Creutzfeldt-Jakob disease
Introduction
Introduction to Kreuzfeldt-Jacob disease Creutzfeldt-Jakobdisease (CJD) is a common type of transmissible central nervous system degenerative disease, which is a human spongiform encephalopathy, and nvCJD may be a new infectious disease of zoonosis. , commonly known as madcowdisease (MCD), but by no means contagious. Sporadic CJD can be transmitted to others through certain tests. At present, quite a few people think that CJD may be a new infectious disease of zoonosis. The disease is mostly caused by middle-aged disease. The main clinical manifestations of progressive dementia, myoclonus, pyramidal tract or extrapyramidal injury are deaths from several months to one year. Pathologically, the cavernous degeneration of the brain, the loss of nerve cells, and astrocyte hyperplasia were the major changes. Widely exist in countries around the world. basic knowledge The proportion of illness: 0.001% Susceptible people: good for middle-aged people Mode of transmission: transfusion Complications: mental disorders acne
Cause
The cause of Kreuzfeldt-Jacob disease
(1) Causes of the disease
The unconventional lentiviral virulence factor is considered to be an amyloid fibril (SAF), and the special protein particle constituting this fibril is called prion (PrP27-30). The properties of this lentiviral virulence factor are It has the characteristics of viral infection, and has different physical and chemical properties and biological characteristics than conventional viruses.
Physical and chemical properties are expressed as:
1 has a high resistance to various disinfection and inactivation;
2 has anti-high heat 80 ~ 100 ° C sterilization ability;
3 has the ability to resist ultraviolet rays and other various radiation;
4 The conventional electron microscope does not see the virus, and the fibrils and protein particles can be found only by special physical and chemical methods.
Its biological characteristics are:
1 Infectious transmission between hosts, the incubation period can be several years or decades;
2 pathology is degeneration, and there are amyloid plaques and gliosis, but no inflammatory reaction, no visible inclusions;
3 no recurrence to relieve the course of disease, continue to progress until death;
4 does not produce interferon, is not affected by interferon, and is not affected by any immunosuppression or immune enhancement during the incubation.
This lentiviral virulence factor is now known:
1 can be inactivated at a high heat of 132 ° C for 60 min;
2 can also be soaked in 10% sodium hypochlorite solution for more than 1h or 1N sodium hydroxide for 30min, repeated 3 times to inactivate.
(two) pathogenesis
In 1982, Prusiner proposed that the CJD system is caused by a special, infectious protein, Prion Protein (PrP), which negates the unusual lentivirus infection theory advocated by Gajdusek many years ago.
PrP is a single-encoding glycoprotein consisting of 253 amino acids (254 amino acids in mouse) located on the short arm of human chromosome 20, and the translatable frame consists of an exon at the end of N. The short peptides rich in proline and glycine are repeated five times. The prion protein is also present on the surface of normal central nervous cells. It is called PrPc, and its molecular weight is 30-33KD. Its spatial conformation is mainly -helical structure and proteinase K. It can be dissolved, and abnormal PrP is called PrPsc, PrPES or PrPCJD. It is very different from PrPc. Its molecular weight is 27-30KD, its spatial conformation is nearly 40% -layer fold, and PrPSC is several times, it forms a diameter of 10~. 20nm, 100-200nm long, this substance may be the early discovery of scrapie-associated-fiber (SAF) and prion liposome, which cannot be digested by proteinase K, PrPSC A large amount of deposition in the brain can destroy the central nervous system of the brain, causing extensive neuronal apoptosis and loss of the brain, and the formation of spongiform encephalopathy.
How does PrPSC enter the central nervous system and how it changes from normal PrPc to abnormal PrPSC? The detailed pathways and mechanisms are still under study. However, different types of CJD have different mechanisms of occurrence; in general, The iatrogenic CJD is a tissue or device that transmits infection, which is about to be contaminated by PrPSC, through deep brain examination, brain surgery, dural transplantation, and repeated exposure to growth hormone or sex hormones from the pituitary. Familial CJD is a mutation of PrP gene, which is a spontaneous structural change of autologous PrPc, resulting in a large amount of PrPSC, leading to degeneration of the central nervous system, and sporadic CJD may be the result of somatic mutation. .
The deposition of this abnormal prion protein in the body can be affected by several factors, and its pathogenesis and clinical manifestations have been proposed. PrPSC has been caused by "endogenous neurotoxicity" to cause a large number of nerve cells to apoptosis and loss. "Endogenous neurotoxicity", including excitatory amino acids, various cytokines, free radicals and nitric oxide, etc. PrPSC may stimulate glial cells to secrete many cytokines, nitric oxide and free radicals, and increase free radicals. Come over and destroy the normal function of neurons, and produce neuronal apoptosis. However, among the many factors affecting the pathogenesis, it plays a major, critical and direct role, just like the point mutation and insertion mutation of the gene. CJD in codon 129 (ATG-GTG), 180 (GTC-ATC), 210 (GAG-AAG), 208 (CGC-CAC) site mutation, directly affecting the clinical manifestations and passage of CJD, these facts can Confirmed by PrP gene detection.
Pathological changes:
Generally seen
Generally speaking, depending on the length of the disease, CJD can die within a few weeks after the onset of the disease, and can die several years or more after the onset of the disease, usually within 10 months after the illness, and the patient with a short course of disease visually Basically normal, the disease is long, the brain weight is reduced, some people report a CJD with a course of 9 years, the brain weight is only 575g at the time of necropsy, at this time, the sulcal widens, the cerebral gyrus narrows, and the cut surface further proves the cerebral cortex, bottom In addition to atrophy, the ventricle is symmetrically enlarged, and the brain stem, cerebellum, and spinal cord are basically normal. CJD brain atrophy is characterized by symmetric brain atrophy. Very severe cases may have striatum, thalamic atrophy, and normal white matter of the brain.
2. Major changes under the microscope
(1) Spongiform degeneration: mainly located in the gray matter of the brain, severe striatum, brainstem and cerebellar molecular layers may also appear. The deep gray matter of the brain is mostly small vacuoles, round, elliptical, irregular, etc. They are fused to each other. The small ones are only 1~2m in diameter, and the larger ones can reach 50m. In the early stage, they are only found in the deep gray matter of the brain. In severe cases, they can extend to the whole layer of gray matter. This small vacuole is often located around nerve cells or glial cells. Less in the nerve cells, spongy degeneration and nerve cell loss, astrocyte hyperplasia coexist, acute onset, rapid progression of spongiform degeneration compared with chronic onset and slow progress.
(2) Loss of nerve cells: The gray cells of the gray matter of the brain are diffusely lost, the most obvious in the third and fifth layers, especially the occipital lobe, the medial nucleus of the dorsal nucleus, the anterior nucleus, and the lateral nucleus cells are also quite serious. The caudate nucleus, the putamen, and the nucleus of the nucleus are similar to the medial nucleus of the thalamus. The globus pallidus, the subthalamic nucleus, the papillary body change slightly, the hippocampus Sommer area is not invaded, and most CJD cerebellum changes. The degree of loss is heavier than that of Purkinje cells. The cerebellar nucleus cells are normal, and the dentate nucleus is slightly changed. The Purkinje cells may have a torpedo-like structure, and the brain stem is normal except for the nucleus. The red nucleus, the substantia nigra, and the reticulate The nucleus and cerebral nucleus are normal. The anterior horn cells may present with simple atrophy, chromatin lysis or agglutination, and the anterior horn cell loss is not obvious. The longer the course of the disease, the more the nerve cells are lost. Conversely, the rapid death or only It is a case of brain biopsy. It is difficult to determine whether there is nerve cell loss, especially in specimens with less obvious spongy degeneration.
(3) Glial cell hyperplasia: Whether it is acute or chronic progressive disease, glial cell hyperplasia is very prominent, mainly astrocytes, especially when the disease course is slow, but its degree of proliferation is not The nerve cells are lost in parallel, and there are fashionable astrocytes with irregular cells and irregular cytoplasm. Usually, microglia hyperplasia, glial nodules and nerve cells are phagocytized.
(4) white matter changes: CJD in chronic and long-term disease can often see white matter in the brain, hippocampus, sputum and optic nerve changes slightly, the posterior root ganglion, peripheral nerve and autonomic nerve are normal.
(5) amyloid plaque: mainly in the cerebellar molecular layer, followed by the dentate nucleus, parietal lobe, hippocampus, amygdala, Coll nucleus, trigeminal spinal nucleus and spinal dorsal horn, the central part of the amyloid plaque consists of no structure Or granular, different sizes, composed of PAS-stained substances, Congo red can also be dyed, CJD disease is shorter than 6 months, can not see this plaque, longer than 15 months of sporadic CJD and family Starch plaques can be seen in the brain of sexual CJD.
3. Seen by electron microscopy
The prominent changes are the terminal end of the neuronal processes and the unclear synaptic membrane gap, and the synaptic vesicles are significantly reduced. The typical findings of CJD are the membrane bound vacuole, the cytoplasmic chromosomes of the nerve cells are reduced or Disappeared, lipofuscin accumulation, myelin thinning, axoplasmic cavitation, astrocyte proliferation, a large number of secondary lysosomes in the cytoplasm, even Rosenthal fibers, amyloid plaques from 7 ~ 10nm size, composed of radial matter, mixed with dense particles of 10 ~ 100nm size, even visible nerve cell protrusions and astrocyte protrusions scattered in this plaque.
4. Immunohistochemistry
Immunohistochemical staining, which is applied to the diagnosis of prion-infected diseases, is undoubtedly a great contribution. PrP antiserum is the first antibody, and the presence and distribution of PrP in the central nervous system are found and confirmed. Dementia caused by other causes, as early as 1988, Kitamoto and Tateishi performed immunohistochemical staining on 30 cases of CJD, 11 cases of GSS and 51 cases of dementia caused by non-prion infection, and the results showed CJD. Only 59.0%, GSS 100.0% was positive, and other types of degenerative diseases, such as Alzheimer's disease, progressive nuclear paralysis, Huntington's disease, spinocerebellar ataxia, and Pick disease were negative, but the original staining method Positive results can only be obtained in CJD brain slices with a disease duration longer than 13 months. The fact is that CJD with a course longer than 13 months is only 11% to 61% of the disease, while CJD with a shorter course is still negative. One deficiency has recently been successful in improving the operation process before dyeing, called hydrolytic autoclaving, so that even CJD with a disease duration shorter than 13 months can better show yang. Sexual results.
5. Pathological features of the new variant CJD
In recent years, 52 cases of sporadic CJD different from traditional CJD have been found in the United Kingdom and France, which is called new variant of CJD. The pathological findings have the following pathological changes of classical CJD. feature:
1 The changes in the thalamus and the bottom are often heavier than the gray matter in the brain;
2PrP deposition is extensive, especially in the occipital optic cortex;
3 The immunohistochemical staining results of PrP antiserum as the first antibody were opposite to the common CJD synaptic type, showing a plaque-type distribution.
Prevention
Kreuzfeldt-Jacob disease prevention
So far, there is no evidence that people with general infections can cause infections in people without skin damage. Studies have shown that exocrines, including tears, nasal discharges, saliva and feces, are not contagious. Epidemiology has not found general medical care exposure. CJD onset.
Based on the above situation, the prevention focus should be on the strict treatment of brain tissue of CJD patients, blood and cerebrospinal cord, as well as surgical instruments that come into contact with or used with patient tissue fluids, dressings and their wastes. Strict disinfection measures should be taken, and surgical instruments can be used at high pressure 132. °C 60min or 10% hypochlorite solution soaked for 60min for 3 times, or 1N sodium hydroxide solution for 30min, a total of 3 times, dressing and autopsy pathology should be incinerated, blood syringe and needle should be used disposable products After use, it should be strictly destroyed and incinerated. The patient should be taken from the medical care. The injection or surgery should avoid skin mucosal damage or gloves to avoid the risk of infection caused by home vaccination.
Complication
Kreuzfeldt-Jacob disease complications Complications, intelligent disorders, hemorrhoids
The lesion damages the broad central nervous system such as the cortex, the basal ganglia, the thalamus, the cerebellum, the brainstem and even the anterior horn of the spinal cord. Due to mental, consciousness, and intellectual disorders, dysfunctions and disorders of various systems may occur, such as medullary paralysis, which may cause difficulty in eating. Cough, lung infection; brain stem lesions can also affect cardiovascular function; long-term bed-induced hemorrhoids.
Symptom
Kreuzfeldt-Jacob disease symptoms Common symptoms Attention deficit fatigue fatigue convulsions convulsions depression dizziness insomnia anxiety dizziness
The disease occurs between 25 and 78 years old, with an average age of 58 years. Both men and women can suffer from CJD. However, in recent years, the new variant CJD reported in the United Kingdom and France has a younger onset age than the classic type, with an average age of 26 years. Most of the disease is sporadic. 15% is family hereditary, and some are iatrogenic, iatrogenic or infectious CJD is found in the application of contaminated deep brain electrodes, corneal transplantation, growth hormone and gonadotropin injection from the pituitary after death, and Dural transplantation, etc., according to reports in the literature, this iatrogenic CJD has more than 300 cases, although its incubation period can be as long as 5 to 20 years.
1. Clinical manifestations can be roughly divided into the following three periods
(1) Initial stage: mainly manifested as fatigue, fatigue, inattention, insomnia, depression, memory difficulties, etc. This period is easy to be diagnosed as neurosis or mild depression, with fashion accompanied by headache, head weight, Dizziness, blurred vision or ataxia and other neurological symptoms.
(2) Mid-term: Also known as dementia-myoclonic stage, this period of memory disorder is particularly prominent, or even out of home can not find home, lost, personality changes, until dementia, and some with aphasia, loss of recognition, loss of limbs, limb muscles Increased physical strength, hyperreflexia, Babinski signs are often positive, and some hyperactivity or seizures, hemiparesis, visual impairment, cerebellar ataxia, muscle rigidity, etc., a few cases may also have limb muscle atrophy, this period is about 2 /3 patients developed myoclonus.
(3) Late stage: presenting urinary incontinence, no mobilization or cortical rigidity, often due to hemorrhoids or lung infections, 85% of CJD patients die 1 year after onset, and a few may be within 3 weeks after onset or up to More than 8 years of death.
In the past two years, 52 cases of sporadic CJD have been found in the UK and France. Their age, clinical manifestations and pathological findings are very different from traditional or classic CJD. This is called new variant CJD, clinical features. Yes:
1 The age of onset is light, with an average age of 26 years ± 7 years;
2 The first symptoms are mostly mental disorders and ataxia;
3 mental disorders include anxiety, depression, solitude, wilting, etc.;
4 memory disorders are more prominent, late development of dementia;
More than 5 episodes of myoclonus;
6 During the EEG examination, no periodic synchronous discharge occurs;
7 feeling abnormally rare;
In the late stage, there were signs of pyramidal tract or extrapyramidal injury.
2. Clinical pathological types
Because the lesion damages the broad central nervous system such as cortex, hypothalamus, thalamus, cerebellum, brainstem and even the anterior horn of the spinal cord, its clinical manifestations and pathological findings can be distinguished as follows:
(1) Frontal vertebral body beam type: clinical manifestations of progressive dementia, myotonia, myoclonic seizures and pyramidal tract signs, ie similar to Jakob spastic pseudosclerosis.
(2) occipital dysfunction: the lesions are mainly affected by occipital temporal lobe, and the clinical manifestations are visual impairment of cortical blindness. At the same time, progressive dementia is associated with myoclonus convulsions, similar to Heidenhain syndrome.
(3) Ataxia type: pathological damage with cerebellum as the weight, clinical manifestations of cerebellar ataxia, and progressive dementia with symptoms of myoclonus convulsions.
(4) Muscular atrophy: the lesion involves the central nervous system, such as the cortex, including the medullary bulb and the anterior horn of the spinal cord, clinical manifestations of progressive dementia, vertebral bundles, prominent manifestations of medullary bulbar palsy and spinal muscular atrophy, etc. See you.
(5) Whole brain or diffuse type: The lesions involve the central nervous system extensively, and the clinical manifestations include progressive dementia with pyramidal tract signs, extrapyramidal signs and cerebellar ataxia.
(6) Variant spongiform encephalopathy: including familial senile dementia.
In addition, 158 cases of CJD confirmed by pathology were reported in foreign countries. The authors divided 152 cases into 3 types: 137 cases of subacute type, 12 cases of intermediate type, and 3 cases of muscle atrophy.
About 1/3 of the sub-acute type have advanced neurological activity disorder, behavior disorder, with ataxia and dizziness. Most patients have the initial symptoms of ataxia, speech difficulties, blurred vision, visual distortion and visual hallucinations. There are dementia, 82% have myoclonus, 11% have dance-Xu-like hyperactivity, rapid mental degeneration and develop into cortical rigidity, short course, rapid progress, usually lasting for several months, the intermediate course is 20 From month to 16 years, with a variety of clinical manifestations, muscle atrophy is atrophy and fatigue of the limbs or cranial nerves. It is worth mentioning that this type has no myoclonus and vision loss, dementia progresses slowly, 1~7 After the year, the condition deteriorated rapidly and died after 1 year. It is emphasized that even if the muscle is atrophy, there is no characteristic change in the EMG, and there is no characteristic change in this type and the intermediate EEG. The diagnosis often depends on the pathological examination. .
Examine
Examination of Kreuzfeldt-Jacob disease
1. Hematuria is routine, biochemical, liver and kidney function are not abnormal.
2. Most of the cells and proteins in cerebrospinal fluid are in the normal range. In a few cases, the protein is slightly elevated. Abnormal protein can be seen in two-dimensional electrophoresis, but there is no positive reaction between humoral immunity and cellular immunity. The 14-3-3 brain protein in cerebrospinal fluid is detected by immunological method. The total sensitivity is 96%, and its specificity is 80%. It is worth noting that for progressive dementia, the specificity of patients with no recent cerebral infarction can be as high as 99%, suggesting that 14-3-3 brain protein determination for CJD Has a very high diagnostic value.
3. Diagnostic value of serum S100 protein
The serum S100 protein concentration was determined to have a specificity of 81.1% for CJD and a sensitivity of 77.8%. Serum S100 protein concentration was significantly different from other diseases in patients who were positive or likely CJD.
4. EEG examination
EEG changes are considered to be an important basis for clinical diagnosis of CJD. EEG changes are not the same in different periods of the disease. In early cases, EEG only showed mild abnormalities or alpha wave reduction, slow wave abnormalities, only Widely existed non-specific slow waves, there may be several differences in the hemispheres on both sides, no characteristic significance. In the middle and late stages of disease development, 0.5 to 1 s periodic spikes appear on the background of low amplitude slow motion, and sharp or three-phase waves are emitted. It constitutes a characteristic EEG of CJD; in the extreme phase, it exhibits a specific periodic synchronous discharge (PSD), which is especially important for the continuous diagnosis of EEG characteristics, which is of great significance for clinical diagnosis.
5. Skull imaging examination
Usually seen in the early head CT without abnormalities, the disease progresses to the middle and late stage, the sulcal widening, the ventricle moderately enlarged, brain atrophy, MRI visible cortical atrophy, white matter, no special findings, exclude other various focal encephalopathy, Contribute to clinical diagnosis.
6. positron brain scanning (PET)
It can be seen that the metabolic rate of the temporal lobe is reduced or the two hemispheres are asymmetric.
7. Brain biopsy
The characteristics of light microscopy and electron microscopy are of great significance for clinical diagnosis.
Diagnosis
Diagnosis and identification of Kreuzfeldt-Jacob disease
Diagnostic criteria
The clinical diagnosis of CJD is difficult in the early stages of the disease. However, it is possible to make a clinical diagnosis by referring to the following points:
1. The vast majority of CJD occurs in middle age.
2. There are both neurological symptoms, such as mutual help disorder, convulsions, etc., as well as mental symptoms, such as memory difficulties, mental retardation and so on.
3. Rapid progress, usually develops into dementia, apathic silence or cortical rigidity within weeks or months after onset.
4. Laboratory inspection
The following changes can be found in a conditional hospital or in a conditional hospital:
(1) EEG: The initial stage is a non-specific slow wave, and periodic synchronous discharge can occur in the extreme phase.
(2) Cerebrospinal fluid: 14-3-3 protein can be found.
(3) Serum: It can be confirmed that the concentration of S100 protein is increased.
(4) Brain biopsy: usually the right frontal cortex is used, and gray spongy degeneration, nerve cell loss, gliosis and PrPSC can be found.
5. Someone diagnosed as CJD by the following conditions, probably CJD and possibly CJD.
(1) Progressive dementia, usually within two years.
(2) Myoclonus, visual acuity, cerebellar symptoms, and inactive silentness accounted for 2 of the patients.
(3) Characteristic EEG changes are periodic synchronous discharges.
The above three items can be diagnosed as CJD, only two or two, and those who do not have the third item, the diagnosis may be CJD; if the patient undergoes brain biopsy, and the sponge state and PrPSC are found, the diagnosis is definitely CJD. Brain protein detection can replace EEG-specific changes.
Differential diagnosis
Clinical diagnosis of CJD should be differentiated from Alzheimer's disease, subcortical arteriosclerotic leukoencephalopathy (Binswager's disease), multi-infarct dementia, multifocal leukoencephalopathy, progressive supranuclear palsy, olive pons cerebellar atrophy, and cerebral cysticercosis.
