Types of Studies Reviewed. The author reviewed all available case reports and any studies of the oral aspects of prion diseases published in peer-reviewed journals and available via PubMed. He then outlined the risk of nosocomial transmission of prions in dental health care.

Results. Sporadic Creutzfeldt-Jakob disease, or sCJD, is the most common of the acquired human prion disorders, and it typically affects elderly people and leads to rapid death. In contrast, variant CJD, or vCJD, has affected young adults from Europe, giving rise to a slow onset disorder comprising both psychiatric and neurological upset. Oral neurological manifestations are rare and seem to occur only in people with vCJD; there are no oral mucosal or gingival manifestations of prion disease. Prions can be detected in the oral tissues—usually the gingivae and dental pulp—of animals experimentally infected with prions. In contrast, prions have not been detected in the pulpal tissue of people with sCJD, and there are no data of pulpal infection in vCJD. There also are no data suggesting that prions are transmitted easily in the dental setting, but there remains the rare risk of such transmission if appropriate infection control measures are not adhered to.

Clinical Implications. Few people in the United States and worldwide have prion disease. Oral manifestations are rare. Evidence suggests that the risk of transmission and acquisition of a prion infection as a result of dental treatment is rare, if appropriate infection control measures are maintained.

In this article, I briefly review case reports and studies of the oral aspects of prion diseases that were published in peer-reviewed journals and available on PubMed. I also outline the risk of nosocomial transmission of prions in dental health care.

	GENERAL CLINICAL ASPECTS OF PRION DISEASES

TOP ABSTRACT GENERAL CLINICAL ASPECTS OF... THE PATHOGENESIS OF PRION... TREATMENT OF PRION DISEASE DENTAL IMPLICATIONS OF PRION... UPDATE: ADDITIONAL STUDY CONCLUSION REFERENCES

 
Scrapie affecting sheep and goats was the first transmissible spongiform encephalopathy, or TSE, to be described. Other animal TSEs now are known, particularly BSE.^2,11–14 The human prion disorders are classified into CJD; Gerstmann-Sträussler-Scheinker, or GSS, syndrome; and kuru. They are subclassified into two main etiologic categories: acquired and inherited (Box). Other than the cases of vCJD in humans, there is no evidence that prions can be transferred from animals to humans.

Inherited prion diseases. Inherited prion diseases account for about 15 percent of all human TSEs, and they comprise GSS syndrome and a group of other familial human prion diseases.^12,13

At least 20 pathogenic mutations of the prion protein-coding gene on chromosome 20 have been described. All of the mutations are inherited in an autosomal dominant manner, and they give rise to a spectrum of neurological features. Affected people can die from CJD-like illnesses.^2,14–16

Acquired prion diseases. Kuru. Kuru is an acquired spongiform encephalopathy. It first was described in the 1950s and was acquired as a result of cannibalistic rituals.¹ All of the affected people were from Papua New Guinea (the Fore linguistic group and neighbors) and tended to be women and young adults. The origins of kuru probably were in a person with sporadic CJD, or sCJD. Although cannibalism ceased almost 50 years ago, there still are occasional new cases of kuru, which suggests a long incubation time of the causative agent.^17,18 The clinical features of kuru are summarized in the table.

Kuru first was described in the 1950s and was acquired as a result of cannibalistic rituals.

Sporadic (classic) Creutzfeldt-Jakob disease. sCJD accounts for the majority of human TSEs worldwide, and it typically arises in middle to late life.¹⁹ There is rapid progression over a period of weeks to an akinetic mutism. Aside from the predominant mental deterioration and myoclonus, there can be extrapyramidal and pyramidal signs, cerebellar ataxia and cortical blindness. Up to one-third of patients may have prodromal symptoms that include insomnia, fatigue, depression, weight loss, headache, general malaise and ill-defined pain.¹⁸

The only useful clinical investigation of sCJD is electroencephalography, which shows characteristic changes. Biopsy of the brain tissue is essential. There are no amyloid plaques in affected brain tissue, though there is spongiform change, neuronal loss and astrocytosis—the spongiform change is a late feature. The causative prion is not present in lymphoid tissue.^20,21

Iatrogenic Creutzfeldt-Jakob disease. Iatrogenic CJD, or iCJD, has affected at least 267 people in 17 countries. The prion is acquired via cadaver-derived growth hormone, pituitary gonadotropins, dura mater homografting, corneal grafts or inadequately sterilized intracerebral surgical equipment.²² iCJD varies clinically from an sCJD-type disease to a disease similar to kuru. Its incubation period and rate of progression seem to be dependent on the site of inoculation of the infectious agent. Intracerebral or optic inoculation gives rise to more rapid onset of the disease than does inoculation that is more peripheral.

As a consequence of understanding iCJD’s cause and the methods to use to avoid future disease, its frequency has fallen considerably. This may be dependent, however, on the extent of the spread of vCJD in Europe and throughout the world.²³

Variant Creutzfeldt-Jakob disease. vCJD is localized geographically to Europe, particularly the United Kingdom. It first was identified in 1996²⁴ and almost always has affected teen-agers or young adults, the mean age of onset being 29 years.²⁵ There have been 128 people diagnosed with definite or probable vCJD in the United Kingdom (117 of whom have died), and there are only small numbers of affected people in other European countries.²⁶

Unlike sCJD, iCJD or kuru, vCJD has a long clinical course (mean, 14 months; range, nine to 35 months). The clinical features of vCJD are summarized in the table.²⁵ Abnormal prion protein, or PrP^Sc, is present in lymphoid tissue of the patients with vCJD.^21,27

There is compelling evidence that vCJD is linked causally to BSE.^28,29 The young ages of patients with vCJD are unlikely to reflect any age-related dietary habit but may reflect age-related genetically determined factors.

	THE PATHOGENESIS OF PRION DISEASE

TOP ABSTRACT GENERAL CLINICAL ASPECTS OF... THE PATHOGENESIS OF PRION... TREATMENT OF PRION DISEASE DENTAL IMPLICATIONS OF PRION... UPDATE: ADDITIONAL STUDY CONCLUSION REFERENCES

 
The biochemistry and physiology of prions are well-reviewed elsewhere.^1,2 Normal prion protein, or PrP^c, is a cell membrane glycoprotein. It occurs in all tissues, though it is concentrated particularly in the synaptic membrane within the central nervous system. The function of PrP^c is not known, though it has been suggested that it may be important in copper metabolism (for example, transportation).¹

There is no effective specific treatment for prion disorders. None of the possible therapeutic strategies has proven yet to be notably effective.

In acquired prion disorders, PrP^Sc causes disease at a posttranslational level of PrP^c production, causing the conversion of PrP^c to PrP^Sc. This pathogenic process is self-propagating, and, therefore, levels of the abnormal protein rise, causing the generation of plaques of amyloid material and neural death. The exact mechanism of neurotoxicity is not known.

	TREATMENT OF PRION DISEASE

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There is no effective specific treatment for prion disorders. Possible therapeutic strategies include inhibiting posttranslational conversion of PrP^c to PrP^Sc (for example, with amyloid dyes, inhibitors of cholesterol biosynthesis, tricyclic acridine and phenothiazines) or increasing the clearance of PrP^Sc (for example, with antibody fragments or branched polyamines). None of these has proven yet to be notably effective. Quinicrine and chlorpromazine are tricyclic derivatives of acridine and phenothiazine that inhibit PrP^Sc formation in vitro; therefore, they may have some clinical promise in the management of prion disease.³⁰ Studies suggest approaches based on the depletion of PrP^Sc may be of importance.³¹

	DENTAL IMPLICATIONS OF PRION DISEASE

TOP ABSTRACT GENERAL CLINICAL ASPECTS OF... THE PATHOGENESIS OF PRION... TREATMENT OF PRION DISEASE DENTAL IMPLICATIONS OF PRION... UPDATE: ADDITIONAL STUDY CONCLUSION REFERENCES

 
Oral manifestations. Oral manifestations of human TSEs comprise dysphagia and dysarthria due to pseudobulbar palsy. In patients with vCJD, there may be orofacial dysesthesia or paresthesia.^25,32 Loss of taste and smell recently was reported as a feature of one patient with vCJD.³³ Thus, unlike many other emerging and re-emerging infectious diseases, the mouth would seem to be affected rarely in patients with prion disease.

Transmission of prions in the dental health care setting. The notion of the transmission of sCJD as a result of dental treatment was proposed 20 years ago.³⁴ A clustering of a small number of dental patients with sCJD was suggested but never proved.^34,35 Case-control studies have not established any association between dental health care and the development of sCJD or iCJD.³⁶ There are no data to suggest any clustering of vCJD in a dental practice.

Infectivity of oral tissues in prion disease. Prions of sCJD and scrapie can be present in the oral tissues. The prion’s possible route of transmission from the brain to the oral tissues and vice versa was suggested on the basis of the observation of neuronal degeneration with probable prion protein accumulation in the trigeminal ganglia of patients with sCJD.³⁷ There is no relevant information concerning vCJD, but a prion of BSE has been detected in the trigeminal ganglion of affected animals.³⁸ Inoculation of a scrapie agent into the peritoneum or dental pulps of hamsters led to eventual prion infection of the trigeminal ganglion of the ipsilateral side of inoculation.³⁹

As prions may be present in oral tissues, nosocomial transmission of prions in the dental setting cannot be excluded.

Prion protein was not detected in the pulpal homogenates of eight U.S. patients with sCJD,⁴⁰ but intraperitoneal injection of a scrapie agent led to infection of the dental pulps of hamsters after about 96 days.³⁹ The concentration of prions, however, was significantly higher in gingival than pulpal tissue of these animals. The prion protein of vCJD is present in tonsillar lymphoid tissue,^21,27 and, thus, it is likely to be present in lingual tonsils. The tendency for a prion of vCJD to occur at a site outside the central nervous system would suggest that it would be present in the trigeminal ganglion.³⁸

As I indicated previously, there are no definitive data to suggest that prion disease has been transmitted by oral tissue, though accidental transmission of scrapie between encaged animals has been suggested to have been caused by biting.⁴¹ Gingival scarification with dental burs previously used to scarify scrapie-infected mice did not lead to subsequent scrapie,⁴² though intraperitoneal injection of infected gingival tissue into mice did give rise to astrocytosis of scrapie. Gingival exposure to scrapie-infected brain homogenate caused scrapie in recipient mice,⁴³ almost regardless of whether the gingivae were intact. The precise infectivity of prion-infected oral tissues remains unclear, but one study of scrapie-infected hamsters established that the infectivity of pulpal tissue was substantially lower than that of gingival tissue.

Likelihood of transmission of prions during dental health care. There is little evidence to indicate that prions are transmitted within the dental clinic setting, mirroring knowledge of the transmission of HIV⁴⁴ and hepatitis C virus.⁴⁵ However, as prions may be present in oral tissues and at least experimentally transmitted in oral tissues to experimental animals, nosocomial transmission of prions in the dental setting cannot be excluded.

As vCJD prion proteins are likely to be found in perioral lymphoid tissue and scrapie prions are present in and transmitted via pulpal and gingival tissue, there is a small risk of transmitting prion proteins during dental care. The most likely means of prion transmission in dentistry would be contaminated dental instruments; thus, measures that reduce this risk are essential for the dental surgical care of patients with known prion disease.

Guidelines for clinically managing the care of patients with prion disease are sparse and reflect the lack of knowledge of the relevant epidemiology of prion disease.^46–48 In general, the infection control procedures for managing the dental care of patients with known prion disease are similar to those for all other patients, though a small number of significant modifications of the infection control procedures are needed. Oral tissues are considered to be of low infectivity, and people who are liable to acquire iCJD (for example, recipients of dura mater, corneal transplants and human pituitary hormones, and people who have undergone neurological procedures) are regarded by the World Health Organization as being at low risk of developing prion disease (and hence require no additional infection control measures).⁴⁷ In contrast, previous U.K. guidelines considered such people to be at some additional risk of developing prion disease.^46–48

All dental instruments used in patients with or suspected of having prion disease must be not be re-used but should be appropriately discarded immediately after clinical use.^46,47 This is because instruments only briefly exposed to prion-infected tissue are contaminated,⁴⁹ prions can bind rapidly to stainless steel, and the protein is not easily dislodged with strong sodium hydroxide or 10 percent formaldehyde. Employed methods of cold sterilization are not effective in the decontamination of prion-exposed clinical instruments.

The current guidelines suggest that no other infection control measures need to be changed to manage the dental care of patients with prion disease. It has been suggested, however, that dental unit waterlines should not be activated and a cuspidor other than that of the dental unit should be used^50,51 to remove the risk of prion contamination.

	UPDATE: ADDITIONAL STUDY

TOP ABSTRACT GENERAL CLINICAL ASPECTS OF... THE PATHOGENESIS OF PRION... TREATMENT OF PRION DISEASE DENTAL IMPLICATIONS OF PRION... UPDATE: ADDITIONAL STUDY CONCLUSION REFERENCES

 
Since I completed my review, the Department of Health in the United Kingdom has published the results of a detailed analysis of the risks of prion transmission in dentistry. The report concluded that the risk of transmitting vCJD in a single dental procedure on an infected patient would be about 1 billion times less likely than transmitting vCJD during a tonsillectomy.⁵² No special decontamination procedures need to be adopted for providing dental treatment for patients with TSEs, and these patients can be treated in general practice as long as good generic decontamination procedures are applied.

	CONCLUSION

TOP ABSTRACT GENERAL CLINICAL ASPECTS OF... THE PATHOGENESIS OF PRION... TREATMENT OF PRION DISEASE DENTAL IMPLICATIONS OF PRION... UPDATE: ADDITIONAL STUDY CONCLUSION REFERENCES

 
Evidence suggests that prion disease will have little relevance to dental health care. Certainly, prion disease rarely seems to give rise to significant oral dysfunction. Epidemiologic evidence does not suggest that prion transmission as a result of dental health care has occurred, nor is it likely to occur frequently, despite the fact that animal studies have established that the oral tissues can become infected with prions and be a potential source of infection to other animals.

Dental instruments used to treat patients with known prion disease should be discarded after use. There is a need for relevant research to establish the potential susceptibility of oral tissues to be infected by prions of vCJD and BSE and to determine the exact infectivity of prion-containing oral tissues.