Psychiatry - O. K. Napryeyenko 2001

Clinical Psychiatry
Transmissible (prion) spongiform encephalopathies

Transmissible diseases (from Latin transmissio — transmission, passage) are defined as those transmitted from a sick person or animal (or a carrier of the infectious agent) to a healthy one. According to modern understanding, prion diseases are simultaneously both infectious and hereditary.

Etiology

In 1982, American biologist Stanley Prusiner discovered a new type of transmissible agents — Prions, which structurally rank among the simplest known infectious agents to date. These are altered host protein molecules that contain no Nucleic Acids. Pathogenic prions are Proteins capable of transmission. They are mutants of the cellular isoform of the normal prion protein. Eighteen Mutations of the human PrP Gene associated with various prion diseases have been identified. Prions withstand boiling for 30–60 minutes and are three times more resistant than known Viruses to freezing, chemical agents (such as alcohols, formaldehyde, and acids), ultraviolet irradiation, and gamma irradiation; furthermore, they are not hydrolyzed by Enzymes. In a dry state, they persist for up to two years. In other words, prions are the absolute last to denature and perish among all living matter.

Pathogenesis of Prion Encephalopathies

Proposed by S. Prusiner in 1991, METABOLISM/2.html">THE CONCEPT OF the pathogenesis of transmissible spongiform encephalopathies posits that humans can be infected with prions via two pathways:

1) Mendelian inheritance (autosomal dominant pattern), meaning through prior gene autoreplication of the infectious agent;

2) Transmission of the infectious agent via alimentary or iatrogenic routes.

The routes of prion infection play a crucial role in disease progression. In descending order of significance, they are: intracerebral, intravenous, intraperitoneal, subcutaneous, and oral.

Peripheral Blood shows no specific biological changes whatsoever (neither during the incubation or preclinical periods, nor even at the height of the disease). This significantly complicates Diagnostics.

It is hypothesized that prions are involved in intercellular recognition and cellular activation, and that their physiological function is to suppress Aging processes. Consequently, prion diseases share morphological and clinical characteristics with presenile and senile neuropsychiatric disorders.

Pathomorphology

The neuropathology of human prion diseases exhibits four classic microscopic features: spongiform changes, neuronal loss, astrogliosis, and amyloid plaque formation.

All cases of prion encephalopathy reveal a minor reduction in Brain mass, occasionally accompanied by moderate Atrophy of the convolutions, primarily in protracted courses of the disease. A large number of oval vacuoles (spongiosis) ranging from 1 to 50 μm in diameter are observed in the neuropil of the brain's Gray matter.

One of the hallmark morphological features of spongiform encephalopathy is the presence of prion protein (PrP) plaques, which appear as rounded eosinophilic structures. Such plaques are characteristic of Kuru and are therefore referred to as Kuru plaques. They are observed less frequently in sporadic and familial Creutzfeldt-Jakob disease, and particularly often (70%) in its variant form. In rare cases, plaques are detected in fatal familial insomnia.

Classification

Two groups of human diseases caused by prions are recognized: 1) transmissible spongiform encephalopathies; 2) spongiform myositis with prion-associated inclusions. The first group includes: Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, fatal familial insomnia, Kuru, and chronic progressive childhood encephalopathy, also known as Alpers' disease.    

Clinical presentation

Creutzfeldt-Jakob disease is a subacute encephalopathy accompanied by slowly progressive neuronal degeneration. It typically manifests in adults with the rapid onset of dementia accompanied by pyramidal and extrapyramidal symptoms. The disease is sporadic, with an incidence of 1:100,000 population. Familial and iatrogenic cases are less common.

Today, it is believed that transmission occurs through the consumption of meat from infected cattle. Cases of human-to-human transmission have also been described (during the administration of Growth Hormone extracted from human pituitaries, and less frequently, via the implantation of intracranial electrodes and corneal transplantation).

Three classic forms of the disease are distinguished: sporadic (approximately 85–90% of cases); familial (about 10–15%); and iatrogenic. Additionally, some researchers distinguish a so-called atypical form.

The sporadic form of the disease is identified across all continents. Its average prevalence ranges from 0.5 to 1.0 per 1,000,000 population. It affects individuals across various age groups (from 17 to 82 years). The duration of the illness varies from several weeks to 8 years, averaging 6 months.

Iatrogenic forms result from The Use of improperly sterilized instruments or electrodes during neurosurgical Procedures, corneal transplantation, or Treatment with pituitary derivatives (growth hormone, gonadotropins). The incubation period depends on the pathways of pathogen entry, its phenotype, infectious dose, and the recipient's genotype. When the agent directly enters the Central Nervous system, the clinical onset of the disease occurs within 10–30 months, manifesting as dementia. In cases of extracerebral infection, the incubation period is 5 years or more, occasionally reaching 35 years. Such patients exclusively exhibit cerebellar ataxia.

Atypical forms differ clinically from the sporadic form, bearing similarities to Kuru and iatrogenic forms of Creutzfeldt-Jakob disease. They predominantly affect younger individuals and are caused by a risk factor described in 1996, which is potentially bovine prion disease. These patients clearly exhibit the following symptoms: ataxia predominating over dementia; a high Abundance of PrP prion amyloid plaques in brain biopsy specimens; such plaques are monocentric (as in Kuru) and surrounded by a spongiform zone. The disease lasts up to one year. Mortality is 100%.

Gerstmann-Sträussler-Scheinker syndrome. This is a rare familial disorder inherited in an autosomal dominant manner. It was first described in 1936. Currently, a sporadic form of the syndrome is also recognized. It affects individuals aged 40–50 years.

Morphologically, it resembles transmissible subacute spongiform encephalopathy. However, it differs by containing a higher concentration of concentric amyloid plaques in the molecular layer of the Cerebellum. It shares similarities with Alzheimer's disease (featuring neurofibrillary structures in the neuronal Cytoplasm), but unlike the latter, its primary amyloid core protein component consists of PrP prions (whereas in Alzheimer's disease, it is the Aβ peptide). It occurs very rarely.

The MAIN CLINICAL MANIFESTATIONS include progressive dementia, cerebellar ataxia, and speech disorders (phonation disturbances), lasting for 6–10 years (an average of 4 years), followed by death.

Fatal familial insomnia is an inherited disease transmitted in an autosomal dominant manner. Both men and women are affected. Pathomorphological changes include neuronal loss (up to 90%) and astrogliosis, occasionally accompanied by spongiosis and amyloid protein deposits. Additionally, up to 60% of Neurons are lost in the limbic-paralimbic, intralaminar, and reticular nuclei. There are no signs of inflammation. The primary pathogenetic mechanism is considered to be a decrease in the efficiency of impulse transmission through the thalamus during Sleep onset.

The clinical presentation comprises 4 stages:

I — progressive insomnia accompanied by The Development of various phobias, up to panic fears (lasting about 4 months);

II — the appearance of hallucinations, anxiety, psychomotor agitation, and hyperhidrosis (about 5 years);

III — total insomnia, irritability, and loss of impulse control. Patients appear significantly older than their biological age. Lasting about 3 months;

IV — complete insomnia, dementia, and death resulting from cachexia or Pneumonia (up to 6 months).

Kuru was observed exclusively in the mountainous regions of Okapa and Fore in Papua New Guinea. This disease, described by Gajdusek and Zigas in 1957, claimed the lives of over 2,500 (10%) indigenous people. According to one hypothesis, the illness arose spontaneously in a single individual as a sporadic case of Creutzfeldt–Jakob disease, after which it was transmissibly transmitted to other members of the tribe who ritually practiced cannibalism. Following the abandonment of this ritual, the disease disappeared.

Chronic progressive childhood encephalopathy (Alpers' disease) is a rare form of progressive transmissible encephalopathy combined with necrotic Liver damage. It develops between birth and 18 years of age, lasting 8–12 months from onset. It has a hereditary nature (transmitted in an autosomal recessive manner).

Morphological features include spongiosis (similar to Creutzfeldt–Jakob disease); neuronal dystrophy; astrogliosis in the Cerebral Cortex of the occipital region, the striatum, and to a lesser extent in the parietal region; sclerosis of Ammon's horn; dystrophic Changes in the posterior columns of the Spinal Cord; and a reduction in the number of Purkinje Cells in the cerebellum. Characteristic centrilobular necrotic changes are present in the liver.

Clinically, it manifests as severe headaches, multiple stroke-like episodes (with epileptiform seizures), visual impairment, progressive hypotension, chronic hepatitis progressing to liver cirrhosis, and occasionally hemorrhagic pancreatitis. Death most frequently results from Liver failure.

Cases of prenatal onset of Alpers' disease have been described, characterized by intrauterine growth retardation, microcephaly, maxillary malformations (micro- and retrognathia), joint mobility disorders, and fetal akinesia. Even more rarely, the disease manifests after 18 years of age.

Prion-inclusion spongiform myositis. It is most commonly diagnosed at 50–60 years of age and older, and is therefore also described as progressive Muscle wasting in the elderly. Both sporadic and familial forms of the disease are known.

Histologically, it presents as necrotic myopathy characterized by vacuoles containing helical congo-philic fibrils. Immunohistochemically, the amyloid masses of these vacuoles consist of prion proteins, Aβ Peptides, and apolipoprotein E. These same substances are also found within muscle fibers as filamentous deposits.

The clinical picture is characterized by the gradual development of generalized and muscular weakness, frequently accompanied by myalgias that are unresponsive to steroid therapy. Occasionally, the disease follows a fulminant course.

The literature suggests the possible existence of other prion-related diseases affecting Muscle tissue.

Currently, a definitive Diagnosis of neuropsychiatric prion diseases can only be established through histological examination. Differential diagnosis should primarily rule out viral, rickettsial, and bacterial infections.

No specific treatments have been developed yet; management is limited to palliative therapeutic measures.

Prevention is possible by avoiding the transmission of the infectious agent via alimentary and iatrogenic pathways. Genetic Counseling should be sought to identify hereditary factors.

The long-term prognosis is unfavorable.

Expert evaluation. Medico-social, military, and forensic-psychiatric issues are resolved on an individual basis, taking into account the form and stage of the disease progression.

CONTROL QUESTIONS

1. MODERN CONCEPTS OF the etiology, pathogenesis, and pathomorphological features of Various Forms of human transmissible spongiform encephalopathy.

2. Classification of neuropsychiatric disorders associated with the prion agent.

3. Characterize Creutzfeldt–Jakob disease.

4. Characterize Gerstmann–Sträussler–Scheinker syndrome.

5. Describe fatal familial insomnia.

6. Characterize Alpers' disease.

7. Describe the main complications and possible causes of death in prion encephalopathies.