Prion diseases

Prion diseases

1. Prion Diseases

2. Prions are abnormal forms of a cellular protein that cause rapidly progressive neurodegenerative disorders that may be sporadic, familial or transmitted

3. This group of diseases includes Creutzfeldt-Jakob disease, Gerstmann - Sträussler - Scheinker syndrome, fatal familial insomnia , and kuru in humans Scrapie in sheep and goats ; Mink-transmissible encephalopathy; Chronic wasting disease of deer and elk; and B ovine spongiform encephalopathy

4. All associated with abnormal forms of a specific protein termed prion protein ( PrP ). They are all characterized morphologically by “spongiform change” caused by intracellular vacuoles in neurons and glia , and clinically by a rapidly progressive dementia

5. Pathogenesis Prion diseases are conceptually important because they exemplify degenerative disorders that are caused by “spreading” of misfolded proteins , a remarkable phenomenon that allows a pathogenic protein to acquire many of the characteristics of an infectious organism

6. Normal PrP is a 30-kD cytoplasmic protein present in neurons. Disease occurs when PrP undergoes a conformational change from its normal α-helix-containing isoform ( PrPc ) to an abnormal β-pleated sheet isoform , usually termed PrPsc (for scrapie ) Associated with the conformational change, PrP acquires resistance to digestion with proteases, such as proteinase K .

7. Accumulation of PrPsc in neural tissue seems to be the cause of the pathologic changes in these diseases, but how this material induces the development of cytoplasmic vacuoles and eventual neuronal death is still unknown. Western blotting of tissue extracts after partial digestion with proteinase K allows detection of PrPsc , which is diagnostic.

8. The conformational change resulting in PrPsc may occur spontaneously at an extremely low rate (resulting in sporadic cases) or at a higher rate if various mutations are present in PrPc , such as occurs in familial forms of Creutzfeldt-Jakob disease (CJD) and in Gerstmann- Sträussler-Scheinker syndrome (GSS) and fatal familialinsomnia (FFI)

9. Molecular Genetics The gene encoding PrP , termed PRNP, shows a high degree of conservation across species. A variety of mutations in PRNP have been found to underlie familial forms of prion diseases . In addition, a polymorphism at codon 129 that encodes either methionine (Met) or valine ( Val) influences development of the disease: individuals who are homozygous for either Met or Val are overrepresented among cases of CJD compared with the general population

10. Creutzfeldt-Jakob Disease (CJD) Most common prion disease CJD is a rare disorder that manifests clinically as a rapidly progressive dementia Sporadic form of CJD has an annual incidence of approximately 1 per 1,000,000 people and accounts for about 90% of cases; familial forms are caused by mutations in PRNP. The disease has a peak incidence in the seventh decade

11. W ell-established cases of iatrogenic transmission, notably by corneal transplantation , deep implantation of electrodes in the brain , and administration of contaminated preparations of naturally derived human growth hormone

12. Clinical features The onset is marked by subtle changes in memory and behavior followed by a rapidly progressive dementia, often associated with pronounced involuntary jerking muscle contractions on sudden stimulation (startle myoclonus ). Signs of cerebellar dysfunction , usually manifested as ataxia, are present in a minority of affected individuals. The disease is uniformly fatal . The average survival is only 7 months after the onset of symptoms

13. Variant Creutzfeldt-Jakob Disease Different from typical CJD in several important respects : the disease affected young adults, behavioral disorders figured prominently in the early stages of the disease neurologic syndrome progressed more slowly than in individuals with other forms of CJD . Neuropathologic findings and molecular features were similar to those of CJD

14. Variant form of CJD was linked to exposure to bovine spongiform encephalopathy Pathologically, variant CJD ( vCJD ) is characterized by the presence of extensive cortical plaques surrounded by a “halo ” of spongiform change. No alterations in the PRNP gene are present and the disease appears to be limited to date to codon 129 Met/Met homozygotes . Onset of vCJD is linked to consumption of the bovine spongiform encephalopathy agent in contaminated foods or blood transfusion, raising significant public health issues

15. MORPHOLOGY The progression of the dementia in CJD is usually so rapid that there is little if any grossly evident brain atrophy The pathognomonic finding is a spongiform transformation of the cerebral cortex and, often, deep gray matter structures ( caudate, putamen ); this multifocal process results in the uneven formation of small, apparently empty, microscopic vacuoles of varying sizes within the neuropil and sometimes in the perikaryon of neurons

16. In advanced cases there is severe neuronal loss , reactive gliosis , and sometimes expansion of the vacuolated areas into cystlike spaces (“status spongiosus ”). Inflammation is notably absent. Electron microscopy shows the vacuoles to be membrane-bound and located within the cytoplasm of neuronal processes. Kuru plaques are extracellular deposits of aggregated abnormal protein; they are Congo red- and PAS-positive and usually occur in the cerebellum but are abundant in the cerebral cortex in cases of vCJD

17. In all forms of prion disease, immunohistochemical staining demonstrates the presence of proteinase K-resistant PrPsc in tissue.

18. Fatal Familial Insomnia (FFI) Sleep disturbances characterize its initial stages, is also caused by a specific mutation in the PRNP gene. The mutation, which leads to an aspartate substitution for asparagine at residue 178 of PrPc

19. In the course of the illness, which typically lasts fewer than 3 years, affected individuals develop other neurologic signs, such as ataxia, autonomic disturbances , stupor, and finally coma. A noninherited form of the disorder (fatal sporadic insomnia) has also been described

20. MORPHOLOGY Most striking alteration is neuronal loss and reactive gliosis in the anterior ventral and dorsomedial nuclei of the thalamus; neuronal loss is also prominent in the inferior olivary nuclei. Proteinase K-resistant PrPsc can be detected by immunostaining or western blotting.

21. PREVENTION AND CONTROL At present, there are no effective vaccines or specific treatment available for prion diseases. Infection control measures are therefore the mainstay of prevention A number of strategies can be adopted to enhance surveillance.

22. These include: 1. Establishment of a National Surveillance Centre which performs neuropathological and immunological tests for prion proteins. 2. Making physicians aware of monitoring and surveillance efforts. 3. Autopsies should be performed in all cases of prion diseases to confirm diagnosis. 4. Animals and high risk human population should be screened.

23. Prion diseases constitute a unique infection control problem because they exhibit unusual resistance to conventional chemical and physical decontamination methods S ummary of the recommendations made by the Centers for Disease Control and Prevention (CDC, Atlantaj ." World Health Organization (WHO)6I and other healthcare professionals for infection control precautions for patients with known or suspected CJD is given below

24. 1. Precautions have to be taken for all patients of known or suspected prion disease, patients with rapidly progressive dementia and those who have received dura mater transplants or human growth hormone injection, 2. No additional precautions other than standard universal safety precautions need to be observed for these patients. 3. All tissue from these patients must be labelled as 'biohazard' or 'Suspected CJD' before being sent to the laboratory, 4. No special precautions are required for handling food utensils or disposal of body fluids.

25. 5. Laundry should be managed as for other blood borne pathogens. 6. The morgue must be notified that a patient had CJD. 7. Patients with suspected or known prion disease should not serve as donors for organs, tissues or blood components. 8, Infection control professionals must be notified of all patients with a known or suspected prion disease, They must also be informed when such patients are scheduled to undergo any invasive procedure where personnel or instruments will be exposed to infectious material.

26. Decontamination of contaminated medical devices Tissues such as brain, spinal cord and eyes are high risk tissues Tissues and fluids such as CSF, kidney, liver, spleen, lung and lymph nodes are low risk tissues

27. Devices contaminated with low risk tissues can be cleaned and disinfected or sterilized by use of conventional protocols of heat or chemical sterilization or high level disinfection

28. Devices contaminated with high risk tissues must be cleaned and sterilized by autoclaving at 134°C for ~18 minutes in a prevaccum sterilizer or at 121-132 °C for 1 hour in a gravity displacement sterilizer. Devices that cannot be cleaned must be discarded. Neurosurgical instruments used in such cases could be disposable.

29. Non-critical equipment contaminated with high risk tissue should be cleaned and disinfected with 1:10 sodium hypochlorite (i.e. bleach) or 1N sodium hydroxide depending on material compatibility Contaminated environmental surfaces must be cleaned and disinfected with 1:10 sodium hypochlorite

30. Environmental surfaces contaminated with these tissues require to be disinfected as for standard blood-contaminated surfaces. In the case of a percutaneous exposure to CSF or brain tissue of an infected person-although scientifically unproven-the wound should be rinsed with 0.5% sodium hypochlorite for several minutes and then washed with soap and water. Mucous membrane exposure should be managed by irrigating thoroughly with saline for several minutes

31. Recent Developments Toward Diagnostic Tests

32. Summary