Prion disease are slowly progressive brain damage associated with infectious proteins (prions). Pathognomonic symptoms of these diseases are the development of dementia, behavioral, motor disorders, extrapyramidal disorders, cerebellar manifestations, myoclonia, other neurological and psychopathic signs. Diagnosis of nosologies includes clinical, laboratory, and instrumental criteria. Etiotropic treatment has not been developed at the present stage, pathogenetic and symptomatic therapy is usually used.
ICD 10
A81 Atypical viral infections of the central nervous system
General information
Prion infections are classified as slow infections of humans and animals. For the first time such a pathology was described by German neurologists Jacob and Kreutzfeldt in 1920-1923. Only at the end of the twentieth century, the American molecular biologist Prusiner discovered pathogens – prion proteins. Prion disease are registered in all countries of the world with a frequency of about 1-15 cases per 1 million people per year. All ages are susceptible to the disease, while due to the long incubation period, disorders are usually registered at 3-4 decades of life.
Causes
The cause of diseases is infectious protein compounds. Prions are a new class of pathogens consisting only of modified human protein molecules, never containing nucleic acids. The source is a sick person or an animal. Prion mutations of a normal protein can be inherited. The main ways of infection:
- alimentary (with food);
- parenteral (with infected blood during medical manipulations);
- vertical (from mother to fetus);
- sexual (from a man to a woman).
Risk factors
The high-risk group for morbidity is made up of doctors (surgeons, obstetricians, gynecologists, pathologists), laboratory staff, veterinarians, meat processing industry workers, cooks, injecting drug users. Risk factors:
- eating meat, organs from sick animals;
- invasive manipulations and operations, including organ transplantation;
- transfusion of infected blood;
- the use of drugs containing hemocomponents.
Pathogenesis
The study of the pathogenesis of prion disease continues. It is believed that normally prion protein is contained in the brain, participates in the interneuronal transmission of the pulse. Its essential role in the regulation of age-related changes in neurocytes is assumed. During contact with the pathological form of the prion, a transformation of an ordinary protein into an altered protein occurs. Many oval vacuoles of the gray matter of the brain are revealed.
Vacuoles are found in any layer of the cerebral cortex, both separately and in groups divided into sections. Sometimes vacuoles merge into microcysts (more than 200 microns), which significantly distorts the cytoarchitectonics of gray matter. In addition to the cortical layer, spongy changes in the neuropile and vacuolization of the cytoplasm of neurons are observed along all fields of the ammonic horns, along the dentate fascia, in the subcortical nuclei, thalamus and cerebellar cortex.
Classification
Prion disease are a group of diseases that are heterogeneous in terms of the method of infection and clinical manifestations, so there is no generally accepted classification for them today. It is possible to divide nosologies by sporadic, hereditarily linked and infectious forms, as well as depending on the predominantly affected organ:
- Spongiform transmissible encephalopathies: Creutzfeldt-Jakob disease, Kuru, fatal familial insomnia, Gerstmann-Straussler-Scheinker syndrome, Alpers disease, etc.
- Spongiform myositis with prion-associated inclusions (progressive muscle wasting disease in the elderly, etc.).
Prion disease symptoms
Prion disease are characterized by a long incubation period – decades pass from the moment of infection to the first symptoms. Often, progressive dementia is registered first in these conditions. Patients lose self-criticism, self-service skills, suffer from memory disorders, cognitive functions, become irritable, demanding of others. In the later stages, symptoms of urination disorders, total muscle rigidity are added.
Creutzfeldt-Jakob disease
One of the first manifestations is rapidly progressing dementia, the period of personality breakdown rarely takes more than 2 years. Patients are apathetic, suffer from depression, headache, often – visual, hearing impairments, insomnia. There are unsteadiness of gait, spastic paresis, myoclonia. In a third of cases, epileptic seizures are observed.
Alpers syndrome
It occurs in infancy, usually manifests with generalized convulsive seizures, delays in psychomotor and physical development and progressive dementia. Children with an early form of pathology are born with microcephaly, deformity of the bone and joint system, disorders of intrauterine development, low body weight. Sometimes the disease begins to develop at the age of 16-18.
Fatal familial insomnia
Debuts with panic attacks, phobias, anxiety, increased sweating. Patients have circadian rhythms disrupted, hallucinatory, motor disorders appear. Later, there is a period of complete lack of sleep, sudden weight loss, the appearance and progression of symptoms of dementia. At the terminal stage, patients do not respond to the speech addressed to them, they are not able to get out of bed.
Kuru
At the beginning of the disease, the symptoms of kuru include headache and joint pain. Then they are joined by severe weakness, trembling of the head and limbs, as a result of which patients move only with support or in a wheelchair. There is athetosis, myoclonic seizures. The progression of kuru leads to dementia. In the late stage, patients are bedridden, often lose weight significantly due to the inability to chew and swallow food, do not control urination and defecation.
Progressive muscle wasting disease in the elderly
It is characterized by slowly increasing weakness in the muscles, myalgia, not stopped by steroid agents. The disease begins with episodes of falls, stumbling, inability to fasten clothes, difficulty swallowing food. Then there is atrophy of muscle fibers, immobilization of patients. There is a danger of asphyxia when eating and drinking water due to the weakness of the esophageal muscles.
Gerstmann-Straussler-Scheinker syndrome
In Gerstmann-Straussler-Scheinker syndrome, dementia occurs less frequently and progresses more slowly than in other prion diseases (up to 5-10 years). Characteristic symptoms are cerebellar disorders of walking and voluntary movements, disorders of orientation in space, swallowing and sound reproduction. In the terminal stage of the disease, deep dementia, dysarthria develops.
Complications
One of the frequent complications of prion disease are pneumonia, respiratory failure due to hypotension of intercostal muscles. With improper care for bedridden patients, bedsores, abscesses, sepsis occur. Elderly people can receive various injuries within their own homes and on the street.
Patients’ neglect of hygiene procedures increases the likelihood of purulent skin diseases, ascending infections of the genitourinary tract are not uncommon. Inadequate nutrition (monodieta), refusal to take medications leads to decompensation of chronic pathology, high risk of hypertensive crisis, diabetic coma, acute cardiovascular insufficiency.
Diagnostics
Diagnosis of prion disease is mainly carried out by neurologists. Doctors of other specialties are involved in the presence of indications. It is mandatory to examine all sexual partners of patients, especially if there are unprotected sexual contacts. Basic laboratory-instrumental and clinical studies:
- Physical examination. An objective examination may reveal dementia, signs of ataxia, apraxia, agnosia. A number of patients have hallucinatory disorders, apathy or motor arousal, nystagmus, ptosis and strabismus.
- Identification of infectious agents. An immunoblot using monoclonal antibodies, a cerebrospinal fluid test (RT-QuIC) is used. Amino acid substances 14-3-3, S100ß, neuron-specific enolase, common tau protein are determined in the liquor, but these compounds are more characteristic of Creutzfeldt-Jakob prion disease. Histological examinations are performed posthumously.
- Instrumental methods. For the purpose of differential diagnosis, skull radiography, electroencephalography, electromyography are used, but the pathological changes detected during these procedures are not pathognomonic for prion diseases. On MRI and CT scans of the brain, 80% of patients have nonspecific atrophic symptoms of changes in the cerebral cortex.
Differential diagnosis
Differential diagnosis is carried out with Parkinson’s disease, in which there is damage to the neurons of the brain stem, and Alzheimer’s, accompanied by severe dementia, but almost always without damage to the cerebellum. Neurosyphilis is characterized by manic-depressive episodes with progressive dementia, for herpetic encephalitis – disorders of the cranial nerves, hemi- and paraparesis.
Treatment
Persons with symptoms suspected of prion diseases should be hospitalized. Bed rest or semi-bed rest is assigned. In the case of severe psychopathic disorders, it is necessary to ensure the safety of the patient and staff. There is no diet, except for the exclusion of raw meat from the diet. Many patients with prion infections refuse to eat, so parenteral nutritional support may be prescribed.
Conservative therapy
Protocols for the management of patients with prion diseases have not been developed at present. The search for etiotropic drugs is at the stage of active research and experiments with encouraging results. Medical support mainly consists of symptomatic, pathogenetic therapy; often patients need intensive care, palliative care.
- Pathogenetic therapy. It is based on the use of infusion solutions, antiepileptic drugs. Antioxidants (vitamins A, E, C), rapamycin, and cannabinoids have a possible positive effect.
- Symptomatic therapy. Antidepressants, anticonvulsants, painkillers, sedatives, medications necessary to compensate for other systemic diseases (antihypertensive, etc.) are used.
Experimental therapy
Published in 2019, the results of experiments on the treatment of prion-infected mice showed that there is a therapeutic effect of liposomal interfering RNA-peptide complexes (LSPCs) in the form of a violation of prion replication in the brain in 90% of the subjects and an increase in their survival (22%). Similar results were obtained with intracerebral administration of lentiviruses. Research continues.
A promising direction is considered to be the study of the influence of artificially created non-pathogenic prion-like proteins that can self-propagate, while reducing the replication of infectious units, delaying and suppressing neurodegenerative processes. There is a concept of monoclonal antibodies that recognize prion compounds, inhibit their replication and delay the development of disease in animals.
It is assumed that doxycycline has a positive preventive effect in the preclinical period in patients who carry the genes of fatal familial insomnia. In a number of experiments, animals treated with heterologous prion protein showed a delayed onset of clinical symptoms, a significant increase in the average survival time compared to the control group.
Prognosis and prevention
The prognosis for patients due to the lack of etioropic drugs is extremely unfavorable. Mortality in prion diseases reaches 100%, life expectancy after diagnosis depends on the form of prion infection and ranges from four months in Kuru to 4-10 years (Gerstmann-Straussler-Scheinker syndrome).
No specific prevention has been developed. Non–specific methods – compliance with the rules of disinfection and sterilization in hospitals, during endoscopic procedures, in pathology bureaus. It is important to ensure food safety, avoiding the use of raw meat. Given the sexual path of infection, it is necessary to use barrier contraceptives. Methods of genodiagnostics of prion diseases are proposed.