New variant of human prion disease

In late 1995, two cases of sporadic CJD were reported in the United Kingdom in teenagers. ty.7.,48» Only four cases of sporadic CJD had previously been recorded in teenagers, and none of these cases occurred in the United Kingdom. In addition, both cases were unusual in having kuru-type plaques, a finding seen in only around 5 per cent of CJD cases. Soon afterwards a third very young sporadic CJD case occurred.(49» These cases caused considerable concern and the possibility was raised that they might suggest a link with BSE. It was clearly of some importance to see if any further such extraordinarily rare cases occurred in the United Kingdom. By March 1996, further extremely young onset cases were apparent and review of the histology of these cases showed a remarkably consistent and unique pattern. These cases were named 'new variant' CJD although it was clear that they were also rather atypical in their clinical presentation; in fact most cases did not meet the accepted clinical diagnostic criteria for probable CJD. Extensive studies of archival cases of CJD or other prion diseases failed to show this picture and it seemed that it did represent the arrival of a new form of prion disease in the United Kingdom. The statistical probability of such cases occurring by chance was vanishingly small and ascertainment bias seemed most unlikely as an explanation. It was clear that a new risk factor for CJD had emerged and appeared to be specific to the United Kingdom. The United Kingdom government Spongiform Encephalopathy Advisory Committee concluded that, while there was no direct evidence for a link with BSE, exposure to specified bovine offal prior to the ban on its inclusion in human foodstuffs in 1989, was the most likely explanation. A case of vCJD was soon after reported in France/50» Direct experimental evidence that vCJD is caused by BSE was provided by molecular analysis of human prion strains and transmission studies in transgenic and wild-type mice (see aetiology). While it is now clear that vCJD is human BSE, it is unclear why this particular age group should be affected and why none of these cases had a pattern of unusual occupational or dietary exposure to BSE. However, very little is known of which foodstuffs contained high-titre bovine offal. It is possible that certain foods containing particularly high titres were eaten predominately by younger people. An alternative is that young people are more susceptible to BSE following dietary exposure or that they have shorter incubation periods. It is important to appreciate that BSE-contaminated feed was fed to sheep, pigs, and poultry and that although there is no evidence of natural transmission to these species, it would be prudent to remain open minded about other dietary exposure to novel animal prions.

The clinical presentation is with behavioural and psychiatric disturbances and in some cases with sensory disturbance. (5:!.) Initial referral is usually to a psychiatrist and the most prominent feature is depression, but anxiety, withdrawal, and behavioural change is also frequent. (52» Suicidal ideation is infrequent and response to antidepressants poor. Delusions, which are complex and unsustained, are common. Other features include emotional lability, aggression, insomnia, and auditory and visual hallucinations. A prominent early feature in some was dysaesthesiae or pain in the limbs or face or pain which was persistent rather than intermittent and unrelated to anxiety levels. A minority of cases have been noted to have forgetfulness or mild gait ataxia from an early stage, but in most cases overt neurological features are not apparent until some months into the clinical course.(53,) In most patients a progressive cerebellar syndrome develops with gait and limb ataxia. Dementia usually developed later in the clinical course with progression to akinetic mutism in the majority of cases. Myoclonus was seen in most patients, in some cases preceded by chorea. Cortical blindness develops in a minority of patients in the late stages of disease. Upgaze paresis, an uncommon feature of classical CJD, has been noted in some patients/53» The age at onset in the initial 14 cases reported ranged from 16 to 48 years (mean 29 years) and the clinical course was unusually prolonged (9-35 months, median 14 months). The EEG is abnormal, most frequently showing generalized slow-wave activity, but without the pseudoperiodic pattern seen in most sporadic CJD cases. Neuroimaging by CT is either normal or shows only mild atrophy. However, a high signal in the posterior thalamus on T2-weighted MRI is seen in a proportion of cases.(4 53» The sensitivity and specificity of this sign is unclear at present. Cerebrospinal fluid 14-3-3 protein may be elevated. PrP gene analysis showed that all cases available for study were homozygous for methionine at codon 129. No known or novel pathogenic mutations were found in the coding sequence.(54) Recently it has become clear that vCJD can be diagnosed by detection of characteristic PrP immunostaining and PrPSc(4 s5» It has long been recognized that prion replication, in experimentally infected animals, is first detectable in the lymphoreticular system, considerably earlier than the onset of neurological symptoms. Importantly, PrPSc is only detectable in vCJD, and not other forms of human prion disease studied. The PrP Sc type detected on Western blot in vCJD tonsil has a characteristic pattern designated type 4t. (46» A positive tonsil biopsy obviates the need for brain biopsy which may otherwise be considered in such a clinical context to exclude alternative, potentially treatable diagnoses.

The neuropathological appearances of vCJD are striking and consistent. While there is widespread spongiform change, gliosis, and neuronal loss, most severe in the basal ganglia and thalamus, the most remarkable feature was the abundant PrP amyloid plaques in cerebral and cerebellar cortex. These consisted of kuru-like, 'florid' (surrounded by spongiform vacuoles), and multicentric plaque types. The 'florid' plaques, seen previously only in scrapie, were a particularly unusual but highly consistent feature. There was also abundant pericellular PrP deposition in the cerebral and cerebellar cortex. A further highly unusual feature was the extensive PrP deposition in the molecular layer of the cerebellum.

Some of the features of vCJD are reminiscent of kuru, in which behavioural changes and progressive ataxia predominate. In addition, peripheral sensory disturbances are well recognized in the kuru prodrome. Kuru plaques are seen in around 70 per cent of cases and are especially abundant in younger kuru cases. The observation that iatrogenic prion disease related to peripheral exposure to human prions has a more kuru-like than CJD-like clinical picture may well be relevant and would be consistent with a peripheral prion exposure.

The relatively stereotyped clinical presentation and neuropathology of vCJD contrasts sharply with sporadic CJD. This may be because vCJD is caused by a single prion strain and may also suggest that a relatively homogeneous genetically susceptible subgroup of the population with short incubation periods to BSE has been selected to date.

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