Matthew A. Hammons, MD · William R. Nunery, MD
The term prion disease refers to a group of fatal neurodegenerative disorders for which no treatment or cure is available. With the emergence of variant Creutzfeldt-Jakob disease (CJD) in the past decade, ophthalmologists have become more aware of prion diseases because of the risk of disease transmission through transplanted or injected materials.
Researchers believe that prions are naturally occurring glycoproteins that are normal constituents of neuronal cell membranes and lymphoreticular tissue.1 Another theory is that the disease-causing particles may contain a small amount of nucleic acid and be more virus-like (virion) in nature.2
Currently, the protein-only theory is widely favored. The purpose of these normal prions (PrPc) is unknown; however the prions may function in neural transmission.3-5 Abnormal, disease-causing prions (PrPsc) occur when the normal alpha helix dominated codons between 120 and 230 are folded into beta sheet configurations.6-11 Normal prions are cleared from the neuromuscular junction by protease K. Abnormal, disease-causing prions, however, appear to be resistant to protease K breakdown and clearance.
In addition, exposing PrPc to PrPsc results in conversion of the normal protein to PrPsc through a crystallization process in which PrPsc acts as a template to encourage beta folding in the tertiary structure of PrPc.11,12
Four categories of human prion diseases have been described:
These conditions are collectively referred to as transmissible spongiform encephalopathies (TSEs). Each has in common, to varying degrees, long latency periods (1 to 40 years), progressive dementia, and cerebellar degeneration. Death is universal and usually occurs within 4 to 24 months after the onset of symptoms.1
CJD was first described in 1921 and historically accounts for 80% to 85% of human spongiform encephalopathies. CJD may be subdivided into sporadic, familial, and variant (vCJD) types.1 Sporadic CJD occurs in one case per million population per year. The gender incidence is equal. The median age of onset is 64 years of age and death occurs 4 to 6 months after the onset of symptoms.
Early manifestations may include memory loss, abnormalities in movement coordination, and psychiatric abnormalities.13 Progressive dementia with cerebellar degeneration and late myoclonus is typical. From an ocular standpoint, CJD may first affect the occipital cortex and present with decreased vision. This is referred to as the Heidenhain syndrome.14,15
Cortical blindness may eventually occur in 25% to 50% of CJD cases.16-18 Oculomotor abnormalities, nystagmus, supranuclear palsy, and impaired smooth pursuit may occur. Eyelid retraction, ptosis, blepharospasm, and decreased blink have been reported in CJD.19
Inherited or familial CJD comprises a group of more than 20 distinct syndromes that collectively account for more than 10% to 15% of CJD cases. These inherited CJD syndromes occur worldwide but are more common in Chile and among Libyan Jews, in whom the incidence may be as high as 40 per million per year. Clinical characteristics are similar to sporadic CJD.
Variant CJD is the human counterpart of bovine spongiform encephalopathy (BSE). BSE was first recognized among British cattle in 1987.20 The BSE prion was thought to either have crossed the species barrier from sheep or to be a spontaneous occurrence. The BSE prion was subsequently amplified through the practice of feeding ruminant-derived meat and bone meal back to cows.
As many as 50,000 BSE-infected cattle may have entered the human food supply before 1986, with mathematical models suggesting as many as 700,000 BSE-infected cattle in the human food supply by the peak of the BSE epidemic in the early 1990s.21 Since 1986, BSE cases have been identified in 20 European countries, Japan, Israel, and Canada.22
One cow with BSE was identified in Washington state in December 2003. The cow was the first animal identified in the United States.22 In 1992, restrictions intended to eliminate feeding of ruminant tissues to other ruminants were put in place and the number of cases of BSE worldwide has declined each year since.23 Due to its similarity to scrapie in sheep, a disease that does not cross the species barrier to humans, BSE was initially not thought to be a threat to humans.
In 1996, a human CJD-like case occurred and was subsequently linked to the same prion causing BSE.24-28 This human disease entity was dubbed vCJD due to its similarity to sporadic CJD. Distinct clinical differences do exist.
Variant CJD tends to occur in younger patients than CJD, with the mean age of death 29 years. The clinical course also tends to run longer at a median of 12 months compared to 4 months for CJD.29 Initial manifestations include behavioral changes such as anxiety and depression, complaints of dysesthesias or pain in the extremities, and the absence of periodic electroencephalogram changes.2 These symptoms are followed by progressive cerebellar degeneration. By the time of death, patients are immobile and mute.23 Giant amyloid plaques are found on brain biopsy.
Forty cases of vCJD had been reported by the end of 199830 and 70 cases by June 2000.5 As of December 2003, 153 probable and confirmed vCJD cases had been identified, including those of three persons residing in Ireland, Canada, and the United States who are believed to have been exposed to BSE in the United Kingdom.31
Based on the latency period of up to 30 or 40 years, the peak incidence of vCJD from the British BSE epidemic may occur around 2015. Mathematical models predict new cases numbering anywhere from hundreds to 200,000 cases per year, totaling numbers in the millions.32-36 These estimates are hampered, however, by inadequate information regarding the numbers of persons exposed to contaminated beef, ease of passage across the species barrier, genetic factors mediating susceptibility to prion disease, and effectiveness of prevention of new cases of BSE.
Kuru was recognized as a transmissible spongiform encephalopathy in 1957 when it was described among the Fore tribe of New Guinea.37 This condition was propagated via ritual cannabilism among the tribe. While cannibalism was stopped in 1960, new cases were described up to 40 years later. No evidence, however, indicates the spread of kuru by any mechanism except ritual cannibalism.2 Patients with Kuru present with cerebellar ataxia and late dementia with a mean latency period of 12 years but a range of 4 to 40 years.5
Gerstmann-Straussler-Scheinker Syndrome is a rare form of inherited prion disease. Inheritance is autosomal dominant and occurs at a rate of one per 100 million persons per year worldwide.9,38,39 Clinical characteristics are similar to CJD with vacuolar changes more prominent in the cerebral cortex than the cerebellum.2 Amyloid plaques are present on autopsy.2 The disease tends to occur at a younger age than CJD.1
The fatal familial insomnia syndrome is a transmissible spongiform encephalopathy. This disorder shows an autosomal-dominant inheritance pattern and has been described in several Italian kindred populations. A sporadic form also exists.23 Fatal familial insomnia was first described in 1986 and presents in patients between 40 and 60 years of age. Symptoms include untreatable insomnia, hyperthermia, tachycardia, hypertension, and motor disturbances.2
Prion disease may be acquired sporadically or transmitted via inheritance, oral ingestion of prion materials, or iatrogenic transmission. Fewer than 5% of CJD cases are iatrogenic.23 Oral ingestion of skeletal muscle is thought to be the least effective route of administration for prion disease but still accounts for the majority of cases of vCJD to date.1
Ophthalmologists and other surgeons may participate in the amplification of PrPsc in the human population through the use of tissue xenografts, allografts, bovine- or human- derived injectable products, or the use of prion-contaminated instruments.
Numerous cases of iatrogenic prion disease transmission have been documented.40,41 Eighty deaths have occurred after preserved dural allografts, two cases after bovine pericardial xenografts for tympanic membrane reconstruction, three corneal grafts, two stereotactic electroencephalogram electrode transmissions, four neurosurgical instrument transmissions, and four cases after human cadaveric gonadotropin injections.
Of the three supposed cases of CJD transmission via corneal transplant, only one was confirmed via brain biopsy of the donor and recipient, while the other two were suspected based on either clinical characteristics or disease in either donor or recipient.42
Isolated cases of CJD have been suspected after bone, kidney, and liver transplants. From 1966 until 1977, human growth hormone was harvested from pooled cadaver pituitaries and injected in approximately 200,000 children worldwide.40,43-45 Before 1997, 94 of those children had died from prion disease with an eventual expected incidence of 1 out of every 300 injected.
Because disease-causing prions are immunologically indistinguishable from normal ones, no useful tests to screen potential donors for prion infection exist. Various screening tests have been proposed, however. Abnormal prions may be detectable on tonsillar biopsy.46 Elevated protein 14-3-3 and increased S-100 protein levels have been found in patients with CJD, but these tests are nonspecific.47,48 Currently, the most reliable means of confirming prion disease is via brain biopsy. Suspicion of possible donor infection is mainly by history, with difficulties being imposed by the long latency periods.
In addition to being difficult to detect, prions are resistant to standard forms of deactivation. Detergents, dry heat, freezing, formaldehyde, peroxide, ethanol, gas sterilization, ethylene oxide, ultraviolet, or ionizing radiation do not alter prion infectivity. Reduction in tissue infectivity has been demonstrated with 1N to 2N sodium hydroxide for 1 to 2 hours, 2.5% bleach for 1 hour, and steam autoclaving at 125º C for 1 hour. Steam autoclaving at 72º C for 4 hours is ineffective.40,49,50
Three ophthalmology-specific disease transmission issues are worth considering. These are the use of bovine tissues in ocular surgery, botulinum toxin injections, and corneal transplants. Many bovine-derived materials are available for use in reconstructive, orbital, and cranial surgeries. These include bovine bone anophthalmic implants, bovine pericardium, bovine amniotic membrane, and bovine scleral wraps. Because of the unknown penetrance of disease-causing prions in the world cattle supply, the difficulty in testing bovine materials for abnormal prions, and the relative difficulty in deactivating prions, the risk of xenografting bovine tissues to humans is unknown.
Current World Health Organization recommendations are to avoid the use of bovine materials in the manufacture of medicinal products and the use of materials from other animal species in which TSEs naturally occur.40 Because many other autogenous or synthetic materials are available for use in orbital surgery, bovine material should be avoided.1
Botulinum toxin is currently used in ophthalmology in the treatment of benign essential blepharospasm and hemifacial spasm, as well as for cosmetic purposes. Pooled human albumin is used in the manufacturing process, and each vial of toxin carries with it the exposure to donor albumin from 2,000 to 10,000 donors.
Although no cases of prion transmission have been documented from the use of botulinum toxin injections, the long latency period for prion disease, the relatively recent history of botulinum injections, the number of persons injected worldwide, and the potential that the reservoir of prion disease in the human population has recently increased make botulinum injections a cause for concern.1
Pooled human albumin used in the formulation may not be as effective in transmitting prion disease as was pooled cadaveric human growth hormone, because neural tissue derivatives are significantly more infective than peripheral blood products. Also, manufacturing processes of albumin may diminish the risk, and no increased incidence of prion disease has been noted among patients who have received frequent blood transfusions — notably hemophiliacs.
However, abnormal prions have been demonstrated in the buffy coat, plasma, and cryoprecipitate fractions of blood and on lymphocytes of patients with CJD.32,40,51,52 The risk of prion disease transmission with botulinum injections remains unknown and these injections should be reserved for incapacitating dystonic disease unless full disclosure of prion risk is made available to the patient.1
Corneal transplants represent an area for concern for the ophthalmologist with respect to prion disease. The risk of transferring prion disease through the use of individual allografts such as cornea, collagen, sclera, amniotic membrane, or pericardium is proportional to the risk that the donor may harbor abnormal prions, although the risk is probably greatest when neural tissues or pooled human tissues are used and when the tissue is transplanted near the recipient’s central nervous system.
The current risk assessment must factor in the possibility that disease-causing prion penetrance in the human population has increased recently and is not yet detectable due to the long latency period. Each of these allograft materials except cornea has an autogenous or synthetic substitute of equal or superior effectiveness and can be avoided.1
Corneal allografts for the restoration of vision may be an exception to this allograft risk-to-benefit ratio. Kennedy and colleagues53 and others54 have estimated the current risk of a corneal donor in the United States having CJD at 1.3 per 45,000. This is based on historic levels of CJD and the observation that no evidence to support a significant increase in prion disease prevalence in the United States. exists at this time.
In 1997, an incident occurred in which patients received ocular tissue from a donor who was eventually diagnosed as having CJD. This involved the donation of two corneas and both sclera to three patients. When it became known that the donor had classic CJD, two of the patients elected to have their transplants removed while one refused removal. All three of the patients were well at 4 years after the incident.42
Despite the possibility that BSE may eventually lead to outbreaks of vCJD in the United States, corneal grafts have no substitutes, and the benefit is to restore sight. Therefore, the risk-to-benefit ratio favors the continuation of corneal transplantation at this time, while continuing to monitor the possibility of increasing prion risk in the future.1
As mentioned above, no treatment is known for the spongiform encephalopathies. Amphotericin B may prolong the onset of the disease in hamsters if given immediately after prion inoculation.55 Other medications that have proved relatively effective when administered at the time of experimental infection include Congo red, dextran sulfate, and polyoxometalates from the tungstoantimonate family.
Unfortunately, none of these drugs are effective once the clinical signs of disease appear.13 Treatment with anti-prion protein antibodies has been reported as curing infected cells in vitro. In addition, transgenic animals for anti-prion protein antibodies have been demonstrated to be less susceptible to peripheral infection than wild type controls.
Such findings may support the possibility of a vaccine against TSEs in the future.13 Remission of human CJD has never been confirmed.2 At this time, all patients who contract spongiform encephalopathies die within 4 to 24 months.1
Time will reveal the magnitude of prion disease penetration into the human population. The large number of confirmed cases of BSE in the world cattle population in the past 20 years raises the specter that there is likelihood that prion disease has been amplified in the human population as well. Ophthalmic surgeons must be aware of these issues and factor them into treatment decisions such that the best and safest care is provided to patients.