Creutfeldt-Jakob Disease (CJD)

History of CJD

Creutzfeldt-Jakob disease was first recognised as a specific disease in 1921. typically, CJD presents as a progressive mental deterioration, sharing several clinical features with Alzheimer's disease (AD). But AD is a non-transmissible disorder. In the initial clinical stages AD and CJD can be so similar that the two diseases cannot always be distinguished while the patient is alive. For details see Death on the Menu.

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From published studies, it is obvious that the term CJD has been used by many authors and has covered a wide spectrum of clinical symptoms, which are known to vary from case to case.

Three Groups of CJD Cases

Epidemiological studies of the worldwide occurrence of CJD have revealed the existence of three groups.

(1) Familial CJD

These cases occur within the same family and represent approximately 5 to 15% of CJD cases. The major distinguishing features of familial disease are the longer duration of illness and its onset at an earlier age.

Some familial cases are classified as Gerstmann-Sträussler-Scheinker syndrome (GSSS). This is a rare type of CJD and was first described in an Austrian family in 1936. Subsequently, GSSS has been reported in about a dozen other unrelated families as well as in sporadic form. GSSS cases have been demonstrated to be infectious by experimental transmission of disease to other animals with extracts of brain tissue from human patients, suggesting that the agent may be carried via a germline as in AIDS and is not a genetic disease. (a Genetic disease is not infectious.) But how can an infectious disease be a genetic disease?

Affected ewes mated with affected rams produce offspring, which nearly always become affected. Vertical transmission has been also observed in BSE cattle. Recently CJD has been reported in a mother and baby daughter in the UK suggesting vertical transmission in humans.

(2) Iatrogenic CJD

Iatrogenic CJD constitutes a small percentage and are caused by accidental inoculation (through contaminated instruments) and through the use of contaminated human growth hormone (hGH). Since 1985, more than 65 cases of CJD have been described among recipients of pituitary-derived hGH. These cases have been reported in the USA, UK and France. The clinical presentation in the hGH recipients begins with cerebellar function deterioration, with severe ataxia, especially of the legs, while mental deterioration is a late manifestation. It is interesting to note that the clinical presentation of these hGH patients also resembles that of the "new strain" of CJD cases.

(3) Sporadic CJD

Cases of CJD whose origin is in question are termed sporadic. Sporadic CJD, which forms the majority of cases, is rare, but found worldwide. CJD presents a broad variety of clinical manifestations, involving dementia during middle and late life. Compared with Alzheimer's disease, CJD follows a more rapid course over a period of four to seven months.

Since the first appearance of bovine spongiform encephalopathy (BSE), CJD has been identified in young patients with leading clinical features, such as difficulty in balancing and ataxia. This is sporadic CJD. The young victims, like older patients, do not have dementia as the leading symptom.

The incidence of sporadic CJD used to peak between 55 and 75 years (5). Some exceptions have been reported amongst more than 3,000 cases worldwide. Nine cases have been documented in patients under 30 year olds, the youngest being 16. Three of these "under-aged" CJD patients were well-known cases of surgical (iatrogenic) transmission. The incidence of sporadic CJD in people under the age of 40 had been estimated to be about 1 per 20 million. From the worldwide statistical figures of sporadic cases, the chance of three CJD cases occurring in one year in this age group, should have been of the order of 1 in 1012. Since this time the appearance of BSE and CJD has been confirmed in a large number of "under-aged" patients in the UK.

Odd cases of sporadic CJD

Foley et al (15) and then Brownell et al (16) reported a number of cases of progressive encephalopathy occurring in middle-aged patients under the heading 'The Ataxic-cerebella form of CJD'. The outstanding clinical features, in order of their appearance reported, were rapidly progressive ataxia of cerebella, with imperfect articulation of speech and involuntary rhythmic jerking movements.

Subsequently, several further cases with initially ataxic symptoms of CJD have also been reported in Europe, the USA and Japan. In this ataxic-cerebella form of CJD the symptoms appear to start in the same way as those observed in "nvCJD" and kuru patients. As the ataxia progresses, a distinct tremor becomes apparent. At times there has been disagreement as to which of these cases should be included in the CJD group.

New Variant CJD

Since the appearance of BSE, Narang (1990) reported four "atypical" cases with unusual clinical course with leading clinical features such as difficulty in balancing and ataxia in 47 to 84 year old patients different from those seen in typical sporadic CJD cases.

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Some of the early symptoms include behavioral and mood changes with depression. Balancing and walking become difficult. Patients feel as if they are going to fall and need support.

These symptoms become more marked, with a swaying and weaving gait. The patient tends to trip and stumble. The symptoms are similar to those seen in the ataxic-cerebella form of CJD and kuru.

In the UK during 1994 and 1995, a further ten cases of CJD were reported in relatively young persons where the clinical course was not typical of sporadic CJD. Their age and clinical presentation differentiated them from "classical CJD", and the term new variant CJD (nvCJD) was introduced in the UK.

Like scrapie there are two types of sporadic CJD cases. Type 1, is caused by Type I scrapie. Three main distinguishing features are: a) the classical CJD starts with dementia. b) Confluent spongiform changes are very unusual in the cerebellum in classic CJD. 3) PrP plaques are rarely observed in classic CJD.

Type 2 CJD has been termed "new variant" (nvCJD) and is caused by the BSE strain of the agent. Three main points distinguishing them are: a) Starts with leading clinical features, such as difficulty in balancing and ataxia. B) Confluent spongiform changes are seen in the cerebellum c) The other main distinguishing feature of "nvCJD" is the distribution of PrP plaques, which are unique and different from those traditionally observed in classic CJD. 

Pathological difference between "classical CJD" and nvCJD

In "nvCJD" the distribution of lesions and PrP plaques in brains different from that traditionally observed in classic CJD. CJD is diagnosed by microscopic examination of the brain sections. The pathological changes are distinctive with spongiform changes. A particularly striking feature is the damaged cerebral cortex, especially in the occipital lobes. Variation in the intensity, the distribution of lesions and the stage of development from case to case are evident from the reported cases. However, confluent spongiform changes are very common in the cerebellum (the part that controls body balance) in nvCJD and never seen in classic sporadic CJD cases. This is second main outstanding distinguishing feature of nvCJD.

What are plaques? Plaques are formed by specific accumulation of protein in brain. By immunohistochemical staining process, two types of plaques have been identified in the CJD brain.

(i) amyloid ß-protein positive plaques termed amyloid plaques are a "hallmark" of Alzheimer's Disease. A small number of amyloid plaques have been observed in about 15% of CJD cases.

(ii) Protease-resistant protein (PrP 27-30 kDa) positive plaques derived from PrP33-35 kDa precursor protein (PrP-c), commonly called "prion" protein, is coded by a normal host gene. It is important to point out that PrP positive plaques have not been observed in Alzheimer's Disease or any other non-SE neurological disorder. The most consistent striking microscopical feature is the staining of PrP plaques varying in size from 2-3µm (Fig). Pericellular PrP plaques are extensively distributed throughout the cerebrum and cerebellum in nvCJD brains and never seen in classic sporadic CJD cases. This is the third main outstanding distinguishing feature of nvCJD.

Differences are very obvious in the size and distribution of PrP plaques in the cerebellum of recipients of pituitary-derived hGH CJD cases compared to young sporadic CJD patients infected with the BSE agent. In one patient (EB) who had received blood, where the PrP plaques were much smaller in size as seen in hGH cases.

The identical size and distribution of PrP plaques in brains of hGH treated cases and blood recipient cases suggests that the blood transfusion case was infected through infected blood.

How atypical CJD cases were discovered? In the atypical cases, the clinical symptoms and pattern of brain damage were markedly different from those seen in typical sporadic CJD. Based on conventional and accepted diagnostic criteria for CJD, none of these cases on clinical ground would have been considered as even "probable" cases of CJD. Initially, they had been identified as CJD cases because their brains were examined by a technique, which I had developed. This included brain examination and a urine test.

The "old classic" CJD
"New" strain CJD
Classic disease starts with "dementia" Starts with difficulty in "balancing"  and walking
No Spongiform changes in the cerebellum Extensive Spongiform changes  in the cerebellum
PrP Plaques are rare unique distribution of PrP plaques in their brains.

I believe classical sporadic cases are caused by accidental inoculation of Type 1 scrapie from sheep, whilst the sporadic cases with leading symptoms of balance develop after ingestion of the BSE strain of the agent.

nvCJD Disease in all age groups: Over 8 years, during 1989-1996, I have examined clinical histories of 33 CJD cases aged between 18 and 84. Six under the age of 40 and fifteen over the age of 40 had the following symptoms:

1) Leading clinical features such as difficulty in balancing and ataxia.

2) Brain revealed spongiform changes in the cerebellum.

3) PrP plaques were extensively distributed throughout the cerebrum and cerebellum.

Based on these newly developed features because they were new the term nvCJD was introduced. As the classification of nvCJD is based on these three features then all age group of patients have developed CJD after eating infected food.

I believe this is not a new disease in humans. Such cases did occur in the past and were classified as classical CJD.

These findings suggest that all age groups are susceptible to the strain of the agent derived from BSE cattle. Age should not be a criterion to substantiate the claim that older people are not being infected with this strain of the agent.

Based on these findings, the present estimate as of September 1999 that only 46 persons have died from this strain, may in fact, be a gross misrepresentation of the true numbers.

CJD and blood transfusion evidence presented also demonstrates that a small percentage of CJD cases are being caused by accidental use of contaminated blood from CJD victims. Clinical histories of these cases have been described in detail in “Death on the Menu”.

Reviews of the literature have revealed that nvCJD is caused by the BSE strain of the agent. However, this is one of the old, rare strain of scrapie in sheep - the "trembling type", not a new strain. It originated from Type 2 scrapie sheep with trembling and ataxia.

In experimental animals, blood of CJD patients has been shown to be infectious, both during the incubation period and the clinical phase of CJD. Klein et al (1992) and Tateishi (1985) independently transmitted the disease from crude suspension made in normal saline of the brain, cornea, and untreated cerebrospinal fluid (CSF), blood samples and urine from a patient infected with CJD.

One epidemiological study, Esmonde et al (1993) in the UK out of 202 definite and probable cases identified 21 CJD patients who had received a blood transfusion, and 29 who had donated blood. The mean interval from blood transfusion to the onset of the clinical symptoms of CJD was reported to be 174 months.

The clinical features recorded in the blood transfusion CJD recipients were similar to those observed in the sporadic cases, and therefore Esmonde et al suggested that blood transfusion is not a major risk factor for CJD. At the same time the authors also concluded that evidence does not exclude the possibility that isolated cases of CJD are caused by the transmission of the causative agent through transfused blood.

A result of comparative pathology combined with immunohistochemical staining demonstrates the possibility that isolated cases are being caused by the transmission of the causative agent through transfused blood. I have identified in my case studies at least 12 CJD victims who have been blood donors. I understand that the brain pathology of CJD victims where the disease was caused by growth hormone treatment is different from the pathology of classical and nvCJD in that there is a different distribution of PrP plaques. In one case where the patient had had a blood transfusion about four years before symptoms appeared, an examination of the brain revealed a distribution of PrP plaques similar to that seen in growth hormone human-to-human transmission.

In the light of this it would be prudent to examine the brains of people who have died of CJD and who have had recent blood transfusions to be re-examined. All new cases should be properly tested.

From time and again the point has been made that there is a subpopulation of humans with a different PrP gene and these will not develop CJD. It is obviously clear now as I stated in my evidence to the BSE Inquiry, it is the effect of vaccine that prevents humans from being infected with the BSE strain of the agent and not genetic variation as many scientists have been suggesting.