Spectre of CJD plague recedes

THE threat of an epidemic of Creutzfeldt-Jakob disease caused by beef infected with BSE is receding, latest figures indicate. [Note these figures do not include CJD misdiagnosed as Alzheimer's --webmaster]

Forty-six suspected cases were referred to the National CJD Surveillance Unit in Edinburgh in the first five months of the year, only slightly up on previous years. The figures will be published by the Government this month. At that rate this year's total will be 110, compared with 79 in 1995 and 115 in 1994. At least five of the 46 are suspected of being the new variant linked to BSE.

Although many suspected cases turn out not to be CJD ­ in previous years only about half have been confirmed as genuine ­ a big rise in referrals would have been seen as confirmation of an impending epidemic. Last March, when government scientists first announced a likely link between BSE and CJD, some scientists predicted up to 500,000 deaths.

James Ironside, the consultant neuropathologist at the surveillance unit who first identified the new variant, said the chances of a devastating epidemic reduced with each month of low referrals.

"But the fact that we have not seen a huge increase in referrals does not mean we won't see an increase in cases over the next few years and it does not weaken the hypothesis of a link between BSE and CJD," he said.

Symptoms of Early-Onset Variant-CJD

"The most striking and consistent neuropathological abnormality in all cases was PrP plaques. In the eight necropsy cases, plaques were extensively distributed throughout the cerebrum and cerebellum, with smaller numbers in the basal ganglia, thalamus, and hypothalamus. Many of these plaques resembled kuru-type plaques with a dense eosinophilic centre and pale periphery, and, unusually for this type of lesion, were surrounded by a form of spongiform change (figures 1 and 2). This unusual feature was not seen in any of the other 175 sporadic CJD cases investigated....

"These qualitative differences in the nature of the neuropathological lesions and morphology of PrP deposits were matched by an apparent increase in the amount of PrP deposited in all grey-matter regions compared with sporadic cases, 12 iatrogenic cases, six cases of inherited CJD and in four cases of Gerstmann-Strausler-Scheinker syndrome...."

"The ten cases in this report are remarkable in that they have a specific neuropathological profile which, to our knowledge, has not been described previously, and which is so consistent that neuropathological samples from the cases are virtually indistinguishable. The cases are further characterised by having remarkable low ages at onset for CJD and other atypical features, including a generally protracted and unusual clinical course and absence of EEG changes typical of CJD. These findings raise the possibility that the cases represent a new clinicopathological variant of CJD."

Distinguishing variant-CJD within sporadic [non-inherited] CJD

Will's article on v-CJD describes the pathologic findings along with the clinical findings. The frequent pathologic finding in v-CJD was the presence of numerous plaques which showed immunostaining with PrP. In sporadic CJD, plaques aren't frequent, and spongiform change is the major feature. The presence of plaques is a feature of Kuru but has been described before as an infrequent finding in CJD. When plaques are present in CJD, the disease has tended to be seen in younger individuals and has tended to be associated with cerebellar symptoms. A review of this can be found in an article by Pearlman, Towfighi, et al. in Neurology in 1988.

V-CJD is distinguishable conclusively only at post mortem, and more closely resembles Kuru than CJD. Only cases younger than 45 years have been reported as V-CJD, and it is possible that the differing pathology is a consequence of youth and also that other, earlier cases will turn up in historical collections.

Bruton CJ et al (1995), Neurodegeneration 4(4):357-368 Diagnosis and incidence of prion (Creutzfeldt-Jakob) disease - A retrospective archival survey with implications for future research. The article suggests that only 60% of CJD had been reported in the past, and that younger cases presented similarly to what is now called V-CJD].

It is certainly true that reported cases of CJD have risen by 30% comparing the 7-year period before 1986 with the 7-year period afterwards, and that this is statistically significant (p < 0.05), but it is more probable that reporting has increased than that deaths have increased. I do not exclude the possibility that there has been a real increase in CJD incidence and I agree that if there is an effect it is also likely to appear at older ages. At present, however, the statistical evidence does not support a real increase in incidence, either amongst young or old populations.

It is particularly notable that around 10% of all CJD cases in Britain are younger than 45 years (compared to 4.5% in the US and elsewhere) and that this was so before the first reports of BSE (9% before 1986, 11% after 1986, no significant change, p = 0.6), although cases under 20 years are highly unusual.

Three cases amongst dairy farmers is also unusual, but there have been statistically significant excesses in other occupational groups not especially exposed to beef (eg: ministers of religion) and there are many thousands of occupational groups in which a chance clustering could occur. No excess deaths in other "beef-exposed" group have emerged (eg: abattoir workers, meat packers, vets, veterinary pathologists). Only the beef-exposed excesses make it to the news.

There is a statistical problem with small clusters (2-3 pathologists etc) because, although the disease is rare, clusters will always appear in some groups and it is so easy to define the groups ex post facto (eg: Sheila Gore's letter in the BMJ in April) - first find some cases, then find a common exposure to "explain" them. Pathologists may be at risk of CJD but the data is not statistically significant. The corneal and dura mater numbers are quite big, and it does look like the efficiency of infection from transplants is very high and far more than 1/1,000,000 of donors are infectious. The best estimate of spongiform encephalopathy in humans [which includes CJD] seems to be 70 per million or 70 times the CDC death certificate rate of CJD.

1994 was a high incidence year in all the countries in the European surveillance collaboration, with the Netherlands highest at 1.05 per million. Source: UK CJD Surveillance Unit

Summary: 33 cases of sporadic CJD in UK dying under 45 years of age, UK population is 57.07 million. 185 cases out of 206 examined since 1990 were considered sporadic [non-familial].

Perspectives on CJD:

1. Infectious and Parasitic Diseases- Diseases which are contagious (can be transmitted from one human or species to another), as well as a few diseases of unknown but possibly infectious origin. Includes Bacterial and Viral Diseases. Example: Tuberculosis, AIDS.
2. Neoplasms-New (neo) growth of tissue which does not serve any physiologic function. Neoplasm can be benign (harmless) or malignant (harmful), meaning cancer. Example: Leukemia, Lung Cancer, Breast Cancer, Prostate Cancer, Bone Cancer, Colon Cancer.
3. Endocrine, Nutritional, and Metabolic Diseases- Endocrine Glands are the hormonal glands, including the Thyroid, Ovary, and Pancreas. Example: Diabetes. Metabolic diseases are abnormalities of one's ability to metabolize. Example: Cystic Fibrosis.
4. Blood and Blood-Forming Organs- Includes blood loss, blood coagulation (clotting) and deficiencies in blood cells. Example: Iron Deficiency Anemia, Sickle Cell Anemia, Hemophilia, Lymphoma, Leukemia, and Spleen.
5. Mental Disorders- Organic psychotic conditions such as Alzheimer's, but mainly other psychoses and non-psychoses such as depression disorders. May be associated with suicide, drug and alcohol abuse. Also includes physiological conditions arising from mental factors, including Anorexia Nervosa and Bulimia.
6. Nervous System and Sense Organs- Diseases which affect the Central Nervous System (spinal cord and brain), and the Peripheral Nervous System (all nervous tissue other than the spinal cord and brain). Example: Intracerebral Aneurysm, Meningitis, Parkinson's Disease.
7. Circulatory System- Diseases which affect the arteries and veins, as well as the heart. Example: Myocardial Infarction (heart attack), Pulmonary Embolism (blood clot in lungs), Congestive Heart Failure, Abdominal Aortic Aneurysm.
8. Respiratory System- Diseases which affect the system which aids in exchange of oxygen in the lungs into the blood stream. Example: Emphysema, Pneumonia.
9. Digestive System- Diseases which affect the system which breaks down food, carries it through the body, and eliminates it from the body. Example: Appendicitis, Perforated Ulcers, Cirrhosis.
10. Genitourinary System- Diseases which affect the kidney, bladder, and reproductive organs. Example: Renal Failure.
11. Complications of Pregnancy, Childbirth, and the Puerperium (3-6 weeks after childbirth)- Example: Ectopic Pregnancy, Miscarriage.
12. Skin and Subcutaneous Tissue- Diseases which affect the skin, fatty tissue, and muscle. Example: Acute Lymphadenitis.
13. Musculoskeletal System and the Connective Tissue- Diseases which affect the bones, joints, ligaments, and tendons. Example: Lupus, Rheumatory Arthritis.
14. Congenital Anomalies- Abnormalities that manifest during gestation and become relevant at the time of birth or afterwards. Example: Congenital Heart Disease, Hydrocephalus.
15. Certain Conditions Originating in the Perinatal Period (the period before and after birth, roughly from the 20-28th week of gestation to 7-28 days after birth)- Diseases in which the fetus or newborn is affected by maternal conditions or birthing complications. Example: Drug Abuse, Fetal Alcohol Syndrome, Cocaine, Chronic Circulatory or Respiratory Conditions, Low Birth Weight, Placenta or Umbilical Cord Complications.
16. Symptoms, Signs, and Ill-defined Conditions- Example: Coma, Cardiogenic Shock, Sudden Infant Death Syndrome, Asphyxia, Respiratory Arrest.
17. Injury and Poisoning- Example: Intracranial Injury, Injury to Liver, Open Wound, Crushing Injury, Burns, Hypothermia, Anaphylactic Shock.

CJD, Italian Style

Purtroppo non esistono ancora terapie capaci di modificare la storia naturale della malattia di Creutzfeldt-Jacob, la cui evoluzione è rapidamente progressiva. Basti pensare che il 90 per cento dei pazienti muoiono entro un anno e i casi di sopravvivenza superiore a due anni sono veramente eccezionali.

Che si tratti di una malattia infettiva è noto da tempo; già nel 1968 infatti, alcuni ricercatori avevano osservato che il tessuto cerebrale prelevato grazie alle autopsie ed iniettato negli scimpanzè poteva indurre il quadro tipico dopo un adeguato periodo di incubazione.

Dal 1968 ad oggi molte informazioni sono state raccolte, tuttavia le modalità con cui la malattia si contrae in natura non sono ancora note con precisione. La possibilità di trasmissione da un individuo malato ad uno sano non è stata accertata; allo stesso modo non sono state identificate sorgenti di infezione nell ambiente esterno.

L unico modo di trasmissione sicuramente dimostrato è quello che in termini tecnici viene definito iatrogeno , ossia effetto avverso conseguente a un trattamento medico o chirurgico. In alcuni casi si è verificata la malattia dopo un trapianto corneale o dopo l impianto in profondità di elettrodi infetti.

In Francia sono stati documentati negli ultimi anni 25 casi in persone trattate tra il 1984 e il 1985 con ormone della crescita estratto dall ipofisi di cadaveri. Queste tragiche esperienze hanno indotto lo sviluppo di studi atti ad individuare metodi adeguati di prevenzione.

L ormone estratto dai cadaveri, che in Francia si è rivelato più pericoloso che altrove, è stato sostituito dovunque nel mondo con un ormone biosintetico. Sono state inol tre redatte linee guida per il trattamento del materiale venuto a contatto con tessuti infetti. La combinazione di metodi chimici e fisici, se applicata scrupolosamente, si è dimostrata in grado di garantire la sicurezza di strumentazioni e altri materiali. Particolari misure devono inoltre essere prese durante le autopsie dei casi sospetti.

E chiaro che maggiori possibilità di prevenzione potranno derivare solo da un aumento delle conoscenze. La dimostrata suscettibilità di alcune persone ad ammalarsi e l esistenza di casi familiari rappresentano in questo senso un dato importante. E stato infatti evidenziato che i soggetti ammalatisi dopo l esposizione ai trattamenti a rischio possiedono tutti un particolare gene.

A cura del Centro Informazioni per le Malattie Rare
Istituto di Ricerche Farmacologiche Mario Negri
Centro di Ricerche Cliniche per le Malattie Rare "Aldo e Cele Daccò"

Adapted from Stekel, Nowak, and Southwood. "Predictions of future BSE spread," Nature 21 May 1996. Two methods of estimating future cases were used, giving higher and lower bounds. Thousands of new cases are predicted through the end of the century.

According to records of the Ministry of Agriculture Foods and Fisheries [MAFF] at least seventeen calves, of the 23.000 cows confirmed with BSE since the June 1988 feed ban, were between 20 and 30 months.

Source: A. Osterhaus, member of the European Scientific Veterinary Committee and other Dutch scientists: letter to the Dutch Minister of Agriculture, dated April 1st 1996.

In 1994, Maff released figures (in response to shadow Minister of Agriculture Strang) stating that in the period from the June 1988 feed ban till December 1993, three calves younger than two years (24 months) were BSE-infected. The figures of infected cows between 24 and 36 months were:

1988	6
1989	47
1990	70
1991	81
1992	39
1993	22
Totals	265

Source: Institute for Animal Science and Health, ID-DLO, Lelystad, Netherlands

25 May 96 Listserve Commentary on above tables:

Cross-contamination with pig or poultry feed after 1990 has likely affected some herds. This was entirely predictable. As a result we should see a marked difference in the pattern between the two herd types, ie those not subsequently reinfected and those significantly infected after 1990. The UK herd is thus likely to split into two groups over the next couple of years, those with essentially no cases from animals born after 1989/90 and those with significant cases from after that time. It is this group that I presume are targeted with the proposed culling program.

Disposal of culled animals. It is clear that the entire incineration and rendering industry of the EC is unable to cope with even those animals over 30 months. I have noticed an inability of many to fully comprehend this. Calls for a full cull of affected UK herds are nice politics but essentially not possible. The environmental consequences are also not at all good.

A rational and sensible way of handling it would be to butcher out the SBO's [specified bovine offals] and incinerate them. Then process the non-SBO's into M&B meal but place it's use under severe restriction, after all the evidence is rather strong that this is fit for human consumption so it's use for specific animal feed should at least be considered. One should note that this effectively doubles the number of animals that can be processed. The sort of restriction I had in mind would be along the following lines:

a) Feed mills that use this M&B must be prohibited from producing any ruminant feed at all of any kind from that site.

b) Vehicles used for the M&B meal and produce that contains it should be prohibited from carrying anything else. (Ie a plate?)

c) End users (most likely poultry and specialised pork finishers) that are permitted to use it must be approved by MAFF. Typical regulations might restrict it's use to sites that have no ruminants, and any chance of ruminants on surrounding sites becoming contaminated must be nil.

BSE Eradication: Progress as of November 1995

154,592 confirmed BSE cases in 32,906 herds by 3 Nov 95.

BSE by County: worst herds located in E, SW and SE England
* warblecide eradication zones declared in 1988/89

	BSE by County
Regions:	Cases/herd	Total Cases
South West England*	6.2	57,530
Midland & Western England*	4.4	31,384
South East England*	7.1	17,172
Northern England**	3.4	15,987
Wales*	3.0	14,589
Eastern England	6.8	10,501
Scotland	2.4	7,429
Total	4.7	154,592