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Referred vs. diagnosed nvCJD
Reporting data from CJD Unit
New imaging diagnostic tool for CJD
What all can CJD be mis-diagnosed as?
Cyclosporin: can it stop mitochondrial death, Alzheimer, CJD?
Accuracy of the clinical diagnosis
Are prion diseases always transmissable?

nvCJD: after the hype, some real data

Lancet March 29 1997 editorial

The front page of the UK tabloid the Daily Mirror (March 21, 1996) read ". . . now experts say it could kill 500 000 of you". On the same day, the supposedly more sober and reliable broadsheet, The Guardian, rated the number at risk as "many millions". The Daily Mail (another tabloid) asked "Could it be worse than AIDS?". Such was the confusion and panic following the announcement in the House of Commons of ten cases of new variant CJD almost a year ago.

By contrast, the reaction of scientists was generally more cautious, though most recognised that a new phenomenon had been discovered. Some observers proposed measures to safeguard public health and quantify risk. For example, Gore recommended that there should be "Quarterly publication of surveillance data for patients referred to the CJD Surveillance Unit: patients under 40 at referral (whenever referred); those aged 40 years or more (referred after 1 May 1990).1

Gazing into crystal balls--otherwise known as epidemiological modelling--was inevitable. For instance, in a speculative commentary, Cousens et al put the future number of nvCJD infections somewhere between fewer than 100 and around 80 000.2 This guesswork received dramatic coverage in the UK press. The Independent's story commented that "the human toll will be high . . . people who ate a lot of hamburgers in the late Eighties are believed to be most at risk".

Today Will et al report data for the 12 months starting March, 1996. Of 37 cases referred to the CJD Surveillance Unit, four have been proven histopathologically to be nvCJD. Necropsy findings from four further referrals are awaited. It now seems clear that Gore's call for quarterly publication of referred patients would provide an unreliable estimate of new cases of nvCJD. Patterns of referral are likely to be influenced by many non-clinical variables.

Fleminger and Curtis have drawn attention to one of these--namely, the problem of media-induced hypochondriasis.3 They wrote that many psychiatrists "may be asked to assess patients who have a fear that they have contracted the disease. Anxiety, depression and subjective cognitive symptoms may be a feature either of hypochondriasis or of CJD". Last weekend, The Sunday Times did not help matters by reporting the total number of cases of nvCJD as 17.4 A call to the National Creutzfeldt-Jakob Disease Surveillance Unit in Edinburgh would have revealed that the number of confirmed cases in the UK is 14. Continued careful monitoring, including necropsy examination, of all referrals to the CJD Surveillance Unit is clearly essential. Enterprising, but ultimately hazardous, mathematical predictions and journalistic misreadings may be less so.

1 Gore SM. Bovine Creutzfeldt-Jakob disease? BMJ 1996; 312: 791-93.

2 Cousens SN, Vynnycky E, Zeidler M, Will RG, Smith PG. Predicting the CJD epidemic in humans. Nature 1997; 385: 197-98.

3 Fleminger S, Curtis D. Prion diseases. Br J Psychiatry1997; 170: 103-05.

4 Craig O. Mourning Matthew. Sunday Times 1997; March 16: 13

Reporting of suspect new variant Creutzfeldt-Jakob disease

Lancet 20 Mar 1997
R G Will, R S G Knight, M Zeidler, G Stewart, J W Ironside, S N Cousens, P G Smith

The number of cases of Creutzfeldt-Jakob disease (CJD), including the number of cases of new variant CJD (nvCJD), is published monthly by the Department of Health. The number of referrals of suspect cases to the CJD Surveillance Unit is included but the number of referrals of suspect nvCJD is not listed separately and this has led to controversy.1 Reporting of numbers of suspect cases of nvCJD might provide an early indication of likely future numbers of actual cases if the clinical features of nvCJD were relatively specific and if a large and consistent proportion of cases referred were subsequently confirmed as nvCJD.

On March 21, 1996, all neurologists in the UK were circulated with a description of the clinicopathological features of nvCJD, based on details published in The Lancet on April 6, 1996,2 and asked to refer any suspect cases to the CJD Surveillance Unit in Edinburgh. The young age of those with nvCJD at death (currently mean 30 years, range 1950 years) has been a characteristic of nvCJD and since March, 1996, there has been an increase in the number of referrals of cases of suspect CJD under the age of 50 years. Excluding familial and iatrogenic cases, up to Feb 28, 1997, 37 cases of suspect CJD aged less than 50 years have been referred since March, 1996, at a rate of 15 per month, with no increase in the rate of referral during this period.

Neuropathological examination is essential for the definite diagnosis of nvCJD. 11 of the referred cases have died and necropsy has been done in nine. Of these nine, one has been confirmed as nvCJD, one classic CJD, and three as other conditions. The results of necropsy are awaited in four cases. In one patient who died without necropsy, the diagnosis of nvCJD was confirmed by brain biopsy and the one patient who died without necropsy or brain biopsy has been classified as probable nvCJD on the basis of clinical features and investigations. The diagnosis of nvCJD has been confirmed by brain biopsy in two patients who are still alive. Four of the 37 referred cases aged less than 50 years have been classified as nvCJD and one as probable nvCJD (table).

In the remaining 24 referred cases still alive (excluding the two confirmed as nvCJD on brain biopsy), the diagnosis is uncertain, although in the great majority nvCJD is very unlikely because of alternative clinical diagnoses (12), clinical recovery (3), clinical improvement (1), or lack of clinical progression over several months (2). In two of the cases with recovery, the initial clinical presentation was highly suggestive of nvCJD. The diagnosis of nvCJD was confirmed within 3 months of referral in the four neuropathologically verified cases and 12 of the outstanding cases were referred more than 4 months ago. The relatively low proportion of cases diagnosed as nvCJD reflects the importance of reviewing a wide spectrum of clinical presentations in order to achieve a high degree of case ascertainment and also reflects good cooperation with the referral process.

Classification of suspected CJD referrals aged less than 50 years March 21, 1996, to Feb 28, 1997

Deaths 11:
	Necropsy 9:
		1 nvCJD
		11 classic CJD
		3 other diagnoses
		4 results awaited
	No necropsy 2:
		1 nvCJD on brain biopsy
		1 probable nvCJD

 Alive 26:
		2 nvCJD on brain biopsy
		18 CJD clinically unlikely
		6 diagnosis uncertain
On current evidence, only a small proportion of referred cases of suspect CJD aged less than 50 years old are subsequently classified as nvCJD. Although this proportion may change, for example when necropsy results become available, the number of referrals of CJD under the age of 50 years is a poor indicator of eventual numbers of cases of nvCJD. Furthermore one case of classic CJD has been identified from the younger referrals with clinical features that were not clearly distinct from nvCJD. No validated criteria have yet been established to classify referred cases as possible nvCJD and the difficulties of classifying cases in life are underlined by the referred cases with clinical recovery.

Accurate reporting of confirmed or probable cases of nvCJD is essential and will continue, but on current evidence reporting of the numbers of referrals by age is unlikely to be very informative.

1 Butler D. CJD variant stirs debate on release of data. Nature 1996; 383: 658.

2 Will RG, Ironside JW, Zeidler M, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 1996; 347: 92125.

Diffusion-weighted magnetic resonance imaging in Creutzfeldt-Jakob disease

Lancet 20 Mar 1997
P Demaerel, A L Baert, L Vanopdenbosch, W Robberecht, R Dom

We report the magnetic resonance (MR) imaging findings in a 68-year-old woman with histologically proven Creutzfeldt-Jakob disease (CJD). She developed a progressive dementia, ataxia, and myoclonic jerks over 3 weeks. On admission she had no spontaneous speech and could understand only simple instructions. Characteristic electroencephalogram changes consisting of periodic sharp waves were observed. Brain MR imaging 4 weeks after onset of symptoms showed subtle signal alterations in the left caudate and lentiform nucleus on T2-weighted imaging. Diffusion-weighted imaging showed gross abnormalities involving most of the cortex of the left hemisphere (figure) and confirmed the abnormalities in the basal ganglia. 99mTc single-photon emission tomography (SPET) showed diminished perfusion in the left parietooccipital lobe and in both frontal lobes. Follow-up MR imaging 4 weeks later showed progression of the abnormalities in the basal ganglia but less conspicuous abnormalities in the cortex. The patient died 9 weeks after onset of symptoms. The necropsy findings confirmed CJD.

Diffusion-weighted imaging detects tiny changes in water mobility, resulting in ultra-rapid detection of a disturbed cellular homoeostasis, when cell damage and a shift from extracellular to intracellular space occurs. The examination time is of the order of 4 seconds. It is well-known that the sensitivity of diffusion-weighted imaging to detect ischaemia exceeds by far the sensitivity of any other imaging technique.1 Recently the MR imaging appearances of CJD have been reviewed.2

Abnormalities were seen in the basal ganglia in 79% of the patients, but no abnormalities were seen in the remaining 21%. Spongiform degeneration, astrocytic gliosis, and neuronal loss are characteristic neuropathological findings. On routine MR images, these changes are more difficult to appreciate in the cortex than in the basal ganglia, which are surrounded by unaffected white matter. Positron emission tomography and 99mTc-SPET have shown metabolic and blood flow changes in CJD but sensitivity and specificity of these examinations have not yet been determined.3 Up to now there have been no comparisons between these functional studies and diffusion-weighted imaging. Advantages of diffusion-weighted imaging are low cost, as it can be implemented on existing MR scanners, better anatomical resolution, absence of radiation exposure, and extremely short examination time.

We call for the use of diffusion-weighted imaging in suspected cases of CJD which will be followed up to necropsy so as to build up definitive evidence of the potential of this technique to substantiate the diagnosis of CJD.

1 Sorensen AG, Buonanno FS, Gonzalez RG, et al. Hyperacute stroke: evaluation with combined diffusion-weighted and hemodynamically weighted echo-planar MR imaging. Radiology 1996; 199: 391401.

2 Finkenstaedt M, Szudra A, Zeer I, et al. MR imaging of Creutzfeldt-Jakob disease. Radiology 1996; 199: 79398.

3 Grunwald F, Pohl C, Bender H, et al. 18F-fluorodeoxyglucose-PET and 99mTc-bicisate SPECT in Creutzfeldt-Jakob disease. Ann Nucl Med 1996; 10: 13134.

Cyclosporin, mitochondrial death, and Alzheimer

Pittsburgh Post-Gazette Mar 18, 1997 If a drug can be found that kept that mechanism from working, doctors might be able to preserve more brain cells -- and thus brain function -- following a stroke or brain injury and perhaps slow the progression of diseases such as Parkinson's and Alzheimer's. It has been established that these neurons can be poisoned by glutamate. Glutamate accounts for about 70 percent of the "excitatory" signals transmitted in the brain, Reynolds said. When brain cells die, they release massive amounts of glutamate. The released glutamate is picked up by other, still healthy cells. The glutamate overwhelms these cells, however, overstimulating them and causing them to die.

Neuroscientists have thus concluded that blocking the effects of glutamate might prove an effective treatment for stroke and trauma; indeed, a number of glutamate blockers or antagonists already are being tested in local hospitals on stroke patients. In the case of brain trauma, however, research by Pitt' Dr. Donald Marion has shown that cooling the body for a day or two can be as effective if not more effective than these experimental drugs.

One problem with glutamate-inhibiting drugs is that they block not only the unwanted glutamate but all glutamate, including that used in normal brain functioning, Reynolds said. That can cause unwanted side effects, such as hallucinations. A better class of drug would block only a chemical or process not involved in normal brain function, he noted. Glutamate causes calcium to enter the cell, leading to cell death. And calcium, it seems, makes a bee line to the mitochondria. The mitochondria convert glucose into ATP, which serves as an energy source for the rest of the cell. The calcium signals the mitochondria to speed up production of ATP. But too much calcium eventually upsets the balance of enzymes and electrical charges necessary to produce ATP. Production slows to the point that the mitochondria begin consuming ATP.

"That's the start of the end for the cell," Reynolds said. At this point, his laboratory studies of neurons have shown that something called the permeability transition pore opens in the mitochondrion's outer membrane, shutting down its operation. As the mitochondria die, the cell loses the power to sustain itself and it too dies. "The only time when we know this pore is turned on is cases when the neuron is going to die," Reynolds said. "What we need, unquestionably, are drugs to block that thing.

In the case of brain trauma or stroke, a drug that blocked the permeability transition pore might keep some cells from dying until blood flow was restored and brain chemistry settled down to normal within a matter of hours or days, Reynolds said.

In degenerative diseases, such as Alzheimer's or Parkinson's, neurons die over a period of years. Each disease is caused by a slightly different mechanism, but in each the net effect is to make neurons a bit more fragile, so that they are more vulnerable to injuries, or changes in oxygen and nourishment that would not affect a healthy cell. In these cases, a drug that blocked the permeability transition pore might make these cells a bit more resilient to these upsets, slowing the progression of the disease.

Though cyclosporine can block the pore, the dosages required are too high to be practical, Reynolds said, so another drug will have to be discovered or invented before treatment is a reality. And whether such a drug would make a difference in clinical use is a matter of speculation, he acknowledged.

What can CJD be confused with?

Other CNS disorders with focal spongiform change
CAA site
  • Alzheimer's disease
  • Pick's disease
  • Diffuse Lewy body disease
  • Dementia of frontal lobe type
  • Dementia in motor neurone disease

    Sponge - like changes in other CNS disorders Grey matter:

  • status spongiosus
  • oedema
  • metabolic encephalopathies
  • neuronal storage disorders
  • tissue fixation and processing artefacts White matter:
  • oedema
  • ischaemia
  • metabolic encephalopathies
  • spongy degeneration of the white matter in infancy
  • Canavan's disease
  • tissue fixation and processing artefacts An informal survey of neuropathologists, however, registered a theoretical range of 2-12% of all dementias as actually CJD (Harrison, 1991). And hundreds of thousands of Americans suffer from severe dementias every year (Brayne, 1994; United, 1995). Two other studies average about a 3% CJD rate among dementia patients (Mahendra, 1987; Wade, 1987).

    A preliminary 1989 University of Pennsylvania study showed that 5% of patients diagnosed with dementia were actually dying from Creutzfeldt-Jakob disease (Boller, 1989). It would seem CJD is seriously underdiagnosed at present (Harrison, 1991).

    GSS mis-diagnosed as atypical multiple sclerosis in a family of sheepbreeders.

    Acta Neuropath. 56: 87-92, 1982. by Peiffer, J. :

    Peiffer (1982) described a family of sheepbreeders in which a father and 2 sons had GSS. All 3 also had congenital hip dysplasia, as did at least 3 other members of the kindred, all females. Atactic symptoms, dysarthria, and personality changes characterized the clinical course of this disorder, which might be labeled atypical multiple sclerosis.

    More mis-diagnosed atypical dementias.

     Owen F; Poulter M; Collinge J; Leach M; Shah T; Lofthouse R; Chen YF; Crow TJ;
    Harding AE; Hardy J; et al. Exp Neurol 112: 240-2 (1991) Division of Psychiatry,
    Clinical Research Centre, Harrow, Middlesex, United Kingdom. 
    A number of mutations have been demonstrated in the open reading frame (ORF) of the prion protein (PrP) gene in patients with familial Creutzfeldt-Jakob disease or Gerstmann-Straussler syndrome. On the basis of detecting an insertion in the ORF of the PrP gene in a patient originally suspected to be suffering from familial Alzheimer-type dementia, we screened 101 individuals with atypical dementias for the known PrP gene mutations. Insertions were found in five individuals, whereas none of the other reported mutations in the PrP gene was detected in the present study. One of the five insertions was larger than that described previously, suggesting that the individuals with these mutations are unlikely to be all lineally related and that insertions in the PrP gene may not be uncommon in prion diseases.

    Accuracy of the clinical diagnosis of corticobasal degeneration

    Neurology 48: 119-125 (1997)
    Litvan I, Agid Y, Goetz C, ... Bartko JJ

    The accuracy of the clinical diagnosis of corticobasal degeneration (CBD) is unknown. To determine its diagnostic accuracy, we presented 105 cases with known neuropathologic diagnoses, including CBD (n = 10), progressive supranuclear palsy (PSP, n = 24), Parkinson's disease (n = 15), diffuse Lewy body disease (n = 14), multiple system atrophy (n = 16), postencephalitic parkinsonism (n = 7), Pick's disease (n = 7), Creutzfeldt-Jakob disease (n = 4), Alzheimer's disease (n = 4), vascular parkinsonism (n = 3), and Whipple's disease (n = 1), as clinical vignettes to six neurologists unaware of the autopsy findings. Reliability was measured with the kappa statistics.

    The neurologists' clinical diagnoses were compared with clinicopathologic diagnoses for sensitivity, specificity, and positive predictive values at first and last clinic visits. The group reliability for the diagnosis of CBD significantly improved from moderate for the first visit (mean = 34 months after onset) to substantial for the last (68 months after onset). For the first visit, mean sensitivity for CBD was low (35%), but specificity was near-perfect (99.6%). For the last visit, mean sensitivity minimally increased (48.3%), and specificity remained stable.

    False-negative misdiagnoses mainly occurred with PSP. False-positive diagnoses were rare. The extremely low sensitivity of the clinical diagnosis of CBD suggests that this disorder is markedly underdiagnosed. Although the validity of the clinical diagnosis might have been improved if neurologists could have examined these patients, more important is that this disorder was misdiagnosed by the primary neurologists. In our data set, the best predictors for the diagnosis of CBD included limb dystonia, ideomotor apraxia, myoclonus, and asymmetric akinetic-rigid syndrome with late onset of gait or balance disturbances.

    Are prion diseases always transmissable?

    Listserve 15.03.97

    "TSEs are not so infective that they can be easily transmitted to the other members of a family. As far as i know the literature, there is not one published case of a lethal transmission of a human TSE within a family."

    "I agree with this as it is written, which is not to say there have not been accounts of husband/wife or father/son/son all having the disease."

    "In fact, it should not be assumed that all variations of TSE are transmissable. The name may be a misnomer. The leading contender in my view would be a type of familial CJD (cerebral anyloid angiopathy -- CAA) where a stop codon replaces a tyrosine at position 145 (second residue of first NMR helix). This produces a partial molecule that no longer qualifies for N- glycosylation, disulphide, or GPI anchor. It was not transmissable by intra-cerebral injection to mice. Without the GPI anchor, migration up the lipid bilayer of a periferal nerve may not be feasible. Possibly, Y145X can cause a problem only when produced within the cell; perhaps it (or others) are unable (in some tissues at least) to recruit normal conformers and so depend on steady de novo synthesis of an internal mutant allele. (The actual composition of amyloid is unfortunatly not established in many instances.)" PNAS 93: 744-8 (1996) BBRC 192:525-531 (1993)

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