NPEL: Unconventional Transmissible Agent (Prion) Diseases

NEUROPATHOLOGY- UNCONVENTIONAL TRANSMISSIBLE AGENT (PRION) DISEASE

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I. INTRODUCTION AND SUMMARY
II. HISTORICAL PERSPECTIVE
III. KURU AND SCRAPIE
IV. EPIDEMIOLOGY
V. CLINICAL FEATURES
VI. NEUROPATHOLOGY
VII. ETIOLOGY, PATHOGENESIS AND TREATMENT

I. INTRODUCTION AND SUMMARY

Creutzfeldt-Jakob Disease (CJD) is a rapidly progressive, transmissible disease of the central nervous system (CNS) caused by an unusual agent that has been designated as the "prion" (proteinaceous infectious particle) by Prusiner.
CJD presents in middle life, however, cases as young as 27 years and as old as 78 years have been reported. The onset of the disorder is often subtle with vague symptoms of insomnia, confusion, peculiar sensations, and visual complaints. Within weeks to months of the onset, a profound, progressive dementia develops, often accompanied by evidence of cerebellar, basal ganglia, focal motor, or lower motor neuron involvement. Myoclonus provoked by startle is a prominent feature of the disease. Death generally occurs within one year.
Ten percent of cases of CJD occur in a pattern consistent with autosomal dominant inheritance. There are no laboratory or radiologic findings specific for CJD, and, in fact, the evaluation of a patient suspected of having the disease usually produces normal findings.
The diagnosis is one of exclusion made on the basis of a careful history and physical examination. Confirmation of the diagnosis is achieved by postmortem examination of the brain. There is no known treatment for CJD excepting supportive measures.

II. HISTORICAL PERSPECTIVE

CJD was first described by Creutzfeldt (one case) and Jakob (five cases) in the early 1920's. Although only two of their original six cases are classified as examples of CJD using current diagnostic criteria, the disease continues to bear the eponym that recognizes Creutzfeldt and Jakob's original contribution. For much of the 20th century, CJD remained a medical curiosity and was felt to represent a rare, degenerative disease of the CNS.
In 1968, Gibbs, Gajdusek and coworkers reported the successful transmission of CJD to the chimpanzee by intracerebral inoculation of brain tissue obtained from patients with the disorder. This landmark observation established CJD as one of the eight transmissible encephalopathies of animals and humans.
Subsequent studies have demonstrated the ability to transmit the disease using cerebral spinal fluid (CSF), kidney, liver, lung and lymph nodes from affected individuals. Transmission has not been accomplished following inoculation of ovary, testes, semen, hair, skin, saliva, feces, urine, sweat, tears, milk, or placenta from affected cases. Transmission to susceptible primates has been reported through inoculation via the intravenous, intramuscular, subcutaneous, intradermal, corneal, and oral routes, although only with extremely high doses of affected tissue via the latter route.

III. KURU AND SCRAPIE

An understanding of the characterization of CJD as an unconventional transmissible agent disease requires a brief consideration of two related conditions, the human condition Kuru and the animal condition Scrapie.

Kuru, first described by Gajdusek and Zigas in 1957 following their examination of 114 cases of the disorder, causes a progressive cerebellar ataxia in the people of the Fore linguistic group living in the Eastern Highlands of Papua New Guinea. Very few new cases of Kuru have been reported in recent years due to the elimination of its vector, cannibalism.
Scrapie, a cerebellar disease of sheep and goats, was known to be a transmissible disorder based on studies that took place in the 1930's and 1940's. In 1959, Thomas Hadlow, a veterinarian who was aware of the transmissible nature of scrapie, recognized the clinical and pathologic similarities between it and Kuru. This recognition, combined with the observation by pathologist Igor Klatzo that the neuropathology of scrapie, Kuru and CJD are all strikingly similar, led to the transmission experiments that proved the true nature of CJD in 1968.
Other disorders now considered to be unconventional transmissible agent diseases include bovine spongiform encephalopathy ("mad cow disease"), chronic wasting disease in mule deer and elk, transmissible mink encephalopathy, the recently described fatal familial insomnia, and the Gerstmann-Sträussler syndrome. The latter two entities, like Kuru and CJD, use the human as their naturally occurring host.
The eight diseases share common features.
- The signs and symptoms of the disease are restricted to the central nervous system.
- There is a long incubation period (months to years) prior to the onset of symptoms.
- Following its onset, the disorder is progressive leading to death.
- The pathology is characterized by spongiform change, neuronal loss, astrocytosis and gliosis in selected brain regions.
- The transmissible agent (prion) has unusual properties that distinguishes it from viruses and viroids and other infectious agents.
Although other organ systems, particularly the reticuloendothelial system, may harbor the agent, the signs and symptoms of disease are restricted to the CNS. Exposure to the transmissible agent may take place months to years prior to the development of symptoms, but once these are present there is a rapid progression to death, usually in 6 months to 1 year. The neuropathology is strikingly uniform in both humans and animals, although a distinctive topography of the lesion is found in the brain in each disorder. All eight entities are thought to be due to an unconventional transmissible agent, the prion, that has been best characterized in experimental models of scrapie and will be further described below.

IV. EPIDEMIOLOGY

CJD is a form of rapidly progressive dementia that represents the only unconventional transmissible agent disease of humans that is seen worldwide. The disease occurs with an annual incidence of approximately 0.5 to one case per one million people per year. Subtypes of CJD that have been described include an amyotrophic form, a so-called Heidenhain variant characterized by prominent, early visual symptoms, and a variant with extensive white matter involvement. Until the exact nature of the causative agent is known, there is no rationale for considering these subtypes to represent separate diseases.
CJD usually presents in middle life in the sixth decade, however cases occurring in the third and eight decades have been reported. In one large series, the average age of onset was 60 years and the mean duration of illness 7.6 months. Men and women are affected equally, although large series from several countries suggest a slight female predominance. Approximately 10% of all cases of CJD are familial, with a pattern consistent with autosomal dominance inheritance, and another 5-10% have a clinical course that continues for 2 years or more. In these latter cases, there is a tendency for them to be familial and to have a younger age of onset, although the pathology does not differ from more typical CJD. Race does not appear to predispose to the development of CJD.

V. CLINICAL FEATURES

The following clinical case from my own file illustrates the salient features of CJD. The patient was a 63 year old man who first noticed difficulty completing the New York Sunday Times crossword puzzle. He use to finish a puzzle in a few hours, and now the task took him at least three days to accomplish. Within 2-4 weeks, he no longer was able to balance his checkbook. He also developed increasing difficulty using his right hand followed by unsteady walking. On admission to the hospital for neurologic evaluation, the patient was disoriented in three spheres and showed prominent memory loss. Snout, grasp, and suck reflexes were elicited and occasional myoclonic jerks were noted. CSF was clear and colorless, under normal pressure, and without cells or other abnormalities. Cerebral angiogram, radionucleotide brain scan, and computerized tomographic (CT) scan were all normal. The EEG had delta and theta background activity with rhythmic bursts of spike wave complexes. Over the next three months the patient deteriorated markedly, and he was no longer able to feed himself or ambulate. He became incontinent of urine and feces and displayed repeated jerking movements of his arms and legs. The patient died of pneumonia five months after the initial manifestations of his illness. An autopsy restricted to examination of the brain confirmed the diagnosis of CJD.
CJD is characterized clinically by prominent, profound dementia, myoclonus and a characteristic electroencephalographic (EEG) abnormality. The onset of CJD is often subtle with vague presenting symptoms of insomnia, confusion, peculiar sensations, and visual complaints. Patients frequently believe that they are overtired due to stress, physical exertion or because of a viral illness, or think they are mildly depressed. Following this, there is a progressive dementia that is unusual and distinctive due to its extraordinary rapidity. Patients often evolve from a relatively normal state to one of being comatose in as little as 4 months. As with other forms of dementia, previously acquired cognitive abilities and memory are lost, and as the disease progresses there is also a loss of language function. Patients are usually mute in the terminal stages of CJD. Early pathologic involvement of the occipital cortex may lead to blindness (Heidenhain variant), and loss of anterior horn cells may cause significant weakness (amyotrophic variant). In both of these, however, dementia becomes the predominant clinical feature.
The physical sign of greatest constancy in CJD is that of myoclonus, since it is present in more than 80% of patients. The myoclonic jerking is not specific for CJD, and has been described in other neurologic conditions including AD. However, this feature in combination with a rapidly progressive dementia should cause one to strongly suspect the diagnosis of CJD. The myoclonus is more prominent as the disease progresses but becomes less prominent and disappears terminally. It has been described frequently as a response to startle that may affect the entire body, or the jerking may be restricted to a single limb. Other physical findings that are seen less commonly include pyramidal and extrapyramidal signs, cerebellar signs, a lower motor neuron syndrome, and seizures.
Laboratory and radiologic studies, with the exception of the EEG, are normal or nonspecific in CJD. Complete blood count and metabolic studies are unremarkable. Examination of CSF infrequently discloses a mild elevation of protein. In patients in whom cerebral angiography has been performed, no abnormalities have been reported. CT scanning may show cortical atrophy or enlargement of the ventricles, but this is a nonspecific finding that in most cases is minimal in degree. Magnetic resonance imaging (MRI) and positron emission tomography are of no proven usefulness in the diagnosis of CJD. The EEG is usually abnormal revealing either generalized slowing or more characteristically pseudoperiodic sharp wave activity (Figure III-11-1).

VI. NEUROPATHOLOGY

The neuropathology of CJD is extraordinary and highly typical of the disease.
- Grossly, the brain appears normal or shows generalized, cortical atrophy with ventricular enlargement. The degree of atrophy is closely linked with the length of the clinical course. There is nothing characteristic about the gross appearance that distinguishes CJD from other causes of brain atrophy, including AD and normal aging. The cerebellum may or may not be involved in the atrophic process.
- Microscopically, the prominent features include, astrogliosis, varying degrees of neuronal loss, and spongiform change. All regions of the cortical ribbon are involved, but the degree of involvement varies from case to case. In fact, the absence of spongiform change is not incompatible with the diagnosis of CJD since brain tissue from such atypical cases has been used to transmit the disease to experimental animals.
- In typical cases of CJD, the lesions involve the neocortex, striatum, thalamus, grey matter of the brainstem, and cerebellum. Interestingly, the hippocampus is usually relatively spared.
- The spongiform change is cell associated, distinguishing it from the microcystic change or spongy state caused by hypoxic/ischemic damage and edema, or from perineuronal vacuolation caused by tissue processing. Much of the appearance of spongiform change is caused by neuronal intracytoplasmic vacuoles that often leave neurons with only a nucleus and fine wisps of cytoplasm.
- The astrogliosis is usually striking and is particularly prominent in areas of the brain where neuronal loss is severe. Electron microscopy reveals intracytoplasmic membrane-bounded vacuoles that contain swollen cell processes.

VII. ETIOLOGY, PATHOGENESIS AND TREATMENT

The etiology and pathogenesis of CJD are not completely understood, and as such there is no effective treatment. The agent that causes the disease, an entity that is transmissible, elicits neither a cellular nor humoral immunologic response in patients with the disorder. In fact, an inflammatory response is entirely absent in the brain, and patients remain afebrile throughout the course of their illness. After exposure to the agent, an incubation period lasting months to years may ensue before the onset of clinical illness. The agent is unusual in that it is resistant to inactivation by formalin, heat, and ionizing and ultraviolet irradiation. It is also resistant to procedures that modify nucleic acids, and therefore has properties that are different from those of viruses and viroids. Following a series of experiments spanning a number of years, Prusiner and his colleagues in 1982 designated the prion as the likely transmissible agent causing CJD and scrapie. Over the past decade, a partial understanding of the molecular nature of the prion and its relationship to the pathogenesis of CJD have been forthcoming.
The prion appears to be composed primarily of a protein, referred to as prion protein (PrP) coded for by a gene that resides on chromosome 20. The normal isoform of the protein is designated PrPC, but its function is unknown. The isoform that is transmissible is designated PrPSc. The two isoforms are functionally different in that PrPC is protease- sensitive, whereas PrPSc is protease-resistant. No other component of the prion, such as a nucleic acid, has been found to date. Although the pathogenesis of CJD is not yet completely understood, evidence is accumulating to suggest that PrPSc is a post-translational conformational modification of the normal host protein PrPC, and in this modified form is capable of interacting with susceptible hosts (such as those harboring point or missence mutations of the prion protein gene) to cause disease. Current evidence would suggest, therefore, that CJD is both transmissible and genetic, if not infectious.
CJD is not contagious but is highly transmissible, and a number of instances of iatrogenic contamination have been described. These included a patient who received a corneal implant from a donor with CJD, two patients who were exposed to contaminated EEG depth electrodes sterilized by conventional methods, several patients who received growth hormone from contaminated autopsy pituitary glands, and a patient who received a contaminated cadaveric dura mater graft. Because of the known transmissible nature of CJD, strict criteria for precautions in the handling of tissues and other contaminated materials from patients with CJD have been developed. Methods thought to be fully effective for inactivation of the unconventional transmissible agent include steam autoclaving for 1 hour at 132° C and immersion in 1N sodium hydroxide for 1 hour at room temperature.

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