Conference Report - Spongiform Encephalopathies Part 2

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Human Spongiform EncephalopathiesKuru: A Story of Friends and Cannibals

Carl Gajdusek, an expert in chemistry and virology, contributed significant

insight and evidence to the study of a disease that was endemic in New Guinea in

the 1950s -- known as kuru or the " laughing death. " A devastating disease,

characterized by unsteady gait, tremors, blurred vision, stupor, and death

within a year, it was believed by African men to have magic origins as it

affected mostly women and children.[16] After patient investigations, Gajdusek

uncovered the source and mechanism of transmission of kuru. Indeed, as some

people were whispering, it was linked to cannibalism.

 

As illustrated by Dr. Britton, far from the idea of cruel rituals, in those

years, cannibalism in New Guinea seems to have stemmed as a tragic consequence

of extreme poverty. Only men were allowed to eat the little meat that would

become available; women and children would be completely excluded and were,

thus, severely undernourished. Hence, the tradition developed for women to leave

their own bodies to their best friends so as to ensure their survival.

Consumption occurred as a ritual performed in hidden places, far from the men,

and the brain might have represented one of the most precious parts.

 

Once Gajdusek was able to obtain a specimen, he sent it to the National

Institutes of Health for further examination and analysis. Satisfying one of the

most important principles of Koch (a set of criteria used to prove the

infectious nature of a disease), kuru was then shown to be transmissible from

human brain tissue to a chimpanzee who developed symptoms very similar to those

of human patients: shivers, no balance, open jaw, and weight loss. Findings at

the pathology examination were also superimposable.

Sporadic Creutzfeldt-Jacob Disease

The signs and symptoms of kuru were very similar to those of another disease,

the Creutzfeldt-Jacob disease (CJD), originally described in 1920-1921 by

Creutzfeldt and Jacob in Austria.[17,18]

 

As of today, about 250 cases are being diagnosed per year in the United States,

in subjects with a median age of 61 years. In fact, it is a quite rare disease

in individuals younger than 40 or older than 80 years of age. Other sporadic

cases are being reported in other countries without any specific pattern.

 

Patients affected by CJD were found to have dementia, myoclonus, periodic sharp

waves at the EEG, diffuse PrP immunoreactivity, but no deposition of amyloid. In

certain cases, however, sporadic CJD manifested itself with cerebellar ataxia

and dementia, associated with the presence of amyloid plaques. Mutations have

been found at codon 129 of PrP in CJD patients, with homozygous changes to

methionine or valine.[18]

Iatrogenic CJD

Of note, iatrogenic transmission of CJD has been proven in the past in more than

200 cases,[19,20] in relation to corneal transplants (3 cases), dura mater

grafts, administration of purified human growth hormone (140 cases), and

administration of gonadotropins (4 cases) in the 1960s and 1970s. Overall,

between 1965 and 1983, it is estimated that approximately 200,000 patients have

been treated with hormones purified from about 10,000 glands.

 

Contaminated surgical instruments and electrodes have also been found to be an

efficient route of transmission of CJD. The first such case was described in

1970. A patient with progressive dementia was implanted with depth electrodes in

the brain. After routine cleaning and disinfecting, the electrodes were stored

in formaldehyde vapors for about 2 months. They were then used on a 23-year-old

female patient and later on a teenager -- both patients developed CJD.

Experimental evidence of transmission through the electrodes was provided by a

study later performed in chimpanzees. Hence, the conclusion was drawn that steel

instruments may tightly bind prions and be an effective source of infection.[21]

 

Is human-to-human transmission of CJD still a concern today? The risk is

estimated to be very low, but it has to be kept in mind. In October 2000 and in

2001, surgical instruments were used to operate or biopsy 2 patients who later

developed CJD. The same instruments were then used on 8 and 6 other patients,

respectively. Patients who received corneal implants or purified hormones in the

past decades also need to be monitored. Recently, a 47-year-old man developed

CJD, 38 years after receiving cadaveric growth hormone when he was a child.[22]

The risk of developing a prion disease after decades of incubation has been

estimated at 0.3% to 4.4% for subjects receiving cadaveric human growth hormone

and 0.02% to 0.05% for recipients of dura mater grafts.[19]

Familial Spongiform Encephalopathies

While most of the CJD cases seen today are sporadic, CJD may also occur as a

familial form (10% of cases). Following an autosomal dominant pattern of

transmission, it affects approximately 100 families and it may be associated

with 18 different genetic defects (point mutations or DNA insertions).

Approximately 70% of patients have a mutation at codon 78 or codon 200.

 

Two other spongiform encephalopathies may be inherited in an autosomal dominant

fashion: fatal familial insomnia and the Gerstmann-Straussler-Scheinker

syndrome. Both are fortunately very rare -- fatal insomnia has been found so far

in 9 extended families and the Gerstmann syndrome in 50 families. As the

definition suggests, fatal familial insomnia is characterized by progressive

insomnia and a modest cognitive impairment, which is followed by dementia in

later years. Symptoms are related to an atrophy of the medial thalamus that

undergoes spongiform degeneration.[23] The Gerstmann-Straussler-Scheinker

syndrome usually develops after 40 years of age with loss of coordination and

dementia. Unlike other encephalopathies, it may have a longer clinical course of

up to 6 years.

 

Animal Spongiform Encephalopathies and Variant CJD

Among the animal spongiform encephalopathies -- scrapies, transmissible mink

encephalopathy, and bovine spongiform encephalopathy (BSE) -- BSE is certainly

the disease that has wreaked the most havoc in recent years.[20] The

identification of more than 200,000 cases among European cattle led to emergency

measures to control spreading, with slaughter of more than 5 millions animals in

a few years. As presented by Dr. Britton,[1] Table 1 lists the prevalence of

cases per country.

 

The peak of the infection occurred in Great Britain in 1993, when about 1000

cows were being diagnosed with BSE every week. Symptoms in cattle include lack

of coordination and unsteady gait, arched back, head tremors, weight loss, and

aggressive or fearful behaviors. Far fewer cases are being diagnosed lately

after elimination of affected cattle and new, more severe rules for cattle feed

(banning of ruminant remains from meat and bone meals). The main source of

infection, in fact, is believed to be brain and spinal cord tissues from

infected animals.

 

Brain and spinal tissues from affected cows may have entered the human food

chain until the mid-1980s to 1990s. While no cases of a corresponding human

disease were reported before 1995, sporadic cases of a spongiform

encephalopathy, then called variant (v)CJD, were reported in later years. Eating

hamburgers and sausages in the United Kingdom in the mid 1980s to 1990s has been

linked to vCJD in some cases.

Incidence of vCJD

A total of 137 cases of vCJD have been reported so far; 99 were confirmed, 30

are viewed as probable, 3 are pending, and 5 patients are still alive, thus

preventing a formal diagnosis that can be obtained only at autopsy.[1] The good

news in this dire scenario is that the number of vCJD cases has been rising very

slowly when compared with the past extent and speed of transmission of BSE in

cattle. Educated guesses estimate that the number of future cases may be about

40 to 540 in the next 80 years, and some believe that if the incubation period

in humans is sufficiently long, many of those subjects that have been infected

may die of other causes, long before vCJD manifests itself.

 

Why so few cases of vCJD? Scanty evidence is available today to answer this

question, but different factors have been proposed as critical, in addition to

very long incubation times, including small infectious doses, the possibility

that the protein is not recycled in humans, the existence of a species barrier,

inefficient routes of infections, and heterogeneity in susceptibility to

infection. Indeed, the individual genetic make-up seems to affect susceptibility

to vCJD -- all humans who have been found infected so far were homozygous for a

methionine residue at codon 129 of PrP.

 

Nonetheless, in relative terms, vCJD is believed to be more contagious than

sporadic CJD. This seems to be due to the fact that there is a higher level of

infection in the periphery: tonsils, spleen, lymph nodes, and appendix have been

found positive in vCJD but not in sporadic CJD. These findings underscore the

necessity of strict prevention measures to prevent human-to-human transmission

through blood transfusion or surgical instruments.

Preventing BSE and vCJD

As summarized by Dr. Britton,[1] the following key measures have been taken in

the United Kingdom to prevent transmission of vCJD:

 

Ban of ruminant remains from cattle feed;

Elimination of millions of infected cows;

Ban of beef on the bone (T-bone);

Ban of milk products from cows with BSE;

Ban of mechanical removal of meat from bones;

Removal of white blood cells from blood products to be transfused

(leukodepletion or use of imported plasma).

 

General precaution measures that should be exercised by healthcare professionals

to prevent transmission of vCJD include: use of disposable gloves, use of double

gloves, avoidance of sharp injuries, and use of face shields and skin

disinfection with 0.1N NaOH or 10% bleach for 1 minute.

 

More specific recommendations from the World Health Organization include:

 

Incineration;

Autoclave at 134C for 1 hour;

1N NaOH for 1 hour;

20,000 ppm bleach solution;

Surfaces: 2N Na OH or full-strength bleach (5.25%) for 1 hour;

Note: endoscopes and power tools may not be sufficiently decontaminated

(specific guidelines have been issued by the European Society of

Gastrointestinal Endoscopy).[24]

Diagnosis of vCJD

Owing to the uncertain etiopathogenesis, diagnosis of vCJD in living patients

can be only tentative at present. Tests are being developed to document the

presence and nature of the responsible agents, including fluorymetric,

metabolic, and antibody-based assays for the detection of " infectious " prions.

Formal diagnosis can be done at autopsy by histologic examination,

immunohistochemistry, and western blot analysis of affected CNS tissues.

Examination of the brain will reveal the presence of florid plaques (daisy-like

appearance) with a dense core, surrounded by radiating fibrils and spongiform

changes.

 

Clinical signs of vCJD differ from those of sporadic CJD. Most patients with

vCJD develop psychiatric symptoms first, with depression, withdrawal, anxiety,

insomnia, and apathy, which are later followed by headache and loss of

consciousness. More advanced cases may show aggression, hypersomnia, confusion,

gait distortion, sensory distortion, persistent pain, and cognitive impairment.

From a neurologic point of view, later manifestations may include involuntary

movements, upper motor neuron signs, hallucinations, and loss of self-care.

 

Electroencephalograms, magnetic resonance imaging, and positron emission

tomography may help in the differential diagnosis of sporadic CJD. At variance

with the latter, the EEG brain waves may be abnormal, but they do not follow the

patterns seen in patients with sporadic CJD. Increased levels of the 14-3-3

protein may be found in the CSF, but they are not specific for this disease.

Mutations in the prion genes may also be studied to improve understanding of the

specific case and of the disease itself.

 

Criteria for diagnosis of vCJD established by the World Health Organization

include:

 

Progressive neuropsychiatric disorder;

> 6 months duration;

Other diagnoses ruled out;

No familial prion disease;

EEG not typical;

Bilateral pulvinar high signal on MRI; and

Prion positive tonsil biopsy.

 

Options for treatment for vCJD are being explored, but the results from

experimental studies are, so far, rather disappointing. Ideally, treatment

should be undertaken at a very early stage before substantial neuropathologic

changes have taken place.[25] The antimalarial drug quinacrine has been shown to

reduce prion infectivity in vitro, but it did not improve survival in

experimental mouse models of prion disease,[26,27] and its use may be associated

with substantial liver toxicity in some patients.[5] An open phase 1 trial is

ongoing in the United Kingdom. Similarly, chlorpromazine, a drug used for

schizophrenia, is being evaluated for its putative ability to delay the

conversion of PrP to its " malignant " configuration.[28]

 

More than 150,000 different compounds are also being screened for use in

patients with vCJD using different approaches.[5] Testing for in vitro

inhibition of budding yeast prions revealed that kastellpaolitines, a new class

of compounds, as well as phenanthridine, 6-aminophenanthridine, quinacrine, and

chlorpromazine were active in this assay.[29]

 

 

A North American Perspective on BSE and vCJD

In view of such widespread problems in Europe, what is the situation in North

America,[20,30-32] and particularly in the United States? Are Americans at risk

of contracting BSE and/or vCJD? As mentioned by Dr. Britton,[1] American cattle

has been fed, in the past, with meat and bone meal from downer cattle and sheep,

and it is known that prions may be present in an animal years before BSE becomes

apparent. Not only brain, but also spleen, lymph nodes, and spinal cord may be

infected by prions. More than 6000 cow brains have, however, been examined in

the United States, and no BSE cases have been found. Approximately 5000 randomly

selected animals are being checked each year to monitor the situation. Import of

British cattle, beef, and beef products has been banned since 1989, and from

other European countries as well, as required by the spreading epidemic in the

1990s. Animals imported before the ban have been traced, observed, and

destroyed.

 

Still, a potential risk may not be completely excluded. Approximately 1000 cows

and 125 million pounds of beef have been imported in the past decades from

countries later reporting BSE. Many animals dying on farms in the country are

not being tested for the cause of death. And some argue that potentially

noncompliant feed producers are not monitored appropriately. Laboratory testing

of feed for ruminant proteins is still inadequate from a technical standpoint. A

combination of antibody-based immunoassays and microscopy is being evaluated,

and a test based on the detection of 3 amino acid residues exposed on the

surface of abnormal prion proteins, to be used on brain tissue samples, is being

validated in Europe.

 

Hence, a few basic norms of safety should be followed. Consumers should wonder

how the cattle was fed, whether it was imported, and whether the high-risk

tissues were appropriately removed. The question -- " are stringent controls in

place to ensure safe practices? " -- is probably a concern that all parties

involved, regulatory agencies, consumers, and producers alike, should keep in

mind for many years to come to ensure public safety and successful enterprises.

Healthcare professionals, meanwhile, should exert increased surveillance for

vCJD cases both in terms of diagnosis and prevention.

Prevention Measures: Transfusions, Surgical Instruments, and Traveling

Transfusions and surgical instruments represent 2 hot spots for potential

human-to-human transmission of vCJD,[33,34] although no cases of

transfusion-related transmission of TSEs have been reported so far. The risk for

infection through transfusion of blood or blood products is believed to be lower

than following ingestion, but still " appreciable. " Hence, as advised by the

American Red Cross, approximately 3% to 5% of all blood donors are being

indefinitely deferred (excluded from donations) if they have spent more than 3

months in the United Kingdom, or more than 6 months in Europe since 1980.[35]

This involves also about 250,000 military members and their families, who have

been stationed in the past 2 decades outside of the United States. Another

category for indefinite deferral from blood donations includes subjects who have

received bovine insulin produced in Great Britain since 1980.

 

In regard to application of " safe " procedures in surgery, disposable instruments

should be used whenever possible. Otherwise, steel instruments should be

sterilized according to the WHO guidelines with 1N NaOH and autoclaved at 134C

for 1 hour. If delicate, they should be treated with 6M urea or 4M guanidinium

thiocyanate. If in doubt, all instruments should be " quarantined " until a final

diagnosis has been reached for the last patient on whom they have been used and

promptly discarded upon a positive diagnosis of TSE.

 

The Centers for Disease Control and Prevention (CDC), based in Atlanta, Georgia,

has provided advice for those who travel to European countries,[36] particularly

those countries like Great Britain, which reported a high number of cases of

BSE. According to the CDC, the potential risk of contracting vCJD would be

virtually eliminated by avoiding beef and beef products altogether.

Alternatively, travelers should select for their meals solid pieces of muscle

meat, and avoid burgers and sausages whose composition is not well defined. Milk

and milk products are considered safe.

 

Sara M. Mariani, MD, PhD, Deputy Editor, Medscape General Medicine; Site

Editor/Program Director, Medscape Molecular Medicine

 

 

 

Disclosure: Dr. Mariani has no significant financial interests to disclose.

 

 

Medscape General Medicine 5(3), 2003. © 2003 Medscape

 

 

 

 

 

 

 

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