Volume 8: Variant CJD
6. Diagnosis, treatment and care of vCJD patients
Tests performed
Blood tests
Genetic analysis
Lumbar puncture
Computerised axial tomography (CT) scan
Electroencephalogram (EEG)
Magnetic resonance imaging (MRI)
Biopsies
Clinical history - personal and family

6.22 Most of the tests performed on vCJD victims while they were alive occurred when the patient was in the care of a neurologist. Generally, the tests only proved useful in excluding other possible conditions, and even now a conclusive diagnosis of vCJD is not usually possible until post-mortem neuropathological examination of the brain has been performed.

6.23 In the 1999 Psychiatric Bulletin article on the psychiatric features of the first 14 vCJD patients, it was observed that 'limited evidence suggests that investigations such as EEG or brain imaging are unlikely to provide useful diagnostic information during the "psychiatric" phase of these diseases'. ¹ The families of the victims of vCJD often mentioned the distress caused by the failure of the medical profession to diagnose vCJD until late in the illness. The recent development of a tonsil biopsy test (see paragraphs 6.37-6.39 for further details) for protease-resistant prion protein may allow earlier diagnosis. Here, a range of tests, reported in the CJDSU articles and by expert witnesses, is discussed.

Blood tests

6.24 Blood tests are generally carried out on suspect CJD patients to detect or exclude haematological or biochemical disturbances, ² and in particular to detect abnormalities of kidney and liver function, and calcium metabolism, all of which are associated with cognitive impairment. ³ The level of vitamin B12 and folate are measured, as low levels of vitamin B12 sometimes manifest themselves as mental changes. ⁴ Thyroid function is also tested to exclude myxoedema (under-functioning of the thyroid) ⁵ and Hashimoto's disease (an autoimmune disease in which the whole of the thyroid gland is diffusely enlarged and firm). ⁶

6.25 An examination is made for antibodies against the organism causing syphilis and the presence of systemic lupus erythematosus. ⁷ If there is a possibility, based on clinical history, of exposure to heavy metal such as lead, mercury or manganese, tests are carried out to exclude heavy metal poisoning. ⁸

Genetic analysis

6.26 Before a diagnosis of vCJD can be made, the diagnosis of familial CJD must be ruled out. Familial CJD is associated with mutations of the prion protein gene. DNA is therefore extracted from the blood of all suspect cases and screened for prion protein gene mutations. No mutations have been identified in cases of vCJD. ⁹ In all cases the genotype is determined at codon 129 of the prion protein gene.

Lumbar puncture

6.27 Lumbar puncture is a procedure for removing cerebrospinal fluid (CSF) from the lumbar region of the spinal canal and is used in the diagnoses of some diseases of the nervous system. The fluid is tested for evidence of inflammation and syphilis. It can be used to exclude the diagnosis of multiple sclerosis. ¹⁰

6.28 It has been shown in the USA that a specific protein marker (14-3-3 protein) can be detected in the CSF from patients with CJD, raising the possibility that it can be used as a specific marker for disease. ¹¹ The 1997 Lancet article noted that out of five vCJD patients analysed for the presence of protein 14-3-3, two were positive and three negative. ¹² However, the test cannot differentiate between the different types of CJD.

Computerised axial tomography (CT) scan

6.29 This technique produces cross-sectional images of the body and allows examination of the brain to assist in neurological diagnosis. ¹³ The results of this test for 10 of the first 14 cases of vCJD were discussed in the 1997 Lancet article. ¹⁴ Eight patients had normal scans. The two abnormal scans had non-specific abnormalities: calcium deposits in one part of the brain and slightly enlarged areas of the brain.

Electroencephalogram (EEG)

6.30 An EEG records electrical activity in the brain. A number of small electrodes are placed on the scalp and the pattern of activity is recorded. ¹⁵ The 1997 Lancet article noted that the characteristic EEG pattern of sporadic CJD was not seen in the vCJD cases. ¹⁶ Several presented with normal patterns even though they had cognitive impairment, cerebellar signs and involuntary movements. Of those which had abnormal EEGs, all showed slow-wave activity which deteriorated as the illness progressed:

The majority of cases thought to have a functional psychiatric illness developed an abnormal EEG within 3 months of their psychiatric diagnosis. However, one patient had a normal recording 7½ months after the diagnosis of schizophreniform psychosis. ¹⁷

Magnetic resonance imaging (MRI)

6.31 MRI is another three-dimensional way of looking at the brain. The head of the patient is placed in a magnetic field which causes certain atomic nuclei to align in the direction of the field. Pulses of radio-frequency radiation are applied and interpretation of the radiation absorbed and re-emitted allows an image of the brain to be built up.

6.32 Traditionally, the role of MRI in patients with suspected CJD has been to exclude other conditions. In his statement to the Inquiry, Professor Rossor observed that the scan is used to 'exclude structural lesions such as tremors and blockage of the ventricular system, inflammatory disorders and may identify areas of tissue loss or atrophy.' ¹⁸

6.33 Recent work, however, has suggested that MRI can be used in the differential diagnosis of suspected vCJD. Analysis of MRI scans of confirmed vCJD patients revealed high signal in the posterior thalamus (pulvinar). ¹⁹ The signal was found to be specific, being present in 78 per cent of the 36 vCJD patients examined but in none of the 57 control patients. The presence of this specific signal on MRI scans may in the future facilitate the diagnosis of this form of CJD during the clinical course, avoiding the need for invasive diagnostic procedures.

Biopsies

Brain biopsy

6.34 One test that can be used to diagnose vCJD before death is the histopathological examination of a brain biopsy. ²⁰ This examination aims to detect the characteristics of vCJD: 'florid plaques', abundant prion protein deposition, sponginess and severe glial cell ²¹ proliferation in the thalamus. ²²

6.35 However, the ante-mortem examinations of brain biopsies are not thought to be reliable. Dr Will described the main limitation of the brain biopsy. Only a very small piece of brain tissue is removed and this sample might be 'from an area of the brain that is not affected fully by the pathological process, and you may sometimes sample an area that is normal, which may subsequently become abnormal. So a negative test does not exclude a diagnosis'. ²³

6.36 In his oral evidence to the Inquiry, Professor Rossor commented upon the use of brain biopsies in the diagnosis of rare dementing illnesses and emphasised that the procedure carried risk and was not performed if other tests revealed a probable diagnosis. ²⁴

Tonsil biopsy

6.37 Histopathological examination of tonsil biopsies has been suggested as a useful diagnostic test for those with suspect vCJD. An experimental study to examine the reliability of this test was published in 1999. ²⁵ Tonsil biopsies were performed on 20 suspect CJD cases. The biopsies were then examined histopathologically for the characteristic protease-resistant prion protein and prion protein glycosylation pattern seen in vCJD.

6.38 Eight tonsil biopsies tested positive for the protease-resistant prion protein;all these patients were subsequently confirmed as vCJD cases, or their subsequent course of disease was highly consistent with vCJD. All tonsil biopsies negative for the protease-resistant prion protein were later shown to be from cases of either sporadic CJD or iatrogenic CJD. There were no false negative results in vCJD cases and each showed the glycosylate pattern characteristic of vCJD.

6.39 The study concluded that the protease-resistant prion protein could be identified in all vCJD cases tested so far by tonsil biopsy. In practice, the tonsil biopsy might obviate the need for a brain biopsy sample to be taken. However, patient acceptability of tonsil biopsy is low.

Clinical history - personal and family

6.40 When the referring neurologist notifies a suspect case of CJD to the CJDSU, the Unit generally carries out a detailed personal and family clinical history based on a questionnaire. This is described earlier in this volume.

6.41 Professor Rossor pointed out that a detailed family history is obtained in all cases to ascertain if the condition is genetic. If this is suspected, tests are then made for genetic mutations known to be associated with familial dementia such as Huntington's disease, familial Alzheimer's disease, frontotemporal dementia and the familial prion diseases which include disorders such as familial CJD, Gerstmann-Sträussler Syndrome (GSS) and Fatal Familial Insomnia (FFI). ²⁶ However, not all cases of inherited CJD have a positive family history. The patient could be the first in a family to inherit the mutation through parental germ cells.