Investigations and tests
In reaching a diagnosis your doctor will first consider the symptoms and their progression over time, the past medical history, family illnesses and also examination findings. In prion diseases the early symptoms can be shared with many other common illnesses, such as insomnia, altered mood, unusual behaviour, dizziness, or tingling of part of the body. Depending on which symptoms and examination findings predominate in the early stages, your doctor might refer you to a neurologist, psychiatrist or other physician for help. At this first specialist appointment, prion diseases are not always considered because they are rare and the typical signs may not be present, but problems with thinking skills or balance will certainly be noted.
Several investigations may be used to narrow down possible diagnoses, including brain scans (often magnetic resonance imaging or MRI), brain wave tests (electroencephalogram or EEG), spinal fluid tests (cerebrospinal fluid), and blood tests looking for a wide range of biochemical and metabolic disorders, vitamin deficiencies, signs of viral infection, specific antibody tests and thyroid problems. Genetic tests may be requested looking for changes in the DNA causing inherited disorders. Information about some of these tests can be found by following links below. It can take time for these to be done and interpreted.
For many years several research groups and commercial organisations have been trying to develop a simple blood test to diagnose prion diseases. Used in the right way, this could lead to earlier and more accurate diagnosis. In February 2011 the MRC Prion Unit announced a prototype blood test for variant Creutzfeldt-Jakob disease which is described in the section.
- MRI procedure and what to expect during the MRI scan
What is MRI?
MRI stands for Magnetic Resonance Imaging. This is a scanning procedure that uses a combination of a strong magnet, radiowaves and a computer to produce very detailed pictures of your body. The scan will not hurt and has no long-term effect on your body once it is over.
What does an MRI scan show?
An MRI scan provides pictures of the inside of your body. Whereas an ordinary x-ray produces very good pictures of the bones, an MRI scan can show details of the brain, muscles, nerves, cartilage and other internal organs.
Preparation for an MRI scan
As the MRI scanner uses a very strong magnet, there are some safety guidelines that must be followed. Let the staff in the scanning department know as soon as possible if any of the following applies to you:
- you have a pacemaker
- you have an artificial heart valve
- you have ever had surgery on your head or spine
- you have any metallic implants, for example joint replacement
- you have ever had metal in your eyes, for example from welding or metalwork
- you may be pregnant
In some of these cases you may need to have an X-ray to make sure that it is safe for you to have an MRI scan. The staff in the MRI Department will discuss this with you. You will also be asked to remove personal belongings such as your watch, jewellery, keys, credit cards and coins. This is because if you go into the scan room with loose metal objects in your pockets they may be pulled out by the strong magnetic field and fly into the scanner. If you wear your watch into the scanner it may not work when you come out and if you have credit cards in your pocket the information held on the magnetic strip will be wiped off. Metal fastenings on your clothes are all right because the magnetic field is not strong enough to pull them off. However, if they are close to the part of your body you are having scanned they may interfere with the pictures and you may be asked to change into a gown.
What happens during the scan?
You will be asked to lie on the scanner couch where you will be made as comfortable as possible. The position will vary depending on the part of the body that is being scanned. For example, for a scan of the head you will be asked to lie with your neck in a specially shaped support. You should tell the staff if you are not comfortable as you will need to keep very still during the scan which may take up to 45 minutes to complete. There will be an intercom in the scanning room or some other means of communicating with the staff during the scan. Once you are ready to start you will be moved into the scanner. The scanner is a long tube, and the part of your body being scanned must be completely inside this tube. During the scan you will feel nothing, however you will hear the scanner working. Typically, you’ll hear knocking sounds when the procedure is going on. Despite the loud noise, the staff operating the scanner from another room can hear you, if you need to talk to them. Although the staff will be able to reassure you during the scan, some people do find this unpleasant and slightly frightening. Each set of pictures takes about five minutes and while the pictures are being taken you will hear a knocking sound. This noise means the scanner is collecting information to produce the pictures and therefore you must keep very still. If you move while the pictures are being taken they will be blurred and the scan may need to be repeated. Several sets of pictures may be taken during each examination and there will be a short pause between them. The scanner will go quiet between pictures; during this time the staff will be setting up ready to start the next set.
Will I need an injection?
When certain areas of the body are scanned, you may need an injection of a special dye known as a contrast agent that helps to see more detail on the pictures. If you need an injection it will be given into a vein in your arm by a radiologist or one of the radiographers trained to give injections. Sometimes several scans will be taken before the dye is injected and then further scans are taken after the injection.
Can anyone be with me during the scan?
As there are no harmful rays, a friend or relative can stay in the room with you during the scan. Anyone coming into the scan will also be asked questions about pacemakers and metal objects in their body, and will be asked to remove all metallic objects such as watches and jewellery.
What happens after the scan?
There are no after effects from the scan so you can carry on with your normal activities immediately.
When will I receive the results of the scan?
For each scan as many as 50 images may be produced which need to be carefully studied by the radiologists. The radiologists will produce a detailed report that will be sent to your specialist, usually within 7 to 14 days. More complicated analyses comparing information from different scans over long periods of time will only be carried out at the end of the trial, so the results will not be available to you for example, at your routine clinic visits.
- EEG procedure and what to expect during the EEG.
What is an EEG?
EEG stands for electroencephalogram. It is a recording of the ‘brainwaves’ – the electrical activity of the brain. The many nerve cells that make up the brain produce continuous electrical activity when a person is awake, asleep or even in a coma. This can be recorded using small metal discs called electrodes, which are placed on the scalp. The electrical signals are then amplified by specialized equipment to produce what is seen in the EEG tracing. The signals show up on the EEG tracing as wavy lines, representing the fluctuations in electrical activity from moment to moment. Doctors can gain a great deal of information about the workings of the brain by examining these tracings.
What can I expect during an EEG?
After the EEG technician has asked you a few questions about your medical history, they will explain what will happen during the test. The whole procedure normally takes one to oneand- a-half hours, with the recording itself usually running for about 30-45 minutes. The EEG is carried out either with you sitting up in a comfortable chair or lying on a couch.
Preparation for an EEG
The first step is to apply the electrodes - usually about 20 in all - to the scalp. These are placed in standard positions, according to an internationally agreed convention. The technician will begin by measuring around the head with a tape measure to determine the position for each electrode, which they will mark with a skin pencil. The skin where each electrode is to be placed will be cleaned to ensure that the electrical contact is good enough to allow the weak signals from the brain to be recorded properly. You will usually find that your appointment letter asks you to come for your EEG with ‘clean, dry hair’. The request is made because hair products and even the hairs natural oils can make it difficult for the technician to get a good electrode contact with the scalp. The electrodes, which are like little cup-shaped discs, are usually stuck in place with a special paste that also helps to conduct the electrical signals. Some of them may have a special conducting jelly put in them before they are stuck onto the scalp. The technicians are very skilled at doing this and it is not uncomfortable.
What happens during the EEG?
When everything is ready, the technician will ask you to sit or lie in as relaxed a state as you can. This can be quite difficult if you’re feeling nervous in unfamiliar surroundings, but once the test is underway, people usually find that they are gradually able to settle down. It is quite important to relax, since a tense person will have tense muscles around the face and forehead and these will produce electrical signals of their own. The electrodes on the scalp will pick these signals up too, obscuring the EEG and making the recording less useful. During the recording, you will be encouraged to close your eyes, relax and drowse, since this may give more information than if the recording takes place when you are fully awake. Despite being in strange surroundings, people often drop off to sleep during an EEG. The technician will ask you to open or close your eyes from time to time. This is so that they can observe certain changes in the brainwaves. The brainwaves of someone sitting quietly with their eyes closed doing nothing in particular have a characteristic appearance. In this state, the alpha rhythm will commonly be recorded from the back of the head. This is one of the brain’s ‘resting rhythms’. It may become slowed or disappear altogether in many conditions affecting the brain, such as infections, coma or dementia. When the eyes are opened, the alpha rhythm may either disappear altogether or become less prominent. The technician will be testing for this as he or she gets you to open and close your eyes. As well as asking you to open and close your eyes, the technician is also likely to carry out so-called activation procedures. These are methods that are known to reveal abnormalities that might not otherwise be seen. The first of these procedures is hyperventilation or over breathing. The technician will ask you to breathe more deeply than usual, taking regular deep breaths in and out for about three minutes. Most people will tolerate this quite well, although some may feel slightly lightheaded or giddy. Over breathing in this way will commonly produce a change in the brain’s electrical activity and may bring out abnormalities not otherwise seen in the EEG. The second activation procedure used routinely is photic stimulation. In this, a quite bright strobe light is flashed in front of the person at different speeds –producing an effect very similar to the strobe lighting in a disco. This is usually done with the eyes open and then closed.
What happens after the EEG?
The technician will carefully remove all the electrodes from your scalp. There are no after effects from the EEG so you can carry on with your normal activities immediately.
When will I receive the results of the EEG?
A detailed report on the EEG will be sent to your study doctor, usually within 7 to 14 days. These should be available for your outpatient consultation.
- Variant CJD - Direct Detection Assay
A blood test for variant Creutzfeldt‐Jakob disease: briefing note for patients, carers and health professionals
A blood test for variant Creutzfeldt‐Jakob disease (vCJD) has been an important goal of medical research laboratories and companies around the world for many years. It has been very difficult to achieve because the infectious agent (germ) causing vCJD, known as a prion, has unique features that mean that the sensitive methods doctors normally use to detect the presence of a germ (detecting the body’s antibody response to the germ or the germ’s own genetic material) do not work.
The Medical Research Council (MRC) Prion Unit, working with the NHS National Prion Clinic at the National Hospital for Neurology and Neurosurgery (NHNN) in London, has now developed an entirely new type of test following a number of years of intensive research.
The test is at an early (prototype) stage but is able to correctly identify the large majority of patients with symptoms of vCJD and has not yet given any false results in patients with other brain diseases or in healthy individuals. We think this is an important breakthrough and it raises a number of issues which need to be carefully considered. Details of the test have been published by the leading medical journal, the Lancet, on 3rd February 2011. The full text of the paper is available here.
This brief article describes CJD and other so‐called prion diseases, why a blood test is important, how the test works and how to approach us at the National Prion Clinic to inquire further about this test. It is important to be cautious about this news, because although the results so far are very encouraging, we want to go on to look at blood samples from much larger numbers of healthy people and those with other brain diseases to get a better idea of how specific the test is in practice. This will be vital before a version of this test could be considered to routinely screen healthy blood donors.
Why is a blood test important?
vCJD (as with other forms of CJD) tends to be diagnosed only when the patient has had the disease for some time and has developed symptoms that are associated with extensive damage to the brain. There are several reasons why this is the case. The early symptoms of the disease (such as anxiety, depression and tingling pains in the legs) have many much more common causes and so doctors will understandably not attribute these symptoms to something much more serious until other features such as difficulty with movement or balance and loss of mental abilities occur. At this stage, it will be apparent there is a serious brain condition but a series of tests are required to make the diagnosis and these take time to organise and interpret. Because the disease itself typically progresses quite rapidly (over weeks and months), the patient is likely to be showing quite advanced symptoms by the time a confident diagnosis is reached. A simple blood test gives us an opportunity to make the diagnosis at a much earlier stage. While at present there is no treatment we know is effective in stopping progression of these diseases, an early diagnosis does avoid the need for other tests and gives the patient and their family a clear answer. This enables them to make the best use of their time together and spend less of this precious time in hospital. However, experimental drugs are being developed at the MRC Prion Unit and elsewhere with a view to clinical trials in the next few years and we would want to try such treatments at the earliest stage before irreversible brain damage has occurred.
It is now known that vCJD can be passed on by blood transfusion. Several vCJD patients had been blood donors before they developed symptoms of the disease. To date, three individuals who had received blood transfusions from such donors have themselves developed and died from the disease. A further individual, who had also received prion‐infected blood, died of unrelated causes but showed evidence of prion infection at autopsy examination.
Only a very small number of individuals are definitely known to have received such potentially infected blood transfusions. However, several thousand individuals have been notified by the Health Protection Agency that they have received possibly infected blood products such as plasma, clotting factors, or purified antibodies. One individual who had received a clotting factor from a donor who went on to get vCJD died of unrelated causes but showed signs of vCJD infection at autopsy. It is not known whether this individual would have gone on to develop the disease had he not died of other causes.
Prion diseases are known to exist in “carrier states” in laboratory animals and these would be expected in humans too. A “carrier” is a person infected with prions but who does not show any signs of disease in their natural lifetime. Such carrier states are well recognised with other infectious diseases in humans. In the UK population, following an anonymous study of archived tissue specimens, the Department of Health uses an estimate that 1 in 2000 individuals may be silently infected with vCJD prions in its risk calculations. There is considerable uncertainty about this figure, that is, the true number could be significantly higher or lower than 1 in 2000. It is also not known how many of those infected will eventually go on to develop the disease itself. We do know that incubation periods in human prion diseases can be very long, over 50 years in some cases. As these infected but healthy individuals cannot currently be identified in the population, many will be active blood donors and could pass on infection to other people in this way or by medical and surgical instruments used on them becoming contaminated by prions (since prions are quite resistant to normal sterilisation methods). The National Blood Service has taken several actions to try to minimise this risk, for example, by removing white cells from blood, however it is uncertain how effective these measures are at reducing risk, or indeed whether they are really justified should the real number of infected people turn out to be extremely small.
A future development of our blood test may allow us to screen donated blood and further increase the safety of blood transfusions. Also it may in the future allow individuals who have been exposed to vCJD infection to find out if there is evidence that the infection has taken hold in their body. However, considerable further research will need to be done first to find out how specific the test is when tested on large numbers of health donors and to understand how good the test will be at detecting infected blood from healthy individuals rather than those with the established disease.
How well does the test work?
It has been hard to develop a test for prion disease because the body’s immune system does not fight off prion infection by making antibodies (that can be readily detected in a blood test) in the same way it does against germs like bacteria or viruses. It has been challenging to develop a test that can distinguish between the normal prion protein, which we all have in our blood, and the abnormal form linked to the disease which is chemically very similar.
Scientists in the MRC Prion Unit have developed a prototype test. This involves taking a small blood sample from a patient as with any other blood test. A small sample of blood is mixed with special metal beads to which the rogue prion proteins stick tightly. These are then washed to remove the normal prion protein and other blood components that would interfere with the test. Finally, the amount of rogue prion protein attached to the beads is measured using antibodies we have developed that bind very tightly to the prion protein.
The test was applied to a number patient samples including from patients with vCJD, those with
sporadic CJD, other neurological diseases that might be confused with vCJD and a number of healthy blood donors. As vCJD is a rare disease, only relatively small numbers of samples were available for this testing. All samples were given code numbers and the scientists carrying out the test in our laboratory did not know which sample was which. We were able to try the test on 21 samples from different vCJD patients. 15 of these 21 patient samples (around 70%) were shown to be positive by the test. So far, all samples from other neurological diseases or healthy blood donors have tested negative but only relatively small numbers of these have been looked at so far (about 200). At present the test does not work in other forms of prion disease such as sporadic CJD but we are hoping this will be possible with further work in the future.
What happens now and how is the test going to be made available?
We are ready to use the test to assist with diagnosis of patients who are suspected of having vCJD or other diseases that might be mistaken for vCJD. Working with neurological colleagues to begin to use the test will also help us get more information on the test itself and hopefully lead to further improvements and understanding of its usefulness. A request card needs to be completed. Click on the link below to open.
We require at least 2 x 5ml EDTA vacutainer tubes. For sample delivery please see further details here. While we are working to increase the throughput of the test, at this stage it remains relatively labour intensive. Whilst we will attempt to return results at the earliest opportunity, clinicians should allow up to four weeks for results. Please call the Clinic for further details.
The National Prion Clinic at the National Hospital for Neurology is happy to take telephone enquiries about suspected prion disease patients. We are particularly interested in referrals of patients at an early stage of their illness when diagnosis is most difficult.
Please visit the NHS National Prion Clinic website