"Impossible!" critics screamed in reaction to Stanley B. Prusiner, MD's 1982 announcement that "infectious proteins," lacking any nucleic acid material, caused several degenerative encephalopathies. Critics retreated, however, as mounting evidence supported Dr. Prusiner's theory, and in 1997 he received the Nobel Prize in medicine for his research on prions.1
What Is a Prion?
Prusiner coined the term prion, meaning proteinaceous infectious particles.1 Prionsanimal tissue proteinsoccur in higher concentrations in the brain, spinal cord, and eyes. Their function is poorly understood, but findings suggest that these proteins are vital to brain synapse functioning.1
By way of an unknown mechanism, a normal prion protein can become abnormally shaped and pathologically variant. As it comes in contact with other prion proteins, it serves as a template, causing them to mirror the abnormal shape. Unable to be metabolized by protease enzymes, protease-resistant infectious prions replicate exponentially, accumulate in tissue cells, disrupt cellular function, and cause irreversible damage.2 Prions have stealth characteristics and can survive autoclaving and most chemical treatments.2,3
Prion diseases, labeled transmissible spongiform encephalopathies (TSEs), exist in both humans and animals and predominantly affect the central nervous system's gray matter, leading to neural loss, gliosis, and accumulation of amyloid aggregates.4,5 Viewed microscopically, affected brain tissue contains tiny sponge-like holes, the remnants of cellular death.2,6 Animal prion diseases include scrapie in sheep, bovine spongiform encephalopathy (BSE, or "mad cow disease" ) in cows, feline spongiform encephalopathy in cats, and chronic wasting disease in mules, deer, and elk.1
Five human prion diseases have been identified. Creutzfeldt- Jakob disease (CJD) is characterized by progressive deteriorating neurological functioning and myoclonic jerks. Patients generally present with progressive cognitive impairment or cerebellar dysfunction. Disease progression includes behavioral abnormalities, cortical visual abnormalities, higher cortical dysfunction, and pyramidal and extrapyramidal symptoms. All patients eventually develop myoclonic jerks involving one limb or the entire body. The mortality rate is 85% within 1 year, often from pneumonia. CJD affects 1 in 1,000,000 adults, with an average onset age of 68 years.3,4,6
Variant Creutzfeldt-Jakob disease (vCJD) was first reported in 1995. Its etiology was quickly traced to dietary consumption of cow meat taken from BSEinfected animals. Transmission to humans was previously thought impossible because of species barriers between humans and animals. It is a variant of classic CJD because of the following distinguishing characteristics:
Initial psychiatric symptoms may also include peculiar sensory experiences, such as sticky skin. Cognitive decline and ataxia accompany vCJD disease progression. Incubation time prior to symptom onset exceeds 4 years,3 with a median age at death of 28 years.7
Gerstmann-Straussler-Scheinker disease presents with a slow, progressive limb and truncal ataxia with dementia. Similar to Alzheimer's disease, affected brain tissue is replete with neurofibrillary tangles and amyloid plaque. Onset usually begins in people in their 40s with clumsiness and difficulty in walking. Death occurs within 3 to 8 years of symptom onset.4,6
Fatal familial insomnia affects the thalamus, resulting in intractable insomnia, a condition that always results from genetic mutations. Onset age is extremely variable, ranging from 18 to 60 years. Death occurs after 6 months to 3 years of onset.4,6 Unlike other prion diseases, spongiform encephalopathies may be minor or even absent.4
Kuru, historically common in New Guinea until the 1960s, presents with a rapid mental functioning decline, loss of muscle coordination, limb stiffness, and muscle twitching. Death generally occurs within 3 months to 2 years. Prions were acquired from cannibalistic rituals of the dead that included eating brain tissue, which was usually given to women and children.6 New Guinea banned cannibalism in 1957, and incidences of kuru decreased from 1% to only 5 cases annually.3
CJD is the most common prion disease, accounting for ~85% of reported cases, and appears in 3 forms: sporadic, familial, and iatrogenic. Approximately 85% of CJD is sporadic, 15% is familial, and less than 1% is iatrogenic.9 Two populations are disproportionately affected: Libyan-born Israelis and those living in Slovakia.4
Iatrogenic transmission has included transplantation of infected corneas, injection of growth hormone derived from human pituitaries, contaminated surgical instruments or electroencephalogram depth electrodes, human gonadotropin, and human dura mater grafts.3,10
Although vCJD averages 10 to 15 cases annually since its discovery in 1994, the magnitude and geographic distribution remains unknown.2 Whereas 159 cases have been reported in Great Britain, only 2 have been recorded in the United States.4 Previously assumed to be nontransmissible via blood transmission, several vCJD cases have been identified in patients who received transfusions from donors with preclinical vCJD.7 Epidemiologists fear that a large number of people may be incubating the disease, increasing iatrogenic transmissions.
Prion diseases have long incubation periods, ranging from 1.5 to 40 years, and are always fatal.5 The type of cells involved in prion replication remains unknown, although most researchers believe immunocompetent cells are involved.7 vCJD occurs when prions from contaminated meat crosses the gut's epithelium. Prions are known to first accumulate in the spleen and lymph nodes before affecting the brain. Interestingly, prions in nerve trunks appear to be in transit and not actively replicating.7
Diagnosis and Treatment
Probable diagnosis is based on clinical manifestations; definitive diagnosis is only confirmed with postmortem tissue analysis.5 Clinical manifestations resemble numerous other conditions, including Alzheimer's disease, Parkinson's disease, hydrocephalus, herpes simplex encephalitis, cortical basal ganglionic degeneration, chronic meningitis, diffuse Lewy body dementia, schizophrenia, multiple sclerosis, myoclonic epilepsy, multiinfarct dementia, and lithium poisoning.1,4 It is not unusual for multiple clinicians to misdiagnose patients before a prion disease is identified as the probable cause for the patient's symptoms. Given prion's chameleon-like symptoms, some believe the disease's reported prevalence is erroneously low.
Treatments directly targeting prions or slowing disease progression are nonexistent.6 Once clinical symptoms appear, considerable brain damage has already occurred; consequently, practitioners focus on symptom management. Available agents include psychoactive agents for hallucinations, antiepileptic drugs for seizures, and anti-Parkinson agents for extrapyramidal symptoms.4 Some antianxiety agents (eg, clonazepam) help reduce muscle jerking.6
Ideally, treatment should inhibit the conformational change of prions. Researchers would like to target those who are asymptomatic, but the rarity of the disease and its lack of diagnostic tests make this impossible. Mouse models confirm that prion accumulation first occurs in lymphoid tissue before migrating to the brain, and research is underway to identify agents that block lymphoid prion accumulation.5 Several compounds, such as the polyanions, polyene antibacterial agents, tetrapyrroles, and branched polyamines, interfere with prion propagation in animal models, but their toxicity and inability to pass the blood-brain barrier (BBB) make them unlikely candidates.7 Researchers have looked to agents known to be capable of crossing the BBB, and tricyclic derivatives of acridine and the phenothiazines have been demonstrated to inhibit prion activity, but unfortunately they do not affect protease resistance in preexisting prions.7
Tetracyclines have antiprion activity and are currently being tested with animal models.7 Copper is implicated in prion propagation, and chelation therapy is also being investigated. Preliminary findings suggest that the chelator D-penicillamine may delay prion disease onset.4
Prion diseases' long incubation periods, along with their chameleon-like symptoms, remain a major concern. vCJD is especially troubling, despite increased vigilance of the nation's food supply. Many experts believe that current research efforts should emphasize prevention; the development of a vaccine is not only desirable, but necessary.
Dr. Zanni is a psychologist and health-systems consultant based in Alexandria,Va.
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