Kreuzfeldt-Jakob Disease

What is Kreuzfeldt-Jakob Disease?

Kreuzfeldt-Jakob Disease (synonyms: spastic pseudosclerosis, corticotriospinal degeneration syndrome, transmissible spongioformal encephalopathy, mad cow disease) – progressive dystrophic disease of the cerebral cortex, basal ganglia and spinal cord.

It is considered the main manifestation of spongiform encephalopathy (prion disease).

The disease was first described in 1920 by Hans Kreuzfeldt. In 1921, Alfons Jacob noted a combination of mental disorders with symptoms of lesions of the anterior horns of the spinal cord, extrapyramidal and pyramidal systems, and defined the disease as spastic pseudosclerosis or encephalopathy with disseminated lesions of the brain tissue. Spielmeyer suggested calling the disease by the name of the authors who first described it.

Kreutzfeldt-Jakob disease accounts for about 85% of all human prion encephalopathies, affects people of all nationalities and races, men and women, adults and children. There is a slight predominance of the incidence of kuru disease in women, which is associated with the peculiarities of the national traditions (ritual cannibalism) of the Aborigines of New Guinea, when women eat the brains of the dead and receive a high dose of PrPSc. The onset of the disease occurs, usually in middle or late age, in typical cases in the fifth dozen of life, but can occur at any age. Thus, the debut age of the classical form varies from 17 to 87 years (the average age is 64 years), while the average age of the new form is much less and amounts to 29 years.

Causes of Kreuzfeldt-Jakob Disease

Mammalian prion proteins are not similar to yeast prion proteins in amino acid sequence. Despite this, the main structural features (the formation of amyloid fibers and high specificity, preventing the transfer of prions from one type of organism to another) are common. However, prion responsible for mad cow disease has the ability to pass from species to species.

During studies of the brain tissue of animals that died from prion infections, it was shown that prions do not contain nucleic acids, but are proteins. One of the first characterized prion proteins was PrP (from English prion-related protein or protease-resistant protein) weighing about 35 kDa. It is known that PrP can exist in two conformations – “healthy” – PrPC, which it has in normal cells (C – from English. Cellular – “cellular”), in which alpha helix predominates, and “pathological” – PrPSc, prion (Sc- from scrapie), which is characterized by the presence of a large number of beta strands. When released into a healthy cell, PrPSc catalyzes the transition of cellular PrPC into the prion conformation. The accumulation of prion protein is accompanied by its aggregation, the formation of highly ordered fibrils (amyloids), which ultimately leads to cell death. The released prion, apparently, is able to penetrate into the neighboring cells, also causing their death.

The function of PrPC in a healthy cell has not yet been determined. Normally, PrPC protein is associated with the cell membrane, glycosylated with a sialic acid residue. It performs cyclic transitions into the cell and back to the surface during endo- and exocytosis. One such cycle lasts about an hour. In the endocytosis vesicle or on the cell surface, the PrPC molecule can be cut into two roughly equal parts by proteases.

Until the end, the mechanism of spontaneous occurrence of prion infections is not clear. It is believed (but not yet fully proven) that prions are formed as a result of errors in the biosynthesis of proteins. Mutations of genes encoding a prion protein (PrP), translation errors, proteolysis processes are considered the main candidates for the mechanism of prion formation. According to recent studies, prions are capable of Darwinian evolution due to the action of natural selection.

There is evidence to suggest that prions are not only infectious agents, but also have functions in normal bioprocesses. For example, there is a hypothesis that a mechanism of genetically determined stochastic aging is carried out through prions.

A person can become infected with prions contained in food, as they are not destroyed by enzymes of the digestive tract.

Without penetrating through the wall of the small intestine, they end up in the central nervous system. This is how a new variant of Creutzfeldt-Jakob disease (nvCJD) is transmitted, with which people become infected after eating beef containing nervous tissue from cattle heads with bovine spongiform encephalopathy (BSE, mad cow disease).

Prions can penetrate the body and parenterally. Cases of infection with intramuscular administration of preparations made from human pituitary glands (mainly growth hormones for the treatment of dwarfism), as well as brain infection with tools during neurosurgical operations, were described, since prions are resistant to the currently used thermal and chemical sterilization methods. This form of Creutzfeldt-Jakob disease is referred to as iatrogenic (1CJD).

Under certain, unknown conditions, spontaneous transformation of prion protein into prion can occur in the human body. So there is a so-called sporadic Creutzfeldt-Jakob disease (sCJD), first described in 1920 independently of each other by Hans Gerhard Creutzfeldt and Alphonse Maria Jakob. It is assumed that the spontaneous occurrence of this disease is related to the fact that normally a small number of prions constantly appear in the human body, which are effectively eliminated by the cellular Golgi Apparatus. Violation of this ability of “self-cleaning” of cells can lead to an increase in the level of prions above the permissible limit of the norm and to their further uncontrolled spread. According to this theory, the cause of sporadic Creutzfeldt-Jakob disease is impaired function of the Golgi Apparatus in cells.

A special group of prion diseases are hereditary (congenital) diseases caused by a mutation of the prion protein gene, which makes the resulting prion protein more susceptible to spontaneous changes in the spatial configuration and their transformation into prions. This group of hereditary diseases includes the hereditary form of Creutzfeldt-Jakob disease (fCJD), which is observed in a number of countries around the world.

In the case of prion pathology, the highest concentration of prions is found in the nervous tissue of infected people. A significant amount of prions is found in the lymphatic tissue. The presence of prions in biological fluids, including saliva, has not yet been unequivocally confirmed. If the idea of ​​the constant occurrence of a small number of prions is correct, then it can be assumed that new, more sensitive diagnostic methods will open up this number of prions scattered across various tissues. In this case, however, the discussion will deal with the “physiological” level of prions, which do not pose any threat to humans.

Pathogenesis during Kreuzfeldt-Jakob Disease

Once in the body, prion settles on the cell surface, interacting with normal proteins and changing their structure to pathological.

Pathological proteins accumulating on the cell surface block the processes occurring on the membrane, which leads to cell death.

Proteins accumulating on the surface of the cell trigger apoptosis (the programmed process of cell death).

The cell, trying to get rid of proteins on the surface, begins to produce active oxygen compounds, but the protein on the surface does not allow them to go beyond the cell. The active substances destroy the cell itself.

Around the affected cells, inflammatory processes begin with the participation of highly active enzymes that affect adjacent healthy cells.

Symptoms of Kreuzfeldt-Jakob Disease

Forms of Keutzfeldt-Jakob disease
Spontaneous – Classic (sCJD)

According to modern concepts (prion theory), prions in this form of the disease arise spontaneously in the brain, for no apparent external reason. The disease usually affects people over the age of 50 years and manifests with a probability of 1-2 cases per million inhabitants. Initially, it manifests itself in the form of brief memory loss, mood changes, loss of interest in what is happening around. The patient gradually ceases to overpower and current actions associated with everyday life. In the final phase, visual impairment, hallucinations, and speech disorder occur (especially slow speech).

Main characteristics:

  1. about 40% of patients with sporadic form have a subacute course with progressive cognitive impairment, in 40% of cases cerebellar disorders occur, in 20% – their combination;
  2. the clinical picture includes behavioral disorders, disorders of higher cortical functions, cortical visual disturbances (up to cortical blindness), cerebellar dysfunction, a combination of pyramidal and extrapyramidal symptoms;
  3. epileptic seizures;
  4. almost all patients develop focal eyelids, including myoclonus of the eyelid, myoclonus of the lips and / or secondary generalized myoclonic seizures that can be provoked by phono-and photostimulation, tactile stimulation (touch). In most patients, during EEG studies, characteristic periodic or pseudoperiodic paroxysms of acute waves and / or spikes are detected on a general slowed-down low amplitude background of the bioelectric activity of the brain.

In the terminal stage, there are global cognitive impairments that are fatal after 8 months from the onset of the disease.

Hereditary (fCJD)

The disease occurs in families where gene damage for prion protein is inherited. A defective prion protein is much more susceptible to spontaneous transformation into a prion. The symptoms and course of the disease are similar to the classic form.

Iatrogenic (1CJD)

The disease occurs by the unintentional introduction of prions into the patient’s body during medical intervention. Earlier, some drugs, tools, or meninges that were taken from dead people and used to close a wound during brain operations were a source of prions. Today, this source of infection is completely eliminated. The symptoms and course of the disease are similar to the classic form.

New version (nvCJD)

The disease first appeared in 1995 in the UK and from that moment no more than 100 people died from it. Most likely, they became infected with meat products containing bull prions from the brain of “mad cows.” In contrast to the “classical” form, the disease also affects young people aged about 20 years. First of all, it manifests itself in a change of personality. People lose interest in their hobbies, they shun their dearest ones, they succumb to depression. This is followed by weight loss, impaired coordination of movements. The patient is unable to take care of himself, does not follow the basic rules of hygiene, and cannot eat without help from others. Brain damage increasingly impairs basic life functions, and finally, the patient dies. In contrast to the classical form, with the new variant of Kreuzfeldt-Jakob disease, the onset of dementia is distant, and the patient has been aware of his deteriorating condition for a very long time.

Main characteristics:

  • mental disorders and sensory impairments,
  • described several cases of the disease, which debuted with cortical blindness (Heidenhain variant),
  • episyndrome is also represented by myoclonic seizures,
  • cerebellar symptoms detected in 100%.

The clinical criteria for dementia for Kreuzfeldt-Jakob disease are:

  • rapidly progressive – within 2 years – (“devastating”) dementia with disintegration of all higher cortical functions; pyramidal disorders (spastic paresis);
  • extrapyramidal disorders (choreoathetosis);
  • myoclonus;
  • ataxia, akinetic mutism;
  • dysarthria;
  • epileptic seizures;
  • visual disturbances (diplopia).

Stage of the disease

  • Prodromal period – symptoms are non-specific and occur in approximately 30% of patients. They appear weeks and months before the onset of the first signs of dementia and include asthenia, sleep and appetite disturbances, attention, memory and thinking, weight loss, loss of libido, and behavioral changes.
  • The initial period – for the first signs of the disease are usually characterized by visual disturbances, headaches, dizziness, instability and paresthesias. The main part of patients gradually develops, less often – acute or subacute debut. In some cases, as in the so-called amyotrophic forms, neurological signs may precede the onset of dementia.
  • Extended period – usually marked by progressive spastic paralysis of the extremities with accompanying extrapyramidal signs, tremor, rigidity and characteristic movements. In other cases, ataxia, visual impairment or muscle fibrillation and atrophy of the upper motor neuron may occur.

For sporadic Kreuzfeldt-Jakob disease, the following are characteristic: The terminal period is severe dementia up to marasmus. All prionoses are rapidly progressing diseases. The course can be subacute, but usually leads to death no more than 1-2 years from the moment of clearly defined clinical manifestation. The average duration of sporadic is about 8 months. The duration of the new form is longer and reaches an average of 16 months. The average duration of a hereditary form is 26 months, after which death occurs.

Diagnosis of Kreuzfeldt-Jakob Disease

Kreuzfeldt-Jakob disease should be assumed in all cases of dementia that progress rapidly over a period of months or 1-2 years and are accompanied by multiple neurological symptoms.

Certain Kreuzfeldt-Jakob disease:

  • Characteristic neurological and morphological, including pathological-anatomical and neuroradiological symptoms.
  • Proteazoresistant PrP (according to Western blot).
  • Identification of scrapie-associated fibrils.

Probable Kreuzfeldt-Jakob disease:

  • Progressive dementia.
  • Characteristic EEG pattern (for sporadic CJD).
  • At least 2 of the following features:
    – myoclonus;
    – blurred vision;
    – cerebellar symptoms;
    – pyramidal or extrapyramidal symptoms;
    – akinetic mutism.

Possible Kreuzfeldt-Jakob disease:

  • progressive dementia;
  • atypical changes in the EEG (or the EEG is impossible);
  • At least 2 of the following characteristics:
    – myoclonus;
    – blurred vision;
    – cerebellar symptoms;
    – pyramidal or extrapyramidal symptoms;
    – akinetic mutism;
  • the duration of the disease is less than 2 years.

Of the paraclinical diagnostic methods for Kreuzfeldt-Jakob disease, the most informative are:

  • characteristic magnetic resonance imaging (MRI) of the brain (especially in the later stages of the disease) in the form of bilateral hyperintense signals on T2-weighted images (symptom of “honeycomb”), mainly in the area of ​​the caudate nuclei (in the head), pillows main the manner of the thalamus; It is shown that the symptom of “honeycomb” is most characteristic of nvBKYa; there may be signs of atrophy of the cerebral cortex and cerebellum;
  • positron emission tomography (positron emission tomography) is less informative, multiple zones of glucose hypometabolism are detected at the level of subcortical nuclei and the cerebral cortex and hemispheres of the cerebellum;
  • sporadic Kreuzfeldt-Jakob disease is characterized by the detection of three-phase activity on EEG, early paroxysmal activity is usually diagnosed 12 weeks or more from the debut of sporadic Kreuzfeldt-Jakob disease (in 80-88% of patients); focal, bilateral and generalized myoclonic paroxysmal activity is diagnosed in 15, 53 and 100% of cases with prodromal, initial and terminal stages of Kreuzfeldt-Jakob disease, respectively; Various types of periodic paroxysmal activity can be recorded: biphasic or three-phase periodic complexes that occur every 1-2 seconds; periodic complexes with multiphase configuration; periodic polyspike discharges. EEG-pattern “flash-suppression” is characteristic of the terminal stage of the disease with the phenomena of decortication;
  • for the new form, the above-described EEG changes are not characteristic, the EEG pattern may not significantly change compared with the age norm;
  • test results of cognitive functions (for example, less than 24 points on the MMSE short scale;
  • CSF analysis (lumbar puncture should be performed in all cases of the disease), CSF pressure, sugar level, cytosis, presence of bacterial and viral cultures, cryptococcal antigen, etc .; there may be a slight increase in the protein level (but not more than 100 mg / dL); an important diagnostic criterion is the level of the marker in the cerebrospinal fluid – the sensitivity and specificity of this test exceeds 90%;
  • if the diagnosis is unclear, it is possible to conduct an intravital brain biopsy (if there is informed consent from relatives or guardians in the event of incapacity of the patient);
  • morphological and histological examination of brain tissue (cortex, subcortical nuclei) at autopsy (post-mortem diagnosis).

Treatment of Kreuzfeldt-Jakob Disease

Etiotropic treatment of Kreuzfeldt-Jakob disease is not. Symptomatic treatment is carried out. In identifying CJD, it is necessary to cancel all medications that can adversely affect the patient’s mnestic functions and behavior. Many potential therapeutic interventions for Kreuzfeldt-Jakob disease currently remain at the discussion level. Traditional antiviral drugs, such as amantadine, interferons, passive immunization and vaccination of humans and animals, have proven to be ineffective.

Among the drugs have a positive effect on the process:

  • Brefeldin A, destroying the Golgi apparatus, interferes with the synthesis of PrPSc in an infected cell culture.
  • Calcium channel blockers, in particular NMDA-receptors, contribute to the longer survival of infected neuronal cultures.

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