Sporadic Creutzfeldt-Jakob disease mimicking variant Creutzfeldt-Jakob disease

BACKGROUND: The determination of the form of prion disease and early diagnosis are important for prognostic, public health, and epidemiologic reasons. OBJECTIVE: To describe a patient with sporadic Creutzfeldt-Jakob disease (sCJD) who had a clinical history and initial electroencephalogram and magnetic resonance imaging findings consistent with variant CJD (vCJD). RESULTS: Results of a repeated electroencephalogram were suggestive of sCJD, and a subsequent brain biopsy confirmed this diagnosis. CONCLUSIONS: This case cautions against relying solely on T2- and diffusion-weighted pulvinar hyperintensity and clinical features to differentiate between vCJD and sCJD, and further supports established diagnostic criteria for vCJD.     

Creutzfeldt-Jakob disease

Summary The neuropathological findings in 3 cases of Creutzfeldt-Jakob disease are described.The triad of morphological changes, i.e. neuronal loss, status spongiosus of the grey matter and proliferation and hypertrophy of fibrous astrocytes with or without microglial reaction, conforms to the typical pattern of pathology described in the literature. Degeneration of the cerebellum places these cases in the cortico-striato-cerebellar variant of the disease.The distribution of the lesions within cerebrum and cerebellum, with a more severe involvement of phylogenetically older portions, is unusual. In the cerebrum cortices belonging to the limbic system and the striatum were the most severely affected, whilst in the cerebellum the vermis and flocculo-nodular lobe bore the brunt of the pathological process. A similar distribution of the lesions is generally found in kuru.Further similarities with kuru are pointed out i.e. the occurrence of swollen, chromatolytic neurones predominantly within the infragranular layers of the cerebral cortex, of coarse intracytoplasmic vacuolation in many of the large striatal nerve cells and of kuru plaques within the cerebellum. Similarities and differences between the two diseases are discussed.

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Zusammenfassung Die neuropathologischen Befunde von 3 Fällen von Creutzfeldt-Jakobscher Krankheit werden beschrieben.Die Trias der morphologischen Veränderungen — Nervenzelluntergang, Status spongiosus in der grauen Substanz, Proliferation und Hypertrophie faserbildender Astrocyten mit und ohne Mikrogliareaktion — entspricht dem typischen Muster der pathologischen Veränderungen in anderen Fällen der Literatur. Ihre Kleinhirnbeteiligung reiht die Fälle in die cortico-striato-cerebelläre Variante der Krankheit ein.Ungewöhnlich ist die Verteilung der Veränderungen im Großhirn und Kleinhirn mit der Bevorzugung phylogenetisch älterer Anteile. Am Großhirn waren die Rindenabschnitte des limbischen Systems und das Striatum am stärksten befallen; am Kleinhirn hat der pathologische Prozeß hauptsächlich den Vermis und Lobus flocculo-nodularis angegriffen. Eine ähnliche Anordnung der Veränderungen findet sich bei der Kuru-Krankheit.Weitere Ähnlichkeiten mit Kuru werden hervorgehoben, wie das Vorkommen von geschwollenen chromatolytischen Nervenzellen, besonders in den infragranulären Großhirnrindenschichten, von groben intracytoplasmatischen Vacuolen in vielen großen Striatumneuronen und von Kuru-Plaques im Kleinhirn. Ähnlichkeiten und Unterschiede der beiden Krankheitsbilder werden diskutiert.

     

Creutzfeldt-Jakob disease

The historical aspects of spongiform encephalopathies, Creutzfeldt-Jakob disease (CJD) and kuru of man, as well as scrapie and transmissible mink encephalopathy, are outlined. Transmissions of these diseases to animal hosts are presented, with emphasis on CJD transmissions to guinea pigs, hamsters, and mice. The relationship of CJD to scrapie with reference to the pathological findings is discussed. In CJD the incubation period is cut in half in guinea pigs and hamsters in the second passage. The spongiform changes occurring in the neuropil are reviewed. These changes are related to the type of inoculum, e.g., there is more vacuolization after inoculation with brain, and less after inoculation with spleen. Spongiform changes are also dependent upon the route of inoculation; these are more severe in intracerebral inoculation compared to intraperitoneal inoculation. Viremia is present. Maternal transmission and lateral transmission are absent. No virus-like particles are detected, and no other organisms are visible by electron microscopy. Isolations of the causative agent and strains of the agent in spongiform encephalopathies remain elusive. The hypotheses concerning the nature of the agent are critically reviewed. Novel data on the production of tumors derived from CJD brains are presented. Tissue culture cells arising from such brains become permanent lines and are similar to neoplastic lines. When such CJD lines are injected subcutaneously into nude mice, malignant neoplasms are formed. No evidence of an infectious etiology in Alzheimer's disease exists. Reported similarities between this disease and CJD are reviewed. Animal models of CJD are useful for the investigation of dementias.     

New-variant Creutzfeldt-Jakob disease

Surveillance of Creutzfeldt-Jakob disease (CJD) was reinstituted in the United Kingdom in 1990 to monitor any effects of the bovine spongiform encephalopathy (BSE) agent on humans. In 1996, the CJD Surveillance Unit described a new variant of CJD, characterised by an unusually early age of onset, a prolonged clinical course with presenting features that were unusual for CJD, and a characteristic neuropathology. All patients were homozygous for methionine at codon 129 in the prion protein gene, with no mutations or insertions. At present, 23 patients have been diagnosed with this new disorder, but it is impossible at present to predict likely numbers of future cases. Strain typing studies in experimental mice have shown that the transmissible agent in new-variant CJD has identical features to that of the BSE agent, but differs from that in sporadic CJD. The identification of disease-associated prion protein in lymphoid tissue in newvariant CJD raises the possibility of lymphoid biopsy for early diagnosis, and indicates that the transmissible agent may be present in association with circulating lymphoid cells in the blood and other tissues. Although the mode of transmission of the BSE agent to humans is unknown, current evidence favours a dietary mode of spread. However, the precise route of spread, infectious dose and incubation period for BSE in humans are all unknown. Additional studies are required to provide further information, which will allow a more accurate understanding of disease pathogenesis and prediction of future disease trends.     

家族性Creutzfeldt-Jakob病

目的确定家族性Creutzfeldt—Jakob病（CJD）的临床特点并探讨其可能的发病机制。方法对一个CJD家系进行系谱调查,并采用蛋白捕获法进行脑脊液14-3—3蛋白定量;应用PCR方法,结合DNA测序技术,检测朊蛋白（PrP）基因类型。结果（1）两代4例的发病年龄早于散发性CJD,而且有早发的趋势;（2）先证者脑脊液14-3—3蛋白为125ng／ml,高出截点13．9。倍;（3）先证者PRNP第788碱基和789碱基之间插入1个碱基A,致使PRNP第231位点发生插入突变;（4）患者弟弟及其女儿未发现有PrP基因突变。结论先证者为PRNP第231位点插入突变致家族性CJD,其临床表型与散发性CJD无明显不同,但发病年龄早于散发性CJD,同一家系患者死于同一年龄段。     

Iatrogenic Creutzfeldt-Jakob disease

Over the past 2 years, Creutzfeldt-Jakob disease (CJD) has affected several patients who received cadaver pituitary-derived growth hormone (pit-hGH) and one patient who received a cadaveric dura mater graft. The risk of iatrogenic transmission of CJD has long been recognized, but until recently, the low prevalence of the disorder and minimal use of therapeutic products derived from human tissues may have limited the risk. From 1963 to 1985, approximately 10,000 children received pit-hGH. These patients, exposed to pooled products potentially contaminated with the CJD agent, may have significantly increased the number of individuals whose blood and tissues could transmit CJD. This possibility as well as data on the pathophysiology of CJD and scrapie, a related disease of animals, should guide the development of practices that would limit iatrogenic spread of CJD.     

Unilateral Creutzfeldt-Jakob disease

A 73-year-old woman had progressive right hemiparesis, aphasia, and focal motor seizures. EEG showed periodic discharges on the left. She died 8 weeks after onset. At autopsy, there was marked spongiform change, neuronal loss, and severe proliferation of astrocytes predominantly on the left and most prominently in the insular and centroparietal cortex. The changes were consistent with Creutzfeldt-Jakob disease (CJD), but pathology was slight or absent on the right side. This case appears as the first report of what might be called unilateral CJD. Such a condition should be included within the differential diagnosis of progressive unilateral cerebral disorders.     

Update on Creutzfeldt-Jakob disease

PURPOSE OF REVIEW: Prion diseases are transmissible fatal neurodegenerative disorders in which infectivity is associated with the accumulation of PrP(Sc), a disease-related isoform of normal cellular prion protein. The recent emergence of variant Creutzfeldt-Jakob disease has led to major public health concerns, and the need for the development of effective treatments. As PrP(Sc) is associated both with pathology and infectivity, therapeutic approaches to date have largely aimed at preventing its accumulation, but this strategy has produced only modest results in animal models. The link between PrP(Sc) and neurotoxicity is unclear, and alternative pathological processes need to be considered. Here we focus on the latest progress in therapeutic strategies and potential mechanisms of prion neurotoxicity. RECENT FINDINGS: Passive immunisation with anti-prion protein antibodies prevents peripheral prion replication and blocks progression to clinical disease in peripherally infected mice. A new approach, in which neuronal cellular prion protein is depleted in mice with established neuroinvasive prion infection, prevents the onset of clinical disease, blocks neuronal cell loss and reverses early spongiform pathology. This dramatic protective effect occurs despite the continued build-up of extraneuronal PrP(Sc) and continued replication of prion infectivity, effectively producing a sub-clinical state. SUMMARY: New insights into the mechanisms of neurotoxicity in prion diseases support the concept that PrP(Sc) itself is not directly neurotoxic. They suggest that neuronal prion propagation results in the production of a toxic intermediate or depletion of a key constituent. Prevention of the formation of such a species rather than PrP(Sc) accumulation itself is a clear target for prion therapeutics.     

颅脑眼手术后的Creutzfeldt-Jakob病

目的　探讨医源性Creutzfeldt Jakob病 (CJD)的发病与手术间隔时间、临床表现、基因表达、异常朊蛋白 (prionprotein ,PrP)沉积和实验动物传递。方法　颅脑眼手术后 1～ 4年发生肌阵挛、痴呆并经脑活检证实的 3例CJD病人 ,2例行PrP免疫组化染色 ,1例行PrP基因检测和实验动物传递。结果　 2例脑内发现了异常PrP沉积 ,1例PrP基因密码子 12 9为甲硫氨酸 ,缬氨酸杂合子型 ,实验鼠传递成功。结论　颅脑手术后CJD ,其潜伏期明显短于眼部手术 ,PrP沉积均为突触型 ,即使 12 9M/V多态性的脑组织匀浆 ,通过昆明鼠传递也能获得成功。医疗实践中宜警惕本组疾病 ,防止医源性传播。     

Creutzfeldt-Jakob disease in Sweden

OBJECTIVES—To find and investigate,retrospectively, as many cases as possible ofCreutzfeldt-Jakob disease (CJD) in Sweden dying during the period1 January 1985 to 31 December 1996 and to detect any possible case(s)of new variant CJD.
METHODS—The patients were found through computersearch of all death certificates in Sweden on which CJD was mentioned,through information from the Swedish neuropathologists, and spontaneousreports from Swedish doctors and hospitals. Data concerning thepatients were then collected from patients' case records and frombrain histopathology reports.
RESULTS—In total 72 cases of spongiformencephalopathy were confirmed as definite by neuropathology, one ofthem with Gerstmann-Stäussler-Scheinker disease. In 51 further casesthere were no brain pathology data but the diagnosis "probable" (37 patients) or "possible" (14 patients) CJD according to WHO criteriacould be made on clinical grounds. There was a variation in number ofdeaths/year, from a minimum of five (1985) to a maximum of 16 (1990).Sixty patients died during the period 1985-90 and 62 during 1991-6.The sex ratio was nearly 1:1. Calculated for a population of 8.6 million (mean of 12 years) in Sweden this gives 1.18/million/year. Ageat the time of the presenting symptoms ranged from 34 to 84 years. Only one patient was under 40 at the onset of symptoms. He had a spongiform encephalopathy but prion protein staining was negative. The duration ofsymptoms that could be attributed to CJD was 6 months or less in 75 cases, 7-12 months in 16 cases, 1 to 2 years in 15 cases, and morethan 2 years in 16 patients. By definition all patients were demented.Other more common symptoms and signs were aphasia, dysphasia,dysathria, ataxia, myoclonus, pareses of the extremities, rigidity orspasticity, different types of hyperkinesias, and other psychiatricsymptoms (depression, anxiety, and aggressiveness). Less commonsymptoms were hallucinations (mainly visual), visual defects, sensorysymptoms (paraesthesias, itching, or pain), apraxia of swallowing, anddisorders of eye movements.
CONCLUSIONS—The incidence, the symptomatology, theage distribution (age in years at onset and at death), and the durationof illness were similar to those of other countries except for thecases of new variant CJD in the United Kingdom. There is so far noindication of any cases of new variant CJD in Sweden.

     

Creutzfeldt-Jakob disease in Japan

In a nationwide survey of Creutzfeldt-Jakob disease (CJD) in Japan, the point prevalence rate on June 1, 1978 in Fukuoka Prefecture and the estimated national prevalence rate were approximately one per one million population. The minimal period prevalence rate was 0.45 per one million population. The minimal annual incidence and the minimal annual mortality rate were 0.19 and 0.15 per one million population, respectively. The geographic distribution of CJD in Japan was uniform. Clinically, CJD affected the central nervous system diffusely and was rapidly fatal. No specific features were found in family, social, and past histories.     

Creutzfeldt-Jakob disease in Hungary

Human prion diseases or transmissible spongiform encephalopathies are progressive fatal neuropsychiatric diseases. In addition to the evaluation of clinical features, a common diagnostic procedure includes examination of the protein 14-3-3 in the cerebrospinal fluid, performing EEG to detect periodic sharp wave complexes with triphasic morphology, and cranial MRI to demonstrate high signal intensity in the basal ganglia or thalamus. The definite diagnosis requires a neuropathological examination. The analysis of the prion protein gene (PRNP) is initiated mainly after suspicion of a positive family history or an atypical presentation. In Hungary collecting data and setting up the neuropathological diagnosis in suspect prion disease cases originates from the late 1960s. Systematic surveillance was established in 1994 and since 2001 reporting of Creutzfeldt-Jakob disease has been compulsory. According to our database, the incidence of genetic prion disease is increased in Hungary. The most frequent mutation in the PRNP is at codon 200. This might be linked to migration from the Slovakian focus. Acquired forms of prion disease were not detected in our country. The surveillance system is based on referrals from clinicians and pathologists and the aim is to perform the neuropathological examination and analysis of the PRNP on the majority of suspect cases.     

Hyperparathyroidism simulating Creutzfeldt-Jakob disease

A 45 years-old woman presented with loss of initiative and memory, motivated cry and behaviour disturbance with childish traits, quickly progressive along 6 months until total apathy. An EEG showed periodic activity with bilateral triphasic waves against a flattened background activity suggesting Creutzfeldt-Jacob disease (CJD), but investigation for treatable causes of dementia disclosed hypercalcemia and hypophosphatemia. Further investigation showed a mass at the thyroid region that at surgery was identified as an oxyphilic cells adenoma. With electrolyte disturbance correction and posterior surgery there was normalization of both EEG and clinical status. Though it was previously reported mental confusion and EEG alteration associated with hyperparathyroidism we do not know of any previous case of confusion associated with periodic activity in EEG as in this disease. Hyperparathyroidism should be a differential diagnosis in every "de novo" case of CJD.     

Familial Creutzfeldt-Jakob disease.

A Finnish family is described with 9 cases of presenile dementia in 3 generations. The mean age at onset was 52 years (range 46--62 years). Progressive dementia, upper motor neuron signs, muscular rigidity, and twitching, irregular tremors were consistent features in the 6 clinically investigated patients and were associated with spongiform change in the cerebral cortex of one autopsy and two brain biopsy cases. The EEG showed progressive slowing without the occurrence of repetitive high-voltage complexes at any stage of the disease. The average duration of the disease (21 months, range 11--36 months) was longer than in the sporadic form of CJD. The occurrence of CJD within this family follows a pattern consistent with an autosomal dominant mode of inheritance, suggesting the possibility of vertical transmission of the presumptive causative agent for example by genomic integration or transplacental passage. However, the occurrence of the disease only through the paternal line of relationships and the presence of a discordant twin pair argue strongly against transplacental passage or transmission via mother's milk. Simple contact infection also seems unlikely, as conjugal cases were not found among the 7 married patients. The interval between the death of the last affected member in generation IV and the time of onset of the disease in the first affected member of generation V was 10 years. Thus setting a minimum incubation period if case-to-case transmission were occurring. To evaluate the role of a genetically determined susceptibility to infection studies on the HLA antigens and other genetic markers are in progress.     

Creutzfeldt-Jakob disease: a disease overview

Creutzfeldt-Jakob disease (CJD) is the most common form of the human transmissible spongiform encephalopathies, also known as prion diseases. This is a rare neurological disorder which ultimately results in death. Technologists must familiarize themselves with the clinical symptoms and EEG patterns of this disease since appropriate precautions must be taken. This is especially important when running electroneurodiagnostic (END) studies on patients with rapidly progressive dementia or a suspected or known case of CJD. An overview of the various forms of CJD, clinical symptoms, characteristic EEG results, transmission modes, diagnostic tests, and prevention methods are addressed.