2003, the majority of cases of West Nile virus infection in the United States were reported from the western states. The transmission of West Nile virus through blood transfusion and organ transplantation was recognized and blood collection agencies implemented West Nile virus nucleic acid-amplification tests to identify infected donors. Intrauterine transmission of West Nile virus infection was reported. The identification of West Nile virus immunoglobulin M in cerebrospinal fluid is the recommended test to document central nervous system infection, but this test may not be positive in spinal fluid collected less than 8 days after the onset of symptoms. Serial samples of cerebrospinal fluid may be required to identify the antibodies. A clinical trial got underway to evaluate the efficacy of human immunoglobulin with high titers of antibodies to West Nile virus in the therapy of West Nile virus encephalitis and myelitis. SUMMARY: In the summer of 2003, the majority of cases of West Nile virus infection in the United States were reported from states west of the Mississippi river. The identification of West Nile virus IgM in CSF is the recommended test to document CNS infection. A single serum antibody titer is an unreliable test of recent infection.     

Nonheart-beating donation in the neurologically devastated patient

A national shortage of organs for transplantation has led to a renewed interest in an old concept of using nonheart-beating organ donors as a source of organs for transplantation. Nonheart-beating donors are patients who have organ procurement obtained after death has been declared by cardiopulmonary criteria as opposed to the traditional heart-beating donor who has been declared dead by neurological criteria. The practice seems promising to increase the available organ supply. This article reviews the history, classification, protocols, and ethical issues involved with nonheart-beating organ donation.     

胰肾联合移植后应用连续性肾脏替代治疗1例

目的：探讨连续性肾脏替代治疗在胰肾联合移植后急性肾功能衰竭及多器官功能衰竭中应用的疗效。 方法：1例胰肾联合移植患者在术后出现移植肾急性肾功能衰竭、移植胰急性胰腺炎、肺感染、十二指肠空肠吻合口出血、腹膜炎等并发症,在积极的抗排斥、抗感染、抑制胰酶、止血、营养支持治疗的同时进行床边连续性肾脏替代治疗治疗,应用百特BM25机器进行连续性静脉-静脉血液滤过治疗,共治疗22 d。 结果：连续性肾脏替代治疗治疗期间生命体征、血流动力学稳定。并迅速控制了肺水肿,维持了水电解质酸碱平衡稳定。经过22 d共计180 h的连续性肾脏替代治疗治疗,患者移植胰肾功能逐渐恢复,患者住院40 d痊愈出院。 结论：连续性肾脏替代治疗在胰肾联合移植后急性肾功能衰竭及多器官功能衰竭的治疗中发挥了重要作用,是胰肾联合移植后良好的肾脏支持方式。     

Organ transplantation and magical thinking

Organ transplantation can provide important treatment benefits in a variety of situations. While a number of live donor procedures are now possible, procurement of organs from dead donors remains the mainstay of transplant programmes. However, cadaveric donation rates remain much lower than anticipated, and some patients who receive organs struggle to adapt to their new body. The reasons for this are not entirely explained by rational or logical means. This paper uses concepts drawn from magical thinking to try to explain some of the less apparent issues at play within the process of cadaveric organ transplantation, including both the donation and receiving of organs. Three themes are explored as potentially relevant: superstitions and rituals around death and the dead body, incorporation and the meanings attached to the transplanted organ, and survivor guilt. All three are shown to be relevant for some part of the transplantation process in at least a minority of cases. It is therefore suggested that focusing not only on the logical and scientific, but also on the ambiguous and magical may enhance the organ donation process and thus increase donation rates and the psychological adjustment of transplant recipients.     

How I Manage the Adult Potential Organ Donor: Donation After Cardiac Death (Part 2)

To address the gap between organs available for transplant and the number of patients on the transplant waiting list, the Joint Commission on the Accreditation of Healthcare Organizations, Institute of Medicine, United Network for Organ Sharing and the federal government have recommended the increased used of donation after cardiac death (DCD) (JCAHOnline ; UNOS, Highlights of the June Board Meeting, 2006). DCD is defined as organ donation once death is declared after irreversible cessation of circulatory and respiratory functions, as opposed to brain death (donation after neurological death). Though DCD is one of the fastest growing categories of organ donors, it comprises only 8% of all deceased donors (Steinbrook in N Engl J Med 357:209–213, 2007). Prior to 1968, when the Ad Hoc Committee of Harvard Medical School proposed a neurological definition of death based on brain-death criteria, organs from deceased donors came from patients who had suffered cardio-pulmonary demise (IOM, Non-heart-beating organ transplantation: practice and protocols, 2000). Early transplantation from DCD donors met with limited success and most transplant surgeons turned to brain-dead donors. Consequently, DCD fell out of vogue and, until recently, has not been the focus of transplant initiatives.     

Ethical issues in brain death and multiorgan transplantation

There is a consensus in Western society that "brain death" is the medical and legal standard for human death. Patients in persistent vegetative states may have lost their "personhood," but they are not dead. It may be desirable to maintain the physiologic processes of a brain-dead pregnant woman to permit the birth of her child. The determination of brain death and plans for multiorgan transplantation should be conducted independently. It is axiomatic that the multiorgan transplantation donor must be dead. Therefore, living anencephalic infants and patients in persistent vegetative states cannot be organ donors. It is permissable to temporarily maintain the physiologic processes of brain-dead patients in order procure their organs for transplantation. Society will have to decide if money spent on multiorgan procurement and transplantation is better spent in other areas of health care.     

Brain donation for research: Who donates and why?

Understanding what influences people to donate or not donate body organs is critical for the future of transplant surgery and medical research. Are people involved with a brain donor program for research influenced by the same factors, and are they also donors for organ transplantation? Using web-based technology, people involved in an Australian brain donation program (for research) were asked to complete a questionnaire designed to elicit demographic information, motivational factors and information about involvement in organ transplantation programs. The response rate was 82%. The majority of people involved in the program are young, well-educated Australian females. Seventy-eight percent are involved in other organ and tissue donation programs. People involved in the ‘Using our Brains’ program are the same group as those who are organ and tissue donors. An improvement in the overall donation rate might be possible if the resources of the research and transplant organisations were combined.     

Primary leiomyosarcoma of the cavernous sinus associated with Epstein-Barr virus in a kidney graft

Immunodeficient patients have an increased incidence of neoplasms, whether the immunodeficiency is due to genetic disorder, the acquired immunodeficiency syndrome (AIDS), or immunosuppressive therapy. Leiomyosarcoma (LMS) is a rare neoplasm, even if its incidence has increased because of AIDS. Less than fifteen cases were described after organ transplantation. An intracranial localization is exceptional (five cases in the literature) and was never described after organ transplantation, to our knowledge. Our present report focuses on a 45-year-old immunocompromised patient, who received immunosuppressive therapy for renal transplantation. He suffered from atypical peri-orbital headaches six months after transplantation and a mass involving the cavernous sinus was identified. Surgical biopsy was performed. Histologic examination revealed a LMS. Epstein-Barr virus was identified by quantitative polymerase chain reaction in the LMS. Immunosuppression was reduced, the patient received adriamycin and protontherapy was realized. He died two years after the transplantation because of tumor progression and kidney failure.     

Post-transplantation HTLV-1 myelopathy in three recipients from a single donor

OBJECTIVES: This paper reports for the first time three cases of infection by HTLV-I via organ transplantation; all the organs coming from the same asymptomatic infected donor. The need is considered for the implementation of compulsory screenings for HTLV antibodies on organ donors and on blood banks. METHODS: The determination of antibodies for HTLV-I/II on samples of serum and cerebral spinal fluid from the patients and the donor was performed by enzyme immunoassay and western blot. Analysis of proviral DNA was performed by polymerase chain reaction. To detect changes in the sequence of amino acids, the tax gene was sequentiated, amplified, and compared with ATK prototype stocks. Spinal cord magnetic resonance imaging, cerebral spinal fluid, and somatosensory evoked potential studies were carried out in all patients. RESULTS: All three transplanted patients developed a myelopathy within a very short period of time. In all three patients and donor the virus belonged to the Cosmopolitan A subtype. The homology of HTLV-I sequences recovered from the patients and donor was 100% in all four cases. Proviral load was high in all three patients. The factors that certainly contributed to the infection in the first place, and the development of the disease later, were on the one hand the high proviral load and their immunosuppressed condition, and on the other the virus genotype, which proved to be an aggressive variant. However, the analysis of the histocompatibility antigen showed that two of the patients carried an haplotype that has been associated with a lower risk of developing this disease. CONCLUSIONS: It is argued that, although in Spain and other European countries there is not compulsory screening for HTLV antibodies because of the studies that show a low seroprevalence, in view of the cases here reported, and to avoid the serious consequences that such infection has on transplanted patients, compulsory screenings, both on organ donors and on blood banks, should be implemented.     

Binding of rabies virus to purified Torpedo acetylcholine receptor

The binding of 125I- and 35S-labeled rabies virus (CVS strain) to affinity-purified acetylcholine receptor from Torpedo electric organ was demonstrated. The binding of rabies virus to the acetylcholine receptor increased with increasing receptor concentration, was dependent on the pH of the incubation medium, and was saturable with increasing virus concentration. Binding of radioactively labeled virus was effectively competed by unlabeled homologous virus particles. Binding of 35S-labeled rabies virus to the AChR was inhibited up to 50% by alpha-bungarotoxin and up to 30% by (+)-tubocurarine but was not affected by atropine. These results demonstrate direct binding of rabies virus to a well-defined neurotransmitter receptor, namely the acetylcholine receptor and indicate that at least a portion of the virus interaction occurs near the acetylcholine binding site on the receptor. These findings support the hypothesis that the acetylcholine receptor may serve as a rabies virus receptor in vivo.     

Rabies in the critical care unit: diagnostic and therapeutic approaches

Worldwide, human rabies is prevalent where there is endemic dog rabies, but the disease may present unexpectedly in critical care units when suggestive clinical features have passed. In North America transmission from bats is most common and there is often no history of a bat bite or even contact with bats. Laboratory diagnostic evaluation for rabies includes serology plus skin biopsy, cerebrospinal fluid, and saliva specimens for rabies virus antigen and/or RNA detection. Rare patients have survived rabies, and most received rabies vaccine prior to the onset of illness. Therapeutic coma (midazolam and phenobarbital), ketamine, and antiviral therapies (dubbed the "Milwaukee Protocol") were given to a rabies survivor, but this therapy was likely not directly responsible for the favorable outcome. There have been many subsequent failures of similar therapeutic approaches. There is no scientific rationale for the use of therapeutic coma in human rabies. New approaches to treating human rabies need to be developed.     

Failure of therapeutic coma and ketamine for therapy of human rabies

The recent success in treating a human rabies patient in Milwaukee prompted the use of a similar therapeutic approach in a 33-year-old male Thai patient who was admitted in the early stages of furious rabies. He received therapeutic coma with intravenous diazepam and sodium thiopental to maintain an electroencephalographic burst suppression pattern, which was maintained for a period of 46 h, as well as intravenous ketamine (48 mg/kg/day) as a continuous infusion and ribavirin (48 to 128 mg/kg/day) via a nasogastric tube. He never developed rabies virus antibodies and he died on his 8th hospital day. At least three other patients have been treated unsuccessfully with a similar therapeutic approach. Because of the lack of a clear scientific rationale, high associated costs, and potential complications of therapeutic coma, the authors recommend caution in taking this approach for the therapy of rabies outside the setting of a clinical trial. More experimental work is also needed in cell culture systems and in animal models of rabies in order to develop effective therapy for human rabies.     

The long incubation period in rabies: delayed progression of infection in muscle at the site of exposure

The striped skunk (Mephitis mephitis) is a host of rabies in large areas of Canada and the United States. In each of two experiments, equal numbers of skunks in two groups were inoculated intramuscularly with low doses of a field strain of rabies virus (street rabies virus). In each experiment, skunks in one group surviving to 2 months were killed at this time and selected tissues were used for examination by the polymerase chain reaction (PCR) method or by immunohistochemistry for rabies antigen. Results of detailed examinations using PCR technology (experiment 1) indicated that muscle at the inoculation site contained viral RNA at 2 months postinoculation, when other relevant tissues on the route of viral migration and early entrance into the central nervous system were negative. The cellular location of virus/antigen, as determined immunohistochemically in experiment 2, was striated muscle fibers and fibrocytes. Our results indicate a major role of muscle (tissue) infection at the inoculation site in the long incubation period of rabies in skunks. These and related findings will be useful in rabies control and, if applicable to other species, will be relevant in postexposure treatment. Received: 31 July 1996 / Revised, accepted: 11 November 1996     

The circumventricular organs: an atlas of comparative anatomy and vascularization

The circumventricular organs are small sized structures lining the cavity of the third ventricle (neurohypophysis, vascular organ of the lamina terminalis, subfornical organ, pineal gland and subcommissural organ) and of the fourth ventricle (area postrema). Their particular location in relation to the ventricular cavities is to be noted: the subfornical organ, the subcommissural organ and the area postrema are situated at the confluence between ventricles while the neurohypophysis, the vascular organ of the lamina terminalis and the pineal gland line ventricular recesses. The main object of this work is to study the specific characteristics of the vascular architecture of these organs: their capillaries have a wall devoid of blood-brain barrier, as opposed to central capillaries. This particular arrangement allows direct exchange between the blood and the nervous tissue of these organs. This work is based on a unique set of histological preparations from 12 species of mammals and 5 species of birds, and is taking the form of an atlas.     

Manualised group therapy concept for patients with alcoholic cirrhosis awaiting liver transplantation

OBJECTIVES: Patient compliance after transplantation is of key importance since even moderate deviations from the prescribed therapy regime may cause organ rejection. Patients with alcoholic liver cirrhosis require special therapeutic preparation before the liver transplantation. METHODS: A manualised group therapy with the aim of maintaining alcohol abstinence, increasing coping skills and therapy adherence is presented and illustrated with a case history. The manual is based on the elements of psychoeducation and problem-solving training. In a second article the results of the clinical evaluation are described.     

Rabies viral antigen in extracranial organs: a post-mortem study

Rabies is a communicable disease and a significant health hazard. Histopathological confirmation of the diagnosis depends on the demonstration of Negri bodies - characteristic intracytoplasmic inclusions. In cases where these are not seen, immunohistochemistry serves as a useful adjunct. After its establishment in the central nervous system, the rabies virus is known to reach peripheral organs by a centrifugal spread. The present study was undertaken with the aim of demonstrating rabies viral antigen (RVAg) in the extracranial organs. Eleven confirmed cases of rabies were analysed and RVAg was found in the adrenal glands, heart, gastrointestinal tract and pancreas, confirming the centrifugal spread of the virus. The detection of RVAg in the extracranial sites may serve as a useful tool in the ante-mortem diagnosis by subjecting the extracranial tissue to biopsy and subsequent immunohistochemistry.     

Psychiatric aspects of organ transplantation

Technical advances in surgery and the new antirejection agents cyclosporine and muromonab-CD3 have led to improved outcome for organ transplantation. Allograft rejection and complications of immunosuppressant therapy are often associated with considerable stress, so availability of psychiatric consultation is a necessity. As a transplant team consultant, the psychiatrist treats perioperative anxiety, depression, and organic brain dysfunction and addresses medical and ethical aspects of patient selection. Studies indicate that many patients with psychopathological conditions have good postoperative results and that most living kidney donors participate spontaneously and consider donation a positive experience.