Prion diseases in humans: an update

The year 2006 marks 20 years from the first identified bovinespongiform encephalitis in cows and 10 years from the firstdescription of variant Creutzfeldt–Jakob disease in humans.The threatened epidemic in humans now appears unlikely, butpsychiatrists need to be aware of recent developments in priondiseases.

INTRODUCTION

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INTRODUCTION

When the mass incineration of British cattle was a recent memory5 years ago, cases of variant Creutzfeldt–Jakob disease(vCJD) were increasing each year and educating doctors aboutthe disease was a priority. I co-reviewed the psychiatric managementof CJD for Advances in Psychiatric Treatment (Butler & Fleminger, 2001).There were dire predictions about the impact of prion diseaseson human health, but what has happened since? What is the latest research? And what is the relevance of prion diseases for psychiatristsin the coming years?

THE THREATENED EPIDEMIC

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THE THREATENED EPIDEMIC

From the first death in 1995 until the end of 2005, 153 peopledied from vCJD in the UK (http://www.cjd.ed.ac.uk). Therehave been about 18 cases of vCJD in France and 12 in the restof the world. The families and loved ones of those who diedhave had to contend not only with the disease itself but withhealthcare systems that were unprepared, often ignorant andunable to provide a coordinated response. Some of the familiesformed themselves into support groups such as the CJD SupportNetwork and the Human BSE Foundation. They have lobbied forbetter services, greater awareness from health professionalsand easier access to potential treatments. A trust has beenestablished to pay compensation to the victims of vCJD and theirfamilies (http://www.cjdtrust.co.uk).

The number of deaths from vCJD in the UK appeared to peak in2000 when 28 people died. Last year 5 people died. These numbersare surprisingly low in view of the millions of people whowere exposed to infected beef products in the late 1980s. Thetransmission barrier may have been sufficient to prevent thefeared epidemic. Deaths from sporadic CJD continue worldwideat about one per million people per year.

There have been some worrying developments. Cases have beenidentified in a number of countries around the world, and itis likely that people in more countries will be affected. Manywere resident in the UK at some period, but others were probablyexposed in their own country to indigenous bovine spongiformencephalitis (BSE) or imports from the UK.

There has been human to human transmission of vCJD via bloodproducts. This comes with many ethical considerations, suchas how to deal with those who were exposed to these blood products(Bird, 2004). There remains the risk of transmission by duramater grafts, human pituitary hormones or surgical instrumentsbecause traditional sterilisation does not neutralise prions.Prion diseases are widespread in animals around the world,including scrapie in sheep, and are under-tested in some countries.Despite this, BSE has been detected in most European countries,USA, Canada and Japan.

SPORADIC, INHERITED OR TRANSMITTED

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SPORADIC, INHERITED OR...

Prion diseases are associated with an abnormal, protease-resistantform of prion protein known as scrapie prion protein (Prusiner & Hsiao, 1994). The function of prion protein is poorly understood. Some animalsgenetically engineered to lack the protein appear normal. Attemptsto breed a prion protein-free cow are proving time consumingand costly.

The change in prion protein may occur in three different ways (Cohen et al, 1994). In sporadic prion disease, prion proteinchanges to the insoluble form spontaneously. Sporadic CJD accountsfor most cases of CJD. In familial vCJD, an abnormality inthe gene coding for prion protein produces a protein that is unstable and changes into the abnormal protein. It was thesearch for the transmissible agent for diseases such as kuruthat led Prusiner (1982) to coin the term prion which standsfor proteinaceous infectious agent. Prion diseases can be experimentallytransmitted by directly inoculating the brain with the abnormal protein. This is the quickest and most reliable route, althoughincubation takes months and occasionally years. Transmissionby eating is generally more difficult, but kuru was maintainedthrough cannibalistic rituals. The incubation time for kurucan exceed 40 years.

CLINICAL FEATURES AND INVESTIGATIONS

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CLINICAL FEATURES AND...

Sporadic CJD peaks in incidence at between 50 and 70 years ofage. It is a rapidly progressive dementia, often with severecerebellar and extrapyramidal signs and myoclonus, causingdeath usually within a few months (Will & Matthews, 1984). Psychiatric symptoms occur early in the disease in about athird of cases.

Variant CJD differs from sporadic CJD in a number of ways (Will et al, 1996); the National CJD Surveillance Unit published the clinical featuresof the first 100 cases of vCJD (Spencer et al, 2002). Onsetis usually at a young age, mean 26 years, range 12 to 74 years.Patients tend to present to psychiatrists as first-line specialists,with early symptoms of dysphoria, withdrawal, anxiety, irritability,insomnia or loss of interest. Neurological symptoms occur on average 2 months later. These include pain, headaches, droppingthings, sweatiness and loss of consciousness. The combinationof a psychiatric disorder with affective or psychotic features,and persistent pain, dysarthria, gait ataxia, or sensory symptoms,should raise the suspicion of vCJD, particularly if there isa suggestion of cognitive impairment. Mean survival is a littleover 1 year.

A number of investigations are useful. Electroencephalogramsoften show periodic synchronous discharges in CJD that areusually absent in vCJD. Computed tomography is usually normalor shows only atrophy. Magnetic resonance imaging may showa high signal in the posterior thalamus (pulvinar) in vCJD.In sporadic CJD, cerebrospinal fluid is usually positive forthe brain protein 14-3-3 (which may be a marker for neuronaldamage), but this test is not useful for vCJD. Tonsillar biopsyis used for diagnosing vCJD.

Most cases of sporadic CJD, and until recently all cases ofvCJD, have been homozygous for methionine at codon 129 of theprion protein gene (the MM genotype found in around 40% ofthe general population). The announcement in 2004, that someonewith vCJD infection (but not the illness) linked to a blood transfusion had the MV genotype (found in 50% of the generalpopulation) suggests this wider group of people may be at risk,perhaps with different incubation characteristics.

WHAT TO DO IF YOU SUSPECT A PRION DISEASE

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WHAT TO DO IF...

A number of countries have established surveillance centresto monitor the occurrence of prion diseases. In the UK, psychiatristswho suspect that a patient has CJD should make a referral tothe local neurological service which should contact the NationalCJD Surveillance Unit in Edinburgh. Their website (http://www.cjd.ed.ac.uk) includes information about managing CJD and addresses of support organisations. In the USA, doctors should contact the NationalPrion Disease Pathology Surveillance Center (http://www.cjdsurveillance.com).

It has been difficult to find treatments. In 2004, the MedicalResearch Council in the UK launched the PRION-1 trial thatfocuses initially on quinacrine, an anti-malarial that clearsscrapie prion protein in cell culture. Pentosan polysulphatehas shown promising results in animals. It has to be delivereddirectly to the brain. In a high-profile case, a father wona court battle to have pentosan polysulphate made availablefor his son. Attempts to find a vaccine for the abnormal prionprotein are still at an early stage. A better understandingof the mechanism of disease is offering novel treatment approaches,such as finding agents that directly target prion protein.For example, transgenes have reversed prion disease in miceby deleting prion protein genes (Mallucci & Collinge, 2004).

CONCLUSIONS

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CONCLUSIONS

Most of what we wrote in Advances in Psychiatric Treatment is still relevant 5 years on, but prion diseases are better understood.Almost two-thirds of people with vCJD will see a psychiatristat some stage of their illness (Spencer et al, 2002).

Psychiatrists need to know about prion diseases; they need tocomplete good clinical assessments, particularly in unusualcases; and they need to be responsive to this group of patientsand their families. Fortunately, the worst predictions havenot materialised, but it is too early to lower our awarenessof this group of disorders.

REFERENCES

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