Postmortem findings in a case of variant Creutzfeldt-Jakob disease treated with intraventricular pentosan polysulfate.

BACKGROUND: A small number of patients with variant Creutzfeldt-Jakob disease (vCJD) have been treated with intraventicular pentosan polysulfate (iPPS) and extended survival has been reported in some cases. To date, there have been no reports on the findings of postmortem examination of the brain in treated patients and the reasons for the extended survival are uncertain. We report on the neuropathological findings in a case of vCJD treated with PPS. METHODS: Data on survival in vCJD is available from information held at the National CJD Research and Surveillance Unit and includes the duration of illness in 176 cases of vCJD, five of which were treated with iPPS. One of these individuals, who received iPPS for 8 years and lived for 105 months, underwent postmortem examination, including neuropathological examination of the brain. RESULTS: The mean survival in vCJD is 17 months, with 40 months the maximum survival in patients not treated with PPS. In the 5 patients treated with PPS survival was 16 months, 45 months, 84 months, 105 months and 114 months. The patient who survived 105 months underwent postmortem examination which confirmed the diagnosis of vCJD and showed severe, but typical, changes, including neuronal loss, astrocytic gliosis and extensive prion protein (PrP) deposition in the brain. The patient was also given PPS for a short period by peripheral infusion and there was limited PrP immunostaining in lymphoreticular tissues such as spleen and appendix. CONCLUSIONS: Treatment with iPPS did not reduce the overall neuropathological changes in the brain. The reduced peripheral immunostaining for PrP may reflect atrophy of these tissues in relation to chronic illness rather than a treatment effect. The reason for the long survival in patients treated with iPPS is unclear, but a treatment effect on the disease process cannot be excluded.

Diagnosing variant Creutzfeldt-Jakob disease: a retrospective analysis of the first 150 cases in the UK.

INTRODUCTION: Establishing an early clinical diagnosis in variant Creutzfeldt-Jakob disease (vCJD) can be difficult, resulting in extended periods of uncertainty for many families and sometimes a view that patients have been subjected to unnecessary investigations. This issue is accentuated by the progressive nature of vCJD and by the difficulty in achieving a confident clinical diagnosis before an advanced stage of illness. Although diagnostic delay may be a result of the non-specific early clinical features, a systematic analysis of the process of diagnosis was undertaken, with the aim of trying to achieve earlier diagnosis of vCJD. METHODS: Retrospective case file analysis was undertaken of the first 150 definite and clinically probable cases of vCJD identified by the UK surveillance system. RESULTS: There is a significant interval between illness onset and presentation to a primary care physician, which is influenced by the nature of the initial clinical features. Neurological review is invariably sought following the development of clinical signs and a diagnosis is then established relatively quickly. Despite the progressive clinical course, a confident clinical diagnosis is not usually achieved until a relatively advanced stage of illness (mean time to diagnosis 10.5 months) with a more rapid clinical progression accounting for those cases diagnosed earlier after symptom onset. CONCLUSIONS: Early clinical diagnosis in vCJD is not possible in the great majority of cases because of non-specific initial symptoms. Once neurological signs develop, a diagnosis is usually made promptly but this is often at a relatively advanced stage of illness. The inherent delays in the diagnosis of vCJD have implications for those involved in both public health and therapeutics.

The role of cerebrospinal fluid 14-3-3 and other proteins in the diagnosis of sporadic Creutzfeldt-Jakob disease in the UK: a 10-year review.

BACKGROUND: It is 10 years since the detection of cerebrospinal fluid (CSF) 14-3-3 was included in the diagnostic criteria for sporadic Creutzfeldt-Jakob disease (sCJD) by the WHO. Since that time, other CSF proteins, such as S100b and tau protein, have been proposed as surrogate markers for sCJD. The authors aimed to investigate the diagnostic value of each of these three proteins. METHODS: CSF samples collected from patients who were referred to the National CJD Surveillance Unit as suspected cases of sCJD during the period 1997-2007 were analysed for 14-3-3, S100b and tau protein. The sensitivity, specificity, positive predictive value and negative predictive value of each of these markers, either alone or in combination for the diagnosis of sCJD, were assessed. The impact of CSF 14-3-3 analysis on the case classification of sCJD was investigated. RESULTS AND DISCUSSION: CSF 14-3-3 had the greatest sensitivity (86%) when compared with tau protein (81%) and S100b (65%). The combination of a positive CSF 14-3-3 or an elevated tau protein with a raised S100b had the highest positive predictive power for sCJD. During the study period, 100 patients were classified as probable sCJD solely on the basis of the clinical features and a positive CSF 14-3-3. The most sensitive marker for sCJD was a positive CSF 14-3-3. The analysis of CSF 14-3-3 plays a crucial role in the case classification of sCJD.

Variant Creutzfeldt-Jakob disease and exposure to fractionated plasma products.

BACKGROUND: The risk to public health of onward transmission of variant Creutzfeldt-Jakob disease (vCJD) via blood transfusion and plasma product administration is of on-going concern, particularly with the recent reported detection of abnormal prion protein in a person with haemophilia. OBJECTIVES: To describe the history of fractionated plasma product exposure in clinical cases of vCJD in the UK. METHODS: Through examination of records held at the National CJD Surveillance Unit (from relatives, general practices and hospitals). RESULTS: Nine out of 168 UK vCJD cases had a history of receipt of fractionated plasma products on 12 different occasions (1 pre-vCJD risk in 1970, the remaining between 1989-1998). According to the UK CJD Incident Panel risk assessment criteria, 11 were low-risk products and one was low or medium risk. CONCLUSION: It is unlikely that any of the UK vCJD clinical cases to date were infected through exposure to fractionated plasma products. However, the possibility that such transmission may result in vCJD cases in the future cannot be excluded.

Acute neurological problems: frequency, consultation patterns and the uses of a rapid access neurology clinic.

In secondary care, some patients with acute neurological symptoms are never seen by a neurologist. Rapid access neurology clinics could provide patients with timely access to neurology services. We analysed a retrospective cohort of 12,024 consecutive patients attending the 'immediate care' area of the emergency department or the acute medical admissions unit of the Royal Infirmary of Edinburgh. A total of 1,036 patients (9%) presented with a neurological complaint, of whom 680 (66%) did not have any contact with neurology services. The most common problems were epileptic seizure, cerebrovascular diseases and headache. Of the patients with epileptic seizure or headache who were not seen by a neurologist, about 40% might have benefited from neurological assessment. Following the introduction of a weekly rapid access neurology clinic, the most common problems seen were headache, symptoms that turned out to be medically unexplained and epileptic seizure.

Sporadic Creutzfeldt-Jakob disease with cerebellar ataxia at onset in the UK.

OBJECTIVE: To determine the frequency, in the UK, of sporadic Creutzfeldt-Jakob Disease (sCJD) with a cerebellar ataxic onset, and to describe the clinical features of the syndrome. METHODS: A retrospective review of autopsy-proved cases of sCJD cases in the UK, 1990-2005, identifying those presenting with cerebellar features without early cognitive decline. RESULTS: 29 of 618 (5%) patients with sCJD had an isolated cerebellar onset. Mean illness duration was 9 months. Subsequently, 21 (72%) developed myoclonus and 23 (79%) developed pyramidal features. Magnetic resonance imaging showed high signal in the basal ganglia in 11 of 14 (79%) patients. 7 of 15 (47%) patients were valine homozygotic at prion protein gene (PRNP)-129. Only 8 (28%) cases were referred to the surveillance unit after death. CONCLUSION: A better definition of sCJD presenting with an isolated cerebellar syndrome might improve future case recognition and contribute to the determination of its cause.

Dura mater-associated Creutzfeldt-Jakob disease: experience from surveillance in the UK.

Between 1970 and 2003, seven cases of human dura mater-associated Creutzfeldt-Jakob disease (CJD) were identified in the UK. Furthermore, we identified a case of CJD in a porcine dura graft recipient. The mean incubation period of the human dura mater cases was 93 (range 45-177) months. The clinico-pathological features of the cases are described and compared with cases previously reported in the world literature.

Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion.

BACKGROUND: Variant Creutzfeldt-Jakob disease (vCJD) is a novel human prion disease caused by infection with the agent of bovine spongiform encephalopathy (BSE). Epidemiological evidence does not suggest that sporadic CJD is transmitted from person to person via blood transfusion, but this evidence may not apply to vCJD. We aimed to identify whether vCJD is transmissible through blood transfusion. METHODS: The national CJD surveillance unit reported all cases of probable or definite vCJD to the UK blood services, which searched for donation records at blood centres and hospitals. Information on named recipients and donors was provided to the surveillance unit to establish if any matches existed between recipients or donors and the database of cases of vCJD. Recipients were also flagged at the UK Office of National Statistics to establish date and cause of death. FINDINGS: 48 individuals were identified as having received a labile blood component from a total of 15 donors who later became vCJD cases and appeared on the surveillance unit's register. One of these recipients was identified as developing symptoms of vCJD 6.5 years after receiving a transfusion of red cells donated by an individual 3.5 years before the donor developed symptoms of vCJD. INTERPRETATION: Our findings raise the possibility that this infection was transfusion transmitted. Infection in the recipient could have been due to past dietary exposure to the BSE agent. However, the age of the patient was well beyond that of most vCJD cases, and the chance of observing a case of vCJD in a recipient in the absence of transfusion transmitted infection is about 1 in 15000 to 1 in 30000.

Isolated visual symptoms at onset in sporadic Creutzfeldt-Jakob disease: the clinical phenotype of the "Heidenhain variant".

BACKGROUND: The Heidenhain variant of sporadic Creutzfeldt-Jakob disease (sCJD) is commonly understood to represent cases with early, prominent visual complaints. The term is clarified to represent those who present with isolated visual symptoms. This group may pose diagnostic difficulties and often present to ophthalmologists where they may undergo needless invasive procedures. METHOD: A retrospective review of 594 pathologically proved sCJD cases referred to the UK National CJD Surveillance Unit over a 15 year period to identify Heidenhain cases. RESULTS: 22 cases had isolated visual symptoms at onset with a mean illness duration of 4 months. The mean age at disease onset was 67 years. Most displayed myoclonus, pyramidal signs, and a delay in the onset of dementia for some weeks. 17 (77%) were referred initially to ophthalmology. Two underwent cataract extraction before diagnosis. All tested cases were homozygous for methionine at codon 129 of the prion protein gene. CONCLUSIONS: This rare, but clinically distinct, group of patients with sCJD may cause diagnostic difficulties. Because ocular intervention carries with it the risk of onward transmission awareness of this condition among ophthalmologists is important.

Analysis of EEG and CSF 14-3-3 proteins as aids to the diagnosis of Creutzfeldt-Jakob disease.

OBJECTIVE: To improve diagnostic criteria for sporadic Creutzfeldt-Jakob disease (CJD). METHODS: Pooled data on initial and final diagnostic classification of suspected CJD patients were accumulated, including results of investigations derived from a coordinated multinational study of CJD. Prospective analysis for a comparison of clinical and neuropathologic diagnoses and evaluation of the sensitivity and specificity of EEG and 14-3-3 CSF immunoassay were conducted. RESULTS: Data on 1,003 patients with suspected CJD were collected using a standard questionnaire. After follow-up was carried out, complete clinical data and neuropathologic diagnoses were available in 805 cases. In these patients, the sensitivity of the detection of periodic sharp wave complexes in the EEG was 66%, with a specificity of 74%. The detection of 14-3-3 proteins in the CSF correlated with the clinical diagnosis in 94% (sensitivity). The specificity (84%) was higher than that of EEG. A combination of both investigations further increased the sensitivity but decreased the specificity. CONCLUSIONS: Incorporation of CSF 14-3-3 analysis in the diagnostic criteria for CJD significantly increases the sensitivity of case definition. Amended diagnostic criteria for CJD are proposed.

Progressive multifocal leucoencephalopathy and viral antibody titres.

Progressive multifocal leucoencephalopathy (PML) is caused by a papovavirus but serum antibody titres are generally considered unhelpful in clinical diagnosis because antibodies to the commonest causal agent (JC virus) are frequently found in normal adults. There is little published information about CSF titres but usually they have not been useful. Two cases of PML, confirmed by autopsy, are described where CSF antibody to JC virus was measured. In one case the JC antibody titre was significantly higher in the CSF than the serum and we suggest that this finding is diagnostically useful. In this case there was a transient stabilization of the disease following treatment with cytarabine with a change in antibody titres suggestive of reduced viral replication in the central nervous system and a host response to the infection. In the other case, which was untreated, rising serum antibody levels indicated active infection with a host response.

Inter-relationships between type, size and colour of fruits and dispersal in southern African trees.

The indigenous angiosperm tree flora (1,340 species) of southern Africa was analysed for type, size and colour of fruits and class of biotic dispersal agent (consumer). Species producing fleshy (drupes and berries) and dry (pods, capsules and nuts) fruits account for 52% and 47%, respectively, of the flora. The flora contains about 2.5 times as many berry-producing as drupe-producing species. Based on a log-linear model, fruit type, consumer and fruit size are dependent statistically on each other, whereas fruit colour depends on both fruit size and consumer type acting independently of each other. Drupes and berries are consumed by birds and mammals, with berries being favoured by both birds and mammals. At least 23% (307 species) of the flora apparently depends predominantly on birds for seed dispersal. Drupes and berries favoured by birds tend to be small and brightly coloured (red or black), whereas those eaten mainly by mammals tend to be large and dull (yellow or green). Relatively few fleshy fruits are brown. Pods, capsules and nuts tend to be brown or green. Birds apparently tend to avoid eating green fruits. The notion that green coloration has evolved to enhance crypsis and/or to signal unpalatability in unripe fruit to reduce premature exploitation is questioned. Green as a cryptic colour is incompatible with the demonstrated mammalian selection of this colour, while to function aposematically a stronger contrast colour may be required.

99Tcm-HMPAO single photon emission computed tomography in partial epilepsy: a preliminary report.

In the pre-operative assessment of patients being considered for temporal lobe surgery, accurate lateralization and localization of the epileptic focus is mandatory. Surface electroencephalography (EEG) can be misleading and confirmatory evidence, preferably non-invasive, of the site of the epileptic focus is valuable. Sixteen patients with partial epilepsy, six of whom were considered to be good surgical candidates, had technetium-99m hexamethylpropylene amine oxime (99Tcm-HMPAO) scanning. In those patients with poor epileptic control and a well localized EEG focus, there was a correlation between EEG and HMPAO scan abnormalities, whilst in all patients where no correlation existed, the HMPAO scan was normal. We conclude that 99Tcm-HMPAO single photon emission computed tomography may be a useful non-invasive, adjunctive investigation in the preoperative assessment of patients with partial epilepsy.

Primary oral health care in black Americans: an assessment of current status and future needs.

To improve health for all in the United States by the year 2000, dental health needs must be considered a component of total health and primary care. The failure to address dental needs has reached a crisis level, particularly in the black and underserved communities throughout the nation. Data from several nationwide studies have shown that oral disease is greater in black Americans than their white counterparts. More severe periodontal disease patterns, untreated dental decay, and earlier tooth loss were observed. Key minority subgroups received less preventive care.

Unsuccessful intraventricular pentosan polysulphate treatment of variant Creutzfeldt-Jakob disease.

Pentosan polysulphate, delivered by chronic intraventricular infusion, has been proposed as a potential therapy for human prion disease. The first treated patient is still alive several years after treatment started. Here we describe in detail a case of variant Creutzfeldt-Jakob disease in which this treatment was started at a relatively early stage but had no definite clinical benefit. The patient died from disease progression 16 months after diagnosis and 5 months after pentosan polysulphate treatment was commenced.