Sleep disorders in prion diseases

Prion diseases are a group of encephalopathies with neurodegenerative changes caused by an altered protein named prion whose characteristic datum is transmissibility. In most cases they occur in a sporadic form although a group of them are familial associated with mutations in the gene of the prion protein. Genetic polymorphism seems to determine the different family variants. One of the most enigmatic and unusual is Fatal Familial Insomnia (FFI), a hereditary disorder characterised by loss of physiological sleep with oneiric stupor, autonomic and motor hyperactivity, and motor anomalies. The polysomnography of this entity reflects an inability to produce the physiological pattern of NREM and REM sleep, as well as hormonal and vegetative circadian fluctuations; the transition from wakefulness to sleep is markedly altered with the early disappearance sleep spindles. The hypothesis of the origin of these disorders is thalamic neuronal loss, especially in the anterior and dorsomedial nuclei, described in the neuropathology of these patients; besides PET reveals hypofunction of thalamic nuclei, centres responsible for controlling wakefulness-sleep. In Creutzfeldt-Jakob disease the wake-sleep disorders are not considered characteristic; nonetheless, frequent alterations have been found in the electroencephalographic registers of sleep. Besides thalamic neurodegeneration, there could be common etiopathogenic mechanisms in prion diseases in relation to the biological function of the prion protein.     

Prions, prion diseases and decontamination

Prions are extremely resistant to disinfection and sterilization methods used so far. The pathogenic prion protein core (called prion) consists of 142 amino-acids, is resistant to proteolytic enzymes, has a mass of 15 pikograms and is filtrable. Fixed by desiccation or chemicals may retain infectivity for years. It survives dry heat at 200 degrees C for 1-2 hours. Prions are fixed to stainless steel within minutes and remain infectious for long periods. Their pathogenetic properties depend on tertiary spatial structure (conformation) which is specific and transmissible in experiment. The prion decontamination appears by far the most important area of the prion science because very little, or nothing, has been done in the majority of world hospitals to prevent iatrogenic transmission. The number of potentially infectious patients is not known. Therefore, patients undergoing neurosurgery, laryngeal or ophthalmic operations, orthodental treatments and even anaesthetic or endoscopic applications should be classified into risk groups, even if clinically priondisease inapparent. The use (or misuse) of disposable instruments is certainly not the final answer for all cases and classic decontamination procedures, if possible because of the character of medical devices, appear still of greatest importance. We consider the high pathogen safety (HPS) autoclave from FEDEGARI as the best actual equipment for the effective decontamination of prions in the hospital practice. The investment costs are moderate and the handling is simple but must be careful. It appears practicable even in small specialized units.     

Understanding the natural variability of prion diseases

Prion diseases are a heterogeneous group of disorders with an invariably fatal disease course. Although various etiologies have been proposed it is apparent that at least a subset of these diseases are of infectious nature. An essential part of the infectious agent, termed the prion, is mainly composed of an abnormal isoform (PrP(Sc)) of a host-encoded normal cellular protein (PrP(C)). The molecular details of the pathophysiology of this group of diseases are unclear but the conversion of PrP(C) to PrP(Sc) plays a fundamental role. In all human prion diseases, PrP(Sc) is deposited in the central nervous system. These disorders include sporadic, genetic and acquired Creutzfeldt-Jakob disease. The molecular classification of human prion diseases is important in order to understand underlying disease mechanisms and for the development of novel therapy protocols. Current classification systems are based on the assessment of clinical presentation, genetic investigations, neuropathological findings and biochemical analysis of PrP(Sc).     

Clinical findings and diagnosis in genetic prion diseases in Germany

To describe the clinical syndrome and diagnostic tests in patients with genetic prion diseases (gPD) in Germany. Clinical features, MRI, EEG, and CSF markers were studied in 91 patients (28 D178N, 20 E200K, 17 inserts, 13 V210I, 8 P102L, 5 E196K). Dementia (35 %) and ataxia (29 %) were the most common initial symptoms and signs. A wide variety and high frequency of neurological/psychiatric symptoms and signs was found during disease course in all patients independently of the type of the mutation. Psychiatric manifestations were frequent (87 %). Neuropsychological abnormalities were observed in 67 %, and aphasia was the most common disturbance (45 %). In E200K, V210I and D178N patients, visual/oculomotor deficits were followed by ataxia early in the disease. Dementia followed by ataxia at onset was common in patients with insert and E196K mutation. P102L patients had isolated ataxia over a longer time period followed by pyramidal signs. Dementia was present only late in the disease course. All clinical routine tests such as MRI, EEG and CSF tests were less sensitive than in sporadic CJD. We provide the first detailed analysis of clinical signs and symptoms in a large group of patients with gPD. Frequency of clinical symptoms and signs was similar in different mutations in a later disease course, but the sequence of occurrence may be of great diagnostic importance. CSF markers were shown to be more sensitive than MRI and EEG.     

Infectious prion diseases in humans: Cannibalism,iatrogenicity and zoonoses

In contrast with other neurodegenerative disorders associated to protein misfolding, human prion diseases include infectious forms (also called transmitted forms) such as kuru, iatrogenic Creutzfeldt-Jakob disease and variant Creutzfeldt-Jakob disease. The transmissible agent is thought to be solely composed of the abnormal isoform (PrP^Sc) of the host-encoded prion protein that accumulated in the central nervous system of affected individuals. Compared to its normal counterpart, PrP^Sc is β-sheet enriched and aggregated and its propagation is based on an autocatalytic conversion process. Increasing evidence supports the view that conformational variations of PrP^Sc encoded the biological properties of the various prion strains that have been isolated by transmission studies in experimental models. Infectious forms of human prion diseases played a pivotal role in the emergence of the prion concept and in the characterization of the very unconventional properties of prions. They provide a unique model to understand how prion strains are selected and propagate in humans. Here, we review and discuss how genetic factors interplay with strain properties and route of transmission to influence disease susceptibility, incubation period and phenotypic expression in the light of the kuru epidemics due to ritual endocannibalism, the various series iatrogenic diseases secondary to extractive growth hormone treatment or dura mater graft and the epidemics of variant Creutzfeldt-Jakob disease linked to dietary exposure to the agent of bovine spongiform encephalopathy.     

Viral, parasitic and prion diseases of farmed deer and bison

The most important viral disease of farmed deer and bison is malignant catarrhal fever. The other herpesviruses which have been isolated from these species are briefly described. Other viral agents that are recognised in these animals, including adenovirus, parapox, foot and mouth disease, bluetongue, epizootic haemorrhagic disease, bovine virus diarrhoea, rotavirus and coronavirus, are also discussed. Ectoparasites of importance in this group in various parts of the world include a variety of ticks, as well as lice, keds, Oestridae, mange mites and fire ants. Helminth parasites include liver flukes (Fascioloides and Fasciola), gastrointestinal nematodes of the family Trichostrongylidae, pulmonary lungworms of the genus Dictyocaulus and extra-pulmonary lungworms of the family Protostrongylidae. Chronic wasting disease is principally important in North America, where the disease occurs in wild cervids in a limited area and has been reported in farmed deer in a small number of states in the United States of America and one province in Canada. These diseases are summarised in terms of their classification, epidemiology, clinical signs, pathology, diagnosis, treatment and control.     

Comments on present-day spread and epidemiology of BSE and prion diseases

Prion diseases of animals and man are neurological diseases with amyloidal deposition of the respective proteins. As to prion disease, the cellular prion protein is in its abnormal isoform(s) an essential component of prion protein aggregates found in affected tissue. In contrast to all neurodegenerative diseases like Morbus Alzheimer or Huntington's disease, prion diseases are transmissible. Therefore, prion diseases were designated Transmissible Spongiform Encephalopathies (TSE). The diseases have been well known for decades. Scrapie was first described around 1750, a BSE case was reported in the 1850-ties most likely a misdiagnosis, and in 1920/1930 the human Creutzfeldt-Jakob disease (CJD) had been described. Transmission of CJD i. e. Kuru had been suspected in the early 1950 s and was erroneously classified as slow virus disease. The CJD transmission posed a problem to humans when transplants from CJD cases were used for treatment. Fortunately, these iatrogenic transmissions remained limited. But with the advent of BSE and appearance of variant CJD cases in the UK and some places in Europe scientists suspected that transmission from cattle to man could have happened. From animal models we know of successful transmission via several routes. Species barriers do not completely prevent transmission. Rather, transmission barriers might exist controlling individual susceptibility against prions. Modes of transmission, susceptibility to transmission, identification of receptor molecules as well as molecular mechanisms of the transmission process are being investigated with great intensity. Current knowledge leads us to assume that inapparent stages of prion infection wrongly suggest a (non-existent) species barrier. This inapparent infection precedes overt disease, and, hence, most research focuses on the development of highly sensitive assay systems for detection of minute amounts of pathological prion protein in suspected cases. Inapparence also should warn us to underestimate BSE or human vCJD cases; at present, approx. 145 cases occurred in Europe and one probable case in Hong Kong (June 2003). Whether BSE had spread to other parts of the world by animal nutrition components or meat can neither be excluded nor confirmed at this time. New data on transmission and consequences of BSE for the human population are summarised in this review.     

Ophthalmic day case surgery: the role of a dedicated day case unit

A study was undertaken to examine all cases admitted to a new ophthalmic surgical day case unit during its first six months of operation. This paper describes the experience gained in establishing the unit, including operational management, and outlines the factors contributing to the unit's success. A quarter of the patients usually admitted as inpatients have been treated in the day unit, and day case surgery rarely results in unplanned inpatient admission, or subsequent readmission. Provided strict admission criteria are followed, the results show that this facility can accommodate a wide range of common ophthalmological procedures, and that general anaesthesia is compatible with day case management.     

经腹入路腹腔镜下肾上腺手术

目的　探讨腹腔镜下经腹入路行肾上腺手术的方法。方法　本组 4 2例 ,左侧 2 3例 ,右侧 19例。患者全侧卧位 ,经腹腔入路 ,采用 3～ 4个套管针 ,剪开侧腹膜显露肾上极内侧 ,将脾脏或肝脏游离后推开 ,切开肾上腺表面的肾周筋膜 ,游离肾上腺或腺瘤 ,用钛夹钳夹肾上腺中央静脉或肾上腺组织后 ,切除肾上腺或腺瘤。结果　 4 1例于腹腔镜下顺利切除肾上腺或肿瘤。 1例嗜铬细胞瘤病例因肿瘤粘连紧密 ,改为开放手术。切出的瘤体直径 8～ 6 2mm。手术时间平均 82min。出血量平均 6 5ml。术后 5～ 7d出院。结论　采用全侧卧位 ,经腹腔入路手术解剖标记清楚有助于肾上腺及腺瘤的定位 ,避免损伤周围脏器及大血管 ,手术安全性高 ,适用于较大的腺瘤、嗜铬细胞瘤及肾蒂前方的肿瘤     

Ophthalmic manifestations in Lyme borreliosis

We reviewed ophthalmic manifestations in Lyme borreliosis, concentrating on clinical and laboratory diagnosis, differential diagnosis and treatment options. Ocular involvement may occur in every stage of the disease. Conjunctivitis and episcleritis are the most frequent manifestations of the early stage. Neuro-ophthalmic disorders and uveitis occur in the second stage whereas keratitis, chronic intraocular inflammation and orbital myositis have been reported in the third stage of borreliosis.