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CREUTZFELD- JACOB DISEASE INTRODUCTION : “Prion diseases, more commonly referred to as Creutzfeld-Jakob Disease (CJD), are a group of progressive, neurodegenerative conditions that infect both animals and humans” Kathryn Prout, Feb. 2000 “….. the agents have also been called unconventional slow infectious agents. Smaller than viruses, these agents have been described as proteinaceous and infectious, leading Prusiner and colleagues to label them prions” Victoria McGreevy Steelman, 1994 “The source of CJD remains unknown ; however, the agent has been isolated from or transmitted experimentally to many different animals. The range of these hosts is extensive, including monkeys and other primates, sheep, goats, deer, calves, mink, ferrets, cats, raccoons, skunks, mice and other rodents, and rabbits. It has therefore been postulated that these animals may actually be the reservoir for CJD transmission.” Victoria McGreevy Steelman, 1994 CJD is one of a family of diseases called Transmissible Spongiform Encephalopities (TSE’s), caused by an infectious agent which invades the brain and causes mental and physical collapse. The causative agent may reside in the body for long periods of time undetected, but once patient is symptomatic progression is rapid and fatal. Different forms of the disease exist in humans and animals but they all result in spongiform encephalopathy, named so as under microscopic examination there are areas of brain cell with similar appearance to sponge. Specific examples of mammalian TSE’s include: Scrapie TME (Transmissible mink encephalopathy) CWD (Chronic wasting disease): muledeer, elk BSE (bovine spongiform encephalopathy) : cows Humans are susceptible to several prion diseases : * CJD : Creutzfeld-Jakob Disease GSS : Gerstmann-Straussler-Schenker syndrome FFI : Fatal familial Insomnia Kuru Alpers syndrome CJD can be further subdivided into four main types ; Familial Iatrogenic Variant Sporadic/ Classical PRIONS, WHAT ARE THEY AND HOW DO THEY INFECT As mentioned earlier the cause of prion disease are prions. This idea was initially suggested in 1982 by Stanley Prusiner. Normal proteins when formed into a living cell fold up and are thus very flexible and can adapt several shapes, this particular feature being suspected to be the root of this problem. Prion protein, PrP, exist both normally and abnormally, PrPc and PrPsc, the normal form exists naturally in the brain but it’s function is unknown. The abnormal form has unusual properties. Firstly unlike its normal form it is not broken down by enzymes. Secondly it forms clusters/clumps called Scrapie-Associated fibrils (SAF’s), these clumps form amyloids. In some cases of CJD, Amyloid deposits, known as plaques are found in the brain post mortem, these are not dissimilar to other diseases such as Alzheimers and also the normal ageing brain. What causes Prion disease? The diseases are related to the presence of the earlier mentioned PrPsc. In the normal proteins they are broken down by enzymes once they do their job, however abnormal PrP are not broken down. The rogue protein results from a change in the shape of the normal one. Once formed in the body they can recruit and convert more normal ones into abnormal form, setting off a chain reaction leading to an accumulative build up of rogue proteins. This process causes brain damage which interferes with normal brain function. The function of the normal proteins is still unclear, but it has been hypothesised that they are involved in the transport of messages between specific brain cells. In sporadic prion disease, this change in protein structure occurs spontaneously and apparently at random, as a chance event without any known cause. In familial CJD, it is known that there are mutations in the PrP gene which are inherited from one parent. These may produce forms of the PrP molecule which are more likely to be converted into abnormal form. Finally, in CJD acquired by transmission (variant and iatrogenic), PrPsc molecules enter the body via an outside source and corrupt the PrPc of the host. The PrP gene can exist in two forms. We each inherit two PrP gene’s, one from each parent. In just over half the population one of each form is inherited and these people are called heterozygotes. In all other cases, two identical copies are inherited; such people are termed homozygotes. Most people with CJD are homozygotes; it may be that they produce a PrP more vulnerable to conversion, however it is as yet unknown. C JD Sporadic U.K. Familial Iatrogenic Transmission : - largest portion of cases in Classical Not infectious in conventional terms, i.e. Droplet Blood or sexual contact Touch Only transmissible when tissue from an infected person/ animal is passed into the body of another person/ animal Iatrogenic surgical instruments Corneal transplants Human growth hormone Variant linked with contact with BSE contaminated beef Sporadic no link between BSE and CJD Incubation Unsure how long – possibly 20 years or more Diagnosis Definite diagnosis on post mortem For variant – brain and tonsil biopsy Management Supportive, rapid referral to multidisciplinary team. Total care required until death usually resulting from pneumonia Variant The following is a brief overview/ factfile of the various types of TSE’s affecting humans, excluding CJD : * GSS occurs at 2% of rate of CJD. It is distinct from CJD, it occurs every 4th-5th decade. It is characterised by cerebellar ataxia and concomitant motor problems, dementia less common and disease course lasts several years to death. * FFI presents with an untreatable insomnia and dysautonomia. Pathology is characterised by severe selective atrophy of the thalamus. * Alpers Syndrome is the name given to prion diseases in infants. * Kuru refers to a canabilistic tribe in Papau New Guinea. Progressive neurodegenerative disease, thought to have been transmitted via the ritualistic eating of their dead relatives as a sign of respect during mourning. We shall briefly describe Iatrogenic and Inherited CJD firstly and then focus on the two more prevalent types, i.e. vCJD an Classic/ Sporadic CJD. Iatrogenic CJD This is an acquired form of the disease where the rogue proteins are introduced to the individual through surgery or medical treatment. There is no evidence of normal social contact presenting a risk, however once a person is infected the brain and certain other tissues become infectious. Transmission occurs only in a few specific ways ; the majority of suffers of iatrogenic CJD contracted it via contaminated human pituitary growth hormone some cases have come from fertility treatment using human pituitary derived gonadotrophin direct inoculation from cerebral tissue, e.g. corneal grafts and dura mater surgical equipment from neurosurgical use on patient with sporadic CJD Signs & Symptoms mood swings and behavioural change problems with balance and gait. Tremor and rigidity of limbs difficulties with carrying out skilled movements headache, dizziness and double vision dysarthria dementia later in illness Familial CJD In familial CJD there is a mutation of the Prp gene, which seems to make conversion to PrPsc more likely. There are two other previously mentioned brain diseases which closely resemble familial CJD, i.e. GSS and FFI, both are associated with PrP mutations. The mechanics of the prion protein are discussed later on. Signs & symptoms initially depression, memory lapses, maybe unusual fatigue. However rapid progression to dementia distinguishes it from depression. Within weeks, unsteadiness and lack of co-ordination. Sudden jerky movements, rigid limbs, maybe blindness and incontinence This type often strikes at an earlier age than sporadic, the course of illness is longer and patient may survive several years after onset of symptoms. The mentioned mutations can be detected via blood test. Therefore at risk family members can now be screened for the presence of the genes responsible. It may also be possible to tell from the form of the gene whether the person will develop the illness early on or later. The symptoms for GSS starts with clumsiness, unsteadiness and shakiness together with rigidity of limbs. Dementia sets in later and the patients may survive for many years. In FFI the main symptom is a progressive untreatable form of insomnia. FFI differs from other prion diseases as it only affects the Thalamus. RISK FROM BLOOD TRANSFUSION There is differing opinion whether there is a transmission risk with blood transfusions. “There is evidence from research that blood of experimentally infected animals contains an infective agent….. Animal studies have demonstrated that the agent causing scrapie replicates first in the spleen and other lymphoid tissues but reaches highest titer in the brain, where it results in the clinical appearance of the disease. Hence peripheral tissue in contact with blood also harbors PrP infectivity.” Ricketts et al 1997 They also speculate that if CJD is transmissible in blood, cases should occur in young persons, particularly if the incubation period is short, and even if it is long we should have seen evidence by now. Literature from the CJD Support Network also state that CJD sufferers are no more likely to have received blood than nonsufferers so there is no convincing evidence that this is a cause. INVESTIGATIONS CARRIED OUT FOR DIAGNOSIS Blood tests; to rule out any other cause of symptoms. They will also test for the prion disease susceptible genotype EEG; this is primarily useful for diagnosis of sporadic as there is a characteristic period sharp wave complexes MRI; in some cases of classic/ sporadic CJD the protein plaques are visible CSF; there are sometime detectable PrPsc proteins visible Brain biopsy; not very reliable as an unaffected area of brain may be biopsied Tonsil biopsy; the PrPsc for vCJD is present in most cases and is one of very few ways of definite diagnosis Autopsy; this is the only definitive exam as the spongiform vacuoles in the brain tissue are evident under microscopic examination. DIAGNOSTIC CRITERIA FOR VARIANT CJD I a) Progressive neuropsychiatric disorder b) Duration of illness >6 months c) Routine investigations do not suggest an alternative diagnosis d) No history of potential iatrogenic exposure II a) Early psychiatric symptoms, i.e. Depression, anxiety, apathy, withdrawal, delusions b) Persistent painful sensory symptoms, this includes both frank pain and/or unpleasant dysaesthesia c) Ataxia d) Myoclonus or chorea or dystonia e) Dementia III a) EEG does not show the typical appearance of sporadic CJD, i.e. generalised triphasic periodic complexes at approximately one per second (or no EEG performed) b) Bilateral Pulvinar high signal on MRI scan IV a) Positive tonsil biopsy DEFINITE : IA( progressive neuropsychiatric disorder) and neuropathological confirmation of vCJD, i.e. spongiform change and extensive PrP deposition with florid plaques, throughout the cerebrum and cerebellum PROBABLE : I and 4/5 of II and III a) and III b) Or I and IV a) Department of Health, July 2000, Monthly Creutzfeld-Jacob Disease statistics, Department of Health http://www.doh.gov.uk/cjd/stats/july00.htm SPORADIC CJD CJDcauses progressive loss of mental abilities and has neurological symptoms including unsteadiness and clumsiness It affects 1 person per million per year 50 or so new cases per year in the U.K. 85% of these cases are sporadic – having no known cause – changes in protein structure is spontaneous, the remainder comprising familial, iatrogenic and variant CJD Sporadic CJD affects age group 40 – 75 Peak age of onset 60 – 65 years Worldwide distribution SYMPTOMS Non-specific initial signs ; Dizziness Headaches Depression/ mood swings Insomnia Memory lapses There is often a rapid progression to dementia and the onset of obvious neurological symptoms Cognition – memory lapses lengthen Loss of concentration Loss of problem solving skills Disorientation Inability to perform A.D.L.’s Mobility unsteadiness and ataxia can be first symptoms Involuntary jerking and abnormal movement Tremor Rigidity Apraxia – inability to perform complex and sequential tasks Communication – slurring and quiet speech Dysphasia Loss of language content Reduced comprehension Nutrition swallowing difficulties – choking, excessive saliva Malnutrition Vision blurring of vision Poor identification of common items Visual hallucinations Cortical blindness Seizures focal then tonic-clonic in the final stages of disease 70% of patients die within 6 months of onset of symptoms It is possible these patients have no insight into their condition beyond the early part of their disease Eventually these patients are unable to speak, see or move and require total nursing care VARIANT CJD First identified in 1996. Quite distinct from sporadic CJD as it affects a younger age group, course of illness is longer in variant – typically around a year, symptoms at outset are more psychiatric than neurological. On post-mortem there are changes aside from the characteristic spongiform change were found- florid plaques : deposits scattered throughout the brain and surrounded by spongiform change Duration of the disease ranges from 8 – 58 months SYMPTOMS Initially anxiety, depression, withdrawal, personality changes – patients are often referred to psychiatrists which leads to diagnosis delay Sensory – persistent sensory changes, pain and odd sensations in face or limbs pins and needles Onset of more noticeable neurological symptoms Motor – movement disorder is a clear sign. Ataxia – progressive unsteadiness and clumsiness. Rigidity Cognitive – memory loss, poor concentration Communication – disorientation, loss of language skills. Inability to read or write, slurring & quite speech. Dysphasia Nutrition – locking of jaw, lack of swallow abilities Vision – double or blurred vision. Hallucinations, gaze palsy cortical blindness. Ethical decisions regarding artificial means of providing nutrition need to be addressed as soon as possible to avoid difficult decisions later Management Good total nursing care of patient. Provision of support to family/ carers Quick referral to physio, o.t., social services, speechj and language team, nutritionalists, psychiatric community and district nurse teams. INFECTION CONTROL There is no evidence of an increased incidence of CJD in any specific in any specific occupational group that might be exposed. The degree of infectivity during the long asymptomatic period is unknown, but patients are infective throughout the duration of the symptomatic illness. Measures to minimise risk of reprocessing surgical instruments after any surgical procedure ; 1. Effective and thorough cleaning of surgical instruments to remove as much organic debris as possible before sterilisation 2. Instruments designated for a single episode of use should be discarded after use and never reprocessed. 3. Single use kits should always be used for all lumbar punctures 4. Where practical options for single use instruments are available, which do not compromise clinical outcome, considerations should be given to using them 5. Flexible endoscopes should have a unique identifier recorded in the patient, theatre or endoscopy notes after every use to facilitate traceability. RISK GROUPS DEFINITION (1) Known Patients diagnosed as having CJD or related disorders such as GSS, Kuru or other prion diseases (2) Suspected Clinical symptoms suggestive of CJD or related disorders but diagnosis not confirmed (3) At risk Asymptomatic patients potentially at risk of developing CJD or related disorder, i.e. a) recipients of hormone derived from human pituitary glands b) recipients of dura mater grafts c) people with a family history of CJD Blood is very unlikely to present a risk of transmission. Therefore, blood, urine, faeces and swabs can be collected and handled in the normal way ( universal precautions) without special precautions. OXFORDSHIRE HEALTH SERVICE, INFECTION CONTROL SERVICE – Management of patients with Creutzfeld-Jakob Disease (CJD) Or Gerstmann-Straussler-Scheinker Syndrome (GSS) (Transmissible Spongiform Encephalopathies) Infection Control Manual 3.9.1 – 3.9.6. INFECTION CONTROL “Prion disease is not infectious in the conventional sense; normal contact between people has not been shown to represent a risk …….. There is no evidence of risk to carers through contact that would occur in the normal caring situation” “ The abnormal proteins associated with prion disease are resistant to normal sterilisation procedures” “The degree of infectivity of tissues will vary depending on the type of prion disease ; pathogenesis of vCJD seems to be quite distinct from that of sporadic or inherited prion disease…” Kathryn Prout ,(2000) NT Learning Curve – Help at hand for people dealing with prion disease, Nursing Times Feb. 2000 ACTION ON MEDICAL EQUIPMENT PATIE NT GROUP INVOLVIN G BRAIN/SPINE/EY E NOT INVOLVING BRAIN/SPINE/EY E At Risk incinerate disinfect Suspect quarantine quarantin e Known incinerate incinerate Douglas Clarkson,(2000) Cross infection of Creutzfeld-Jakob Disease, Nursing Times Feb 2000, Vol.96, No. 6 “Incineration destroys prions and is consistently recommended as the method of choice whenever possible” Victoria M. Steelman, 1997 N.B. STILL NO DEFINITIVE STERILISATION TECHNIQUES DUE TO PRION PROTEIN RESISTANCE TO HEAT AND CHEMICAL INACTIVATION RESEARCH ONGOING Neurologist & Neurology nurses Social services Physio & Occupational therapy Speech & language therapist District Nurses nurse PATIENT & FAMILY/ CARERS Incontinence specialist Macmillan team/ Marie Curie Respite care centre Community Psychiatric team Dietician Prion unit, St. Mary’s Human BSE Foundation National CJD Support network National CJD surveillance unit Compiled by Natalie Walton & Niall Bennett