what is being done about research on CJD?

Question

my husband passed away of CJD (the human form of Mad Cow) and I need some answers

Answer 1

GENETIC CJD
Genetic CJD is a very rare illness. In this form, CJD is caused by an inherited abnormal gene. The illness is therefore not "caught" in any way and there is no causal relationship between this form and BSE. In most cases, the illness is known within the family because of the family history. Occasionally, genetic cases are seen in which no previous family history is identified. The definitive test in relation to genetic CJD is a blood test in order that the gene can be analysed to see whether there is any genetic abnormality. The United Kingdom has a population of around 58 million and there are only a few deaths due to genetic CJD in a year.







IATROGENIC CJD
Iatrogenic CJD is also very rare. This is CJD which has been accidentally transmitted during the course of medical or surgical procedures. The most important example of this in the United Kingdom relates to CJD transmitted via Human Growth Hormone treatment in childhood. There are only a few deaths per year due to iatrogenic CJD in the United Kingdom. The diagnosis is usually clear from the history of a relevant medical or surgical treatment in the past.







SPORADIC CJD
Sporadic CJD is numerically the most common form of CJD. It is not confined to the United Kingdom and, indeed, has been found in every country in the world where it has been looked for. In general, it affects about one person per million of the population. There are therefore some fifty to sixty deaths per year due to sporadic CJD in the United Kingdom. Similar figures are seen in other countries such as Australia, Canada and the USA. The cause of sporadic CJD remains uncertain. However, the most favoured current theory suggests that the normal prion protein in the brain undergoes a spontaneous change to the abnormal form, thereby resulting in disease. If this theory is correct (and it has not been proven at this point) then the disease arises simply as a chance event inside the brain. On this basis, it would not be "caught" in any way.





VARIANT CJD
Variant CJD was first reported in 1996. At this point in time, the CJD Surveillance Unit has not seen any cases of variant CJD with symptoms that began before 1994. Aside from 6 cases in France, one case in Ireland, one case in Italy and one case in the USA, variant CJD has been confined to the United Kingdom. The current view on variant CJD is that it has resulted from transmission of infection from BSE in cattle to humans via infectivity in food.





We have had many enquiries to the relationship between sporadic CJD and variant CJD. Sporadic CJD is of unknown cause. However, detailed investigation over many years has failed to provide any evidence to suggest that it is related to diet. It was first described in 1921 and therefore predates the BSE epidemic by many years. Sporadic CJD is found in countries throughout the world regardless of the presence of BSE. There is therefore no evidence to suggest that sporadic CJD is in any way the result of BSE. On the other hand, the timing of the appearance of variant CJD and its geographical distribution in the world strongly suggested a connection with BSE in cattle. Laboratory scientific work has shown that the protein agent involved in sporadic CJD has quite different behavioural properties to that seen in the protein agent from variant CJD. In addition, the behaviour of the variant CJD agent is very like that of BSE. There is therefore scientific laboratory evidence to support the view that variant CJD and BSE are related, whereas sporadic CJD is not causally related either to BSE or variant CJD.

Sporadic CJD and variant CJD have certain clinical and pathological differences
The age of onset is generally different in variant and sporadic CJD. Variant CJD has tended to affect younger individuals with an average age of onset of around 27. Sporadic CJD has tended to affect middle-aged and elderly individuals. However, this difference is not absolute. There are those with variant CJD with a relatively older onset (including one case aged 74). Sporadic CJD may also affect very young individuals on occasions, including those in their teens and twenties. There is therefore a small overlap in the age group affected by variant CJD and sporadic CJD. The age of an individual is not an absolute guide to the type of CJD.

The duration of illness is generally different in variant CJD and sporadic CJD. Many cases of variant CJD have durations of a year or more. The duration of sporadic CJD is typically a few months, and, in a few cases, a few weeks. However, there is again no absolute distinction. There are cases of variant CJD who have died after an illness of only a few months and there are occasional cases of sporadic CJD with durations of one or two years or even longer. Therefore, the duration of illness is not an absolute guide to the form of CJD.

The symptoms of sporadic and variant CJD tend to be different. In particular, sporadic CJD tends to present with a clearly neurological illness that follows a very rapidly progressive course. In variant CJD, the initial presentation is often with psychiatric or behavioural symptoms and it may not be clear that the individual has neurological illness until several months after the onset. An experienced neurologist can generally distinguish the clinical patterns of sporadic and variant CJD. However, there is some overlap in the symtpoms of the two forms, and, on occasions, it may be difficult to be certain as to the classification of the type of CJD if this were based on the clinical symptoms alone.

Some investigations which are undertaken in CJD may be of great help. In particular, the EEG and the MR scan may be useful. The EEG shows a typical pattern in the majority of cases of sporadic CJD. This typical abnormality has never been seen in variant CJD. The cerebral MRI shows a typical abnormality in the majority of cases of variant CJD which has not been seen in sporadic CJD.

The neuropathological features of variant and sporadic CJD are different. In determining whether an individual has CJD or not, the only absolute test at present is that of neuropathology. Therefore, if an individual has not had neuropathology undertaken on either a brain biopsy in life or at a post mortem, then one cannot be absolutely sure as to the diagnosis. In addition, the neuropathological features of sporadic CJD and variant CJD are quite distinct and this would represent the main definitive method of distinguishing between this two forms of CJD.

There are individuals who do not undergo brain biopsy in life and do not have an autopsy. These individuals may be diagnosed on the basis of "probable sporadic CJD" or "probable variant CJD". Although this does not represent an absolutely definitive diagnosis , if an individual is considered as having "probable" CJD, then it is very likely indeed that this is what they had. Probable sporadic CJD carries a certainty of around 95% or more. To date, all the individuals who have been diagnosed as probable variant in life , who have subsequently had an autopsy have been found to have had variant CJD

clinical features
SPORADIC CJD
Sporadic CJD (sCJD) is predominantly a disease of late middle-age with a mean age at death in the late 60s. Cases with onset below the age of 50 are relatively rare, but do occur. The cause of sCJD is unknown.

Various early symptoms have been described, predating the main illness (including headache, tiredness, sleep or appetite disturbance and depression), but it is not clear whether these non-specific symptoms are really part of CJD in most cases. The presenting neurological symptoms usually reflect a disturbance in one relatively focal part of the brain but, in most cases, the disease develops rapidly to affect the brain in an increasingly global manner. Impairment of memory, cognition impairment and cerebellar ataxia (incoordination due to disease of the cerebellum) are common early features. Two particularly well-recognised but relatively rare presentations are the so-called Heidenhain and Brownell-Oppenheimer forms. In the first, the disease begins in the area of the brain that deals with vision and the affected individual complains of progressive visual disturbances and eventually blindness. There may be several weeks of purely visual problems before other features develop. In the second, there is a purely cerebellar disturbance with progressive unsteadiness and incoordination which again may progress for several weeks before other features are noted. Whatever the mode of onset, the subsequent clinical course, in most cases, is one of very rapid progression with deterioration being noticeable over even the course of a week. The rapidly evolving clinical picture always includes dementia (loss of memory and cognitive function), with ataxia and myoclonus (an involuntary jerking or twitching of muscles) being present in the majority of cases. Other features include impairment of voluntary movements and rigidity. It is common that walking and speech are lost after a relatively short period and the affected individual generally becomes bed-bound with no real awareness of, or response to, events around them. Epileptic seizures are relatively uncommon. The median duration of sCJD is 4 months and around 65% of cases have an illness duration of less than 6 months. In 14% of cases, there is a relatively long duration of 12 months or more; durations of greater than 2 years are rare (5% of cases).

In a typical case, the invariably progressive, rapid clinical evolution and the short illness duration, readily distinguish sCJD from most other dementing illnesses. However, the differential diagnosis can be problematic, especially if there are atypical features. If the initial symptoms remain focal for a while (such as visual or ataxia as described above), then other diagnoses will almost certainly be considered until the more general illness develops.

The diagnosis is reviewed in the investigations section.





IATROGENIC CJD
Iatrogenic CJD (iCJD) has resulted from neurosurgery (including the use of EEG depth electrodes), corneal grafting, human dura mater implants or exposure, and the use of human cadaveric growth hormone (hGH) and human pituitary gonadotrophin (hGNH). Iatrogenic CJD is very rare and most cases have resulted from hGH treatment or human dura mater grafts.

The clinical features depend somewhat on the route of infection.

hGH cases, resulting from intra-muscular injection of infected material, generally present with a progressive cerebellar syndrome (increasing unsteadiness and incoordination) and other features including dementia tend to occur relatively late in the illness.

Human dura mater cases, resulting from infected material being placed relatively near to the CNS tend to present with a rapidly progressive dementia along with other neurological features and may be clinically indistinguishable from sporadic cases.


The principal investigation of iatrogenic disease must come from the history, in particular a history of treatment with cadaveric-derived hGH or an operation involving the use of a human dura mater graft.

The diagnosis is reviewed in the investigations section.



VARIANT CJD
There is now convincing evidence that variant CJD (vCJD) is due to infection of humans with the BSE agent, most probably via contaminated food.

In contrast to the age distribution of sCJD, the median age of onset in vCJD is 28 years (range 12-74). Whereas sCJD typically presents with rapidly progressive symptoms that are usually clearly neurological in nature, vCJD tends to present with behavioural or psychiatric symptoms and with a relatively slower progression. It may be difficult to determine that there is a neurological illness until some time has passed.

In an analysis of the first hundred cases of vCJD, psychiatric symptoms preceded neurological symptoms in 63% of cases and were found in combination with them in 22% of cases. In only 15% did neurological symptoms precede psychiatric symptoms. In the majority of cases, features of depression are present and many were given antidepressant treatment. Other features included anxiety, agitation, delusions and hallucinations. This presentation may result in the initial referral to psychiatry services rather than neurological ones. Sensory symptoms in the limbs or elsewhere (persistent, unpleasant or frankly painful) affect nearly half the patients but these symptoms are relatively non-specific and such symptoms are relatively common in illnesses like depression. At some point other neurological features develop, with definite neurological abnormality developing at a mean of around 6 months from first symptoms, ataxia often being the most prominent problem. Certain involuntary movements may develop including chorea (fidgety movements) and dystonia (twisting, grimacing movements). Eventually, the clinical picture is one of a dementia with multiple neurological features including myoclonus. The illness duration is greater than that for sCJD, with a median of 14 months (range 6-40).

The differential diagnosis of a progressive neuropsychiatric disorder in relative youth is potentially a wide one and it may be difficult or impossible to make a diagnosis of vCJD in the early stages of illness.

The diagnosis is reviewed in the investigations section.



GENETIC CJD (gCJD)
Familial CJD, Gerstmann Straussler syndrome (GSS) and Fatal Familial Insomnia (FFI) are all related to an underying genetic mutation in the prion protein gene (PRNP) and should perhaps be regarded as one group of diseases but they tend to be considered separately. These diseases have an autosomal dominant pattern of inheritance (if an affected individual has a child, there is a 50% chance of the child inheriting the abnormal disease-causing gene). However, for a variety of reasons, cases of genetic CJD are identified where there is no obvious preceding family history.

The clinical presentation varies with the underlying mutation and other factors. In some instances, the clinical picture is very like that of sCJD and the only definitive way of establishing the genetic nature of the illness is via the family history or genetic testing. The age at onset tends to be younger and the duration of illness longer than for sCJD. Some genetic cases have a particularly long duration (even of several years) and also atypical clinical profiles. GSS tends to present with progressive cerebellar ataxia. In FFI, sleep disturbances and other features predominate.

The presence of an abnormal mutation in the gene can be confirmed by a blood test. The diagnosis of genetic forms is dealt with in the investigations section.

INVESTIGATIONS UNDERTAKEN IN POSSIBLE CJD CASES
INTRODUCTION
An absolutely definitive diagnosis of any form of CJD requires neuropathological examination of brain tissue. This would usually be undertaken at post mortem examination. Rarely, a biopsy of the brain may be taken in life but this is not usually necessary in the investigation of cases of possible CJD.

When a diagnosis of CJD is suspected, investigations are undertaken for two broadly separate reasons. Firstly, investigations are used to exclude other possible diagnoses. Secondly, there are certain investigations which are supportive of the diagnosis of CJD. These supportive investigations are discussed below. It is important to note that some of these investigations (such as the MRI scan and the cerebrospinal fluid examination) may be undertaken for both reasons.



SPORADIC CJD
There are three investigations which might provide support for a diagnosis of sporadic CJD. These are:

The EEG
The CSF 14-3-3 estimation
The MR scan


1. THE EEG
In sporadic CJD, the normal electrical rhythms of the EEG are gradually lost. In the majority of cases generalised bi- or triphasic periodic sharp wave complexes appear with a frequency of around 1-2 per second. In an appropriate clinical context, the appearance of this EEG pattern is strongly supportive of a diagnosis of sporadic CJD. However, not all cases show this typical periodic pattern and generalised periodic complexes may appear in other conditions, some of which are listed below. It is difficult to state definitively the frequency of occurrence of the typical periodic pattern in sporadic CJD. This is essentially because the pattern tends to develop throughout the course of the illness and, in some cases, may not appear until very late. Therefore, finding a positive EEG may require repeat studies (possibly weekly) even very late into the illness course and these may not always be undertaken. However, it is probably that about 60 – 80% of cases of sporadic CJD will eventually develop the characteristic periodic picture.

In some cases, the EEG changes may be initially unilateral and indeed the periodic complexes may be unilateral when they first appear.

Note: (This characteristic periodic pattern is less frequently seen in genetic or human growth hormone related cases. It has not been seen in any case of variant CJD).

Other conditions in which generalised periodic complexes may occur

Alzheimer's disease

Multiple cerebral abscesses

Metabolic encephalopathy

Certain toxic encephalopathies (eg Lithium)

Anoxic encephalopathy

Progressive multifocal leucoencephalopathy

Lewy body disease





2. CEREBROSPINAL FLUID 14-3-3 ANALYSIS


The routine examination of the cerebrospinal fluid in patients with sporadic CJD is generally unremarkable. The CSF typically contains no inflammatory cells and the presence of a significant pleocytosis should lead to consideration of other diagnoses. The total protein content may be elevated (usually less than 1 gramme per litre). Oligoclonal bands confined to the CSF have very rarely been described and their significance in relation to sporadic CJD is doubtful.

However, the analysis of CSF for certain brain specific proteins, particularly 14-3-3, may be very useful in diagnosis. 14-3-3 is a normal neuronal protein and maybe released into the CSF in response to a variety of neuronal insults. It is therefore generally a non-specific finding and 14-3-3 analysis cannot be used as a general screening test for sporadic CJD. Other illnesses, which can give a positive 14-3-3 test, include:

Herpes simplex encephalitis and other viral encephalitides.

Recent cerebral infarction or haemorrhage.

Subarachnoid haemorrhage.

Hypoxic brain damage.

Glioblastoma

Carcinomatous meningitis.

Paraneoplastic encephalopathy.




However, it is usually a straightforward clinical matter to exclude the other possible illnesses which may give rise to an elevated 14-3-3 level. Therefore, in an appropriate clinical context, a positive test is strongly supportive of a diagnosis of sporadic CJD and a negative test is unusual. In the United Kingdom, the National Laboratory for 14-3-3 CSF test is in the National CJD Surveillance Unit.

If a case meets the diagnostic criteria for “possible sporadic CJD” and has a duration of less than 2 years then a positive 14-3-3 test allows the case to be classified as “probable sporadic CJD”.



3. MAGNETIC RESONANCE IMAGING
(CT or Computerised Tomography of the brain is usually normal in sporadic CJD although sometimes atrophy may be seen, particularly with long duration illness).

Magnetic Resonance Imaging is generally undertaken to exclude other illnesses. Cerebral atrophy may be seen in cases of sporadic CJD. However, in addition, in a proportion of cases, abnormalities of signal may be seen in the anterior basal ganglia and sometimes in the cortex. These changes may be helpful in supporting a diagnosis of sporadic CJD. Their precise nature and frequency of occurrence are still under investigation. At present, MR findings are not included in the accepted clinical diagnostic criteria but still may be helpful in individual cases.

VARIANT CJD
(The EEG may be normal in the earlier stages of variant CJD. Throughout the illness it tends to become non-specifically abnormal. The typical periodic discharges of sporadic CJD have not been seen in any case of variant CJD).

There are 3 diagnostic tests which provide support for a diagnosis of variant CJD:

1. The MRI

2. Tonsil biopsy

3. CSF 14-3-3 analysis





1. MAGNETIC RESONANCE IMAGING


The MRI is generally the most useful supportive diagnostic test in variant CJD. It is a relatively non invasive investigation that is generally readily available and, importantly, is undertaken in cases of suspect variant CJD in order to exclude other possible illnesses. However, there is a characteristic abnormality seen in the posterior thalamic region (the so called “pulvinar sign”) which is highly sensitive and specific for variant CJD. The pulvinar sign has been found in 90+% of pathologically proven vCJD cases. Present indications are that FLAIR sequences are most likely to show the abnormality. The stage of illness at which the scan becomes positive is uncertain. However, individual patients generally have MR scans at a time when clinicians feel they are appropriate and, as indicated above, partly to exclude other illnesses. It is at this clinically indicated point that positive scans have been found to be positive. In a few patients, the pulvinar sign has been present on MRI within 3 months of symptom onset.

The finding of a positive MRI scan allows a “possible variant CJD” case to be elevated to the category of “probable variant CJD”.
2. TONSIL BIOPSY


Unlike other forms of CJD, variant CJD shows involvement of the lymphoreticular system (lymph nodes, spleen, tonsil and appendix). There is therefore the possibility of finding the disease-related protein in a biopsy of such tissue. Tonsil biopsy has been used as a supportive diagnostic test in variant CJD. However, this does involve a surgical biopsy and its precise role in the investigation of variant CJD is a little uncertain. Its main role is probably to provide support for the diagnosis in cases who have negative MR scans or who have atypical clinical features. A positive tonsil biopsy cannot lead to a diagnosis of definite variant CJD. But, in the correct clinical context, allows a diagnosis of “probable variant CJD”. The surgical biopsy of tonsil must take into account precautions with relation to possible infectivity. The laboratory processing and analysis of tonsil for the presence of the abnormal prion protein is a specialist matter and should be undertaken by laboratories with experience in this.





3. CSF 14-3-3


The general CSF examination is unremarkable, as with sporadic CJD. Again there should be no pleocytosis and the protein level may be non-specifically modestly raised. The 14-3-3 test is not as sensitive in variant CJD as it is in sporadic CJD. A positive result may provide some support for the diagnosis but a negative result by no means excludes the diagnosis. At present, the CSF 14-3-3 test is not incorporated into the routine clinical diagnostic criteria.







GENETIC CJD


In genetic CJD, the definitive test is the analysis of the PRNP gene for relevant mutations. This test can be performed on a simple blood sample. Although a family history is usually present in cases of genetic CJD, sometimes it is not. Therefore, it is generally necessary to undertake genetic testing if one wishes to absolutely exclude the possibility of genetic disease.



Aside from analysis for mutations, genetic analysis allows for the determination of the codon 129 genotype (MM, VV or MV). This may have potential relevance in the full characterisation of a case of CJD. Over 70% of cases of sporadic CJD have the MM genotype but the disease does occur in the other two genotypes. To date, variant CJD has occurred in only the MM genotype.





IATROGENIC CJD

Diagnosis essentially rests on the history of a relevant known risk factor such as treatment with cadaveric derived human growth hormone or the use of human dura mater graft in surgery.


The neuropathology of CJD



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INTRODUCTION

The neuropathology of the human prion diseases (Creutzfeldt-Jakob disease (CJD) Gerstmann-Straussler-Scheinker syndrome (GSS) and kuru is characterised by 4 features: spongiform change, neuronal loss, astrocytosis and amyloid plaque formation. These features are shared with prion diseases in animals, and the recognition of these similarities prompted the first attempts to transmit a human prion disease (kuru) to a primate in 1966, followed by CJD in 1968 and GSS in 1981. These neuropathological features have formed the basis of the histological diagnosis of human prion diseases for many years, although it was recognised that these changes are enormously variable both from case to case and within the central nervous system (CNS) in individual cases. It is interesting to note that the original case reported by Creutzfeldt and 2 of the original cases reported by Jakob do not show any of these characteristic neuropathological features; the diagnosis in these cases remains uncertain upon review. However, at least 2 of Jakob's original cases show typical neuropathological changes and other cases subsequently reported from his laboratory (including the members of the Backer family) also exhibited classical histological features. It is also of interest to note that prion protein (PrP) gene analysis has recently been performed on one of the Backer family cases, showing a codon 178 Asn mutation with met/val at codon 129. This genotype has been described in other familial forms of human prion disease.


Early neuropathological reports on human prion diseases suffered from a confusion of nomenclature, in which the significance of the diagnostic feature of spongiform change was occasionally overlooked. The subsequent demonstration that human prion diseases were transmissible reinforced the importance of spongiform change as a diagnostic feature, reflected in the use of the term `spongiform encephalopathy' for this group of disorders. Recent advances in the understanding of the infectious agent, along with increasing knowledge on the pathogenetic significance of mutations and polymorphisms in the human prion protein gene have prompted a revaluation of classical neuropathology in this group of diseases, and a tendency to use the generic term `prion disease' rather than spongiform encephalopathy.


Neuropathological assessment of the structural changes in the CNS has been the mainstay in diagnosis of human prion diseases for many years. A new range of investigative techniques, including PrP gene analysis, PrP immunocytochemistry and detection by the Western blot, histoblot and immunoblot techniques, prion rod/SAF detection by electronmicroscopy and transmissibility to both wild-type and transgenic laboratory animals all now have diagnostic applications. In the laboratory investigation of human prion diseases a combined morphological, immunocytochemical and molecular genetic approach is desirable. However, many cases can be diagnosed on morphological assessment alone, including the vast majority of cases of sporadic CJD.


Histological Investigation


Most neuropathological studies in human prion diseases are performed on paraffin-embedded tissues. Tissue blocks from the CNS can be decontaminated in 96% formic acid for 1 hour prior to processing into paraffin wax. Sections are then cut for microscopy and stained for routine analysis with haematoxylin and eosin. Spongiform change is most easily recognised at this tissue section thickness; the use of thick ( 10 microns or more) sections carries the danger of misinterpretation of other sponge-like changes in the cerebral cortex ( see below).


In most cases of human prion diseases the histological features are distinctive and will allow a diagnosis to be reached without undue difficulty. In CJD, the most consistent histological abnormality is spongiform change, which is characterised by a fine vacuole-like appearance in the neuropil, with vacuoles varying from 20-200 microns in diameter (Figure 1). These vacuoles can appear in any layer of the cerebral cortex and may become confluent, resulting in large vacuoles which substantially distort the cortical cytoarchitecture. Vacuolation may also be seen within the cytoplasm of larger neurones within the cortex. Cortical involvement is detectable in most cases of CJD, and is usually accompanied by spongiform change in the basal ganglia, thalamus and cerebellar cortex. Cerebellar involvement is present in most cases, although the severity and distribution of the spongiform change is markedly variable. Confluent spongiform change is unusual in the cerebellum, which may however exhibit a widespread microvacuolar change with smaller vacuoles 20-50 microns in diameter in the molecular layer
Other Histological Features in Human Prion Diseases


A range of other histological abnormalities have been described in human prion diseases, some of which relate to the affect of ageing on the human brain and have no specific association with this group of disorders. These abnormalities include swollen cortical neurones and amyloid angiopathy; other changes are summarised in Table 1. It is critically important to be aware of age-associated histological abnormalities in the human brain and not to interpret these as being indicative of a coexisting CNS disorder. Alzheimer's disease and CJD been described concurrently, although this appears to be an exceptional event. Other more apparently specific abnormalities have been described in cases of CJD which have been studied by ubiquitin immunocytochemistry. These abnormalities include dot-like ubiquitinated strutures in the neuropil, within neurones and around PrP plaques. The latter probably represent dystrophic neurites, while the intracellular lesions may represent lysosomal structures, as suggested by animal scrapie models.




Table 1 Histological changes in human prion diseases


Classical changes spongiform change
neuronal loss
astrocytosis
PrP amyloid plaques
Other changes status spongiosus
neuronal swelling
abnormal neuritic dendrites
white matter necrosis and cavitation
microgliosis
beta protein amyloid angiopathy




Other Conditions Associated with Spongiform-Like Change in the CNS


The importance of spongiform change as one of the histological hallmarks of human prion diseases is widely accepted, and clear distinctions have been made between spongiform change and status spongiosus. Status spongiosus can result from any neurodegenerative disorder which results in widespread neuronal death and collapse of the cerebral cortical cytoarchitecture. It is commonly encountered in Pick's disease and may also occur in Alzheimer's disease, cortical ischaemia and as a consequence of viral encephalitis. Spongiform change per se is not pathonomonic for human prion diseases. Appearances identical to spongiform change have been described in other neurodegenerative disorders (see Table 2), particularly in Alzheimer's disease and diffuse Lewy body disease. In these disorders spongiform change is usually confined to layer 2 of the cerebral cortex and is present in a restricted distribution in the frontal lobes, cingulate gyrus, temporal poles and inferior temporal cortex. In occasional cases of Alzheimer's disease and diffuse Lewy body disease the spongiform change may be particularly conspicuous and necessitate widespread histological sampling along with additional investigative techniques, including PrP immunocytochemistry, to investigate the possibility of human prion disease. It should also be recalled that other neurodegenerative disorders resulting in focal spongiform-like change are associated with distinctive lesions which help clarify diagnosis. Other disorders which may cause a sponge-like appearance in the CNS are listed in Table 2. In these disorders, confusion with spongiform change in human prion disease is not a major difficulty because of the clinical and pathological context in which these changes occur.



Table 2 CNS disorders with focal spongiform change


Alzheimer's disease
Pick's disease
diffuse Lewy body disease
dementia of frontal lobe type
dementia in motor neurone disease

Sponge - like changes in other CNS disorders

Grey matter status spongiosus
oedema
metabolic encephalopathies
neuronal storage disorders
tissue fixation and processing artefacts

White matter oedema
ischaemia
metabolic encephalopathies
spongy degeneration of the white matter in infancy
Canavan's disease
tissue fixation and processing artefacts
Groups and bodies

ACDP
Advisory Committee on Dangerous Pathogens. Government Committee which regularly produces information regarding the handling of dangerous materials.
CVL
Central Veterinary Laboratory. The government laboratory which performs a substantial amount of research into BSE.
DoH
The UK Department of Health.
MAFF
Ministry of agriculture fisheries and food in the UK.
NPU
Neuropathogenesis Unit. A research unit with substantial experience of the investigation of scrapie, jointly funded by the Biotechnology and Biological Sciences Research Council and the Medical Research Council.
SEAC
Spongiform Encephalopathy Advisory Committee. Government formed committee consisting of independent experts in the field of spongiform encephalopathy.

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Scientific and medical terms

Alzheimer's disease
The most common dementing illness of the elderly in the UK. The neuropathology of Alzheimer's is significantly different from that of CJD and the clinical course of the disease is normally of the order of several years.
Amyloid
A chemical struture which can accumulate in brain tissue as a result of a variety of different diseases. In CJD the amyloid is normally made-up of the prion protein.
Amyloidogenesis
The production of amyloid.
Amyloidosis
The build up of amyloid to a degree that it causes damage to the tissues or action of those tissues in the body.
Astrocyte
Common cell type in the brain that supports the functions of the neurons.
Astrocytosis
The proliferation of astrocytes in brain tissue. This is a common finding in CJD neuropathology but it is not specific to this disease.
Ataxia
Inability to coordinate muscle control resulting in irregularity of movements.
Bioassay
The inoculation of an infective substance into another animal in order to see if the second animal develops the same disease. Different dilutions of tht infective substance are used to assess how infective the substance is.
BSE
Bovine spongiform encephalopathy (or mad cow disease).
Clinicopathological correalations
The similarites between the clinical symptoms of a patient and the pathological findings. For example, ataxia in a patient may relate directly to cerebellar degeneration when this part of the brain is examined under the microscope.
CNS
Central nervous system. General term used to described the brain and the spinal cord.
CJD
Creutzfeldt-Jakob disease. The most common human SE which is characterised by a rapidly progressive dementia. Identified in the 1920s through the work of Creutzfeldt and Jakob.
CSF
Cerebrospinal fluid. The clear fluid that surrounds the brain and spinal cord, filling the ventricles of the brain.
DNA
Deoxyribonuclic acid. The chemical that carries the genome in the chromosome of animals, plants and some viruses.
Dominant
The extent to which a gene is expressed; dominant indicates that it is expressed a lot.
Downer cows
A term used in the US to describe cattle that do not have the ability to stand, it has never been proven that any of these cows have BSE.
EEG
Electroencephalogram. The trace of electrical activity in the brain. In patients with CJD this can, but doesn't always, show characteristic signs.
Epidemiology
The study of distribution of cases of a disease.
FFI
Fatal Familial Insomnia. A genetic disease found in humans which does not have the pathological hallmark of the spongiform encephalopathies but is related to a genetic mutation of the prion protein gene.
FSE
Feline spongiform encephalopathy. A recently discovered SE of the domestic cat, thought to be related to the consumption of BSE material in cat food.
Gene
A unit of material which contains DNA and forms part of chromosome which is resposible for one function. Hence the genetic make-up of an individual determines their physical attributes.
Genetic Mutation
A chemical change in the genes of a cell which cause it to have a different function.
Genotype
The genetic make-up of an individual.
GSS
Gertmann-Straussler-Scheinker Disease. A familial SE found in humans and associated with a few specific mutations of the PrP gene.
Iatrogenic
A disorder with is caused by a medical treatment. In CJD a certain number of cases appear to have resulted from injections of infected growth hormone material.
Immunohistochemistry
Chemical techniques used to indentify the deposit of particular chemicals or proteins in tissue. Common used to locate prion protein in brain tissue from SE using an anti-PrP antibody.
Infectious Agent
The chemical organism that causes a particular disorder. Scientific opinion is divided about the biological nature of the agent that causes SEs. The two main theories are the Prion hypothesis and the Virus theory.
Kuru
A TSE found only in the Fore tribe in New Guinea most likely related to ritualistic cannabalism carried out amoung members of the tribe. Transmissibility of the disease has been established through the work of Gadjusek.
Locus
The position a gene occupies in the chromosome.
Maternal transmission
The transmission of disease from the mother to the offspring.
Microglia
Immune cells from inside the CNS
Murine models
models of disease, using mice as the animal being infected.
Myoclonus
Neuroanatomy
The anatomy of the brain, spinal cord and peripheral nervous system.
Passage
The inoculation of an infection into an animal and then harvesting the infective agent from the animal.
Pathogenesis
The production of damage (pathology) in a tissue.
Pathology
The study of disease infected tissue.
PCR
Polymerase chain reaction. A method used to make multiple copies of DNA. A stage used in the examination of a DNA sample to determine whether they have a genetic mutation or not.
Peripheral nervous systems
The nerves and sensory systems outwith the brain and spinal cord.
Phenotype
The effect made on the organism by the genes that it carries. Some genes (see genotype) may have no effect.
Plaques
The accumulation of protein that may build up in brain tissue as a result of infection.
Prion
PROteinaceous INfectious agent. The prion theory suggests that the infective agent of CJD (and the other TSEs) is only composed of a protein and does not contain nucleic acid which would be necessary if the agent was a conventional virius.
PrP
The prion protein. This is a normally occuring protein found on the surface of particular cell types - PrPC. The abnormal form PrPCJD (or PrPScrapie) accumulates in the disease brain and is thought to be the main (or only) consistuent of prions.
RNA
Ribonucleic acid. Often found in viruses as the nucleic acid that carries the genome of the agent.
SAF
Scrapie associated fibrils. These are the fine structures, seen under the electron microscope that are only found in brains of TSEs.
Scrapie
The TSE of sheep or goats.
SE
Spongiform encephalopathy.
Species barrier
The naturally occuring barrier between different species of animal which makes transfer of a disease from one to the other difficult.
Sporadic
Cases of CJD that occur at random throughout the world are categorised as sporadic if they have no genetic mutation or any known iatrogenic infection.
Strains
Different forms of the sheep TSE scrapie have been isolated by transmission to mice. These strains cause variations in the incubation period and pattern of pathology observed in the infected animal. As yet no strains of CJD have been identified.
TME
Transmissible mink encephalopathy. This is a SE of mink found in mink farms in the US. It was initial reported in the 1960s.
TSE
Transmissible spongiform encephalopathy. A disease that has the pathology characteristic
Ultrastructure
The physical and chemical structure of the amyloid or PrP. Often this includes the way in which the proteins are shaped.
Vertical transmission
The transmission of an illness from the parent(s) to the offspring.
Virino
A small item that may be the infective agent of a TSE. It contains protein and nucleic acid.
Viroids
Small virus-like particles. A term used often in TSE to get around the fact that the infective agent is not yet known.
Virus
A infective agent with a specific structure and able to cause its own multiplication after infection of specific cells.

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Answer 2

This particular disease is a tough one to study. It isn't caused by bacteria or a virus. It is a protein that in its original state causes no harm, but for reasons not yet understood the molecules in the protien cause it to become distorted and the disease begins. Anitibiotics and antivirals will have no effect because it's not a pathogen. From what I have read it will take extensive research and will probably be some sort of enzyme therapy that attacks only that particular protein and destroys it. Sadly, that will be a long time in coming.

My condolences for your loss.

Answer 3

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