Health professions and risk of sporadic Creutzfeldt- Jakob disease, 1965 to 2010

In 2009, a pathologist with sporadic Creutzfeldt- Jakob Disease (sCJD) was reported to the Spanish registry. This case prompted a request for information on health-related occupation in sCJD cases from countries participating in the European Creutzfeldt Jakob Disease Surveillance network (EuroCJD). Responses from registries in 21 countries revealed that of 8,321 registered cases, 65 physicians or dentists, two of whom were pathologists, and another 137 healthcare workers had been identified with sCJD. Five countries reported 15 physicians and 68 other health professionals among 2,968 controls or non-cases, suggesting no relative excess of sCJD among healthcare professionals. A literature review revealed: (i) 12 case or small case-series reports of 66 health professionals with sCJD, and (ii) five analytical studies on health-related occupation and sCJD, where statistically significant findings were solely observed for persons working at physicians' offices (odds ratio: 4.6 (95 CI: 1.2-17.6)). We conclude that a wide spectrum of medical specialities and health professions are represented in sCJD cases and that the data analysed do not support any overall increased occupational risk for health professionals. Nevertheless, there may be a specific risk in some professions associated with direct contact with high human-infectivity tissue

Prion-specific and surrogate CSF biomarkers in Creutzfeldt-Jakob disease:diagnostic accuracy in relation to molecular subtypes and analysis of neuropathological correlates of p-tau and A beta 42 levels

The differential diagnosis of Creutzfeldt-Jakob disease (CJD) from other, sometimes treatable, neurological disorders is challenging, owing to the wide phenotypic heterogeneity of the disease. Real-time quaking-induced prion conversion (RT-QuIC) is a novel ultrasensitive in vitro assay, which, at variance with surrogate neurodegenerative biomarker assays, specifically targets the pathological prion protein (PrPSc). In the studies conducted to date in CJD, cerebrospinal fluid (CSF) RT-QuIC showed good diagnostic sensitivity (82\u201396%) and virtually full specificity. In the present study, we investigated the diagnostic value of both prion RT-QuIC and surrogate protein markers in a large patient population with suspected CJD and then evaluated the influence on CSF findings of the CJD type, and the associated amyloid-\u3b2 (A\u3b2) and tau neuropathology. RT-QuIC showed an overall diagnostic sensitivity of 82.1% and a specificity of 99.4%. However, sensitivity was lower in CJD types linked to abnormal prion protein (PrPSc) type 2 (VV2, MV2K and MM2C) than in typical CJD (MM1). Among surrogate proteins markers (14-3-3, total (t)-tau, and t-tau/phosphorylated (p)-tau ratio) t-tau performed best in terms of both specificity and sensitivity for all sCJD types. Sporadic CJD VV2 and MV2K types demonstrated higher CSF levels of p-tau when compared to other sCJD types and this positively correlated with the amount of tiny tau deposits in brain areas showing spongiform change. CJD patients showed moderately reduced median A\u3b242 CSF levels, with 38% of cases having significantly decreased protein levels in the absence of A\u3b2 brain deposits. Our results: (1) support the use of both RT-QuIC and t-tau assays as first line laboratory investigations for the clinical diagnosis of CJD; (2) demonstrate a secondary tauopathy in CJD subtypes VV2 and MV2K, correlating with increased p-tau levels in the CSF and (3) provide novel insight into the issue of the accuracy of CSF p-tau and A\u3b242 as markers of brain tauopathy and \u3b2-amyloidosis

Identification of novel risk loci and causal insights for sporadic Creutzfeldt-Jakob disease: a genome-wide association study

Background: Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene that encodes prion protein are strong risk factors for sCJD but, although the condition has similar heritability to other neurodegenerative disorders, no other genetic risk loci have been confirmed. We aimed to discover new genetic risk factors for sCJD, and their causal mechanisms. Methods: We did a genome-wide association study of sCJD in European ancestry populations (patients diagnosed with probable or definite sCJD identified at national CJD referral centres) with a two-stage study design using genotyping arrays and exome sequencing. Conditional, transcriptional, and histological analyses of implicated genes and proteins in brain tissues, and tests of the effects of risk variants on clinical phenotypes, were done using deep longitudinal clinical cohort data. Control data from healthy individuals were obtained from publicly available datasets matched for country. Findings: Samples from 5208 cases were obtained between 1990 and 2014. We found 41 genome-wide significant single nucleotide polymorphisms (SNPs) and independently replicated findings at three loci associated with sCJD risk; within PRNP (rs1799990; additive model odds ratio [OR] 1·23 [95% CI 1·17-1·30], p=2·68 × 10-15; heterozygous model p=1·01 × 10-135), STX6 (rs3747957; OR 1·16 [1·10-1·22], p=9·74 × 10-9), and GAL3ST1 (rs2267161; OR 1·18 [1·12-1·25], p=8·60 × 10-10). Follow-up analyses showed that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 are associated with increased expression of the major transcripts in disease-relevant brain regions. Interpretation: We present, to our knowledge, the first evidence of statistically robust genetic associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism as molecular causal mechanisms. Risk SNPs in STX6 are shared with progressive supranuclear palsy, a neurodegenerative disease associated with misfolding of protein tau, indicating that sCJD might share the same causal mechanisms as prion-like disorders. Funding: Medical Research Council and the UK National Institute of Health Research in part through the Biomedical Research Centre at University College London Hospitals National Health Service Foundation Trust

A genome wide association study links glutamate receptor pathway to Sporadic Creutzfeldt-Jakob disease risk.

We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 control

UN CASO PRESSANTE DI LEISHMANIOSI

P.A., 7 anni 9 mesi, da 5 giorni astenia, febbre e addominalgie successive a trauma accidentale. Condotta in PS, vengono eseguiti esami ematici e TAC addome con riscontro di epatomegalia e splenomegalia (dl circa 30 cm). La piccola viene trasferita presso la U.O.C. di Chirurgia Pediatrica nel sospetto di rottura splenica. In tale sede, esclusa l’ipotesi chirurgica, per il riscontro di pancitopenia (GB 1570/ mcl, Hb 6 gr/dl, PLT 50.000/mcl) si inviava la paziente presso la nostra U.O.C. di Oncoematologia Pediatrica. All’ingresso in reparto la piccola presentava febbre (TC 38,8°C) e astenia. L’emocromo confermava la pancitopenia, l’ETG addome la splenomegalia (dl 25 cm). Si eseguiva aspirato midollare con evidenza di numerosi parassiti negli istiociti. L’esame sierologico è risultato positivo per leishmaniosi viscerale, (L. infantum, sierologia positiva:1/2560 (IFI)). Ha quindi iniziato trattamento con Ambisome (AmB, 3mg/kg per 5 gg) con miglioramento generale e riduzione della splenomegalia. Al gg+7 dalla terapia, comparsa di stato di incoscienza, areflessia, sguardo lateralizzato con pupille normoreagenti. All’EEG: “crisi subentranti con clonie oculari a dx>sn, talora suppresion burst”. Esegue RMN encefalo: “aree di alterato segnale che coinvolgono le regioni cerebrali parieto-occipitali ed il ponte: quadro suggestivo di Posterior Reversible Syndrome (PRES).” Trasferita in Rianimazione, ha iniziato terapia con IgHD e desametasone con miglioramento progressivo fino alla risoluzione dei segni clinici e dell’imaging. Nonostante la mancata somministrazione della 6° dose di AmB prevista al gg+10, si è assistito alla guarigione completa della parassitosi. La PRES è stata attribuita a tossicità farmacologica da Ambisome, antimicotico a veicolo liposomico, Nelle regioni del Mediterraneo, è il farmaco di scelta per il trattamento della Leishmaniosi viscerale, con efficace risposta e capacità di impedire recidive parassitarie. Tuttavia, l’Ambisome può causare disfunzioni renali, ipokaliemia, febbre e raramente una leucoencefalopatia, talora progressiva e fatale. Tale neurotossicità, dose correlata, è secondaria al legame del farmaco con la mielina, che provoca un aumento della permeabilità di membrana e dispersione delle componenti intracellulari. In conclusione, questo caso evidenzia l’importanza di tre elementi fondamentali nel percorso diagnostico- terapeutico della leishmaniosi viscerale in soggetti di età evolutiva: 1) la diagnosi differenziale con condizioni associate ad importante splenomegalia e simile presentazione clinica (ie: leucemie, linfomi, anemia emolitica, malaria, febbre tifoide, tubercolosi miliare, endocardite batterica, brucellosi, ipertensione portale); 2) un attento monitoraggio nella gestione terapeutica, tenendo presente i costi-benefici di un adeguato trattamento, anche se potenzialmente tossico; 3) l’accurata identificazione dell’agente eziologico, di grande importanza nel trattamento farmacologico perché specie diverse che infettano lo stesso tessuto possono presentare differente suscettibilità ad un determinato farmaco. Bibliografia 1. Sato M, Hirayanagi K, Makioka K, Ikeda Y. Reversal of leukoencephalopathy induced by liposomal amphotericin B in a patient with cryptococcal meningitis. J Neurol Sci. 2015 Mar 15;350(1-2):118-9. 2. di Martino L, Davidson RN, Giacchino R, Scotti S, Raimondi F, Castagnola E, Tasso L, Cascio A, Gradoni L, Gramiccia M, Pettoello-Mantovani M, Bryceson AD. Treatment of visceral leishmaniasis in children with liposomal amphotericin B. J Pediatr. 1997 Aug;131(2):271-7. 3. Antonini G, Morino S, Fiorelli M, Fazi P, Ceschin V, Petti C. Reversal of encephalopathy during treatment with amphotericin-B. J Neurol Sci. 1996 Dec;144(1-2):212-3

Effects of levetiracetam on EEG abnormalities in juvenile myoclonic epilepsy

Purpose: A multicenter, prospective, long-term, open-label study to evaluate the effects of levetiracetam on electroencephalogram (EEG) abnormalities and photoparoxysmal response (PPR) of patients affected by juvenile myoclonic epilepsy (JME). Methods: Forty-eight patients with newly diagnosed JME (10) or resistant/intolerant (38) to previous antiepileptic drugs (AEDs) were enrolled. After an 8-week baseline period, levetiracetam was titrated in 2 weeks to 500 mg b.i.d. and then increased to up to 3,000 mg/day. Efficacy parameters were based on the comparison and analysis of EEG interictal abnormalities classified as spikes-and-waves, polyspikes-and-waves, and presence of PPR. Secondary end point was evaluation of EEG and PPR changes as predictive factors of 12-month seizure freedom. Results: Overall, mean dose of levetiracetam was 2,208 mg/day. Mean study period was 19.3 +/- 11.5 months (range 0.3-38). During the baseline period, interictal EEG abnormalities were detected in 44/48 patients (91.6%) and PPR was determined in 17/48 (35.4%) of patients. After levetiracetam treatment, 27/48 (56.2%) of patients compared to 4/48 (8.3%) in the baseline period (p < 0.0001) had a normal EEG. Thirteen of 17 (76.4%) (p < 0.0003) patients showed suppression of PPR. Cumulative probability of days with myoclonia (DWM) 12-month remission was significantly higher (p < 0.05) in patients with a normal (normalized) EEG after levetiracetam treatment compared to those with an unchanged EEG. Conclusions: Levetiracetam appeared to be effective in decreasing epileptiform EEG abnormalities, and suppressing the PPR in JME patients. This effect, along with a good efficacy and tolerability profile in this population further supports a first-line role for levetiracetam in the treatment of JME