Veterans health administration information systems as a resource for rare disorders research: Creutzfeldt-Jakob disease as a paradigm.

OBJECTIVE: To illustrate the application of Veterans Health Administration (VHA) information systems in both clinical and epidemiologic investigations of a rare disease, our specific aims were: (1) to determine the number and incidence of Creutzfeldt-Jakob disease (CJD) diagnoses in the VHA from fiscal year (FY) 1997 through FY 2010 and (2) to describe the relevant clinical features associated with those diagnoses. METHODS: The VHA Medical SAS Datasets were queried for all unique, incident CJD diagnoses between FY 1997 and 2010. Electronic health records were then reviewed to validate diagnoses using modified criteria. RESULTS: During the study period, 115 CJD diagnoses (43 definite, 27 probable, 19 possible, and 26 suspected) were identified. Annual incidence ranged between 0.8 per million (95% CI, 0.3-1.7) in FY 2009 and 3.7 per million (95% CI, 2.1-6.4) in FY 1997. Dementia was documented in 111 cases (96.5%) and myoclonus in 73 (63.5%). Discharges consistent with CJD were noted in 31 of 78 patients (39.7%) with documented electroencephalography. CONCLUSIONS: For certain rare diseases, VHA information systems can be used to assemble a substantive case series for clinical study. However, the VHA's distinctive demographic characteristics and population dynamics may limit the external validity of epidemiologic investigations.

Coexistence of movement disorders and epilepsia partialis continua as the initial signs in probable Creutzfeldt-Jakob disease.

Movement disorders and epilepsy rarely occur in the early stage of Creutzfeldt-Jakob disease (CJD) but have not been reported concurrently. We report on a 47-year-old patient with probable CJD who presented with generalized chorea and focal dystonia with myoclonic jerks on the right hand. Myoclonic jerks progressed to epilepsia partialis continua within 5 days of admission to the hospital. The diagnosis of our patient was compatible with probable CJD on the basis of clinical course, electroencephalogram, and diffusion-weighted magnetic resonance imaging findings, and presence of 14-3-3 protein in cerebrospinal fluid. To our knowledge, this is the first report of a case developing both movement disorders and epilepsia partialis continua in the early stage of the disease.

The public health impact of prion diseases.

Several prion disease-related human health risks from an exogenous source can be identified in the United States, including the iatrogenic transmission of Creutzfeldt-Jakob disease (CJD), the possible occurrence of variant CJD (vCJD), and potential zoonotic transmission of chronic wasting disease (CWD). Although cross-species transmission of prion diseases seems to be limited by an apparent "species barrier," the occurrence of bovine spongiform encephalopathy (BSE) and its transmission to humans indicate that animal prion diseases can pose a significant public health risk. Recent reports of secondary person-to-person spread of vCJD via blood products and detection of vCJD transmission in a patient heterozygous at codon 129 further illustrate the potential public health impacts of BSE.

Clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease.

BACKGROUND: No method for the clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease (sCJD) has been established except for pathologic examination. OBJECTIVE: To identify a reliable marker for the clinical diagnosis of MM2-type sCJD. METHODS: CSF, EEG, and neuroimaging studies were performed in eight patients with MM2-type sCJD confirmed by neuropathologic, genetic, and western blot analyses. RESULTS: The eight cases were pathologically classified into the cortical (n = 2), thalamic (n = 5), and combined (corticothalamic) (n = 1) forms. The cortical form was characterized by late-onset, slowly progressive dementia, cortical hyperintensity signals on diffusion-weighted imaging (DWI) of brain, and elevated levels of CSF 14-3-3 protein. The thalamic form showed various neurologic manifestations including dementia, ataxia, and pyramidal and extrapyramidal signs with onset at various ages and relatively long disease duration. Characteristic EEG and MRI abnormalities were almost absent. However, all four patients examined with cerebral blood flow (CBF) study using SPECT showed reduction of the CBF in the thalamus as well as the cerebral cortex. The combined form had features of both the cortical and the thalamic forms, showing cortical hyperintensity signals on DWI and hypometabolism of the thalamus on [18F]2-fluoro-2-deoxy-d-glucose PET. CONCLUSION: For the clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease, cortical hyperintensity signals on diffusion-weighted MRI are useful for the cortical form and thalamic hypoperfusion or hypometabolism on cerebral blood flow SPECT or [18F]2-fluoro-2-deoxy-d-glucose PET for the thalamic form.

Clinical features of variant Creutzfeldt-Jakob disease.

Since 1996, over one hundred cases of variant Creutzfeldt-Jakob disease have appeared, mostly in the United Kingdom. In this review, we summarise the major clinical features of this progressive neurodegenerative condition and compare them with those of sporadic Creutzfeldt-Jakob disease. We emphasise the young age (median 26 years) at presentation and the dominant psychiatric/behavioural features, particularly depression. Sensory symptoms are present initially in half the cases and florid psychiatric symptoms, such as delusions or hallucinations, are also common. Given these symptoms, many patients present in clinical practice initially to a psychiatrist but are referred to neurologists when neurological signs become apparent. Although the definitive diagnosis remains neuropathological, a confident pre-mortem diagnosis is now possible when the 'pulvinar sign' is seen on magnetic resonance imaging studies.

Ecosystems supporting clusters of sporadic TSEs demonstrate excesses of the radical-generating divalent cation manganese and deficiencies of antioxidant co factors Cu, Se, Fe, Zn. Does a foreign cation substitution at prion protein's Cu domain initiate TSE?

Analyses of food chains supporting isolated clusters of sporadic TSEs (CWD in N Colorado, scrapie in Iceland, CJD in Slovakia) demonstrate a consistent 2 1/2+ fold greater concentration of the pro-oxidant divalent cation, manganese (Mn), in relation to normal levels recorded in adjoining TSE-free localities. Deficiencies of the antioxidant co factors Cu/Se/Zn/Fe and Mg, P and Na were also consistently recorded in TSE foodchains. Similarities between the clinical/pathological profile of TSEs and Mn delayed psycho-neurotoxicity in miners are cited, and a novel theory generated which suggests that sporadic TSE results from early life dependence of TSE susceptible genotypes on ecosystems characterised by this specific pattern of mineral imbalance. Low Cu/Fe induces an excessive absorption of Mn in ruminants and an increased oxidation of Mn2+ into its pro oxidant species, Mn3+, which accumulates in mitochondria of CNS astrocytes in Mn SOD deficient genotypes. Deficiencies of scavenger co factors Cu/Zn/Se/Fe in the CNS permits Mn3+ initiated chain reactions of auto-oxidant mediated neuronal degeneration to proliferate, which, in turn, up-regulates the expression of the Cu-metalloprotein, prion protein (PrP). Once the rate of PrP turnover and its demand for Cu exceeds the already depleted supply of Cu within the CNS, PrP can no longer bind sufficient Cu to maintain its conformation. Mn3+ substitutes at the vacated Cu domain on PrP, thus priming up a latent capacity for lethal auto-oxidative activity to be carried along with PrP like a 'trojan horse'; where Mn 3+ serves as the integral 'infectious' transmissible component of the misfolded PrP-cation complex. The Mn overactivation of concanavalin A binding to glycoprotein and Mn-initiated autoxidation results in a diverse pathological profile involving receptor capping, aggregation/modification of CNS membrane/cytoskeletal proteins. TSE ensues. The BSE/nv CJD strain entails a 'synthetic' induction of the same CNS mineral disturbance, where 'in utero' exposure to Cu-chelating insecticides/Mn supplements accelerates the onset of a more virulent 'strain' of adolescent TSE.

A case-control study of Creutzfeldt-Jakob disease in Japan: transplantation of cadaveric dura mater was a risk factor.

A case-control study was conducted to reveal the relative risk of cadaveric dura mater graft transplantation for Creutzfeldt-Jakob disease. Fifty-two cases with Creutzfeldt-Jakob disease that were reported to the surveillance of the disease, and 102 age- and sex-matched hospital controls were selected. Information on family history, occupations, and medical history was collected. Eight cases and no control had a history of cadaveric dura mater graft transplantation. Surgical operations without the dura mater graft, blood transfusion, and acupuncture did not elevate the risk.